Onc/Rheum/Adolescent Flashcards

Question

Bone problems in childhood cancer patients

Answer 1

Avascular necrosis a. Complication that can destroy the bone underlying the articular surface of joints – especially in weight-bearing joints of lower extremities b. Associated with high-dose glucocorticoid treatment and bone marrow transplantation e. Investigations i. Crescent sign of avascular necrosis is seen on conventional radiographs ii. It indicates imminent articular collapse. f. Treatment i. Conservative therapy – restriction of weight bearing ii. Decrease or modification of glucocorticoid dose if possible iii. Hip or knee often require surgical intervention – core decompression or joint replacement Altered epiphyseal growth a. Epiphyseal growth is altered temporarily during chemotherapy b. Children with ALL display marked deceleration in growth velocity but generally catch up following chemotherapy completion c. Agents that directly alter bone growth include i. Glucocorticoids ii. Doxorubicin iii. Actinomycin D iv. Methotrexate v. Cisplatin d. Direct irradiation can also retard bone growth Reduced bone mineral density a. MANY treatments reduce bone mineral density in oncology patients i. Cranial irradiation ii. HSCT iii. Glucocorticoids iv. High dose MTX v. Alkylating agents b. Other factors i. GH deficiency – cerebral irradiation ii. Hypogonadism iii. Hyperthyroidism – irradiation iv. Illness itself – deconditioning

Answer 2

Absolute contraindications • Severe haemophilia • Severe DIC • Other related bleeding disorder NOTE: • Thrombocytopenia (regardless of severity) is not a contraindication – some centres give platelets if <20 • Most haematologists do not consider therapeutic anticoagulation to be an important risk factor for bleeding following bone marrow biopsy – practice varies

Answer 3

``` Bone marrow aspirate A needle is passed through the skin and into the iliac crest and a small amount of liquid bone marrow will be withdrawn into a syringe Info: Cellular morphology and cell count Cytogenetics Culture Flow cytometry Immunohistochemistry ``` ``` Bone marrow trephine Is done immediately after the aspiration In some cases a second needle will be inserted into the same site after removal of the aspiration needle Alternatively the first needle may be left in place and used to take the trephine biopsy Info: Marrow’s overall cellularity Detection of focal lesions Extent of infiltration ```

Answer 4

a. Malignancy i. ALL 1. Any child with high risk disease: hypodiploid ALL , MLL rearrangements, induction failure, T cell ALL (IR + HR) ii. AML 1. High risk disease: FLT3 +ve , monosomy 7, monosomy 5, 5q deletion, 3q deletion , complex karyotype ( 3 or more abnormalities) 2. Tx in first CR 3. NOT for favourable risk disease: 8:21 inv 16 iii. CML b. Immunodeficiencies i. Cellular – SCID/ DiGeorge, Wiskott-Aldrich, Hyper IgM ii. Neutrophil – CGD/ LAD c. Bone marrow failure i. Severe aplastic anaemia – Fanconi, Blackfan Diamond, Congenital dyskeratosis, reticular dysgenesis ii. Congenital neutropenias iii. Congenital amegakaryocytic thrombocytopenia iv. Anaemias – thalassemia, sickle cell disease v. HLH, X linked lymphoproliferative disease d. Storage disease i. Leukodystrophies 1. Adrenoleukodystrophy (pre neurological deterioration) 2. Metachromatic leukodystrophy – 12 months before onset of sx 3. Does not reverse neuronal death ii. Globoid cell leukodystrophy (Krabbe) iii. MPS 1. Hurlers, Maroteaux- Lamy, Sly syndrome 2. NOT indicated: Hunters, Sanfilippo, Morquio

Answer 5

a. Bone marrow - pros • Moderately brisk engraftment • Moderate risk of GVHD • DLI available - cons • Increased risks of collection – GA, bleeding, pain • Contains all marrow cells including RBC b. Peripheral blood – needs increased dose - pros • Rapid engraftment • Low risk during collection • Only CD34+ stem cells collected • Availability of donor lymphocyte infusion - cons • Increased rates of GVHD especially chronic GVHD • Not practical procedure on small patient c. Cord blood – lower cell dose - pros • Risk free collection • Less requirement for HLA matching (accept 4/6, normally minimum 5/6) • Low risk of transmitting infection • Low incidence of GVHD (immune immaturity) • Rapid availability - cons • Relatively low does available • Slow engraftment (longer period neutropenia) • No possibility of donor lymphocyte infusion (DLI)

Answer 6

6. Phases of BMT a. Conditioning b. BMT infusion c. Aplasia d. Engraftment e. GVHD acute f. GVHD chronic 7. Summary of phases a. Pre-engraftment = from transplantation to neutrophil recovery (day 20-30) b. Early post-engraftment = from engraftment to day 100 c. Late post-engraftment = after day 100

Answer 7

HLA genes chromosome 6 i. Based on HLA typing ii. Tested in 2 ways: 1. Serologic testing: uses antibody based assays for HLA antigens (does not ensure same genes) 2. Molecular typing: looks at underlying alleles on chromosome  more specific if testing unmatched donors Ideal donor is a matched sibling i. 6/6 (used for related donors) : HLA A, B, DRB1 ii. 8/8 (for matched unrelated donors): HLA A, B, C, DRB1 iii. Mismatches described as graft vs host direction (patient possesses an allele not possessed by the donor, so you would get a graft vs host response) or host vs. graft (donor possesses one or more alleles not present in the patient, which would cause a host response towards the graft) ii. HLA B and C sit very close together on chromosome 6, so C not specifically typed iii. Mismatches at HLA-B and C better tolerated than A and DR

Answer 8

a. Febrile neutropenia b. Sinusoidal obstruction syndrome i. Most serious complications after myeloablative transplant ii. Incidence 10-60% iii. Risk factors 1. Older age (ie adults) 2. Poor performance status 3. Prior abdominal irradiation 4. Elevated busulphan 5. Recent gemtuzuab, ozagmicin (myeloarg), pembrolzumb (Keytruda) iv. Clinical triad 1. Weight gain 2. Painful hepatomegaly 3. Jaunice v. Onset within 30 days of transplant vi. Platelet refractoriness = key feature (but could also represent platelet alloimmunisation or thrombotic microangiopathy) c. GVHD d. Graft failure i. Rare complication of HSCT ii. More common with CBT – rates of 10-15% iii. May result in iatrogenic aplastic anaemia or autologous reconstitution

Answer 9

i. Phase 1 = damage to host tissues by inflammation from the preparative chemo and/or radiotherapy regimen ii. Phase 2 = T cell activation phase 1. Recipient and donor antigen presenting cells as well as inflammatory cytokines trigger activation of donor derived T cells which expand and differentiate 2. Minor MHC play a central role particularly in the setting of matched transplants 3. Initial inflammatory cascade is thought to begin in the gastrointestinal tract and patients with higher volumes of diarrhoea at the time of preparative regimen have a higher likelihood of acute diarrhoea iii. Phase 3 = effector phase 1. T cells mediated cytotoxicity against target host cells 2. Additional production of cytokines – particularly TNF-alpha a. Induces apoptosis of target tissues through TNF-alpha receptor b. Activates macrophages, neutrophils, eosinophils, B and T cells c. Stimulates production of other inflammatory cytokines d. Increases expression of HLA antigens and facilitates T cell lysis iv. SUMMARY 1. Competent cells in the graft 2. Recipient expresses antigens NOT present in the donor 3. Recipient incapable of mounting effective response to eliminate implanted cells 4. Donor T cells respond to recipient tissue antigen a. Class I (A, B, C) present on all nucleated cells b. Class II (DR/ DQ/ DP) present on hematopoietic cells but expression can be induced following injury c. Minor histocompatibility antigens: autosome + sex chromosomes 5. Process: a. Tissue damage  activation of APC b. Donor T cell activation c. Production of cellular and inflammatory effectors

Answer 10

i. SKIN 1. Erythema, pain , blistering 2. Biopsy: apoptotic bodies in the basal layer of the epithelium ii. LIVER 1. Jaundice + deranged LFTs 2. DDX – drug toxicity, VOD, infection 3. Biopsy: bile duct destruction with apoptotic bodies iii. GIT 1. N+V, diarrhoea, abdominal pain, bleeding 2. DDx – infection, drug toxicity (ATB, MMF) 3. Biopsy: apoptotic bodies in the base of crypts

Answer 11

c. Treatment i. Mild cutaneous (grade I) 1. Optimise immunosuppression a. Push cyclosporine to 250 2. Topical steroids ii. Grade II or higher= steroids 1-2 mg/kg 1. First line therapy , gold standard 2. Response – D3 for progression, D 5-7 partial response, D28 for complete response 3. Steroid refractory GVHD has dismal prognosis d. Prognosis (Graded 0-4) i. Grade III – survival rate 25% ii. Grade IV – survival rate 5%

Answer 12

a. Autoimmune like disorders b. Can be limited (skin / liver / both) or extensive (other organ involvement) c. Target organs: i. Skin – pigment/ moisture/ elasticity ii. Joints – effusion/ stiffness/ contracture iii. GIT – malabsorption/ stricture iv. Liver – chronic change to cirrhosis v. Conjunctivae – dry, sicca syndrome vi. Mucosal surfaces – dry, ulcers, lichen planus vii. Bronchial tree – bronchiolitis obliterans d. Risk factors i. HLA mismatch ii. Pre-existing AGVHD iii. HSV infection iv. Age of donor v. Peripheral blood stem cells e. Treatment = immunosuppression i. Prednisolone ii. Cyclosporin iii. Mycofenolate iv. Azathioprine

Answer 13

i. Historically defined by time frame of more / less than 100 days ii. Now mostly defined by clinical symptoms

Answer 14

1. Key points a. Hepatic sinusoidal obstruction syndrome (SOS) = previously known hepatic veno-occlusive disease (VOD) b. Resembles Budd Chiari syndrome clinically – however due to occlusion of the terminal hepatic venules and hepatic sinusoids, rather than hepatic veins and inferior vena cava 3. Pathogenesis a. Injury to hepatic venous endothelium c. Obstruct the sinusoidal blood flow of the liver d. Venous occlusion  necrosis of liver e. Doppler ultrasound of hepatic vessels shows reversal or decreased flow f. Develop hepato-renal syndrome g. May be mild and self-limiting to a rapidly progressing fatal outcome resulting in MSOF 4. Clinical features a. Usually occurs 12 days after HSCT (within 3 weeks) i. Usually PRE-engraftment ii. Rare after 30 days b. Sudden weight gain c. Jaundice d. Hepatosplenomegaly / hepatic tenderness e. Peripheral oedema + ascites 5. Investigations a. ↑ AST, ALT, hyperbilirubinemia b. Thrombocytopenia with refractoriness to platelet transfusion c. USS Dopplers = liver sinusoids may be dilated and congested, reversal of flow 7. Treatment a. Defibrotide b. TIPS 8. Complications a. 50% develop renal insufficiency (Hepatorenal syndrome) b. Multiorgan failure – hepatic encephalopathy and death

Answer 15

1. Key points a. Noninfectious complication that is reported in 7-10% of autologous HCT, but only rarely following allogeneic HCT b. Develops around 7 to 11 days following HCT during the time of neutrophil recovery c. The engraftment syndrome usually causes only mild symptoms 2. Clinical manifestations a. Cutaneous eruption that mimics acute graft vs host disease b. Fever without identifiable infectious source c. Signs of capillary leak syndrome (eg, noncardiogenic pulmonary edema with hypoxia, weight gain) 3. Peri-engraftment respiratory distress syndrome (PERDS) a. Pulmonary component of engraftment syndrome b. Reported in 3-5 percent of autologous HCT c. Associated with increased capillary permeability that occurs during the neutrophil recovery phase following HCT d. Characterized by combination of fever, hypoxemia, pulmonary opacities, absence of infection, fluid overload, or cardiac dysfunction, and presentation within five days of neutrophil engraftment

Answer 16

Pulmonary component of engraftment syndrome b. Reported in 3-5 percent of autologous HCT c. Associated with increased capillary permeability that occurs during the neutrophil recovery phase following HCT d. Characterized by combination of fever, hypoxemia, pulmonary opacities, absence of infection, fluid overload, or cardiac dysfunction, and presentation within five days of neutrophil engraftment

Answer 17

a. Pre-engraftment = from transplantation to neutrophil recovery (day 20-30) i. Febrile neutropenia ii. Mucositis = HSV reactivation (prevalent throughout all phases but one of the few early viruses) iii. Diarrhoea = C diff iv. Pneumonia = nodular (bacterial or mould), diffuse (non-infectious) v. Vascath associated cellulitis or blood-stream infection (Gram positive infection with CONS or Staph aureus are the most common, GN and Candida can also occur) vi. Bacteria: gram neg bacilli, G pos spp, enterococci vii. Candida an issue b. Early post-engraftment = from engraftment to day 100 i. Pneumonia = nodular (bacterial), diffuse (PJP), respiratory viruses ii. CMV becomes more common, HSV an ongoing issue, iii. Pneumocystis (PJP) becomes a problem (bactrim prophylaxis), Candida ongoing c. Late post-engraftment = after day 100 i. VZV becomes more prominent, CMV and HSV ongoing issues, EBV PTLD becomes a concern ii. Encapsulated bacteria predominate iii. Pneumocystis more prevalent, Candida less prevalent

Answer 18

Veno-Occlusive disease A condition resulting from toxic injury to the hepatic sinusoidal capillaries that leads to obstruction of the small hepatic veins • Classic cause of deranged LFTs during pre-engraftment period • Occurs by day 21 – average day 12 Acute GVHD • Most common cause of hepatitis during early post-engraftment period • Both SOS and acute GVHD can present with abdominal pain and rising bilirubin • Patients with hepatic dysfunction due to GVHD usually have concurrent involvement of skin and GIT • Definitive diagnosis can be made by biopsy Hepatic infections • Uncommon during pre-engraftment period • Abnormal liver function tests can be due to hepatic infections eg. CMV, VZV, EBV, HHV6, adenovirus Drug toxicity • Many drugs can be associated with cholestasis Budd Chiari (a condition in which the hepatic veins (veins that drain the liver) are blocked or narrowed by a clot (mass of blood cells)) o Clinical presentation of hepatic SOS is indistinguishable from acute Budd Chiari o Budd Chiari can be established non-invasively by demonstration of thrombosis of the hepatic veins and/or the intrahepatic or suprahepatic inferior vena cava on imaging o NOT particularly associated with HSCT

Answer 19

``` Infectious • C Diff associated • Other enteric pathogens Early Post-Engraftment • CMV colitis • C. difficile • Adenovirus, Enteric pathogens such as Coxackie, rotavirus, norovirus ``` Non-Infectious Pre-Engraftment • Mucositis = common following conditioning regimen • Medications = eg Mg (counteract cyclosporine) result in diarrhoea • Typhlitis (caecum inflammation) (neutropenic enterocolitis) = occurs while neutropenic in engraftment phase Early Post-Engraftment • GVHD = most important and frequent cause of diarrhoea in the early post-engraftment period; usually occurs with other manifestations of GVHD particularly rash • Medications

Answer 20

Nodular Lesions Pre-Engraftment • Usually infectious etiologies during the pre-engraftment and engraftment period Early Post-Engraftment • Invasive aspergillosis is a more frequent cause of nodular infiltrates (40-50%) during early post-engraftment period – risk factors GVHD and CMV • Other less common fungal infections can also occur in early post-engraftment period eg. mucurmycosis (5-10%), Fusarium spp, Scedosporium Late Post-Engraftment • Bacterial or fungal Diffuse Lesions Pre-Engraftment • Usually non-infectious etiologies during to the pre-engraftment period o Examples = pulmonary edema, lung damage due to conditioning regimen o Haemorrhagic alveolitis or cytokine-driven inflammatory process (engraftment syndrome) can result in bilateral infiltrates around the time of engraftment Early Post-Engraftment • Infectious causes MUCH more likely in early post-engraftment period – CMV, respiratory viruses, PJP • Non-infectious causes such as toxicity from conditioning regimen can also occur in post-engraftment period Late Post-Engraftment • Non-infectious = bronchiolitis obliterans/ bronchiolitis obliterans syndrome and cryptogenic organising pneumonia (BOP) • Infections = CMV, respiratory viruses, PCP

Answer 21

Infectious ``` • Most common in early post-engraftment period • Causes o HHV6 – reactivation occurs in 30-50% of patients o HSV o VZV o CMV o EBV o JC polyomavirus o Adenovirus o Toxoplasmosis ```

Answer 22

Chemotherapy • Most common cause of haemorrhagic cystitis during pre-engraftment period is due to toxicity from conditioning (cyclophosphamide, ifosfamide, busulfan, TBI) ``` Viral infection • Viral infections most common in early pre-engraftment period • BK polyomavirus most common • Adenovirus second most common • Less frequent - CMV, JV polyomavirus ``` Haematological causes • Thrombocytopenia • GVHD – rare

Answer 23

Leukaemia - ALL is commonest malignancy of childhood a. Leukaemia accounts for 30% of all malignant disease in children i. 23% ALL ii. 5% AML

Answer 24

1. Epidemiology a. Incidence – 30 per million b. Commonest malignancy of childhood c. Peak presentation 2-5 years d. Slightly more common in boys 2. Risk factors a. Down syndrome b. NF1 c. Bloom syndrome d. Ataxia telangiectasia 4. Pathophysiology a. Lymphoid progenitor cell becomes genetically altered and undergoes dysregulated proliferation and clonal expansion b. Leukaemic blasts thought to arise in bone marrow, but may be systemic by presentation c. Cause unknown

Answer 25

a. Morphology i. 85% B cell in origin (most pre-B ALL) 1. CD10(-) = Pro-B 2. CD10 = Precursor B 3. Pre B 4. Mature B (Burkitt) – has different treatment approach ii. 15% are T cell ALL 1. CD2/ 3/4/5/7/ 8 2. 10% of T cell ALL is ‘early T cell precursor phenotype (ETP ALL)  high rate of remission failure and poor overall survival b. Chromosomal abnormalities – see below

Answer 26

a. Bone marrow infiltration/failure i. Signs of marrow failure 1. Anaemia  fatigue and pallor 2. Thrombocytopenia  petechiae and bleeding 3. Neutropenia  recurrent fever b. Extramedullary disease i. Lymphadenopathy + hepatosplenomegaly ii. Bone pain +++ – particularly lower extremities, can be severe and wake patient at night iii. T cell disease  mediastinal adenopathy causing major airway compression with stridor and/or superior vena cava obstruction iv. Signs of CNS involvement are INFREQUENT at diagnosis: 1. Headache, nausea and vomiting 2. Irritability, nuchal rigidity and papilledema 3. Cranial nerve involvement – most frequently involving CNVII, CNIII, CNIV, CNVI v. Rarely, leukaemia evolves as an intracranial or spinal mass, with symptoms relating to nerve compression vi. Testicular involvement at diagnosis is rare – appears as painless testicular enlargement and is usually unilateral c. Generalised signs and symptoms = weight loss, bone pain, lethargy, joint swelling + fever d. Signs on examination i. Pallor, listlessness, purpuric and petechial skin lesions, mucous membrane haemorrhage ii. Lymphadenopathy, splenomegaly, (less common hepatomegaly) iii. Bone and joint tenderness, swelling or effusion iv. Signs of raised ICP: papilledema, retinal hemorrhages, cranial nerve palsies (as above) v. Respiratory distress related to anaemia OR obstructive airway problems

Answer 27

i. Age = <1 or >10 years ii. Presentation 1. WCC > 50 at diagnosis 2. CSF involvement 3. Testicular involvement iii. Additional cytogenetic + molecular features 1. Hypodiploidy (chromosome number reduced <44) 2. KMT2A/MLL genetic rearrangements - translocations of 11q23 (eg. t4;11) a. Found in most infant ALL 3. iAMP21 amplification 4. Philadelphia chromosome t(9;22) BCR-ABL fusion protein – very poor prognosis a. Characteristic of CML 5. Abnormal 17p, Loss of 13q iv. Response = failure to achieve remission by end of induction (D29) 1. If minimal residual disease (>0.01%) detectable at the end of induction prognosis worse unless treatment intensified

Answer 28

1. Hyperdiploidy (chromosome number increased >50) 2. Trisomies 4, 10 3. ETV-RUNX protein (t12;21) (previously known as TEL-AML protein)

Answer 29

a. Risk-directed therapy = age at diagnosis, initial WCC, immnophenotypic and cytogenetic characteristics of blast populations, rapidity of early treatment response, and assessment of MRD at end of induction b. Standard treatment involves chemotherapy for 2-3 years c. General i. Correct thrombocytopenia + anaemia (if indicated) ii. Treat infection iii. Anticipate and prevent tumour lysis – monitor regularly iv. Prophylaxis for PJP d. Stratified based on risk i. Specific treatment protocols for treatment of infant and T-cell ALL ii. ‘Standard’ and ‘high’ pre-B ALL also treated as separate entities iii. All children > 10 years and WCC >50 are automatically categorized as high risk e. SUMMARY i. Backbone of treatment 1. Induction (achieve remission) - Vincristine + corticosteroid + PEG asparaginase 2. CNS prophylaxis a. Radiation plus IT MTX b. Progressive replacement of radiation by HD MTX 3. Post-induction iii. Interim maintenance = a less intensive ‘rest’ block to allow bone marrow recovery iv. Delayed intensification = final burst of intensive chemo to eradicate any blasts prior to maintenance 4. Maintenance - mainly oral medication at home with monthly visits for IV vincristine and quarterly LP/intrathecal therapy - lasts ~3 years depending on protocol ii. Chemotherapeutics 1. 3 drugs = vincristine, steroid, asparaginase 2. 4 drugs = anthracycline  for T cell and high risk

Answer 30

a. 5 year survival = 85% (standard), 75% (high risk) i. 90% overall cure rates ii. 92% for standard risk iii. 99% for double/triple trisomies or ETV6-RUNX1 b. T ALL = higher risk group than pre-B ALL i. Overall 90% survival ii. Presentation WCC not prognostic in T ALL c. Philadelphia + ALL i. Addition of TKI (imatinib/ dasatinib) improved outcome ii. Current 7 year relapse free survival >70% d. Relapse i. Late (>18 months off therapy) isolated extramedullary relapse 70% with chemotherapy alone (with early achievement of MRD negative status) ii. T cell <30% iii. Early (>18 months since diagnosis and <6 months off therapy) relapse 50% (with transplant) iv. Very early (<18 months since diagnosis) 20-30% with transplant

Answer 31

1. Epidemiology a. 2nd most common leukaemia b. 11% of childhood leukaemia c. Relative frequency of AML increases in adolescence d. Acute promyelocytic leukaemia (APML) = more common in certain regions of the world 3. Clinical presentation a. Bone marrow failure b. Blastic infiltration c. Specific to AML i. Subcutaneous nodules – ‘blueberry muffin’ lesions (especially in infants) ii. Infiltration of gingiva (especially in monocytic subtypes) iii. Signs and symptoms of DIC (especially indicative of APML) iv. Discrete masses – chloromas, granulocytic sarcomas – can occur in the absence of apparent bone marrow involvement; typically seen with t(8;21) translocation 1. Can be seen in the orbit and epidural space 4. Diagnosis a. Bone marrow - >20% of bone marrow homogenous population of blast cells i. Features that characterize early differentiation states of the myeloid-monocyte-megakaryocyte series ii. Aurer rod characteristic of AML 6. Treatment a. Aggressive chemotherapy successful in achieving remission in 85-90% of patients b. Matched-sibling bone marrow or SCT after remission achieves long-term disease free survival in 2/3 of patients c. Chemotherapy alone curative in 1/2 of patients e. APML i. Characterised by gene rearrangement t15;17 = PML-RARA  responsive to all-trans-retinoic acid (ATRA, tretinoin) – combined with anthracyclines and cytarabine ii. Marrow transplantation in first remission unnecessary iii. Very good prognosis if survive induction 7. Supportive care a. Increased supportive care because of intensive therapy resulting in prolonged bone marrow suppression b. High incidence of serious fungal and bacterial infections – especially streptococcal viridans 8. Prognosis a. Current survival rate 60-70%

Answer 32

i. Favourable prognosis 1. t(8;21), t(15;17), inv(16) 2. NPM1 – favourable risk factor if present by itself 3. CEBPA ii. FLT3-ITD – adverse risk factor predicts relapse

Answer 33

1. Acute Leukamias a. Acute leukaemia occurs 15-20x more frequently in children with DS b. Ratio of ALL: AML same as general population i. EXCEPT during first 3 years of life  AML more common c. Outcome of ALL poorer in children with DS i. Partially explained by lack of good prognostic characteristics (eg. ETV6-RUN1) and trisomies ii. Genetic abnormalities associated with inferior prognosis (eg. IKZF1) iii. Remarkable sensitivity of MTX and metabolites – can develop toxicity if standard doses given d. Outcome of AML better in children with DS i. >80% long term survival ii. After induction therapy children receive therapy that is less intensive 2. Myeloproliferative disorder a. 10% of neonates with Down syndrome develop transient leukaemia or myeloproliferative disorder b. Key features i. High leukocyte counts ii. Blast cells in peripheral blood iii. Associated anaemia, thrombocytopenia and hepatosplenomegaly c. Features usually resolve within the first 3 months of life d. Neonates can require temporary transfusion support – however do not require chemotherapy unless life-threatening complications e. Require close follow-up  20-30% develop typical leukaemia i. Often acute megakaryotic leukaemia ii. Usually by 3 years of life (mean onset 16 months) iii. GATA1 mutation are present in blasts from patients with DS who have transient myeloproliferation disease and also in those with leukaemia iv. Transient myeloproliferative disease can also occur in patients who do not have phenotypic features of DS v. Blasts from these patients might have trisomy 21, suggesting a mosaic state

Answer 34

1. Overview a. Accounts for 2-3% of childhood leukaemia b. 99% due to Philadelphia chromosome – t(9;22) (q34;q11)  BCR-ABLE fusion protein 2. Clinical manifestations a. Non-specific – fever, fatigue, weight loss and anorexia b. Splenomegaly – can cause upper abdominal pain 3. Diagnosis a. Peripheral blood = high WCC with myeloid cells at all different stages b. Bone marrow = myeloid cells at different stages, Philadelphia chromosome on cytogenetics 4. Natural history a. Initial chronic phase in which the malignant clone produces an elevated leukocyte count with a predominance of mature forms but with increased number of immature granulocytes i. Also results in mild anaemia and thrombocytosis b. Typically the chronic phase terminates 3-4 years after onset  accelerated or ‘blast crisis’ phase i. Blood counts rise dramatically and clinical picture indistinguishable from acute leukaemia ii. Additional manifestations can occur from hyperleukocytosis including CNS manifestations 5. Treatment a. Imatinib (first generation); dasatinib (second generation) i. Inhibits BCR-ABL tyrosine kinase used in adults and children ii. Major cytogenetic response in >70% of patients iii. Second generation TK inhibitors improved remission rates b. While waiting for response to TK inhibitor, disabling or life-threatening signs and symptoms of CML can be controlled during the chronic phase with hydroxyurea (gradually returns the WCC to normal) c. Prolonged morphological and cytogenetic responses are expected d. HLA-matched family donor allogeneic SCT  80% cure in children

Answer 35

1. Overview a. Rare, aggressive disorder of infancy b. Usually affects children < 2 years c. Rare <1% of childhood leukemia d. Do NOT have Philadelphia chromosome characteristic of CML e. Most patients have mutations in the RAS/MAP kinase pathway - oncogene mutations including NF1, PTPN11, KRAS, NRAS 2. Risk factors a. NF type 1 b. Noonan syndrome i. Half have mutation in PTPN11 ii. Others have mutations in NRAS, KRAS 3. Clinical manifestations a. 1/3rd present with an URTI with hepatosplenomegaly and a rash b. Remainder may have a slower course – pallor, fever, bleeding, infection, cough, malaise 4. Investigations a. FBE i. Monocytosis ii. Thrombocytopenia iii. Anaemia iv. Elevated foetal Hb b. BM  hypercellular myeloid cells, < 20% myeloblasts c. Karyotype/FISH d. Molecular analysis for above mutations 5. Treatment a. Little evidence b. SCT offers best opportunity to cure – much less success than for CML

Answer 36

1. Overview a. 2% of childhood leukaemia in children < 1 years b. Ratio of ALL to AML is 2:1 c. Leukaemic clones have been noted in cord blood at birth before symptoms appear d. Chromosome translocations can also occur in utero during fetal haematopoeisis  malignant clone formation e. >80% of cases have rearrangements in MLL gene (11q23 band translocation; majority t(14;11)) i. Subset of patients have VERY high relapse rate ii. Without this rearrangement – prognosis similar to older children with ALL f. Leukaemic cell morphology – large irregular lymphoblasts, with a phenotype negative for CD10 (common ALL antigen) marker (pro-B) unlike most older children with B-ALL who are CD10+ 2. Clinical manifestations a. Patients with MLL gene rearrangements i. Hyperleukocytosis ii. Extensive tissue infiltration  organomegaly, CNS disease iii. Subcutaneous nodules (leukaemia cutis) iv. Diffuse pulmonary infiltrates  tachypnoea; more often in infants than older children 3. Treatment a. Intensive chemotherapy programs, usually including SCT in those with MLL gene rearrangements b. Infants with AML often present with CNS or skin involvement and have a subtype known as acute myelomonocytic leukaemia – treatment same as older children with AML with similar outcome

Answer 37

1. Key points a. Aggressive and life-threatening syndrome of excess immune activation b. Most frequently affects infants from birth to 18 months of age c. NOT a malignancy d. Syndrome of uncontrolled haemophagocytosis + activation of inflammatory cytokines 3. Pathophysiology a. Syndrome of excessive inflammation and tissue destruction due to abnormal immune activation and excessive inflammation b. Excessive inflammation due to lack of normal down-regulation of activated macrophages and lymphocytes c. NK cells and/or CTLs fail to eliminate activated macrophages – results in excessive macrophage activity and highly elevated levels of IFN-g and other cytokines d. Haemophagocytosis characterised by presence of RBC, platelets or WBC within the cytoplasm of macrophages e. Cytokines found in high levels include IFN-g, TNF, IL-6, IL-10 and IL-12, soluble IL-2 receptor (CD25)

Answer 38

2. Classification a. Primary/ familial HLH = caused by gene mutation i. Overview 1. Most AR 2. Genes may involve perforin mutations (↓ CMI), hypertriglyceridemia, Munc 13-4 mutations (↓ monocyte killing) 3. Decreased/ absent cytotoxicity: perforin granules unable to migrate and fuse with plasma membrane  activation of T cells and macrophages, reduces threshold for developing HLH b. Secondary/ sporadic/ acquired HLH = without known familial HLH i. Infection-associated HLH 1. Viral = EBV, CMV, parvovirus, HSV, VZV, measles, HHV8, H1N1 2. Less commonly due to bacteria (eg. Brucella, GN bacteria, TB), parasites (eg. Leishmaniasis, malaria), and fungi ii. Malignancy-associated HLH 1. Most commonly lymphoid cancers – T, NK and anaplastic large cell lymphomas and leukamias c. Macrophage activation syndrome i. Form of HLH that occurs primarily in patients with JIA or other rheumatological disease

Answer 39

ii. HLH familial mutations 1. PRF1/perforin 2. UNC14D/Muc-13-4 3. STX11/Syntaxin 11 4. STXBP2/Munc18-2

Answer 40

4. Clinical manifestations a. Fever (90-100%) b. Maculopapular and/or petechiae (30%) c. Hepatosplenomegaly (70-100%) d. Lymphadenopathy (20-50%) e. Respiratory distress (40-50%) f. Symptoms of CNS involvement (50%) – aseptic meningitis, ADEM 5. Diagnostic criteria a. A molecular diagnosis consistent with HLH (eg. PRF mutation, SAP mutation) OR b. Having 5/8 of the following i. Fever ii. Splenomegaly iii. Cytopenia = affecting >=2 cell lineages (Hb <9 g/dl, platelets <100,000/uL, neutrophils <1,000/uL) iv. Hypertriglyceridaemia and/or hypofibrinogenaemia v. Haemophagocytosis in the bone marrow, spleen or LN without evidence of malignancy vi. Low or absent NK cell cytotoxicity = NK cell cytotoxicity, intracellular perforin expression, CD107a expression vii. Hyperferritinaemia (>500 ng/ml) viii. Elevated soluble CD25 (IL-2R alpha chain >= 2500 U/ml)

Answer 41

a. Overview i. Variable treatment protocols ii. Steroids +/- chemotherapeutic agents iii. BM transplantation b. Familial i. Etoposide, corticosteroids and intrathecal MTX (not contraindicated by pancytopenia) ii. ATG and cyclosporin for maintenance iii. Stem cell transplant required for cure c. Secondary i. Prognosis may be good if infection treatment ii. If infection unable to be treated, prognosis may be as poor as familial disease, CTx require iii. Theory = cytotoxic effect on macrophages interrupts cytokine production

Answer 42

1. Key points a. Solid tumours of lymphoid origin – lymph nodes or extranodal lymphoid tissues (bone marrow, thymus, tonsils, spleen, GIT, liver or skin) b. They differ from leukaemias only in that they do not originate from the bone marrow and are not characterised first by their presence in the circulation. c. Lymphomas can develop in lymph nodes in almost any part of the body and spread d. NHL cells can also spread into the CSF and/or bone marrow e. Third most common paediatric malignancy, comprising 15% of all paediatric cancers. 2. Two major categories a. Hodgkin’s Disease (HD) b. Non-Hodgkin’s Lymphoma (NHL) 3. Clinical presentation a. Lymphomas more often present with regional lymphadenopathy b. Constitutional symptoms and signs include: fevers, anorexia, body aches and pains, weight loss and night sweats c. Only 1/3 of children with Hodgkin’s Lymphoma and 10% with NHL display constitutional symptoms/signs (less common compared with leukaemias) d. “B symptoms” – Fevers, night sweats and weight loss i. Their presence or absence has prognostic significance in HL

Answer 43

i. Size > 1-2 cm ii. Increasing size over 2-4 weeks iii. Matted, firm, rubbery consistency or fixed to underlying tissues iv. No associated tenderness, erythema, warmth or fluctuance v. Supraclavicular, or low cervical location of LN vi. Regional lymphadenopathy that predominates in non-cervical areas vii. Fevers > 38.5 C for 2-4 weeks viii. Constitutional symptoms ix. Hepatosplenomegaly

Answer 44

Biopsy c. Laboratory i. FBC and film ii. Biochemistry including EUC, CMP, LFT, LDH, Uric Acid, Ferritin, CRP iii. Baseline immunologic profile (Immunoglobulins, T- and B-Cells) iv. Viral serology – EBV, Hepatitis A, B, C, HIV, CMV, HSV, VZV, Varicella d. Radiology i. USS – Of lymphadenopathy, Abdominal ii. CXR iii. CT Scan – Neck, chest, abdomen, pelvis iv. PET Scan v. MRI of bones, CT/MRI of spine, bone scan e. Disease specific tests i. ESR for HD ii. CSF for NHL iii. Peritoneal, pericardial or pleural fluid aspirates (if clinically indicated)

Answer 45

Hodgking lymphoma

Answer 46

1. Key points a. A malignancy of the germinal centre B-Cells that affects the reticuloendothelial and lymphatic systems b. Characterised by the presence of Reed-Sternberg cells (histopathologically) c. Spread: slow, predictable, with extension to contiguous lymph nodes d. Haematogenous spread also occurs (LESS COMMON)  liver, spleen, bone, bone marrow or brain e. Infiltration to non-lymphoid organs is rare f. Highly sensitive to chemotherapy and irradiation g. HL appears to arise in lymphoid tissue and spread to adjacent lymph node areas in an orderly fashion 2. Epidemiology a. 6% of childhood cancers b. Accounts for 40% of childhood lymphomas c. Bimodal peaks of incidence, at 15-35 yo and > 50 yo i. Incidence is rare under 5 yo d. M:F ratio 3:1. e. Most common malignancy in adolescents and young adults 4. Pathogenesis a. Reed-Sternberg (RS) cell = pathognomonic of HL (but also seen in EBV) i. Large cell with multiple or multilobated nuclei ii. Clonal in origin; arise from the germinal B cells but typically has lost most B cell gene expression and function iii. No single simple genetic aberration b. Characterised by variable number of RS cells surrounded by inflammatory infiltrate of lymphocytes, plasma cells and eosinophils of different proportions depending on HL histological subtype c. Reactive infiltration of eosinophils and CD68+ macrophages, and increased concentration of cytokines (eg. IL11, IL-6, TNF)  associate with unfavourable prognosis including: i. Presence of ‘’B” symptoms ii. Decreased response to therapy iii. Advanced stage iv. Reduced survival

Answer 47

6. Clinical manifestations a. Painless, non-tender, firm, rubbery cervical or supraclavicular lymphadenopathy  present in 90% i. Usually some degree of mediastinal involvement ii. Persists despite antibiotic therapy b. Clinically detectable hepatosplenomegaly rare (25%) c. Mediastinal mass (60%) d. Depending on extent of disease i. Symptoms and signs of airway obstruction = dyspnoea, hypoxia, cough ii. Pleural or pericardial effusion iii. Hepatocellular dysfunction iv. Bone marrow infiltration = anaemia, neutrophilia, thrombocytopenia (5%) e. Disease manifesting below the diaphragm is rare (3% of cases) f. B symptoms (30%) important in staging = unexplained fever, weight loss >10% over 6 months, night sweats g. Less common (and not of prognostic significance) = pruritis, lethargy, anorexia, pain worsens after alcohol 8. Diagnosis a. CXR = identify presence or absence of large mediastinal mass; size is important in prognostication b. Biopsy = excisional biopsy preferred c. Bone marrow aspiration = to rule out advanced disease d. Staging = CT neck, chest, abdomen, pelvis + PET scan e. Bloods = FBE, ESR, serum ferritin (prognostication)

Answer 48

9. Staging = Ann Arbor a. A = asymptomatic b. B = B symptoms present e. X = bulky nodal disease, nodal mass >1/3 of intra-thoracic diameter or 10cm in dimension Stage I Involvement of single LN (I) Involvement of single extralymphatic organ or site (IE) Stage II Involvement of 2 or more LN regions on the same side of the diaphragm (II) Localise involvement of extralymphatic organ or site and 1 more LN regions on the same side of the diaphragm (IIE) Stage III Involvement of LN regions on both sides of the diaphragm (III) May be complicated by involvement of the spleen (IIIS) Or by localised involvement of extralymphatic organ or site (IIIE) or both (IIISE) Stage IV Diffuse or disseminated involvement of 1 or more extralymphatic organs or tissues with or without associated LN involvement

Answer 49

10. Treatment a. Treatment determined largely by disease stage, presence or absence of B symptoms, and the presence of bulky nodal disease b. Treatment includes chemotherapy and/or radiotherapy c. Radiation therapy alone can lead to prolonged remission and high cure rates, however  growth retardation, thyroid dysfunction, cardiac and pulmonary toxicity d. Multi-agent combination chemotherapy resulted complete response 70-80%, cure rate 40-50% in those with advanced disease, however  acute and long-term toxicity 11. Prognosis a. 5-year OS for HD of all stages is > 80% b. Favourable Prognostic Indicators i. <10 yo, female, favourable subtypes (LP and NS) and Stage I non-bulky disease. c. Unfavourable Prognostic Indicators i. Persistently elevated ESR, LD histopathology, Stage IV/bulky disease (largest dimension > 10 cm), hypoalbuminaemia, B symptoms, male, poor response to chemotherapy 12. Relapse a. Most relapses occur within the first 3 years after diagnosis; however up to 10 years have been reported b. Relapse CANNOT be predicted accurately with this disease c. Prognosis depends on: the time from completion of treatment to recurrence; the site of relapse (nodal vs extranodal); the presence of B-symptoms at relapse

Answer 50

1. Complications of treatment a. Second Malignant Neoplasms b. Infertility – Azospermia (males), amenorrhoea (females) c. Pulmonary damage d. Cardiac damage e. Spinal cord damage f. Radiation nephritis g. Hypothyroidism

Answer 51

1. Epidemiology a. Accounts for 60% of lymphomas in children b. 2nd most commonly malignancy in those 15-35 years old c. Burkitt lymphoma most common in children 0-14 years d. DLBCL most common in adolescents/young adults 2. Key points a. Malignant solid tumour characterised by undifferentiated lymphoid cells b. Spread: aggressive, diffuse, unpredictable c. Involves lymphoid tissue and can infiltrate the BM and CNS d. Characterised by a high growth fraction and doubling time e. Early diagnosis and treatment is critical f. Rapid chemotherapy response can occur, therefore there is a higher risk for tumour lysis

Answer 52

a. Classification i. Lymphoblastic lymphoma (LBL) 1. Immature 2. If >25% BM involvement classified as ALL 3. 90% T cell origin, 10% B cell origin ii. Burkitt lymphoma (BL) 1. Mature 2. Mostly B cell origin iii. Diffuse large B cell lymphoma (DLBCL) – further divided into sub-types 1. Mature 2. Most are B cell origin 3. Germinal centre B-cell like  favourable prognosis and accounts for majority of paediatric cases of DLBCL 4. Activated B-cell like and primary mediastinal B cell type  poorer prognosis iv. Anaplastic large cell lymphoma (ALCL) 1. Mature 2. 70% T cell origin, 20% null cell origin, 10% B cell origin b. Summary: i. BL and DLBCL = mainly B cell origin ii. LBL = 90% T cell origin iii. ALCL = 70% T cell origin

Answer 53

6. Murphy staging a. Stage I: Involvement of single tumour or single anatomic area excluding the mediastinum or abdomen b. Stage II: Two or more lymph node regions on the same side of the diaphragm or resectable primary abdominal c. Stage III: Involvement of lymph node regions on both sides of the diaphragm; all primary mediastinal, paraspinal or extensive intra-abdominal disease d. Stage IV: Any of the above and initial involvement of the CNS, BM or both

Answer 54

7. Clinical manifestations a. 70% of children present with advanced stage disease (stage III or IV) – including extranodal disease with bone marrow and CNS involvement b. B symptoms can be seen (fever, weight loss, night sweats) uncommon except ALCL – but NOT prognostic c. Capillary leak syndrome seen in ALK + ALLs d. Site specific manifestations (some oncological emergencies) i. Rapid lymph node enlargement ii. Abdominal primary (ileocaecal area, appendix or colon) (35%) 1. Present with pain, distension, jaundice, GI issues, abdominal mass 2. Ascites, increased abdominal girth or intestinal obstruction iii. Mediastinal primary (26%) 1. Cough or dyspnoea with thoracic involvement 2. Superior mediastinal syndrome – can occur as a consequence of large mediastinal mass causing obstruction of blood flow or airways iv. Head and neck primary (13%) 1. Present with lymphadenopathy, mandibular swelling, single enlarged tonsil, nasal obstruction, rhinorrhea, cranial nerve palsies v. CNS (rare) – Present with headaches, vomiting, irritability, signs of raised ICP (papilloedema) vi. Constitutional symptoms (fevers, malaise, night sweats and weight loss) uncommon except in ALCL vii. Localised bone pain viii. Spinal cord tumours – cord compression and acute paraplegias  emergent radiotherapy ix. Tumour lysis syndrome – especially common in BL and LBL 8. Investigations a. Basic bloods including LFTs and LDH b. Bone marrow aspiration + biopsy c. LP + CSF cytospin d. CT neck, abdomen, pelvis (head if suspicious of CNS disease) e. Pet scan f. Tumour tissue – tested on flow cytometry for immnophenotypic origin (T, B or null) and cytogenetics (karyotype) g. Additional tests – FISH, PCR. Microarray

Answer 55

9. Treatment a. Treatment of potential life-threatening complications of NHL: i. SVC syndrome in lymphoblastic lymphoma ii. TLS in Burkitt’s or Burkitt’s-like NHL b. Surgery = for diagnostic biopsy and/or excision c. Radiation Therapy = emergency airway obstruction or CNS complications, may be used for local control or residual mass (e.g. advanced stage lymphoblastic lymphoma). d. Chemotherapy = combination chemotherapy is usual, with overall cure rates of > 60-80% i. Low stage NHLs: Treated with CHOP (It includes the drugs cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone) - (+/- Rituximab – Anti-CD20) ii. Higher-stage lymphoblastic lymphomas are treated on leukaemia protocols iii. Higher-stage non-lymphoblastic NHLs require extremely aggressive chemotherapy with significant infection risks, but still have generally good remission rates e. Relapse of disease = reinduction chemotherapy, followed by HSCT 10. Relapse a. Minimal residual disease (MRD) – prognostic in ALCL and LBL b. Patients who have progressive or relapsed disease  re-induction chemotherapy + allogeneic or autologous stem cell transplantation 11. Prognosis a. Localised disease = 90-100% chance of survival b. Advanced disease = 70-95% chance of survival

Answer 56

a. Long-term complications i. Solid tumours ii. Leukaemia iii. Cardiac disease iv. Pulmonary complications v. Thyroid disease vi. Infertility

Answer 57

Subtype Non-Hodgkin lymphoma 1. Key points a. M:F ratio 2-3:1 b. Mean age 11 years (non-endemic form) c. Most common primary site = intra-abdominal (sporadic type) or jaw (endemic type) d. Extremely rapidly-growing, therefore high risk for tumour lysis with initiation of treatment 2. Classification a. Endemic type African Peak age: 7 yo Jaw, orbit, paraspinal, abdomen, ovary CNS involvement > BMA Breakpoints upstream of c-myc b. Sporadic type Worldwide Peak age: 11 yo Abdomen, BM, nasopharynx, ovary BMA involvement > CNS Within c-myc 3. Cytogenetics a. 90% have t (8;14) - c-myc gene on chromosome 8; chromosome 14 – heavy chains 4. Treatment a. Paediatric BL and DLBCL are treated with similar chemotherapy regimens i. If localised disease – chemotherapy for 6 weeks to 6 months  excellent prognosis ii. If advanced disease – multi-agent chemotherapy for 4 to 6 months b. Primary mediastinal B cell lymphoma (PMBCL) – note inferior outcome when treated with the standard protocols c. Rituximab i. Monoclonal Ab directed at CD20  improves outcomes in adults with B-NHL ii. No good studies on paediatric efficacy 5. Prognosis a. Localised disease >90% b. Disseminated (but not B-ALL) 80-90% on newer protocols

Answer 58

Subtype Non-Hodgkin lymphoma 1. Key points a. Comprise 30-35% of paediatric NHLs i. 90-95% are derived from immature T-Cells (very similar to T-Cell ALL) ii. Remainder pre-B Cell phenotype (as in ALL) b. Cytologically, these tumours are indistinguishable from ALL and when greater than 25% of BM involvement exists, they are classified as ALL 2. Clinical presentation a. 50-70% manifest as anterior mediastinal mass. b. Patients present with respiratory distress and signs and symptoms associated with SVC syndrome c. May also present as painless, non-tender masses in the head and neck region, or with supraclavicular or axillary lymphadenopathy d. Abdominal involvement is rare, but a classic presentation is an older child with intussusception. e. Spread to the CNS and BM may occur, but uncommon 3. Treatment a. Requires 12-24 months of therapy including chemotherapy, intrathecal chemotherapy and cranial radiation in some cases b. Similar protocol to those used for acute leukaemia

Answer 59

Subtype Non-Hodgkin lymphoma 1. Key points a. Heterogeneous group of tumours b. Phenotypically includes B-Cell, T-Cell and indeterminate neoplasms c. Comprises 15-20% of paediatric NHLs. The 3 phenotypes occur with equal frequency 2. Classification a. Diffuse Large B-Cell Lymphoma (DLBCL) i. Predilection for mediastinum and abdomen ii. Rarely involve the CNS or bone marrow iii. More like Hodgkin’s Lymphoma than the other NHLs b. Anaplastic Lymphoma i. Express CD30 (Ki-1); ALK fusion protein. ii. Also manifest in mediastinum, as well as involving skin, lymph nodes, testes and bone iii. Majority of patients require multivalent chemotherapy iv. CNS prophylaxis (intrathecal chemotherapy) may be required v. CNS disease treated with intrathecal chemotherapy + radiotherapy c. Peripheral T-Cell Lymphoma i. Often involves the skin, CNS, lymph nodes, lung, testes, muscles and GIT

Answer 60

1. Key points a. Lymphoid and/or plasmacytic proliferations occurring post solid organ transplantation or HSCT b. Results from immunosuppression c. One of the most serious and potentially fatal complications of transplantation d. In most patients B cell proliferation results from infection with EBV in the setting of immunosuppression and decreased T cell immune surveillance 2. Epidemiology a. Overall incidence 1% in transplant population b. Most common malignancy complicating solid organ transplantation – accounting for 20% of cancers i. Lower risk for HSCT, renal and liver transplants ii. Higher among heart and lung transplants iii. Highest following multi-organ transplant c. PTLD accounts for a minority of secondary cancers following HSCT d. Majority (>80%) occur in the first year post transplant 3. Risk factors a. EBV serostatus of the recipient i. Increased risk among EBV-negative recipients of EBV-positive donor organs b. T cell immunosuppression 4. Clinical manifestations a. Highly variable b. Non-specific constitutional symptoms c. Lymphadenopathy d. >50% present with extra-nodal mass (GIT, lungs, skin, liver, CNS) 5. Treatment a. Immunosuppression b. Immunotherapy with CD20 Mab rituximab c. Chemotherapy d. Radiation therapy e. EBV specific cytotoxic T cells – persistent disease 6. Prevention a. Limiting immunosuppression b. Aggressive withdrawal and tapering of agents required for graft acceptance c. Anti-viral prophylaxis 7. Prognosis a. Survival rate of 25-35%

Answer 61

Post transplant lymphoproliferative disorder

Answer 62

1. Key points a. Heterogenous clinical presentation and course b. Tumours that undergo spontaneous regression to very aggressive tumours unresponsive to very intensive multimodal therapy 2. Primary site + metastases a. Site i. Develop at ANY site of sympathetic nervous system 1. 50% adrenal gland 2. 50% paraspinal and sympathetic ganglia ii. Abdomen (70%), thorax (15%), pelvic/sacral (5%), neck (4%) b. Metastases = more common in children >1 years at diagnosis i. Occurs via local invasion or distant haematogenous or lymphatic routes ii. Most common site  regional or distant LN, long bones and skull, bone marrow, liver + skin iii. Lung and brain metastases rare (3% of cases) 3. Epidemiology a. Most common extracranial solid tumour in children b. Accounts for 8-10% of childhood malignancies and 1/3 of cancer in infants d. Median age at diagnosis 22 months; 90% of cases are diagnosed by 5 years of age (rare after age 6) 4. Pathology a. Embryonal cancer of the peripheral sympathetic nervous system = derived from primordial neural crest cells i. Undifferentiated small round cells (neuroblastoma) ii. Tumours of mature and maturing Schwannian stroma with ganglion cells (ganglioneuroblastoma or ganglioneuroma)

Answer 63

Neuroblastoma

Answer 64

a. Most cases unknown b. Familial neuroblastoma = accounts for 1-2% of all cases i. Mutations in PHOX2B and ALK genes ii. BARD1 gene also identified as genetic contributor c. Associated conditions i. Neural crest disorders –Hirschsprung disease, central hypoventilation syndrome, ROHADD ii. NF type I iii. Congenital cardiovascular malformations iv. Beckwith-Wiedemann syndrome and hemihypertrophy v. Turner syndrome d. Environmental factors = maternal and paternal chemical exposures, farming work, electronics

Answer 65

6. Clinical manifestations a. Reflects the tumour site and extent of disease b. Symptoms can mimic many other disorders  delayed diagnosis c. Localised disease i. Asymptomatic ii. Symptoms due to mass effect 1. Spinal cord compression a. Anatomic connection between the SNS and the spinal cord accounts for the propensity of the NB to infiltrate the intervertebral foraminae b. Motor deficits are most common followed by radicular back pain, bladder and bowl dysfunction, and rarely sensory deficits c. Only 5% have clinical evidence of epidural compression 2. Bowel obstruction 3. Superior vena cava syndrome 4. Neck  adenopathy, Horner’s syndrome 5. Thorax  respiratory distress, Horner’s, incidental 6. Pelvic/sacral  mass, dysuria, constipation d. Metastatic disease i. Non-specific symptoms such as fever, pallor, anorexia, bone pain and irritability ii. Ptosis and periorbital ecchymoses suggests orbital metastases iii. Infants <1 year can present stage 4s  widespread subcutaneous tumour nodules, massive liver involvement, limited bone marrow disease and a small primary tumour without bone involvement or other metastases e. Systemic symptoms i. Produce catecholamines  sweating, hypertension (NB. hypertension may also be due to renal artery compression) ii. Tumour lysis syndrome iii. DIC 9. Investigations a. Primary site imaging – CT/MRI b. Bilateral BMATs c. Tumour biopsy = histology, molecular d. MIBG scan e. Bone scan (if non-MIBG avid) +/- pet f. Urine catecholamines (HVA/VMA) – 90% sensitivity in children >1 year i. Homovanillic acid and vanillylmandelic acid

Answer 66

INSS (Surgical) 1: localised, fully excised, lymph nodes negative 2A: localised, incompletely excised, ipsilateral lymph nodes negative 2B: localised, ipsilateral lymph nodes positive, contralateral nodes negative 3: Unresectable unilateral tumour infiltrate across midline OR unilateral tumour with contralateral lymph node involvement OR midline tumour with bilateral extension by infiltration 4: mets to distant lymph nodes/ bone/ bone marrow/ liver/ skin 4S: Stage 4 in infant <1 year INRG Stage L1 = localised disease without image-defined risk factors Stage L2 = localised disease with image-defined risk factors Stage M = metastatic Stage MS = metastatic ‘special’ where MS is equivalent to 4s

Answer 67

11. Treatment a. Dependent on age + tumour stage + cytogenetic and molecular profile b. Low risk (44%) = surgery alone c. Intermediate risk (20%) i. Many factors determine the amount of chemo required – age, stage, histo, biology/genetics ii. Vary from 28 cycles of chemo +/- CRA iii. Chemotherapy  surgery /- radiotherapy d. High risk (35%) i. Intensive chemotherapy = cisplatin/etoposide/cyclophosphamide/vincristine/doxorubicin/topotecan ii. Surgery iii. High-dose chemotherapy and stem cell rescue 1. Carboplatin/etoposide/melphalan and cyclo/thiotepa (COG) 2. Busulfan/melphalan (SIOP) iv. Radiation v. Immunotherapy e. Stage 4S = very favourable prognosis and many regress spontaneously without therapy i. Chemotherapy or resection of the primary tumour does NOT improve survival rates ii. If massive liver involvement and respiratory compromise, low dose cyclophosphamide or hepatic irradiation may alleviate symptoms 10. Prognostic factors a. Histological i. Presence and amount of Schwannian stroma ii. Degree of tumour cell differentiation iii. Miosis-karyorrhexis index b. Pathological i. Poor prognosis 1. MYCN (N-myc) proto-oncogene = 25%  highly associated with advanced stage + poor outcome 12. Outcome + Prognosis a. Intermediate-risk (including children with stage 3)  excellent prognosis with >90% survival b. High risk  poor prognosis 25-35% c. For children with stage 4S who require treatment to alleviate symptoms  survival 81% d. Management of relapse i. Low risk = further surgery +/- chemotherapy ii. Intermediate risk = further surgery +/- chemotherapy iii. High risk = palliation, MIBG and Radionucleotide therapy, standard chemotherapy, studies, allogeneic SCT

Answer 68

1. Key points a. Primary malignant renal tumour b. Can arise in 1 or both kidneys c. Metastases = lungs, regional LN, liver 2. Epidemiology a. Most common primary malignant renal tumour b. Second most common abdominal tumour in childhood (6-7% of all childhood cancers) c. 75% of cases occur in children <5 years; peak age 2-3 years d. Bilateral tumours peak at a younger age 3. Risk factors a. Sporadic – in most cases b. 2% of patients have family history – autosomal dominant (BCR2 or TP53) c. 10% associated with multiple malformation syndrome

Answer 69

WT1 (gene located on 11p13) encoding transcription factor –15-20% of tumours Mutations in CTNNB1 encoding beta-catenin regulatory factor – 15% of tumours Mutations in WTX encoding role in regulation pathway – 20% of tumours P53 gene – seen in 75% of Wilm’s tumour with anaplastic histology

Answer 70

6. Clinical manifestations a. Incidental discovery of asymptomatic abdominal mass – most common presentation i. At presentation can be very large; as it is retroperitoneal mass can grow large ii. Usually does NOT cross midline (cf. neuroblastoma) b. Hypertension – 20% of patients i. Secondary to increased renin activity c. Coagulopathy – caused by an acquired von Willebrand syndrome d. Less common i. Abdominal pain, haematuria, fever ii. Rapid enlargement and anaemia result from bleeding – rare presentation iii. WT thrombus extending into the inferior vena cava (4-10%) and rarely into right atrium 7. Investigations a. Basic bloods = microcytic anaemia from iron deficiency or anaemia of chronic disease, polycythaemia, elevated platelet count, and acquired deficiency of vWF or factor VII b. Imaging - AXR - USS - CT/MRI (claw sign) c. Biopsy - discouraged as results in disease upstaging - only perform if unusual presentation/imaging d. Histology (from excision) - histology most important prognostic predictor: presence of anaplasia determines aggressiveness of tumour and response to treatment

Answer 71

1: complete resection, tumour limited to kidney, renal sinus not involved 2: complete resection but tumour extends through renal capsule or into renal sinus 3: incomplete resection, LN involved, tumour rupture, previous biopsy 4: haematogenous spread or distal LN 5: bilateral

Answer 72

9. Treatment a. Differences around the world = chemo first, nephrectomy first; we do both b. Surgery = total nephrectomy standard of care in unilateral Wilm’s tumour but small studies showing nephron sparing possible c. Chemotherapy = most cases require it i. VCR/AC-d for most ii. Doxorubicin/cyclophosphamide/etoposide/carbo for HR d. Radiotherapy = stage 3, +/- lung mets Bilateral - chemotherapy first - nephron sparing surgery aiming to preserve as much kidney as possible - +/- post op chemo - prognosis usually favourable 10. Outcome + Prognosis a. Favorable stage I-III have >90% 5 year survival, 90% if stage IV b. Anaplastic stage II-IV have 50% 5 year survival c. Bilateral have 70% 5 year survival Overall 60% 4 year survival, but much better outcomes if not anaplastic

Answer 73

a. Radiosensitive i. Doxorubicin/ actinomycin-D ii. Radiation recall b. Cardiotoxicity i. Doxorubicin + radiotherapy c. Single kidney hyperfiltration d. Second malignant neoplasm e. Menopause, infertility – if radiotherapy involves entire abdomen (usually if ruptured)

Answer 74

BWS/isolated hemihypertrophy WAGR/WT-1 related mutation Siblings of familial Wilms, offspring of bilateral Wilms

Answer 75

a. Most common solid renal tumour identified in the neonatal period b. Most frequent benign renal tumour of childhood c. 3-10% of all paediatric renal tumours d. Many diagnosed with prenatal USS e. Can present with polyhydramnios, hydrops and premature delivery f. Most patients are diagnosed <3 months of age (whereas WT rarely diagnosed before 6 months) g. Radical nephrectomy treatment of choice h. Local recurrence uncommon i. Rare malignant variations – metastases to the lung, liver, heart and brain

Answer 76

Mesoblastic nephroma

Answer 77

Mesoblastic nephroma

Answer 78

a. Uncommon in children – 3% of malignant tumours of the kidney b. Peak incidence 1-4 years of age; usually presenting as abdominal mass c. M > F d. Bone is the most common site of distant metastases, followed by lung, abdomen, retroperitoneum, brain and liver e. Staging work-up should include bone scan f. Early stage disease has excellent prognosis (non-metastatic) and use intensive chemotherapy (3-4 drugs)

Answer 79

a. Rare but aggressive cancer (2% of kidney tumours) b. 80% occur in children <2 years c. Haematuria common presenting feature d. Both rhabdoid tumour of the kidney and CNS atypical rhabdoid tumours have deletions and mutations in hSNF5/InII gene and are considered to be related e. Prognosis poor – 5 year survival <30% f. High metastatic rate g. 15% have synchronous brain lesions h. Fever, haematuria and hyperglycaemia can occur

Answer 80

a. Rare in children; 2-5% of all renal tumours b. 20% have metastatic disease at diagnosis – lung, liver, bone, brain c. Older age (10 years) d. Present with frank haematuria, flank pain and/or palpable mass OR incidental finding e. May have specific cytogenetic abnormality – ASPL-TFE3 gene fusion) f. Can be associated with von Hippel-Lindau disease g. Local LN involvement is not a poor prognostic indicator h. Nephrectomy alone may be enough for early-stage RCC i. Survival i. 90-100% for stage 1 ii. 10% for stage 4

Answer 81

1. Epidemiology a. 4-5% of paediatric malignancies b. Most common soft tissue sarcoma c. Accounts for >50% soft tissue sarcomas d. 2/3 arise <6 years of age e. Tumour of mesenchymal tissue (connective tissue, bone/fat/cartilage/vascular/haematopoetic) 2. Risk factors a. Unknown b. Li-Fraumeni syndrome 3. Site a. Occurs at any site = head and neck (40%), genitourinary tract (20%), extremities (20%), other (20%) i. Extremity lesions more likely in older children and to have alveolar histology 4. Pathogenesis a. Believed to arise from same embryonic mesenchyme as striated skeletal muscle b. On the basis of light microscopy belongs to the same general category of small round cell tumours i. Includes Ewing sarcoma, neuroblastoma, NHL

Answer 82

a. Classification based on histology – determines treatment planning and prognosis b. 2 subtypes i. Embryonal type = 70-75% (no translocations) 1. Spindle and/or round cell tumour in loose myxoid or dense collagen stroma 2. 2 variants a. Botryoid type = typically vaginal or nasopharyngeal site b. Spindle cell = paratesticular ii. Alveolar type = 20-25% of cases 1. Characterised by a. T(2;13) or PAX3-FKHR (FOXO1) b. T(1:13) or PAX-FKHR 2. Grow in nests that often have cleft like spaces resembling alveoli 3. Occurs most often in the trunk and extremities Worse prognosis

Answer 83

Rhabdomyosarcoma

Answer 84

6. Clinical manifestations a. Mass – may or may not be painful b. Strongly influenced by site c. Symptoms caused by displacement or obstruction of normal structures i. Nasopharynx = nasal congestion, mouth breathing, epistaxis, difficulty swallowing + chewing ii. Regional extension into cranium = cranial nerve paralysis, blindness, signs of increased ICP with headache and vomiting iii. Face or cheek = swelling, pain, trismus, and if extension paralysis of cranial nerves iv. Neck = progressive swelling with neurological symptoms after regional extension v. Orbital = proptosis, periorbital edema, ptosis, change in visual acuity, local pain vi. Middle ear = pain, hearing loss, chronic otorrhoea, mass in the ear canal; extension can result in cranial nerve paralysis and signs of intracranial mass on involved side vii. Larynx = unremitting croupy cough d. Other presenting features i. Trunk or extremity = usually noticed after trauma and thought to be a haematoma; if swelling does not resolve or increases, malignancy should be suspected ii. Genitourinary tract = haematuria, obstruction, recurrent UTI, incontinence, mass detectable on abdominal or rectal examination iii. Paratesticular = painless, rapidly enlarging mass in scrotum iv. Vaginal = grape-like mass of tumour bulging through the vaginal orifice; sarcoma bulges out of the virginal orifice (sarcoma botryroides) can cause urinary tract or large bowel symptoms 1. Vaginal bleeding or obstruction of urethra or rectum may occur e. Tumours of any location may disseminate early and cause symptoms of pain or respiratory distress associated with pulmonary metastases f. Extensive bone involvement can produce symptomatic hypercalcaemia 7. Investigations a. Early diagnosis requires high index of suspicion b. Imaging i. CT or MRI to evaluate the primary tumour site include regional LN ii. CT chest iii. Bone scan +/- PET iv. BBMATs v. CSF (in parameningeal) c. Biopsy i. Very important aspect of diagnosis – LN also need to be sampled ii. Histology = small, round, blue cell tumour iii. Require Immunohistochemical stains including analysis of PAX/FOXO1 expression

Answer 85

9. Treatment a. Surgery i. Aggressive but non-mutilating ii. Up front best but only if likely clear margins without danger or functional impairment b. Radiotherapy c. Chemotherapy i. Essential (for occult and obvious metastases, and to help with local control) ii. Vincristine, actinomycin-d, cyclophosphamide (VAC) iii. Ifosfamide, doxorubicin, topotecan, irinotecan iv. HDCT not proven, not standard v. Maintenance chemo – vinorelbine/cyclo vi. Biologics eg. temsirolimus (mTOR inhibitor) 10. Prognosis a. Localised = 70-75% survival b. Metastatic = 25-30% survival c. Resectable tumour + favourable histology  80-90% prolonged disease free survival d. Unresectable tumour i. Orbit  high likelihood of tumour ii. Other sites  65-70% long-term disease free survival e. Disseminated disease  poor prognosis; 50% achieve remission and only 50% of these are cured f. Older children have poorer prognosis Alveolar worse prognosis (a/w translocations 1:13 and 2:13)

Answer 86

1. Key points a. Heterogenous group of sarcomas b. All rare c. 3% of all childhood malignancies d. Relatively rare in childhood – most information about natural history and treatment from adult studies e. Median age of diagnosis 12 years f. Commonly arise in the trunk or lower extremity 2. Histological sub-types a. Synovial sarcoma (42%) b. Fibrosarcoma (13%) c. Malignant fibrous histiocytoma (12%) d. Neurogenic tumours (10%) 3. Treatment a. Surgical resection mainstay of therapy b. Careful evaluation for long or bony metastases c. Chemotherapy + radiotherapy required for large, high-grade and unresectable tumours d. Role of chemotherapy for non-rhabdomyosarcoma not as well defined i. Most have poor response to chemo ii. Except synovial sarcoma and infantile fibrosarcoma e. Radiotherapy standard for large/residual f. Pazopanib (TKI) g. Patients with unresectable or metastatic disease treated with multi-agent chemotherapy in addition to irradiation and/or surgery h. Patients with completely resected small (<5cm)) generally treated with surgery alone – generally excellent outcome regardless of whether tumour high or low grade

Answer 87

Osteosarcoma Second is Ewing sarcoma, but Ewing sarcoma MORE common in patients <10 years old Both are more likely to occur in second decade of life (10-20)

Answer 88

``` Age: Second decade Race: All Cell: Spindle-cell producing osteoid Predisposition: Retinoblastoma, Li-Fraumeni syndrome, Richmond-Thomas syndrome Site: Metaphysis of long-bone (O is closer to M) - distal femur and proximal tibia most common Presentation: local pain and swelling, history of injury Radiographic: - sclerotic destruction - sunburst pattern - Codman triangle DDx: Ewing, osteomyelitis Mets: Lungs, bone Treatment: - chemotherapy - ablative surgery - NOT radiosensitive Prognosis: - without mets = 70% - with mets = 30% ```

Answer 89

Age: Second decade Race: White Cell: Undifferentiated small round cell, probably of neural origin Predisposition: None Site: Diaphysis of long bones (E is closer to D), flat bones - most commonly pelvis, femur Presentation: Local pain and swelling, fever Radiographic: - lytic lesions - Multilaminar periosteal reaction (onion skinning) DDx: Osteomyelitis, eosinophilic granuloma, Lymphoma, Neuroblastoma, Rhabdomyosarcoma Mets: Lung, bone Treatment: - chemotherapy - radiotherapy, surgery - VERY radiosensitive Prognosis: - without mets 70% - with mets 30%

Answer 90

1. Epidemiology a. Most common primary bone tumour in children/adolescence b. Peaks 15-19 years 2. Risk factors a. Syndromes i. Hereditary retinoblastoma (RB1 gene) ii. Li Fraumeni syndrome (p53) iii. Rothmund-Thomson syndrome e. Benign conditions with malignant transformation = Paget disease, endochondromatosis, multiple hereditary exostoses, fibrous dysplasia 4. Pathology a. A mesenchymal malignancy in which the malignant cells produce osteoid

Answer 91

b. Classification i. Conventional (80-90%) 1. Osteoblastic 2. Chrondroblastic 3. Fibroblastic ii. Other c. 4 pathological subtypes = osteoblastic, fibroblastic, chondroblastic and bone [no difference in outcome, although chondroblastic may not respond as well to chemotherapy] d. Two variants of osteosarcoma = contrasting high-grade osteosarcoma which arise in the Diaphyseal region of long bone and invade the medullary cavity i. Parosteal osteosarcoma = low-grade, well differentiated tumour that does NOT invade the medullary cavity and most commonly is found in the posterior aspect of the distal femur 1. Surgical resection alone often curative 2. Low potential for metastatic spread ii. Periosteal osteosarcoma = rare variant that arises on the surface of the bone 1. Higher rate of metastatic spread than paraosteal type and intermediate prognosis

Answer 92

3. Clinical manifestations a. Pain, limp and swelling b. Initial complaints often attributed to sports injury or sprain c. Nocturnal pain concerning feature d. On examination may have reduced ROM, joint effusion, tenderness or warmth 5. Investigations a. Bloods = usually normal, may have elevated ALP or LDH b. X-ray = lesion may be mixed lytic, sclerotic or both in appearance, new bone formation USUALLY visible i. Classic radiographic appearance sunburst pattern – secondary to ossification in the soft tissues (typical but NOT sensitive or specific) ii. Periosteal bone formation with lifting of the cortex may lead to the appearance of ‘Codman’s triangle’ c. MRI = evaluate tumour for its proximity to nerves and blood vessels, soft tissue + joint extension, and skip lesions d. CT chest and Radionucleotide scanning = assess for lung and bony mets e. Biopsy = diagnosis ALWAYS verified by histology i. Needs to be done in a manner that it will not compromise the ultimate limb salvage procedure ii. Histology = highly malignant, pleomorphic, spindle cell neoplasm associated with the formation of osteoid and bone

Answer 93

8. Prognostic factors a. Presence of metastases b. Axial location c. Large tumour size d. Surgical resection e. Response to chemo - <10% viable tumour (good), >10% viable tumour (bad) 9. Treatment a. Surgery i. Complete surgical removal of primary tumour AND metastases if present ii. Limb salvage surgery b. Radiation therapy i. Restricted to inoperable tumours ii. Need very high doses of 70Gy+ c. Chemotherapy i. Pre-operative = cisplatin, doxorubicin, MTX 1. +/- ifosfamide and etoposide ii. Side effects = deafness, cardiac and renal dysfunction 10. Relapse a. Lung metastases only – cure possible with surgical resection only b. No chemotherapy known to be curative but may enable complete resection of disease 11. Prognosis a. One of the most important prognostic factors = histologic response to chemotherapy b. Surgical resection alone  curative only for patients with paraosteal osteosarcoma c. Chemotherapy + surgery  5 year disease free survival of non-metastatic extremity osteosarcoma 65-75% d. Poor prognosis for those with pelvic tumours e. 20-30% of patients who have limited number of pulmonary metastases can be cured with aggressive chemotherapy and resection f. Patients with bone metastases and those with widespread lung metastases have extremely poor prognosis

Answer 94

1. Key points a. Undifferentiated sarcoma of bone, but may also arise from soft tissue i. 10% are extra-osseous b. Ewing sarcoma family of tumours = refers to a group of small, round cell, undifferentiated tumours thought to be of neural crest origin  including Ewing sarcoma of bone and soft tissue, and peripheral primitive neuro-ectodermal tumour c. Treatment the same irrespective of whether they arise from bone or soft tissue d. Site of tumour = extremities and central axis (pelvis, spine, and chest wall) i. Primary tumours arising from the chest wall are referred to as Askin tumours 2. Epidemiology a. 2nd most common bone tumour b. Extremely rare in African or Chinese populations 4. Pathology a. All are high grade b. Need immunohistochemistry to differentiate from other small round cell tumours i. CD99 + ve in >95% c. Molecular i. Rearrangement of EWS gene on Cx 22q12 ii. Mostly occurs with FL-1 gene on 11q24 1. T(11;22) in 85% 2. T(21;22) in 10%

Answer 95

3. Clinical manifestations a. Similar to osteosarcoma – pain, swelling, limitation of motion, and tenderness over involved bone/soft tissue b. Huge chest wall primary tumours  respiratory distress c. Paraspinal or vertebral primary  spinal cord compression d. Often associated with systemic manifestations = fever, weight loss (osteosarcoma less likely to have systemic symptoms) 5. Diagnosis a. X-ray = destructive osteolytic lesion of the diaphysis with destruction of the osseous cortex, elevation of the periosteum and infiltration of the surrounding tissue, characteristic onion-skinning b. Other imaging - MRI - CT c. Bone marrow asps - to assess for mets d. Biopsy i. Immunohistochemical staining assists in the diagnosis of Ewing sarcoma to differentiate it from other small, round, blue cell tumours such as lymphoma, rhabdomyosarcoma and neuroblastoma ii. Specific chromosomal translocation t(11;22) or variant often present

Answer 96

9. Treatment a. Local control = Surgery +/- radiotherapy (54Gy) i. Ewing sarcoma radiosensitive b. Metastases = whole lung irradiation (16 Gy) c. Multiagent chemotherapy (usually pre op) d. High dose chemotherapy with autologous stem cell re-infusion/rescue (high risk disease or relapse) 10. Prognosis a. Small, non-metastatic, distally located tumours have best prognosis  75% cure b. Pelvic tumours have worse outcome c. Metastatic disease at diagnosis, especially bone or bone marrow have poor prognosis  <30% survive long-term 11. Relapse a. Late relapse, even as long as 10 years after diagnosis, possible b. Very poor prognosis i. Chemotherapy – VTC + gem/doc ii. HDCT iii. Surgery/RT iv. Palliation c. Note - Secondary malignancy after radiotherapy

Answer 97

AKA exostosis a. Most common benign bone cyst b. Most develop in childhood – arising from the metaphysis of long bone, particularly distal femur and proximal humerus, lesion enlarges with child until skeletal maturity c. Most discovered at age 5-15 years  bony, non-painful mass d. X-ray = stalks or broad-based projections; marrow space of the involved bone are continuous with lesion e. Malignant degeneration rare in children, 1% in adults

Answer 98

a. Presence of multiple osteochondromas b. Severely involved children can have short stature, limb-length inequality, premature partial physeal arrests, deformity of UL and LL c. Require careful monitoring

Answer 99

Types: non-ossifying fibroma, fibrous cortical defect, metaphyseal defect a. Fibrous lesion of bone that occur in 40% of children > 2 years b. Most likely represent a defect in ossification rather than neoplasm and are usually asymptomatic c. Most incidentally discovered; occasionally present with pathologic fracture d. X-ray = sharply marginated eccentric lucency in the metaphyseal cortex; may be multilocular and expansile i. Long axis of lesion runs parallel to the bone, 50% are bilateral or multiple e. Most do not require biopsy or treatment due to characteristic radiographic appearance f. Treatment = spontaneous regression occurs after skeletal maturity i. Curettage and bone grafting may be recommended for lesions occupying >50% of the bone diameter due to risk of pathological fracture

Answer 100

Retinoblastoma

Answer 101

1. Key points a. Embryonal malignant tumour of the retina b. Most common intra-ocular tumour in children c. 11% of cases in first year of life – median age at diagnosis 18 months d. Male = female e. Survival rate in developed countries extremely high – progresses to metastatic disease and results in death of 50% of children worldwide f. Unilateral + bilateral i. 75% unilateral ii. 25% bilateral (Always heritable – germline RB1 mutation) g. Spread - Spread by direct extension; Haematogenous or lymphatic spread to distant sites including bones, bone marrow and lungs 3. Natural History a. Tumour grows to fill eye and destroy the globe b. Metastatic spread is diagnosed within the first 12 months of clinical presentation 4. Etiology + genetics a. Retinoblastoma gene i. Loss of function of the retinoblastoma gene (RB1) via gene mutation or deletion ii. Located on chromosome 13q14 and encodes the retinoblastoma protein (tumour suppressor that controls cell cycle transition) iii. 2 mutations are required for retinoblastoma; ‘two hit’ hypothesis for retinoblastoma to develop b. Classification i. Hereditary = Usually younger age + multifocal and bilateral 1. Most children have spontaneous new germinal mutations 2. Note that 15% of unilateral retinoblastoma due to germinal mutations 3. ALL 1st degree relatives need retinal examination to identify retinomas or retinal scars, which may suggest hereditary retinoblastoma even though retinoblastoma did not develop ii. Sporadic = Usually older children + unifocal and unilateral

Answer 102

a. Retinoblastoma gene i. Loss of function of the retinoblastoma gene (RB1) via gene mutation or deletion ii. Located on chromosome 13q14 and encodes the retinoblastoma protein (tumour suppressor that controls cell cycle transition) iii. 2 mutations are required for retinoblastoma; ‘two hit’ hypothesis for retinoblastoma to develop

Answer 103

5. Clinical manifestations a. Leukocoria – white pupillary reflex – in child <2 years of age b. Strabismus c. Nystagmus d. Decreased vision, orbital inflammation, hyphema and pupil irregularity can occur with advancing disease e. Pain can occur in secondary glaucoma f. 10% of retinoblastoma detected on routine screening 6. Diagnosis a. Ophthalmology examination i. Fundoscopy = chalky, white-gray retinal mass with soft, friable consistency ii. Complete evaluation under anaesthesia b. Histology – note that biopsies are CONTRAINDICATED i. Retinoblastoma appears as a small round blue cell tumour with rosette formation iii. Tend to outgrow their blood supply, resulting in necrosis and calcification c. Orbital USS, CT or MRI = evaluate extent of intra-ocular disease and extra-ocular spread i. Occasionally (60%), a pineal area (primitive neuroectodermal) tumour is detected in a child with hereditary and bilateral retinoblastoma (trilateral retinoblastoma) ii. MRI allows for evaluation of optic nerve involvement d. If metastases present (RARE at diagnosis) i. CSF, bone marrow, and bone scan

Answer 104

Retinoblastoma i. Persistent fetal vasculature (PVF) ii. Coats disease = exudative retinal vascular disorder characterised by retinal telangiectasias and subretinal exudation  serous retinal detachment iii. Vitreous haemorrhage iv. Toxocariasis = from dogs v. Familial exudative vitreoretinopathy

Answer 105

8. Treatment a. Principles of treatment i. Determined by size and location, if metastases are present, whether hereditary or sporadic disease 1. Primary goal = cure ii. Secondary goal = preserving vision and decreasing risk of late effects (secondary malignancies) iii. Avoid radiation if possible iv. Careful follow-up to check for recurrence b. Unilateral disease = enucleation if there is no potential for the salvage of useful vision c. Bilateral disease = chemoreduction in combination with focal therapy (laser photocoagulation or cryotherapy) i. If feasible, small tumours can be treated with focal therapy with careful follow-up for recurrence or new tumour growth ii. Larger tumours often respond to multiagent chemotherapy 1. If chemotherapy fails, external beam irradiation can be considered 2. Brachytherapy, or episcleral plaque radiotherapy has less morbidity iii. Enucleation may be required for unresponsive or recurrent tumours e. Prognosis and likelihood of globe salvage is poor when i. Delayed diagnosis >6 months ii. Cataract iii. History of intraocular surgery iv. Radiotherapy or choroidal/ optic nerve/ orbital invasion f. Chemotherapy = vincristine, carboblatin, etoposide 9. Prognosis a. 95% cure with modern treatment in developed countries b. Routine opthal examinations should continue until the child is 7 years+ c. Prognosis for children with retinoblastoma that has spread outside the eye is poor d. <10% with metastatic disease e. Trilateral retinoblastoma is almost universally fatal f. Children with germline RB1 mutations at significant risk for secondary malignancies  soft tissue sarcomas, malignant melanoma; a risk further increased by radiation therapy i. Most common cause of death for patients with heritable retinoblastoma is a secondary malignancy and not the initial primary retinoblastoma

Answer 106

1. Key points a. Germ cells are precursors that make eggs + sperm b. Classification i. Gonadal = 1/3 ii. Extra-gonadal (aberrant migration) = 2/3 c. Malignant germ cell tumours (GCTs) and gonadal tumours are rare d. Most malignant tumours of the gonads in children are GCTs f. Sacrococcygeal tumours predominantly occur in girls g. Testicular GCTs occur predominantly <4 years and after puberty 2. Risk factors a. Klinefelter syndrome = increased risk of mediastinal GCTs b. Down syndrome, undescended testes, infertility, testicular atrophy, testicular microlithiasis, testicular dysgenesis syndrome, and inguinal hernias  risk of testicular cancer i. Risk of testicular cancer in patients with cryptorchidism is reduced but not eliminated if orchidopexy is performed before 13 years 3. Pathogenesis a. GCTs = arise from primordial germ cells b. Non-GCTs = arise from coelomic epithelium c. Testicular and sacrococcygeal GCTs arise during early childhood 4. Site a. Extragonadal i. CNS = rare (aggressive) ii. Cervical = rare (teratoma, infant) iii. Mediastinal = 5% (adolescents)  Klinefelter 47 XXY iv. Retroperitoneum = 10% (infants/children) v. Sacrococcygeal = 50% (infants/ children) b. Gonad i. Testis = 25% (adolescents) ii. Ovary = 10% (adolescents)

Answer 107

5. Clinical manifestations a. Dependent on location, essentially mass effect i. Ovarian tumours – usually large by the time of diagnosis ii. Extra-gonadal GCTs – occur in midline, including suprasellar region, pineal region, neck, mediastinum, and retroperineal and sacrococcygeal areas b. Symptoms relate to mass effect c. Intracranial GCTs often present with anterior and posterior pituitary defects 6. Diagnosis a. Tumour markers i. AFP = elevated with endodermal sinus tumours and may be minimally elevated with teratomas 1. Infants normally have higher levels of AFP; fall to normal adult levels at 8 months ii. bHCG = elevated with choriocarcinoma and germinomas iii. LDH = non-specific; but can be used to help confirm diagnosis and help monitoring b. Imaging = CT/MRI c. Biopsy

Answer 108

i. Occur in patients with gonadal dysgenesis and all or parts of a Y chromosome ii. Gonadal dysgenesis is characterized by failure to fully masculinize the external genitalia iii. If the syndrome is diagnosed, imaging of the gonad with USS or CT is performed, and surgical resection of tumour is usually curative iv. Prophylactic resection at the time of diagnosis is recommended, because gonadoblastomas, some of which contain malignant GCT elements, often develop v. May produce abnormal amounts of estrogen

Answer 109

i. Occur in many locations and present as masses – sacrococcygeal region most common site ii. Not associated with elevated markers unless malignancy is present iii. Sacrococcygeal teratomas occur most commonly in infants and may be diagnosed in utero or at birth, with most found in girls iv. Rate of malignancy in this location varies from <10% in children younger than 2 months of age to >50% in children older than 4 months of age

Answer 110

i. Occur intracranially, in the mediastinum and gonads ii. Ovary  dysgerminomas; testes  seminomas iii. Usually tumour marker negative masses despite being malignant iv. Endodermal sinus or yolk sack + and choriocarcinoma appear highly malignant by histologic criteria 1. Both occur at gonadal and extragonadal sites 2. Embryonal carcinoma most often occur in the testes 3. Choriocarcinoma and embryonal carcinoma rarely occur in the pure form and are usually found as part of a mixed malignant GCT

Answer 111

i. Very uncommon in paediatrics ii. Occur predominantly in the in the ovary iii. Epithelial carcinomas (usually an adult tumour), Sertoli-Leydig cell tumours, and granulosa cell tumours may occur in children iv. Carcinomas account for about 1/3 of ovarian tumours in females younger than 20 years of age; most of these occur older teens and are of the serous or mucinous subtypes v. Sertoli-Leydig cell tumours and granulosa cell tumours produce hormones that can cause virilization, feminization, or precious puberty, depending on pubertal stage and the balance between Sertoli cells (estrogen production) and Leydig cells (androgen production) vi. Diagnostic evaluation usually focuses on the chief complaint of inappropriate sex steroid effect and includes hormone measurements, which reflect gonadotropin independent sex steroid production vii. Appropriate imaging also is performed to rule out a functioning gonadal tumour viii. Surgery usually is curative ix. No effective therapy for non-resectable disease has been found

Answer 112

Treatment a. Complete surgical excision – except for intra-cranial tumours, where the primary therapy consists of radiation therapy and chemotherapy b. Cisplatin based chemotherapy regimens usually curative in GCTs that cannot be completely resected, even if metastases are present c. Sex cord stromal tumours tend to be refractory to chemotherapy d. Testicular tumours i. Inguinal approach is indicated, and complete resection includes spermatic cord ii. When complete excision cannot be accomplished – pre-operative chemotherapy is indicated, with second-look surgery iii. For completely resected non-seminomatous testicular tumours – debate about whether patient can be observed following surgery iv. Teratomas (mature or immature) and completely resected malignant tumours – surgery alone e. Ovarian tumours i. Unless contralateral tumour also involved, fertility sparing surgery 9. Prognosis a. Overall cure rate for GCT > 80% b. Age most predictive factor for extra-gonadal GCTs – children >12 years have increased risk of death c. Histology has little effect on prognosis d. Non-resected extra-gonadal GCTs have worse prognosis

Answer 113

• Hepatic tumours are rare in children; account for 1% of malignancies in children • 50-60% of hepatic tumours in children are malignant o >65% of these malignancies being hepatoblastomas (remainder HCCs) • More common childhood malignancies including neuroblastoma, Wilm’s tumour, and lymphoma  metastasize to the liver • Benign liver tumours = haemangiomas, hamartomas, and haemangioendotheliomas o Haemangioendothelioma – most common

Answer 114

Hepatoblastoma

Answer 115

i. Familial adenomatous polyposis 1. Most common genetic polyposis syndrome 2. Mutation in APC (adenomatous polyposis coli) 3. Pre-cancerous lesions within surface epithelium of intestine 4. Polyps generally develop late in the 1st decade of life or in adolescence (mean age of presentation is 16 yr) 5. At time of diagnosis 5 or more polyps are present in the colon and rectum. 6. By young adulthood  number typically increases to hundreds or even thousands ii. Beckwith-Wiedemann syndrome 1. Increased expression of insulin-like growth factor 2 2. Routinely screened with alpha-fetoprotein (AFP) and abdominal ultrasound iii. Hemihyperplasia – enlargement of one part or side of the body causing asymmetry 1. Routinely screened with alpha-fetoprotein (AFP) and abdominal ultrasound iv. Type 1a glycogen storage disease v. Li Fraumeni vi. Goldenhar syndrome vii. T18, T21

Answer 116

1. Key points a. Most common malignant liver tumour in children b. Occurs predominantly in children <3 years of age; median age 1 year c. Metastatic spread = hepatoblastoma more commonly involves regional LN and the lungs 2. Risk factors a. Prematurity and low birthweight associated with increased incidence of hepatoblastoma b. Syndromes associated 3. Clinical manifestations a. Large, asymptomatic abdominal mass b. Arises from the right lobe x3 more commonly than left lobe and is usually unifocal c. As disease progresses  fatigue, fever, weight loss, anorexia, vomiting, and abdominal pain may ensue d. Rarely – presents with haemorrhage secondary to trauma or spontaneous rupture e. Paraneoplastic i. Paraneoplastic features of hepatoblastoma are not uncommon at presentation 1. Thrombocytosis 2. Increased alkaline phosphatase ii. β-hCG secretion  isosexual precocious puberty in boys 4. Investigations a. Biopsy = necessary to establish diagnosis and prognosis 1. Pure fetal histology subtype  favourable outcome 2. Small cell undifferentiated subtype – associated with normal AFP levels and worse outcome b. Bloods i. AFP = used in the diagnosis and monitoring  Elevated in almost all hepatoblastomas ii. Bilirubin and LFTs = usually normal iii. Anaemia common iv. Thrombocytosis occurs in 30% v. Serologic testing for viral hepatitis (hepatitis B and C) – usually negative c. Imaging i. Plain X-rays ii. USS – differentiate malignant hepatic mass to malignant mass iii. CT or MRI – defining intra-hepatic tumour involvement + the potential for surgical resection iv. CT chest – to evaluate for chest metastases 5. Treatment a. Cure of malignant hepatic tumours in children relies on complete resection of the tumour i. As much as 85% of the liver can be resected – hepatic regeneration occurs within 3-4 months b. Hepatoblastoma = surgery + systemic chemotherapy i. 30% of children  tumours resectable at diagnosis ii. If unresectable with or without metastatic disease  pre-resection chemotherapy + excision  chemo c. Liver transplant – more effective as the primary surgery than salvage 6. Prognosis a. Low stage tumours – survival >90% with surgery and adjuvant chemotherapy b. Tumours unresectable at diagnosis – survival of 60% c. Metastatic disease further reduces survival – but complete regression of disease can often be obtained with chemotherapy + surgical resection and isolated pulmonary metastatic disease – survival of 25%

Answer 117

1. Key points a. Occurs mostly in adolescents b. Often associated with hep B or C i. More common in East Asia where hepatitis B is endemic ii. Incidence decreased since introduction of hepatitis B vaccination c. Occurs in bimodal pattern  younger age peak overlapping the age of hepatoblastoma presentation d. Also occurs in the chronic form of i. Hereditary tyrosinaemia ii. Galactosaemia iii. Glycogen storage disease iv. Alpha1-antitrypsin deficiency v. Biliary cirrhosis e. Metastatic spread i. Regional LN ii. Lungs 2. Pathogenesis a. Arises from abnormal or cirrhotic liver and presents as multicentric, invasive tumour consisting of large pleomorphic cells of epithelial origin b. Cirrhosis in children less common than adults; congenital liver disorders are more common c. Classification i. Classical ii. Fibrolamellar – occurs in adolescents and young adult patients 1. NOT associated with cirrhosis 3. Clinical manifestations a. Hepatic mass with abdominal distension b. Symptoms of anorexia, weight loss, and abdominal pain c. Can present as an acute abdominal crisis with rupture of the tumour and haemoperitoneum 4. Diagnosis a. Bloods i. AFP = elevated in 60% of children ii. Bilirubin = usually normal iii. LFT = usually abnormal b. Imaging i. USS = can differentiate malignant from benign vascular lesions ii. CT or MRI = accurate method for defining extent of intra-hepatic tumour involvement and the potential for surgical resection iii. CT chest = evaluate for chest metastases 5. Treatment a. Complete resection is crucial for curative treatment i. Accomplished in 30-40% of cases – difficult due to multicentric origin of HCC ii. Combination chemotherapy following surgery is necessary b. For unresectable tumours – chemotherapy followed by surgical assessment c. Liver transplant option for unresectable tumours d. Even with complete resection 30% of children long-term survivors

Answer 118

Age - HBL<3 ; HCC>3 Predispositions - HBL: Things you're born with (prematurity, genetic predisposition) - HCC: Chronic liver injury (HBV, HCV, ETOH, metabolic disease) Treatment - Complete resection is key to cure for both - Cisplatin and carboplatin can cure HBL - Metastatic HCC incurable Investigations - AFP not specific

Answer 119

* Most common benign liver tumour * Associated with hypothyroidism – receptors on the tumour inactivate T4 * Hypothyroidism resolves with tumour involution * Steroids, propranolol + interferon hasten natural involution

Answer 120

* Account for 75% of all thyroid nodules presenting in children * Investigations = TFTs, USS of thyroid and lymph nodes, FNA * If TSH is suppressed  thyroid scan done

Answer 121

1. Key points a. More common in adolescent females than males b. A type of skin cancer that develops from the pigment-producing cells known as melanocytes 2. Risk factors a. UV light i. In older patients and teenagers melanoma occurs on sun exposed areas ii. In younger patients melanoma does not appear to be associate with sun exposure as it often occurs in skin not routinely exposed to sun b. Fair skin c. FHx of melanoma 3. Pediatric risk factors a. Giant hair nevus (>10cm) b. Dysplastic nevus syndrome c. Xeroderma pigmentosum 4. Clinical presentation a. Rapidly enlarging nevus that is dark, has changed colour, irregular borders, or bleeds easily b. >50% of paediatric melanomas are non-pigmented 5. Diagnosis a. Biopsy 6. Management a. Surgical + adjuvant chemo +/- molecular inhibitors 7. Prognosis a. Variable

Answer 122

* Rare in paediatric population * One of the most common nasopharyngeal tumours in pediatric populations * Usually associated with EBV in paediatrics

Answer 123

• Adrenocortical tumours (ACTs) = from adrenal cortex • Phaechromocytomas (PHEO) = derived from catecholamine-producing chromaffin cells of the adrenal medulla o If catecholamine producing tumours arise outside the medulla – paragangliomas

Answer 124

* Very rare and aggressive mesenchymal tumour * Occurs predominantly in adolescents and young adult mails * Associated with a diagnostic chromosomal translocation between the Ewing tumour gene and the Wilm tumour gene t(11;22)(p13;q12)

Answer 125

• Rare in paediatrics, even with predisposing conditions 1. Two predisposing conditions for CRC a. HNPCC = Lynch syndrome i. Autosomal dominant ii. Germline mutation in DNA mismatch repair genes – MLH1/MSH2MSH6/PMS2 iii. Extra-colonic malignancies 1. Endometrial Ca 50%-60% = BIGGEST risk 2. Other = stomach, small intestine, hepatobiliary system, renal pelvis and ureter, brain 3. Possible increased risk of pancreas, prostate, breast and cervix b. Familial adenomatous polyposis i. Autosomal dominant ii. Mutation in APC tumour iii. Extra-colonic malignancies 1. Upper gastrointestinal polyps 2. Duodenal adenomas 3. Nodular thyroid, thyroid cancer 4. Hepatoblastoma 5. Brain tumour 2. Other conditions increasing risk of CRCL a. MYH-associated polyposis b. Peutz-Jeghers syndrome i. Autosomal dominant ii. Features 1. Benign hamartomatous polyps in the GIT 2. Hyperpigmented macules on the lips and oral mucosa c. Juvenile polyposis

Answer 126

1. Key points Histiocytosis is a disease in which there are too many histiocyte cells in the skin and other organs. Normal histiocyte cells are part of the immune system (antigen presenting cells) a. Rare histiocytic disorder i. Must be distinguished histologically and immuno-phenotypically from other histiocytic and dendritic cell disorders, metastatic or solid haematopoietic neoplasms, and LHL and MAS b. Characterised by single or multiple osteolytic bone lesions demonstrating infiltration with histiocytes c. May infiltrate every organ – limited to one organ system (eg. bone) in half of patients d. Normal Langerhans cell = APC of the skin e. Most common in children 1-3 years of age i. In this age group, it is often acute, disseminated disease f. More indolent disease is more common in older children and adults 2. Key pathological findings a. Birbeck granule b. Antigen CD207 (langerin) expressed c. CD1a +ve

Answer 127

3. Clinical manifestations a. Bone (80%) i. Bone pain from lytic bone lesions ii. May result in pathological fractures b. Skin (40%) i. Eczematous rash resembling candida infection ii. Ulcerative lesions in skin folds/genital region iii. Brown to purplish papules on any part of the body – Hashimoto-Pritzker rash c. Lymphadenopathy (20%) + bone marrow i. Bone marrow involvement  anaemia, thrombocytopenia d. Liver (16%) – risk organ i. Ranges from cysts  hepatomegaly  liver dysfunction e. Spleen (13%) – risk organ f. Oral mucosa (13%) g. Lung (10%) – less frequent in children h. CNS (6%) i. CNS involvement can occur – characterized by gliosis ii. Neurodegeneration – ataxia, cognitive dysfunction iii. Endocrinopathy 1. 25% of patient will have pituitary involvement within 10yrs of LCH diagnosis 2. Diabetes insipidus is the most frequent endocrine abnormality a. Prior (4%)  concomitant (18%)  or after diagnosis. 3. Other endocrine manifestations a. Hypogonadism b. Growth failure c. Impaired OGTT, DM 4. Investigations a. Tissue biopsy b. Screen for system involvement – FBE/ LFTS/ Coags c. Skeletal survey – plain films show radiolucent areas without reaction, punched out lytic lesions d. Bone marrow

Answer 128

5. Treatment a. Single system disease: curettage/ low dose RTx/ injection of methylpred b. Multisystem  CTx i. Vinblastine/ etoposide should be included ii. Response rate is high 6. Prognosis a. Single system disease is benign b. Multisystem disease has good prognosis with CTx

Answer 129

1. Tumours associated a. Wilm’s tumour b. Hepatoblastoma c. Neuroblastoma – less common 2. Genetics a. Uniparental disomy (UDP) of 11p15.5 or gain of methylation of H19 imprinting centre (IC1) carry highest risk of tumour – Wilm’s and hepatoblastoma b. Cyclin-dependent kinase 1C (CDKN1C) – at risk of neuroblastoma 3. Screening a. Abdominal USS = every 3-6 months until aged 4 years b. Renal USS including adrenals = every 3 months between ages of 4 and 8 years c. AFP = every 2-3 months in the first 4 years of life d. Periodic CXR and urinary homovanillic acid (HVA) and vanilmandelic acid (VMA) to screen for neuroblastoma suggested but not incorporated into most screening protocols

Answer 130

Brain tumours (behind leukaemias)

Answer 131

Brain tumours (leukaemias most common overall)

Answer 132

1. Epidemiology a. 2nd most common malignancy in childhood and adolescence; incidence highest in children <5 years b. Most common solid malignancy c. 20-25% of all paediatric malignancy d. Overall mortality approaches 30% - 70-75% 5 year survival i. Highest mortality of any malignancy ii. Leading cause of death in children e. Highest morbidity (primarily neurological) of any malignancy 2. Etiology a. Not well defined b. Male predominance in the incidence of medulloblastoma and ependymoma c. Familial and hereditary syndromes account for 5% of tumours d. Cranial exposure to ionizing radiation 3. Clinical manifestations – summary a. Varied b. Depends on age, tumour size + location c. Infants = vomiting, irritability, lethargy, increased HC (macrocephaly), bulging fontanelle d. Older children = as above, headaches, early morning vomiting, changes in vision + strabismus, seizures, focal neuro, change in personality, change in gait, ‘learning disability’ 5. Location a. Supratentorial 30-50% b. Midline = 10-15% c. Infratentorial = 50-60% 6. Investigations a. Imaging i. Magnetic Resonance Imaging – brain +/- spine ii. Magnetic Resonance Spectroscopy = measurement of metabolites 1. N-acetyl aspartate: marker of neuronal and axonal integrity 2. Choline: marker of cell membrane turn-over 3. Creatine/phosphocreatine: stable, used internal control iii. No place for CT scan – MISSES posterior fossa tumours 7. Diagnosis a. Almost always based on histopathology i. Grade 1. I/II: low grade (cytologic atypia in grade II) 2. III/IV: high grade (mitoses, nuclear atypia, vascular proliferation, necrosis) ii. Molecular profile b. Staging i. Not always relevant because rare dissemination outside CNS ii. CSF/Spine imaging for embryonal tumours c. Localisation i. Brainstem/cerebellum/hemisphere d. Patient age 8. Treatment a. Surgery i. Mainstay of treatment Also radiotherapy (not for children <3) iv. Major cause of late side-effects 1. Dose and volume dependant 2. Neurocognitive and psychosocial deficits increase with time 3. Cognitive impairment more pronounced in younger children 4. Endocrinology a. Hypothyroidism b. Growth hormone deficiency v. Significant risk of second malignancy Chemotherapy (issues with BBB)

Answer 133

1. Tumours of the supporting cells a. Gliomas / astrocytoma b. Ependymoma c. Oligodendrocytoma d. Mixed gliomas 2. Tumours of primitive tissue a. Medulloblastoma b. Neuroblastoma c. pNET d. Atypical rhabdoid/ teratoid 3. Tumours of the meninges (meningioma) 4. Germ cell tumours 5. Craniopharyngioma 6. Metastases (lymphoma, Wilms’, neuroblastoma) < 1 ``` Alternatively Glial - Astrocyte - Oligodendrocyte Non-Glial - Neuron - Precursor stem cell ```

Answer 134

* Mean age at presentation 6 years * Posterior fossa lesion leads to symptoms of raised ICP * CN involvement (CNVI-X) is common * Occur in NF2 * MRI = hypointense on T1, hyperintese on T2, gadolinium enhancement prominent, calcifications common * Histology = perivascular pseudorosettes, ependymal rosettes, monomorphic nuclear morphology

Answer 135

* Low grade tumour * Characterised by indolent course * Typical site is cerebellum * Low metastatic potential in children * Occur in 20% of individuals with NF1 * MRI = contrast enhancing nodule within the wall of a cystic mass * Histology = Rosenthal fibres (also present in Alexander disease)

Answer 136

Medulloblastoma

Answer 137

* Most common malignant brain tumour in children * Male > female * Short symptomatic course of weeks usually with evidence of hydrocephalus * Histology = small round blue cell tumour [other small round cell tumour = Ewing’s, neuroblastoma, Wilms, retinoblastoma, hepatoblastoma] * Associated with syndromes = Gorlin, Li-Fraumeni, Turcot, Gardner, Cowden

Answer 138

Brain tumour • Uncommon • Usually aged <2 years • Large heterogenous posterior fossa tumour

Answer 139

* Uncommon and relatively benign * Age 10-14 at presentation * Derived from the Rathke cleft with a large suprasellar tumour component an is calcified in 90%

Answer 140

a. Secondary neoplasms i. Cumulative incidence 10% ii. Most common 1. BCC 2. Meningioma 3. Malignant CNS tumour – glioma, astrocytoma 4. Soft tissue sarcoma 5. Thyroid cancer iii. Risk of secondary neoplasm associated with maximum cranial irradiation dose b. Neurocognitive effects i. Common complication in children with CNS tumours ii. Serial decrease in IQ points, greater in children <7 years iii. Spatial learning difficulties iv. Adaptive behaviour deficits c. Cerebrovascular disease i. Increased risk for late-occurring CVA complications including stroke d. Endocrine abnormalities i. Most common 1. GH deficiency 2. Pubertal delay 3. Hypothyroidism e. Ototoxicity i. Platins commonly used for CNS malignancy f. Psychological g. Social

Answer 141

a. Delayed neurological changes after PF tumour resection i. 1-5 days post-surgery b. Symptoms i. Difficulty verbalizing ii. Excessive irritability iii. Nystagmus iv. Mutism v. Emotional lability c. Cause unknown d. 20% incidence after resection of medulloblastoma

Answer 142

``` • WHO grade I-II = LGG o >90% survival at 20 years o Key is improving morbidity • WHO grade III-IV = HGG – cellular atypia, mitotic rate, vascular proliferation, rate o Survival 30% at 3 years o GBM <10% ```

Answer 143

a. Astrocytoma i. Pilocytic astrocytoma (grade I) ii. Low-grade glioma (grade I or II) iii. Fibrillary/infiltrating astrocytoma (grade II) iv. Pilomyxoid astrocytoma (grade II) b. Astrocytoma (by location) i. Optic pathway/ hypothalamic glioma ii. Posterior fossa pilocytic astrocytoma iii. Tectal glioma c. Ganglioglioma d. Oligodendroglioma e. PXA f. Dysembropastic neuroepithelial tumour (DNT)

Answer 144

1. Key points a. Comprise the largest group of CNS tumours in children – mostly juvenile pilocytic astrocytomas b. 2/3 occur in posterior fossa c. Almost all tumours involving the optic pathway are juvenile astrocytomas (JPA) d. Generally good outcomes e. Histology = low to moderate cellularity with fibrillated areas rich in Rosenthal fibres 3. Treatment a. Observation b. Surgery +/- chemotherapy (non-resectable) +/- radiation therapy c. Intervene if visual deterioration d. Chemotherapy = carboplatin, vincristine, vinblastine e. Single pathway disease – BRAF pathway aberration – accounting 80% of low-grade tumour i. MEK inhibitor ii. BRAF inhibitor iii. mTOR inhibitor 4. Outcome a. Generally good outcome b. Indolent course; may stabilise at any point or even regress c. Better prognosis in NF1 d. Overall survival 85-90%

Answer 145

1. Key points a. Locally infiltrative astrocytic tumours b. Leptomeningeal spread in <10% a diagnosis c. Biopsy of high-grade poorly understood 2. Classification a. Anaplastic astrocytoma b. Glioblastoma multiforme 3. Treatment a. Surgery = rarely able to achieve GTR b. Chemoradiation with temozolomide is standard of care in adults c. Overall survival <20% 4. Prognosis a. Clinical = degree of tumour resection, tumour grade b. Biological = p53 expression, proliferation index c. Children <3 have better prognosis

Answer 146

1. Key points Type of GLIOMA a. Heterogenous group of tumours – account for 40% of paediatric CNS malignancies b. Occur throughout the CNS c. Based on histological features: cellular atypia, mitotic rate, vascular proliferation, necrosis d. 90% low grade, <10% high grade 2. Classified to grade = low grade (I-II) high grade (III-IV) 3. Types a. Pilocytic b. Diffuse c. Anaplastic d. GBM e. DIPG – separate type of diffuse intrinsic pontine glioma 4. Management principles a. Combination = most patients; surgery + radiation therapy +/- chemotherapy i. Complete response to chemotherapy is uncommon b. Observation = primary approach in selected group of patients i. NF-1 – LGA of the optic chiasm/optic pathway may be found incidentally ii. Midbrain astrocytoma – resolution of clinical symptoms after ventricular shunting, do not require further intervention d. Patients with midline tumours in the hypothalamic/optic chiasmatic region poorer prognosis e. Outcome i. Complete surgical resection  survival approaches 80-100% ii. Partial resection (<80%)  survival 50-95% depending on location f. NOTE: astrocytomas associated with tuberous sclerosis have responded to everolimus 5. Prognosis a. Low grade > 90% survival at 20 years b. Anaplastic astrocytomas – 30% at 3 years c. GBM < 10% d. Morbidity is high – radiation induced malignancy

Answer 147

* Pilocytic astrocytomas most common (20% all brain tumours) * Others: low grade glioma, fibrillary/ infiltrating astrocytoma, pilomyxoid astrocytoma * Can also be classified by location – optic pathway, posterior fossa, tectal

Answer 148

a. Key points i. Most common astrocytoma in childhood; accounting for 20% of all brain tumours ii. PA of the optic nerve and chiasmi region common finding in patients with NF-1 (15% incidence) iii. Mostly locally aggressive iv. Long clinical course v. Low metastatic potential and RARELY invasive b. Site = anywhere in the CNS i. Classic site cerebellum ii. Other common sites = hypothalamic/3rd ventricular region + the optic nerve and chiasmal region c. Investigations i. MRI 1. Often enhancing 2. Cystic components – often large, posterior fossa and OPG most common 3. Often associated hydrocephalus – aqueduct or 4th ventricle block ii. Histology 1. Compact fibrillary tissue with loose microcystic spongy areas 2. Rosenthal fibres – condensed glial filaments iii. Molecular features 1. 100% have molecular change in MAPK/ ERK/ BRAF pathway a. Potential for targeted therapy d. Treatment = surgical resection i. Avoid RTx if possible (esp NF1, ↑ secondary malignancies + Moya Moya) ii. CTx (carboplatin may delay radiation) iii. Increasing role of BRAF and MEK inhibitors e. Prognosis i. 80-100% survival with total resection; high morbidity ii. < 80% resection  50-95% survival (depending on site) iii. < 5% undergo malignant transformation

Answer 149

a. Group of tumours characterised by pattern of diffuse infiltration of tumour cells amongst normal neural tissue and potential for anaplastic progression b. Fibrillary LGA accounts for 15% of brain tumours c. Histology = greater cellularity than normal brain parenchyma, with few mitotic figures, nuclear pleomorphism and microcysts d. Molecular features = p53 mutation, overexpression of platelet derived growth factor alpha chain, platelet derived growth factor receptor alpha e. MRI = lack of enhancement after contrast agent infusion f. Evolution of fibrillary infiltrating astrocytoma into malignant astrocytoma is associated with cumulative acquisition of multiple molecular abnormalities

Answer 150

• Less common in children and adolescents than adults • Account for 7-10% of all childhood tumours • Very poor outcome, highly aggressive, high mortality (OS <20%) • Rare in children • Includes o WHO III – anaplastic astrocytoma o WHO IV – glioblastoma multiforme o DIPG

Answer 151

High grade glioma a. Includes anaplastic astrocytoma, oligodendroglioma, anaplastic oligoastrocytoma b. Histology = greater cellularity than low grade diffuse astrocytomas: cellular and nuclear atypia, mitosis and microvascular proliferation c. Limited evidence on molecular abnormalities d. ↑p53 mutations, loss of 19q/22q heterozygosity

Answer 152

High grade glioma a. Distinct disease in childhood b. Histology = characteristic findings include dense cellularity, high mitotic index, microvascular proliferation, and foci of tumour necrosis c. Molecular markers i. IDH1/2 mutations are rare in childhood (common in adulthood ii. H3F3A present in 1/3 of paediatric tumours iii. Other associations – p53 d. Imaging = heterogenous, irregular enhancement, necrosis haemorrhage, high perfusion on FLAIR e. Management i. Surgical resection followed by involved-field radiation therapy f. Outcome i. Anaplastic astrocytoma – 5 year survival 15-30% ii. GBM – 5 year survival 1-2%

Answer 153

High grade glioma a. Brainstem tumours constitute 10-20% of all brain tumours in children – 80% are diffuse brainstem glioma b. 1/5 mutation in ACVR1 c. Diagnosis based typically on RI d. Very aggressive disease e. Characterised by short history, cranial nerve enhancement f. Imaging i. Basilar artery encasement ii. T2 hyperintense expansion of pons iii. T1 isohypointense iv. Minimal enhancement g. Treatment + outcome i. No treatment curative ii. Radiation therapy standard of care iii. Chemotherapy of no benefit iv. 90% mortality at 2 years

Answer 154

1. Key points a. Derived from ependymal lining of ventricular wall or from spinal canal b. Composed of neoplastic ependymal cells c. SLOW growing tumour d. Occur anywhere along neuraxis - 70% occur in the posterior fossa e. 50-60% for all types survival f. 10% spread to leptomeningeal area g. Increased in NF-2 h. Usually sharp interface with native brain 2. Epidemiology a. Occur predominantly in childhood; account for 10% of childhood tumours b. Mean age in children 6 years 3. Clinical presentation a. Clinical presentation insidious and depends on location of tumour c. Myxopapillary ependymoma = slow-growing tumour arising from the filum terminale and conus medullaris and appears to be a biologically different subtype 4. Diagnosis a. MRI = well circumscribed tumour with variable and complex patterns of gadolinium enhancement, with or without cystic structures; T1 hypointense, T2 hyperintense b. Histology = perivascular pseudorosettes, ependymal rosettes, monomorphic nuclear morphology, non-palisading foci of necrosis c. Molecular features 5. Management a. Surgery + irradiation +/- chemotherapy i. Not usually chemosensitive b. Extent of surgical resection major prognostic factor; surgery alone rarely curative 6. Prognosis a. Overall = 50-60% b. Risk factors for poor prognosis i. Younger age ii. Anaplastic histology iii.

Answer 155

Embryonal Tumours = Primitive Neuroectodermal Tumour (PNET) Medulloblastoma is most common individual malignant brain tumour • Embryonal tumours or PNET – most common group of malignant CNS tumours of childhood • New terminology • Have potential to metastasize to the neuraxis and beyond • All classified as WHO grade IV tumours • Includes o Medulloblastoma o Supratentorial PNET o Ependymoblastoma o Medulloepithelialoblastoma o Pineoblastoma o Atypical teratoid rhabdoid tumour (ATRT)

Answer 156

Medulloblastoma

Answer 157

1. Key features a. Embryonal neurepithelial tumour b. Cerebellar tumour – usually occurring in the midline c. ONLY occurs in posterior fossa d. Spread along the neuraxis – metastatic disease in 1/3 at presentation 2. Epidemiology a. 20% of CNS paediatric tumours b. Most common malignant brain tumour c. More common in males (65%), median age 5-7 years d. 60-80% 5 year survival; static 3. Chang system of staging a. M0 = no metastases b. M1 = microscopic tumour cells in CSF c. M2 = gross nodule seeding intracranially d. M3 = gross nodule seeding in spinal subarachnoid space e. M4 = extra-neuraxis metastases 4. Molecular subtyping i. WNT1 = good ii. MYC+, p53 = bad iii. SHH = intermediate 5. Investigations a. MRI-B = homogenous, contrast enhancing, hyperintese on FLAIR b. Vary by subgroup 6. Treatment a. Surgery = maximal tumour resection b. Radiotherapy = CSI i. All patients ii. Higher risk = higher dose c. Chemotherapy i. Adjuvant chemo during and after RT ii. Higher risk require more aggressive chemotherapy regimens 7. Prognosis a. 60-80% 5-year survival for average risk; reduced if metastases b. Dependent on - extent of resection, stage, histology, molecular markers

Answer 158

b. WNT = CTNNB1 mutation  WNT signalling and MYC + - favourable prognosis i. 1/10 , M:F, children affected ii. Rarely metastasizes iii. Good prognosis: 100% cure rate iv. Suggested by b-catenin mutation, monosomy 6, methylation profiling/ gene expression suggestive of WNT c. SHH = PTCH1/ SMO/SUFU mutation: GLI2 amplification, MYCN + - i. Affects infants ii. Histology – classic, desmoplastic/ nodular/ LCA iii. Uncommonly metastasizes iv. Good prognosis in infants, otherwise poor (kids with p53 + SHH) v. Suggested by Gab1 antibody,, SHH specific signalling mutation, methylation/ gene expression consistent with SHH d. Group 3 = MYC poor prognosis i. M>F, infants ii. Classic/ LCA histology iii. Frequently metastasizes iv. Affects photoreceptors/ GABA ergic pathways, MYC ++++ e. Group 4 = generally poor prognosis i. Children, M> F ii. Classic + LCA histology iii. Frequently metastasizes iv. Intermediate risk v. CDK6/MYCN amplification, minimal MYC/MYCN

Answer 159

* NOTE: in new WHO now known as ‘embryonal tumour NOS’ * Very heterogenous group of tumours * Predominantly tumour of childhood or adolescence – mean onset 5.5 years * 3-5% of all childhood tumours * Rare * WHO grade IV * Histologically similar to MB and often treated similarly – however distinct entity * Do worse

Answer 160

1. Key points a. Embryonal malignancy b. Highly malignant tumours c. Usually in children < 3 years old d. Disseminated disease in 20% e. Short clinical history 2. Classification a. Supratentorial = 25% b. Infratentorial c. Spinal 3. Histology = small round blue cell tumours , 90% show loss of INI1 nuclear staining (SMARCB1) 4. Molecular features = partial or complete deletion of chromosome 22q associated with INI1 gene 5. Imaging = cysts, haemorrhage, T1 hypointense, T2 iso-hypointense a. Looks like PNET/ Medulloblastoma 6. Treatment a. Aggressive chemo/ radiotherapy i. Poor prognosis ii. Median survival 12 months even with complete resection iii. Consider 2nd look surgery after chemotherapy iv. Early RT used in majority of survivors b. Check for germline mutation – at risk for renal and soft tissue tumours

Answer 161

1. Key points a. Accounts for 2-4% of childhood CNS tumours b. Most common CNS tumour in children < 1 year; account for 10-20% of CNS tumours in infants c. Intraventricular epithelial neoplasms arising from choroid plexus d. Children present with signs and symptoms of raised ICP; may present with macrocephaly and focal neuro deficits e. Most commonly occur supratentorially in the lateral ventricles f. Tumours associated with Li-Fraumeni syndrome g. Simian virus 40 may play a role in etiologic role in choroid plexus tumour 2. Classification a. Choroid plexus papilloma = well circumscribed lesion that closely resembles normal choroid plexus histologically b. Choroid plexus carcinoma = malignant tumour with metastatic potential to seed into the CSF pathways 3. Diagnosis a. Immunopositivity for transthyretin (pre-albumin) is useful in confirming the diagnosis 4. Treatment and prognosis a. Complete surgical resection of choroid plexus papilloma  cure approaches 100% b. Choroid plexus carcinoma  cure 20-40% i. Radiotherapy +/- chemotherapy may improve outcome

Answer 162

The sellar region includes the sella turcica and the pituitary gland, together with the ventral adenohypophysis and dorsal neurohypophysis. The parasellar region encompasses the cavernous sinuses, suprasellar cistern, hypothalamus, and ventral inferior third ventricle. 1. Differential diagnosis a. Pituitary adenoma b. Pituitary hyperplasia -pregnancy, primary hypothyroidism and primary hypogonadism c. Other benign tumours i. Craniopharyngioma ii. Meningioma d. Cyst e. Abscess f. AV fistula in cavernous sinus g. MRI is the single best imaging modality to help distinguish 2. Clinical presentation a. Neurological symptoms = visual impairment or headache b. Incidental finding c. Hormonal abnormalities

Answer 163

Sellar mass 1. Key points a. Solid/ mixed solid-cystic tumour – arises from the remnants of the Rathke’s pouch along a line from the nasopharynx to the diencephalon b. Minimally invasive, adhere to adjacent brain parenchyma, and engulf normal brain structures i. Benign histologically ii. Large tumours extend in all directions – frequently resulting in obstructive hydrocephalus c. Location = intrasellar or suprasellar i. 95% have a large suprasellar component ii. Most involve both the suprasellar and intrasellar spaces (75%) iii. Minority (20%) purely suprasellar, purely intrasellar is rare 2. Epidemiology a. Common tumour of childhood; accounts for 7-10% of all childhood tumours b. 50% present clinically during childhood and adolescence – peak 5-14 years in children c. Most have CTNNB1 gene mutation d. 3rd most common after glioma + medulloblastoma 5. Differential diagnosis a. Other tumours in the parasellar area = pituitary macroadenoma, meningioma, optic glioma, germinoma, teratoma, lymphoma, metastasis b. Non-neoplastic cysts c. Infiltrative disorders = sarcoidosis, histiocytosis d. Specific DDx i. Rathke cleft cyst 1. No solid or enhancing component 2. Calcification rare 3. Unilocular 4. Majority are completely or mostly intrasellar ii. Pituitary macroadenoma (with cystic degeneration or necrosis) 1. Can look very similar 2. Usually has intrasellar epicenter with pituitary fossa enlargement rather than suprasellar epicenter 3. Despite occasional presence of T1 bright cysts, calcification is often absent

Answer 164

3. Clinical manifestations a. Endocrinological abnormalities i. Results from direct damage or compression of normal structures ii. Growth failure 95% - most common presenting features in children iii. Frequency of endocrine abnormalities (GH> GnRH >TSH> ACTH) 1. GH = 75%, GnRH = 40%, TSH = 25%, ACTH = 25% iv. Diabetes insipidus can occur if the pituitary stalk is involved v. (Hyperprolactinaemia NOT a common feature cf. pituitary adenoma) b. Visual disturbance i. Present in 70% - bitemporal hemianopia most common ii. Other abnormalities c. Headache and vomiting 4. Investigations a. Lateral skull X-ray = 90% have calcification b. MRI = heterogenous lesion, solid and cystic components i. Mixed density with calcification (T2 black) ii. Calcification of the suprasellar region in 60-80% of patients iii. 1 or more cysts present in 75% iv. Cholesterol crystals v.  cystic calcified parasellar lesion is very likely to be a craniopharyngioma c. Endocrine testing d. Visual field testing

Answer 165

6. Treatment a. Surgery = indicated in almost all cases b. Radiotherapy = for residual disease 7. Morbidity a. Significant treatment related morbidity b. Endocrinological i. Panhypopituitarism = hypogonadism, hypothyroidism, adrenal insufficiency, and/or GH insufficiency ii. Hypothalamic dysfunction = obesity, disorders of temperature regulation, sleep disorder, or diabetes insipidus iii. Complications of obesity c. Neurological i. Neurocognitive deficits – particularly among patients with hypothalamic involvement ii. Hypothalamic obesity iii. Sleep disorders and disrupted circadian rhythm iv. Behavioural problems d. Visual defects i. Most patients have visual defects prior to treatment ii. May be exacerbated by either surgery or radiation therapy 8. Prognosis a. 50-90% five year survival 9. Secondary tumours a. Use of radiotherapy associated with secondary development of meningioma and malignant glial tumours

Answer 166

1. Key points a. Rare in childhood, increases in frequency towards adolescence 2. Clinical features a. Often secretory i. ACTH most common ii. GH + PRL second most common b. Prolactinomas 50% - most common in older children i. Associated with MEN1 ii. Causes growth arrest, pubertal delay, amenorrhoea, hypogonadism 3. Treatment: a. Trans-sphenoidal adenectomy b. Dopamine agonist may reduce tumour size and control PRL (bromocriptine)

Answer 167

1. Key points a. Heterogenous group of tumours b. Arise from midline structures – pineal and suprasellar regions i. Other sites – sacrococcygeal, adults – anterior mediastinum, retroperitoneal c. 5-10% are multifocal 2. Epidemiology a. 3-5 % of pediatric brain tumours b. More prevalent in Asian populations c. Peak incidence 10-12 years of age 3. Classification a. Non germinomatous: embryonal CA, endodermal sinus tumour, choriocarcinoma, teratoma, mixed tumours b. Germinomas (60-65%) 4. Clinical features: a. Peak 10-12 years b. Diabetes insipidus, + hypopituitarism c. Visual changes d. Features of hydrocephalus 5. Investigations: a. +ve bHCG/ AFP (in serum and CSF) b. Pituitary stalk thickening/ pineal region c. Can be bifocal d. Main differential = Langerhans cell histiocytosis 6. Treatment a. Chemotherapy + low dose radiation b. CTx = carboplatin, etoposide, ifosfamide 7. Prognosis a. Survival exceeds 90%

Answer 168

1. Key points a. Most common malignancies after germ cell tumours that occur in the pineal region 2. Classification a. Pineoblastoma – occurs predominantly in childhood i. Considered a subgroup of childhood PNET b. Pineocytoma c. Mixed pineal parenchymal disease 3. Treatment a. Surgical removal b. Chemotherapy

Answer 169

1. Key points a. Rare disorder b. Caused by tumour in the diencephalon – region of brain including the hypothalamus and thalamus c. Onset usually within first 3 years of life 2. Clinical manifestations a. Failure to thrive i. Abnormal progressive thinness and weakness (emaciation) ii. Linear growth usually maintained b. Hyper alertness c. Hyperkinesia d. Euphoria e. Nystagmus f. Hydrocephalus g. Visual field defects h. Optic pallor i. Vomiting 3. Prognosis a. Can be lethal if not treated 4. Diagnosis a. MRI 5. Treatment a. Surgery, radiation

Answer 170

``` Homogenous ● SLE ● Mixed CT disease ● Drug induced lupus ● JIA ``` ``` Speckled ● SLE ● Sjogren’s ● Polymyositis/dermatomyositis ● Systemic sclerosis/scleroderma ``` Nucleolar ● Diffuse systemic sclerosis/scleroderma ● Polymositis Centromere ● Limited systemic sclerosis/ scleroderma Peripheral ● SLE ● Systemic sclerosis/sleroderma

Answer 171

o ENAs = extractable nuclear antibody ▪ Include = anti Ro, anti La, smith, RNP, Jo, SCL-70 ▪ Never seen in normal individuals ▪ SLE = Smith, Ro, La (associated with neonatal lupus syndrome, cutaneous lupus and thrombocytopenia ● Ro (SSB) = SLE, Sjogrens, congenital heart block ● La (SSB) = recurrent spontaneous abortions, congenital heart block, neonatal lupus ● Smith = particularly CNS ▪ Sjogrens = Ro, La ▪ Scleroderma/ CREST/MCTD = RNP/ SCL70 ▪ Diffuse systemic sclerosis = SCL70 ▪ Polymyositis-scleroderma = PML-SCL o dsDNA – another subtype of ANA ▪ For SLE - +ve in 60-70% of patients with SLE ▪ Associated with lupus nephritis – high specificity ▪ Can also reflect disease activity

Answer 172

● Stain the cytoplasm of neutrophils, detected by immunofluorescence ● cANCA = PR3 = cytoplasm 🡪 Wegner ● pANCA = MPO = perinuclear staining 🡪 MPA, CSS, IPNCGN, (other = SLE, IBD, PSC, HSP , Kawasaki disease)

Answer 173

● Include o Anticardiolipin = IgG and IgM o Anti-Beta 2 microglobulin = IgG and IgM o Lupus anticoagulant ● May be transiently +ve in setting of infection ● Needs to be present in two tests 12 weeks apart

Answer 174

``` Clinical sign o Joint effusion OR o 2+ of ▪ Joint line tenderness ▪ Limited ROM ▪ Pain with movement ▪ Warmth ```

Answer 175

1. JIA (some sub-types) 2. SLE 3. RA 4. Scleroderma 5. Dermatomyositis 6. MCTD 7. Sjogren’s disease

Answer 176

1. Ankylosing spondylitis 2. Psoriatic arthritis 3. Reiter’s disease 4. IBD related arthopathy

Answer 177

1. Epidemiology a. 1/1000 b. By definition, onset < 16 years of age c. MUST have symptoms for 6 weeks d. Usually associated with FHx (genetic predisposition + trigger) e. Phenotypes very diverse 2. Pathogenesis a. Not clearly understood b. Underlying immunogenetic susceptibility + external trigger c. T lymphocytes release proinflammatory cytokines: TNF alpha, IL6, IL1 d. Leads to inflammatory synovitis: i. Villous hypertrophy + hyperplasia ii. Hyperemia + edema of synovial tissue iii. Advanced disease 🡪 pannus formation, erosion of articular cartilage and contiguous bone 3. Clinical manifestations a. Arthritis i. Morning stiffness, joint swelling, effusions, loss of function ii. Any joint iii. Large > small iv. Also, axial, SI, TMJ v. Pain not as common as adults b. Systemic symptoms – systemic and polyarticular mainly fever, LOW, fatigue, anaemia c. Extra-articular i. Growth ii. Osteopenia iii. Cardiopulmonary iv. Uveitis d. Red flags i. Fever ii. Night time pain iii. Pain out of keeping with the degree of inflammation iv. Weight loss v. Lymphadenopathy / hepatosplenomegaly vi. Bone pain

Answer 178

5. Diagnostic criteria a. Age at onset: <16 yr b. Arthritis (swelling or effusion, or the presence of 2 or more of the following signs: limitation of range of motion, tenderness or pain on motion, increased heat) in ≥1 joint c. Duration of disease: ≥6 wk d. Onset type defined by type of articular involvement in the 1st 6 mo after onset: i. Polyarthritis: ≥5 inflamed joints ii. Oligoarthritis: ≤4 inflamed joints iii. Systemic-onset disease: arthritis with rash and a characteristic quotidian fever e. Exclusion of other forms of juvenile arthritis 4. Diagnosis a. Clinical i. Diagnosis of JIA is clinical, in the presence of: 1. Age < 16 years 2. Arthritis – swelling/ effusion, ↓ ROM, joint line tenderness, pain on motion in > 1 joints 3. Sx lasting > 6 weeks b. Investigations i. FBE + film – inflammatory thrombocytosis, anaemia, leukocytosis ii. Inflammatory markers – CRP, ESR iii. Viral serology, ASOT – exclude viral infections iv. Serology 1. ANA = 15% positive in normal children, may help to predict risk of uveitis 2. RF = low yield, used for classification, if positive predicts severe course illness v. If MAS suspected = clotting cascade, ferritin, D dimer, fibrinogen, LDH, TG, LFTs 1. Expect ferritin of 500-1000 in systemic JIA; >1000 more consistent with MAS vi. Further investigations 1. Ig – approx 4% IgA deficient 2. HLA-B27 = 10% Caucasian children, used for classification 3. LFT = often elevated transaminases 4. Ferritin = disproportionate elevation in systemic JIA vs 5. Clotting/ D dimer = suggestive of MAS c. Imaging i. Plain films 🡪 periarticular osteopenia, soft tissue swelling, joint space narrowing, erosions, new bone apposition and poor bone growth ii. Ultrasounds – for effusions (eg. hip) iii. Bone scan/T – for exclusion of other causes

Answer 179

a. Systemic arthritis = arthritis with or preceded by quotidian (daily) fever for at least 3 days, accompanied by one or more of i. Evanescent erythematous rash ii. Lymphadenopathy iii. Hepatomegaly and/or splenomegaly iv. Serositis b. Oligoarthritis = arthritis of 4 or fewer joints within the first 6 months – MOST COMMON c. Polyarthritis = arthritis of 5 or more joints in the first 6 months i. RF positive = tends to be adolescent girls with a course similar to adult RA ii. RF negative d. Psoriatic arthritis = arthritis AND psoriasis OR arthritis with 2 of i. Dactylitis ii. Nail pitting or onycholysis iii. Psoriasis in first degree relative e. Enthesitis related arthritis = arthritis AND enthesitis OR arthritis OR enthesitis with 2 of i. Sacroiliac joint tenderness of inflammatory lumbo-sacral pain ii. HLA-B27 positive iii. Onset >6 years in male iv. Acute (symptomatic) anterior uveitis v. History of HLA-B27 positive disease in 1st degree relative f. Undifferentiated = fits no above criteria

Answer 180

a. Goals i. Reduce inflammation ii. Reduce pain iii. Preserve ROM + strength iv. Allow for normal growth + development b. First line i. NSAIDS 1. 25-35% response rate to monotherapy at 4-6weeks ii. Steroids 1. Oral, IV, intra-articular injections 2. Systemic steroids often used in setting of fever, serositis, MAS, and as bridge to steroid sparing treatment effect 3. Intra-articular a. Disease control lasts >6-12 months b. Prevent leg length discrepancy/flexion deformity 4. Do not induce remission 5. IA steroids + MTX important for sustained remission c. DMARDs i. Non-biologic 1. Methotrexate a. Weekly oral / subcutaneous b. Need concurrent folic acid c. Check immune status prior – must have varicella d. 6-12 weeks to take full effect e. Only drug subjected to RCT for JIA f. Good efficacy = 70% respond; 60% flare on ceasing g. Monitoring = FBE, LFT 3 monthly h. AE = mouth ulcers, nausea, headache, infection ii. Biologics 1. TNF alpha inhibitors = etanarcept , infliximab, adalimumab a. Indications = inadequate response to MTX, poor prognostic factors, severe disease b. Early aggressive combination therapy methotrexate + TNF-alpha 2. Anti IL1 = anakinra + anti-IL 6 = tocilizumab a. Used for sJIA b. If severe disease anakinra started immediately 3. Anti-cell surface markers = rituximab e. Treatment algorithm i. Trial NSAIDS for 4-6 weeks 1. Rarely enough for polyarticular disease/ systemic arthritis 2. 25-35% response rate at 4-6 weeks ii. If no response / functional limitations (contracture/ leg length discrepancy) 🡪 intra-articular steroids iii. If no response 🡪 DMARDs 1. MTX the oldest and least toxic DMARD, may take up to 6-12 weeks to see affect 2. Combination of TNF alpha blockade may be added if inadequate response 3. IL-1 receptor antagonists may be better for systemic symptoms iv. Systemic steroids are generally avoided: only for severe systemic illness awaiting response to DMARD (do not induce remission on their own) f. Supportive i. Check immunisation status prior ii. Screen for diseases that can reactivate - eg TB iii. Annual influenza vaccination iv. Dietary evaluation – adequate calcium, vitamin D, protein, and caloric intake v. Physical therapy and occupational therapy – adjuncts to any treatment program vi. Role of general paediatrician 1. Monitor growth 2. Nutrition 3. Bone health 4. Immunisation 5. Adherence 6. Coordinate care

Answer 181

9. Complications a. Uveitis - see next section b. Osteopenia c. Orthopaedic complications i. Leg length discrepancy 1. Leg that is affected becomes longer due to hyperemia and inflammatory growth factors: accelerates growth initially – however premature growth plate closure 🡪 short bones ii. Flexion contractures iii. Popliteal cysts iv. Contractures v. Osteopenia d. Psychosocial e. Macrophage activation syndrome – systemic JIA 10. Prognosis a. Prior to anti – TNF, 50% of children would have active disease persisting into childhood b. Persistent oligoarthritis = good prognosis, majority achieve remission c. Extended oligoarthritis = poor prognosis, chronic uveitis d. Polyarticular JIA = require early aggressive therapy, poor prognosis i. Poor prognostic factors = young age, RF seropositivity or rheumatoid nodules, anti-CCP, large number of affected joints, hip/hand/wrist disease e. Systemic JIA = poor prognosis, difficult to control i. Poor prognostic factors = polyarticular distribution, fever lasting >3 months, increased inflammatory markers f. 30-40% long-term disability 11. Long-term management issues a. Uveitis b. Growth i. Local deformity ii. Overall iii. Growth hormone c. Bones d. Drug monitoring e. Pain management f. Rehabilitation g. Psychosocial developmental h. Vocational planning i. Transition planning

Answer 182

a. <= 4 joints in first 6 months b. Large joints c. Hip involvement UNUSUAL – think mimic or ERA d. Female: male 4:1 e. ANA +ve in 60% f. Asymptomatic anterior uveitis 20-30% risk i. Most common within 2 years but continue slit lamp screening until 10-12 years

Answer 183

a. >4 joints b. Clinically – small and large joints, symmetrical c. Consider other sites – TMJ, cervical spine d. RF positive <10% e. Sero positive tend to be RA pattern – nodules, early erosions, lower rate of remission

Answer 184

a. Key points i. Arthritis + psoriasis ii. Dactylitis iii. Nail pits +/- skin involvement iv. Asymmetric large/ small distribution v. Family history psoriasis vi. Uveitis common b. Epidemiology i. 1-2 / 10,000 children ii. F>M iii. Onset 25-40years most commonly – can occur in preschool and early adolescent years iv. 5% patients with psoriasis c. Clinical manifestations i. Suspect in any child with oligo-polyarthritis + nail changes/dactylitis +/- FHx psoriasis ii. Cutaneous 1. Psoriasis before arthritis most common 2. Red, scale plaques on extensor surfaces iii. Nail changes 1. Pitting 2. Onycholysis 3. Hyperkeratosis iv. Arthritis 1. Most commonly oligoarthritis asymmetrical random involvement 2. DIP joint arthritis with dactylitis is classic 3. Large (knees and ankles) and small (fingers and toes) joints may be involved 4. Sacroilitis uncommon (30%) v. Enthesitis = 20-60% vi. Iritis / uveitis d. Investigations i. As for ankylosing spondylitis ii. HLAB27 (not a risk factor) but if positive more likely axial involvement iii. 50% ANA positive iv. X-ray = DIP involvement with erosions (pen in cup deformity) e. Treatment = same as AS

Answer 185

a. Key points i. Arthritis + enthesitis ii. HLA-B27 positive iii. Typically boys >6 years iv. Inflammatory lower back pain and/or sacroilitis v. Family history of ank spond vi. Associated with acute anterior uveitis b. Clinical manifestations i. Symmetric and most commonly affects lower limbs 1. During the first 6 mo of disease – arthritis typically asymmetric, involving ≤4 joints ii. Knees, ankles, and hips most frequently affected iii. Inflammation of the small joints of the foot (tarsitis) is highly suggestive iv. Sacroiliac joint arthritis = up to 40% develop clinical or radiographic evidence c. Prognosis i. May progress to AS

Answer 186

Occurs in all forms of JIA Involvement in 50% Often asymptomatic Findings: decreased mouth opening, clicking/crepitations, tenderness

Answer 187

Arthritis in ≥1 joint with, or preceded by, fever of at least 2 wk in duration that is documented to be daily (“quotidian”*) for at least 3 days and accompanied by ≥1 of the following: 1. Evanescent (nonfixed) erythematous rash 2. Generalized lymph node enlargement 3. Hepatomegaly or splenomegaly or both 4. Serositis (pleura/pericardium/peritoneum)

Answer 188

Arthritis affecting 1-4 joints during the 1st 6 mo of disease. Two subcategories are recognized: 1. Persistent oligoarthritis—affecting ≤4 joints throughout the disease course 2. Extended oligoarthritis—affecting >4 joints after the 1st 6 mo of disease

Answer 189

Arthritis affecting ≥5 joints during the 1st 6 mo of disease | Sub-classified as RF positive or negative

Answer 190

Arthritis and psoriasis, or arthritis and at least 2 of the following: 1. Dactylitis 2. Nail pitting and onycholysis 3. Psoriasis in 1st degree relative

Answer 191

Arthritis and enthesitis, or arthritis or enthesitis with at least 2 of the following: 1. Presence of or a history of sacroiliac joint tenderness or inflammatory lumbosacral pain or both 2. Presence of HLA-B27 antigen 3. Onset of arthritis in a male >6 yr old 4. Acute (symptomatic) anterior uveitis 5. History of ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter syndrome, or acute anterior uveitis in a 1st-degree relative

Answer 192

a. Inflammation of the uvea (middle portion of the eye – composed of iris, ciliary body/ choroid) b. Individuals that have HLA-B27 are at increased risk c. Location of uveitis i. Anterior (iritis/ iridocyclitis/ciliary body) 🡪 MOST COMON ii. Intermediate (vitreous humour) iii. Posterior (chorioretinal) d. Examination i. Anterior = pain and redness, constricted pupil + pain, leukocytes in anterior chamber ii. Posterior = more likely to be painless e. Treatment i. Underlying cause ii. Topical steroids/ intraocular steroids if posterior f. Complications i. Band keratopathy (calcium deposition) ii. Synechiae (adhesion of iris to lens) iii. Cataract iv. Hypertension v. Glaucoma

Answer 193

a. Occurs in 25% children with JIA b. Most develop arthritis BEFORE uveitis c. Bilateral in 70-80% - highest risk within 4 years of onset d. Risk factors i. Age <6 years ii. Female iii. ANA positive iv. RF negative v. JIA subgroup - oligoarticular disease vi. Time from diagnosis (75% occurs within 3 years of the diagnosis) e. Classification i. Acute = SYMPTOMATIC ii. Chronic = ASYMPTOMATIC f. Screening (high risk 3 monthly, intermediate risk 6 monthly, low risk 12 monthly) g. Treatment i. Mydriatics ii. Corticosteroids iii. DMARDs iv. MTX + anti-TNF (adalimumab, inflimxab) if severe

Answer 194

AKA Stills disease in adults Epidemiology a. M=F b. Onset < 16 years of age c. 5-10% of cases d. No peak age of onset 2. Clinical manifestations (fever, arthritis, rash) a. Fever - quotidian (daily pattern) - 98% b. Arthritis 88% i. May not be a prominent feature early in disease ii. Can affect hands, wrists, ankles, knees, hips, C spine and TMJ c. Rash 81% i. Linear or circular and are most commonly distributed over the trunk and proximal extremities ii. “Salmon pink” iii. Nonpruritic iv. Migratory, lesions lasting <1 hr v. Triggers (Koebner phenomenon - lesions brought on by superficial trauma, heat) d. Other features i. Lymphadenopathy (31%), ii. Hepatomegaly, iii. Splenomegaly, iv. Pericarditis, v. Hepatitis, vi. Pulmonary manifestations 4. Investigations a. Anaemia b. ESR = usually elevated i. Sudden fall in ESR/ platelet count often heralds the onset in MAS c. Ferritin = extreme hyperferritinemia > 1000 – common, even in absence of overt MAS 5. Prognosis a. Very variable b. Can be monophasic/ polycyclic / persistent i. Monophasic = resolves after 6 months, does not recur ii. Polycyclic = recurrences of active systemic JIA with periods of disease inactivity in between iii. Persistent c. 40-50% of patients completely resolve d. Patterns of disease i. Systemic manifestations (ie fever + rash) but little to no arthritis ii. Persistent systemic manifestations and progressive arthritis iii. Progressive destructive arthritis despite resolution of systemic manifestations 6. Complications a. Macrophage activation syndrome b. Growth retardation ii. Due to combination of steroids + systemic inflammation iii. Less of an issue with modern immunosuppressants c. Osteoporosis i. Less common due to new immunosuppressants d. Pulmonary complications i. Include 1. Interstitial lung disease 2. Pulmonary hypertension 3. Lipoid pneumoniae 4. Alveolar proteinosis e. Other i. Leg length discrepancies ii. Restricted jaw opening iii. Amyloidosis (20%)

Answer 195

1. Key points a. Severe complication of SJIA and important cause for morbidity + mortality b. Synonymous with HLH secondary to rheumatic disease c. M = F d. Usually occurs in the first few days/ weeks of systemic JIA onset – but can occur at ANY time during disease e. Occurs in 10% of children with sJIA, up to 30-40% subclinically f. May follow infectious trigger or drug 2. Pathogenesis a. NK cell function i. Low NK activity 🡪 low number of NK cells 🡪 increased perforin ii. Low NK activity with mildly decreased NK cells but LOW perforin expression b. Pro-inflammatory cytokine storm i. Fever, hyperferritinaemia, coagulopathy ii. Bone marrow suppression with cytopenias c. Infiltration of T cells, APCs and macrophages i. Bone marrow, liver, spleen, LN, brain d. Persistent T activation + NK cell dysfunction i. Propagation of vicious cycle with more cytokines + further activation of immune cells 3. Rheumatologic triggers a. Systemic JIA – 10% b. Lupus c. KD

Answer 196

4. Clinical manifestations a. Key triad i. Unremitting fever - NOT quotidian ii. Rash iii. Splenomegaly b. Other features i. Lethargy ii. Hepatomegaly + lymphadenopathy iii. Rash – petechial, purpuric iv. Encephalopathy v. Seizures vi. Coma, shock 5. Investigations a. Ferritin – higher than JIA, well over 1000 b. DROP in ESR (due to fibrinogen consumption) 🡪 important clue to differentiate sJIA c. Cytopenia (at least 2 out of 3) d. Hypertriglyceridemia / hypofibrinogenemia e. Low or absent NK cell f. Elevated soluble CD24 (IL2 receptor alpha) g. Abnormal LFTs h. Histology = haemophagocytosis 6. Diagnostic criteria a. 2004 criteria i. Fever ii. Splenomegaly iii. Cytopaenia 2/3 lines iv. HyperTG v. Ferritin >500 ``` TOP 10 FEATURES ● Falling platelets ● Bone marrow haemophagocytosis ● Elevated ferritin ● Fever ● Falling leukocytes ● Elevated LFTs ● Falling ESR ● Raised TG ● Hypofibrinogenaemia ● CNS dysfunction ```

Answer 197

7. Treatment a. High dose steroids b. Anakinra – IL-1 receptor antagonist c. Second line = cyclosporine, cyclophosphamide, etoposide, anakinra d. BMT 8. Prognosis a. Mortality 8-22%

Answer 198

1. Key points a. Group of inflammatory disorders characterize by negative serology b. Common features i. Sacroiliitis ii. Asymmetrical oligoarthritis – usually peripheral LL iii. Enthesitis – inflammation of bone where ligaments/tendons attach (lateral calcification and joint fusion) iv. Anterior uveitis v. Familial association vi. Increase incidence HLAB27 2. Conditions a. Ankylosing spondylitis -> ‘adult’ disorder b. Enthesitis related arthritis (ERA) -> subtype of JIA c. Arthritis associated with IBD d. Reactive arthritis post GI / GU infections 3. Epidemiology d. Increased frequency of HLA-B27 (> 90% of cases) i. Found in 90% of JAS, 50% of ERA, 7% of healthy individuals 5. Clinical manifestations a. Distinguishing features compared with other forms of juvenile arthritis i. Arthritis of the axial skeleton (sacroiliac joints) and hips ii. Enthesitis (inflammation at site of tendon, ligament, joint capsule attachment to bone) iii. Symptomatic eye inflammation (acute anterior uveitis) iv. Gastrointestinal inflammation (even in the absence of IBD) 6. Investigations a. Inflammatory markers = variable elevation b. Serology i. RF = negative ii. ANAs = negative (exception psoriatic arthritis – may be positive) c. HLA B27 = present in > 90% of children with juvenile ank spond (less in ERA and other types) 7. Treatment a. Similar to JIA b. 1st line = NSAIDs/ IA steroids c. 2nd line = DMARDs i. Sulfasalazine/ MTX ii. Biologics = TNF-alpha inhibitors d. Supportive i. Physical exercise ii. OT 8. Complications a. Ankylosis = fusion of adjacent bones

Answer 199

1. Key points a. Inflammatory arthritis characterised by progressive stiffening and fusion of the axial skeleton (SIJ and vertebrae) b. Usually begins with oligoarthritis and enthesitis (most common presentation in children) c. Often lower extremities + involves the hips (DIFFERENT to oligoarticular JIA) d. Systemic symptoms are UNCOMMON (think about IBD) 2. Epidemiology b. M>F c. HLA B27 90% positive, population positive 8% d. Adolescents/young adults 3. Clinical manifestations a. Insidious onset – may begin with oligoarthritis and enthesitis b. Recurrent episodes of back pain – sacroilitis (inflammatory -> worse in morning, improved with activity) vii. Examination 1. Loss lumbar lordosis 2. Decreased lateral flexion/flexion/extension 3. Positive SIJ stress test 4. Positive Schober’s test c. Other common features i. Asymmetrical oligoarthritis of large joints 3. Hips (unlike oligo JIA), knees, ankles, intertarsal joints ii. Enthesitis 1. Plantar fasciitis, achille’s tendonitis 2. Patella insertion, hips iii. Anterior uveitis -- up to 25% iv. Aortitis and AR 4. Investigations a. FBE - increase WCC, thrombocytosis b. Increased ESR c. Absent / negative serology d. HLA B27 positive 90% e. X-ray i. Heel spurs ii. Sacroiliitis = pseudowidening, sclerosis, fusion, squaring of vertebral, bamboo spine due to spondylitis f. MRI = most sensitive for sacroilitis 5. Treatment a. Conservative – back care, bedding, avoid contact sports, physio, physical therapy, low impact exercise b. First line i. NSAIDS, IA steroid of enthesitis ii. Oral steroids, sulphasalazine, MTX c. Biologicals – some evidence in children i. Anti TNF – infliximab, adalimumab, etanercept

Answer 200

1. Polyarthritis affecting large and small joints a. Most common – follows exacerbations of bowel disease b. Not associated with HLAB27 c. No sacroilitis 2. Sacroilitis a. Less common b. Independent to IBD course c. HLAB27 positive d. Similar to ankylosing spondylitis

Answer 201

● Typically affects hip, often post URTI ● Boys 3-10 years ● Acute onset severe pain in the hip (groin), with referred pain to the thigh or knee, lasting approximately 1 week ● ESR and WBC usually normal ● Radiologic or ultrasound– widening of the joint space secondary to effusion ● Aspiration of joint fluid often necessary to exclude septic arthritis and typically results in dramatic clinical improvement ● Trigger presumed to be viral, although responsible microbes have not been identified

Answer 202

1. Key points a. Joint inflammation due to a sterile inflammatory reaction after a recent infection b. 75% are HLA-B27 +ve c. Usually occurs in young males 2. Classification a. Reactive arthritis = post enteropathic/urogenital infections b. Post infectious arthritis = arthritis after other infections not classically considered in reactive arthritis group 3. Etiology a. Enteropathic infections = salmonella, shigella, Yersinia, campylobacter jejuni, cryptosporidium parvum, giardia b. Genitourinary infections = chlamydia, urea plasma c. Other = GAS, Neisseria gonorrhoea 4. Pathogenesis a. Reactive arthritis = molecular mimicry: autoreactive T lymphocytes cross react with antigens presented by HLAB27 b. Post-infectious arthritis = viruses isolated from joint OR viral antigen-immune complex deposited in joint 5. Clinical manifestations a. Reactive arthritis i. 2-4 weeks post infection ii. Transient pain / joint swelling < 6 weeks iii. Usually oligoarticular, LL > UL iv. May be associated with dactylitis + enthesitis v. Cutaneous manifestations vi. Systemic symptoms = fever, malaise, fatigue vii. Reiter’s disease = conjunctivitis, urethritis, arthritis b. Post-infectious arthritis i. Pain/joint swelling usually transient, lasting < 6 weeks 6. DDx = gonococcal arthritis, septic arthritis 7. Investigations a. Same as other seronegative arthropathy b. No XR changes c. Urine/faecal/blood specs for source d. ASOT/anti-DNASe B = identify post-strep 8. Treatment a. Usually not required – resolves b. Pain management – NSAID c. Intra-articular steroids rarely used 9. Complications/ Prognosis a. Usually resolves without complication b. May precede development of IBD, chronic arthritis, spondyloarthritis c. Rare complications = uveitis, carditis

Answer 203

1. Epidemiology a. Less common in children (1-6/100,000) b. More common and severe in non-white population c. F>M 5-9:1 (worse in adolescence) d. Haematological + renal manifestations more severe in children compared to adult onset e. Up to 50% of individuals with SLE diagnosed <16 years [lecture: 15-20% childhood onset] f. UNUSUAL in <8y and Caucasian children g. Peaks in females 19-29 years 2. Risk factors a. Gender – 90% female, mostly in reproductive years b. Genetic predisposition (complement deficiencies, famhx other AI disease, HLA DR2 and DR3) 3. Pathogenesis a. Chronic autoimmune disease characterized by polyclonal B cell activation + production of autoantibodies 🡪 widespread inflammation (form of type 3 hypersensitivity) b. Antigens released during cell necrosis/ apoptosis i. Reduced ability to clear nucleic acids/ increased levels of apoptosis = ↑ antigens in blood stream ii. Production of autoantibodies to nucleic acids iii. Formation of immune complexes deposit in tissues 🡪 local complement activation

Answer 204

Relapsing remitting course Most common: - constitutional (fever, malaise, LOW) - 40-70% - MSK (arthritis, arthralgia) - 20-75% - Hepatosplenomegaly - (15-75%) - Haematologic (cytopenias) - Mucocutaneous (rash, ulcers) - 50% - Renal (nephritis, nephrotic syndrome) - 20-80% - LAD abnormalities (15-30%) ``` Mnemonic: DOPAMINE RASH Discoid rash Oral ulcers Photosensitivity Arthritis Malar rash (butterfly rash, spares nasolabial folds) Immune markers Neurologic (seizures, psychosis) ESR Renal ANA Serositis Haematologic (cytopenias) ``` Detail: b. Systemic i. Fever ii. Weight loss iii. Fatigue, malaise iv. Anorexia, nausea, vomiting v. Myalgia and arthralgia vi. Lymphadenopathy vii. Hepatosplenomegaly c. Peripheral vasculitis i. Swollen fingers ii. Raynaud’s iii. Sclerodactyly (localized thickening and tightness of the skin of the fingers or toes) iv. Calcinosis (calcium deposits in any soft tissue) v. Peri-ungual erythema (around the nails) vi. Brown finger nails vii. Telangiectasia viii. Livedo reticularis (mottled skin) ix. Superficial phlebitis d. Cutaneous i. Malar rash 1. Butterfly distribution 2. Cheeks + bridge of nose 3. SPARES nasolabial folds 4. Mild erythema, spotty to very angry ii. Oral ulcers 1. Hard palate 2. Painless, shallow 3. Surrounding erythema 4. Vasculitic injection 5. Check nose iii. Other rashes 1. Face, fingers + toes, hard palate, scalp/ears/extensor surfaces (discoid lupus) 2. Vasculitic, Petichiae, purpura 3. Photosensitivity – blisters/ sun exposed areas e. Musculoskeletal i. 90% arthritis 1. Less swollen than JIA 2. Often more painful 3. Non-erosive but can get deformities from ligamentous stretching ii. Osteopenia iii. Arthralgias iv. Myalgias v. Myopathy (rare) f. Nephritis i. Heterogeneity in presentation of the disease + unpredictable

Answer 205

4 or more of the following criteria, with 1 clinical and 1 lab ``` Clinical criteria Acute cutaneous lupus or subacute cutaneous lupus Chronic cutaneous lupus Oral ulcers or nasal ulcers Non-scarring alopecia Synovitis involving two or more joints Serositis Renal Neurologic (seizures, psychosis) Haemolytic anaemia Leukopenia (<4 000/mm3) or lymphopenia (1 000/mm3) Thrombocytopenia (<100 000/mm3) ``` ``` Immunologic criteria ANA Anti-dsDNA Anti-Sm Low complement Direct Coombs test Antiphospholipid antibodies ```

Answer 206

a. Haematological i. FBE and film – anaemia, lymphopenia, thrombocytopenia ii. Reticulocyte count and DCT positive iii. Coags iv. DAT – haemolytic anaemia b. Inflammatory – CRP / ESR (ESR > CRP), Ferritin c. Biochemistry – UEC/ LFT/ CMP d. Complement levels = CH50, C3, C4 i. Typically decreased in active disease, improve with treatment e. Coagulation screen f. Renal Ix = urine dipstick, MCS, Pr:Cr ratio, biopsy g. Thyroid screen h. Immunity status – eg VZ IgG i. Serology Immune markers: ANA (antinuclear antibody) ● High sensitivity (95-99%) and low specificity (50%) ● Positive in 95-99% of individuals with lupus ● 20% of healthy individuals also have positive ANA ● NOT reflective of disease activity ● Probability of having SLE if ANA is negative 0.15% ● 1:160 weak positive, 1:1200 strong positive ● ANA negative lupus is extremely rare Anti-dsDNA ● Lower sensitivity (40-65%) and high specificity (98%) ● Positive in 60% of individuals with lupus ● Low prevalence in healthy individuals ● Correlates with disease activity ● Correlates with nephritis ENA (extractable nuclear antibodies) - include anti smith, Ro/SSA, La/SSB, RNP (ribonucleotide protein), ribosomal P - anti Ro/La a/w neonatal lupus - anti ribosomal P a/w neuropsychiatric manifestations Antiphospholipid antibodies (cardiolipin, beta2microglobulin) ● Positive in 2/3 of individuals with SLE ● Associated with thrombophilia Anti histone antibody ● Associated with drug induced lupus ● Also positive in 20% of individuals with lupus

Answer 207

i. Triggered by minocycline, anticonvulsants, sulphonamides, antiarrhythmic agents, other durgs ii. Usually occurs in patients who are prone to SLE iii. Associated with antihistone antibodies iv. Hepatitis more common v. Males = females vi. LESS likely to have = anti-dsDNA, low C’, renal or neurological disease vii. Resolves after withdrawal of medication (can take months-years)

Answer 208

a. Goals i. Treat acute flares ii. Prevent disease flares iii. Minimise treatment related complications iv. Minimise impact of incurable severe chronic disease b. Lifestyle = avoid sun exposure + sunscreen c. Pharmacological i. Hydroxychloroquine 1. Recommended for ALL individuals with SLE 2. Roles a. Treats mild SLE manifestations (rash and mild arthritis) b. Prevents SLE flares c. Improves lipid profiles d. +/- Beneficial impact on mortality and renal outcomes. 3. Toxicities a. Retinal pigmentation + color vision impairment 🡪 6-12 mo ophthalmology exams ii. Steroids 1. Mainstay for treatment of significant manifestations of SLE 2. Work quickly to improve acute deterioration iii. Steroid sparing immunosuppressive agents = MTX, leflunomide, AZA, MMF, cyclophosphamide 1. Moderate disease = MTX/ leflunomide, azathioprine a. Note delay in starting medication + therapeutic effect b. MTX = 8-16 weeks 2. Severe = IV/ oral cyclophosphamide a. Reserved for the most severe, potentially life-threatening SLE manifestations, such as renal, neurologic, and cardiopulmonary disease. b. Highly effective in controlling disease c. Toxicities i. Cytopenias ii. Infection iii. Haemorrhagic cystitis – ensure hydration iv. Premature gonadal failure v. Increased risk of future malignancy. iv. New agent = belimumab 1. Monoclonal Ab against BLyS – B cell activating factor a. Adjunctive therapy i. Plasmapheresis ii. IVIG iv. Dialysis v. Anticoagulation

Answer 209

11. Complications a. Mortality i. Short-term 1. Recurrent infections 2. Complications of GN 3. Neuropsychiatric ii. Long-term 1. Atherosclerosis 2. Malignancy b. Atherosclerosis + CVD i. Chronic immune dysregulation + inflammation ii. Evident in young to mid adulthood c. Musculoskeletal i. Osteoporosis ii. Compression fractures iii. AVN – steroids d. Recurrent infections e. Hypertension f. Infertility g. Malignancy h. CNS – Organic brain syndrome, seizures, psychosis, neurocognitive dysfunction i. Ocular – Cataracts, glaucoma, retinal detachment, blindness j. Endocrine – Diabetes, obesity, growth failure, infertility, fetal wastage 12. Prognosis a. Prognosis WORSE for paediatric onset SLE b. Flare and quiescence pattern of disease c. Untreated high mortality rate d. 5-year prognosis 100% e. 10-year prognosis 90% i. Factors associated with worse outcome 1. Non-adherence 2. CNS or cardiac disease 3. Early HTN with renal disease f. Mostly closely related to renal disease g. Poor outcomes still in QOL, lower SES and chronic disease

Answer 210

1. Key points a. 1-2% of babies born to mothers with autoimmune disease b. Risk approx 2-10% in Ro/La +ve mother (unlikely iff negative) c. 2% of offspring to mothers with anti-Ro/La Ab have CHB d. 15-25% recurrence risk in future pregnancies 2. Pathogenesis a. Passive transplacental passage of Anti-Ro, Anti-La, and less commonly Anti-U1RNP (usually only have cutaneous/haem manifestations) 3. Clinical manifestations a. Cutaneous – 72% i. Most common manifestation ii. Annular/ macular rash iii. Affects face, trunk and scalp – central clearing, scaly vi. Usually appears within first 6 weeks of life after exposure to UV life (can develop up to 6 months) 1. Most commonly appears in the first week – not present at birth vii. Lasts 3-4 months (lecture 6-8 months) with spontaneous resolution when maternal IgG Ab gone viii. Rash flares with UV light b. Congenital heart block – 65% i. Occurs in 1-2% mothers with Ro/ La ii. 16-18% recurrence rate iii. 80-85% cases of congenital heart block due to neonatal lupus iv. Anti Ro antagonizes L type calcium channels on human atrial cells and triggers inflammation, leading to fibrosis of AV, Sa nodes and bundle of HIS v. Can be detected in utero by fetal echo beginning at 16 weeks gestation vi. Rare after 30/40 vii. Can vary from first degree to complete with progressive cardiomyopathy viii. Only nonreversible feature c. Hepatitis – 52% i. Asymptomatic elevation of LFT and bilirubin (usually self resolves) ii. Mild hepatosplenomegaly, cholestasis iii. Most settle by 6 months d. Haematological i. Anaemia ii. Neutropenia iii. Thrombocytopenia iv. Rarely aplastic anaemia e. Other i. CNS = hydrocephalus, macrocephaly 4. Diagnosis a. Maternal anti-Ro/ anti La b. +ve test in mother OR fetus confirms diagnosis c. Should also check FBE / LFT and TFT d. Fetal echo and ECG 5. Management a. Prenatal i. Prenatal screening 1. Recommended for all women with SLE, Sjogrens, other autoimmune disease, or PHx of NL in previous pregnancy 2. Weekly pulsed Doppler fetal TTE iii. Paediatric cardiologist should monitor with fetal ECG from 16 weeks to delivery if anti Ro/ La +ve (Ab begin to be transferred at this time) b. Neonatal i. Cardiac pacing may be required 🡪 20-30% mortality in neonatal period 1. 65% require cardiac pacemaker ii. IVIG +/- steroids sometimes used – no evidence iii. Severe cardiomyopathy warranting transplantation 6. Prognosis a. Excellent prognosis if cutaneous only b. With cardiac pacing children with conduction system disease w/o cardiomyopathy also have good prognosis

Answer 211

1. Epidemiology a. 1-2% population b. Peak is 30-50 years c. F>M 2: 1 2. Clinical features a. Arthritis i. Distal deforming symmetrical polyarthropathy 1. Involves: PIP, MCP, wrist, MTP, ankle ii. Insidious onset and chronic iii. Pain worse in morning, decrease with activity iv. Stiffness and swelling v. Loss of function b. Extra-articular manifestations i. Cardiac = early onset IHD, pericarditis, myocarditis ii. Pulmonary = pleural disease, effusion, lung nodules, fibrosing alveolitis iii. Eyes = scleritis, episcleritis, keratoconjunctivitis iv. Neuro = carpal tunnel, tarsal tunnel, mononeuritis multiplex v. Skin = cutaneous nodules, vasculitis, Sjogrens vi. Renal = secondary damage due to amyloid deposition vii. Anaemia of chronic disease viii. Hepatosplenomegaly + lymphadenopathy 3. Natural history a. Self-limiting <20% b. Palindromic – relapsing and remitting, rare c. Short duration progressive 20% d. Long duration progressive 60-90% 4. Investigations a. FBE = anaemia, leuckocytosis b. ESR/ CRP = elevated c. Serology = 85% RF positive, anti-CCP in adults, 30% ANA positive

Answer 212

1. Key points a. Capillary vasculopathy b. Most common idiopathic inflammatory myopathy of childhood c. <18 years d. Affects skin + skeletal muscle 2. Epidemiology a. 3 cases / million/ year b. No racial predilection c. Peak age of onset 4-10 (second peak 45-65 years) d. F>M 2:1 3. Etiology a. Multifactorial = genetic predisposition + environmental trigger iv. Assoc with family history of autoimmune disease 4. Pathogenesis = capillary vasculopathy, immune complex deposition

Answer 213

Rash (heliotrope/Gottron), muscle weakness, lipodystrophy and calcinosis a. Rash i. First symptom in 50%, concurrent with weakness in 25% ii. Photosensitivity with generalized erythema in sun exposed area (‘Shawl sign’) iii. Heliotrope rash = discoloration of eyelids with periorbital edema (85%) iv. Gottron papules = bright pink/ pale shiny plaques over the PIP and DIPs (90%) v. Facial erythema crossing the nasolabial folds (40%) [cf. SLE] vi. Thickening of small vessels in folds and gums vii. Thickened erythematous rash on palms (Mechanic’s hands) – anti-Jo-1 Ab b. Weakness i. Symmetrical, proximal weakness – most obvious in limb girdles, neck and trunk muscles ii. Often difficult to differentiate from fatigue iii. Inability to perform sit up/ head lag/ Gower sign iv. Trendelenberg often positive v. Esophageal and respiratory muscles can also be affected 🡪 dysphonia, nasal speech, palatal elevation with gag, dysphagia and reflux c. Lipodystrophy and calcinosis i. Calcinosis 1. Sign of longstanding or untreated disease 2. Deposition of calcium phosphate, hydroxyapatite, fluorapatite crystals 🡪 subcutaneous plaques/ nodules ii. Lipodystrophy = loss of SC and visceral fat over face and upper body, associated with metabolic syndrome d. Other i. Systemic = anorexia, fever, myalgia ii. Nail fold capillary changes (80%) = dilated, leaking vessels, telangiectasias iii. Skin ulcerations = poor phenotype iv. Arthritis = non-erosive arthritis, usually affects knees v. GIT = ulceration, perforation, haemorrhage, esophageal dysfunction vi. Pulmonary = can get interstitial lung disease (10%)

Answer 214

7. Diagnostic criteria a. Presence of classic rash (heliotrope eyelid rash / Gottron papules) b. PLUS 3 features of muscle weakness i. Weakness = symmetrical, proximal ii. Muscle enzyme activation = CK, AST, LDH, aldolase iii. EMG changes = short, small polyphasic motor unit potentials, fibrillations, sharp waves etc iv. Muscle biopsy c. New diagnostic criteria also list MRI features

Answer 215

Immunosuppression b. Steroids i. Mainstay of treatment ii. Give IV if GI involvement iii. If severe disease (respiratory oropharyngeal involvement) = high dose pulsed methylpred iv. Vitamin D supplementation due to risk of osteoporosis c. MTX i. Can be used as a steroid sparing agent ii. AE = immunosuppression, blood count dyscrasias, hepatitis, pulmonary toxicity, N/V, teratogenicity iii. Give adjunctive folic acid iv. Avoid live virus vaccines d. Hydroxychloroquine i. Second line DMARD ii. Used to reduce rash and maintain remission iii. Needs ophthalmologic monitoring iv. AE = retina toxicity, haemolysis in patients with G6PD, GI intolerance, and skin/hair discoloration e. IVIG, MMF, cyclosporine, cyclophosphamide = severe disease f. Non-pharmacological i. Nutrition = may require NG or PEG feeds ii. Respiratory = may require ventilation/tracheostomy if severe respiratory weakness iii. MSK = OT and physiotherapy

Answer 216

10. Prognosis a. Pretreatment = 1/3 improved, 1/3 chronic disease, 1/3 died b. Current mortality rate 1% c. Period of active symptoms < 1.5 years d. 25% continue to have chronic weakness, 40% have chronic rash 11. Complications a. Osteoporosis (Non-weight bearing, Medications) b. Calcinosis – 30% i. Well recognized in association with delay in diagnosis & treatment or inadequate treatment ii. Develops within a few years of diagnosis iii. Skin – usually on extremities trauma exposed (knees, elbows, buttocks) iv. Deep tumoral (periarticular) muscle calcification – may affect joint motion v. May ulcerate c. Lipodystrophy – 20% i. Acquired lipodystrophy & associated insulin resistance, acanthosis nigricans, type 2 DM – recognised with JDM ii. Progressive slow, symmetrical loss of SC fatty tissue that mainly involves the upper body d. Cardiac – arrythmias (rare) e. Bowel wall vasculitis – ischaemia, GI bleeding, perforation f. Aspiration pneumonia + respiratory failure

Answer 217

Sclerosis - stiffening of a tissue or anatomical feature, usually caused by a replacement of the normal organ-specific tissue with connective tissue. Scleroderma - increased synthesis of collagen (leading to the sclerosis) in skin, blood vessels, muscles, and internal organs. 1. Epidemiology a. Rare – 1/100,000 (peak 30-50s) b. Localised more common than systemic disease 10:1 c. Linear and plaque morphea the most common types d. > 8 years, F>M: 3:1 < 8 years, F = M 2. Etiology a. Genetic -> HLA B8, HLA DR3 b. Autoantibodies: i. ANA >75% (nucleolar pattern) ii. ENA antibodies – SCL-70 = topoisomerase I diffuse iii. ANA anti centromere antibody = CREST 3. Pathogenesis a. Combination of vasculopathy, autoimmunity, immune activation and fibrosis f. Cytokines induce fibroblasts to reproduce and synthesize excessive amounts of collagen

Answer 218

a. Juvenile Localised Scleroderma (JLS/Morphea) = no involvement of internal organs i. Most common type in children ii. Skin changes more commonly distal to elbows and knees iii. Linear = lines of thickened skin, can be full thickness and very disfiguring iv. Morphea = round patches of thickened skin, usually only skin and dermis v. Classification 1. Circumscribed (plaque) morphea 2. Generalised Morphoea 3. Bullous morphea 4. Linear morphea a. Limbs/trunk b. En coup de sabre = scalp and/or face c. Pary Romberg = hemifacial atrophy 5. Deep morphea b. Juvenile Systemic Sclerosis (JSSc) = involvement of internal organs i. Diffuse – most common type of generalized in children 1. Raynaud phenomenon followed, within one year, by puffy skin changes 2. Truncal and acral skin involvement 3. Nailfold capillary pattern – dilatation, dropout and tortuosity 4. Early and significant organ involvement – lung, GIT, myocardial 5. Anti-SCL-70 and anti-RNA polymerase positive ii. Limited (includes CREST variant) – Rare in children 1. Raynaud phenomenon for years, ocassionaly decades 2. Skin limited to hands, face, feet and forearms 3. Nailfold capillary pattern 4. 10-15% incidence of late pulmonary hypertension, +/- skin calcification, gastrointestinal disease, telangiectasias (CREST syndrome) or interstitial lungs disease a. Calcinosis & centromeric ANA pattern b. Reynaud’s phenomenon c. Esophageal involvement d. Sclerodactyly (stiffness and tightening of skin of hands) e. Telangiectasia (seen on face and limbs) 5. Renal disease rare 6. Anti-centromere (ACA) positive in 50-60% 7. CREST variant of limited sclerosis

Answer 219

Subtype of scleroderma a. Calcinosis & centromeric ANA pattern b. Reynaud’s phenomenon c. Esophageal involvement d. Sclerodactyly (stiffness and tightening of skin of hands) e. Telangiectasia (seen on face and limbs)

Answer 220

a. SKIN i. Raynaud’s phenomenon is usually first manifestation 1. Pallor > cyanosis > hyperemia (2 out of 3 for Dx, each lasts min-hours) ii. Skin changes typically have 3 phases 1. Bilateral painless oedema – fingers, hands, face 2. Thickening and tightening (sclerosis) – tight and itchy, spread proximally from hands and leads to contractures 3. Atrophy and limb contractures – atrophy and wasting iii. Other changes – calcification, telangiectasia, nail fold capillary changes, epidermal thinning, hair loss, decreased sweating b. MUSCULOSKELETAL i. Polyarthropathy of small joint of hands/feet (RA distribution) – non progressive ii. Myopathy and myositis 🡪 common iii. Carpal tunnel syndrome vi. Myopathy and myositis c. EYES i. Dry and sore eyes (similar to Sjogren’s) d. GIT i. Oesophagus: dysfunctional motility 1. Dysphagia: LOW 2. GORD 3. Aspiration pneumonia ii. Small intestine 🡪 stasis with malabsorption symptoms iii. Large intestine 🡪 constipation (dilation and atony may also affect colon) iv. Rectal prolapse and faecal incontinence (associated with sphincter incompetence) e. LUNGS i. Interstitial pulmonary fibrosis ii. Pulmonary HTN 🡪 interstitial lung disease, long standing limited cutaneous sclerosis (pulmonary artery involvement) f. HEART i. Myocardial defects ii. Fibrosis 🡪 conduction defects iii. Dilated cardiomyopathy 🡪 also seen in SLE but rare iv. Pericardial defects 🡪 pericarditis g. KIDNEYS i. Renal disease is uncommon in kids (cf adults) ii. HTN iii. Scleroderma renal crisis 🡪 sudden onset accelerated HT iv. Renal failure 🡪 major cause of death in systemic sclerosis

Answer 221

a. Major (required) = proximal skin sclerosis/induration of skin b. Minor criteria (2 required) i. Cutaneous = sclerodactyly ii. Peripheral vascular = Raynaud phenomenon, nailfold capillary abnormalities (telangiectasias), digital tip ulcers iii. Gastrointestinal = dysphagia, GERD iv. Cardiac = arrythmias, heart failure v. Renal = renal crisis, hypertension vi. Respiratory = pulmonary fibrosis, decreased DLCO, pulmonary arterial hypertension vii. Neurological = neuropathy, carpal tunnel viii. Musculoskeletal = tendon friction rubs, arthritis, myositis ix. Serological = ANA (anti-centromere, anti-topoisomerase (Scl-70), anti-fibrillarin, anti-PM/Scl, anti-fibrillin or anti—RNA polymerase I or III)

Answer 222

8. Treatment a. UV therapy / topical steroids can be used for superficial structures b. If deeper structures involved i. Corticosteroids + MTX ii. 3 months of IV steroids/ oral steroids c. Other treatments for systemic sclerosis i. Raynaud’s 1. Environmental = avoid cold, hand and foot warmers, avoid carrying bags 2. Pharmacological a. CCB b. Topical nitrates c. PDE inhibitors ii. Renal disease + HTN = ACE-I iii. Skin = MTX or MMF iv. Pulmonary alveolitis + fibrosis prevention = cyclophosphamide + MMF v. NOTE: Steroids – with caution, association with renal crisis 9. Prognosis a. Localized scleroderma usually self-limited 🡪 softens after duration of 3-5 years b. Prolonged activity associated with linear and deep disease subtypes c. Systemic disease can have more variable prognosis – usually slowly progressive i. 15-year survival rates 74-87% ii. Most common cause of death is CHF due to myocardial + pulmonary fibrosis

Answer 223

1. Key points a. Raynaud’s disease – without underlying condition i. Prevalence – 5% female population – common in teenage girls 2. Clinical manifestations a. Triad of blanching, cyanosis then hyperemia of extremities i. Arterial constriction = pallor ii. Venous congestion = cyanosis iii. Vasodilation = hyperemia 3. Associations a. Scleroderma b. Mixed CTD (connective tissue disease) c. SLE 4. Risk factors for developing CTD a. Older age at presentation b. Digital tip pitting or ulceration c. Nail fold cap changes d. +ve ANA e. +ve anti SCl 70 5. Risk a. Risk of teenage girl with normal physical and serological exam developing CTD is 3% b. In presence of any abnormality 🡪 25% 6. DDx a. Acrocyanosis b. Chillblains

Answer 224

Large vessel Takayasu Giant cell arteritis (rare in children) Medium vessel Polyarteritis nodosa Cutaneous polyarteritis nodosa Kawasaki disease Small vessel ANCA associated Microscopic polyangiitis Wegner’s = granulomatosis with polyangiitis (pANCA)* Churg-Strauss = eosinophilic granulomatosis with polyangiitis (cANCA)* Non-ANCA HSP Anti-GBM Isolated cutaneous leukocytoclastic vasculitis Hypocomplementaemia urticarial vasculitis Variable Behcet Cogan syndrome

Answer 225

Large vessel Takayasu Giant cell arteritis (rare in children) Medium vessel Polyarteritis nodosa Cutaneous polyarteritis nodosa Kawasaki disease Small vessel ANCA associated Microscopic polyangiitis Wegner’s = granulomatosis with polyangiitis (pANCA)* Churg-Strauss = eosinophilic granulomatosis with polyangiitis (cANCA)* Non-ANCA HSP Anti-GBM Isolated cutaneous leukocytoclastic vasculitis Hypocomplementaemia urticarial vasculitis Variable Behcet Cogan syndrome

Answer 226

Large vessel Takayasu Giant cell arteritis (rare in children) Medium vessel Polyarteritis nodosa Cutaneous polyarteritis nodosa Kawasaki disease Small vessel ANCA associated Microscopic polyangiitis Wegner’s = granulomatosis with polyangiitis (pANCA)* Churg-Strauss = eosinophilic granulomatosis with polyangiitis (cANCA)* Non-ANCA HSP Anti-GBM Isolated cutaneous leukocytoclastic vasculitis Hypocomplementaemia urticarial vasculitis Variable Behcet Cogan syndrome

Answer 227

1. Key points a. Most common vasculitis of childhood b. Characterised by leukocytoclastic vasculitis + IgA deposition in small vessels In the skin, joints, GIT and kidney 2. Epidemiology a. 14-20/100,000 b. M>F 1.2-1.8:1 c. 90% cases occur in children, usually 3-10 years of age d. More common in autum/ winter /spring (often follows respiratory infection 3. Etiology + pathogenesis iv. IgA deposition seen in walls of small vessels c. Pathogenesis = still unknown i. Infectious trigger usually precedes ii. Deposition of IgA in tissues 4. Clinical manifestations a. Cutaneous i. Palpable purpuric rash (ESSENTIAL) with petechiae, ecchymoses ii. Typically, symmetric, in gravity dependent areas iii. Extensor surfaces b. Arthritis and arthralgias i. Occur in 75% ii. Self-limited, oligoarticular c. Gastrointestinal i. Abdominal pain, vomiting, diarrhoea ii. Paralytic ileus iii. Melena iv. Intussusception d. Renal i. Occurs in 50% ii. Haematuria, proteinuria, HT, nephritis, nephrotic syndrome iii. Usually 4 days to 4 weeks after presentation iv. Classically focal segmental proliferative GN e. CNS i. Intracerebral haemorrhage ii. Seizures iii. Headache iv. Behaviour changes 5. Investigations a. Elevated inflammatory markers b. ASOT +ve in 30% c. Serum IgA does not require measurement d. Urinalysis = 90% have haematuria, only 5% persistent/ recurrent e. Skin biopsy = leukcocytoclastic vasculitis with perivascular neutrophils, deposition of IgA and C3 6. Treatment a. Supportive = monitor BP, check for testicular torsion, monitor for hematuria/proteinuria b. Steroids = controversial i. Reduce abdominal and joint pain but does not alter overall prognosis/ prevent disease 7. Prognosis a. Most children have acute, self-limited course b. 30% experience one or more recurrences, typically within 4-6 months of diagnosis c. Renal disease occurs in 1-2% of children (8% of these go on to have ESRD)

Answer 228

1. Epidemiology a. More common in Asians b. Onset 10-40 years , 20% diagnosed < 19 c. F> M 2-4: 1 2. Pathogenesis a. Chronic large vessel disease - involves aorta and is major branches (ESSENTIAL) c. Inflammation 🡪 blood vessel dilatation and aneurysm formation d. Scarring and intimal proliferation 🡪 stenotic/ occluded vessels 3. Clinical manifestations a. Depends on vessel affected - subclavian, renal and carotid most commonly involved b. Systemic symptoms: fever, malaise weight loss, headache c. Hypertension d. Abdominal pain e. Later manifestations = diminished pulses, asymmetric blood pressures, claudication, Raynaud phenomenon, renal failure f. Rash, myositis, arthritis, myocarditis, ILD, GN splenomegaly 4. Diagnosis a. Based on angiographic abnormalities on CT/ MR A AND one of the following: i. Decreased peripheral artery pulses/claudication ii. BP difference between arms / legs of > 10 mmHg iii. Bruits iv. Hypertension 5. Investigations a. Imaging b. Elevated acute phase reactants c. No autoantibodies d. Radiographic assessment main investigation – MRA/ CTA and arteriography 6. Treatment a. Steroids mainstay of therapy b. Steroid sparing agents – MTZ/ azathioprine, cyclophosphamide 7. Complications a. Arterial stenosis b. Aneurysms c. Occlusion/ haemorrhage d. Valvular disease 8. Prognosis a. 20% patients are monophasic, other patients have relapses b. Overall survival = 93% at 5 years, 97% at 10 years

Answer 229

1. Epidemiology a. Rare in childhood b. Mean age of dx 9 c. M=F d. Often follows infection with group A strep/ chronic hepatitis B 2. Pathology a. Necrotizing vasculitis, small-medium vessels d. NO granulomas/ complement or immune complex deposition 3. Pathogenesis a. Immune complexes thought to be involved b. NO clear genetic associations 4. Clinical manifestations a. Constitutional symptoms – weight loss, fever, malaise b. Abdominal pain – due to mesenteric arterial inflammation c. Kidneys most commonly affected d. Renovascular arteritis 🡪 HT, haematuria, proteinuria e. CVS 🡪 myocarditis, coronary arteritis, pericarditis and arrhythmias f. Arthralgias, arthritis and myalgias are common g. CNS 🡪 stroke/ TIA/ mononeuritis/ seizures h. Lungs NOT involved i. Cutaneous manifestations – purpura, livedo reticularis, ulcerations, painful nodules (can occur independently) 5. Diagnosis a. Requires tissue biopsy/angiography 6. Treatment a. Steroids- oral / pulsed b. +/- IV cyclophosphamide c. Treat underling cause if hepatitis B identified d. Relapsing / refractory disease 🡪 MTX, dapsone, azathioprine, thalidomide, cyclosporine, anti-TNF agents 7. Complications a. Ulceration/ infection of nodule b. HT, Chronic renal disease c. Decreased cardiac function, coronary artery disease 8. Prognosis a. Less mortality than adult PAN b. Cutaneous rarely transitions to systemic disease Cutaneous polyarteritis nodosa (CPAN) is a rare form of cutaneous vasculitis that involves small and medium sized arteries of the dermis and subcutaneous tissue without systemic involvement. It presents with tender subcutaneous nodules, digital gangrene, livedo reticularis and subcutaneous ulcerations.

Answer 230

ANCA = anti neutrophil cytoplasmic antibody 1. Key points a. Ab directed against neutrophil cytoplasmic Ag b. cANCA = PR3 ANCA = granulomatosis with polyangiitis (GPA or Wegners) c. pANCA = MPO ANCA = microscopic polyangiitis (MPA/renal limited vasculitis) 2. Etiology a. Unknown 3. Clinical manifestations a. Can present with slow progressive symptoms/ sudden acuity b. Focal segmental necrotising PAUCI-IMMUNE crescentic GN c. Fevers/malaise/weight loss d. Joints/eyes/ skin/nervous system/ heart can also be involved 4. Investigations a. Immunofluorescence b. ELISA = confirm positive IF, detect specific antigen Ab directed against i. MPO = myeloperoxidase ii. PR 3 = proteinase 3 5. Treatment a. Immunosuppression = steroids, cyclophosphamide, rituximab b. Severe necrotising GN and pulmonary haemorrhage – indications for PLEX c. Maintenance = AZA, glucocorticoids 6. Prognosis a. >80% mortality if untreated – 10% over 10-20 years with treatment

Answer 231

General ● Necrotising, granulomatous, small vessel vasculitis with predilection for respiratory tract and kidneys ● Mean age at diagnosis is 14 ● F>M 3-4:1 ● Pathology = necrotizing vasculitis, crescentic GN with no immune complex deposition ``` Respiratory 84% ● Sinusitis + nasal ulceration ● Epistaxis ● Otitis media ● Hearing loss ● Pulmonary haemorrhage ● Subglottic stenosis ● Saddle nose deformity Kidney 88% ● Haematuria, proteinuria, HTN Eyes 44% ● Conjunctivitis ● Scleritis ● Uveitis ● Optic neuritis ● Invasive orbital pseudotumour Skin 60% ● Palpable purpura Nervous system 12% ● Peripheral neuropathy ```

Answer 232

● Small vessel necrotizing vasculitis, clinically similar to Wegener/GPA ● Rare in children ● Pathology: necrotizing vasculitis, crescentic GN with no immune complex deposition - NO granulomas ● Manifestations similar to WG, but sinus disease is less common

Answer 233

AKA Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as allergic granulomatosis ANCA vasculitis ● Small vessel granulomatous vasculitis characterized by refractory asthma + peripheral eosinophilia ● Rare in children ● Pathology = necrotizing vasculitis, crescentic GN with no immune complex deposition - perivascular eosinophilic infiltrates ● Dx criteria = 4 of: biopsy showing eosinophils in extravascular area, > 10% peripheral eosinophils, asthma, pulmonary involvement, sinus abnormality, peripheral abnormality ● Clinical manifestations o Asthma predominant o Cartilage destruction and renal involvement is RARE (20%) o More commonly involves nerves, GT, pericardium and skin ● ANCA – pANCA +ve in 40-60% MPO > PRC

Answer 234

1. Key points a. Most clinical manifestations are believed to be due to vasculitis b. Can involve blood vessels of all sizes (small, medium and large) AND both arteries and veins c. Clinical course characterised by exacerbations + remissions 2. Epidemiology a. Uncommon in children - 5% of cases b. Usually in late childhood – 8-12 years c. No sex prevalence 3. Pathogenesis - unknown 4. Clinical manifestations a. Recurrent exacerbations and disease-free intervals b. Ulcers - painful, oral, can also have genital after puberty c. Ocular manifestations - uveitis, vireitis, retinal vasculitis d. Cutaneous lesions = erythema nodosum, papulopustular acneiform lesions, folliculitis, purpura, ulcers i. Pathergy – pustular reaction after sterile needle puncture e. Vasculitis i. Arterial or venous thrombosis – including DVT, cerebral dural sinus thrombosis ii. Aneurysm formation f. Arthritis = oligoarthritis, non-deforming g. Abdominal pain, dyspepsia h. CNS abnormalities = meningoencephalitis, cranial nerve palsies, psychosis, thrombophlebitis i. Rare manifestations = orchitis, renal vasculitis, glomerulonephritis, or amyloidosis and cardiac involvement 5. Diagnosis a. Usually not made until child is 20-30 years b. Oral ulcers recurring 3 times within 12 months c. AND 2 of the following: i. Recurrent genital ulcerations ii. Eye lesions (uveitis / retinal vasculitis) iii. Skin lesions (erythema nodosum, pseudofolliculitis, acneiform nodules d. Positive pathergy test result 6. Investigations = nil specific 7. Treatment a. LIMITED evidence b. Steroids, colchicine, chlorambucil, azathioprine, cyclosporine and tacrolimus have been used c. Colchicine = commonly used in those without internal organ involvement i. Improves oral and genital ulcers, skin features + disease activity 8. Prpognosis a. Variable clinical course b. Need to monitor for uveitis c. Mortality is low

Answer 235

1. Key points a. Typically manifests at 35-45 years, 90% of cases among women b. Mean age at diagnosis in children is 9-10 years; 75% are girls 2. Pathogenesis a. Genetic predisposition + infectious trigger b. Lymphocytes + plasma cells infiltrate salivary glands 🡪 destroy structure c. May occur in conjunction with RA, SLE, systemic sclerosis, polymyositis 3. Classification a. Primary Sjögren syndrome (sicca complex) – isolated disorder b. Secondary Sjögren syndrome – associated with other rheumatic disorder (SLE, scleroderma, mixed CT disease), usually precedes the associated autoimmune disease by years

Answer 236

4. Clinical manifestations a. Recurrent parotid gland enlargement, parotitis – most common manifestations in children (>70%) b. Xeropthalmia (dry eyes) = itchy, gritty, photophobia, blurred vision c. Xerostomia (dry mouth) = increased dental caries, halitosis, dysphagia, fissured tongue) +/- recurrent parotitis +/- duct obstruction d. Many other systemic features – lungs, pancreas, renal, MSK, haematological, PNS, CNS 5. Investigations a. Objective signs of dryness of eye i. Schirmer test – abnormal tear production (≤5 mm of wetting of filter paper strip in 5 min) ii. Rose-Bengal staining – damaged ocular epithelial conjunctival and corneal cells. iii. Slit lamp examination b. ESR = elevated c. FBE = normochromic normocytic anaemia, leukopenia, eosinophilia d. Polyclonal hypergammaglobulinemia e. Serology i. ANA = 80% ii. RF = 66% iii. Anti Ro/SS-A = 75% iv. Anti La/SS-B = 65% v. Anti–β-fodrin autoantibodies f. Biopsy = lymphocytic infiltration 6. Diagnostic criteria = 4+ of the following criteria a. Clinical symptoms i. Oral: recurrent parotitis or enlargement of parotid gland, dry mouth (xerostomia) ii. Ocular: dry eyes (xerophthalmia) recurrent conjunctivitis without obvious allergic or infectious etiology, keratoconjunctivitis sicca iii. Other mucosal: recurrent vaginitis iv. Systemic: fever, non-inflammatory arthralgias, hypokalemic paralysis, abdominal pain b. Immunological abnormalities: >=1 of anti-SSA, anti-SSB, high titre antinuclear antibody, RF c. Other abnormalities or investigations i. Biochemical: elevated serum amylase ii. Hematologic: leukopenia, high sedimentation rate iii. Immunologic: polyclonal hyperimmunoglobulinemia iv. Renal: renal tubular acidosis v. Histologic proof of lymphocytic infiltration of salivary glands or other organs (i.e., liver) vi. Objective documentation of ocular dryness (Bengal red staining or Schirmer test) vii. Positive findings of parotid gland scintigraphy d. Exclusion of all other autoimmune diseases

Answer 237

8. Treatment a. Artificial tears, fluids b. Steroids / NSAIDS/ hydroxychloroquine can be used c. Rarely use strong immunosuppressants (cyclosporine, cyclophosphamide) 9. Complications a. ↑ risk of MALT lymphoma b. Associated with neonatal lupus syndrome c. Maternal Sjögren syndrome can be an antecedent to the neonatal lupus syndrome

Answer 238

o AKA Benign nocturnal pains of childhood o Peak age 4-8 years old o Affect 15-30% of children o Intermittent, bilateral pain – mainly affects anterior thigh + calf (NOT joints) o Can wake a child from sleep but resolves quickly with massage or analgesics o Otherwise well – diagnosis of exclusion

Answer 239

o Diffuse MSK pain in at least 3 areas of the body persisting for at least 3 months in the absence of an underlying condition o At least 5 well defined tender points on examination o Associated symptoms ▪ Poor sleep ▪ Fatigue ▪ Chronic anxiety/ tension ▪ Chronic headaches ▪ Soft tissue swelling o Pathophysiology – relates to abnormal pain processing, abnormal levels of substance P in CSF, disordered mood, dysregulated HPA axis o Treatment ▪ Education ▪ Exercise-based intervention ▪ Pain coping/stress management ▪ Pharmacological = TCA, SSRI, anticonvulsants

Answer 240

o Episodic intense, pain and erythema in the hands and feet o Can be triggered by exercise + heat exposure o Most cases are sporadic o Rare AD form = SCN9A mutation in chromosome – encodes sodium channel in dorsal root ganglia o Associations ▪ Myeloproliferative disease ▪ Peripheral neuropathy ▪ Hypertension ▪ Rheumatic disease o Treatment ▪ Avoid precipitants ▪ NSAIDs, anticonvulsants, antidepressants

Answer 241

o Characterised by burning limb pain that is subsequent to an injury, immobilsiation or other noxious event affecting an extremity o Key features ▪ Pain disproportionate to the inciting event ▪ Allodynia (pain is caused by a stimulus that does not normally elicit pain) ▪ Hyperalgesia (experience an enhanced sensitivity to pain) ▪ Swelling of the distal extremities ▪ Indicators of autonomic dysfunction - cyanosis, mottling, hyperhidrosis o Treatment ▪ Physical therapy ▪ CBT ▪ Low-dose amitriptyline

Answer 242

1. Key points a. Most common condition causing joint hypermobility b. Affects 10-20% of people 2. Risk factors a. F>M b. Adolescence c. Asians, west Africans 3. Clinical manifestations a. Musculoskeletal i. Recurrent acute pain from joint sprains and ligament/tendon injuries ii. Recurrent subluxations and dislocations iii. Injuries due to poor proprioception iv. Marfanoid body habitus b. Skin manifestations i. Hyperextensible ii. Easy bruising iii. Wide, paper-thin and sunken scars c. Gastrointestinal + urological i. Hernias ii. Bowel symptoms iii. Pelvic floor weakness d. Chronic pain e. Cardiovascular autonomic dysfunction 4. Investigations = nil 5. DDx a. Marfan = features NOT present – scoliosis, kyphosis, dilatation of the aortic root and aortic arch, aortic dissection, ectopia lentis, or dural ectasias b. EDS = subtle; makes no difference in management 6. Treatment a. Physical therapy b. Splints and orthoses

Answer 243

● Group of autoinflammatory diseases caused by error of the innate immune system ● Episodes of self-limited fever that occur in the absence of infection ● Common pathogenesis: o Mutations in pathways continuing pattern recognition receptors (PRPs) o PRPS (which include toll like receptors) recognize common aspects of viral / bacterial molecular structures o PRP recognizes pathogen 🡪 activates intracellular proteins: regulate NFk-b, cell apoptosis, and IL-1 beta o Mutations in this pathway = increased secretion of IL-1 beta ``` ● Common features o Clinical ▪ Fevers ▪ Rashes ▪ Arthritis ▪ Serositis ▪ Ocular involvement o Investigations ▪ Elevated inflammatory markers during flares but normal between autoimmune disease ▪ No autoantibodies ``` Classification 1. Familial Mediterranean Fever (FMF) 2. Tumour necrosis factor receptor associated periodic syndrome (TRAPS) 3. Hyperimmunoglobulin D syndrome 4. Cryopyrin associated periodic syndromes a. Muckle wells syndrome b. Familial cold autoinflammatory syndrome (FCAS)/ familial cold urticaria (FCU) c. Chronic infantile neurologic cutaneous and articular disease/ neonatal onset multisystem inflammatory disease d. Pyogenic antarthritic, pyoderma gangrenosum and acne (PAPA) e. Blau syndrome 5. Periodic fever aphthous stomatitis, pharyngitis and adenitis (PFAPA)

Answer 244

1. Key points a. Most common mendelian autoinflammatoy disease b. 1-3 days of fever + serositis + arthritis + rash c. Complicated by AA amyloidosis 2. Epidemiology a. Primarily in groups of Mediterranean origin: Jews, Turks, Armenians, individuals of Arab descent b. Rare among Ashkenazi jews, Germanss and Anglo- Saxons c. Carrier rate in Armenians 1/500 3. Genetics + pathogenesis a. AR b. MEFV gene i. Expresses an amino acid pyrin / marenostrin - expressed in myeloid cells ii. Up to 70 mutations identified – M694V, V726A, M6801, E148Q, M 6941 c. Exact pathogenesis unclear i. Increased levels of IFN-g and other pro-inflammatory cytokines ii. Pyrin – regulatory component of the ‘ inflammasome’ 🡪 complex of proteins that trigger release of IL-1 beta and mediators of apoptosis - inhibits processing or pro-Il-1- beta to IL-1- beta iii. Mutations lead to stimulation of Il-1 beta processing and secretion 🡪 uncontrolled inflammation d. Other proposed mechanisms = C5a inhibitor deficiency

Answer 245

4. Clinical manifestations a. 65% present before 5 years, 90% before 20 years b. Well between flares c. Triggers = exercise, cold, stress, fatigue, surgery, menstruation d. Acute episodes lasting 1-4 days of fever + i. Sterile peritonitis (abdominal pain) ii. Arthritis/ arthralgia iii. Pleuritis e. Other symptoms i. Erysipelas like rash ii. Myalgia iii. Splenomegaly iv. Hypothyroidism v. Orchitis vi. Aseptic meningitis f. Associated with HSP, polyarteritis nodosa, Behets disease 5. Investigations + diagnosis a. Elevated inflammatory markers during attack b. Elevated serum amyloid protein c. Genetic testing using PCR and restriction analysis (will miss rare mutations)

Answer 246

6. Treatment a. Colchicine i. Unknown mechanism, but suppresses neutrophil phagocytosis and chemotaxis ii. Prevents attacks in 65%, improves number in 20-30%> 5-10% refractory iii. Decreases probability of developing amyloidosis iv. Continued during pregnancy + lactation v. Side effects 1. Diarrhoea + GI symptoms 2. Bone marrow suppression – rare 3. Dose-related transaminitis 4. Myopathy b. IL-1 inhibitor = anakinra 7. Complications a. Amyloidosis i. Serum AA is an acute phase reactant – found in high levels during attacks ii. Deposits ectopically – kidney, GIT, spleen, lung, testes thyroid, adrenals iii. Rarely can result in cardiac amyloidosis iv. Most common presenting sign is proteinuria; can progress to nephrotic syndrome + renal failure v. 30-50% of untreated children, 75% of adults with FMF develop renal amyloidosis vi. Risk factors 1. Homozygous for M694V mutation 2. Country of origin – Middle East higher risk b. Small bowel obstruction c. Infertility d. Infection e. Thromboembolism

Answer 247

AKA Dutch fever 1. Epidemiology a. More common Dutch/ French population 2. Genetics + pathogenesis a. AR b. Mutations of mevalonate kinase (MVK) gene on chromosome 12 c. MVK: peroxisomal enzyme that enhances metabolism of mevalonic acid (part of cholesterol synthesis pathway) d. Patients have decreased MVK activity in lymphocyte 🡪 increased mevalonic acid levels in plasma e. Exact pathophysiology remains unclear 3. Clinical manifestations a. Onset within 1st year of life b. Recurrent episodes of fever lasting 3-7 days c. Triggers = illness, immunisation, surgery d. Abdominal pain +/- diarrhoea, nausea and vomiting e. Cervical lymphadenopathy +/- splenomegaly f. Other features = diffuse macular rash, aphthous ulcers, headaches g. Symptoms resolve after fever declines h. Rash and symmetric polyarthritis/ arthralgia may persist 4. Investigations + Diagnosis a. FBE – leukocytosis during attack b. Elevated immunoglobulin D – present in 80% of patients, not diagnostic (can be increased in other autoinflammatory disease) c. Elevated acute phase reaction d. Mevalonic acid in the urine may be elevated during febrile episodes (usually normal between episodes) e. Genetic testing available for MVK 5. Treatment a. NSAIDS – may treat symptoms and fever b. Steroids – often used for those not improved by NSAID c. Anakinra, etanercept (TNF-alpha inhibitor) may be effective 6. Complications + Prognosis a. Symptoms may persist for years but become less prominent in adulthood b. Usually normal lifespan c. Incidence of AA amyloidosis in patients is LOW d. Joint contractures and abdominal adhesions may occur e. Mevalonic aciduria– severe mental retardation, ataxia, myopathy, cataracts, FTT

Answer 248

1. Genetics + pathogenesis a. AD b. Mutation in TNF receptor 1A gene TNFRSF1A (chromosome 12) c. Defective TNFR1 molecule on the cell surface is unable to neutralize TNF alpha 2. Clinical manifestations a. Presents in first decade of life b. Intermittent febrile episodes with abdominal pain, nausea and vomiting i. May present as acute abdomen c. Other symptoms i. Oligoarthritis ii. Myalgias iii. Rash = erythematous macular rash, annular patches or serpiginous iv. Ocular = conjunctivitis, unilateral periorbital edema d. Episodes LONGER than FMF, 3 days to 3 weeks 3. Investigations a. Elevated acute phase reactants b. Low serum levels of soluble type 1A TNF receptor, increased serum levels of TNF 4. Treatment a. NSAID – if mild disease b. Prednisolone – can attenuate the length and severity of the attacks c. Colchicine has NO effect d. Biologic agents i. Etanercept ii. Anakinra iii. Anti-TNF MAb = in some cases has led to paradoxical worsening of disease 5. Complications a. AA amyloidosis – in up to 25% i. Affects kidneys/ liver ii. Risk factors = cysteine mutations and positive family history

Answer 249

1. Key points a. Group of AD disorders b. Mild to severe i. Cold autoinflammatory syndrome (FCAS1) ii. Muckle-Wells syndrome (MWS) iii. Neonatal-onset multisystem inflammatory disease (NOMID) (also known as chronic infantile neurologic cutaneous and articular syndrome, or CINCA) 2. Genetics + Pathogenesis a. AD or de novo mutations b. Mutation in NLRP3 (CIAS1) – encodes cryopyrin 3. Common manifestations a. All characterised by febrile attacks + urticarial rash i. Rash mimics urticaria ii. Histology = perivascular infiltrates are PMN rather than mast cells 4. Differences a. FCAS – Familial Cold Autoinflammatory Syndrome i. Least severe ii. Febrile attacks 1-3 hours (up to 8 hours) after cold exposure iii. Resolve within 24 hours iv. Associated symptoms = polyarthralgia, conjunctivitis v. AA amyloidosis rare b. MWS – Muckle Well Syndrome i. Not cold-induced ii. Presents with fevers, myalgias, arthralgias, urticarial-like rash (same as FCAS) iii. Associated with development of progressive sensorineural hearing loss iv. Complications 1. SNHL 2. AA amyloidosis – 30% c. CINCA = Chronic Infantile Neurologic Disease With Mental Retardation (= NOMID) i. Most severe entity ii. Neonatal onset iii. Clinical manifestations 1. Daily fevers 2. Dysmorphic features 3. Rash 4. Neurological disease 5. Destructive arthropathy – particularly of knees iv. Complications = chronic aseptic meningitis, leading to increased ICP, optic disc edema, visual impairment, progressive sensorineural hearing loss, intellectual disability 5. Treatment a. Symptomatic treatment with NSAID, steroids + colchicine b. NOMID = anakinra (IL-1 receptor antagonist) – lifechanging c. FCAS and MWS i. Rilonacept – soluble IL-1 receptor decoy ii. Canakinumab – long-acting, fully humanized IgG1 anti–IL-1β monoclonal antibody

Answer 250

● AD ● Mutations in the pSTP1P1 gene (chromosome 15) 🡪 adaptor protein proline serine threonine phosphatase interacting protein ● Clinical manifestations o Recurrent episodes of sterile, pyogenic arthritis resulting in joint destruction 🡪 develops in childhood o Pyoderma gangrenosum, severe cystic acne with skin ulcerations 🡪 develops in adolescence o Fever not a major feature ● Treatment o Corticosteroids o IL-1 antagonists o TNF inhibitors

Answer 251

1. Key points a. NON-Mendelian periodic fever b. Most common recurrent fever syndrome in children 2. Epidemiology a. Sporadic b. No ethnic predilection 3. Clinical manifestations a. Presents 2-5 years of age b. Recurrent fever, malaise, tonsillitis (negative throat culture), cervical lymphadenopathy and ulcers c. Episodes last 4-6 days regardless of treatment d. 8-12 episodes a year e. Hepatosplenomegaly 4. Investigations a. Elevated acute phase reactants, leuckocytosis 5. Treatment a. Respond dramatically to a single dose of prednisolone b. Cimetidine 20-40 mg/kg may induce remission c. Tonsillectomy may improve symptoms in some 6. Prognosis a. Most children spontaneously resolve after 4-8 years

Answer 252

1. Key points a. Group of conditions characterised by extracellular deposition of insoluble fibrous amyloid proteins 2. Classification (based on biochemical analysis) a. AL = amyloid composed of monoclonal immunoglobulin light chain, idiopathic/ myeloma associated b. AA = amyloid A protein (secondary / reactive), hereditary periodic fever syndromes, chronic inflammatory and infective disorders c. TTR amyloidosis = associated with AD and rare autosomal dominant familial causes 3. Pathogenesis a. Amyloid = microscopic fibrils containing a nonfibrillar component, amyloid P b. AA amyloid is formed from serum amyloid A (SAA) which is an acute phase reactant produced by the liver c. SAA protein undergoes cleavage, misfolding and aggregation forming beta pleated sheets known as fibrils d. Amyloid then deposits in various organs 🡪 spleen, adrenal, liver, GIT , kidney 4. Etiology a. Hereditary amyloidosis = mutation in the amyloid fibril b. Amyloid A (AA) amyloidosis = develops in patients with chronic inflammatory states i. Only AA amyloidosis occurs commonly in children ii. Reduced incidence due to new DMARD and biologic agents iii. Associated conditions 1. Periodic fever syndrome a. FMF b. TRAPS c. CAPS – MWS (30%) 2. Inflammatory disease 3. Chronic infections 4. CF 5. SLE, dermatomyositis, JIA, RA

Answer 253

5. Clinical manifestations a. Usually begins 10 years after onset of inflammatory disease b. Renal = 90% i. Proteinuria ii. Nephrotic syndrome 🡪 renal failure c. GI = 20% i. Chronic diarrhoea ii. GI bleeding iii. Abdominal pain iv. Malabsorption v. Hepatosplenomegaly d. Other i. Testes = 90% ii. Anaemia iii. Other = amyloid goiter, hepatomegaly, splenomegaly, adrenal involvement, and pulmonary involvement 6. Investigations a. Biopsy i. Biopsies can only be taken from rectal mucosa, gingival tissue and abdominal fat ii. Histologically characterised by eosinophilic material that stains with Congo red dye and apple green birefringence in polarized light b. Other i. Elevated acute phase reactants ii. High levels of immunoglobulins iii. IN AL amyloidosis: increased plasma cells in bone marrow/ serum or urine monoclonal immunoglobulins

Answer 254

7. Treatment a. Aggressive management of underlying cause b. Colchicine = FMF c. Chlorambucil = JIA (however associated with malignancy) d. Biologic agents i. Anti-TNF agents ii. IL-1 antagonists = anakinra (IL-1 receptor), rilonacept (soluble IL-1 decoy), canakinumab (humanised IgG1 anti IL-1 beta) iii. IL-6 antagonist = tocilizumab 8. Prognosis a. 40-60% patients die from ESRF, median survival 2-10 years b. ESRF causing of death in 40-60% c. Risk factors = older age, lower albumin, pre-existing CKD, prolonged elevation of SAA

Answer 255

1. Key points a. Rare multisystem granulomatous disorder b. 2 age-dependent patterns occur in children – paediatric onset adult sarcoidosis + early-onset sarcoidosis c. Rare in childhood: 0.22-0.27/100,000 children d. Increases with age, peak onset 20-39 year 2. Pathogenesis a. Remains unclear b. Some trigger elicits exaggerated immune response 🡪 formation of granulomas c. Granulomas are noncaseating, epitheloid granulomatous e. Sarcoid macrophage can also secrete calcitriol, leading to hypercalcemia and hypercalciuria

Answer 256

3. Clinical manifestations a. Paediatric onset adult sarcoidosis i. Similar to adult sarcoidosis ii. Systemic features predominate – fever, weight loss, malaise iii. Pulmonary involvement most frequent 🡪 thoracic lymph nodes, bilateral lymphadenopathy, parenchymal infiltrates and military nodules iv. Extrathoracic lymphadenopathy, hepatomegaly and splenomegaly can occur v. Cutaneous disease: plaques, nodules, erythema nodosum vi. Ocular involvement: uveitis, conjunctival granulomas, orbital/ lacrimal gland infiltration vii. Renal disease (rare): proteinuria, transient pyuria, microscopic haematuria, renal insufficiency viii. Hypercalcemia, hypercalciuria (less common in children) b. Early onset sarcoidosis i. Triad 1. Rash 2. Uveitis 3. Polyarthritis ii. Like Blau without family history iii. Pulmonary disease is less common iv. Arthritis usually polyarticular, symmetric with large boggy effusions v. Noncaseating granulomas demonstrated with biopsy of skin/joint synovium c. Blau syndrome i. AD familial form ii. Mutations in the CARD15/NOD2 gene on chromosome 16 iii. Early onset granulomatous inflammation – rash, uveitis, arthritis 4. Investigations/ diagnosis a. Blood i. FBE = anaemia, leukopenia and eosinophilia ii. Elevated acute phase reactions + hypergammaglobulinaemia iii. Hypercalcemia + hypercalciuria = less common in children iv. ACE = may be elevated (produced by epithelioid cells) b. Biopsy i. Histology = non-caseating granulomas ii. BAL c. Imaging i. CXR, ii. PET = may identify active lesions d. PFT = restrictive lung disease e. Opthal slit lamp examination f. Kveim Sltzbach test: intradermal injection of human sarcoid tissue extract, monitor for granuloma formation

Answer 257

5. Treatment a. No consensus b. Steroids usually the mainstay c. Other immunosuppressive agents: MTX, TNF alpha antagonists, azathioprine, hydroxychloroquine, thalidomide d. Monitor with regular PFS, echocardiogram/ECG, urinalysis, renal function tests, hepatic enzymes, calcium, ophthalmologic examination every 3-6 months e. ACE and inflammatory markers can be monitored – ACE does not always correlate 6. Prognosis a. Not well defined in childhood b. Outcome worse if there is multiorgan/ CNS involvement c. Children with EOS have a poorer prognosis i. Greatest morbidity is associated with ocular complications – cataract, synechiae, loss of visual acuity or blindness ii. Progressive polyarthritis may result in joint destruction d. The overall mortality rate in childhood sarcoidosis is low

Answer 258

● History of overuse, often involves running with a change in training (eg, increased mileage or pace). ● Diffuse anterior, peripatellar pain. ● Knee may "give way". ● Pain with squatting, running (downhill), stairs, or arising after prolonged sitting. ``` ● Tender medial/lateral patella ● Normal movement ● Effusion rare ● Patellofemoral compression test +ve ● VMO atrophy ● Lower extremity malalignment ``` ● Most common condition seen in adolescents referred to sports medicine specialists. ● Knee effusion, abnormal knee motion, or ligamentous laxity require assessment for intra-articular damage.

Answer 259

Radiopedia: Osteochondritis dissecans (OCD) is the end result of the aseptic separation of an osteochondral fragment with the gradual fragmentation of the articular surface and results in an osteochondral defect. It is often associated with intraarticular loose bodies. ● History of acute injury or highly active patient with pain that worsens with exercise. ● Poorly localized pain with activity that may progress to stiffness, swelling, and mechanical symptoms of locking or catching ● Tenderness over the medial femoral condyle in the flexed knee. ● Plain radiographs, including tunnel views of the knee, show crescent shaped lucency on the medial femoral condyle.

Answer 260

Tibial tuberosity apophyseal avulsion ● Overuse – particularly jumping ● Growth spurt ● Increases with activity ● Pain at tibial tubercle. ● Tenderness at tibial tubercle ● Focal swelling and warmth directly over the apophysis ● No effusion or ligamentous laxity ● Imaging is not necessary unless red flags

Answer 261

Patellar apophyseal avulsion ● Overuse – particularly jumping ● Common during growth spurt. ● Increases with activity ● Pain at inferior patellar pole ● Tenderness at inferior pole of patella ● Focal swelling and warmth directly over the apophysis ● No effusion or ligamentous laxity ● Imaging is not necessary unless red flags

Answer 262

1. Types of eating disorder a. Anorexia nervosa b. Bulimia nervosa c. Binge eating disorder d. Avoidant/ restrictive food intake disorder 2. Epidemiology a. Dieting and focus on body image in adolescent girls very common b. Anorexia 0.5-1%, bulimia 2-3%, binge eating 2-3% c. Adolescent onset i. Incidence of AN is relatively stable - Males account for 10-15% total AN ii. Age of AN and BN increasing d. Affects all ethnicities and social groups e. Lifetime prevalence 7% (according to US study) f. 3rd most common chronic incidence in female illness g. Highest rate of mortality amongst mental illnesses h. Atypical AN increasing risk 3. Etiology a. Genetic factors – 50% of variation of AN and BN explained by genetic factors i. First degree relatives: 6-10x ii. Twin studies – greater concordance in monozygotic twins iii. Predisposing personality traits b. Biological factors i. Starvation reproduces symptoms of eating disorders (preoccupation with food, anxiety, irritability, low mood, social withdrawal) ii. Purging can also result in short term improvement in mood related to instability of dopamine/ serotonin c. Environmental i. Familial = eating behaviour, weight concerns, communication ii. Ballet, gymnastics, modelling iii. Sociocultural norms iv. Dieting = the biggest risk factor for eating disorder 1. Around 2/3 of eating disorders arise in girls who have been moderate dieters in the past

Answer 263

5. Abnormal dieting a. Associated with decreasing weight goals b. Associated with increasing body criticism c. Increasing social isolation d. Loss of menstruation or failure to start menstruating at the right time e. Vomiting 6. Warning signs a. Preference for eating along b. Extremely limited food choices c. Cooking for others, but not eating d. Rituals around eating e. Excessive fluid intake f. Frequent visits to the bathroom after eating g. Frequent weighing h. Obsessive exercising

Answer 264

• Criteria o Restriction of energy intake relative to requirements leading to significantly low body weight in the context of age, sex, developmental trajectory and physical health. (weight that is less than minimally normal or expected) o Intense fear of gaining weight or becoming fat, or persistent behaviour that interferes with weight gain, even though at a significantly low weight o Disturbance in the way in which one’s body weight or shape is experienced (persistent lack of recognition of the seriousness of the current low body weight) [usually <90% IBW] * Subtypes = restrictive type/purging type * Severity = mild (BMI or BMI centile >17), moderate (16-17), severe (15-16), extreme (<15)

Answer 265

• Criteria o Recurrent binge eating  Binge eating = eating in a discrete period an amount of food that is definitely larger than most would eat in a similar situation and time period + a sense of lack of control over eating during episodes o Inappropriate compensatory weight control behaviours o Frequency > 1/ week for 3 month o Self-evaluation unduly influenced by body weight/ shape o Absence of AN • Severity = mild (1-3/week), moderate (4-7/week), severe (8-13/week), extreme (>14 week)

Answer 266

• Criteria o Episodes of binge eating o Binges associated with 3 of: rapid eating/ feeling uncomfortably full / eating when not hungry/ eating alone/ feeling disgusted after o Occur at least once a week for 3 months o NO ASSOCIATED COMPENSATION o Not in the context of bulimia/ AN

Answer 267

• Criteria o Eating or feeding disturbance with persistent failure to meet nutritional needs associated with  Significant weight loss/ growth failure  Significant nutritional deficiency  Dependence on enteral feeding or oral nutritional supplements  Marked interference with psychosocial functioning o Not better explained by absence of food or culturally sanctioned practice o ABSENCE OF AN/BN, NO BODY IMAGE DISTURBANCE o Not another medical condition/ mental disorder • Subtypes o Phobias – eg. Fear of vomiting o Somatising o ASD (and ‘fussy eaters’)

Answer 268

• Atypical anorexia nervosa o Features of AN BUT overweight or normal weight o Usually premorbid weight elevation and loses a large amount of weight – has all the cognitions and behaviours of anorexia * Atypical BN * Purging disorder * Binge eating disorder (low frequency/ limited duration) * Night eating syndrome

Answer 269

9. Assessment a. Assess = type, duration, severity, complications b. Normal medical history + family history c. Specific ED questions i. How restricting started ii. Pattern of food consumed iii. Any binging/ purging iv. Exercise history (including private) v. Maximum and minimum weight ‘goal weight’ vi. Rapidity of weight loss d. 24 hour dietary history i. Quantities, variety ii. Fluids iii. Dairy products iv. Any other specific eating habits (eating alone etc) v. Family dietary patterns e. Exercise history f. Periods g. HEADSS assessment h. Mood/anxiety/OCD i. Common to AN and BN – anxiety, depression ii. AN – OCD iii. BN – substance abuse, sexual abuse, personality disorders i. Physical symptoms i. Cold intolerance ii. Constipation iii. Fatigue iv. Poor concentration v. Dizziness/ syncope vi. Screen for symptoms associated with any potential medical conditions 10. Examination a. Plot growth - % median BMI i. Remember BMI increases with age b. Temperature c. Look for hypothermia/ acrocyanosis, livedo reticularis d. CVS: HR, BP, postural changes e. Other features – caries, parotid enlargement, adenoapthy f. Signs of other chronic medical conditions 11. Investigations a. Baseline bloods - FBE, UEC, CMP, ESR, LFT, Fe studies b. Blood gas c. Endocrine assessment = FSH, LH, Oestradiol/testosterone d. Celiac e. Bones = vit D, bone age, bone densitometry (Medicare funded once a year) f. ECG 12. Differential diagnosis a. Malignancy b. Thyroid disease c. Occult infection d. Celiac disease, IBD

Answer 270

1. Epidemiology a. Women > men – lifetime prevalence 3x higher in females than males b. Median age of onset 18 years 2. Aetiology a. Family history b. Genetics – there is a clear genetic risk c. Temperament/personality factors d. Obsessionality e. Dieting + loss of weight – key risk factor f. Age of onset/sex differences 3. Comorbid conditions a. Anorexia b. OCD c. Social phobia

Answer 271

a. Note most resolve with restoration of weight EXCEPT for reduced BMD and possibly atrophy b. OROFACIAL i. Caries ii. Parotid enlargement iii. Submandibular adenopathy c. CARDIOVASCULAR i. Bradycardia/palpitations ii. Postural hypotension iii. Functional changes 1. Decreased cardiac output: reduced exercise capacity, attenuated BP response to exercise 2. Bradycardia: due to increased vagal tone, decreased metabolic rate iv. Structural changes 1. Decreased cardiac mass and myocardial fibrosis 2. Mitral valve prolapse (as heart muscle decreases in size whilst structural valve tissue remains the same). Present in up to 20% 3. Pericardial effusions – tend to resolve with weight gain v. ECG changes 1. May get small volume ST/ T wave changes and prolonged QT ?significance [long QT is a marker of electrolyte disturbance or medications – SCD related to QT dispersion] 2. Increased HR variability d. ENDOCRINOLOGY i. Sex hormones + Reproduction 1. ↓ oestradiol, FSH, LH, testosterone 2. Arrested psychosexual development 3. Loss of libido 4. Amenorrhoea (precedes weight loss in 1/3 to ½ due to 1 hypothalamic defect) a. Due to decreased pulsatility of GnRH b. Hypogonadotrophic hypogonadism c. Resumption of menses with weight gain – difficult to predict; usually BMI > 19 5. Unplanned pregnancy more common; rates of infertility same ii. Growth hormones = ↑ GH high ↓ IGF-1 iii. Thyroid = sick euthyroid (↓T3/T4, normal or low TSH) iv. ↑ cortisol (loss of diurnal variation, failure of dexamethasone suppression) – acne, hirsutism v. Arrested growth vi. Fatigue, cold intolerance, hypothermia e. RENAL i.  urea (dehydration,  GFR), low urea if malnutrition ii. Mild proteinuria, haematuria, pyuria iii. Renal calculi f. BONES i. Healthy children = gain 45-60% BMD in second decade, peaking in 3rd decade, declines 1-2% per year ii. 50% of AN have BMD < 2.5 SD iii. Bone loss can persist even after weight restoration – increases risk for long term fractures iv. Resultant osteopenia/osteoporosis v. Multifactorial 1. Amenorrhoea – oestrogen deficiency 2. Low BMI 3. Low dietary Ca/vitamin D 4. High cortisol levels 5. Deficient IGF- 1 levels 6. Strenuous exercise g. GIT i. Gastroparesis (which means partial paralysis of the stomach, is a disease in which the stomach cannot empty itself of food in a normal way) ii. Constipation iii. Oesophagitis iv. Decreased intestinal motility v. Constipation + rectal prolapse vi. Elevated LFTs + amylase vii. SMA syndrome (rare) = when the reduction of fatty tissue that separates superior mesentery artery and aorta leads to compression of duodenum between these two vessels = small bowel obstruction h. HAEMATOLOGY i. Cytopenias and bone marrow suppression can occur i. METABOLIC i. Low K, Na, Mg, PO4, glucose, temperature ii. Lipid abnormalities j. NEUROLOGY i. Brain atrophy evident on imaging (pseudoatrophy – returns to normal after recovery) (unknown about subtle long-term effects) ii. Ventricular enlargement iii. Reduced basal blood flow to brain, increased flow to medial temporal lobe areas seen in psychosis (improves after weight gain) iv. Peripheral neuropathy v. Likely imbalance in dopamine/serotonergic pathways vi. Hypothalamic dysfunction: thermoregulation, satiety, sleep k. DERMATOLOGICAL i. Xerosis (abnormally dry skin) ii. Lanugo like body hair iii. Hair loss iv. Carotenoderma (orange pigmentation of the skin resulting from carotene deposition) v. Acne vi. Hyperpigmentation, seborrheic dermatitis, acrocyanosis, petechiae, livedo reticularis, paronychia l. PSYCHOLOGICAL i. Social isolation, depression, anxiety, obsessional symptoms, perfectionistic traits, rigid cognitive styles ii. Loss of libido,  alertness/concentration, dysphoria iii. Introversion, poor peer relationships, low self-esteem

Answer 272

a. Key points i. Acute vs long term treatment (medically unstable vs weight restoration vs cure) ii. Controversy over treatment outcomes iii. Only clear outcomes proven for adolescent AN with family based treatment b. Treatment goals i. Resume growth and puberty ii. Return to menstruation iii. Normalise eating iv. Treat underlying psychological conditions c. Approaches i. Inpatient – no clear benefit 1. Medical stabilisation = nutrition, bed rest ii. Outpatient 1. Day program – southern health, Butterfly foundation 2. Individual therapy – CBT-E*, Adolescent Focused Therapy* 3. Family therapy – multifamily therapy* 4. Family based treatment*** 5. Karolinska Institute d. Indications for admission i. Physical 1. HR < 50 (40 in some centres) 2. Postural drop of > 20 systolic 3. Dehydration 4. Hypothermia (T < 36) 5. Electrolyte abnormalities eg. low K ii. Psychiatric 1. Suicide or other at risk behaviour (eg. acute bulimic phase) 2. Other = severe weight loss (> 30% pre morbid weight), failure of outpatient treatment, concerns of growth failure f. Principles of management i. Bed rest ii. Slow up titration iii. Monitor for refeeding syndrome g. Use of medications i. No evidence that medication changes clinical course ii. SSRIs 1. Most trials show NO benefit for weight restoration 2. Useful with comorbid depression + OCD 3. No evidence of benefit AFTER weight restoration iii. Atypical antipsychotics 1. Occasional use 2. No evidence it changes course of treatment 3. Olanzapine or quetiapine – used in conjunction with FBT to help manage the distress of eating disorder symptoms at meal times 4. Olanzapine RCT – do not get weight gain or help with delusional thinking, it did help anxiety of eating disorder thoughts

Answer 273

a. Syndrome of electrolyte disturbance seen after feeding introduced after a period of starvation b. Pathophysiology i. Starvation = low CHO intake  low insulin secretion ii. Fat catabolism predominates therefore FFA and ketones > glucose iii. In severe starvation, body stores of K, Mg, PO4 depleted, although serum levels are maintained iv. Refeeding  CHO metabolism  increased insulin  stimulates PO4, K, Mg into cells  fall in serum concentration v. Occurs within 3-4 days of refeeding 1. Phosphate and K+ generally drop after 48 hours c. Consequences i. Deranged electrolytes 1. Hypophosphataemia = hallmark of refeeding 2. Other = HypoK, HypoMg, Na+ and fluid retention 3. Thiamine deficiency 4. Hyperglycaemia ii. Life-threatening sequelae = arrythmia, cardiac failure, confusion, convulsions, coma d. Management i. Replacement of deranged electrolytes ii. Usually start with 500 mg TDS phos and daily phosphate levels – then wean by 2 weeks

Answer 274

7. Prognosis a. Mortality rate 12x higher than the annual death rate from all causes in females 15 to 24 years b. Crude mortality is 5% per decade (6% overall, 2% in adolescents) i. 50% due to cardiovascular complications, 50% due to suicide c. Highest mortality of any mental health condition d. Overall i. <50% fully recover ii. 30% partially recover iii. 20% remain chronically ill e. Core symptoms = weight restoration (60%), menstruation (60%), normalized eating (50%) f. Average length of illness is 5-7 years ``` 8. Prognostic factors Poor outcome • Onset <11 years of age, or onset in adulthood • Psychiatric and somatic comorbidities • Obsessionality and impulsivity • Purging and binging behaviour • More significant weight loss • Family dysfunction • Longer duration of illness ``` Good outcome • Early age at onset/ adolescent onset (<14 years, but must be >11 years) • Good relationship with family • Shorter duration of illness

Answer 275

1. Key points a. Developed in the 1980s (published in 2002) in the UK b. Suitable for children with anorexia up to 19 years of age with less than 3 years duration c. Outpatient treatment that aims to assist parents in the process of bringing about the recovery of their child in the home setting d. 20 sessions – 6-12 months 2. Treatment consists of 3 phases over approximately 6 months (nowadays) a. Phase 1 = intensive refeeding i. Parent refeed until reach 90-95% of IBW ii. Anorexia is externalised to manage guilt and expressed emotion iii. Siblings role is to support the young person’s distress iv. Weekly sessions v. 6 meals per day b. Phase 2 = transition to adolescent control i. Patient very gradually learns to take control of eating without parental control ii. Parental control and siblings role is faded very gradually iii. Completed at menstruation or 100% IBW iv. Fortnightly sessions c. Phase 3 = return to adolescent control i. Aim is to return the adolescent family cycle to normal after the delay caused by anorexia ii. May include issues present at onset or helping parents to spend more time together iii. Can also include comorbid conditions iv. Monthly sessions 3. Core principles a. Agnostic view of AN i. Causes of AN are NOT the focus of treatment; causes of AN are unknown ii. Dispels notion family is to blame for AN + family not viewed as cause of AN b. Separate client from the anorexia i. Adolescent viewed as having little control over the anorexia ii. Model seeks to separate the patient from the AN iii. Through separation parents encouraged to take action against the illness NOT child c. Privilege families resourcefulness d. Hospitalisation is temporary solution e. Target of intervention is the anorexia (NOT the child or family) f. Structural change made to defeating AN i. May indirectly have a therapeutic effect ii. The therapist only challenges the structural elements of the family that interfere with weight gain iii. Attention is given to developing a strong parental alliance, strengthening the sibling sub-system and fostering open communication g. Therapist resists expert stance h. Medical safety precedes adolescent issues 4. Evidence a. 50-70% chance of recovery (compared to individual therapy) b. Less likely to get readmitted c. Note no difference in IP vs OP

Answer 276

1. Epidemiology a. Tends to emerge in later adolescence b. Typified by impulsivity +/- features of borderline personality disorder c. May be associated with PHX of obesity 2. Management a. Psychoeducation b. Dietary management i. Regular meals ii. DELAY purging (less likely to vomit if delayed by > 30 minutes) iii. Distraction c. Cognitive behavioural therapy i. Le Grange study 2015 ii. Improved rates of abstinence in family based therapy compared to cognitive based therapy after 6 months of therapy d. SSRIs i. High doses – evidence of working ii. Fluoxetine is the only SSRI better than placebo (eg. 60 mg) iii. Needs to be high dose iv. Need to ensure it is not purged v. Other medications – topiramate + lisdexamphetamine e. Increasing evidence for FBT i. Good outcomes BN with CBT/medication (? FBT) 1. More evidence for individual work

Answer 277

1. Terminology a. Sex assigned at birth = determined by chromosomes, gonads, hormones and physical appearance; essentially constant b. Gender = social construct c. Gender identity = a person’s internal sense of being male, female, or a blend of both or neither i. Expressed from a very early age d. Gender expression/role = the way many people show their gender to others (eg. haircuts, clothing) e. Gender dysphoria i. Medical term that describes the distress a transgender or gender diverse person experiences in relation to this incongruence ii. Being transgender is considered part of spectrum of gender diversity – gender dysphoria is associated with severe psychiatric disadvantage f. Transgender = when person experiences incongruence between one’s experienced or expressed gender or one’s assigned gender 2. Epidemiology a. 1.2% transgender, 2.5% unsure in NZ study b. Average age of presentation 12yo, most report concerns from 3-4yo 3. Comorbidities a. Self-harm 80% b. Attempted suicide 50% c. Physical abuse 30% d. Verbal abuse 67% e. Social exclusion 40%

Answer 278

a. Stages of clinical intervention i. Triage assessment = pubertal status, mental health needs, medical needs ii. Multidisciplinary assessment – 2 independent mental health assessments iii. STAGE ONE 1. Puberty blockers a. Reversible b. GnRH analogues – Lucrin or zolodex 2. Main complication = reduced bone density due to depressed sex hormone levels 3. Start in Tanner stage 2 or above 4. Stops development of secondary sexual characteristics whilst continue to grow physically, emotionally and cognitively iv. STAGE TWO 1. Estrogen 2. Testosterone 3. Illegal before age 18 unless go to Family Court - age 14-15 is ideal v. STAGE THREE 1. Surgery and ongoing hormones 2. Top surgery in men = therapeutic 3. Bottom surgery not recommended – impact on sexual function and reproduction b. Fertility counselling i. All children + adolescents receive fertility counselling prior to any medical intervention ii. Young people assigned female at birth but identifying as male 1. Testosterone reduces fertility but pregnancy remains possible in future if ceased 2. Storage of eggs or ovarian tissue can be offered but not necessarily recommended as possibility of future pregnancy without intervention, the invasiveness of the retrieval procedure and the requirement for estrogen stimulation iii. Young people assigned male at birth but identifying as female 1. Infertility occurs following use of estrogen 2. Storage of sperm if patient is post pubertal is recommended 3. Storage of testicular tissue via biopsy is recommended + offered if patient is pre-pubertal or in early puberty c. Symptom management i. Often fixing one thing helps everything – e.g. sleep ii. Migraine preventers can be helpful; sandamigran (pizotifen), beta blocker, clonidine, topiramate iii. Sleep hygiene; consider TCA, amitriptyline d. Lifestyle/energy management i. Social, academic, physical 1. Some kids miss up to 4 years of school! 2. Recovery after activity ii. Not doing too much iii. Commitment to attend something on a regular basis iv. Consider what did they want to do before they got sick, how can they get there e. Other i. Family and emotional support – including siblings ii. Aim to reduce consequences of illness iii. Psychology often most helpful when recovering

Answer 279

1. Key points a. Also known as systemic exertion intolerance disease (SEID) b. Controversial disease entity 3. Etiology = unknown a. Infection – EBV, other viruses i. Typically after infective process in Australia ii. Multiple, EBV most frequent; not only viral iii. Presents similarly to overtraining syndrome in elite athletes iv. NOTE: in Japan, typical onset end of primary school – chronic sleep deprivation and stress rather than post infective b. Immune dysfunction c. Endocrine-metabolic dysfunction d. Neurally mediated hypotension e. ?autoimmune association – often have elevated ANA

Answer 280

a. Fakuda criteria i. Fatigue 1. Clinically evaluated, unexplained 2. Persistent or relapsing 3. 6+ months 4. New onset 5. Not result of ongoing exertion 6. Not alleviated by rest 7. Substantial impact on daily life ii. 4+ of associated symptoms 1. Impaired memory/concentration 2. Sore throat 3. Tender LN 4. Muscle pain 5. Joint pain without arthritis 6. Headache 7. Unrefreshing sleep 8. Post exertional malaise >24 hours – key feature b. 2015 IOM diagnostic criteria i. Diagnosis requires 3 of the following 1. A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities that persists for more than six months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is substantially alleviated by rest 2. Post-exertional malaise - Worsening of a patient's symptoms and function after exposure to physical or cognitive stressors that were normally tolerated before disease onset. 3. Unrefreshing sleep ii. At least one of the following two manifestations also required 1. Cognitive impairment - Problems with thinking or executive function exacerbated by exertion, effort, or stress or time pressure. 2. Orthostatic intolerance - Worsening of symptoms upon assuming and maintaining upright posture. Symptoms are improved, although not necessarily abolished, by lying back down or elevating the feet.

Answer 281

4. Clinical manifestations a. Relatively sudden onset of fatigue, often associated with a typical infection such as an upper respiratory infection or mononucleosis b. Overwhelming fatigue associated with additional symptoms (eg, altered sleep and cognition) c. Symptoms are characteristically exacerbated by excessive physical activity d. Affected patients are typically highly functioning individuals who are "struck down" with this disease e. Prior history of psychiatric disorder is common f. Highest frequency in winter months 5. Treatment a. Cognitive behavioural therapy i. Effective in some patients ii. May be useful in those with idiopathic chronic fatigue b. Exercise therapy 6. Prognosis a. Duration of illness – average 5 years but can be a lot longer b. Engaging in education best predictor of functional and emotional wellbeing