PAEDS - ONCOLOGY/HAEM AND GENETICS/ENDOCRINE Flashcards
FANCONI SYNDROME
What is fanconi syndrome?
- Generalised reabsorptive disorder of renal tubular transport in the PCT resulting in…
– Type 2 (proximal) renal tubular acidosis
– Polydipsia, polyuria, aminoaciduria + glycosuria
– Osteomalacia/rickets
FANCONI SYNDROME
What are some causes of fanconi syndrome?
- Usually secondary to inborn errors of metabolism
– Cystinosis (AR > intracellular accumulation of cysteine, most common)
– Wilson’s disease, galactosaemia, glycogen storage disorders
ANAEMIA OVERVIEW
What are some causes of decreased red cell production?
What are some clues?
- Ineffective erythropoiesis (Fe, folate deficiency, CKD)
- Red cell aplasia
- Normal reticulocytes, abnormal MCV in nutrient deficiencies
ANAEMIA OVERVIEW
What are some causes of haemolysis?
What are some clues?
- G6PD deficiency, haemoglobinopathies, hereditary spherocytosis
- Raised reticulocytes, abnormal appearance on blood films, +ve direct antiglobulin test if immune cause
ANAEMIA OVERVIEW
How does haemolysis cause anaemia?
What is the difference in haemolytic anaemias in neonates + children?
- Red cell survival reduced significantly but bone marrow production increases too, anaemia = bone marrow cannot compensate
- Neonates = immune haemolytic anaemias, children = instrinsic abnormalities (G6PD)
ANAEMIA OVERVIEW
List 4 features of haemolytic anaemias
- Anaemia
- Hepatosplenomegaly
- Unconjugated bilirubinaemia
- Excess urinary urobilinogen
ANAEMIA OVERVIEW
What are some causes of anaemia in the neonate?
- Reduced RBC production = congenital red cell aplasia + congenital parvovirus infection > red cell aplasia
- Haemolytic anaemia = immune (haemolytic disease of newborn) or hereditary (G6PD etc)
ANAEMIA OVERVIEW
What are the main causes of anaemia of prematurity?
- Inadequate erythropoietin production
- Reduced red cell lifespan
- Frequent blood sampling whilst in hospital
- Iron + folic acid deficiency after 2-3m.
IRON DEF ANAEMIA
What are some sources of iron?
What can affect iron absorption?
- Breast milk, formula, cow’s milk or weaning (cereals)
- Markedly increased when eaten with food rich in vitamin C + inhibited by tannin in tea
IRON DEF ANAEMIA
What is…
i) transferrin saturation?
ii) total iron binding capacity?
i) Proportion of transferrin bound to iron
ii) Total space on transferrin for Fe to bind
IRON DEF ANAEMIA
What are some side effects of treatment with oral iron supplementation?
- Constipation
- Black coloured stools
- Nausea
SICKLE CELL DISEASE
What is the pathophysiology of sickle cell disease?
How does it arise?
- Abnormal variant (haemoglobin S) which polymerises to be an abnormal sickle (crescent) shape + so more fragile + easily destroyed > haemolytic anaemia
- Amino acid substitution (glutamine > valine)
SICKLE CELL DISEASE
What is the genetics behind sickle cell disease?
- Autosomal recessive
- Abnormal gene for beta-globin on C11
- Heterozygous = sickle-cell trait
- Homozygous = sickle cell disease (HbSS)
SICKLE CELL DISEASE
What is acute chest syndrome?
What can cause it?
Management?
- Fever or resp Sx (CP, tachypnoea) with new infiltrates on CXR
- Can be due to infection (pneumonia, bronchiolitis) or non-infective (pulmonary vaso-occlusion or fat emboli)
- Emergency > Abx or antivirals, blood transfusions for anaemia, may need NIV or intubation
SICKLE CELL DISEASE
Name 2 other vaso-occlusive crises
- ‘Hand-foot syndrome’ common leading to dactylitis
- Priapism in men > urological emergency, aspiration
SICKLE CELL DISEASE
Sickle cell disease may present with acute anaemia (sudden drop in Hb).
What can cause this?
- Haemolytic crises (sometimes with associated infection)
- Aplastic crises (parvovirus causes cessation of RBC production)
- Sequestration crises
SICKLE CELL DISEASE
What is a sequestration crisis?
What is the management?
- Sudden hepatic or splenic enlargement, abdo pain + circulatory collapse from accumulation of sickled cells blocking blood flow
- Supportive = blood transfusions, fluid resus, splenectomy can prevent this + used in recurrent crises as can lead to splenic infarction > increased infection susceptibility
SICKLE CELL DISEASE
What are some investigations for sickle cell disease?
- Prenatal Dx via CVS
- Detection via Guthrie test
- FBC = low Hb, high reticulocytes
- Blood film = sickled RBCs
- Dx with Hb electrophoresis showing high amounts of HbSS + absent HbA
SICKLE CELL DISEASE
What are some complications of sickle cell disease?
- Short stature + delayed puberty
- Stroke + cognitive issues
- Pulmonary HTN
- Chronic renal failure
- Psychosocial issues
SICKLE CELL DISEASE
What is the general management for sickle cell disease?
- Fully immunised (PCV, HiB, meningococcus)
- Avoid vaso-occlusive crisis triggers
- PO phenoxymethylpenicillin prophylaxis
- PO folic acid as increased demands due to haemolysis
- Hydroxycarbamide + hydroxyurea can stimulate HbF production to prevent painful crises
- Bone marrow transplant curative + offered if failed response
SICKLE CELL DISEASE
What is the management of an acute crisis?
- PO or IV analgesia according to need (?opiates)
- IV fluids, oxygen
- Infection treated with Abx, blood transfusion for severe anaemia
- Exchange transfusion if severe (e.g. neuro complications)
THALASSAEMIA
What is thalassaemia?
Consequence?
What are the 2 types?
- AR disorder arising from ≥1 gene defects, resulting in a reduced rate of production of ≥1 globin chains
- RBCs more fragile + breakdown easily
- Alpha = defect in alpha globin chains
- Beta = defect in beta globin chains
THALASSAEMIA
What is a complication of beta-thalassaemia major which isn’t common in developed countries?
- Extramedullary haematopoiesis can occur if no regular blood transfusions
- Leads to hepatosplenomegaly + bone marrow expansion leading to maxillary overgrowth + skull bossing
THALASSAEMIA
What are some investigations for beta thalassaemia?
- FBC + blood film = hypochromic microcytic anaemia
- HbA2 raised in beta-thalassaemia trait, HbA2 + HbF raised in major
- Serum ferritin to differ between Fe anaemia + check iron overload
- Hb electrophoresis for Dx
- DNA testing via CVS before birth
THALASSAEMIA
What is the main complication of thalassaemia?
How might this present?
- Repeated + Regular blood transfusions can cause chronic iron overload
- Heart (cardiomyopathy, heart failure)
- Liver (cirrhosis)
- Pancreas (diabetes)
- Pituitary (delayed growth + sexual maturation)
- Skin (hyperpigmentation)
- Arthritis + joint pain
THALASSAEMIA
What is the management of thalassaemia?
- Lifelong monthly blood transfusions for the most severe cases
- Desferrioxamine for iron chelation to prevent overload
- Bone marrow transplant can be curative, reserved for beta thalassaemia major
HAEMOPHILIA
What are some investigations for haemophilia?
- FBC + blood film
- Prothrombin time (factors 2, 5, 7, 10, extrinsic) normal
- Activated partial thromboplastin time (intrinsic) = greatly increased
- Severity dependent on amount of FVIII:C or FIX:C levels
- Prenatal Dx with CVS
HAEMOPHILIA
What is the management of haemophilia?
- IV infusion of recombinant FVIII or FIX concentrate if active bleeding (or prophylactic to reduce arthropathy risk)
- Desmopressin stimulates vWF release for bleeding/prevention, TXA
- AVOID aspirin, NSAIDs + IM injections (can worsen bleeding)
HAEMOPHILIA
What is a complication of the treatment for haemophilia?
- Formation of antibodies against the clotting factor can render it ineffective
VON WILLEBRAND DISEASE
What is the physiological role of von Willebrand factor?
- Facilitates platelet adhesion to damaged endothelium
- Acts as carrier protein for FVIII:C, protecting it from inactivation + clearance
VON WILLEBRAND DISEASE
What is von Willebrand disease (vWD)?
What causes it?
Types?
- Deficiency of vWF leading to defective platelet plug formation + deficient FVIII:C > most common inherited bleeding disorder
- AD, type 1 most common + mildest
- Severity increases with type 2, type 3 has very low or no vWF (AR)
VON WILLEBRAND DISEASE
What are some investigations for vWD?
- FBC (normal platelets) + blood film, biochemical screen including renal + liver function
- Prolonged bleeding time
- Prothrombin time normal
- APTT = elevated or normal
- vWF antigen decreased, vWF multimers variable
VON WILLEBRAND DISEASE
What is the management of vWD?
- Pressure applied if active bleeding
- Minimise bleeding with desmopressin or TXA
- Severe = plasma derived FVIII concentrate or vWF infusion
- AVOID aspirin, NSAIDs + IM injections as can worsen bleeding
VON WILLEBRAND DISEASE
How is desmopressin given?
What does it do?
- Nasal or s/c
- Release of vWF + FVIII concentrate
COAGULATION DISORDERS
What are acquired disorders of coagulation?
Secondary to
- Haemorrhagic disease of the newborn due to vitamin K deficiency
- Liver disease as location of clotting factor production
- ITP + DIC
COAGULATION DISORDERS
What can cause vitamin K deficiency?
- Inadequate intake = neonates, long-term chronic illness
- Malabsorption = coeliac, cystic fibrosis
- Vitamin K antagonists = warfarin
ITP
What is immune thrombocytopenic purpura (ITP)?
- Commonest cause of thrombocytopenia in childhood
- T2 hypersensitivity reaction with destruction of circulating platelets by anti-platelet IgGs
ITP
What is the management of ITP?
- Often acute + self-limiting
- Severe bleeding may need prednisolone, IVIg, blood/platelet transfusions
HAEMOLYTIC DISEASE OF THE NEWBORN
what is the management in utero?
- transfusion of O negative packed cells cross-matched with maternal blood at 16-18 weeks
HAEMOLYTIC DISEASE OF THE NEWBORN
what are the complications?
- kernicterus which can cause extrapyramidal, auditory and visual abnormalities and cognitive deficit
- late-onset anaemia
- graft-versus-host disease
- portal vein thrombosis + portal hypertension
ALL
What do blood and bone marrow tests show in ALL?
FBC and blood film = WCC usually high
Blast cells on film and in bone marrow
HODGKINS LYMPHOMA
What blood results may you see in someone with Hodgkin’s lymphoma?
- high ESR
- FBC = anaemia (normochromic normocytic)
- reed sternberg cells
- low Hb
- high serum lactase dehydrogenase
NON-HODGKINS LYMPHOMA
What are the signs and symptoms of non-hodgkins lymphoma?
Fever and sweating
Enlarged rubbery non-tender nodes
Systemic ‘B’ symptoms, e.g. fever
GI and skin involvement
AML
what are the clinical features of AML?
Anaemia -> breathlessness, fatigue, pallor
Infection
Hepatosplenomegaly
Peripheral lymphadenopathy
Gum hypertrophy
Bone marrow failure and bone pain
AML
What would you expect to see on an FBC and bone marrow biopsy in someone you suspect to have AML?
FBC = anaemia and thrombocytopenia and neutropenia
BM biopsy = leukaemic blast cells (with Auer rods)
CML
what are the clinical features of CML?
Insidious onset
Symptomatic anaemia
Abdominal pain - splenomegaly
Weight loss, tiredness, palor
Gout - due to purine breakdown
Bleeding - due to platelet dysfunction
CML
what are the investigations for CML?
FBC - anaemia, raised myeloid cells, high WCC (eosinophilia, basophilia, neutrophilia)
Increased B12
Blood film - left shirt, basophilia
Bone marrow biopsy - increased cellularity
Philadelphia chromosome seen in 80+% of cases t(9;2) - Stimulates cell division
CML
What is the treatment for CML?
Chemotherapy
Tyrosine kinase inhibitors, e.g. Imatinib - Given orally
Stem cell transplant
CML
Why does the Philadelphia chromosome cause CML?
FORMS fusion gene BCR/ABL on chromosome 22 –> tyrosine kinase activity –> stimulates cell division
CLL
what are the investigations for CLL?
● Normal or low Hb
● Raised WCC with very high lymphocytes
● Blood film – smudge cells may be seen in vitro
CLL
What is the treatment for CLL?
Watch and wait
Chemotherapy
Monoclonal antibodies, e.g. rituximab
Targeted therapy, e.g. bruton kinase inhibitors (ibrutinib)
GENETICS OVERVIEW
What is genomic imprinting + uniparental disomy?
Give an example
- Most genes both copies are expressed, some genes are only maternally or paternally expressed (imprinting)
- Prader-Willi + Angelman’s syndrome both caused by either cytogenic deletions of the same region of chromosome 15q or by uniparental disomy of chromosome 15
GENETICS OVERVIEW
Explain the process of gonadal mosaicism
- Father = mosaic sperm (some sperm with mutated gene, some sperm normal)
- Mother = all eggs with normal gene
- Offspring = fertilised egg > union of male DNA (sperm) with mutated gene + female DNA (egg) with normal gene
- Every cell of embryo has one copy of mutated + one copy of normal
TURNER’S SYNDROME
What are some complications of Turner’s syndrome?
- Coarctation or bicuspid aortic valve
- Increased risk of CHD > HTN, obesity
- DM, osteoporosis, hypothyroidism
- Recurrent otitis media + UTIs
- Horseshoe kidney, susceptible to x-linked recessive conditions
KLINEFELTER SYNDROME
What are some complications of Klinefelter syndrome?
- Increased risk of breast cancer compared to other males
- Osteoporosis
- Diabetes
- Anxiety + depression
ANGELMAN’S SYNDROME
What is Angelman’s syndrome?
What is it caused by?
- Genetic imprinting disorder due to deletion of maternal chromosome 15 or paternal uniparental disomy
- Loss of function of maternal UBE3A gene
ANGELMAN’S SYNDROME
What is the clinical presentation of Angelman’s syndrome?
- “Happy puppet” = unprovoked laughing, clapping, hand flapping, ADHD
- Fascination with water
- Epilepsy, ataxia, broad based gait
- Severe LD, delayed development
- Widely spaced teeth, microcephaly
NOONAN’S SYNDROME
What is Noonan’s syndrome?
- Autosomal dominant condition with defect on chromosome 12, normal karyotype
NOONAN’S SYNDROME
What is the clinical presentation of Noonan’s syndrome?
- Short stature, webbed neck, widely spaced nipples (Male Turner’s)
- Pectus excavatum, low set ears
- Hypertelorism (wide space between eyes)
- Downward sloping eyes with ptosis
- Curly/woolly hair
NOONAN’S SYNDROME
What are some complications of Noonan’s syndrome?
- CHD = pulmonary valve stenosis
- Cryptorchidism which can lead to infertility (fertility in women normal)
- LDs, bleeding disorders (XI deficient)
WILLIAM’S SYNDROME
What is William’s syndrome?
- Random deletion of genetic material on one copy of chromosome 7 resulting in only single copy of genes from other chromosome 7
WILLIAM’S SYNDROME
What is the clinical presentation of William’s syndrome?
- Very friendly + sociable
- Starburst eyes (star-pattern on iris)
- Wide mouth, big smile + widely spaced teeth
- Broad forehead, short nose + small chin
- Mild LD, short stature
WILLIAM’S SYNDROME
What are some complications of William’s syndrome?
- Supravalvular aortic stenosis
- ADHD
- HTN + hypercalcaemia
CONGENITAL HYPOTHYROIDISM
What is the clinical presentation of congenital hypothyroidism?
- Prolonged neonatal jaundice
- Delayed mental + physical milestones
- Puffy face, macroglossia + hypotonia
- Failure to thrive + feeding problems
- Coarse facies + hoarse cry
JUVENILE HYPOTHYROIDISM
What is associated with an increased risk of juvenile hypothyroidism?
- Increased risk with Down or Turner syndrome
PRECOCIOUS PUBERTY
What is the pathophysiology and potential causes of central precocious puberty?
Pathophysiology: LH++, FSH+ > oestrogen from ovary ++ or testosterone from testis ++ & adrenal +
Causes:
- Familial,
- hypothyroidism,
- CNS (neurofibroma, tuberous sclerosis)
PRECOCIOUS PUBERTY
What causes premature pubarche (adrenarche)?
How can you tell?
- Accentuation of normal maturation of androgen production by adrenal gland (adrenarche), can be late-onset CAH or adrenal tumour
- Urinary steroid profile to help differentiate
PRECOCIOUS PUBERTY
What are the risk factors with premature pubarche (adrenarche)?
- More common in Asian + Afro-Caribbean, increased risk of PCOS later in life
CAH
What is the clinical presentation of CAH in females?
- Tall for age, facial hair, absent periods, deep voice + precocious puberty
- Severe = virilised genitalia (ambiguous), labial fusion + enlarged clitoris
CAH
What is the general management of CAH?
- Lifelong glucocorticoids (hydrocortisone) to suppress ACTH > normal growth
- Lifelong mineralocorticoids (fludrocortisone) if there’s salt loss, infants may need NaCl
- Additional hydrocortisone to cover illness/surgery
- Antenatal dexamethasone controversial treatment, risks>benefits currently
SEXUAL DIFFERENTIATION
What are some causes of sexual differentiation disorders?
- CAH (#1)
- Congenital hypopituitarism (Prader-Willi)
- Ovotesticular disorder of sex development (true hermaphroditism) leading to both testicular + ovarian tissues as XX + XY containing cells present
DELAYED PUBERTY
What are some causes of hypogonadotropic hypogonadism?
- Constitutional delay in growth + puberty (FHx)
- Chronic diseases (IBD, CF, coeliac)
- Excess stress (anorexia, intense exercise, low weight)
- Hypothalamo-pituitary disorders (panhypopituitarism, Kallman’s + anosmia, GH deficiency)
DELAYED PUBERTY
What are some causes of hypergonadotropic hypogonadism?
- Chromosomal abnormalities (Turner’s XO, Klinefelter’s 47XXY)
- Acquired gonadal damage (post-surgery, chemo/radio, torsion)
- Congenital absence of the testes or ovaries
DELAYED PUBERTY
In delayed puberty, what are some causes of…
i) short stature (delayed + short)?
ii) normal stature (delayed + normal)?
i) Turner’s, Prader-Willi + Noonan’s
ii) PCOS, androgen insensitivity, Kallmann’s + Klinefelter’s
DELAYED PUBERTY
What are some investigations for delayed puberty?
- FBC + ferritin (anaemia), U+E (CKD), coeliac antibodies
- Hormonal testing
- Genetic testing/karyotyping
- XR wrist to assess bone age (low in constitutional delay)
- Pelvic USS to assess ovaries + other pelvic organs
- MRI head if ?pituitary pathology + assess olfactory bulbs (Kallmann)
DELAYED PUBERTY
What are the hormonal tests you would do in delayed puberty?
- Early morning serum gonadotropins (FSH/LH)
- TFTs
- GH provocation testing (insulin, glucagon)
- IGF-1 levels
- Serum prolactin
PICA
what are the causes?
- developmental problems e.g. autism
- mental health problems e.g. OCD, schizophrenia
- malnutrition or hunger
- stress
PICA
what are the investigations?
- blood tests - anaemia, lead levels
- stool tests - parasites
- x-rays
KALLMAN SYNDROME
what is it?
genetic disorder that can be inherited via autosomal dominant, autosomal recessive and x-linked
KALLMAN SYNDROME
what are the clinical features?
- hypogonadotropic hypogonadism
- anosmia
- synkinesia (mirror-image movements)
- renal agenesis
- visual problems
- craniofacial anomalies
ANDROGEN INSENSITIVITY SYNDROME
what is the inheritance pattern?
x-linked recessive
ANDROGEN INSENSITIVITY SYNDROME
what are the results of hormone tests?
- raised LH
- normal/raised FSH
- normal/raised testosterone
- raised oestrogen
ANDROGEN INSENSITIVITY SYNDROME
what is the management?
- bilateral orchidectomy to avoid testicular tumours
- oestrogen therapy
- vaginal dilators or vaginal surgery
- generally patients are raised as female
- offered support and counselling
FRAGILE X SYNDROME
What causes it?
Trinucleotide expansion repeat of CGG caused by slipped mispairing = ≤44 normal, 60–200 = premutation carriers, >200 = fragile X
PRECOCIOUS PUBERTY
What is the pathophysiology of pseudo precocious puberty?
Low LH + FSH as gonadal or extra-gonadal source leads to increased testosterone or oestrogen
PRECOCIOUS PUBERTY
What are the causes in males?
Less common, more worrying
– Pituitary adenoma (bilateral testicular enlargement suggests gonadotropin release)
– CAH or adrenal tumour (small testes)
– Gonadal tumour (unilateral testicular enlargement)
PRECOCIOUS PUBERTY
What is a genetic cause of precocious puberty?
McCune Albright syndrome (café-au-lait, short stature)
CAH
What is a major risk factor?
Consanguineous parents
GONADOTROPIN DEFICIENCY
Give 2 causes of primary hypogonadism
Hypergonadotropic hypogonadism
Klinefelter’s Syndrome (47XXY)
Tuner’s Syndrome (45X)
GONADOTROPIN DEFICIENCY
Give 2 causes of Hypogonadotropic hypogonadism
- Kallmann’s Syndrome
- Tumours - craniopharyngiomas, germinomas
HYPOTHALAMIC TUMOURS
what are the risk factors for developing hypothalamic tumours?
neurofibromatosis
undergone radiation therapy
HYPOTHALAMIC TUMOUR
what is the clinical presentation?
- euphoric ‘high’ sensations
- failure to thrive
- headache
- hyperactivity
- loss of body fat and appetite
- vision loss
- precocious puberty
PRECOCIOUS PUBERTY
What are the causes of pseudo precocious puberty?
Causes:
– Adrenal (tumours, CAH)
– Granulosa cell tumour (ovary)
– Leydig cell tumour (testicular)
CAH
How does salt-losing crisis present?
– Vomiting, weight loss, floppiness + circulatory collapse
– Hyponatraemic, hyperkalaemic, metabolic acidosis, hypoglycaemic
CAH
What is the management of salt-losing crisis?
IV 0.9% NaCl + dextrose,
IV hydrocortisone
OBESITY
what are the causes of obesity in children other than lifestyle factors?
- growth hormone deficiency
- hypothyroidism
- Down’s syndrome
- Cushing’s syndrome
- Prader-Willi syndrome
OBESITY
what are the consequences of obesity in children?
- orthopaedic problems: slipped upper femoral epiphyses, Blount’s disease (a development abnormality of the tibia resulting in bowing of the legs), musculoskeletal pains
- psychological consequences: poor self-esteem, bullying
sleep apnoea
benign intracranial hypertension - long-term consequences: increased incidence of type 2 diabetes mellitus, hypertension and ischaemic heart disease
TYPE 1 DIABETES
what is the triad of symptoms?
what other symptoms may be present?
- polyuria
- polydipsia
- weight loss
- secondary enuresis
- recurrent infections
TYPE 1 DIABETES
what are the investigations for a new diagnosis?
- FBC, U+Es, glucose
- blood cultures
- HbA1c
- TFTs + TPO
- anti-TTG
- insulin antibodies, anti-GAD + islet cell antibodies
DKA
what is required to diagnose DKA?
Hyperglycaemia (i.e. blood glucose > 11 mmol/l)
Ketosis (i.e. blood ketones > 3 mmol/l)
Acidosis (i.e. pH < 7.3)
DKA
what are the principles of DKA management in children?
- correct dehydration evenly over 48hrs
- give an initial bolus followed by ongoing fluids
- insulin should be delayed by 1-2hrs to reduce chance of cerebral oedema
- 0.05-0.1 units/kg/hr of insulin
DKA
what are the different classifications of DKA?
Mild - pH 7.2-7.29 or bicarb <15mmol/L, dehydration = 5%
moderate - pH 7.1-7.19 or bicarb <10mmol/L, dehydration = 7%
severe - pH <7.1 or bicarb <5mmol/L, dehydration = 10%
DKA
what fluids are given to children not in shock?
initial bolus - 10ml/kg 0.9% NaCl over 1 hour
ongoing fluids - 0.9% NaCl with 20mmol KCl in each 500ml bag
1. calculate fluid deficit based on % dehydration
2. subtract initial 10ml/kg bolus from this
3. add maintenance fluids
DKA
what are the complications?
cerebral oedema
hypokalaemia
aspiration pneumonia
hypoglycaemia
