Syndromes/Eponymous Flashcards

Question

Opsoclonus Myoclonus Ataxia Syndrome

Answer 1

Features: Neuroblastoma a/w myoclonic jerking and random conjugate eye movements, +/- cerebellar ataxia Likely immune mediated Often progresses to neuropsychologic sequelae

Answer 2

Features: Neuroblastoma a/w intractable secretary diarrhoea d/t tumour secretion of vasointestinal peptides

Answer 3

Features: Neuroblastoma a/w other neural crest disorders, e.g. congenital hypoventilation syndrome, Hirschprungs Gene: PHOX2B

Answer 4

Progression of untreated congenital cardiac defect with intracardiac communication: L-R shunt -> increased pulmonary blood flow -> increased pulmonary vascular resistance -> inverted shunt to R-L -> cyanosis

Answer 5

Features: Developmental disorder, affecting facies, growth, intellectual disability, limb defects Gene: NIPBL Inheritance: AD, XL, de novo

Answer 6

DHCR7 mutations Deficiency in enzyme 7-dehydrocholesterol reductase -> abnormal cholesterol metabolism Inheritance: AR ``` • Craniofacial malformations • Developmental delay • Growth failure • Cholesterol deficiency Under virilised male (46XY DSD) ```

Answer 7

Cutaneous hypersensitivity with classic lesions brought on by superficial trauma Feature of sJIA

Answer 8

Rare but potentially fatal complication of systemic juvenile idiopathic arthritis, can occur at any time Features: high fevers, lymphadenopathy, hepatosplenomegaly, encephalopathy Thrombocytopenia, leukopenia, elevated ferritin (can be really high e.g. >10,000), low ESR Treat with IV methylpred

Answer 9

= Jugular Vein Suppurative Thrombophlebitis • Typically anaerobic gram –ve rod – Fusobacterium necrophorum oral flora • Begins as pharyngitis or tonsillitis -> thrombophlebitis -> seeding of multiple organs with septic emboli particularly lungs • Acute fever, hypoxia, tachypnea, WOB • CXR – multiple cavities • Pneumonia may lead to respiratory failure in untreated cases • Anaerobic BC, USS of jugular veins CT of chest -> Dx Lemierre’s syndrome is a condition characterized by thrombophlebitis (inflammation d/t blood clot) of the internal jugular vein and bacteremia caused by primarily anaerobic organisms (fusobacterium necrophorum most commonly), following a recent oropharyngeal infection. This has been an uncommon illness in the era of antibiotic therapy, though it has been reported with increasing frequency in the past 15 years. Lemierre’s syndrome should be suspected in young healthy patients with prolonged symptoms of pharyngitis followed by symptoms of septicemia or pneumonia, or an atypical lateral neck pain. Metastatic infections following the IJ thrombophlebitis occur in >2/3 of cases (lungs, joints, liver, muscle, pericardium, brain and skin). Diagnosis is often confirmed by identification of thrombophlebitis of the internal jugular vein and growth of anaerobic bacteria on blood culture. Treatment involves prolonged antibiotic therapy occasionally combined with anticoagulation.

Answer 10

Alice in Wonderland syndrome (AIWS) is a rare neurological disorder characterized by distortions of visual perception, the body image, and the experience of time. People may see things smaller than they are, feel their body alter in size or experience any of the syndrome's numerous other symptoms. Since there are also many known causes of AIWS, diagnosis requires a thorough neurological work-up. In children, the most common cause is brain inflammation; in adults, it is migraine.

Answer 11

Brugada Syndrome is an ECG abnormality with a high incidence of sudden death in patients with structurally normal hearts. Brugada syndrome is due to a mutation in the cardiac sodium channel gene. A/W early cardiac death. Only proven therapy is an implantable cardioverter-defibrillator (ICD). Diagnostic criteria: Brugada sign on ECG (Coved ST segment elevation >2mm in >1 of V1-V3 followed by a negative T wave) plus at least one clinical criteria of: Documented ventricular fibrillation (VF) or polymorphic ventricular tachycardia (VT), Family history of sudden cardiac death at <45 years old, Coved-type ECGs in family members, Inducibility of VT with programmed electrical stimulation, Syncope, Nocturnal agonal respiration.

Answer 12

Wolff-Parkinson-White (WPW) Syndrome is a combination of the presence of a congenital accessory pathway and episodes of tachyarrhythmia. Pre-excitation refers to early activation of the ventricles due to impulses bypassing the AV node via an accessory pathway. In WPW the accessory pathway is often referred to as the Bundle of Kent, or atrioventricular bypass tract. ECG features of WPW in sinus rhythm are: PR interval <120ms Delta wave – slurring slow rise of initial portion of the QRS QRS prolongation >110ms ST Segment and T wave discordant changes – i.e. in the opposite direction to the major component of the QRS complex Pseudo-infarction pattern can be seen in up to 70% of patients – due to negatively deflected delta waves in the inferior / anterior leads (“pseudo-Q waves”), or as a prominent R wave in V1-3 (mimicking posterior infarction).

Answer 13

Postural orthostatic tachycardia syndrome (POTS) is a condition characterized by too little blood returning to the heart when moving from a lying down to a standing up position (orthostatic intolerance). Orthostatic Intolerance causes lightheadedness or fainting that can be eased by lying back down. In people with POTS, these symptoms are also accompanied by a rapid increase in heart rate.

Answer 14

Late sequelae of acute rheumatic fever. Jaccoud arthropathy is a benign, chronic arthropathy that involves loosening and lengthening of periarticular structures and tendons in the hands and/or feet. The deformities are painless, "correctable" with manipulation, and do not cause functional impairment. The arthropathy is not associated with active joint inflammation.

Answer 15

Sandifer syndrome is a condition that involves spasmodic torsional dystonia with arching of the back and rigid opisthotonic posturing, associated with symptomatic gastroesophageal reflux, esophagitis, or hiatal hernia.

Answer 16

Excessive inflation (stretch receptors) triggers this reflex which is protective to further inflation as it inhibits inspiratory neurons

Answer 17

Congenital tracheomegaly A lung disorder that causes the respiratory tract to dilate or enlarge. People with this condition develop frequent respiratory tract infections and recurrent cough.

Answer 18

Wilson Mikity syndrome (WMS) refers to chronic lung disease in premature infants, characterized by early development of cystic interstitial emphysema (PIE). This is now sometimes considered as part of the spectrum of bronchopulmonary dysplasia.

Answer 19

1) situs inversus totalis 2) chronic sinusitis 3) bronchiectasis (Primary ciliary dyskinesia)

Answer 20

Modified Mallampati scoring of airways Class 1 – fully visible tonsils, uvula, soft palate Class 2 – visibility of hard and soft palate, upper portion of tonsil and uvula Class 3 - soft and hard palate and base of uvula visible Class 4 – only hard palate Significant correlation between Mallampati score + AHI on sleep study For every point increase in Mallampati score odds ratio of OSA increase more than 6 fold Tonsil size - Brodsky’s classification of tonsillar size Grade 0 – tonsil in tonsillar fossa Grad 1 - tonsil 25% oropharynx Grade 2 – 25-50% Grade 3 – 50-75% Grade 4 - >75% For every point increase in tonsillar size, the odds ratio of having OSA increase >2 fold

Answer 21

Sudden and temporary loss of muscle tone Pathognomonic for narcolepsy if present Rarely the first symptom of narcolepsy Usually brief (seconds to minutes) but in children may last for hours or days (‘status cataplecticus’)

Answer 22

Also known as hypogenetic lung syndrome, is characterized by a hypoplastic lung that is drained by an anomalous pulmonary vein into the systemic venous system. It is a type of partial anomalous pulmonary venous return and is one of the several findings in congenital pulmonary venolobar syndrome. CXR: a crescent shaped vertical shadow in the right lower lung

Answer 23

Noonan syndrome is a common genetic disorder with multiple congenital abnormalities. It is characterized by congenital heart disease (hypertrophic cardiomyopathy, pulmonary stenosis with dysplastic valve), short stature, a broad and webbed neck, sternal deformity, variable degree of developmental delay, cryptorchidism, increased bleeding tendency, and characteristic facial features that evolve with age. Dysplastic valves are frequently seen.

Answer 24

Alagille syndrome (arteriohepatic dysplasia) is the most common syndrome with intrahepatic bile duct paucity (often erroneously called intrahepatic biliary atresia). Other features: - Unusual facial characteristics (broad forehead; deep-set, widely spaced eyes; long, straight nose; and an underdeveloped mandible) - Ocular abnormalities (posterior embryotoxon, microcornea, optic disk drusen, shallow anterior chamber) - Cardiovascular abnormalities (usually peripheral pulmonic stenosis, sometimes others) - Vertebral defects (butterfly vertebrae, fused vertebrae, spina bifida occulta, rib anomalies) - Tubulointerstitial nephropathy.

Answer 25

``` Developmental delay (IQ range: 41-80), elfin facies (full face, broad forehead, flattened bridge of the nose, long upper lip, and rounded cheeks), as well as idiopathic hypercalcemia of infancy. Cardiac (pulmonary stenosis, supravalvular aortic stenosis). ```

Answer 26

``` For aortic stenosis Aortic valve is replaced with persons own pulmonary autograft Pulmonary allograft (from cadaver) is used to replace the persons own pulmonary valve ```

Answer 27

Aneuploidy, only 1 X chromosome 1/2500 girls Webbing of the neck, a low posterior hairline, small mandible, prominent ears, epicanthal folds, high arched palate, a broad chest presenting the illusion of widely spaced nipples, cubitus valgus, and hyperconvex fingernails. The diagnosis is often first suspected at puberty when breast development fails to occur. Short stature , the cardinal finding in virtually all females with Turner syndrome, may be present with little in the way of other clinical manifestations. 30% have coarctation of aorta

Answer 28

Symptomatic ECG: • Normal or rightward QRS axis and RVH or RBBB (LVH seen in older children) • RVH on ECG is usually replaced by LVH by 2 years of age CXR: • Marked cardiomegaly and pulmonary edema or pulmonary venous congestion Asymptomatic ECG: • LAD and LVH CXR: • Heart may be normal or slightly enlarged • Rib notching between 4th- 8th ribs may be seen in older children (>8 years) with large collaterals • Post-stenotic dilatation of descending aorta (distal to the coarctation) often produces a figure of 3 sign on the plain film

Answer 29

Most common of the T-cell disorders 1 in 3,000 births Triad: thymic agenesis, hypocalcaemia, cardiac anomalies. 22q11.2 deletion disrupts development of the 3rd and 4th pharyngeal pouches during early embryogenesis, leading to hypoplasia or aplasia of the thymus and parathyroid glands. Other structures forming at the same age are also frequently affected, resulting in anomalies of the great vessels (right-sided aortic arch), esophageal atresia, bifid uvula, congenital heart disease (conotruncal, atrial, and ventricular septal defects, interrupted aortic arch (20% have DiGeorge), ToF), a short philtrum of the upper lip, hypertelorism, an antimongoloid slant to the eyes, mandibular hypoplasia, and posteriorly rotated ears . The diagnosis is often first suggested by hypocalcemic seizures during the neonatal period. Clinical manifestations = CATCH-22 a. Cardiac = majority of patients have severe CHDs; most commonly include TOF (25%), interrupted aortic arch (15%), VSD (15%), persistent truncus arteriosus (9%), and isolated aortic arch anomalies (5%) b. Abnormal facies = hypertelorism, micrognathia, short philtrum with fish-mouth appearance, antimongoloid slant, telecanthus with short palpebral fissures, and low-set ears, often with defective pinna c. Thymic hypoplasia or aplasia = mild to moderate decrease in T cell number d. Cleft = anomalies in the palate (70-80%) with speech and feeding disorders e. Hypocalcaemia = in 60%, due to hypoparathyroidism f. General Short stature, mental retardation and hypotonia in infancy are frequent Occasionally, psychiatric disorders (eg. schizophrenia and bipolar disorder) develop

Answer 30

Tall • Long thin fingers (arachnodactyly) • Increased arm span compared with height, hyperextension of joints, and lens subluxation • May have pectus excavatum, scoliosis, aortic or mitral regurgitation, and aortic root dilatation. Marfan syndrome (MFS) is an inherited, systemic, connective tissue disorder caused by mutations in the gene encoding the extracellular matrix (ECM) protein fibrillin-1. It is primarily associated with skeletal, cardiovascular, and ocular pathology. The diagnosis is based on clinical findings, some of which are age dependent. Although there is variable phenotypic expression of Marfan syndrome (MFS), aortic root dilatation and ectopia lentis are cardinal features of the disease and various systemic features support the diagnosis. Overgrowth of the long bones (dolichostenomelia ) is often the most obvious manifestation of MFS and may produce a reduced upper segment to lower segment ratio (UL/LS) or an arm span to height ratio >1.05 times.

Answer 31

Ehlers-Danlos syndrome (EDS) is the term used for a group of relatively rare genetic disorders of connective tissue that are characterized by one or another of several features, including skin hyperextensibility, joint hypermobility, and tissue fragility. 1 in 5000 Joint dislocations or subluxations are common in most forms of EDS, and joint pain and premature degenerative arthritis are often consequences of the disorder. Pes planus is common in all forms, and pectus excavatum and a high arched palate can also be present in all of the forms of EDS. Musculoskeletal pain is common in patients with joint hypermobility, and complex regional pain syndrome has been described as a rare complication with both the hypermobility and classic forms of EDS.

Answer 32

Rare, genetic birth defect affecting about 1 in 40,000 births. About 97% of those affected are male. Prune belly syndrome is a congenital disorder of the urinary system, characterized by a triad of symptoms: - Cryptorchidism (undescended testes) - Abdominal wall defects (A partial or complete lack of abdominal wall muscles. There may be wrinkly folds of skin covering the abdomen) - Genitourinary defects (unusually large ureters, distended bladder, accumulation and backflow of urine from the bladder to the ureters and the kidneys (vesicoureteral reflux)) 1. Key points a. Genetic basis unknown b. X-linked defect suggested by majority males being affected c. Disorder can occur in females d. Triad i. Abdominal muscle deficiency ii. Severe urinary tract abnormalities iii. Bilateral cryptorchidism in males 2. Clinical manifestations a. Antenatal – oligohydramnios, pulmonary hypoplasia b. Stillbirth c. CKD – 50% d. Urogenital i. Bilateral hydroureteronephrosis ii. VUR e. Pulmonary i. Respiratory insufficiency ii. Recurrent infections f. Other i. Chronic constipation ii. Impaired exercise tolerance iii. Growth retardation iv. Cardiac abnormalities in 10% 3. Treatment a. Renal transplantation

Answer 33

Caused by oligohydramnios secondary to renal ageneis or other renal anomalies -> reduced foetal urine output -> oligohydramnios Features: - positional limb deformities (club feet, hip dislocation) - facial features (pseudoepicanthus, recessed chin, posteriorly rotated and flattened ears, flattened nose) - pulmonary hypoplasia

Answer 34

``` Autosomal recessive (also AD) Characterized by an abnormality of skin development (areas of missing skin on the scalp called aplasia cutis congenita) and malformations of the hands and feet (terminal transverse limbs defects). The aplasia cutis may involve only the skin or include the skull under the skin. The terminal transverse limb defects may include webbed fingers or toes (syndactyly) and short or missing fingers or toes (brachydactyly or oligodactyly, respectively). Other signs and symptoms may include additional skeletal abnormalities of the limbs; cutis marmorata telangiectatica congenita (a blood vessel disorder); pulmonary hypertension; heart defects; and neurological problems. Severity can vary greatly among people with the syndrome and may be lethal in some cases. ```

Answer 35

Focal dermal hypoplasia (FDH, MIM #305600), also known as Goltz syndrome or Goltz-Gorlin syndrome, is an X-linked dominant multisystem disorder that is lethal in utero in males. The primary feature of FDH is patchy dermal hypoplasia, with herniation of fat through defects in the dermis. There are a number of associated anomalies, including dental, hair, nails, extremities, central nervous system (CNS), and facial clefting.

Answer 36

1. Key points a. Valproate known teratogen, unknown mechanism b. Use: anticonvulsant and BPD Rate: 5-15% 4. Clinical features a. Dysmorphic facies – clefts (when multiple AEDs), epicanthic folds, broad nasal bridge, short anteverted nose, smooth long philtrum, thin arched eyebrows b. Hypospadias, UDT c. MSK – radial ray, polydactyly, absent humerus/radius, contractures of hands, overlapping toes, split hand d. CHD – 25% VSD, AS, PS, PDA e. Craniosynostosis f. Neural tube defects – BP 1-2% (general population 0.2-0.5%) g. Developmental delay h. Behavioral problems i. Uncommon – coloboma of iris, brain anomalies, respiratory, abdominal wall, renal j. Withdrawal can occur – feeding difficulty, hypoglycaemia, jitteriness, irritability, hypothermia

Answer 37

``` Hereditary condition (AD) associated with multiple non-cancerous (benign) skin tumours, lung cysts (and pneumothoraces), and an increased risk of kidney lesions (cysts, benign tumors, and kidney cancer). BHD syndrome is caused by alterations (mutations) in the FLCN gene (encoding folliculin) and is inherited as an autosomal dominant trait. ```

Answer 38

Spontaneous oesophageal rupture resulting from sudden increased intra-oesophageal pressure. Most commonly associated with emesis with incomplete cricopharyngeal relaxation. The classic ‘‘Mackler’s triad’’ of esophageal rupture—chest pain, vomiting, and subcutaneous emphysema—has been estimated to occur in only 14-25% of cases. Up to two-thirds of patients may demonstrate subcutaneous emphysema on physical examination, whereas Hamman’s sign (a crunching sound synchronous with each heart beat) is rare. Other nonspecific signs include tachypnea and tachycardia, with 82% of patients meeting systemic inflammatory response syndrome criteria Oesophageal contents may leak into the mediastinum and pleural space resulting in mediastinitis and a mortality of 40–90% if not recognised and treated promptly Left posterolateral distal oesophagus is most commonly the site of rupture. Radiographic imaging (CXR, CT scan) commonly reveal pneumomediastinum, mediastinal fluid, and pleural effusion

Answer 39

1. Description a. Autosomal recessive 2. Clinical manifestations a. Onset of ataxia usually before 10 years b. Explosive dysarthric speech and nystagmus c. Intelligence preserved 3. Cardiac manifestations a. Cardiomyopathy in 30% of cases – hypertrophic cardiomyopathy with normal LV systolic function is the most common finding b. Advanced stages – the LV enlarges, the LV wall thickness decreases and LV systolic function decreases c. CHF is the terminal event, with most patients dying before the age of 40 years 4. Investigations a. ECG = T vector change in the limb leads or left pre-cordial leads; occasionally, LVH, RVH, abnormal Q waves, or short PR intervals 5. Management a. As per cardiomyopathy

Answer 40

1. Genetics + pathogenesis a. 1 in 140 000 – 17 000 (Newfoundland) b. AR – digenic – mutations in 2 genes c. At least 19 genes identified – BBD1, BBD19 d. Each protein is localized to primary cilia, basal bodies, pericentriolar region e. Function i. Cilia assembly: intraflagellar transport ii. Microtubule dependent trafficking iii. Cell cycle regulation 2. Clinical manifestations ``` Primary features • Rod-cone dystrophy • Postaxial polydactyly • Truncal obesity • Learning disabilities • Hypogonadism • Renal anomalies – similar to nephronophthisis ``` ``` Secondary features • Speech delay/disorder • Developmental delay • Behavioural abnormalities • Eye abnormalities = strabismus, cataracts, astigmatism • Brachydactyly/syndactyly • Ataxia/poor coordination/ imbalance • Mild hypertonia • Orodental abnormalities • Cardiovascular abnormalities • Hepatic involvement • Craniofacial dysmorphism ```

Answer 41

1. Genetics + pathogenesis a. AR b. 8 mutations known c. Defects in cilia function 2. Clinical manifestations a. Often lethal b. Bilateral renal cystic dysplasia c. Biliary duct dysgenesis d. Postaxial polydactyly e. CNS i. Occipital encephalocele ii. Prosencephlic dysgenesis iii. Rhombic roof dysgenesis iv. Hydrocephalus v. Dandy-Walker malformation

Answer 42

1. Genetics + pathogenesis a. X linked dominant – lethal, embryonically in males b. OFD-1 gene c. Important in right-left axis patterning, microtubule organization, cilia formation 2. Clinical manifestations a. Malformations of face, mouth, hands and feet b. CNS – hydrocephalus, agenesis of corpus callosum c. Renal i. Cystic disease similar to ADPCKD but no renal enlargement and cysts mainly of glomerulus ii. ESRD – late childhood onwards

Answer 43

1. Genetics + pathogenesis a. Autosomal dominant b. Mutations of TCF2 gene, encodes hepatocyte nuclear factor-1-beta c. HNF1-beta = regulator of gene expression in several organs – liver/ kidney/ pancreas i. Role of epithelial differentiation – gene expressed in preglomerular stages of metanephros, especially medullary and cortical CD branches ii. ? directly regulates transcription of PKHD 1 (?inhibition of PKHD 1 contributes to cyst formation) 2. Clinical manifestations a. Most commonly found genetic abnormality in antenatal bright kidneys b. Renal manifestations i. Various malformations 1. Multicystic dysplastic kidney 2. Hypoplasia, asplasia and dysplasia 3. Cysts including glomerular cysts 4. Malformations such as horseshoe kidney, small kidney 5. Hyperuricaemic nephropathy ii. Progression to ESRF in 10-20% of patients c. Associated features i. T2DM – onset usually in adulthood, but can occur earlier 1. MODY type 5 ii. New onset diabetes after transplantation (NODAT) iii. Hyperuicaemic gout iv. Abnormal genital tract – vaginal aplasia, abnormal uterus, epididymal cysts, atresia of vas deferens v. MANY other features

Answer 44

a. Association of: i. Male pseudohermaphroditism ii. Early onset nephrotic syndrome secondary to diffuse mesangial sclerosis (DMS) iii. Mutations in WT-1 gene  predisposition in Wilm’s tumour b. All phenotypic females presenting with DMS should undergo chromosomal analysis to ensure that they are not male c. DMS does not appear to recur post Tx d. DMS has also been associated with mutations in PLCE1

Answer 45

• Association of o Male pseudohermaphroditism o Progressive glomerular disease • Proteinuria generally presents between 2-6 years of age; can occur in infancy • Slow decline in renal function to CKD5 which is unresponsive to therapy • Associated with WT-1 mutations o Different mutations to DDS – result in normal protein production o Risk of Wilm’s tumour does not appear to be increased • Characteristic renal histological changes are those of FSGS • High risk of gonadoblastoma – consideration to remove abnormal gonads

Answer 46

a. Genetics + pathogenesis i. X-linked disorder ii. OCRL1 gene – encodes phosphatidylinositol phosphate 5-phosphate protein b. Clinical manifestations i. Triad 1. Congenital cataracts 2. Mental retardation 3. Faconi syndrome ii. Typically present in infancy with cataracts, progressive growth failure, hypotonia and Faconi syndrome iii. Significant proteinuria common iv. Blindness and renal insufficiency can develop v. Behavioral abnormalities – tantrums, stubbornness, stereotypy and obsessions c. Treatment i. No specific therapy ii. Cataract removal

Answer 47

1. Key points a. Group of disorders characterised by hypokalaemic metabolic alkalosis with hypercalciuria and salt wasting b. Electrolyte abnormalities similar to frusemide c. Occurs in 1/50,000-100,000 2. Etiology a. Most AR b. Associated with 5 distinct defects in loop of Henle transporters – Na-K-2Cl co-transporter in TAL of LOH c. Each contributes to sodium and chloride transporter (except class V - Bartter syndrome with hypocalcaemia) 3. Classification a. Antenatal Bartter syndrome (type I, II, and IV) i. Also called hyperprostaglandin E syndrome ii. Typically, manifest in infancy and has more severe phenotype than classic Bartter syndrome (type III) iii. Perinatal onset = polyhydramnios, neonatal salt wasting, severe episodes of recurrent dehydration b. Classic Bartter syndrome (type III) = present in childhood with FTT and recurrent episodes of dehydration c. Type IV Bartter = associated with SNHL

Answer 48

4. Pathogenesis a. Biochemical features (hypokalaemic metabolic alkalosis with hypercalciuria) resemble those seen with chronic use of loop diuretics = reflect a defect in Na, Cl and K transport in the ascending loop of Henle b. Defective NaCl uptake in LOH c. Distal tubular sodium sites overwhelmed  polyuria up to 4-8 L/m2/day d. Polyuria  volume contraction  RAAS stimulation i. Hypertrophy of JGA ii. Hyperaldosteronism 1. Aldosterone  Na uptake and K excretion  exacerbates hypokalaemia 2. Aldosterone  H+ secretion distally  worsening alkalosis iii. Elevated renin e. Hypokalaemia  stimulates PG synthesis  further activates RAAS f. Unable to generate +ve potential in tubular lumen from reduced Na reabsorption  reduced calcium clearance  hypercalciuria + nephrocalcinosis g. Long-term hyperplasia of DCT 5. Clinical manifestations a. Classic Bartter i. Insidious onset early in life ii. FTT/ longitudinal retardation iii. Impaired ability to concentrate/ dilute urine iv. Polyuria, polydipsia, salt carving v. Prone to hypernatraemic dehydration vi. Non-specific fatigue, dizziness and chronic constipation vii. Muscle cramps and weakness secondary to chronic hypokalaemia b. Severe antenatal/ Hyper PGE syndrome i. Severe antenatal salt wasting 1. Polyhydramnios (with high chloride) 2. Premature delivery ii. Life-threatening volume depletion (NaCl loss and polyuria) for a number of weeks (may not by hypokalaemic initially – ROMK) iii. Subsequently develop symptoms similar to ‘classical’ Bartter c. Other features i. Dysmorphic features – triangular facies, protruding ears, large eyes with strabismus, drooping mouth ii. Consanguinity – suggesting of autosomal recessive disorder iii. BP usually normal – although those with antenatal form can have severe salt wasting, resulting in dehydration and hypotension

Answer 49

6. Investigations a. Bloods i. Hypokalaemia ii. Metabolic alkalosis iii. +/- hyponatraemia iv. +/- mild hypoMg (more characteristic of Gitelman) v. Renal function usually normal vi. Elevated renin, aldosterone and PGE levels (particularly elevated in antenatal form) b. Urine i. Calcium = high ii. Potassium = high iii. Sodium = high iv. Chloride = low v. Urine osmolality >100 mOsm/kg c. USS = nephrocalcinosis resulting from hypercalciuria may be seen on USS (type I and II) d. Biopsy = rarely performed 7. Diagnosis a. Diagnosis in neonate suggested by severe hypokalaemia – usually <2.5 mmol/L – with metabolic alkalosis b. Hypercalciuria is typical c. Hypomagnesmia is seen in a minority of patients but more common in Gittelmans syndrome 8. DDx a. Diuretic abuse b. Chronic vomiting – distinguished by measurement of urinary chloride, which is elevated in Bartter syndrome and low in patients with chronic vomiting 9. Treatment a. Prevent dehydration b. Maintain nutritional status c. Correct deranged electrolytes i. Potassium supplementation often at very high doses 1. KCl often poorly tolerated ii. Potassium sparing diuretics (eg. aldosterone antagonist) may be of value iii. High sodium diet and may require sodium supplementation iv. Indomethacin (PG inhibitor) can also be effective – reduce hyperPGE effect and reduce renal blood flow v. Mag supplementation if hypoMg 10. Prognosis a. With close attention to electrolyte balance, volume status and growth, the long term prognosis is good b. In a minority of patients chronic hypokalaemia, nephrocalcinosis, and chronic indomethacin therapy  chronic interstitial nephritis + chronic renal failure

Answer 50

1. Key points a. Rare autosomal recessive cause of hypokalaemic metabolic alkalosis b. Distinct features i. Hypocalciuria [Cf. hypercalciuria in Bartters] ii. HypoMg 3. Pathogenesis a. Mild sodium wasting only (not the site of bulk resorption) b. Compensatory increase in TALH (paracellular calcium absorption) c. Increased Na in DCT results in more aldosterone related exchange for K/ H  hypokalemia/ metabolic alkalosis d. Mechanism of hypomagnesemia not well understood 4. Clinical manifestations a. Typically present at a later age than those with Bartter syndrome and may have symptoms similar to older children with Bartter syndrome b. Hx recurrent muscle cramps and spasms (due to low Mg) c. Salt craving d. Nocturia, polyuria and occasional hypotension or normal BP e. Dizziness, joint pain f. Usually do NOT have a history of recurrent episodes of dehydration g. Growth failure is less prominent 5. Diagnosis a. Blood i. Hypokalaemia ii. Metabolic alkalosis iii. HypoMg iv. High renin but NORMAL aldosterone from hypokalaemic suppression b. Urine i. Calcium = VERY LOW ii. Mg = ELEVATED iii. Chloride = low c. Note serum renin and aldosterone levels are usually normal, and PG E secretion is not elevated 6. Treatment a. Correct hypokalaemia b. Correct hypoMg i. May require IV Mg if symptomatic or <0.5 mmol/L 1. Diarrhoea a common side effect 2. Correction of hypoMg will improve renal potassium wasting and function hypoparathyroidism c. Sodium supplementation or treatment with PG is usually not necessary as patients do not have episodes of volume depletion or elevated PG excretion

Answer 51

a. Genetics + pathogenesis i. X linked ii. 60% Xp11.22 – CLC-5 channel inactivation iii. 15% OCRL1 gene – also mutated in Lowe syndrome iv. Some patients have OCRL1 mutation (responsible for Lowe syndrome) also meet Dent disease criteria (= Dent-2 disease) b. Clinical manifestations i. Proximal tubulopathy with characteristic abnormalities that include 1. LMW proteinuria 2. Faconi syndrome – glycosuria, aminoaciduria, phosphaturia ii. Other features 1. Hypercalciuria, nephrolithiasis, nephrocalcinosis + haematuria 2. Progressive renal failure (ESKD between 3rd and 5th decade) 3. Hypophosphatemic rickets c. Treatment i. Treat hypercalciuria = low NaCl, thiazide diet ii. Treat bone disease = oral PO4, vitamin D iii. Replacement of Na/K/H2O as required (PCT dysfunction)

Answer 52

Inactivation of tumour suppressor gene i. 1 mutant P53 allele inherited 1. ‘Guardian of the genome’ – P53 recognises chromosomal damage and prevents cell from dividing until repaired 2. Initiates apoptosis if beyond repair ii. Sarcomas, leukaemias, gliomas; cancers of breast, bone, lung, brain 1. If adrenocorticocarcinoma or choroid plexus carcinoma, LFS unless proven otherwise iii. If medulloblastoma + Li-Fraumeni, almost certainly Sonic Hedgehog subtype

Answer 53

Inactivation of tumour suppressor gene i. AD, defect in tumour suppressor genes NF1 and NF2 ii. Proliferation of cells of neural crest origin  neurofibromas iii. NF1 = neurofibroma, optic glioma, acoustic neuroma, astrocytoma, meningioma, phaeochromocytoma, sarcoma iv. NF2 = bilateral acoustic neuromas, meningiomas

Answer 54

Retinal and CNS haemangioblastomas, renal cell carcinoma, phaeochromocytoma ii. Germline mutation in VHL tumour suppressor gene Inactivation of tumour suppressor gene i. Autosomal dominant, mutation of tumour suppressor gene VHL ii. Cysts, benign and malignant tumours iii. Cancers = hemangioblastoma of cerebellum and retina, phaeochromocytoma, renal cancer

Answer 55

Inactivation of tumour suppressor gene i. Autosomal dominant, mutations in TSC1 or TSC2 tumour suppressor genes 1. Gene products of TSC1 (hamartin) and TSC2 (tuberin) inhibit mTORC1 (mammalian target of rapamycin complex 1) signaling, a growth promotion pathway ii. Ash leaf patches/ shagreen patches/ facial angiofibromas, learning difficulties/ ASD/ seizures iii. Fibroangiomatous nevi, myocardial rhabdomyoma

Answer 56

Defect in DNA repair i. Short stature, photosensitive telangiectatic erythema ii. Excessive number of broken chromosomes due to repair defects iii. Increased risk leukaemia, lymphoma, solid tumours

Answer 57

i. AR, defect in DNA repair ii. Short stature, skeletal and renal anomalies, pancytopenia iii. Increased risk leukaemia, myelodysplastic syndrome, liver neoplasias, rare had and neck tumours, GI and GU cancers

Answer 58

Defect in DNA repair i. AR ii. Failure to repair UV damaged DNA iii. BCC, SCC and melanoma

Answer 59

i. AR, defect in DNA repair ii. Mutation in ATM tumour suppressor gene (11q22-23) iii. Neurodegenerative; ataxia, telangiectasia, immunodeficiency with sinopulmonary infections, impaired organ maturation, X-ray hypersensitivity iv. Lymphoma, leukaemia; less commonly CNS and nonneural solid tumours

Answer 60

Hypopigmentation, immune deficiency, thrombocytopaenia and/or neurological deficits

Answer 61

Partial oculocutaneous albinism, neutrophil defects, neutropenia and neurological abnormalities

Answer 62

Oculocutaneous albinism and platelet storage pool deficiency

Answer 63

Wilms tumour, aniridia, genitourinary abnormalities, and mental retardation 11p13

Answer 64

Overgrowth syndrome * Macrocephaly * Deep rooted eyes and ears * Macrosomia * Organomegaly

Answer 65

Old term for reactive arthritis: Conjunctivitis, urethritis, arthritis

Answer 66

L5 marked with pen, another mark 10cm above in midline, patient bends forward without bending knees, distance should exceed 15cm

Answer 67

● Rare AD disorder ● Mutations in gene encoding CARD 15 (caspase recruitment domain 15 protein)/ NOD 2 ● Early onset granulomatous arthritis, uveitis, rash and flexion contractions ● Fever not a major feature ● Treated with corticosteroids

Answer 68

AAAS mutations * Achalasia * Alacrima * Cognitive deficits * Neuromuscular deficits * Hyperkeratosis

Answer 69

LIPA mutations * Bilateral adrenal calcification * Hepatosplenomegaly i. Rare autosomal recessive disorder ii. Mutations encoding human lysosomal acid lipase iii. Cholesteryl esters accumulate in lysosomes in most organ systems  organ failure iv. Infants in the 1-2 months  hepatosplenomegaly, steatorrhea, abdominal distension and FTT v. Adrenal insufficiency and bilateral adrenal calcifications are present vi. Death results in first year of life

Answer 70

Mitochondrial DNA deletions * External ophthalmoplegia * Retinal degeneration * Cardiac conduction defects * Other endocrine disorders

Answer 71

GLI3 mutations * Hypothalamic hammartoblastoma * Hypopituitarism * Imperforate anus * Postaxial polydactyly

Answer 72

CDKN1C mutations * Intrauterine growth retardation * Metaphyseal dysplasia * Genital abnormalities

Answer 73

* Thyroid autoimmune disease * Type 1 diabetes * Other autoimmune diseases

Answer 74

Waterhouse–Friderichsen syndrome (WFS) is defined as adrenal gland failure due to bleeding into the adrenal glands, commonly caused by severe bacterial infection. Typically, it is caused by Neisseria meningitidis. The bacterial infection leads to massive bleeding into one or (usually) both adrenal glands.

Answer 75

(Wiki) A genetic disorder inherited in an autosomal dominant manner that is characterized by early, and frequently severe, high blood pressure associated with low plasma renin activity, metabolic alkalosis, low blood potassium, and normal to low levels of aldosterone. Liddle syndrome involves abnormal kidney function, with excess reabsorption of sodium and loss of potassium from the renal tubule, and is treated with a combination of low sodium diet and potassium-sparing diuretics (e.g. amiloride). It is extremely rare, with fewer than 30 pedigrees or isolated cases having been reported worldwide as of 2008. This syndrome is caused by dysregulation of the epithelial sodium channel (ENaC) due to a genetic mutation at the 16p13-p12 locus. - > high amounts of channel in collecting duct - > pseudohyperaldosteronism - > excessive retention of sodium and water

Answer 76

Primary hyperaldosteronism Hypernatraemia Hypokalaemia HTN Reduced plasma renin

Answer 77

Term used to describe signs of prolonged glucocorticoid excess Cushing disease = Cushing syndrome due to pituitary adenoma secreting ACTH

Answer 78

Complication of T1DM i. Dwarfism associated with glycogen-laden liver ii. Related to chronic underinsulinisation – less common nowadays iii. A complication of poorly controlled T1DM characterised by 1. Growth attenuation 2. Delayed puberty 3. Hepatomegaly with abnormal glycogen storage and steatosis 4. Cushingoid features iv. Catch up growth occurs if diabetic control is restored. v. Clinical features include moon face, protruberant abdomen, proximal muscle wasting and enlarged liver

Answer 79

Hypogonadotropic hypogonadism Anosmia/hyposmia Impaired smell and impaired puberty

Answer 80

XY pure/complete gonadal dysgenesis They typically have normal female external genitalia, but functionless gonads (fibrous tissue termed "streak gonads"), and if left untreated, will not experience puberty.

Answer 81

2. Abnormality of GH receptor = GHR mutation  Laron syndrome a. >20 different mutations described in GHR gene b. Children resemble severe IGHD (ie. the same as having no growth hormone) c. Birth tends to be 1 SD below the mean, and severe short stature develops by 1 year of age d. ↑ GH, ↓ IGF e. Do not get a normal pubertal growth spurt as you require normal sex steroids AND GH

Answer 82

Cerebral gigantism Advanced bone age, tall child, normal adult height * Macrocephaly, high forehead, frontal bossing, * Hypertelorism, prominent jaw, high arched palate, * Intellectual disability (mental retardation) * Hypotonia * Poor coordination Rare Diseases: Sotos syndrome is a genetic disorder, described in 1964, characterized by excessive growth before and after birth, a large, elongated (dolichocephalic) head, distinctive facial configuration, and a non-progressive neurological disorder with intellectual disability. Advanced bone age is present in approximately 75 to 85% of patients. Sotos syndrome is caused by mutations (abnormalities) in the NSD1 (nuclear receptor-binding SET domain protein 1) gene. Mutations in this gene have been identified in approximately 90% of affected patients (Sotos syndrome 1).

Answer 83

Also known as acute idiopathic blue finger or paroxysmal finger haematoma. It presents with a sudden onset of painful swelling of a single finger (but can be more than one). The distal segment is usually spared. It is a rare benign syndrome and resolves spontaneously. Raynaud phenomenon usually involves more than one digit and does not spare the distal segment.

Answer 84

AKA Type 1A pseudohypoparathyroidism Inactivating mutation GNAS1 gene (same gene as Mcune Albright syndrome but inactivating rather than activating mutation) - inheritance determines syndrome: maternally inherited = pseudohypoPTH 1a/b/c, paternally inherited = pseudopseudohypoPTH Manifestations - Obesity - Short stature - Round facies - Subcutaneous ossification - Brachydactyly type E (shortening mainly of 4th+/-5th metacarpals/tarsals) - IUGR - Developmental delay - Tetany - End organ resistance to several hormones, e.g. PTH, TSH (2nd most common)

Answer 85

* Phase of avid bone mineralisation with hypocalcaemia due to rapid movement of calcium from the bone to the skeletal compartment * Tends to occur during early phases of recovery from a severe mineralisation defect or after a prolonged period of calcium resorption from bone * A parallel increase in uptake of Mg leading to hypoMg may increase severity of hypocalcaemia * Examples = vitamin D therapy in the setting of severe rickets, parathyroidectomy

Answer 86

a. AR b. Mutation in chloride iodine transport protein (SCL26A4) – expressed in thyroid gland and cochlear i. Pendrin allows transport of iodide from the follicular cell to the colloid c. Key features i. Hypothyroidism ii. Sensorineural deafness iii. Goiter – can be present at birth iv. Other = vestibular dysfunction, temporal bone abnormality d. Common presentation – euthyroid goiter and sensorineural hearing loss later in life e. Goitre worsens if iodine deficiency – manage with iodine supplement

Answer 87

a. Key features i. Agenesis of corpus callosum ii. Distinctive Chorioretinal lacunae iii. Infantile spasms iv. Severe ID b. Patients almost all female c. Seizures evident during the first few months and are resistant to anticonvulsants d. EEG = independent activity across hemispheres, hemihypsarrhythmia

Answer 88

* Characterise by bilateral facial weakness * Often associated with bilateral CNVI palsy * Results from hypoplasia/ agenesis of brainstem nuclei * Usually present with facial weakness resulting in difficulty feeding

Answer 89

Duane Retraction Syndrome • Congenital limitation of horizontal globe movement + globe retraction on attempted adduction • Abnormal innervation by the oculomotor nerve of the lateral rectus muscle

Answer 90

• Posterior fossa abnormalities including o Cystic dilatation of the fourth ventricle o Hypoplasia of the cerebellar vermis o Hydrocephalus o Enlarged posterior fossa • Variable degrees of neurological impairment • Unknown cause

Answer 91

i. Inflammatory encephalopathy characterised by progressive refractory partial seizures, cognitive deterioration and focal deficits that occur with gradual atrophy ii. Frequently presents in 6-8 year old children, although adolescents and adults can be affected iii. Etiology unknown iv. Treatment = high dose steroids, IVIG, rituximab v. Only definitive treatment is functional hemispherectomy

Answer 92

i. AKA LEOPARD syndrome ii. Key features 1. Lentigines – flat, black-brown macules 2. Hypertrophic cardiomyopathy 3. Short stature 4. Pectus deformity 5. Dysmorphic facial features – widely spaced eyes, ptosis Differential for neurofibromatosis 1

Answer 93

i. Multiple café au lait patches ii. Flexural freckling iii. No neurofibromas, optic nerve gliomas, bone lesions iv. Macrocephaly, learning problems can occur v. Cased by SPRED1 mutations vi. Resembles a mild form of NF-1

Answer 94

The typical presentation of MFS is that of ophthalmoplegia with ataxia and areflexia. Patients generally do not have significant lower extremity weakness compared with GBS. CNVI most often involved Antibodies against GQ1b (a ganglioside component of nerve) are present in 85 to 90 percent of patients with MFS. The GQ1b antibody is strongly associated with involvement of oculomotor nerves and is also found in most patients with prominent oculomotor weakness and GBS.