Genetics Flashcards
HYPOMELANOSIS OF ITO
Genetics: unknown
Inheritance: de novo (typically)
Clinical Features: unilateral or bilateral macular hypo- or hyperpigmented whorls, streaks and patches (sometimes following lines of Blaschko), hair and tooth anomalies are common, ocular abnormalities (strabismus, nystagmus), musculoskeletal system (growth asymmetry, syndactyly, polydactyly, clinodactyly, scoliosis), CNS abnormalities (microcephaly, seizures, ID), cardiac defects
Investigations: R/O Incontinentia pigmenti, which is genetically inherited and requires genetic counselling in future
Management: symptomatic
Preauricular skin tag
Associated with:
- Goldenhar syndrome
- Treacher-Collins syndrome
- Wolf-Hirschhorn syndrome
Clinodactyly of the 5th finger
Associated with:
- Trisomy 21
- Normal familial variant
Macroglossia
Associated with:
- Beckwith Wiedemann syndrome
- Mucopolysaccharidosis
- Neurofibromatosis
- Glycogen storage disease - type 2
- Klippel-Trenaunay-Weber syndrome
Microretrognathia
Associated with:
- Pierre Robin sequence
- Treacher-collins syndrome
Encephalocele
Postaxial polydactyly
Bilateral clubfoot
Hypospadias
Fused labia with clitoromegaly
Imperforate anus
Amniotic band syndrome
Happy child, wide open mouth, seizures
ANGELMAN SYNDROME
Genetics: UBE3A gene deletion/mutation on Ch 15
Imprinting disorder (lack of maternal contribution/uniparental disomy of paternal gene)
Clinical Features: Microcephaly, hand flapping, ADHD, atypical laughing/smiling, Seizures, Hypopigmentation (skin/eyes), smooth palms, increased sensitivity to heat, prominent mandible, wide mouth, protruding tongue, arm tremors, jerky movements
Investigations:
- Methylation testing of Chromosome 15
Monitoring
- Hyperactivity and poor sleep improves over time
- Seizures escalate around time of puberty (especially in girls)
- avoid carbamazepine, vigabatrin and tiagabine
ACHONDROPLASIA
Gene: FGFR3 gene, codon 380
Inheritance: behaves Autosomal Dominant
Clinical features: Frontal bossing, depressed nasal bridge, sausage fingers, disproportionate size (short extremities, large head), small chest, protruding belly, trident hand
Associations:
- Hydrocephalus (d/t foramen magnum stenosis)
- Middle ear dysfunction (40% hearing loss, frequent AOM)
- Delayed motor milestones (often not walking until 18-24mo)
- Obstructive sleep apnea
- Delayed speech + articulation difficulties
- Dental crowding
- Bowing of legs (may need surgical correction)
- Obesity
Work-up
- Skeletal radiographs (short vetebral pedicles, large calvarial bones)
- Genetic testing
Long-term
- Monitor for developmental delay, scoliosis, arthritis, hydrocephalus
- Referral to ENT, dentistriy
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ALAGILLE SYNDROME
Genetics: JAG1, NOTCH2 mutations
Inheritance: Autosomal Dominant
Clinical Features: Butterfly vertebrae (clefting, failure of fusion), Posterior embryotoxon, Conjugated hyperbilirubin due to bile duct paucity, Peripheral pulmonary artery steonosis, renal disease, pancreatic insufficiency, growth delay, ID/GDD
Investigations:
- Radiographs: XR spine
- Ultrasound of gallbladder/HIDA
- Echocardiogram
- Genetics - sequence analysis of JAG1/NOTCH2
Monitoring
- Multidisciplinary (Genetics, GI, Nutrition, Nephro, Ophtho, Cardio)
- Ursodiol for cholestasis
- Liver transplant for ESRD
- Fat soluble vitamin supplementation
- Avoid contact sports and alcohol
ATAXIA TELANGIECTASIA
Inheritance: Autosomal Recessive
Complex immunodeficiency disorder with DNA repair defect
Clinical Features: Initially normal, develop ataxia ~2-3yo [usually first 6y of life] (wheelchair bound by 15yo), oculomotor apraxia (cannot make fast eye movements), Telangiectasia (last to appear), Immunodeficiency (decreased Ig, T-cell dysfunction), Malignancy (leukemia, lymphoma), recurrent sinus/pulmonary infections can lead to bronchiectasis
Investigations:
- Elevated AFP
- Low serum IgA
- Genetic testing
Monitoring:
- Supportive
- Death in 20s
Macroglossia, hemihypertrophy, omphalocele
BECKWITH WIEDEMANN SYNDROME
Inheritance: Imprinting disorder (Ch11p15); Autosomal dominant
Higher risk in IVF pregnancies
Clinical Features: Polyhydramnios, LGA baby, Macroglossia, Abdominal wall defects (omphalocele), pre-auricular ear creases/pits, renal abnormalities, hemi-hypertrophy, hyperplasia of organs, renal abnormalities, neoplasms (Wilms, adrenal carcinoma, hepatoblastoma)
Investigations: Chromosomal microarray
Monitoring:
- Hypoglycemia (infants)
- Abdo US q3mo until 8yo
- Serum AFP q3mo until 4yo
- CXR periodic (thoracic neuroblastoma)
- Renal US annually (8-16y)
- Ortho (hemihypertrophy)
CHARGE SYNDROME
Genetic: CHD7 mutations
Inheritance: Autosomal Dominant
Clinical Features:
- Coloboma
- Heart defect (conotruncal, AV canal, aortic arch)
- Atresia choanae (TEF, cleft lip and palate)
- Retardation of growth (short +/- GH deficiency)
- GU anomalies (single kidney, hydronephrosis, renal hypoplasia, micropenis, hypoplastic labia, cryptorchidism)
- Ear anomalies (question mark ear)
Can have facial asymmetry due to CNVII palsy, square face with flat midface, broad nose, swallowing difficulties due to CN abnormalities.
Investigations: Genetic testing, echocardiogram, abdominal U/S
Management:
- ENT, Ophtho, Nephro/Urology, Cardiology referral
CYSTIC FIBROSIS
Genetics: gene that codes for the CFTR protein (majority are ΔF508)
Inheritance: Autosomal Recessive
Mechanism: CFTR dysfunction = ↓Cl secretion and ↑Na absorption, leading to dehydrated/viscous mucus
Clinical Features (I’m CF Pancreas)
- Infertility
- Meconium ileus
- Cough
- Failure to thrive
- Pancreatic insufficiency
- Asthma (refractory)
- Nasal polyps
- Clubbing
- Rectal prolapse
- Electrolyte abnormalities (metabolic alkalosis, ↓Na, ↓Cl, ↓K)
- Atypical organisms from sputum
- Sludge (cholelithiasis/cystitis, pancreatitis, sinusitis)
Respiratory: bronchiectasis, pneumothorax, respiratory failure
Gastrointestional: DIOS, intussusception, biliary cirrhosis, hepatic steatosis, GERD, inguinal hernia, steatorrhea, fat-soluble vitamin deficiency (A, D, E, K)
Delayed puberty, hypertrophic osteoarthropathy/arthritis, amyloidosis, aquagenic palmoplantar keratoderma (skin wrinkling), hypoproteinemia
Diagnosis:
Requires clinical features OR sibling with CF OR positive NBS
AND
Elevated sweat chloride OR abnormal nasal potential difference OR identification of 2 disease-causing CF mutations
Management:
- Suppressive antibiotic therapy
- Mucociliary clearance (chest PT)
- inhaled mucolytics (DNase if >6yo)
- Bronchodilators
- Inhaled 3%NaCl
- Antiinflammatory: NSAIDs and macrolides (3x/wk)
- Nutrition: enzyme replacement, vitamin supplements, high-fat, high protein diet, MCTs added
- Insulin PRN
- Ursodiol to prevent/treat liver disease
- CFTR modulators
- Lung transplant
Characterized by proteinuria, edema, ambiguous genitalia. What to screen for?
DENYS-DRASH SYNDROME
Genetics: WT1 gene mutation
Clinical Features:
- Nephropathy
- Ambiguous genitalia
- Bilateral Wilms tumours (<2yo)
- Proteinuria in infancy → nephrotic syndrome (edema) → ESRD
DiGEORGE SYNDROME
Genetics: 22q11.2 microdeletion
Clinical Features:
- Cardiac abnormalities (TOF most commonly)
- Abnormal facies (malar hypoplasia, square face, mild hypertelorism, prominent ears)
- Thymic hypoplasia + immunodeficiency
- Cleft palate + velopharyngeal insufficiency
- Hypocalcemia, hypoPTH
- 22 chromosome
Learning difficulties/ID, psychiatric issues (schizophrenia), hearing loss
Investigations: serum calcium, echocardiogram, chromosomal microarray
Management:
- Referral to Audiology, Cardiology, Ophthalmology, Immunology
- Repeat calcium levels q3-6mo, TSH, PTH
- Immune function testing
DUCHENNE MUSCULAR DYSTROPHY
Genetics: Dystrophin gene mutation
Inheritance: X-linked recessive
Clinical Features: Presents at 2-3yo; proximal > distal muscle weakness, lower extremities > upper extremities, Gowers sign, Calf pseudohypertrophy, Cardiomyopathy (~15yo), Fractures, Scoliosis, Impaired pulmonary function, Obstructive sleep apnea, decreased gastric motility
Investigations: ↑CK, EMG abnormal, muscle biopsy, genetic testing for dystrophin gene (molecular)
Confined to wheelchair by age 12, death in 20s
Management:
- Multidisciplinary Neuromuscular clinic: Neurology, Rehab, Cardiology, Orthopedics, Respirology, Physiotherapy, Bone health
- Steroids to try and prolong course (↑motor function, ↑pulmonary function, ↓development of cardiomyopathy, ↓scoliosis)
DYSKERATOSIS CONGENITA
Inherited multisystem telomere disorder. (AD and AR)
MAJOR Features:
- Abnormal skin pigmentation
- Nail dystrophy
- Leukoplakia (usually tongue, can involve conjunctiva, anal, urethral or genital mucosa)
- Bone marrow failure
Clinical features: Some genetic types are at risk of pulmonary/hepatic fibrosis. Can have excessive tearing. 25% have LD/ID. Short stature in 15-20%
Investigations: Telomere length study. CBC to evaluate for bone marrow failure.
Management:
- Cancer predisposition (possible): solid tumours, MDS, AML
- Androgen therapy
- Bone marrow transplant
FANCONI ANEMIA
Genetic: FANC genes
Inheritance: X-linked recessive (most common)
Consider on differential for any unexplained cytopenia.
MINIMIZE RADIATION EXPOSURE because of carcinogenic risk
Bone marrow failure appears within 1st decade of life.
(↓platelets, ↑MCV, ↑HgbF appear first → neutropenia → anemia)
Clinical Features:
- Skeletal (absence of radii and/or thumb abnormalities [hypoplastic, supernumerary, bifid or absent], feet or leg anomalies, congenital hip dislocation)
- Skin hyperpigmentation of trunk, neck and skin folds, CALMs, vitiligo (alone or in combo)
- Short stature +/- GH deficiency or hypothyroidism
- Dysmorphic features: microcephaly, epicanthal folds, small eyes, abnormal shzpe, size or positioning
- Males (all infertile): underdeveloped penis, undescended, atrophic or absent testes, hypospadias or phimosis
- Females: reduced fertility, malformations of ovary, uterus and ovary
- 10% ID
- IUGR/LBW
Predisposition to MDS (myelodysplasia), AML and SCC.
Investigations:
- Lymphocyte chromosomal breakage study
- Imaging: U/S abdomen, echocardiogram
- If short stature - work-up for GH deficiency
- Blood work should include: liver, thyroid, metabolic and immune system
Management:
- HSCT - only curative therapy
- Androgen therapy
- Referrals if abnormalities identified
- Multidisciplinary team including a Hematologist
- Mild-moderate CBC AbN + no transfusion = CBC q3mo + annual BMA + BMBx PRN
- Glucose levels q6mo for hyperglycemia
- TSH annually
- Solid tumour screen with physical exam annually
FETAL ALCOHOL SPECTRUM DISORDER
Clinical Features:
- Microcephaly
- Epicanthal folds
- Short palpebral fissures
- Flat midface
- Short nose
- Smooth philtrum
- Thin upper lip
- Underdeveloped jaw
- ADHD
- Behavioural issues
FRAGILE X
Genetics: FMR1 gene (↑CGG repeats)
Inheritance: X-linked dominant
Clinical features
- Facial features: Elongated face, protruding ears, high arched palate
- HEENT: Recurrent otitis media/sinusitis
- Flat feet, hyperextensible finger joints
- Macroorchidism (post-pubertal)
- Hypotonia, stereotypic movements (hand flapping)
- ID, ADHD
- Shy, poor eye contact, social anxiety
- ASD spectrum
Investigations: Cytogenetic analysis, sequencing of FMR1 gene
Management:
- Monitor for seizures or strabismus
- Support for learning: SLP, behavioural therapy, sensory interaction, OT, special education
- Self-injurious behaviour - Risperidone/Quetiapine
- ADHD behaviour - stimulants
- Anxiety - SSRI
FRIEDREICH ATAXIA
Genetics: Chromosome 9q13, X25 gene - codes for Frataxin (GAA repeat)
Inheritance: Autosomal recessive
Clinical Features:
- Foot deformity/Frequent falls
- Recessive/Repeats (GAA)
- Iron accumulation in mitochondria
- Eyes move (nystagmus)/Extensor plantar response
- Diabetes mellitus/Dysarthria
- Scoliosis/Staggering gait/Sensory loss (vibration/proprioception)
Associated Diagnoses:
- Cardiomyopathy
- Diabetes mellitus
- Kyphoscoliosis
Investigations: Genetic testing, Neuroimaging of brain/spinal cord
Management:
- Supportive
- Death ~mid-30s due to cardiac complications
- Usually wheelchair bound by late teens
HEMOPHILIA A/B
Genetic:
Inheritance: X-linked recessive
Clinical features: bleeding, hemarthroses, muscle hematoma, ICH
Investigations:
- Prolonged PTT, Low Factor (VIII or IX), normal INR (usually)
- Gene testing for confirmation
Management
- Mild (>5 to ≤30%): DDAVP (VIII) - if effective
- Moderate (1-5%)
- Severe (<1%): Prophylactic factor replacement (3X/wk for VIII and 2X/wk for IX)
HEREDITARY SPHEROCYTOSIS
Genetics: abnormalities in ankyrin (ANK1) or spectrin (SPTB)
Inheritance: Autosomal dominant (primarily)
Clinical features: splenomegaly, hemolytic anemia, pallor, jaundice, fatigue, exercise intolerance, hypoplastic/aplastic crises from infection
Investigations: peripheral blood smear for spherocytes, osmotic fragility
Management:
- Folic acid to prevent deficiency and subsequent decrease in hematopoiesis
- Splenectomy (ideally ≥5yo)
- Vaccinate against encapsulated organisms
- Penicillin prophylaxis
HYPOHIDROITIC ECTODERMAL DYSPLASIA
Genetics: EDA gene
Inheritance: X-linked recessive
Clinical features:
- Partial/complete absence of sweat glands
- Anamalous dentition
- Hypotrichosis
- Facial: frontal bossing, square forehead, everted lips, prominent chin, pointed ears, conical incisors
Cannot regulate temperatures - develop fevers
Can have immunodeficiency
Investigations: molecular genetic testing
Management:
- Prevent overheating with cool baths and water soaks in hot environments
- Dental evaluation by 2yo (for dental prostheses and implants)
- Lubricating eye drops
INCONTINENTIA PIGMENTI
Genetics: IKBKG gene
Inheritance: X-linked dominant
Clinical features: Alopecia, Dental anomalies (conical, late dentition), Seizures, ID, Retinal neovascularization, strabismus, optic nerve atrophy, cataracts
4 stages: bullous, verrucal, pigmentary, atretic
Investigations: molecular sequencing of IKBKG
Management:
- Surveillance for seizures and retinal detachment
- Referral to Ophtho, Genetics, Dermatology (if unsure of diagnosis), Neurology
- MRI Brain (if neovascularization or ataxia)
KLINEFELTER SYNDROME
Genetics: XXY
Inheritance: de novo
Clinical features:
- Neurologic
- Developmental delay
- GU: microorchidism, micropenis, hypospadias
- Tall stature
- Gynecomastia
Associated with: metabolic syndrome, insulin resistance
Investigations: Karyotype
Management:
- Testosterone replacement therapy in adolescents (if no spontaneous puberty)
- Increased risk for testicular and breast cancer
LOEYS-DIETZ SYNDROME
Genetics: TGFBR1/TGFBR2
Inheritance: Autosomal Dominant
Strong predisposition for allergic triad, aggressive arterial aneurysms and pregnancy-related complications (uterine rupture)
Clinical Features:
- Vascular: arterial aneurysms +/- dissections (cerebral, thoracic, abdominal)
- Skeletal: pectus excavatium/carinatum, scoliosis, joint laxity, arachnodactyly, instability, C-spine maformation, club feet
- Facial: widely spaced eyes, strabismus, bifid uvula, craniosynostosis
- Skin: velvety and translucent skin, easy bruising, dystrophic scars
Investigations: Molecular genetic testing
Management:
- Aortic dissection at younger ages and smaller aortic diameters than Marfan
- Surgical fixation of cervical spine instability to prevent spinal cord damage
- Frequent monitoring with echocardiograms +/- MRA/CTA
- Counsel to avoid sports, competitive and isometric exercise
MARFAN SYNDROME
Genetics: FBN1 gene (encodes fibrillin-1)
Inheritance: Autosomal Dominant
Clinical features:
- Face: long, narrow, enophthalmos, down-slanting palpebral fissures, malar hypoplasia, micro/retrognathia, high-arched palate with dental crowding
- CNS: Normal intelligence, ectopia lentis, myopia
- CVS: Pectus excavatum/carinatum, aortic dilation/dissection, mitral valve prolapse
- Derm: Straie
- Extremities: Arachnodactyly, reduced elbow extension, positive wrist/thumb sign
- Tall stature
- Scoliosis
- Pneumothoraxs
Investigations: Molecular genetic testing, annual echo +/- CTA or MRA
Management:
- Beta-blockers or ARB to reduce hemodynamic stress
- Avoid contact sports due to risk of aortic dilation/dissection
- Avoid contact sports due to risk of aortic dilation/dissection
- Multidisciplinary team: ophtho, cardio, ortho, cardiothoracic surgery
McCUNE ALBRIGHT SYNDROME
Genetics: missense mutation in GNAS1 gene
Inheritance: NOT INHERITED - mutation → mosaicism
Cutaneous pigmentation is usually most extensive on the side with more severe bony involvement.
Clinical Features:
- Fibrous dysplasia of the bone - can present with limp, pain, or fracture (base of skull and proximal femurs most common)
- Café-au-lait macles
- Hyperfunctional Endocrinopathies: Precocious puberty (menarche by 2-3yo, mild or subclinical hyperthyroidism, increased GH
- Oversecretion of FGF23 → phosphaturia →rickets or osteomalacia
Investigations: XR/CT skull for craniofacial fibrous dysplasia, labs (endo), genetic testing
Management:
- Bone pain - IV pamidronate or bisphosphonates
- Regular vision screening
- Screen for scoliosis
- Calcium and PTH assessed periodically
MILLER-DIEKER PHENOTYPE LISSENCEPHALY
Genetics: Chromosome 17 (de novo deletion most common)
Inheritance: Autosomal Dominant
Clinical Features: Prominent forehead, midface hypoplasia, small upturned nose, low set, abnormally shaped ears, small jaw, thick upper lip
Associated conditions: Seizures (<6mo), ID/GDD, Spasticity and hypotonia, feeding difficulties, abnormal muscle stiffness
Investigations: Symptomatic and chromosomal microarray
MYOTONIC DYSTROPHY
Genetics: 19q13.3 of DMPK (CTG repeat) in DM1
Inheritance: Autosomal dominant
Typical pattern of weakness: facial muscles, hand intrinsic muscles, ankle dorsiflexors
Clinical Features:
- Congenital: hypotonia, arthrogryposis, poor feeding, respiratory failure
- Childhood: cognitive/behavioural problems before 10yo, skeletal and respiratory muscle weakness, myotonia, cataracts, cardiac arrhythmias
Investigations: Genetic testing, EMG/NCS if diagnostic uncertainty, CK usually only mildly elevated
Management: Supportive (neuromuscular clinic, neurology, cardiology, respirology)
NEUROFIBROMATOSIS TYPE 1
Genetics: NF1 (tumour suppressor)
Inheritance: Autosomal Dominant
Diagnostic Criteria (≥2 of):
- ≥6 CALM (≥5mm if child; ≥15mm if postpubertal)
- ≥2 neurofibromas or ≥1 plexiform neurofibroma
- Axillary or inguinal freckling
- Optic glioma (<10yo)
- ≥2 Lisch nodules (<20 years of age)
- Tibial pseudoarthrosis or sphenoid dysplasia
- 1st degree relative with NF1
Associated Conditions: Seizures, Scoliosis, Tumours (pheochromocytomas, gliomas, juvenile myelomonocytic leukemia, breast cancer)
Investigations: NF1 molecular genetic testing; Imaging - MRI
Management:
- Annual physical examination with routine BP and scoliosis monitoring
- Annual ophtho assessment
- Monitoring if approaching criteria (most meet it by 8yo)
- Normal intelligence (may have LD)
- MRI if clinically suspecting internal tumours
- Routine tumour surveillance and management
- Prenatal preimplantation genetic diagnosis can be considered
NEUROFIBROMATOSIS TYPE 2
Genetics: NF2 gene (tumour suppressor)
Inheritance: Autosomal Dominant (2 hit phenomenon)
Clinical features: bilateral vestibular schwannomas, meningioma, subscapular cataracts, plexiform schwannomas, neurofibromas
Investigations: Molecular genetic diagnosis
Management: Ophthalmology, MRI of brain (annually after 10yo), audiology, brainstem-evoked potentials
NOONAN SYNDROME
Genetics: multiple genes involved (50% PTPN11)
Inheritance: Autosomal Dominant
Clinical Features: hypertelorism, ptosis, short/webbed neck, low-set, posteriorly rotated ears, short stature coarse facial features, curly/wooly hair, low posterior hairline, wide forehead, neck skin webbing, micrognathia, widely spaced nipples, pectus carinatum, lymphedema, chylothorax, cryptorchidism
Associated syndromes: Pulmonary Valve Stenosis, Hypertrophic Cardiomyopathy, Scoliosis, JMML, ALL, neuroblastoma, brain tumours, amegakaryocytic thrombocytopenia, hypocellular marrow causing pancytopenia
Investigations: genetic testing, echocardiogram, renal U/S, audiology, vision assessment, coag screen during childhood
Management:
- Feeding assessment
- Growth and neurodevelopmental monitoring
- Monitor for seizures, craniosynostosis, hydrocephalus and Chiari malformation
- Scoliosis monitoring
PRADER-WILLI SYNDROME
Genetics: paternal chromsome 15
Inheritance: imprinting/maternal UPD
Clinical Features: severe hypotonia, feeding difficulties, excessive eating/morbid obesity, delayed motor/speech, cognitive impairment, temper tantrums/stubborn/manipulative, OCD, hypogonadism (male/female): incomplete pubert/infertility, strabismus, scoliosis
Investigations: DNA methylation studies on chromosome 15
Management:
- Infancy: feeding support, physiotherapy, possible surgery for cryptorchidism, screen for strabismus
- Childhood: strict monitoring of food intake/BMI to prevent T2DM, GH therapy, sleep disturbances, educational/behavioural plans; Topiramate may help skin picking, screen for strabismus, Ca/Vit D to prevent osteoporosis
- Adolescence: preplacement of sex hormones at puberty, SSRIs
RETT SYNDROME
Genetics: MECP2
Inheritance: typically de novo; can be X-linked Dominant
Clinical Features: microcephaly, seizures (by 3yo), usually meet developmental milestones for first 6-9 months before rapidly losing milestones (coordination, speech and use of hands) - never regain the skills they’ve lost, autonomic difficulties - cold hands and feet
Diagnostic criteria (need all for clinical diagnosis)
- Pattern of development, regression then recovery or stabilization
- Partial or complete loss of purposeful hand skills such as grasping with fingers, reaching for things or touching things on purpose (between 2-3yo)
- Partial or complete loss of spoken language
- Repetitive hand movements, such as hand-wringing, washing, squeezing, clapping or rubbing
- Gait abnormalities, including walking on toes or with an unsteady, wide-based, stiff-legged gait
Investigations:
Management: Symptomatic
- Multidisciplinary team: PT/OT/SLP
- Nutrition therapy
- Splints/braces for scoliosis and hand movements
- Medications for respiratory difficulties, seizures and/or long QT syndrome
RUSSELL SILVER SYNDROME
Genetics: abnormal methylation of 11p15.5 and maternal UPD on chromsome 7
Inheritance: mostly de novo, AD/AR (depending on familial type)
Clinical Features: postnatal growth restriction (normal HC), failure to thrive (but maintenance of normal head growth), feeding difficulties, triangular facies with prominent forehead and small, pointed chin and clinodactyly. Downturned corners of mouth. Males can have cryptorchidism and micropenis. Recurrent hypoglycemia can occur. speech delay, GDD/ID, LD. CALMs.
Investigations: methylation analysis, array for UPD 7, deletion/duplication studies
Management:
- surveillance of growth, hypoglycemia and speech
- Multidisciplinary team (including urology, endocrinology and GI when appropriate)
4-month-old female infant with FTT, history of loose, greasy stools and pallor on physical examination. Laboratory investigations reveal anemia, neutropenia and thrombocytopenia. What is the most likely diagnosis?
SHWACHMAN DIAMOND SYNDROME
Genetics: SBDS gene
Inheritance: Autosomal Recessive
Clinical Features: Pancreatic insufficiency (FTT, steatorrhea), Cytopenias (primarily neutropenia), Skeletal Abnormalities (due to metaphyseal dysostosis), recurrrent pyogenic infections
Associated conditions: Myelodysplastic syndrome, AML
Investigations: neutropenia>anemia>thrombocytopenia, abnormal fecal fat and elastase, low serum trypsinogen, normal sweat test (differentiates from CF), mutations in SBDS gene on chromosome 7
XR - widened, irregular metaphyses, thickened and irregular growth plates
AXR - hypodense appearance of pancreas due to fatty replacement
Management
- exocrine pancreatic insufficiency - treated with pancreatic enzyme replacement therapy
- fat-soluble vitamin replacement
- Monitor cytopenias and for leukemic transformation
- early dental evaluation and follow-up for enamel defects
SMITH-LEMLI-OPTIZ SYNDROME
Genetics: DHCR7 gene
Inheritance: Autosomal Recessive
Clinical Features: microcephaly, ID/LD, autism features, syndactyly or polydactyly. Cardiac, pulmonary, renal and GI/GU malformations are common. Hypotonic infants with feeding difficulties.
Investigations: serum cholesterol and precursors (adrenal insufficiency screen), sequence analysis of DHCR7 gene
Management:
- Cholesterol supplementation (egg yolk)
- HMG-CoA reductase inhibition to prevent toxic precursors proximal to enzymatic block
- often need G-tubes/dietitian
- Avoid sun and antipsychotics
- screen for cholestatic and noncholestatic liver disease
SOTOS SYNDROME (Cerebral gigantism)
Genetics: NSD1
Inheritance: typically de novo; Autosomal Dominant
**not due to endoc
Clinical Features: distinct facial features (sparse frontotemporal hair, downslanting palpebral fissures, malar flushing, long thin face), LD, overgrowth (height and HC), autism features, advanced bone age, cardiac anomalies, joint hyperlaxity, scoliosis, seizures
Investigations: molecular genetic testing
Management: referrals based on symptoms
TREACHER COLLINS SYNDROME
Genetics: TCOF1, POLR1C
Inheritance: Autosomal Dominant, Autosomal Recessive
Clinical features: Bilateral downslating palpebral fissures, underdeveloped lower jaw/zygomatic bone, retracted tongue, micrognathia, dental issues, external ear malformation (absent, small, malformed, canals atretic/stenotic/rotated), significant feeding/breathing issues, conductive hearing loss, bilateral choanal atresia, normal intellect
Investigations: Molecular genetic testing
Management: Multidisciplinary; craniofacial reconstruction required, audiology, SLP, may require tracheostomy
TRISOMY 13 - PATAU SYNDROME
Genetics: Trisomy 13
Inheritance: de novo
50% die within 1st month; 70% by 1st year
Clinical features: midline defects, holoprosencephaly, seizures, cutis aplasia, omphalocele, cleft lip/palate, clenched fists, polydactyly, failure to thrive, CHD, renal anomalies
Investigations: Karyotype, Imaging (EEG, Brain MRI, Echocardiogram, RBUS), Audiology
Management: Supportive
TRISOMY 18 - EDWARD’S SYNDROME
Genetics: Trisomy 18
Inheritance: usually de novo
50% die within 1st week; 90% die within 1st year
Clinical Features: microcephaly, hypertonia, CHD (VSD/ASD, PDA), cryptorchidism, clenched fists (overlapping digits 2/3 and 5/4), rocker-bottom feet, IUGR, renal anomalies (horseshoe, polycystic, hydronephrosis)
Investigations: Karyotype, Imaging (echocardiogram, abdo U/S)
Management: Supportive
TRISOMY 21 - DOWN SYNDROME
Genetics: Trisomy 21
Inheritance: de novo; balanced translocation
Clinical Features: facial features (epicanthal folds, upslanting palpebral fissures, flat nasal bridge), Brushfield spots in iris, hypotonia, conotruncal defects CHD (AVSD), GI malformations (duodenal atresia, TEF, Hirschsprung, imperforage anus), celiac disease, 5th finger clinodactyly, single palmar crease, sandal gap toes
Associated Conditions: 10% develop transient myeloproliferative disorder; 1% lifetime risk of leukemia, OSA (>50%), obesity, hearing loss
Investigations: karyotype, CBC, TSH, Echocardiogram, XR of C-spine if symptomatic (neck pain, head tilt, gait instability), Abdo U/S, UGI/small bowel follow-through if concerned about duodenal atresia, Polysomnography by 4yo
Management:
- 1mo-1y: TSH at 6+12mo,
-
1-5y: Growth, Development, examine TMs, audiogram q6mo until 3y or until pure tone audiogram obtained. Sleep study by 4yo. Annual ophtho, Cspine XR btwn 3-5y, PT/OT/SLP PRN
- Trampoline/contact sport safety, if cardiac/pulmonary disease, 23-valent pneumococcal vaccine >2yo
- 5-13y: Growth, Development, annual audiology, q2y ophtho, screen dry skin, gyne
- 13-21y: annual audiology, q3y ophtho, screen dry skin, sexuality
- All years: screen myopathy, OSA & sx of celiac disease, annual CBC/TSH (6+12mo in 1st year of life), discuss complementary/alternative tx, C-spine positioning,
TUBEROUS SCLEROSIS COMPLEX (TSC)
Genetics: TSC1 / TSC2
Inheritance: Autosomal Dominant
Clinical Features (ASHLEAF): confetti skin lesions, ungual fibromas, dental pits, subependymal giant cell astrocytomas (SEGAs), lymphangioleiomyomatosis (LAM - in females), retinal hamartomas;
- Ashleaf spots (>3)
- Shagreen patches
- Heart rhabdomyosarcoma
- Lung hamartomas
- Epilepsy from cortical tubers
- Angiomyolipoma in kidney
- Facial angiofibroma
Associated Conditions: Autism, ADHD, ID, disruptive behaviours, anxiety, depression; Infantile Spasms
Investigations: TSC1/TSC2 molecular genetic testing, Brain MRI, EEG, Echocardiogram, RBUS, Ophthalmologic assessment
Management:
- mTOR inhibitors help;
- Vigabatrin works for seizures
- Surgery as needed (neurosx, cardiac, renal)
- Brain MRI + Echo Q1-3yo
- EEG if Sz
- Abdo MRI is abdo findings
- Sx screen for LAM every visit ( CT if suspected → PFTs if positive)
- Annual skin exam
- Annual ophtho exam if findings
- Avoid smoking, estrogen use
TURNER SYNDROME
Genetics: XO
Inheritance: de novo
Clinical Features: Webbed neck, redundant nuchal skin, low posterior hairline, shield chest with wide-spaced nipples, left-sided CHD (bicuspid aortic valve, coarctation), congenital lymphedema (hands and feet), dysplastic nails, skeletal abnormalities (short 4th and 5th metacarpals, cubitus valgus, scoliosis, congenital hip dislocation), short stature, renal abnormalities (horseshoe kidney, duplex collecting system), streaked ovaries
Associated Conditions: Delayed puberty, Infertility, Autoimmune disorders (Diabetes, hypothyroidism, celiac disease, IBD)
Investigations: Karyotype, TSH, FSH/LH, RBUS, Echocardiogram, Audiology for nonsyndromic hearing loss
Management: Referral to Ophthalmology (strabismus, hyperopia), growth hormone for short stature, estrogen therapy if no spontaneous puberty by 13yo, screening for autoimmune disorders
What are the conditions associated with VACTERL association?
Vertebral defects
Anal atresia
Cardiac defects
Tracheoesophageal fistula
Esophageal atresia
Renal anomalies
Limb abnormalities
WAARDENBURG SYNDROME
Genetics: PAX3 (1+3), 2: MITF, SNAI2, 4: EDN3, EDNRB, SOX10
Inheritance: Autosomal Dominant (usually)
Clinical Features:
- Type 1: median white forelock, depigmented patches (vitiligo), SNHL, heterochromia, unibrow (synophrys), premature graying, hypertelorism
- Type 2: Similar to type 1 with no hypertelorism and more SNHL
- Type 3: Similar to type 1 with limb abnormalities
- Type 4: ALWAYS have Hirschsprung disease
Investigations: Molecular studies
Management: Audiology
WAGR SYNDROME
Genetics: chromosomal 11 deletion
Inheritance: typically de novo
Clinical Features:
- Wilms tumour
- Aniridia (or cataracts, glaucoma, nystagmus)
- Genitourinary anomalies (hypospadias, cryptorchidism, streak ovaries, bicornuate uterus)
- Retardation - Intellectual disability
Associated Conditions: Obesity, ADHD, OCD, autism
Investigations: Chromosomal microarray, AFP
Management: Supportive care, routine US surveillance for Wilms tumour until 9yo; Ophthalmologic evaluation q6m when <8yo
WILLIAMS SYNDROME
Genetics: Deletion of Chromsome 7
Inheritance: typically de novo (transmission Autosomal Dominant)
Clinical Features: “elfin facies” (broad forehead with bitemporal narrowing, periorbital fullness, malar hypoplasia, long philtrum, full lips with side mouth), prominent earlobes, stellate iris, friendly “cocktail party personality”, ID, supravalvular aortic stenosis +/- coarctation, pulmonary artery stenosis, renal artery stenosis, hernias (umbilical, inguinal), rectal prolapse, hypothyroidism, hypercalcemia, FTT
Investigations: chromosomal microarray, ELN molecular genetic testing, serum/urine calcium, thyroid function testing, RBUS, Echocardiogram, Audiology
Management: Ophthomology referral, monitor for hypercalciuria, aggressive constipation management to minimize rectal prolapse, supportive care
WILSON DISEASE
Genetics: AT7B gene
Inheritance: Autosomal recessive
Copper accumulates in liver first, then other tissues (basal ganglia, cornea, kidney)
Clinical Features: acute hepatitis then in 2nd/3rd decades of life → basal ganglia involvement (dystonia, fine motor problems, gait disturbances), psychiatric symptoms (depressive, impulsive or psychotic features), Kayser-Fleischer ring
Associated Conditions: Coombs negative hemolytic anemia, proximal tubular deficit, cardiac problems, osteopenia
Investigations: Elevated liver enzymes (classically AST>ALT and bilirubin > ALK), ↓ceruloplasmin, ↑urine copper, liver biopsy, genetic testing if diagnosis is questionable and to screen siblings
Management:
- Copper chelating agents: penicillamine or trientine dihydrochloride
- Zinc supplementation interferes with copper absorption (can be monotherapy after chelation or in asymptomatic individuals)
- Avoid foods with high copper content
- Transplant for those with fulminant liver failure or severe liver disease failing medical therapy
Eczema, thrombocytopenia, immunodeficiency?
WISKOTT-ALDRICH SYNDROME
Genetics: mutation in WASP gene
Inheritance: X-linked recessive
Clinical Features: eczema, thrombocytopenia, immunodeficiency, Recurrent infections (sinopulmonary)
- Mnemonic = WATER (Wiskott, Aldrich, Thrombocytopenia, Eczema, Recurrent sinopulmonary infections)
Associated Conditions: lymphoreticular malignancies
Investigations: CBC (eosinophilia, microthrombocytopenia), elevated IgE, poor vaccine responses
Management: Immunoglobulin replacement, HSCT or gene therapy, splenectomy for thrombocytopenia (but increases infection risk)
HYPER IgE SYNDROME - JOB SYNDROME
Genetics: STAT3 gene
Inheritance: Autosomal Dominant
Clinical Features: Eczema, cold abscesses (usually S aureus), recurrent pneumonias with pneumatoceles (usually S aureus), mucocutaneous candidiasis, cardiofacial dysmorphisms (coarse facies, wide nose, deep-set eyes), skeletal abnormalities (short stature, retained teeth, frequent bone fractures)
Investigations: CBC/diff, lymphocyte subsets for evaluation of T cells, Immunoglobulin levels, lymphocyte proliferation, vaccine titers, R/O ataxia telangiectasia and 22q11.2 deletion; ↑IgE, eosinophilia, STAT3 sequencing
Management: immune therapies (depending on degree of immunodeficiency) - prophylactic antibiotics, immunoglobulin replacement therapy, skin emollients, surgical intervention for drainage of abscesses
ALPORT SYNDROME
Genetics: COL4A5 gene (80%)
Inheritance: X-linked recessive (80%)
Clinical Features: progressive SNHL by early adulthood, lens and retina anomalies (anterior lenticonus), esophageal/tracheobronchial leimyomas; presents with episodic gross hematuria concurrent with an illness, progressive kidney disease (more common in males)
Investigations: UA for hematuria/proteinuria, renal biopsy (focal glomerulosclerosis, tubular atrophy, interstitial fibrosis, interstitial foal cells), Audiology
Management: proteinuric control with ACEi/ARBs, supportive for ESRD (late adolescence for males, later for females), renal transplant
STURGE-WEBER SYNDROME
Genetics: GNAQ gene
Inheritance: de novo (mosaicism)
Clinical Features: unilateral capillary malformation of the face (port-wine birthmark) with ipsilateral brain involvement (leptomeninges), as well as abnormal blood vessels of eyes, ID/GDD, seizures (contralateral side) with prolonged postictal deficits, hemiparesis
STURGE = Stain, Tram track calcifications, Unilateral, Retardation, Glaucoma, Epilepsy
Associated conditions: Glaucoma (ipsilateral)
Investigations: Brain MRI, ophthalmologic evaluation
Management: seizure control, relief of headaches, prevention of stroke-like episodes, monitoring for glaucoma and laser therapy for cutanaeous capillary malformations, monitor for psychological trauma (bullying)
MUSCULAR DYSGENESIS - PROTEUS SYNDROME
Genetics: AKT1 gene
Inheritance: de novo (mosaicism)
Clinical Features: overgrowth of ectodermal/mesodermal tissues, asymmetric overgrowth of extremities, verrucous cutaneous lesions (usually on soles of feet), angiomas of various types, thickening of bones, excessive growth of muscles without weakness, facies (long, narrow head, downslanting palpebral fissures, ptosis, depressed nasal bridge, wide nares)
Associated Conditions: Seizures, ID, visual loss, VTEs (DVT/PE)
Management: Symptomatic
CONGENITAL CONTRACTURAL ARACHNODACTYLY - BEALS SYNDROME
Genetics: FBN2 gene
Inheritance: Autosomal Dominant
Clinical Features: tall and slender, phenotypically resembling Marfan syndrome with congenital contractures (usually elbows, knees, hips, fingers and ankles), crumpled looking ears, kyphoscoliosis
Investigations: molecular genetic testing, echocardiogram
Management: symptomatic
CROUZON SYNDROME
Genetics: FGFR2 gene mutation
Inheritance: Autosomal Dominant
Clinical Features: craniosynostosis, facial dysmorphism (prominent forehead, hypertelorism, proptosis, midface hypoplasia, cleft lip/palate, beaked nose, prognathism), normal intelligence
Associated Conditions: Dental issues, Hearing loss, Hydrocephalus
Differential Diagnosis: Apert syndrome, Pfeiffer syndrome
Investigations: Molecular genetic testing, XR spine (r/o vertebral anomalies) CT/MRI Head for surgical correction and monitor for hydrocephalus
Management: Craniofacial surgery multidisciplinary team, hydrocephalus surveillance
EHLERS DANLOS SYNDROME
Genetics: multiple types - collagen defect
Inheritance: AD (classic), AR (few other forms)
Clinical Features: Hypermobility, MVP, aortic root dilation, hernias, rectal prolapse, skin hyperextensibility, atrophic scars, smooth skin, molluscoid pseudotumours, subcutaneous spheroids, easy bruising, easy dislocations/subluxations, cramping, fatigue, chronic pain
Investigations: molecular genetic testing, echocardiogram (aortic dilation, MVP)
Management: physiotherapy, non-weight bearing exercises promote strength (avoid those that strain joints), pregnancy shoudl be monitored closely, vascular type - monitoring for life-threatening complications
OSTEOGENESIS IMPERFECTA
Genetics: COL1A1/COL1A2
Inheritance: Autosomal Dominant
Clinical Features: Triangular-shaped face, large skull, normal intelligence, hearing loss, easy bruising, Radiographic findings (wormian bones, ‘codfish’ vertebrae, osteopenia, fractures)
Types
- I: nondeforming OI with blue sclerae
- II: perinatally lethal OI
- III: progressively deforming OI
- IV: common variable OI with normal sclerae
Investigations: Molecular genetic testing, radiographs
Management: Bisphosphonate infusions to decrease bone resorption, Growth hormone to increase linear growth, multidisciplinary care including involvement from ortho, rehab, dentistry, ENT
PIERRE ROBIN SEQUENCE (isolated)
Genetics: SOX9
Inheritance: de novo
Clinical Features: micrognathia, glossoptosis, airway obstruction, cleft palate or high arched palate
Associated conditions: If myopia+skeletal abnormalities - consider Stickler syndrome (and also check for DiGeorge)
Management: Prone positioning so tongue falls forward to relieve respiratory obstruction. Surgical procedures (tracheostomy, mandibular distraction) to facilitate oral feedings, enhance respiration
CRANIOFACIAL MICROSOMIA - GOLDENHAR SYNDROME
Genetics: unknown
Inheritance: de novo
Clinical Features: Facial asymmetry, microtia, preauricular tags, microphthalmia, cleft lip/palate, epibulbar dermoid, vertebral anomalies, CHD
Investigations: Clinical diagnosis
Management: Craniofacial multidisiplinary team, ophthalmology
What genetic disorder is associated with an increased risk of sarcoma, breast cancer, leukemias and adrenal tumours?
LI-FRAUMENI SYNDROME
Genetics: CHEK2, TP53
Inheritance: Autosomal Dominant
Associated Conditions: soft-tissue sarcomas, osteosarcoma, premenopausal breast cancer, brain tumors, leukemias, adrenocortical carcinoma
Investigations: molecular genetic testing
Management:
- Breast cancer monitoring with annual MRI and biannual clinical breast examination for patients >20yo
- Annual pelvic examination and mammography >40yo
- Prophylactic mastectomy is offered to those with TP53 mutations
- Routine colonoscopy q2-3y for those >25yo
- Avoid radiation and carcinogen (tobacco, sun, alcohol) exposure
CRI-DU-CHAT SYNDROME
Genetics: Chromosome 5 deletion
Inheritance: de novo
Clinical Features: shrill, high-pitched cry (in first few weeks of life), hypertelorism, low-set ears, wide and flat nasal bridge, epicanthic folds, microcephaly with protruding metopic suture, micrognathia, CHD, cleft palate or high-arched palate, hypotonia, short stature, ID
Investigations: chromosomal microarray, echocardiogram if concern for CHD
Management: Supportive
WOLF-HIRSCHHORN SYNDROME
Genetics: deletion of short arm of chromosome 4
Inheritance: de novo (typically
Clinical Features: “greek warrior helmet” appearance (hypertelorism, high forehead with prominent glabella, broad/flat nasal bridge), microcephaly, cleft lip/palate, CHD, GU malformations, hypotonia, structural brain anomalies
Associated Conditions: Hepatic adenomas, Intellectual Disability, Seizures, CVID, IgA deficiency
Investigations: chromosomal microarray, IgA levels, CBC, renal function testing, echocardiogram, MRI, EEG as needed
Management: Supportive with multidisciplinary team
CHARCOT-MARIE TOOTH DISEASE
Genetics: PMP22 gene duplication
Inheritance: Autosomal dominant
Clinical Features: Slowly progressive, symmetric distal weakness (foot drop causing frequent tripping), atrophy of distal muscles, contractures of hands and feet due to weak distal muscles, pes cavus (high-arched feet), hammer toes, gradual loss of distal sensation
Investigations: EMG/NCS, molecular genetic testing
Management: Supportive care (stretching, orthotics), may require orthopedic surgery, no gene therapy available at present time
Motor delays, gout, nephrolithasis, spasticity, dystonia, self-injurious behaviours
Lesch-Nyhan Syndrome
- X-linked recessive
- Gene = HPRT (leads to elevated uric acid)
Presentation:
- gout, nephrolithiasis
- developmental delay (motor then GDD)
- movement (choreoathetosis, spasticity, dystonia)
- self injury (ie. biting fingers and mouth)
- megaloblastic anemia
Triphalangeal Thumbs
Diamond-Blackfan Anemia:
- Autosomal dominant
- Doesn’t present with pancytopenia
- Just profound anemia (macrocytic anemia with no retics)
- Presents in infancy (by age 2-6 months)
- Findings:
- Growth delay
- Craniofacial abnormalities (hypertelorism)
- Thumb abnormalities
- Treatment:
- Steroids (80% respond)
- If refractory then pRBC transfusions every 1-2 months with chelation for iron
- Can do BM transplant only if HLA matched sibling donor (otherwise survival much lower)
Bifid thumbs/ Hypoplastic thumbs
Fanconi anemia (“congenital aplastic anemia”)
- Inherited autosomal recessive inheritance
- Typically have bone marrow failure by age 5-10
- Present usually at school age
- Findings:
- Café au lait spots
- Short stature
- Abnormal thumbs and radii
- Microcephaly
- Renal abnormalities
- Cardiac defects
- Pancytopenia with macrocytic anemia
- Treatment:
- BM transplant
- Androgen therapy
- Higher risk of leukemia, MDS, squamous cell carcinoma, head/neck cancers
What is uniparental disomy? Name a syndrome that it is inherited in this manner?
- when a person gets both chromosomes (or parts of chromosomes) in the pair from the same parents, instead of getting one form each parent 2. Prader Willi and Angelman (chromosome 15q11) PWS: think Trump - small balls, small hands, intellectual disability and obesity from hyperphagia - mom’s part is silenced and the part you’re meant to get from your dad just isn’t there (mom silences (Melania), dad missing (Donald))
You diagnose a child with CF based on an abnormal sweat chloride. The reason for doing DNA testing is: a. confirm diagnosis b. rule out whether the parents are carriers c. to diagnose her cousin who is failing to thrive with CF d. to give the parents some idea about prognosis e. so that antenatal testing can be done on subsequent pregnancies
d. to give the parents some idea about prognosis
The sister of a patient with cystic fibrosis is 6 weeks pregnant and wants to know if her unborn child has cystic fibrosis. What do you suggest: a) wait until 16 weeks gestation and then perform amniocentesis b) perform chorionic villus sampling and genetic testing now c) refer the parents for genetic testing d) perform a sweat test on the mother e) you cannot accurately diagnose cystic fibrosis until after the child is born
c) refer the parents for genetic testing - 50% chance that the sib is a carrier (assuming she would know if she actually had CF, the chance that she’s a carrier is actually 2/3) - amnio or CVS not recommended unless high risk (mutations in both parents)
Parents of a child with unilateral cleft palate come in for advice regarding next pregnancy. You advise that: a. There is no recurrence risk b. 4% recurrence risk c. 25% of offspring will be affected
b. 4% recurrence risk
Obese parents adopt a 3 month child. What is true regarding the child’s risk of obesity: a. if biologic parents are thin then child is unlikely to be obese b. even if biologic parents are thin, the child is likely to be obese c. obesity is more common in upper socioeconomic groups d. if child is obese at 1 year then there is a 90% chance of obesity as an adult
a. if biologic parents are thin then child is unlikely to be obese
A child has multiple ash leaf spots, and seizures. The mother is pregnant and wants to know whether or not her unborn child will have the same problems. What do you tell her about the risks to the fetus? a) 50% if female b) 50% if male c) 50% regardless of gender d) 25% regardless of gender e) the recurrence risk is minimal
e) the recurrence risk is minimal TS: AD inheritance but 2/3 sporadic - if parents are unaffected the risk of another child having TS is low but still higher than the general population because of the chance of germ line mosaicism
Inheritance pattern of ectopic thyroid: a) autosomal recessive b) autosomal dominant c) sporadic d) X-linked recessive e) X-linked dominant
c) sporadic (thyroid agencies including ectopic thyroid is usually sporadic, 2% will have family history)
You are seeing a pregnant woman during her first. Her father has hemophilia. Regarding the risk of her transmitting the disorder to her own children you tell her: A. None will have it b. 50% of her sons will have it and all of her daughters will be carriers c. 50% of her sons will have it and 50% of her daughters will be carriers
c. 50% of her sons will have it and 50% of her daughters will be carriers X-linked disorder
Which of the following has AD inheritance? a. Tuberous Sclerosis b. Fragile X c. CF d. Hereditary Spherocytosis
ANSWER: a. Tuberous Sclerosis, though 2/3 sporadic b. Fragile X - X-linked dominant, FMR1 mutation c. CF - autosomal recessive d. Hereditary Spherocytosis - 75% autosomal dominant, 25% autosomal recessive
Which has autosomal dominant inheritance? a. Congenital adrenal hyperplasia b. PKU c. Beta-thalassemia d. Hereditary spherocytosis
ANSWER: d. Hereditary spherocytosis - 75% autosomal dominant, 25% autosomal recessive a. Congenital adrenal hyperplasia - autosomal recessive b. PKU - autosomal recessive c. Beta-thalassemia - usually autosomal recessive; rarely can be AD
Teenager presents with large armspan, suspect Marfans Syndrome. What is the mode of inheritance? a. Autosomal Dominant b. Autosomal Recessive c. X linked d. Sporadic
a. Autosomal Dominant FBN1 mutation 25% de novo mutations
Newborn presents with the following lab values pH 7.1; HCO3 decreased, normal sodium/potassium, Elevated lactate, ammonia and neutropenia. Diagnosis: a) galactosemia b) MCAD c) methamelonic acidemia d) urea cycle defect
c) methylmalonic acidemia - organic acidemia (metabolic acidosis, high ammonia, neutropenia caused from BM suppression that happens with metabolic acidosis) - dx: urine organic acids -issue: unable to metabolize methylmalonic acid which is made in the breakdown of amino acids and some fatty acids - tx: low protein diet
What broad category of diseases do you think of in an infant with vomiting, lethargy, poor feeding and seizures but who is afebrile and has a normal WBC?
inborn error of metabolism
10 day old baby with failure to thrive, jaundice, hepatomegaly, blood culture positive for E.Coli. a. What underlying disorder may the child have? b. What test can you do to confirm this diagnosis ?
a. What underlying disorder may the child have? Galactosemia (see above). b. What test can you do to confirm this diagnosis ? ● Erythrocyte galactose-1-phosphate uridyltransferase (GALT) activity. ● DNA testing for mutations in GALT gene - presents 4-7 days of life (after lactose has been introduced in diet - i.e. breast or bottle feeding established) - also get ketonuria
Child presents with an ammonium level in the 400-range. What 3 things would you do in your management?
- IV rehydration, including dextrose (stop protein catabolism) 2. remove ammonia (dialysis or meds - sodium phenyacetate and sodium benzoate, arginine) 3. confirm with repeat specimen 4. additional testing: serum amino acids, urine organic acids, liver function and transaminases (can have liver failure, lights)
What are 3 symptoms of hyperammonemia?
lethargy, vomiting, cerebral edema, coma - encephalopathy
You are working in an emergency department, and a 5-month-old baby presents with a history of poor intake and occasional vomiting over the past 24 hours. You find that his glucose is 2.8. The remainder of his bloodwork is unremarkable. He has no ketones present on urinalysis. List 2 diagnoses on your differential.
- hyperinsulinemia 2. fatty acid oxidation defect (fatty acids have a ketone on the end - with FAO defects, you can’t cut that ketone off so you have high fatty acids, but no ketones) Hypoketotic hypoglycemia - if your sugar is low, your body should make ketones as an alternate fuel no ketones = high insulin, fatty acid oxidation defect
3 week old with previous e coli sepsis and persistent jaundice. What is the likely problem? a. Increased osmotic fragility b. RBC galactose phosphate uradyl transferase deficiency c. RBC glu – 1 – phosphate dehydrogenase deficiency
b. RBC galactose phosphate uradyl transferase deficiency Galactosemia
3-day-old infant with lethargy, vomiting, hypotonia and progressively worsening level of consciousness and coma. There is subtle evidence of intracranial hypertension. He has a respiratory alkalosis. Most likely: a. encephalitis b. urea cycle defect c. maple syrup urine disease d. phenylketonuria e. Leigh syndrome
b. urea cycle defect amino acids–> ammonia and organic acids ammonia (BAD)–> urea cycle –> urea (pee it out) MSUD: defect in enzyme that breaks down some amino acids (so you have no ammonia being made) Leigh disease: subacute necrotizing encephalomyelopathy
You are called because an infant’s PKU screen is positive. Your next step is: a. order a quantitative urine Phenylalanine level b. order a quantitative blood Phenylalanine level c. repeat the screen d. order a urinary phenylketone level
b. order a quantitative blood Phenylalanine level
The child of a father with phenylketonuria will have which of the following: a) no problems b) developmental delay c) multiple congenital anomalies d) microcephaly e) IUGR
a) no problems inheritance AR - would expect child to be a carrier, but would only be affected if mother also a carrier signs PKU: MR, growth retardation, fair skin, eczema Maternal PKU not treated in pregnancy causes microcephaly, IUGR, MR, congenital heart defects
6 month old with hx of dev delay is brought in to ER and needs resusc. Is now stable. What would you need to help make diagnosis: a. CT scan b. Lactate, carnitine, ammonia c. Serum organic acids d. Urine amino acids
b. Lactate, carnitine, ammonia Shock - think organic acidemia
Child with poor feeding, vomiting, lethargy, seizures, afebrile. Ammonia and gas normal. What do you suspect?
amino acidopathy or galactosemia
In a patient with MCAD deficiency what would be the most likely laboratory finding: a) respiratory alkalosis b) nonketotic hypoglycemia c) increased urine/plasma ketone level d) increased plasma carnitine level e) normal transaminases
b) nonketotic hypoglycemia - hypoketotic hypoglycemia, no acidosis, low urinary ketones - illness triggered by prolonged fasting (cannot mobilize fat stores)
Abetalipoproteinemia causes all EXCEPT: a) ataxia b) hyperlipidemia c) acanthocytosis d) retinitis pigmentosa e) diarrhea and FTT
b) hyperlipidemia - hereditary inability to synthesize lipoproteins -have very low cholesterol and triglycerides (all the fats get stuck in the gut wall) - lack of fat soluble vitamins (no vit E - spinocerebellar degeneration, no vit A - night blindness)
14 mos male, FTT, vomiting, met acidosis, pH 7.31, bicarb 14, K 3.5, Na140, Cl 118, urine pH 6.3 a distal RTA b Bartter c organic acidopathy d nutrit. Deprivation
a. distal RTA - hyperchloremic non anion gap metabolic acidosis - distal RTA - high urine pH Bartter - alkalosis organic acidopathy - anion gap
6 month old baby with pallor, hepatosplenomegaly, irritable. Xray shown with very white bones. Diagnosis: a. osteopetrosis b. vitamin D deficient rickets c. osteosarcoma
a. osteopetrosis Ca, PO4, ALP all normal
Infant (a few weeks old?) with generalized tonic clonic seizure. He looks well and is well grown. Glucose is 1.7. The most important thing to measure is? a. Urine ketones b. Lactate/Pyruvate ratio c. Serum cortisol
a. Urine ketones
Hypoglycaemia, low ketones, low FFA, high insulin in a macrosomic baby - what is the diagnosis?
hyperinsulinemic hypoglycemia of infancy
Hypoglycaemic baby with reducing substances in urine - what is the diagnosis?
Galactosemia
Hypoglycemia, micropenic, cleft palate, cholestatic jaundice - what is the diagnosis?
Hypopituitarism (midline defects)
Hypoglycemia + hepatomegaly. What group of disorders to consider?
Glycogen storage disorders (like G6P deficiency)
Glucose of 1.2, cardiomegaly on chest x-ray. What is the most likely etiology of this presentation? a. cardiac lesion b. sepsis c. inborn error of metabolism
c. inborn error of metabolism Pompe (type II glycogen storage disease) - cardiomegaly and macroglossia - glycogen accumulates in tissues which makes them large and not work well
3 week baby with lethargy, poor feeding, and hepatomegaly. Has a normal lactate, ammonia, pH, CO2. What is the most likely diagnosis? a. Maple syrup urine disease b. Propionic academia c. Galactosemia d. Urea cycle defect
c. Galactosemia - hyperglycinemia also on the differential of an apparent metabolic disorder with normal ammonia and gas
What is the most likely presentation of an inborn error of metabolism? a. encephalopathy preceding focal neuro deficit b. generalized hyper-reflexia c. abnormal pupillary reaction
a. encephalopathy preceding focal neuro deficit MELAS (mitochrondrial myopathy, encephalopathy, lactic acidosis, stroke-like episode) - mimics stroke with focal neuro defects
A 3 month old is suspected of having an inborn error of metabolism, and has neurological and cardiac involvement. Which of the following can be given before a definitive diagnosis is made to prevent further sequelae: a. Thiamine b. Carnitine
b. Carnitine - good for organic acidemias, FAO defects, carnitine deficiency; lethargy and cardiomyopathy common presenting features of FAO defects B12: oragnic acidemia B6 (pyridoxine): seizures unresponsive to antiepileptics
3 day old with lethargy, decreased level of consciousness and vomiting. On exam he has hyperpnea and respiratory alkalosis. His fontanelle is full and he has signs of mild increase in intracranial pressure. What is his diagnosis? a. Maple Syrup urine disease b. Urea cycle defect c. Encephalitis
b. Urea cycle defect
Liver dysfunction long term complication of: a. MCAD b. OTC c. PKU d. Maple syrup urine disease
ANSWER: a. MCAD - lipid metabolism defect b. OTC - urea cycle defect c. PKU - amino acidemia d. Maple syrup urine disease - organic acidemia
2½-year-old child is referred with language delay and inferior ectopia lentis. You should a) molecular studies for Marfan syndrome b) echocardiogram to rule out aortic root abnormalities c) fibroblasts/skin biopsy for enzyme d) quantitative serum amino acids e) platelet count and coagulation studies for hypercoagulability
d) quantitative serum amino acids Homocystinuria: IQ down, lens dislocated down Dx: elevated methionine or homocystine in blood or urine Tx: high dose vitamin B6
Most likely to be associated with hearing loss: a) prematurity b) congenital CMV c) APGAR of 2 at 1 minute d) sibling with language delay e) furosemide given to mother during pregnancy
b) congenital CMV o TORCH (CMV most common acquired form of congenital hearing loss)
Newborn who has webbed neck, lymphedema at hands and feet, hypertrophic cardiomyopathy (picture given- don’t think they told you if it was a girl or a boy) a) XO b) Noonans c)Williams
b) Noonans Turners is similar but has left sided heart defects (coarctation) - note primary hypogonadism - amenorrhea and infertility - not a feature of Noonan’s
Child with facial nevus in V1 distribution. Came to the hospital with focal seizure. What is the suspected diagnosis? What is the CT head finding expected? Name 2 other complications.
- Sturge-Weber 2. CT head shows calcifications, MRI could show leptomeningeal angioma 3. complications: glaucoma, seizures, hemiparesis, intellectual disability, stroke-like episodes
Picture of rocker bottom feet – what condition do you need to think about? What are 3 other features?
Edward syndrome (trisomy 18) - prominent occiput - clenched hands with overlapping fingers - prominent heels - small mouth and jaw, short neck
Mother brings her son to see you for assessment of behaviour difficulties. He has been in generally good health. He is large (97, 95, 95%iles) and has prominent ears. He has a broad forehead and hyperextensible joints. Which of the following does he have? a) fragile X b) Klinefelters c) Sotos
a) fragile X fragile X : - remember large ears and long narrow face and hyperactivity
5 mo with white forelock, 1 iris blue 1 brown. What next investigation would you do? What condition is this? a. Renal ultrasound b. Hearing test c. Echo cardiac d. Cranial ultrasound
b. Hearing test Waardenburg syndrome - sensorineural hearing loss common, non progressive
An 8 year old otherwise well child has a hemi-vertebrae noted on CXR. What investigation will you do in the course of your work-up: a. MRI of the head b. MRI of the spine c. Abd U/S d. Echo
c. Abd U/S - VACTERL From genetics review - if it was a newborn would do an echo, but given healthy 8 year old, she probably doesn’t have a serious cardiac lesion; don’t know what’s happening with kidneys though
What are the components of VACTERL association?
vertebral defects anal atresia cardiac defects TEF renal anomalies limb anomalies (missing thumbs, underdeveloped forearms)
Hemivertebra girl. What next imaging
AUS and echo
Child has developmental delay. On exam you note that he is microcephalic, he has small palpebral fissures, a thin upper lip and a poorly defined philtrum. What is his diagnosis a. Cornelia De Lange b. Smith Lemli Opitz c. Fetal Alcohol Syndrome
c. Fetal Alcohol Syndrome
A child who is described as having a learning disability, has big ears. Mom has an LD as well. What to tell mom to expect: a. Problems with tics b. Problems with athetosis c. Problems with hyperactivity d. Problems with tremor e. Problems with nystagmus
c. Problems with hyperactivity
3 year old girl was normal developmentally for a while but has shown regression in the past year. Now she has microcephaly, and abnormal hand movements a. Retts b. Fragile X c. Autism d. TORCH infection e. childhood disintegrative disorder
a. Retts
Child with supravalvular aortic stenosis, prominent lips, developmental delay, and hypercalcemia. This is indicative of: a. DiGeorge b. Williams c. Noonans d. Downs e. Fetal alcohol syndrome
b. Williams
What are the components of DiGeorge syndrome?
- cardiac (TOF) - abnormal facies (hypertelorism, down slanting palpebral fissures, short philtrum) - thymic hypoplasia/T cell abnormality - cleft palate - hypocalcemia from hypoparathyroidism - 22q11 deletion
Which feature is typical for achondroplasia? a. proximal limb shortening b. distal limb shortening c. short mid-portion of the bone d. non-specific shortening
a. proximal limb shortening
In a patient with Romano-Ward syndrome, what would suggest the diagnosis: a. presence of cafe-au-lait spots b. congenital defects c. sensorineural hearing loss d. family members have it
d. family members have it - cardiac syndrome, long QT, family history is key - most cases inherited from an affected parents, few cases are de novo mutations; inheritance is AD with incomplete penetrance *Long QT plus congenital deafness (SNHL) = Jervell and Lange-Nielson syndromes (autosomal recessive)
Fetal alcohol syndrome a. 4 facial dysmorphisms b. 2 clinical features of the syndrome
a. smooth philtrum, thin upper lip, short palpebral fissures, micrognathia b. microcephaly, intellectual disability, small stature
Photo shown of infant with short palpebral fissures, smooth philtrum, short nose and thin upper lip. He presents with irritability. This infant’s condition is due to maternal exposure to: a) cocaine b) heroin c) cigarettes d ) alcohol e) Dilantin
d ) alcohol
Which is a common characteristic in fetal hydantoin syndrome: a) microcephaly b) hypoplastic nails c) intrauterine growth restriction d) seizures e) cataracts
b) hypoplastic nails fetal hydantoin - fetus exposed to hydantoin (phenytoin)
List 4 screening tests you would routinely do for a child with Down’s Syndrome
- ophtho exam for strabismus, cataracts, nystagmus - hearing test - q6 months until bilateral hearing test possible - screen for hypothyroidism annually - screen for celiac (symptoms annually, BW PRN) - hemoglobin screen annually
Child with trisomy 21. 3 discrete round completely hairless areas on the scalp. No other findings. a. What is the most likely diagnosis? b. What will you tell mom is the natural history of this problem
a. alopecia areata b. ● Spontaneous resolution in 6-12 month ● Recurrence: common
Child with Down syndrome. List three associated hematological disorders
● Neonatal polycythemia ● Neonatal leukemoid reaction ● Transient myeloproliferative disorder ● Anemia (iron deficiency due to poor intake) ● Leukemia (1%)
Family physician calls you about term neonate who weighs 2300 g. Neonate has lymphoedema, low set hair line and wide chest. What test would you send for diagnosis?
Probably Turner as opposed to Noonan because is term and very small. Noonan not usually SGA. - Karyotype for Turner, RASopathy panel for Noonan
List two investigations that should be done in a neonate with suspected Turner syndrome and their expected findings
AUS - horseshoe kidneys 4 limp BP and echo - aortic valvular disease (bicuspid aortic valve), or coarctation
Scenario of a boy with Fragile X. Mom is a carrier. There is a sister in the family. Mom asks you if you could test the sister to see if she is a carrier. She is currently in grade 5 and doing well. Do you test the daughter?
No! If she is healthy, then the recommendation is to wait until she is an adult and can make her own decisions about what she wants to know. Counsel that she may want investigations before pregnancy if she wants to know about potential risk for her children.
5 Clinical features of turners and 2 cardiac complications
- hearing loss, strabismus, shield chest, widely spaced nipples, increased carrying angle of arms, short stature, ovarian failure, hypothyroidism 2. bicuspid aortic valve, coarctation of aorta
List 3 features of Pierre-Robin sequence.
micrognathia, retrognathia high arched palate/cleft palate glossoptosis (tongue drops back and obstructs because it is relatively large for the oral cavity)
Child with suspected Duchenne muscular dystrophy. a. What is diagnostic on biopsy (be specific)? b. What 2 things do you want to know to help with genetic counseling?
a. lack of dystrophin in myofibers, endomysial connective tissue proliferation b. X-linked recessive condition (2/3 inherited) - what is the specific genetic defect in the child? - is mom a carrier of this defect - if yes, 50% chance or having another boy with DMD, if no, was a spontaneous mutation and there is no risk - is the family planning to have more children?
Child with hemihypertrophy. What condition would you suspect that would require serial follow-up?
Beckwith-Wiedemann ● Cancer risk high until 8 y.o. (~7.5%) o Need regular surveillance with abdo US + alpha fetoprotein measured every 3 mon. until 8 y.o. o Then Renal US every 1-2 year as medullary sponge kidney and nephrocalcinosis can happen later
Child with Wilm’s tumor. Which is associated? a. Down syndrome b. Prader-Willi syndrome c. Beckwith-Weideman d. Angelman’s syndrome
ANSWER: c. Beckwith-Weideman – Wilm’s Tumour, Hepatoblastoma, Neuroblastoma, Adrenocortical carcinoma a. Down syndrome – acute myeloid leukemias
Cancers are associated with several disease states. Name one cancer associated with each of the following. - Beckwith Wiedemann - Down syndrome - Aniridia
- Beckwith Wiedemann- Wilm’s, Hepatoblastoma, higher risk of neuroblastoma - Down syndrome – Leukemia (Specifically acute myeloid leukemia) - Aniridia – Wilm’s Tumour
3d old term infant with absence of abd muscles and undescended testes bilaterally. TFI 90/kg/d. Na 120, K 5, Glu 2.6, normal urea, creatinine 119. U/O 10 cc in last 24 hrs. Kid NPO. Wt 4kg. What is causing this kid’s problems?
Prune belly syndrome - obstructive uropathy
Alpha-1 antitrypsin. Most likely presentation in children? a. jaundice b. emphysema c. bronchiectasis d. pneumonia
a. jaundice
Boy with MELAS, what do you tell him is his risk of passing it on to his kids?
Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes - no chance of passing it on to his kids because mitochondrial disorders are all inherited maternally
Child with distress, cannot pass NG through nares. Choanal atresia. List 3 other findings on physical exam you’d look for?
CHARGE (CHD7 gene mutation) Coloboma Heart defects (TOF, AV canal) Atresia choanae Retardation of growth (short stature) and motor development GU abnormalities (micropenis, cryptorchidism, hypoplastic labis in females) Ear deformities/hearing loss
Mother with DiGeorge syndrome has a child with cleft-palate. What 3 things should you do for investigation/management in the child (3)?
- check calcium (hypocalcemia) and PTH (hypopara) - echo (TOF, truncus arteriosus) - renal U/S (renal hypoplasia) - immunodeficiency W/U: CBC and diff, T and B cell numbers, immunoglobulins - CXR for absence of thyme silhouette
List 4 features of Rett syndrome.
- loss of previously acquired developmental milestones 2. repetitive hand wringing, and loss of purposeful hand movements 3. acquired microcephaly 4. seizures 5. ataxia 6. poor weight gain
3 major skeletal diagnostic criteria for Marfans?
- armspan greater than height 2. lower segment longer than upper segment 3. hindfoot deformity 4. pectus carinatum 5. positive thumb sign and wrist sign 6. scoliosis or thoracolumbar kyphosis 7. reduced elbow extension 8. protrusio acetabulae
Give a condition that corresponds to coloboma
CHARGE syndrome Wolf-Hirschorn syndrome 13q deletion syndrome
Give a condition that corresponds to dislocated lens
Marfan’s (superior dislocation) Homocysteinuria (inferior dislocation)
Give a condition that corresponds to aniridia
WAGR (Wilms tumour, aniridia, GU abnormalities, MR) Miller syndrome (aniridia with Wilm’s tumour)
Give a condition that corresponds to glaucoma
Sturge Weber Trisomy 21 NF1 Mucopolysaccharidoses
List 4 non-infectious risk factors of hearing loss in the newborn period.
- family history of hearing loss - outer ear malformation/craniofacial malformations - apgars 0-4 at 1 minute - NICU stay >2 days - ototoxic drug use - hyperbili needing exchange transfusion - mechanical ventilation
Which of the following is characteristic of Rett syndrome: a. ataxia b. seizures c. head bobbing d . hand wringing e. admit and place on a Phenylalanine free diet
d . hand wringing
A 25 year old mother of a child with Down syndrome (47XY (+21)) comes for advice regarding subsequent pregnancies. : a. no advice can be offered until karyotype of parents is known b. no antenatal workup needed as recurrence risk is <5% c. if level 2 ultrasound is abnormal at 16 weeks, then do amniocentesis d. antenatal karyotyping should be done with all subsequent pregnancies e. Chromosomes should be offered for any future pregnancy
e. Chromosomes should be offered for any future pregnancy - the recurrence risk is small but it’s still reasonable to offer prenatal testing if the family wants (47XY (+21)) - this is your standard T21 karyotype (would be different if there was a translocation in which case the parents would need to be tested and risk of recurrence is much higher)
A 20-year-old mother and 25-year-old husband have just had a child with clinical features of Down syndrome. What is the most likely karyotype: a) trisomy 21 b) mosaicism c) translocation 14/21 d) translocation 21/22
a) trisomy 21
Which of the following is done routinely in a 1-week-old infant with trisomy 21: a) lateral c-spine films b) abdominal ultrasound c) ophthalmology consult d) auditory brainstem response e) do nothing
e) do nothing standard OAEs for hearing testing are fine
In the follow-up of a child with Down syndrome, which would be appropriate: a) CBC and smear b) lipid studies c) thyroid function d) hepatitis B serology e) antigliadin antibody
c) thyroid function - TSH on newborn screen, then at 6 & 12 months, then annually a) CBC and smear - technically do not need a smear, just a CBC annually
You diagnose a boy as having fragile X by DNA testing. His sister is performing poorly at school, and parents are concerned that she has fragile X. You: a. order DNA testing on sister to rule out fragile X b. order cytogenetics on sister to see if she is a carrier c. order cytogenetics on mother to she if she is a carrier d. do nothing - females do not get fragile X
a. order DNA testing on sister to rule out fragile X DNA testing is the same as molecular testing; in fragile X you specifically need DNA PCR to make the diagnosis cytogenetics is microarray, FISH and karyotype
In a child with Fragile X, all would be present EXCEPT: a) motor delay b) speech delay c) microcephaly d) large ears e) autistic-like features
c) microcephaly They have large heads
Which condition is associated with macroglossia and an umbilical hernia: a) congenital hyperthyroidism b) infant of a diabetic mother c) Beckwith-Wiedemann syndrome d) Down syndrome
c) Beckwith-Wiedemann syndrome
A 1-month-old child has macroglossia, hemihypertrophy, and an umbilical hernia, consistent with Beckwith-Wiedemann syndrome. You recommend the following: a) CT head b) regular abdominal ultrasounds c) intermittent checks for hypoglycemia d) measurement of leg-length discrepancy e) DNA testing for Beckwith-Wiedemann syndrome
b) regular abdominal ultrasounds Re DNA testing - can make clinical diagnosis if 3 major criteria are present
Characteristics of Schwachman-Diamond syndrome a) decreased pancreatic enzyme excretion b) normal neutrophil count c) hypocellular bone marrow d) increased risk of diabetes mellitus
a) decreased pancreatic enzyme excretion - malabsorption, FTT - also have neutropenia/myelodysplastic syndrome, bone marrow failure - make cells but cannot push them out, so marrow is not hypocellular - bone abnormalities (thoracic dystrophy)
Which of the following findings would help to rule out Klinefelter syndrome: a) normal upper/lower body segment ratio b) muscular habitus c) testosterone level 5.0 d) testicular volume of 15 cc e) behavioural/learning difficulties
d) testicular volume of 15 cc - have small testes (prepubertal even - 4ml) - all the other options do also go against Klinefelters, but not strongly enough to rule it out
Picture of child with Down Syndrome. Child noted to be hypotonic. Term, normal Weight. Questions is what test most expediously confirms diagnosis. a. Chromosome analysis b. TSH, T4 c. Muscle biopsy
a. Chromosome analysis FISH or rapid aneuploidy testing would be quickest way get diagnosis (TAT 24-48h); but still need to do a karyotype after to see if there is a translocation
1 week old infant with T21. What should be done prior to discharge home? a. ABR b. Ophthalmology consult c. Abdo U/S d. Echocardiogram
d. Echocardiogram
14 y.o. with T21. What test should be done annually? a. X-ray of cervical spine b. TSH c. Audiology d. Ophthalmologic exam
b. TSH c. Audiology
vomiting infant with T21, next step? what are you worried about?
AXR - concern is for duodenal atresia; also consider Hirschsprung, bad GERD
Beckwith-Wiedeman syndrome U/S. A question about how frequently ultrasound should be done.
- AUS q3 months until age 8 - then annually from age 8-mid adolescence for kidney abnormalities, especiallymedullary sponge kidney
Child with Wilm’s tumor. Which is associated? a. Down syndrome b. Prader-Willi syndrome c. Beckwith-Weideman d. Angelman’s syndrome
c. Beckwith-Weideman
Child with large port wine stain in a distribution of the 1st trigeminal nerve. What do you work him up for? a. optic glioma b. cerebral arteriovenous malformation c. glaucoma d. liver disease
c. glaucoma (Concern is for Sturge Weber)
Picture of a baby sucking on a pacifier and looking relatively content. Severe thrombocytopenia. Has a large lesion overlying his left forehead and eyelid (not a port-wine stain). What is the most likely finding on labs? a. normal INR and PTT b. elevated fibrinogen c. schistocytes and RBC fragments on smear d. neutropenia and anemia
c. schistocytes and RBC fragments on smear Kasabach-Merritt syndrome (hemangioma with thrombocytopenia) -fibrinogen is decreased - can have anemia (MAHA), but not neutropenia
Trisomy X - symptoms?
- Tall stature
- Hypotonia
- Abnormal clinodactyly
- Language based learning disorder, dyslexia
- Anxiety
- ADHD
Stickler syndrome
- Features:
- Pierre-Robin syndrome
- Myopia and ophtho complications (choroidoretinal and vitreous degeneration, retinal detachment)
- SNHL
- joint hypermobility
- Do eye exam in Pierre Robin to look for Sticklers
What is risk of healthy child being carrier of CF when sibling has CF?
66%
Since they are healthy, they can’t have CF, so ⅔ = 66% of punnett square
