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
*
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
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
