Genetics Flashcards by Robyn Duffus

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

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Preauricular skin tag

Associated with:

Goldenhar syndrome
Treacher-Collins syndrome
Wolf-Hirschhorn syndrome

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Clinodactyly of the 5th finger

Associated with:

Trisomy 21
Normal familial variant

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Macroglossia

Associated with:

Beckwith Wiedemann syndrome
Mucopolysaccharidosis
Neurofibromatosis
Glycogen storage disease - type 2
Klippel-Trenaunay-Weber syndrome

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Microretrognathia

Associated with:

Pierre Robin sequence
Treacher-collins syndrome

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Encephalocele

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Postaxial polydactyly

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Bilateral clubfoot

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Hypospadias

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Fused labia with clitoromegaly

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Imperforate anus

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Amniotic band syndrome

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ANGELMAN SYNDROME

Genetics: UBE3A gene deletion/mutation on Ch 15

Imprinting disorder

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

Investigations:

Chromosomal microarray

Monitoring

Hyperactivity and poor sleep improves over time
Seizures escalate around time of puberty (especially in girls)

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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

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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

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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)

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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

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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

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DENYS-DRASH SYNDROME

Genetics: WT1 gene mutation

Clinical Features:

Nephropathy
Ambiguous genitalia
Bilateral Wilms tumours (<2yo)
Proteinuria in infancy → nephrotic syndrome → ESRD

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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

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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)

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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

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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

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**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: * **F**oot deformity/**F**requent falls * **R**ecessive/**R**epeats (GAA) * **I**ron accumulation in mitochondria * **E**yes move (nystagmus)/**E**xtensor plantar response * **D**iabetes mellitus/**D**ysarthria * **S**coliosis/**S**taggering gait/**S**ensory 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; * **A**shleaf spots (\>3) * **S**hagreen patches * **H**eart rhabdomyosarcoma * **L**ung hamartomas * **E**pilepsy from cortical tubers * **A**ngiomyolipoma in kidney * **F**acial 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?

**V**ertebral defects **A**nal atresia **C**ardiac defects **T**racheoesophageal fistula **E**sophageal atresia **R**enal anomalies **L**imb 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: * **W**ilms tumour * **A**niridia (or cataracts, glaucoma, nystagmus) * **G**enitourinary anomalies (hypospadias, cryptorchidism, streak ovaries, bicornuate uterus) * **R**etardation - 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, f**riendly "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

**WISKOTT-ALDRICH SYNDROME** Genetics: mutation in WASP gene Inheritance: X-linked recessive Clinical Features: **eczema, thrombocytopenia, immunodeficiency**, Recurrent infections (sinopulmonary) 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 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 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

Genetics Flashcards

(73 cards)