Genetics Flashcards
Initial Investigations for DSD?
1) Karyotype
2) Adrenal steroids: 17-OPH
3) Gonadal function: LH FSH, T, dihydro-T, AMH
4) Lytes
5) U/S
NF-1: clinical features (mucocutaneous)?
- Lisch nodules
- Cafe-au-lait spots
- Neurofibromas
- skin fold freckling
NF-1: mode of inheritance?
AD
NF-1: diagnostic criteria
2+ of the following:
- 6 hyperpigmented café-au-lait macules
- 2+ neurofibromas or 1 plexiform neurofibroma
- Axillary or inguinal freckling (often appears in late childhood)
- Optic glioma (<10 years of age)
- 2+ Lisch nodules (iris hamartomas, <20 years of age)
- Tibial pseudoarthrosis or sphenoid dysplasia
- First-degree relative with NF1 (although a significant percentage are de novo mutations)
Turners: what renal anomaly?
Horseshoe kidney
Carnitine palmitoyltransferase II deficiency (CPTII deficiency) -
Type of metabolic D/o
Genetic
Tx
- FA oxidation disorder: Prevents body from using certain fats for energy, especially during fasting
- Mutation in CPT2 gene → makes enzyme carnitine palmitoyltransferase 2 → essential for FA oxidation
- Mutation prevents use of FA for metabolism → hypoketotic hypoglycemia, myalgia, weakness. FA & long-chain acylcarnitines (FA + carnitine) may build up in cells and damage liver, heart & muscles
- Genetic: Rare, AR inheritance, 3 main types
- Treatment
1) High-carb (70%) & low fat (<20%) diet : fuel for glycolysis, prevent hypoglycemia and reduce body fat utilization- Use of carnitine to convert potentially toxic long-chain acyl-CoAs
2) Prevent primary manifestations - Glucose infusions during intercurrent infections to prevent catabolism
- Frequent meals + Avoid extended fasting and prolonged exercise
3) Prevent secondary complications: - hydration during episode of rhabdomyolysis & myoglobinuria to prevent renal failure
- Use of carnitine to convert potentially toxic long-chain acyl-CoAs
22q11: clinical features and Dx
Dx: Microarray
Features: CATCH 22
1) facial features: short forehead, hooded eyelids, upslanting palpebral fissures, malar flatness, bulbous nasal tip, hypoplastic alae nasi, protuberant ears, VPI (cleft), hypernasal speech, chronic OM, SNHL/CHL
2) congenital heart disease (Conotruncal heart defects, aortic arch anomalies)
3) hypoparathyroidism, hypocalcemia
immune deficiencies: recurrent infections, T-cells low and/or impaired function, autoimmune disease
4) developmental delay. learning disability
psychiatric illness
Myotonic Dystrophy: Types, inheritance, Clinical Feats, Dx
Types: I (congenital), II (mid), III (late)
Inheritance: AD
Feats:
1) Characteristic face (Inverted V-shaped upper lip; thin cheeks; Narrow head; high & arched palate)
2) Myotonia
3) Cardiac, GI issues, endo/ID deficiencies
Dx: DNA analysis
Tuberous Sclerosis (TS): mode of inheritence
AD
Tuberous Sclerosis: mnemonic for features
ASHLEAF A- ashleaf spots S- Shagreens patches H- Heart Rhabdomyomas L- Lung Lymphangiomyoma (LAM) E- Epilepsy from cortical tubers (Inf Sp) A- Angiomyolipomas - kidney F- Facial angiofibromas
MRS TUBER HEAD
M- Mitral Regurg
M- Ment Ret
R- Rhabdomyomas
S- Subependymal nodules
T- TS
H- Hamartomas
E- Ependymoma
A- Ash leaf lesions
D- Dominant (autosomal)
Depigmented lesions
Achondroplasia: mode if inheritance
AD
Achondroplasia: clinical features
Face: Macroceophaly frontal bossing Midface hypoplasia Neurologic: Normal intelligence
Extremities: SHort arms + legs (esp proximally, “rhizomelic shortening” Bowed legs Lumbar lordosis Trident fingers
Other:
Short stature
Sleep apnea
Foramen Magnum/Spinal stenosis
Achondroplasia : Dx + testing
Imaging: Skeletal survey, CT head for Foramen magnum
Lab: Molecular genetic testing for FGR3, sleep study
Achondroplasia: management
- no GH supps
- AA instability: no contact sports
- monitor:
- hearing screens
- spinal stenosis
- sleep apnea
- HC for hydrocephalus
Syndromes with difficult airways
- Treacher Collins:
- micrognathia - PRS:
- glossooptosis, micro/retrognathia, CP - Goldenhar:
- craniofacial microsomia - Russel Silver:
- triangular face, pointed chin, large forehead
Adrenoleukodystrophy: Mode of inheritance, Clinical Features
Mode: X-linked
Features: 5 phenotypes
Most common: childhood ALD
- Behaviour: hyperactivity (often mistaken for ADHD) & worsening school performance
- Impaired auditory discrimination, Impaired spatial orientation
- Visual disturbances (cerebral cortex involvement, seemingly inconsistent visual capacity), strabismus
- CNS: Ataxia, Seizure (nearly all pts)
- Adrenal dysfunction
What genetic syndrome MOST associated with right aortic arch anomaly and TOF?
DiGeorge
Denys-Drash:
- Mode of inheritence
- Features
- At risk of what cancer?
- Mode: AD (WT1 mutation)
- Nephropathy + ambiguous genitalia + bilateral Wilms tumour
Renal: proteinuria in infancy, nephrotic syndrome and ESRD - Wilms: < 2yo, frequently bilateral
Macune Albright Syndrome:
- Mode of inheritence
- Features
Mode:
Features: TRIAD of 1) peripheral precocious puberty (ovarian hyperfunctioning and erratic estrogen secretion) 2) irregular cafe-au-lait macules 3) fibrous dysplasia of bone.
Associated hyperthyroidism, overgrowth syndrome, cushing syndrome, hypophosphatemic rickets.
Wiskott Aldrich Syndrome
1) Mode of Inh
2) Features
1) X- linked (WASP mutation)
2) Eczema + petechiae + immunodeficiency (combined T cell and B cell immunodeficiency)
Low platelets and small in size (microthrombocytopenia), eosinophilia, elevated IgE
Williams syndrome: cardiac anomaly?
- Supravalvular aortic stenosis may be sporadic, familial, or associated with Williams Syndrome → can present with critical aortic stenosis (LV failure, low CO)
Williams Syndrome: features
- Characterized by elfin facies (full face, broad forehead, flattened nasal bridge, long upper lip, rounded cheeks)
- Spasticity, hypoplastic nails, dental anomalies, joint hypermobility
- Idiopathic hypercalcemia of infancy, nephrocalcinosis, hypothyroidism, hypersensitivity to sound, poor weight gain
VACTERL: what and mode of transmission
VACTERL association, at least 3 of: Vertebral defects Anal atresia Cardiac defects Tracheo-Esophageal fistula Renal anomalies Limb abnormalities Unclear genetic etiology; occurs sporadically; diagnosis is clinical Management is mostly symptomatic
Turners: cardiac anomaly
Bicuspid AV
Coarct
Syndromes associated with Choanal Atresia
CHARGE syndrome (most common), Treacher-Collins, Kallmann syndrome, VACTER association
CHARGE syndome
coloboma, h eart disease, a tresia or stenosis of the choanae, r etarded growth and development or central nervous system (CNS) anomalies or both, g enital anomalies or hypogonadism or both, and e ar [external, middle, inner ear] anomalies or deafness or both
Rhabdomyoma - associated with what ?
TS
PWS:
Clinical Presentation
Lab testing
Clinical:
- Face: Bitemporal narrowing, Triangular mouth
- Neurologic: Hypotonia, Global developmental delay, Mild to moderate intellectual disability, Behavior problems (compulsive, stubborn)
- GI: Feeding difficulties, Hyperphagia in childhood
- GU: Hypoplastic genitalia
- Endocrine: Delayed puberty, Short stature, Osteoporosis
- Extremities: Small hands/feet
- Poor growth in early childhood, obesity in late childhood/adolescence
Laboratory testing
Methylation testing of Prader-Willi critical region on chr 15 (cytogenetics)
Annual TFTs
Russel Silver Syndrome: CF
IUGR/ FTT, short stature, triangular face (prominent forehead and pointed chin), clinodactyly, hypospadias, hypoglycemia
Cafe-au-lait : syndromes
NF1, NF2, McCune-Albright syndrome
Weak: Ataxia-telangiectasia, Fanconi anemia, Russell-Silver, tuberous sclerosis, Turner, Noonan, MEN1, MEN2, Kabuki
BWS: features, genetic defect, at risk for what tumours
Somatic overgrowth syndrome, defect on ch11 imprinting centres
Macrosomia, hemihypertrophy, organomegaly, macroglossia, omphalocele, umbilical hernia, hyperinsulinism (Transient)
At risk for: Wilms, hepatoblastoma, neuroblastoma, rhabdomyosarcoma
Noonan: cardiac anomalies
80% of patients with NS have cardiac involvement - most common is PV stenosis; ASDs also frequent, 20% have hypertrophic cardiomyopathy
Marfan: Mode of inh, features
AD
Features include hyperextensible joints, pectus excavatum or carinatum, murmur (mitral valve prolapse), aortic dilation/dissection, tall stature, large armspan, long face, malar hypoplasia, high arch palate with dental crowding, positive wrist/thumb sign, pneumothorax, scoliosis
G6PD vs H Spherocytosis - mode of inheritence
AD (HS) vs G6PD (X-linked)
Fragile X: mode of inh, features
X-linked
Face: long narrow face, large ears, prominent jaw, tall forehead
Neuro: intellectual disability (most common inherited intellectual disability), speech delay, ADHD, anxiety
GU: macroorchidism
Galactosemia:
- deficiency
- Presentation
- Dx
- Tx
- GALT (galactose-1-phosphate uridyltransferase) deficiency
Presents first few days/weeks of life- Vomiting, hyperbilirubinemia, poor weight gain
- Cataracts, liver failure,, renal tubular acidosis, E. coli sepsis, language delay
- Diagnosis: direct enzyme assay using erythrocytes
- Tx: Galactose-free diet
Waardenburg Syndrome - associated with what
- characterized by pigmentary abnormalities of the hair, skin, and eyes (e.g. congenital heterochromia, white forelock). There are 4 types of Waardenburg syndrome.
- Congenital deafness occurs in 1/5 patients (sensorineural as per OMIM). Occasional findings include cleft lip and palate, and neural tube defects (e.g. spina bifida, myelomeningocele)
Marfan Syndrome: inheritance + exam findings
AD inheritance – Positive thumb sign – Pectus excavatum – Scoliosis – Long arms
