Genetics Flashcards
What is the inheritance pattern of Achondroplasia?
- Usually a spontaneous mutation (75%)
* If inherited, AD, completely penetrant inheritance pattern
Features of Achondroplasia
• Disproportionate short stature (mean height 49-51 inches)
• Rhizomelic shortening, “trident” fingers
• Macrocephaly, frontal bossing, depressed nasal bridge, malar hypoplasia
○ 5% may have symptomatic hydrocephalus
• Fatal apnea (~10%) especially before age 2yrs
○ Misshaped and small foramen magnum
○ Vascular and cervicomedullary constriction
○ Restrictive pulmonary disease
○ OSA is very common
• Middle ear dysfunction – CHL
• Kyphosis
• Spinal stenosis is uniformly present
• Knee instability in toddlers, varus deformity (bowlegs)
• Orthodontic problems (crowding and overbite)
• Cognitive development and function is typically normal
○ ~10% with severe learning disabilities, ID or ASD
• Hypotonia, disproportionate limbs and joint hypermobility
Developmental and anticipatory guidance for children with Achondroplasia
- Screening for hearing loss (hearing test annually) and language development
- Neurological history and physical with each visit, with consideration for CT/MRI
- Guidance around safe sleep habits and risk of SIDS
- Screening for OSA
- Gross motor and fine motor development
- Review weight gain and weight control
- Accessibility for the child’s needs (OT and device requirements)
- Psychosocial well being
- Avoidance of gymnastics or collision sports
What oncogenic concerns are present for children with Beckwidth-Wiedemann?
Embryonal tumours
• Hepatoblastoma
• Wilm’s tumour
- Rhabdomyosarcoma
- Neuroblastoma
- Adrenocortical carcinoma
What is the genetic basis for Beckwidth-Wiedemann?
Imprinting disorder on 11p15.5 (maternal copy is not expressed)
Diagnostic Criteria for Beckwidth Wiedemann
3 major OR 2 major and 1 minor criteria OR proven genetic methylation error at 11p15.5 or heterozygous CDKN1C mutation and 1+ clinical finding
• Major features/findings: Macrosomia (Wt & Lt >97th), macroglossia, hemihyperplasia, omphalocele, embryonal tumour, visceromegaly, ear AbN (anterior linear crease, posterior helical pits), cleft palate (rare), cardiomyopathy (rare), FamHx+ (1+ family member)
• Minor features/findings:
Polyhydramnios/prematurity, neonatal hypoglycemia, vascular lesions (nevus simplex, hemangiomas), characteristic facies (midface retrusion, infraorbital crease), cardiomegaly/structural cardiac AbN, diastasis recti, advanced bone age
What are anticipatory guidelines for Beckwidth-Wiedemann patients?
- Alphafetoprotein done every 3 months until age 4
* Abdominal ultrasound done every 3 months until age 8
What is CHARGE Syndrome?
- Coloboma/Cranial nerve dysfunction (1, 7, 8, 9, 10)
- Heart defects
- Atresia of choanae
- Retardation of growth
- Genitourinary defects
- Ear defects
What behavioural associations are seen with CHARGE syndrome?
- Obsessive compulsive disorder
- Attention deficit hyperactivity disorder
- Autism
- May see aggression and have self-abusive behaviors
What is the recurrence risk of cleft palate?
- If inherited with a disorder, likely AD inheritance pattern
- 2-6% chance in unaffected parents after a single affected child
What environmental risk factors are associated with cleft lip/palate?
- medications → phenytoin, valproate, topiramate, MTX (folic acid antagonist)
- cigarette smoking
- alcohol
- folate deficiency
When is cleft lip/palate usually repaired?
- 3 months for lip repair (facilitates feeding)
* <12 months for palate (to help with speech and development)
What long-term complications need to be considered for cleft lip/palate?
- hypernasal speech
- malposition of teeth
- recurrent otitis media and subsequent hearing loss
Diagnostic Criteria for Marfan Syndrome
• In the absence of family history:
- Aortic Z-score ≥2 AND ectopia lentis
- Aortic Z-score ≥2 AND FBN-1 mutation associated with aortic aneurysm
- Aortic Z-score ≥ 2 AND systemic score ≥7 pts
- Ectopia lentis AND FBN-1 mutation associated with AA
• In the presence of family history:
- ectopia lentis AND fmhx of first degree relative
- systemic score ≥ 7 pts and fmhx of first degree relative
- Aortic Z-score ≥ 2 and fmhx of first degree relative
What is the most common cardiac abnormality in Marfan Syndrome?
- Dilated ascending aorta
* MVP is 2nd most common
How to differentiate between Marfan Syndrome and Homocystinuria?
- AD inheritance vs. AR (homocysteinuria)
- both have lens dislocations (ectopia lentis) but it is supratemporal in MS and “down and in” in homocystinuria
- joints are hypermobile in MS and rigid in homocystinuria
- Vasodilatory disease in MS and vaso-occlusive disease in homocystinuria
- There is no ID in Marfan Syndrome but may be profound in homocystinuria
Clinical features of Marfan Syndrome
- Joint hypermobility
- Dolichocephaly, retrognathia, micrognathia
- Ectopia lentis
- Striae
- Long, thin and tall body habitus
- Anterior chest deformities (pectus excavatum or carinatum)
- Abnormal curvatures of the spine (most common thoracolumbar scoliosis)
- Thumb-sign, wrist sign
Diagnostic criteria for Ehler’s Danlos
4 major features • Family history • Hyperextensible joints with frequent dislocations • Widened atrophic scars • Hyperextensible skin
Genetic inheritance pattern for Ehler’s Danlos
- AD inheritance, but 50% de novo
- Genetic basis - COL5A1 (46%) or COL5A2 (4%)
- Skin biopsy - electron microscopy (suggestive, altered fibrillogenesis) or protein analysis by electrophoresis (type collagen) - not perfect
Management of Ehler’s Danlos patients
• Non weight-bearing activity (for muscle strength & coordination) - e.g. swimming!
○ Avoid contact, fighting, running, football
• +/- NSAIDs, Deep stitches to allow healing, tape cuts to minimize stretch
○ Avoid ASA
• +/- Physiotherapy for motor delays
• Management of chronic pain & MH issues
• If MVP/Ao Dilation –> annual echo
Genetic inheritance of Cornelia de Lange
Autosomal dominant inheritance pattern but 99% of cases are de novo
• Nipped B-like gene mutation
• chance of recurrence in a sibling 2-5%
Clinical features of Cornelia de Lange
- Short stature
- Hypertonic
- Microcephaly, brachycephaly (flat posterior head), long philtrum, micrognathia, low set ears, SNHL, CHL due to AOM, synophrys, myopia, long curly lashes, ptosis, anteverted nostrils, depressed nasal bridge
- High arched palate, cleft palate/lip, widely spaced, late erupting teeth
- CVS - septal defects
- GI - GERD, pyloric stenosis , GI dysfunction
- GU - hypoplastic male genitalia, undescended testes
- Single palmar crease, 5th clinodactyly, oligodactyly (missing digits), syndactyly of 2nd and 3rd toes
- Skin - cutis marmorata, hirsutism, low posterior hairline
- Mental retardation - IQ 50
What is the most common inherited cause of proximal RTA?
Cystinosis!
Genetic defect in cystinosin (cystine-transporting protein) that also leads to dysregulation of vesicle trafficking, lysosomal biogenesis, mTOR signaling, and autophagy
Cystine accumulation → enhanced cell death via apoptosis, mitochondrial dysfunction, oxidative stress, and inflammation
Clinical features of cystinosis
- Proximal tubular acidosis
- Systemic metabolic disorder
- Accumulation of cystine crystals in the cornea (the eye is the first apparently affected organ next to the kidneys)
- Skeletal deformities (e.g., genua valga, scoliosis, stress fractures)
- Functional disabilities (e.g., bone pain, walking impairment) later in life
- Severe early-onset hypophosphatemic rickets
- Hypothyroidism
- Cysteamine toxicity with copper deficiency
- Cystine crystal laden macrophages are known to be present in the bone marrow
- Premature skin ageing with the subcutaneous infiltration of a palpable amorphous material, thinning of the epidermis, and presence of teleangiectasia, and dome-shaped, skin-colored papules over the nose, and chin
- High incidence of a Chiari 1 malformation or cerebellar tonsillar ectopy
Treatment/Management for cystinosis
• Nutritional support - prevention of rickets and improvement of growth, free access to water, Na, K, HCO3, phosphate, vitamin D, Cu, carnitine
• Hormonal replacement therapy
○ Growth hormone
○ Levothyroxine for hypothyroidism
○ Insulin
• ACE-i for proteinuria
• Cystine-depleting therapy
○ Cysteamine must be given every 6 hours, does not prevent Fanconi’s or corneal crystals
○ Procysbi (q12 hours but difficult to take re: timing and eating restrictions)
• Renal replacement therapy in ESRD
• After kidney transplantation, cysteamine should be administered as soon as possible as it does not interfere with the reabsorption of immunosuppressive agents
• Corneal cystine crystal deposition - treated with cysteamine hydrochloride topical aqueous solutions (eye drops)
What are the clinical features of DiGeorge Syndrome?
- C - cardiac abnormalities - tetrology of fallot, critical pulmonary stenosis, conotruncal defects
- A - abnormal facies (hyperthelorism, low set ears, long tubular nose with hypoplastic alae, shortened philtrum)
- T - thymus hypoplasia
- C - cleft lip/palate
- H - hypocalcemia
- 22 - 22q11.2 deletion
What should be done in the immediate management of DiGeorge Syndrome patients?
- Echocardiogram
- CXR (for thymus)
- serum calcium, phosphate, TSH, free T4, PTH
- swallowing and nutritional assessment
- no live vaccines until immune system can be formally assessed
- Genetic testing via FISH specific for 22q11.2
Genetic inheritance for Duchenne’s Muscular Dystrophy?
- Abnormal gene at the Xp21 locus
* X-linked (though some women may be affected via Lyon hypothesis)
Classic features of Duchenne’s Muscular Dystrophy?
- Gower’s sign
- Proximal muscle weakness
- Calf muscle hypertrophy
- Delayed gross motor skills
- High CK
- Respiratory weakness and recurrent infections
- If advanced/progressive - chronic CO2 retention
- Intellectual disability
- Cardiomyopathy
- Scoliosis
Diagnostic test for Duchenne’s Muscular Dystrophy?
• Primary test: PCR for dystrophin gene mutation
- If positive, may defer muscle biopsy - If negative, definitive test is muscle biopsy
A child with Duchenne’s Muscular Dystrophy requires elective surgery. What must be done pre-op?
This child is at risk of malignant hyperthermia. The surgical and anesthesia team must be alerted and preparations made regarding induction drugs (i.e. avoidance of succinylcholine and inhalational anesthetics) and availability of Dantrolene
What is the inheritance pattern of Hyperhidrotic ectodermal dysplasia?
Generally X-linked recessive, but AD and AR forms also exist
Clinical features of Ectodermal dysplasia?
- Complete or partial absence of eccrine/sweat glands
- Malformed, dagger-like teeth
- Dry, thin, hypopigmented skin
- Saddle-nose (depressed nasal bridge)
- Friable or absent hair
Clinical manifestations for Fetal Alcohol Syndrome (3)
1) abnormal facial features
- smooth, long philtrum
- short palpebral fissures
- thin lip vermillion
2) CNS dysfunction i.e. intellectual disability, agenesis of corpus callosum, holoprosencephaly
3) pre-/post-natal growth deficiency (<10th %ile)