Genetics

Genetic Disorders
 Common, 2% live births have significant congenital malformation, 5% have
genetic disorder
 Chromosomal abnormalities ex. Trisomy 21, Edward (Tris18), Patau (Tris 13)
Turner XO, Kleinfelt XXY
 Mendelian disorders (single gene defect)
 Unusual genetic mechanism ex fragile X
 Multifactorial (genetic + environmental combination)

Down’s Syndrome: Trisomy 21

Definition: Genetic disorder arising from an additional chromosome 21
Epidemiology: the most common genetic disorder causing severe learning disabilities,
incidence is 1/650 live births (w/o antenatal screening), slightly M>F
Etiology: extra chromosome 21, caused my non-disjunction (94%), translocation (5%),
Mosaicism (1%)
Risk Factors: for non-disjunction related to maternal age, for translocation related to
parental carriers of translocated chromosome 21
Presentati on

 Antenatal screening: u/s showing nuchal thickening, amniocentesis to check

chromosomal pattern
o Maternal serum: low alpha-fetoprotein, low unconjugated estriol,
elevated human Choriunic gonadotrophin
 Craniofacial appearance: microcephaly, round face, flat nasal bridge, upslant on
palpebral fissures, epicanthic folds (across ridge of palpebral fissure), small
round mouth w protruding tongue, brushfield spots in iris [pigmented], small
ears, flat occiput, third fontanelle
 Other appearance: single palmar crease, incurve of 5th finger, wide space btw
large and second toe, short neck,
 Hypotonia
 Congenital heart defect (esp ASD) (40%)
 Duodenal atresia
 Hirschsprung’s disease
Investi gati ons:

 Bloods for FISH karyotyping

Management:

 Parental Education and Communication

 Discuss how disease arises, short and long term implications
 Risk of recurrence, antenatal diagnosis for future pregnancies
o If non-disjunction, risk of recurrence approx 1/200, risk increases a lot
after 35
o In translocation risk of recurrent is 10-15% if the mother is the carrier of
translocated gene and 2.5% if father is carrier, if a parent carries a 21:21
 translocation all offspring will have downs, if neither carries
translocation risk is <1%
 Written information, self-help groups
 Support services to optimize cognitive and social progress
 Nutritionist – particularly for suboptimal feeding in newborn, prevention of
obesity in children and adolescents
 Cardiology evaluation – echocardiogram
 Audiology and opthamology reviews annually
 Dental care
 Screen for atlantoaxial instability by age 3
 Screen for celiac by age 3
 Pneumococcal, RSV, influenza vaccines
 Genetic counseling
Complicati ons:

 Delayed motor milestones

 Moderate – severe learning difficulties
 Small stature
 Immune
o Increased susceptibility to infection
o Increased risk of leukemia (15xs increased risk) and solid tumours
o Hypothyroidism, celiac disease (increased risk of autoimmune diseases)
 Cardiac
 Resp – recurrent upper and lower resp infection cause of morbidity
 Gastrointestinal
o Duodenal atresia, TEfistula, pyloric stenosis, Hirschstrung’s
 Orthopedic
o Risk of atlantoaxial instability, leads to torticollis, gait abnormality, loss
of strength, impaired bowel and bladder function
o hypotonia
 Neuro
o Epilepsy
o Autism, ADHD
o Alzheimers
 Hearing impairment (secretory otitis media infections) [stenotic ear canals and
Eustachian tubes]
 Visual impairment – cataracts, squints, myopia

Prognosis: 85% live to 1 year, 50% live longer than 50 years, HF and valvular disease
and high pulmonary vascular resistance, GI abnormality

Edwards’ Syndrome: Trisomy 18

Clinical features:

 Low birthweight
 Prominent occiput
 Small mouth and chine
 Short sternum
 Flexed/overlapping fingers
 Rocker bottom feet
 Cardiac and renal malformation
Dx confirmed with chromosomal analysis, may be detected in 2 nd trimester screening
Risk of recurrence is low unless due to balanced chromosome rearrangement in one of
parents

Pataus’ Syndrome: Trisomy 13

Clinical Features:

 Structural defect of brain

 Scalp defects
 Small eyes and other eye defects
 Cleft lip and palate
 Polydactyly
 Cardiac and renal malformation
Dx confirmed with chromosomal analysis, may be detected in 2 nd trimester screening
Risk of recurrence is low unless due to balanced chromosome rearrangement in one of
parents

Turner’s: XO
Definition: Either a complete absence (50%) or partial deletion of one X chromosome
(50%)
Risk: not related to maternal age, risk of recurrence v low
Epidemiology: over 95% result in miscarriage, 1/2500 live females
Presentati on

 Morphological features: webbed neck, broad chest with spaced nipples, low
hairline, low-set ears, ptosis, high-arched palate
 Lymphoedema
 Short stature
 Impaired sexual development
 infertility
Complicati ons

 Without treatment incomplete pubertal development

 Cardiac complications (coarctation, dissection, bicuspid aortic valve, HT)
 Learning disabilities
 Hip dislocation, scoliosis, hypoplastic nails
 Gonadal dysgenesis, ‘streak gonads’,
Management

 Growth hormone for short stature

 Estrogen and progesterone replacement to establish 2nd sexual characterstics in
adolescents
 Monitor for health problems:
o Hypothyroidism
o Obesity and DM
o HT
o Cardiac abnormalities
o Hearing (otic canals can be stenosed)
 In cases of Y chromosome, remove gonad to prevent gonadoblastoma
Kleinfelter Syndrome: XXY
Definition: Additional X
Epidemiology: males only, 1-2/1000 live born males
Risk Factors: advanced parental age leading to chromosome non disjunction
Presentati on/Complicati ons:

Testosterone dependent effects:

 Hypogonadism, small testes, azoospermia, oligospermia, infertility
 Gynecomastia
 Reduced face and body hir
 Osteoporosis
 Altered body habitus - long arms and legs: torso, female fat distribution
Neurodevelopmental problems: delayed speech/language, learning disability, ADHD,
dyslexia, psychiatric problems (anxiety, depression)
Cardiac: mitral valve prolapsed, varicose veins, recurrent DVT
Management:

 Testosterone supplementation at puberty (period injections or patch)

o Virulization normalizes desire, inc muscle strength & mass, protects
against osteop
 Monitor for developmental/learning delay
 Echo for cardiac complications
 Bone density studies
 Counselling for infertility
Prognosis: life expectancy not altered, XXXY and XXXXY have greater complications,
decrease in libido

Prader-Willi Syndrome
Definition: genetic syndrome characterized by hyperphagia and obesity, hypogonadism,
characterstic physical features and behavioural and cognitive manifestations
Epidemiology: 1/10-15, 000, both sexes equally affected
Etiology: lack of expression of genes on chromosome 15, deletion of a parental 15 occurs
in 75%
Presentati on:

 Infants: non specific, hypotonia, failure to thrive

o Central hypotonia, poor sucking
 Genital hypoplasia (clitoral/testicular)
 Characteristic facies: almond shaped palpebral fissure, narrow bitermporal
diameter, thin upper lip
 Small hands and feet
 Childhood: obesity, hyperphagia
 Developmental delay, mental retardation
 Short stature
 Hypopigmentation
 Sleep apnea
Investi gati ons:

Prescreen with amniocentesis or chorionic villus sampling

Prader-Willi scale assesses likelihood of disease based on clinical findings
Bizarre food seeking behaviour is clue
Lab test: DNA based methylation detects abnormal imprinting, GnRH, LSH, FSH and sex
hormones indicate hopogonadotrophic hypogonadism
Complicati ons:

 Morbid obesity, DM, CVD, sleep apnea

 Binge eating  gastric necrosis/extreme distention
 Mental retardation
Management:

Early Intervention: address feeding, hypotonia, delayed gross motor skills, support for
development
Growth hormone replacement for short stature
Calorie restricted diet and exercise program
Surveillance for ophthalmologic problems and osteoporosis
Screen for other endocrine problems ex DM, hypothyroid
Prognosis: life expectancy good if obesity managed

Fragile X
Definition: gap in distal long arm of X chromosome, X linked recessive disorder, second
most common genetic cause of severe learning difficulty
Epidemiology: males, 1/4000, femal carriers may have mild-moderate learnig
difficulties, 1/5th of males with genotype abnormality are phenotypically normal
 ‘premutatio’ = 55-199 copies of repeat, no intellectual disability but is unstable
 Fill mutation = >200 copies
Dx: CGG trinucleotide repeat in FMR1 gene
Clinical Findings:
 Moderate to severe learning difficulty (IQ 20-80, mean = 50)
 Macrocephaly
 Macro-prchidism (post pubetally)
 Characterstic facies – long face, large everted ears, prominent mandible, broad
forehead
 Other features: mitral prolapsed, joint laxity, autism, hyperactivity

Some AD disorders
 Achondroplasia
 Familial Hypercholesterolaemia,
 Huntingtons
 Neurofibromatosis
 Tuberous sclerosis
 Osteogenesis imperfecta
 Marfans
o Genetic disorder of fibrillin, a building block of connective tissue and
component of myofibrils (structural component of aorta, lung, dura and
suspensory ligament of eye)
o Marfanoid body habitus: tall, long arms, short torso, scleraldactyly,
pectus deformities, high arched palate
 o Associated complications:
 Disclocation of lens
 Resp: spontaneous pneumothorac, apical blebs
 Cardio: aortic dissection, dilated aorta, mitral valve prolapsed
 Ortho: hypermobility of skeletal system, decreased ligament
integrity  developmental delay of gross motor skills
o Management
 Monitor echocardiography and MRI, once aorta dilates use
Bblockers, over 5cm sx nec
 Opthamology surveillance
 Occupational/physiotherapy
 Pain management
 Rigorous activities/contact sport should be avoided

DiGeorge Syndrome
 Cause:
o deletion on the 22nd chromosome leads to maldevelopment of 4th
branchial arch (defect 22q11) usually spontaneous, affects 1/4000 births
 CATCH
o C – cardiac anomalies (TofF, interrupted aortic arch, runcus arteriosus)
o A - abnormal facies – Hypertelorism (inc space btw eyes), down slanting
palpebral fissures, prominent/lowest ears, micrognathia)
o T - thymic aplasia, recurrent infections particularly viral
o C –cleft palate
o H – hypocalcaemia (from parathyroid maldevelopment) tetany, seizures
 Mild cognitive impairment/learning difficulties
Treatment:
 Monitor
 BM/thymic transplant
 Ab treatment/prophylaxis
 Correction of cardiac defects

Serum Sickness
 Type 3 hypersensitivity reaction
 Antibody-antigen complex become lodged in small vessels leading to
complement activation and inflammatory response
 Usually drug induced: penicillin, cephalosporin, sulphonamide
 Or blood products, allegen extracts, vaccines
 Can occur sporadically following infection
Presentati on:
 1-3 wks post exposure, fever (high), malaise, irritability, derm findings
(urticaria, polymorphous rash, pruritic eruptions) arthritis, arthraligia
(hips>knees>elbows), less commonly hematuria, nephritis, neuropathy,
myocarditis, pericarditis
Diagnosis:
 special attention to recent meds, vaccines and illness
 Labs: decreased complement, ESR elevated, urinalysis with
proteinuria/hematuria
 Bx skin – immunocomplement deposition in capillary walls
Treatment:
 support, remove offending agent, decrease inflammation, topical/systemic
steroids
 Usually self limited, complications do not usually occur