Genetics - microdeletions/imprinting disorders

Question 1

William syndrome - genetics, features

Answer 1

Autosomal dominant 7q11.23
Clinical presentation - Irritable infant, Child with short stature and developmental delay
Specific behavioural profile – overfriendliness, social disinhibition, excessive empathy, attention problems, non-social anxiety
Elfin‐like facial appearance, puffy eyes, hyperterolism, wide mouth, long flat philtrum, thick vermillion border, upturned nose w flat nasal bridge, small jaw
Cardiovascular: SV aortic stenosis, peripheral pulmonary stenosis, RAS, HTN
Endocrine: Hypercalcaemia, Hypercalciuria, Hypothyroidism, early puberty
Mild to moderate ID, hypotonia, anxiety/ADHD

Question 2

DiGeorge syndrome = Velocardiofacial Syndrome - genetics, features

Answer 2

Autosomal dominant 22q11.2 continugous gene deletion syndrome, 1/4000; 3rd and 4th pharyngeal POUCH fail to develop.
Clinical presentation: neonate w anomalies inc thymic hypoplasia and hypocalcaemia, older child with DD/short stature
Congenital heart disease: conotruncal abnormalities = TOF, interrupted aortic arch, VSD, truncus arteriosus
Palatal abnormalities: Velopharyngeal incompetence, cleft palate, bifid uvula
Facial features: Periorbital fullness, short palpebral upslanted fissure, large nose tip w hypopastic nares, small mouth/ears, asymmetric crying face
Immune: thymic hypoplasia = impaired T cells
Endocrine: PTH deficiency/hypocalcaemia
DD, speech/language delay, mean IQ 75, autism, schizophrenia, hearing loss
Feeding and swallowing problems, constipation

Question 3

Wolf Hirshom Syndrome - genetics, features

Answer 3

Partial deletion of chromosome 4 – at 4p16.3; majority de novo, Critical region – WHSCR1 and WHSCR2 gene
Pre and postnatal growth restriction, microcephaly, CHD (VSD/ASD/PS)
Distinctive facial features: high forehead & wode nose, hyperterolism, glabella prominence, high/arched eyebrows, downturned mouth
Severe ID, recurrent aspiration

Question 4

Prader-Willi - genetics, features

Answer 4

15q12; ABSENCE of paternally functioning gene - either deletion, UDP maternal or abnormal paternal imprinting
1/350,000-400,000
Key Features: neonatal hypotonia, undescended testes, hyperphagia after infancy, ID, obesity, hypopigmentation, small hands and feet, ASD/OCD, micrognathia, short stature, hypothyroid, hypogonad
Prenatal Hx: reduced foetal activity, polyhydramnios, breech
Ix: methylation studies detects all cases, microarray for deletions/some UPD
PWS panel = karyotype, methylation studies, FISH and microsatellite probes for MUPD
Average life expectancy 33.2 years

Question 5

Angelman - genetics, features

Answer 5

15q11.2-13; ABSENCE of maternally functioning gene - either deletion, UDP paternal or abnormal maternal imprinting; can also be UBE3A mutation (5-10%)
Features: severe ID, DD, speech impairment, postnatal microcephaly by age 2, wide mouth/teeth, large tongue, flat back of head,
Movement/balance disorder w gait ataxia, tremors.
Happy puppet - laughter/smiling, no speech, happy demeanour, excitable, hand flapping, likes water, short attention span
Sleep disturbance, seizures (80%) - large amp slow-spike waves

Question 6

Beckwith Wideman - genetics, features

Answer 6

Association with IVF (loss of IC2 methylation); 1/13,700, M=F
LOSS of maternal genes – paternal over-expression; 11p13 = overactive IGF-2 (GF)
50% loss of methylation at mat IC2, 20% paternal UPD 11, 5% gain of methylation at mat IC1, 5-10% CDKN1C mutation
Imprinted genes = IGF2, gene H19 (involved in IGF2 suppression), WT1 (Wilms tumour gene), many others
Autosomal Dominant (15%), Sporadic (85%)
Neonate – macrosomia, hypoglycaemia, exomphalos, polyhydramnios, preterm delivery, hypoglycaemia, hypotonia
Dysmorphism: earlobe crease anterior, ear lobe pits posterior, metopic ridge, large fontanelle, midface hypoplasia
Overgrowth - macrosomia, macroglossia, hemihypertrophy, cryptorchidism, organomegaly (kidneys 97%, spleen 80%, liver 70%)
Oncology (esp <8yo): wilms, hepatoblastoma, adrenocortical carcinoma, neuroblastoma, rhabdomyosarcoma, nephroblastoma, gonadoblastoma = screen USS 3/12 until 8yo
Hypoglycaemia due to hyperinsulinsim from pancreatic islet cell hyperplasia, subsides by 4mo
Omphalocele/umbilical hernia/diastasis recti
Mild-moderate ID – secondary to hypoglycaemia
Prognosis: good if survive infancy (21% mortality), macroglossia may reduce w growth, feeding problems

Question 7

Russel Silver - genetics, features

Answer 7

LOSS of paternal genes – maternal over-expression
50-60% 11p methylation defect (turning OFF IGF-2), <10% maternal UPD7
Facies: prominent forehead, triangular face, pointed chin, downturned corners of mouth
General: SGA w large head (LBW <2SD from mean + poor growth w normal HC)
Hemihypertrophy, feeding difficulties, hypoglycaemia, hypotonia, wide/late-closing fontanelles, mild DD, clinodactyly
Investigations: Methylation testing 11p, UPD7 studies (DNA from parents), SNP array can sometimes detect UDP7
Treatment: GH