Paediatric Syndromes

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Di George Syndrome

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22q11.2 deletion (95%), otherwise 10p13 deletion
1 in 4000
AD inheritance (majority de novo)
Complete Di George = thymic aplasia (1%), remainder parital Di George
Results from dysmorphogenesis of 3rd/4th pharyngeal pouches --> hypoplasia of thymus/parathyroid glands
Features (CATCH-22):
- Cardiac (esp TOF + truncus arteriosus, DORV, CoA)
- Abnromal facies (short philtrum, hypertelorism, antimongoloid eye slant, mandibular hypoplasia, low-set, notched ears)
- Thymic hypoplasia (60 - 80% with low T cells)
- Cleft palate
- Hypocalcaemia/hypoparathyroidism
Other feats incl. oesophageal atresia, bifid uvula, Schizophrenia/ADHD, enamel hypoplasia, dysplastic kidneys
1/3 have CHARGE association - Coloboma, Heart defect, Atresia (Choanal), Retardation of growth, Genital hypoplasia, Ear abnormalities incl. deafness

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1 / 44

Multiple gene deletions of long arm of Ch7
1 in 7,500
Feats include:
- Elfin like facial features
- Cocktail party demeanor
- Widely spaced teeth
- Flat nasal bridge
- Long philtrum
- Developmental delay with STRONG language skills
Cardiac probs:
- Supravalvular AS
- Peripheral PS
Dx by FISH or microarray

Noonan Syndrome

AD inheritance
Mutation in RAS/Mitogen activated protein kinase signalling pathways on different genes (70%) - not same gene, therefore CLINICAL DIAGNOSIS
1 in 1,000 (similar to Tri 21)
AKA Turner's for boys
Feats:
- Physical (MR SHEEN)
MOUTH: deeply grooved philtrum, micrognathia, high arched palate
ROEDEMA: oedema of hands/feet (early)
STATURE: short, pectus excavatum, winging of scapula
HEAD: excess skin on nape, low post hairline, high ant hairline, macrocephaly, traingular face, short webbed neck
EYES: hypertelorism, ptosis, epicanthal folds, refractory errors
EARS: low-set, posteriorly rotated, thick helix, COM
NOSE: small + upturned
- Cardiac: PS (50%), ASD/VSD, Cardiomyopathy
- Genital: undescended testes
- Developmental: delayed
- Haematological: blood clotting disorders

Alagille Syndrome

AD
1 in 100,000
Microdeletion of 20p12 corresponding to JAG1 gene
Feats:
- Cardiac: Peripheral PS, PS, TOF
- Liver: Bile duct paucity (absence/marked reduction in number of interlobular bile ducts)
- Facies: Broad forehead, deep-set widely spaced eyes, long straight nose, short pointed chin
- Vertebral: Butterfly vertebrae, fused vertebrae, spina bifida occulta

Cornelia De Lange Syndrome

Majority are spontaneous mutations - 50% d/t mutation of NIPBL gene on Ch5
1 in 30,000
CLINICAL DIAGNOSIS, but can test for above mutation
Feats (FOB):
FACE: microcephaly, synophrys, long eye lashes, long philtrum, low-set ears, short upturned nose, thin downturned lips
OTHER: developmental delay (severe speech delay + mild-moderate MR), seizures (23%), congenital heart disease (VSD/ASD in 25%), GORD (90%), behavioural problems
BODY: excessive body hair, abN limbs (micromelia, oligodactyly, clinodactyly, syndactyly)

Trisomy 13 (Patau Syndrome)

Trisomy 13
1 in 10,000
Increased risk with increased maternal age
Feats:
CNS: MR, microcephaly, micropthalmia
MSK/SKIN: polydactyly, low-set ears, prominent heel, rocker bottom feet, omphalocoele, overlapping of fingers over thumb, cutis aplasia, cleft palate
GENITALS: kidney defects, abN genitals
CLUE: single umbilical artery
80% die in first year of life
Unless parent is translocation carrier, risk of recurrence <1%

Trisomy 18 (Edwards Syndrome)

Trisomy 18
1 in 6,000
80% are female
Most die before birth
Increased risk with increased maternal age
Feats:
CARDIAC: VSD/ASD, PDA, CoA, Bicuspid aortic/pulm valve
RENAL: malformations
GIT: Omphalocoele, oesophageal atresia
MSK: Arthrogryposis
DEVELOPMENT: delayed
PHYSICAL FEATS: microcephaly, prominent occiput, low-set ears, micrognathia, cleft lip/palate, upturned nose, narrow palpabrel fissures, hypertelorism, short sternum, ptosis, clenched hands, absent radius, webbed 2nd/3rd toes, rocker-bottom feet
50% die in first week of life
Only 8% survive beyond 1 yo

Trisomy 21 (Down Syndrome)

1 in 733 (doesn't account for spontaneous abortion)
Tri 21
Hall's criteria for Dx
- Hypotonia
- Poor moro reflex
- Flat face
- Upward slanted palpebral fissures
- Small dysplastic features
- Joint hyperflexibility
- Short neck, loose skin folds
- Short 5th digit with clinodactyly
- Single transverse palmar crease
- Pelvic dysplasia
Other feats:
Craniofacial - brachycephaly, flat occiput, prominent epicanthal folds, speckled irises (Brushfield spots), 3 fontanelles with delayed closure, midface hypoplasia, mild microcephaly, short hard palate, small nose with flat nasal bridge, protruding tongue
MSK - short metacarpals/phalanges, wide-spaced 1st/2nd toes, short sternum
GIT - duodenal atresia, TOF, annular pancreas, Hirschsprung's, imperforate anus
Skin - cutis marmorta
Susceptibilities:
- congenital heart disease, esp AVSD (less commonly ASD/VSD)
- hypothyroidism
- megaloblastic luekaemia + lymphoproliferative disorders (solid tumoure rare in Tri21)
- immune dysfunction
- diabetes
- hearing and vision problems
- Alzheimer's disease-like dementia (4th decade of life)
- developmental delay
Dx: by clinical feats and karyotype, but also do chromosome analysis to rule out translocation cuase, as recurrence risk is 100%

Turner Syndrome

1 in 2,000
45, XO (ie absence of second X chromosome in girls)
Clincal feats:
From birth
- oedema of dorsum of hands/feet
- loose skin folds at nape of neck
- low birth weight
- low body length
Childhood
- webbing of neck
- low posterior hairline
- small mandible
- prominent ears
- epicanthal folds
- high-arched palate
- broad chest with wide spaced nipples
- cubitus valgus
- hyperconvex finger nails
- short stature
- sexual maturation failure (adrenarche normal, but delayed pubarche, and have premature menopause (infertile by 2 yo)
NORMAL INTELLIGENCE
Other problems:
- Congenital heart disease, esp bicuspid aortic valve, aortic dilatation, partial anomalous pulmonary venous drainage, CoA, AS, MV prolapse
- Premature coronary artery disease
- Renal malformations (risk of HTN and UTI's)
- 30 - 50% have thyroid autoantibodies, therefore potential for autoimmune thyroid disease
- increased risk of coeliac disease
Mx - growth hormone in early childhood for short stature and oestrogen replacement in adolescence

Beckwith-Wiedemann Syndrome

Overgrowth disorder
1 in 13,700 (increased in IVF 3-4 fold)
85% sporadic, 15% familial
d/t dysregulation of imprinted expression in Ch11p15.5 region (paternal gene imprinted). Affects critical genes in domain 1 (IGF-2 (overexpression of foetal growth factors) and H19 (tumour suppressor gene))
5 common feats:
Macroglossia
Macrosomia
Midline abdominal wall defects
Ear creases/pits
Neonatal hypoglycaemia
Other possible feats incl. port wine stain, prominent occiput, midface hypoplasia, hemihypertrophy, cardiomyopathy, nephromegaly, hearing loss
INCREASED RISK of childhood cancer (600-fold) esp embryonal tumours (Wilm's + hepatoblastoma), and less likely andrenal coritcal carcinoma, neuroblastoma and rhabdomyosarcoma
Screened for Ca with 3 monthly abdo U/S until 8 yo and 6 weekly AFP for hepatoblastoma

Fragile X Syndrome

1 in 3,600 (less common in girls)
Most common cause of inherited mental retardation
Caused by CGG triplet repeat affecting FMR1 (Fragile x Mental Retardation 1) gene on ChX (FMR protein required for neural development)
Boys show complete penetrance, whereas girls only 50% d/t other normal X chromosome
Feats:
- intellectual impairment (IQ ave 40 in boys) - often with autistic type behaviours, ADHD and anxiety
- large, protruding ears
- long face
- high arched palate
- hyperextensible finger joints
- double jointed thumbs
- pes planus
- post-pubescent macro-orchidism
- hypotonia
- higher risk of seizures
Dx:
- Direct PCR testing and Southern Blot analysis
Number of repeats important
Premutation = 50 - 200
Fragile X syndrome = >200

Pierre-Robin Sequence

1 in 8,500 - 1 in 14,000
Multiple causes (no single genetic cause)
Results from abN growth and migration of the mandible in early development, therefore tongue no completely out and residual defect in palate
Feats:
- Posterior displacement of the tongue --> airway obstruction
- Cleft palate (usually U-shaped)
- Mandibular hypoplasia --> micrognathia

Waardenburg Syndrome

1 in 50,000
AD inheritance
5 major feats:
1. Sensorineural hearing loss
2. Hair hypopigmentation (white hair lock)
3. Dystopia canthorum (lateral displacement of inner canthi)
4. Heterochromia irides (or brilliant blue eyes)
5. First degree relative with WS
5 minor feats:
1. Skin hypopigmentation
2. Synophrys
3. Broad nasal root
4. Hypoplasia alae nasi
5. Premature (<30yo) graying of hair
Subtypes by gene affected:
Type I - PAX3
Type II - MITF
Type IV - PAX3 = have Hirschsprung's
(type II and IV may be AR inherited)

Bardet Biedl Syndrome

1 in 150,000
AR inheritance with variable expression
Ciliopathic condition
Feats:
- Obesity
- Retinitis pigmentosa (initially night blindness then progressive degeneration)
- Postaxial polydactyly
- Hypogonadism
- Renal failure
- Mental retardation (not essential)

Usher Syndrome

1 in 23,000
AR inheritance with multiple different genes can be responsible
Feats (DEAF and BLIND):
- sensorineural deafness
- gradual visual impairment (secondary to retinitis pigmentosa, therefore initially degeneration of rod cells (night blindness/periopheral vision loss) then cone cells/macula (central acuity loss)

Paediatric Syndromes

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