Genetic Syndromes Flashcards
Achondroplasia
Most common skeletal dysplasia - **autosomal dominant **- FGFR3 mutation - 50% sporadic. Generally normal lifespan but risk of cervical cord compression
1:20000
Non-Proportional dwarfism
Limbs: Rhizomelic shortening - upper part of limbs. Trident shaped hands. Ligament laxity. Varus/valgus
Face: Frontal bossing, Small midface with flattened nasal bridge. Dental malocclusion
**Spine **: Kyphosis/lordosis, scoliosis, gibbus
CVS: Pulm HTN from OSA
Ears: OM
Narrow Foramen Magnum - Hydrocephalus
Danger of cervical CC due to narrow foramen magnum =- offer LL neurology for SCC
Tx: orthopaedic - kyphoscoliosis
Neurosurgical - decompress the foramen magnum or shunt hydrocephalus
Near-normal life expectancy if heterozygous
Specialised Growth Charts
Spirometry - reduced lung capacity & OSA
Trisomy 21
Poland Syndrome (unknown aetiology and not heritable)
Radar O Reilly!
Absent pectorals
Short or webbed fingers on ipsilateral side
1:20000 M:F 3:1. R>L
Sx:
GI abnormalities
Abnormalities of pectorals, humerus, ulna, radius
Oligo (missing) or Brachy (short) or Syn (webbed) dactyly
Dextrocardia
Diaphragmatic hernia
Liver/biliary abnormalities
Single palmar crease on same side
Moebius Syndrome
Facial paralysis, unable to move eyes side to side, no eye closing
Underdeveloped 6 and 7th nerve
?Vascular disruption in embryology. Sometimes auto dom
Sx:
Normal intelligence
Poor lateral eye movements
Lack facial expression - facial paralysis
High palate, hypotonic tongue, upper lip retraction
Can have VIII affected -> hearing loss
Talipes, oligodactyly
Strabismus
Potter Sequence
Classic: bilateral renal agenesis
T1: ARPKD
T2: Renal agenesis
T3: ADPKD
Sx:
Oligohydramnios -> compression by uterus -> physical deformities
LL abnormalities - talipes, bowing, sirenomelia (usually fatal)
Parrot beak nose, redundant skin, skin fold from canthus across cheek.
Low ears
GU anomalies, Anal atresia, Atresia of duodenum/colon/oesphagus, Diaphragmatic hernia
Weaver syndrome
**Autosomal dominant **
Rapid growth beginning in the prenatal period
Macrocephaly
Flattened occiput
Long philtrum
Retrognathia
Round face in infancy
Prominent chin crease
Large ears
Strabismus
Hypertelorism
Epicanthal folds
Downslanting palpebral fissures
Loose skin, thin deep-set nails, thin hair, short ribs, limited elbow and knee extension, camptodactyly, and a coarse, low-pitched voice.
Sotos syndrome
Overgrowth and advanced bone age
1:14000
LGA
Elongated Macrocephaly, Down slanting palpebral fissures and a pointed chin.
Hypertelorism, prominent forehead, large hands, feet, ears, nose and genitalia
Intellectual impairment; autistic traits.
Frequent behavioural impairments include ADHD, phobias, OCD, tantrums, and impulsive behaviours.
Vocal: stuttering, difficulty with sound production, or a monotone voice.
Hypotonia -> dev delay
Other signs include scoliosis, seizures, heart or kidney defects, hearing loss, and problems with vision
NSD1 mutation
Turner Syndrome
1:2500
50% due to XO
Hypogonadism & short stature (growth and pubertal failure)
Hands: Cubitus valgus, oedema of hands and feet, hyperconvex nails, short 4th/5th
Head: Webbed neck, low hairline, high arched palate,
Chest: Wide spacing of nipples, shield chest, Cardiac scarring
Chronic OM
CVS: bicuspid aortic, Aortic coarctation, aortic dissection
Gonadal dysgenesis: streak ovaries, amenorrhea, delayed puberty (15% start but delay)
Renal: Congenital renal, HTN, T2DM, Hyperlipidaemia
Learning difficulties
Screening for Abnormalities - Thyroid
GH replacement
Oestrogen/progesterone replacement - Pubertal staging
School support
Noonan Syndrome
Auto Dom
1:1000-2500
Mean IQ 85
30%: Coag defects - vW, low plt, Factors abnormal
Short
Facies: hypertelorism, epicanthic fold, ptosis, micrognathia, low-set and posteriorly rotated ears, depp philtrum, small upturned nose
Chest: widely spaced nipples, cubitus valgus, pubertal delay
CHD: Pulmonary stenosis, ASD, VSD, HOCM
Cryptorchidism, herniae
Russell-Silver
1:75000
Uniparental disomy of Chr 7 and defect on Chr 11
Relative macrocephaly (Normal HC). IUGR -> SGA. Poor growth
Limb: hemi-hypertrophy, clinodactyly, camptodactyly, toe syndactyly
Head: triangular face with high forehead and micrognathia, relatively large head, blue sclera, prominent nasal bridge, late closure of AF, short and webbed neck (Sprengel’s deformity)
Hypospadias or undescended testes
Hypoglycaemia & feeding difficulties
Denys-DRASH or DRASH syndrome
Abnormality in the WT1 gene
Triad:
1. Pseudohermaphroditism
2. Mesangial renal sclerosis
3. Wilms’ tumor.
Early nephrotic syndrome -> mesangial renal sclerosis -> kidney failure usually before 3y
SX: loss of playfulness, decreased appetite, weight loss, growth delay, abnormal skeletal development, insomnia, abdominal pain, constipation, and anuria.
WAGR syndrome
Wilms tumour
Aniridia
Genitourinary anomalies (Gonadoblastoma)
Mental Retardation
Mutation on chromosome 11 in the microdeletion of 11p13 - FISH (fluorescent in situ hybridization)
Mx:
Regular kidney surveillance for Wilms’ tumour until at 6–8 y
Thereafter follow-up of late onset nephropathy
Females may have streak ovaries, increase the risk of gonadoblastoma
Beckwith Wiedemann
Foetal overgrowth
1:14000
Most sporadic, some Auto Dom
3 Major or 2 major & 3 minor:
Major
1. Pre or postnatal overgrowth
2. Macroglossia
3. Abdominal wall defects
Minor
* Ear lobe creases or posterior helical pits
* Facial naevus flammus
* Hypoglycaemia
* Organomegaly
* Hemihypertrophy (25%)
Higher likelihood of prematurity. Commonly hypoglycaemia. Some req diazoxide. CHD in <10%.
Tongue -> feeding problems, OSA, speech problems
Overgrowth associated with advanced bone age
Neoplasia in 5-10% - commonly Wilm’s, then adrenocortical carcinoma, hepatoblasoma, neuroblastoma - higher risk in hemihypertrophy
Learning difficulties - NN hypoglycaemia
Mx:
* AFP monitor to 4 y
* Reg USS until 8 yrs
By adolescence can lead a normal life if no sequalae of hypoglycaemia
Prader Willi
Lack of active 15q11-q13. The genes in the PWS region are normally only active on the paternal chromosome
Dysfunction of hypothalamus
- Hypotonic - weak cry or suck
- Failure to thrive
- Unregulated appetite (hyperphagia)
- Learning disabilities
- Growth hormone deficiency/short stature,
- Small hands and feet, narrow forehead, light skin & hair
- Scoliosis
- Sleep disturbances with excessive daytime sleepiness
- Speech apraxia/dyspraxia
- OCD symptoms, skin picking, and labile emotions
Cornelia de Lange
Spontaneous genetic mutations
Slow growth pre & post birth -> short stature
* Intellectual disability
* Abnormalities of bones in the arms, hands, and fingers
* Hypertrichosis
* Microcephaly
* Hearing loss
* GI issues
* CLP
Facies: arched eyebrows often meet in the middle (synophrys), long eyelashes, low-set ears, small and widely spaced teeth, small and upturned nose
Social interaction issues
Rubenstein Taybi
Facies: Downslanted palpebral fissures, long eyelashes, high-arched eyebrows. Low-hanging nasal septum (columella), high palate, and an extra cusp on the lingual side of a front tooth (talon cusps
- Brachydactyly
- Keloid scarring
- Broad hallux phalanx and Broad thumb
- Convex nasal ridge
- Downslanted palpebral fissures
- Failure to thrive and Feeding difficulties in infancy
- Global developmental delay
- High palate
- Hypertelorism
- Intellectual disability
- Joint hyperflexibility
- Low-set ears
- Short stature
- Telecanthus
MPS general examination
Coarse facial features
Thick lips, large face, frontal bossing, flat midface, prominent sutures, flat nose
Limb: CTS correction, Joint stiffness, contractures
Head: Corneal clouding after 1 yr (not in Hunter’s)
Fundi - cherry red spot
Nasal discharge
UA obstruction
CVS: congestive cardiac failure
Abdo: umbilical hernia, hepatosplenomegaly
Joint stiffness, contractures
Kyphosis, gibbus, scoliosis, cervical rod surgery
Offer: Dev examination, fundoscopy
Hunter vs Hurler
and Others…. Morquio, Maroteaux, Sanfilippo
…………………………Hunter Hurler
Inheritance: X link rec Auto rec
Corneal: No Yes
Severity: Less More
Scapulae nodules: Yes No
Morquio - severe features, normal intelligence, cervical issues
Maroteaux - sim to above
Sanfilippo - less severe physical, profound learning difficulties
Klinefelter XXY
1:1000-1500 males
Tall w long limbs
Delayed puberty or gynecomastia ( increased risk of breast Ca)
Testicular <6ml
Poor growth of pubic hair or facial hair
Below average intelligence
XYY
Above average height and normal intelligence
Increased behavioural issues
Normal genitalia and puberty
McCune Albright
Endocrine, bone and skin abnormalities
GNAS 1 mutation -> switch on GHRH receptor, MSH recptor, LH receptor, ACTH receptor
Hyperthyroidism, Cushing, precocious puberty.
O/E
* Tall or short
* Increased pigmentation with ragged edge
* Evidence of precocious puberty
* Hyperthyroid or Cushing
* Bone disease - fractures, CN compression
* Osteomalacia - increased renal phosphate loss
Apert Syndrome
Autosomal dominant
Acrocephalosyndactyly.
The cranium, midface, and the bones and soft tissues of the hands and feet are affected.
Craniosynostosis, midface hypoplasia, and symmetric syndactyly of the extremities, with cutaneous and bony fusion.
Turribrachycephaly (towering skull deformity), hypertelorism, and low-set ears are also prominent features.
Airway obstruction due to small nasopharyngeal and oropharyngeal dimensions, +- choanal atresia or tracheal stenosis
OSA = risk of cor pulmonale
Proptosis with risk of corneal injury, amblyopia, strabismus, and optic nerve atrophy.
Crouzon Syndrome
Crouzon syndrome shares many clinical features with Apert syndrome, but the viscera and extremities are spared.
Also known as craniofacial dysostosis (malformation of the face and skull bones)
Autosomal dominant
Craniosynostosis, midface hypoplasia, mandibular prognathism, and shallow eye sockets with hypertelorism and proptosis.
Premature fusion of the coronal sutures, brachycephaly (short and broad head)
Intellectual delay may occur secondary to increased ICP and hearing impairment.
Conductive hearing loss due to ear canal abnormalities (atresia or stenosis).
Airway obstructive problems are similar to those seen in Apert syndrome.
Goldenhaar Syndrome
Incomplete development of ear, nose, soft palate, lip and mandible unilaterally.
Limabl dermoids
Preauricular skin tags
Strabismus
Scolliosis
?Genetic cause - unknown
