Genetics Flashcards
What percentage of Turner’s are 45,X/46,XY mosaicism ?
50%
Clinical features of Turner’s syndrome
Neonates-SGA, webbing of the neck, protruding ears, cystic hygroma, lymphedema of hands and feet
Physical features: short webbed neck, wide spaced nipples, shield chest, lymphedema of hands and feet, short stature/SGA, increased carrying angle
CHD-bicuspid aortic valves (30%), CoA (20%)
Renal anomalies-horseshoe Kidney, pelvic kidney, double collecting system, complete absence of one kidney, UPJ obstruction
Hypogonadism-streak gonads, primary amenorrhea
MSK: patellar dislocation, congenital hip dislocation, madelung deformity (chondrodysplasia of distal epiphysis), scoliosis
Endocrine: Hypothyroidism, T2DM, low BMD
Autoimmune: IBD, increased risk of celiac disease (and hypothyroidism as above)
Eye/Ear: strabismus, cataracts, recurrent otitis media, SNHL, red-green colour blindness
Increased risk of behaviour concerns and LD in motor/visuospatial perception
Other: Low posterior hairline, redundant nuchal skin
What tumour are patients with mosaic Turners at risk for?
Risk of developing gonadoblastoma
NOTE: All girls with new Turner’s diagnosis should have FISH for SRY. If Y chromosome present, need to consider laparoscopic gonadectomy
Management of patients with Turner syndrome (AAP guidelines)
Refer to Endo for GH, Estrogen replacement at puberty
Refer to Genetics (information and preconception counseling)
ECHO
AUS (horseshoe kidney, streek gonads)
Hearing and Eye screen
Yearly Hypothyroid screen with autoantibodies
Celiac and IBD- test based on symptoms
If school concerns, early psychoed. Testing
Support groups/Turner’s societies for patient and family if interested
Clinical features of Noonan’s syndrome
Growth:
Short stature***
Dysmorphisms: Epicanthal folds Ptosis Hypertelorism*** Low nasal bridge Downward-slanting
Heart: Mostly RIGHT SIDED lesions PV stenosis (most common)*** Hypertrophic cardiomyopathy*** ASD VSD
GU: Cryptorchidism*** Small penis and testes Hernia Delayed puberty Infertility (in some)
Heme:
Bleeding diathesis
Thrombocytopenia, Splenomegaly
Mild inc. risk of AML/ALL
MSK: Shield chest Webbed neck*** Wide carrying angle Pectuscarinatum or excavatum Clinodactyly Vertebral anomalies
Eye:
Nystagmus
Myopia
Oncology: Neuroblastoma Acute leukemia Low grade glioma Rhabdomyosarcoma
Other:
SNHL
Low/normal IQ
Management of Noonan’s syndrome
ECHO
Hearing and eye exam
Psychoed assessment
Endocrine for puberty and fertility; consideration of GH
Mechanism of inheritance of Noonan’s
AD
PTPN11 (most common), SOS1, RAF1
Revised Ghent criteria for Marfans
In the absence of family history of MFS, the presence of one of any of the following criteria is diagnostic for MFS:
- Aortic criterion (aortic diameter Z ≥2 or aortic root dissection) and ectopia lentis*
- Aortic criterion (aortic diameter Z ≥2 or aortic root dissection) and a causal FBN1 mutation
- Aortic criterion (aortic diameter Z ≥2 or aortic root dissection) and a systemic score ≥7 (see ‘Systemic score’ below)*
- Ectopia lentis and a causal FBN1 mutation as defined above that has been identified in an individual with aortic aneurysm
In the presence of family history of MFS, the presence of one of any of the following criteria is diagnostic for MFS:
- Ectopia lentis
- Systemic score ≥7 points*
- Aortic criterion (aortic diameter Z ≥2 above 20 years old, Z ≥3 below 20 years, or aortic root dissection)*
Systemic score :
●Wrist AND thumb sign: 3 points (wrist OR thumb sign: 1 point)
●Pectus carinatum deformity: 2 (pectus excavatum or chest asymmetry: 1 point)
●Hindfoot deformity: 2 points (plain pes planus:1 point)
●Pneumothorax: 2 points
●Dural ectasia: 2 points
●Protrusio acetabuli: 2 points
●Reduced upper segment/lower segment ratio AND increased arm span/height AND no severe scoliosis: 1 point
●Scoliosis or thoracolumbar kyphosis: 1 point
●Reduced elbow extension (≤170 degrees with full extension): 1 point
●Facial features (at least three of the following five features: dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia): 1 point.
●Skin striae: 1 point
●Myopia >3 diopters: 1 point
●Mitral valve prolapse (all types): 1 point
List clinical features of Marfan’s
Cardiac
- Aortic root dilatation
- AV valve dysfunction
- MVP
Opthomalogic
- Ectopia lentis
- Myopia
- Increased risk of cataracts and glaucoma
MSK
- Reduced U to L segment ratio
- Pectus carinatum
- Arachnodactyly, camptodactyly
- Thoracolumbar scoliosis
- Protrusio acetabuli
- Joint laxity
- Pes planus
Pulmonary
- Restrictive lung disease
- Distal airspace blebs–>PTX
Skin
-Striae atrophica
Other
-Dural ectasia
How is Marfan’s inherited and what is gene inherited?
AD
Mutations in ECM protein fibrillin-1 (FBN-1) on chromosome 15 (15q21)
What conditions do you need to rule out to make a diagnosis of Marfans?
Homocysteinuria-think if developmental delay*** MVP syndrome MASS phenotype Familial ectopia lentis Weill-Marchesani syndrome Shprintzen-Goldberg syndrome
What investigations are needed to make a diagnosis of Marfans?
- Genetics-FBN1 mutation, TGFβR2 mutation
- Urinary cyanide nitroprusside or amino acid studies (excludes homocystinuria)
- Echocardiogram
- Eye exam
What percentage of Marfans are de novo mutations?
30%
Long term management and surveillance for Marfans
Yearly evaluations for CVS, scoliosis, or ophthalmologic problems
Physiotherapy
Activity restrictions
-Avoid strenuous exertion, competitive athletics, and isometric activities such as weight lifting
Aortic root dilation-consider losartan
Endocarditis prophylaxis
List physical exam findings consistent with Marfans
Reduced U to L segment ratio Pectus carinatum/excavatum Arachnodactyly Camptodactyly Walker Murdoch (full overlap of the distal phalanges of the thumb and 5th finger when wrapped around the contralateral wrist ) Steinberg or thumb sign (distal phalanx of the thumb fully extends beyond the ulnar border of the hand when folded across the palm) Pes planus Reduced extension of elbows Thoracolumbar scoliosis Joint laxity Dolicocephaly Enopthalmos Retrognathia Malar hypoplasia Striae atrophica
List 3 conditions other than Marfans that can cause ectopia lentis
Homocystinuria
Weill-Marchesani
Familial ectopia lentis
What is the genetics of Klinefelter syndrome?
Due to non-dysjunction meiosis (in 50%)
Most are XXY
More XXs=more developmental delay
Can be mosaic
Clinical features of Klinefelter syndrome
General:
Tall stature***
Slim
Decreased U/L segment ratio
Cognitive: *** -LD (most language based) -Executive functioning difficulties -Anxiety
GU:
- Small testes/penis***
- Gonadal failure (high FSH/LH)***
- Gynecomastia
- Cryptoorchidism
- Delayed puberty
- Infertility
Endo:
-Low BMD (related to hypogonadism)
Oncology:
Breast cancer
Germ cell mediastinal masses Leukemia
Lymphoma
Management of Klinefelters
Testosterone replacement
-No later than 11-12yrs
Gynecomastia
-Can be treated with aromatase inhibitors, if fails surgery
Consider early sperm banking
Psychoed for LD and psychosocial disabilities
What is the genetic defect in Russell Silver and how is it inherited?
Chromosome 7p11
Epigenetic modifications – hypomethylation or imprinting, can be uniparental disomy of chromosome 7
Clinical features of Russell Silver syndrome
Dysmorphisms:
- Prominent forehead
- Triangular face
- Micrognathia
- Downturned corners of the mouth
- Pseudohydrocephalus/normal head circumference
- 5th digit clinodactyly***
Growth/development:
- Severe IUGR***
- Body asymmetry (hemihypertrophy or leg length discrepancy)
- Feeding difficulties
- 1/3 Mild developmental delay
Cardiac
-CHDs, none specific
Skin:
-Café au lait macules***
Endo:
- Fasting hypoglycemia***
- GH deficiency
GU:
- PUV
- Hypospadias
Oncologic:
- Craniopharyngioma
- Testicular seminoma
- Wilm’s
- Hepatocellular carcinoma
What is the genetic mutation in achondroplasia and how is it inherited?
Autosomal Dominant
75% de novo
FGFR3 gene
Clinical features of achondroplasia
Facial features:
- Large head
- Midfacial hypoplasia
- Prominent forehead
Resp:
- OSA***
- Recurrent infections
MSK:
- Proximal bone shortening (rhizomelia)***
- Long narrow trunk
- Trident finger configuration
- Reduced AP diameter of thorax (short ribs)
- Thoracolumbar kyphoscoliosis***
- Hyperextensible joints
- Gibbus deformity (worsens with walking)
- Leg bowing ***
Development:
- Delayed motor milestones (walk 18-24mo)***-due to hypotonia and mechanical difficulty balancing large head
- Normal IQ
Growth:
- Short stature/dwarfism – plot on own curves***
- GH controversial
Misc:
- Dental malocclusion***
- Obesity
- Recurrent AOM***
Neuro:
- Hydrocephalus
- Craniocervical junction compression
- Lumbar spinal stenosis
Where is the spinal cord compression in achondroplasia and what are the associated symptoms?
- Cranocervical compression:
- Early in childhood → cord compression
- FTT, hypotonia, quadriparesis, central and obstructive sleep apnea, sudden death - Lumbosacral spinal stenosis
- Adulthood
- Paresthesias, numbness, leg claudication, bowel and bladder symptoms
What is the average adult height in achondroplasia?
4 ft for men and women
Management of achondroplasia (AAP health supervision guidelines)
Anticipatory guidance:
- Rear facing car seat for as long as possible
- Use an infant seat with firm back and neck supports
- Avoid mechanical swings/slings
- No C-sitting position
- Use feeder sesats for upright positioning
- Avoiding the use of walkers, jumpers, or backpack carriers
Sleep study
-Prior to discharge of neonates!
Monitor HC and foraminal size with MRI/CT
PFTs to screen for restrictive pulmonary disease if symptoms
Referral to Neurosx if abnormal neuro exam, rapidly increasing HC, significant apnea, small foramen magnum size on MRI
Referral to orthopedics for severe kyphoscoliosis
Anaesthetic risks (minimize neck manipulation, avoid spinal anaesthesia)
PT and bracing (minimize kyphosis and severe lordosis)
Hearing test yearly
Is Growth hormone effective in achondroplasia?
NO
What percentage of infants with achondroplasia have unexpected infant death?
2-5%
Related to compression of arteries at level of foramen magnum
What is the inheritance pattern of ectopic thyroid?
Sporadic
Rarely autosomal recessive
Diagnostic criteria for Ehlers Danlos
- Skin hyperextensibility
- Widened atrophic scars.
- Joint hypermobility (assessed using the Beighton scale)
- Family history (some types are AD others AR)
Other features: Easy bruising Poor wound healing MV prolapse Artery aneurysms Hernias Recurrent rectal prolapse in childhood
What is uniparental disomy and give an example?
Child inherits both copies of the chromosome from the same parent
Examples: Prader-Willi(loss of paternal chromosome = paternal UPD)
Angelman syndromes (loss of maternal chromosome = maternal UPD)
Russell Silver
Beckwith Wiedmann
In a patient with trisomy 21, what is the probability of having another child with trisomy 21?
50%
What is the risk of recurrence of T21 ?
- Free Trisomy 21-non disjunction
1% - Unbalanced translocation
Higher recurrence rate
t(21;21)= 100% recurrence, t(14,21)=5-7% recurrence** most common translocation - Mosaicism
- No increased risk
Physical features of Trisomy 21
Small brachycephalic head Epicanthal folds Flat nasal bridge Upward-slanting palpebral fissures Brushfield spots Small mouth Small ears Excessive skin at the nape of the neck Single transverse palmar crease Short fifth finger with clinodactyly Wide spacing between the 1st and 2nd toes
Complications associated with Trisomy 21
Growth
- Short stature
- Obesity
Cardiac
-AVSD, VSD, secundum ASD, PDA, TOF
GI
- Duodenal atresia or stenosis
- Imperforate anus
- Esophageal atresia with TEF
Respiratory
-OSA
Endocrine
- Hypothyroidism
- Increased risk of T1DM
- Infertility in most males
Hematologic/Oncologic
- Polycythemia
- Transient myeloproliferative disease
- Increased risk of AMKL/ALL
Hearing/Vision
- Refractive errors
- Strabismus
- Nystagmus
- Cataracts
- Hearing loss
- Frequent AOM
Neurologic
-Atlantoaxial instability
-
Development
- Social development relatively spared
- Expressive language impairment
- Inattentiveness, stubbornness, routine and sameness
AAP health supervision for T21 at birth
CBC at birth TSH and T4 at birth Echocardiogram Red reflex (cataracts) ABR, OAE
AAP health supervision for T21 at 1 month-1 year
Repeat ABR at 3 months, 6 months Counsel about risk of AOM Screen for OSA Screen for myelopathic symptoms TSH at 6 months, 12 months, then annually Optho exam in 1st 6 months
AAP health supervision for T21 at 1-5 years
Audiogram-Q 6 month until 4 years, then annually Annual CBC Annual TSH Sleep study if symptoms Celiac screen if symptoms Avoid contact sports, trampoline < 6 yrs OT/PT/SLP as needed
AAP health supervision for T21 at 5-13 years
Annual hearing test Vision Q2 years Annual CBC Annual TSH Sleep study if symptoms Celiac screen if symptoms Behavioral (ADHD, psychiatric, autism) Sexual health, contraception
AAP health supervision for T21 at 13 years+
Vision Q3 years Annual hearing Annual CBC Annual TSH Sleep study if symptoms Celiac screen if symptoms Echo if symptoms (risk of mitral or aortic valvular disease) Contraception Obesity counseling Transition to adult care
List skin conditions associated with T21
Alopecia areata Cutis marmorata Fissured tongue Seborrheic dermatitis Palmar plantar hyperkeratosis Geographic tongue
When should you screen for atlanto axial instability in T21?
Only if symptomatic
Can’t do xrays until > age 3
What are the diagnostic criteria for tuberous sclerosis?
2 major or 1 major plus 2 minor features
Major Criteria – Cortical tuber Subependymal nodule Subependymal giant cell astrocytoma*** Facial angiofibroma or forehead plaque*** Ungual or periungual fibroma (nontraumatic) Hypomelanotic macules (>3)*** Shagreen patch*** Multiple retinal hamartomas*** Cardiac rhabdomyoma*** Renal angiomyolipoma*** Pulmonary lymphangioleiomyomatosis
Minor Criteria: Cerebral white matter migration lines Multiple dental pits Gingival fibromas Bone cysts Retinal achromatic patch Confetti skin lesions, Nonrenalhamartomas Multiple renal cysts Hamartomatous rectal polyps
How do you diagnose TS?
Brain MRI confirms the diagnosis
Genetic testing forTSC1, TSC2 mutations if patient does not meet all the clinical criteria
What screening tests need to be done in TS?
Brain MRI every 1-3 yr
Renal imaging (ultrasound, CT, or MRI) every 1-3 yr,
Neurodevelopmental testing at the time of beginning 1st grade
How are NF-1 and TS inherited?
AD
Most often de novo mutation
NF-1 criteria
2 of the following 7 features are present
- 6 CALMS (> 5mm prepubertal, >15 mm postpubertal)
- Distinctive osseous lesions – sphenoid wing dysplasia, pseudoarthrosis
- Family history – 1st degree relative
- 2 or more Lisch nodules
- Optic glioma
- 2 neurofibroma or 1 Plexiformneurofibroma
- Axillary or inguinal freckling freckling
How is NF-1 diagnosed?
Clinically!
Optho exam is most important test!
Molecular testing for the NF1 gene if only 1 criteria, if unusually severe disease, if prenatal/pre-implantation diagnosis
Screening tests for NF-1
Yearly ophthalmologic examination
Neurologic assessment, MRI if symptoms
BP monitoring
Screen for scoliosis
Neuropsychologic and educational testing should be considered as needed
NF-2 criteria
1 of the following 4 features is present:
(1) Bilateral vestibular schwannomas
(2) a parent, sibling, or child with NF-2 and either unilateral vestibular schwannoma or any 2 of the following: meningioma, schwannoma, glioma, neurofibroma, or posterior subcapsular lenticular opacities
(3) unilateral vestibular schwannoma and any 2 of the following: meningioma, schwannoma, glioma, neurofibroma, or posterior subcapsular lenticular opacities
(4) multiple meningiomas (2 or more) and unilateral vestibular schwannoma or any 2 of the following: schwannoma, glioma, neurofibroma, or cataract.
List 3 symptoms/signs of sturge weber (other than port wine stain)
Seizures Hemiparesis Strokelike episodes H/A Severe delay/learning disabilities
List 3 characteristics of Port Wine stains found in sturge weber
Unilateral
Present at birth
Always involve upper face eyelid
V1 distribution
What is the prognosis of epilepsy in Sturge Weber?
Most develop seizures within 1st year of life
Focal tonic clonic contralateral to malformation
May become refractory to AEDs
Progressive hemiparesis
What investigations should you order in suspected Sturge Weber?
MRI Brain
Opthalmologic evaluation
List 3 steps in long term management of Sturge Weber
Control seizures
Monitor for glaucoma, buphalthmos
Screen for behavioural issues/learning disabilities
Laser therapy for PWS
Consider hemispherectomy if refractory seizures in 1st 2 years of life
What cancers are patients with NF-1 predisposed to?
Malignant peripheral nerve sheath tumor (MPNST) Pheochromocytoma Rhabdomyosarcoma Leukemia Wilms tumor
What is the gene affected in congenital central hypoventilation syndrome and how is it inherited?
PHOX2B gene
90% - polyalanine repeat expansion mutation (PARM)
(NOTE: more alanine = more likely to need vent support)
10% - non-PARM, missense, nonsense, or frameshift mutation
Autosomal dominant
90% de-novo mutation, but 10% inherit from parents who are mosaic
List clinical features of ROHHAD (Rapid-Onset Obesity, Hypothalamic Dysfunction, Hypoventilation, Autonomic Dysregulation)
- Rapid weight gain
- Hypoventilation
- Hypothalamic dysfunction: ≥1
- ->Rapid-onset obesity
- ->HyperPRL
- ->Central hypothyroidism
- ->Disordered water balance
- ->Delayed/precocious puberty
- ->Failure of response to GH stimulation
- ->Corticotropin deficiency, and –Tumour of neural crest origin
- Intellectual decline
What is obesity hypoventilation syndrome?
Hypoventilation during wakefulness in obese patient
BMI >30 + Awake PaCO2 > 45
What is the pathophysiology of obesity hypoventilation syndrome?
Reduced respiratory compliance
Increased airway resistance
Reduced FRC
Metabolic alkalosis (from OSA) leads to compensatory respiratory acidosis during wakefulness
How do you treat obesity hypoventilation syndrome?
NIV during sleep
Describe the genetics of Beckwith Wiedemann
Paternal UPD for chromosome 11p15
85% of cases are sporadic
List clinical features of BWS
- Macrosomia (gigantism)
- Hemihypertrophy
- Macroglossia
- Anterior ear lobe creases
- Abdominal wall defects
- Exophthalmos
- Hepatosplenomegaly
- Nephromegaly
- Hypoglycemia secondary to hyper-insulinemia from pancreatic β-cell hyperplasia
What tumours are associated with BWS?
Embryonal Tumours • Wilms tumour*** • Hepatoblastoma*** • Neuroblastoma • Rhabdomyosarcoma • Adrenocortical carcinoma
What is the initial work up for a baby with suspected BWS?
Assess for airway difficulties
Feeding specialist
Assess neonates for hypoglycemia
AUS to assess for organomegaly, structural abnormality, and tumours
AFP to assess for hepatoblastoma
Health supervision guidelines for BWS
Developmental screening
Screen for embryonal tumors
AUS every 3 months until 8 y.o
AFP every 3 months in the first 4 years of life for hepatoblastoma
NOTE: AUS also screens for renal anomalies and nephrocalcinosis/nephrolithiasis
What is the genetic mutation in Sotos syndrome?
NSD1 mutation
List clinical features of Sotos syndrome
> 90th percentile for length and weight at birth
Rapid growth for the first 4-5 years and then normalizes
- Macrocephaly/Dolichocephalic head
- Prominent forehead and jaw
- Hypertelorism
- “Antimongoloid” slant of the palpebral fissures
- High-arched palate
- Large hands and feet with thickened subcutaneous tissue
- Clumsiness and awkward gait
- At risk for hepatic carcinoma
Describe the genetics of Fragile X
FMR1 gene on the X chromosome
Variable number of trinucleotide (CGG) repeats
Larger the triplet repeat expansion= worse mental retardation
Expansion of > 200 repeats = full mutation
50 – 200 repeats = premutation
List clinical features of Fragile X
-Mental retardation
-Autistic behaviour (25% meet criteria for ASD)
-ADHD or LD
-Macro-orchidism
-Characteristic facial features
o Long face
o Large ears
o Prominent, square jaw
o Relative macrocephaly (HC > 50th %le)
-Mild connective tissue disorder (joint laxity, MVP)
-Epilepsy (10-20%)
-Family history of POF (female with prematutation)
What test do you order for Fragile X?
Molecular testing for FMR1 gene (looking for CGG repeats)
List the clinical features of VACTERL
Vertebral Anomalies
-Butterfly, hemi, wedge, sacral agenesis, rib anomalies, scoliosis, tethered cord
Anorectal Malformation
-Imperforate anus, anal atresia, fistula
Cardiac Defects
-CHD, situsinversus, vascular anomalies, arrhythmias
TEF/EA
Renal Defects
-Renal agenesis, cystic/dysplastic kidney, horseshoe kidney, ureteral anomalies
Limb defects
-Radial abN, thumb abN, polydactyly, limb or digit hypoplasia
List conditions associated with hemivertebrae
Congenital scoliosis VACTERL Aicardi syndrome OEIS Gastroschisis Jarcho-Levin syndrome Gorlin syndrome
List 3 effects of maternal PKU
Microcephaly
CHD
Intellectual disability
What is one complication of maternal hyperthermia ?
NTDs
CHD
Clinical features of CHARGE syndrome
C-Coloboma H-Heart disease A-Atresia of choanae R-Mentral retardation, retarded growth G-Genital anomalies, hypogonadism E-ear anomalies, deafness
Other features include:
- IUGR
- Cleft palate
- Feeding difficulty
- Cranial nerve abN
- Hypogonadotropic hypogonadism
- FTT
- IQ from normal to developmental delay
- Immunodeficiency has been associated
Describe the genetics of CHARGE syndrome
CHD7 gene
Autosomal dominant
Describe genetics of Williams syndrome
Hemizygous deletion on chromosome 7q11.23
Clinical features of Williams syndrome
Dysmorphism: elfin-like, broad forehead, medial eyebrow flare, strabismus, flat nasal bridge, malar flattening, a short nose with a long philtrum, full lips, and a wide mouth
Short stature
Cardiac:
-Supravalvular aortic stenosis or branchpulmonary artery stenosis
Endo:
- Hypercalcemia***
- Diabetes mellitus
- Subclinical hypothyroidism***
Development:
- Impaired cognition and development (higher average verbal IQ than performance IQ)
- “Cocktail party”personality
- Receptive language delay
- ADHD and Anxiety
GU:
- CAKUT (Renal artery stenosis***, horseshoe kidney)
- HTN***
- Nephrocalcinosis*** due to hypercalciuria and dysfunctional voiding
Other:
-SNHL or Conductive HL
What tests should you do in a child with suspected Williams?
- Echo
- Renal U/S, Cr/BUN and U/A
- Auditory and vision testing
- Serum calcium
- Thyroid function
- BP → yearly measurements
- Developmental assessment
What are the clinical features of DiGeorge syndrome?
Dysmorphisms: Low set, posteriorly rotated, protruding ears, hypertelorism, bulbous nasal tip, short philtrum of the upper lip, small mouth (mandibular hypoplasia) and bifid uvula Cleft palate Cardiac anomalies (TOF, TA, interrupted aortic arch type 2B) Thymic aplasia Hypoparathyroidism (hypocalcemia) Esophageal atresia Renal anomalies (e.g. Horseshoe kidney) Undescended testes Hypogonadotropic hypogonadism Short stature Developmental delay/LD/psychosis
Genetics of DiGeorge
Autosomal dominant
Deletion in chromosome 22q11.2
What is the embryology of DiGeorge syndrome?
Multiple anomalies of 3rd/4th pharyngeal pouch structure
What percentage of patients with Di George have behaviour/psychiatric problems such as schizophrenia?
50%
How do you make a diagnosis of DiGeorge?
- Clinical findings + reduced CD3+ T cells
OR - FISH 22Q11.2 deletion
What tests should you order in a patient with suspected DiGeorge?
Echo Serum calcium and phosphorus levels CBC and differential CXR-thymus Renal U/S Lymphocyte immunophenotyping Immunoglobulins
What are the clinical features of Angelmans?
Wide mouth, protruding tongue, prominent mandlible
Severe to profound intellectual disability
Postnatal microcephaly
Seizures
Movement disorder: Gait ataxia and/or tremulous movement of limbs
Behavior characteristics: Frequent laughter or smiling, happy demeanor,an easily excitable personality, fascination with water and mouthing behaviors
Hand flapping movements are common (‘Happy Puppet”)
Sleep problems
Developmental delay-esp expressive language
Describe the genetics of Angelman syndrome
Loss of maternally imprinted chromosome 15q11-13
Maternal deletion
OR
Paternal UPD
What genetic tests should you order for Angelman syndrome?
Microarray will pick up deletion, but will not tell you whether deletion was from mom or dad
Therefore need methylation studies!
- Methylation studies
- If above positive, chromosome microarry to determine type of deletion
Chromosome microarray - If methylation studies negative, UPD studies to determine if the patient has paternal UPD using microsatellite DNA markers or SNPs
Management of Angelman syndrome
- Developmental assessment
- EEGs
- Evaluate for feeding problems and gastroesophageal reflux
Genetics of Prader Willi syndrome
Paternally-derived chromosome 15 with 15q11 deletion deletion
OR
Maternal UPD
Clinical features of PWS
Hypotonia in infancy
Poor feeding in infancy with FTT
Hyperphagia and obesity in children and adults
Genital hypoplasia(hypogonadotropic hypogonadism) and cryptorchidism
Small hands and feet
Dysmorphic facial features: Almond-shaped eyes, thin upper lip
Mild intellectual disability
OSA
Sleep and behavior problems
Genetics of Alagille syndrome
Autosomal dominant
JAG-1 (>90%) or NOTCH-2 gene mutation
Clinical features of Alagille syndrome
Chronic cholestasis: Intrahepatic bile duct paucity
Cardiac: Peripheral pulmonic stenosis
Butterfly vertebrae
Posterior embryotoxon
Dysmorphic features: Broad nasal bridge, triangular faciesand deep set eyes
Short Stature
Pancreatic Insufficiency
How do you diagnose Alagille syndrome?
Liver biopsy findings: reduced number of bile ducts (may not be apparent in infants <6 mos)
JAG-1 or NOTCH-2 mutation
Management of Alagille syndrome
Treat cholestatic liver disease conservatively (i.e.manage pruritus and malabsorption as needed)
End stage disease develops in 20% → Liver Transplant
Nutrition support with fat soluble vitamins
Genetics of Smith Lemli Optiz
Autosomal recessive
Chromosome 11q12-q13
Defect in a cholesterol biosynthetic enzyme (C7-dehydrocholesterol-reductase)
Low plasma cholesterol and accumulated precursors
Clinical features of Smith Lemli Optiz
Microcephaly
IUGR (often SA)
FTT and feeding problems
Craniofacial anomalies: Antevertednares, broad alveolar ridges,epicanthal folds, bitemporal narrowing, retromicrognathia, low set, posteriorly rotate ears
Cleft palate
Ophtho: Ptosis, Cataracts
CNS:Agenesis of corpus callosum, holoprosencephaly
Cardiac:ASD, VSD, PDA
Endo: Adrenal Insufficiency
GI: Pyloric stenosis, Hirschsprungs
GU: Ambiguous genitalia (normal genital if 46XX), hypospadias, cryptorchidism, renal hypoplasia, hydronephrosis
MSK: Postaxial polydactyly, syndactyly of the 2nd-3rd toes, equinovarus deformity
Severe intellectual disability
How do you diagnose Smith Lemli Optiz ?
Low plasma cholesterol with elevated 7-dehydrocholesterol
Treatment of Smith Lemli Optiz
Supplementary dietary cholesterol (egg yolk)
HMGCoA reductase inhibition→prevents synthesis of toxic precursors proximal to enzymatic block
Genetics of Cornelia de Lange
Autosomal dominant
Mutation NIPBL gene 50-60%
Clinical features of Cornelia de Lange
Facial dysmorphisms: Synophyrys, low anterior hairline, arched eyebrows, mandibular hypoplasia, aneverted nares, long philthrum, thin down-turning upper lip
Microcephaly
IUGR
Growth retardation
Severe intellectual disability
Upper limb and digit anomalies (proximally placed thumb)
GERD and Pyloric stenosis
Endocrinopathies→Hirsutism
How is Waardenburg syndrome inherited?
AD
Clinical features of Waardenburg syndrome
Localized areas of depigmented skin and hair
White forelock
SNHL
Heterochromia irides
Dysmorphic features: Synophrys and dystopia canthorum (lateral displacement of inner canthi of the eye giving appearance of broad nasal bridge)
Limb abnormalities Hirschsprung disease
Clinical features of trisomy 18 (Edward Syndrome)
Microcephaly
Cardiac: VSD, PDA, ASD
Craniofacial anomalies:
Micrognathia, narrow nose, low-set malformed ears, prominent occiput, small mouth
MSK:
- Rocker bottom feet
- Clinodactyly and overlapping fingers (flexion deformities of the fingers)
- Clenched fists
- Syndactyly
- Narrow hips with limited abduction
- Short sternum
- Hypoplastic nails
IUGR
FTT
Hearing Loss
GI:
- Omphalocele
- Meckel’s
- Malrotation
Renal anomalies
Severe developmental disabilities
Clinical features of trisomy 13 (Patau syndrome)
Cutis aplasia*
Microcephaly*
CNS: Holoprosencephaly* and seizures
Cleft lip and palate*
Craniofacial anomalies: Hypotelorism, sloping forehead, bulbous nose, low set malformed ears
Ophtho: Glaucoma, micropthalmia and coloboma
Cardiac:* VSD, ASD, PDA, coarctations of aorta, bicuspid aortic or pulmonary valve
MSK: Thin posterior ribs, postaxial polydactyly* and clinodactyly, club foot
Omphalocele or umbilical hernia
IUGR andFTT
Hearing loss
Renal anomalies
Severe developmental disabilities
Superficial hemangiomas
Genetics of Osteogenesis Imperfecta
Majority AD
AR (5-7%)
COL1A1, COL1A2, LEPRE1, or CRTAP
Pathophysiology of Osteogenesis Imperfecta
Caused by structural or quantitative defects in type I collagen = primary componentof the extracellular matrix of bone and skin
What is the classic triad of OI?
(1) Fragile bones
(2) Blue sclerae
(3) Early hearing loss
Clinical features of OI type I
Mild, normal life expectancy Blue sclerae Brittle bones (fractures decrease after puberty) No deformities Hearing loss Dentinogenesis imperfecta in some
Other features: easy bruising, joint laxity, mild short stature
Clinical features of OI type 2
LETHAL in perinatal period
Clinical features of OI type 3
Second most severe Progessive structural bone deformities Fractures usually occur in utero Macrocephaly Triangular facies Extreme short stature
Clinical features of OI type 4
Severe, but not as bad as OI type 3
Normal sclerae
Recurrent fractures after ambulation, with resulting moderate bowing
Tooth abnormalities
Clinical features of OI type 5/6
Clinically have OI type IV, but with different radiographic findings
-Hyperplastic callus, calcification of the interosseous membrane of the forearm and a radiodense metaphyseal band
Diagnosis of OI
Collagen biochemical studies using cultured dermal fibroblasts
DNA sequencing to identify mutations in COL1A1, COL1A2, LEPRE1, or CRTAP
List 3 features of OI (other than fractures) (past SAQ)
-Blue sclerae
-WormianBones
-Early deafness
-Short Stature
-Scoliosis
-Neurologic complications include basilar invagination, brainstem
compression, hydrocephalus, and syringohydromyelia.
-Recurrent pneumonias and declining pulmonary function
-Cor pulmonale
Treatment of OI
PT for ambulation support
Ortho for fracture management
Bisphosphonates
GH may improve bone histology
Recurrence risk of second child having OI in unaffected couple ?
5-7%
Clinical features of OI type 7/8
Recessive form Overlap types II and III but have distinct features: White sclerae Rhizomelia Small to normal head circumference
Most common anomaly associated with single umbilical artery
Renal abnormalities
Clinical features of septo-optic dysplasia
Midline defects
- Corpus callosum agenesis
- Absent septum pallucidum
- Optic nerve hypolasia
- Small anterior pituitary
- Panhypopituitarism to isolated deficiencies (GH deficiency, hypothyroidism or DI)
Genetics of Rett’s syndrome
MECP2 gene
Almost exclusively females
Clinical features of Rett’s syndrome
- Deceleration of head growth/Microcephaly
- Stereotypic, repetitive wringing hand movements
- ASD
- GTC seizures
- Ataxia and fine tremor in hands
- Sighing respirations with intermittent periods of apnea
- Feeding disorders, FTT
- Higher rate of cardiac arrhythmias leading to sudden death
What is the recurrence risk of isolated cleft lip and palate?
4% recurrence risk
2.7% (unilateral), 5.4% (bilateral)
What is the syndrome that causes AD CLP?
Van der Woude syndrome
What percentage of infants with complete DiGeorge have CHARGE association?
1/3
Coloboma, genital hypoplasia and ear anomalies including deafness
What test is important in patient with suspected Waardenburg?
Hearing test
What is Amelogenesis imperfecta
Hereditary condition
Enamel defects of the primary and permanent teeth without evidence of systemic disorders
List 3 types of chromosome tests
Karytope
FISH
Microarray-microdeletions/duplications
What is molecular/DNA testing?
Sequences a gene
Detects SINGLE GENE disorders
(e.g. CFTR, FRAX for Fragile X, TSC1/TSC2, FBN1 for Marfans)
Late complications of Turners syndrome
Low BMD T2DM Hyperlipidemia HTN IBD, Celiac Infertility
Most common cardiac lesion in DiGeorge
TOF
What ongoing surveillance should you do in DiGeorge?
Calcium, PTH CBC +diff Immunologic evaluation Opthomalmology Audiology Cervical spine (>4 years) Scoliosis exam Dental evaluation Developmental screening Psychiatric screening Gynecologic/contraceptive services
At diagnosis only -echocardiogram, renal ultrasound, ECG, TSH
NF-1 features by age Infancy/preschool School Age Adolescence Adulthood
Infancy/preschool
- Plexiform neurofibroma
- Tibial dysplasia
- Development
School Age
- Optic glioma
- Lisch nodules
- Short stature
- HTN
- Scoliosis
Adolescence
-Dermal neurofibromas
Adulthood
- Malignancy
- Osteopenia
List 3 triple repeat disorders
Fragile X
Huntington
Congenital myotonic dystrophhy
Components of Pierre RObin Sequence
Mandibular hypoplasia
Posteriorly displaced tongue
Cleft palate
