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
