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