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Flashcards in Genetics Deck (136)
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1

What percentage of Turner's are 45,X/46,XY mosaicism ?

50%

2

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

3

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

4

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


5

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

6

Management of Noonan's syndrome

ECHO
Hearing and eye exam
Psychoed assessment
Endocrine for puberty and fertility; consideration of GH

7

Mechanism of inheritance of Noonan's

AD
PTPN11 (most common), SOS1, RAF1

8

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

9

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

10

How is Marfan's inherited and what is gene inherited?

AD
Mutations in ECM protein fibrillin-1 (FBN-1) on chromosome 15 (15q21)

11

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

12

What investigations are needed to make a diagnosis of Marfans?

1. Genetics-FBN1 mutation, TGFβR2 mutation

2. Urinary cyanide nitroprusside or amino acid studies (excludes homocystinuria)

3. Echocardiogram

4. Eye exam

13

What percentage of Marfans are de novo mutations?

30%

14

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

15

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

16

List 3 conditions other than Marfans that can cause ectopia lentis

Homocystinuria
Weill-Marchesani
Familial ectopia lentis

17

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

18

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

19

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

20

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

21

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

22

What is the genetic mutation in achondroplasia and how is it inherited?

Autosomal Dominant
75% de novo
FGFR3 gene

23

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

24

Where is the spinal cord compression in achondroplasia and what are the associated symptoms?

1. Cranocervical compression:
-Early in childhood → cord compression
-FTT, hypotonia, quadriparesis, central and obstructive sleep apnea, sudden death

2. Lumbosacral spinal stenosis
-Adulthood
-Paresthesias, numbness, leg claudication, bowel and bladder symptoms

25

What is the average adult height in achondroplasia?

4 ft for men and women

26

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

27

Is Growth hormone effective in achondroplasia?

NO

28

What percentage of infants with achondroplasia have unexpected infant death?

2-5%
Related to compression of arteries at level of foramen magnum

29

What is the inheritance pattern of ectopic thyroid?

Sporadic
Rarely autosomal recessive

30

Diagnostic criteria for Ehlers Danlos

1. Skin hyperextensibility
2. Widened atrophic scars.
3. Joint hypermobility (assessed using the Beighton scale)
4. 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