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Flashcards in Genetics Deck (136)
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1
Q

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

A

50%

2
Q

Clinical features of Turner’s syndrome

A

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
Q

What tumour are patients with mosaic Turners at risk for?

A

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
Q

Management of patients with Turner syndrome (AAP guidelines)

A

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
Q

Clinical features of Noonan’s syndrome

A

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
Q

Management of Noonan’s syndrome

A

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

7
Q

Mechanism of inheritance of Noonan’s

A

AD

PTPN11 (most common), SOS1, RAF1

8
Q

Revised Ghent criteria for Marfans

A

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
Q

List clinical features of Marfan’s

A

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
Q

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

A

AD

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

11
Q

What conditions do you need to rule out to make a diagnosis of Marfans?

A
Homocysteinuria-think if developmental delay***
MVP syndrome
MASS phenotype
Familial ectopia lentis
Weill-Marchesani syndrome
Shprintzen-Goldberg syndrome
12
Q

What investigations are needed to make a diagnosis of Marfans?

A
  1. Genetics-FBN1 mutation, TGFβR2 mutation
  2. Urinary cyanide nitroprusside or amino acid studies (excludes homocystinuria)
  3. Echocardiogram
  4. Eye exam
13
Q

What percentage of Marfans are de novo mutations?

A

30%

14
Q

Long term management and surveillance for Marfans

A

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
Q

List physical exam findings consistent with Marfans

A
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
Q

List 3 conditions other than Marfans that can cause ectopia lentis

A

Homocystinuria
Weill-Marchesani
Familial ectopia lentis

17
Q

What is the genetics of Klinefelter syndrome?

A

Due to non-dysjunction meiosis (in 50%)
Most are XXY
More XXs=more developmental delay
Can be mosaic

18
Q

Clinical features of Klinefelter syndrome

A

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
Q

Management of Klinefelters

A

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
Q

What is the genetic defect in Russell Silver and how is it inherited?

A

Chromosome 7p11

Epigenetic modifications – hypomethylation or imprinting, can be uniparental disomy of chromosome 7

21
Q

Clinical features of Russell Silver syndrome

A

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
Q

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

A

Autosomal Dominant
75% de novo
FGFR3 gene

23
Q

Clinical features of achondroplasia

A

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
Q

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

A
  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
Q

What is the average adult height in achondroplasia?

A

4 ft for men and women

26
Q

Management of achondroplasia (AAP health supervision guidelines)

A

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
Q

Is Growth hormone effective in achondroplasia?

A

NO

28
Q

What percentage of infants with achondroplasia have unexpected infant death?

A

2-5%

Related to compression of arteries at level of foramen magnum

29
Q

What is the inheritance pattern of ectopic thyroid?

A

Sporadic

Rarely autosomal recessive

30
Q

Diagnostic criteria for Ehlers Danlos

A
  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
31
Q

What is uniparental disomy and give an example?

A

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

32
Q

In a patient with trisomy 21, what is the probability of having another child with trisomy 21?

A

50%

33
Q

What is the risk of recurrence of T21 ?

A
  1. Free Trisomy 21-non disjunction
    1%
  2. Unbalanced translocation
    Higher recurrence rate
    t(21;21)= 100% recurrence, t(14,21)=5-7% recurrence** most common translocation
  3. Mosaicism
    - No increased risk
34
Q

Physical features of Trisomy 21

A
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
35
Q

Complications associated with Trisomy 21

A

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
36
Q

AAP health supervision for T21 at birth

A
CBC at birth
TSH and T4 at birth
Echocardiogram
Red reflex (cataracts)
ABR, OAE
37
Q

AAP health supervision for T21 at 1 month-1 year

A
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
38
Q

AAP health supervision for T21 at 1-5 years

A
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
39
Q

AAP health supervision for T21 at 5-13 years

A
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
40
Q

AAP health supervision for T21 at 13 years+

A
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
41
Q

List skin conditions associated with T21

A
Alopecia areata
Cutis marmorata
Fissured tongue
Seborrheic dermatitis
Palmar plantar hyperkeratosis
Geographic tongue
42
Q

When should you screen for atlanto axial instability in T21?

A

Only if symptomatic

Can’t do xrays until > age 3

43
Q

What are the diagnostic criteria for tuberous sclerosis?

A

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
44
Q

How do you diagnose TS?

A

Brain MRI confirms the diagnosis

Genetic testing forTSC1, TSC2 mutations if patient does not meet all the clinical criteria

45
Q

What screening tests need to be done in TS?

A

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

46
Q

How are NF-1 and TS inherited?

A

AD

Most often de novo mutation

47
Q

NF-1 criteria

A

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
48
Q

How is NF-1 diagnosed?

A

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

49
Q

Screening tests for NF-1

A

Yearly ophthalmologic examination

Neurologic assessment, MRI if symptoms

BP monitoring

Screen for scoliosis

Neuropsychologic and educational testing should be considered as needed

50
Q

NF-2 criteria

A

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.

51
Q

List 3 symptoms/signs of sturge weber (other than port wine stain)

A
Seizures
Hemiparesis
Strokelike episodes
H/A
Severe delay/learning disabilities
52
Q

List 3 characteristics of Port Wine stains found in sturge weber

A

Unilateral
Present at birth
Always involve upper face eyelid
V1 distribution

53
Q

What is the prognosis of epilepsy in Sturge Weber?

A

Most develop seizures within 1st year of life
Focal tonic clonic contralateral to malformation
May become refractory to AEDs
Progressive hemiparesis

54
Q

What investigations should you order in suspected Sturge Weber?

A

MRI Brain

Opthalmologic evaluation

55
Q

List 3 steps in long term management of Sturge Weber

A

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

56
Q

What cancers are patients with NF-1 predisposed to?

A
Malignant peripheral nerve sheath tumor (MPNST)
Pheochromocytoma
Rhabdomyosarcoma
Leukemia
Wilms tumor
57
Q

What is the gene affected in congenital central hypoventilation syndrome and how is it inherited?

A

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

58
Q

List clinical features of ROHHAD (Rapid-Onset Obesity, Hypothalamic Dysfunction, Hypoventilation, Autonomic Dysregulation)

A
  • 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
59
Q

What is obesity hypoventilation syndrome?

A

Hypoventilation during wakefulness in obese patient

BMI >30 + Awake PaCO2 > 45

60
Q

What is the pathophysiology of obesity hypoventilation syndrome?

A

Reduced respiratory compliance
Increased airway resistance
Reduced FRC
Metabolic alkalosis (from OSA) leads to compensatory respiratory acidosis during wakefulness

61
Q

How do you treat obesity hypoventilation syndrome?

A

NIV during sleep

62
Q

Describe the genetics of Beckwith Wiedemann

A

Paternal UPD for chromosome 11p15

85% of cases are sporadic

63
Q

List clinical features of BWS

A
  • Macrosomia (gigantism)
  • Hemihypertrophy
  • Macroglossia
  • Anterior ear lobe creases
  • Abdominal wall defects
  • Exophthalmos
  • Hepatosplenomegaly
  • Nephromegaly
  • Hypoglycemia secondary to hyper-insulinemia from pancreatic β-cell hyperplasia
64
Q

What tumours are associated with BWS?

A
Embryonal Tumours
•	Wilms tumour***
•	Hepatoblastoma***
•	Neuroblastoma
•	Rhabdomyosarcoma
•	Adrenocortical carcinoma
65
Q

What is the initial work up for a baby with suspected BWS?

A

Assess for airway difficulties

Feeding specialist

Assess neonates for hypoglycemia

AUS to assess for organomegaly, structural abnormality, and tumours

AFP to assess for hepatoblastoma

66
Q

Health supervision guidelines for BWS

A

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

67
Q

What is the genetic mutation in Sotos syndrome?

A

NSD1 mutation

68
Q

List clinical features of Sotos syndrome

A

> 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
69
Q

Describe the genetics of Fragile X

A

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

70
Q

List clinical features of Fragile X

A

-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)

71
Q

What test do you order for Fragile X?

A

Molecular testing for FMR1 gene (looking for CGG repeats)

72
Q

List the clinical features of VACTERL

A

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

73
Q

List conditions associated with hemivertebrae

A
Congenital scoliosis
VACTERL
Aicardi syndrome
OEIS
Gastroschisis
Jarcho-Levin syndrome
Gorlin syndrome
74
Q

List 3 effects of maternal PKU

A

Microcephaly
CHD
Intellectual disability

75
Q

What is one complication of maternal hyperthermia ?

A

NTDs

CHD

76
Q

Clinical features of CHARGE syndrome

A
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
77
Q

Describe the genetics of CHARGE syndrome

A

CHD7 gene

Autosomal dominant

78
Q

Describe genetics of Williams syndrome

A

Hemizygous deletion on chromosome 7q11.23

79
Q

Clinical features of Williams syndrome

A

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

80
Q

What tests should you do in a child with suspected Williams?

A
  • Echo
  • Renal U/S, Cr/BUN and U/A
  • Auditory and vision testing
  • Serum calcium
  • Thyroid function
  • BP → yearly measurements
  • Developmental assessment
81
Q

What are the clinical features of DiGeorge syndrome?

A
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
82
Q

Genetics of DiGeorge

A

Autosomal dominant

Deletion in chromosome 22q11.2

83
Q

What is the embryology of DiGeorge syndrome?

A

Multiple anomalies of 3rd/4th pharyngeal pouch structure

84
Q

What percentage of patients with Di George have behaviour/psychiatric problems such as schizophrenia?

A

50%

85
Q

How do you make a diagnosis of DiGeorge?

A
  1. Clinical findings + reduced CD3+ T cells
    OR
  2. FISH 22Q11.2 deletion
86
Q

What tests should you order in a patient with suspected DiGeorge?

A
Echo
Serum calcium and phosphorus levels
CBC and  differential 
CXR-thymus
Renal U/S 
Lymphocyte immunophenotyping
Immunoglobulins
87
Q

What are the clinical features of Angelmans?

A

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

88
Q

Describe the genetics of Angelman syndrome

A

Loss of maternally imprinted chromosome 15q11-13
Maternal deletion
OR
Paternal UPD

89
Q

What genetic tests should you order for Angelman syndrome?

A

Microarray will pick up deletion, but will not tell you whether deletion was from mom or dad

Therefore need methylation studies!

  1. Methylation studies
  2. If above positive, chromosome microarry to determine type of deletion
    Chromosome microarray
  3. If methylation studies negative, UPD studies to determine if the patient has paternal UPD using microsatellite DNA markers or SNPs
90
Q

Management of Angelman syndrome

A
  • Developmental assessment
  • EEGs
  • Evaluate for feeding problems and gastroesophageal reflux
91
Q

Genetics of Prader Willi syndrome

A

Paternally-derived chromosome 15 with 15q11 deletion deletion
OR
Maternal UPD

92
Q

Clinical features of PWS

A

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

93
Q

Genetics of Alagille syndrome

A

Autosomal dominant

JAG-1 (>90%) or NOTCH-2 gene mutation

94
Q

Clinical features of Alagille syndrome

A

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

95
Q

How do you diagnose Alagille syndrome?

A

Liver biopsy findings: reduced number of bile ducts (may not be apparent in infants <6 mos)

JAG-1 or NOTCH-2 mutation

96
Q

Management of Alagille syndrome

A

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

97
Q

Genetics of Smith Lemli Optiz

A

Autosomal recessive
Chromosome 11q12-q13

Defect in a cholesterol biosynthetic enzyme (C7-dehydrocholesterol-reductase)

Low plasma cholesterol and accumulated precursors

98
Q

Clinical features of Smith Lemli Optiz

A

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

99
Q

How do you diagnose Smith Lemli Optiz ?

A

Low plasma cholesterol with elevated 7-dehydrocholesterol

100
Q

Treatment of Smith Lemli Optiz

A

Supplementary dietary cholesterol (egg yolk)

HMGCoA reductase inhibition→prevents synthesis of toxic precursors proximal to enzymatic block

101
Q

Genetics of Cornelia de Lange

A

Autosomal dominant

Mutation NIPBL gene 50-60%

102
Q

Clinical features of Cornelia de Lange

A

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

103
Q

How is Waardenburg syndrome inherited?

A

AD

104
Q

Clinical features of Waardenburg syndrome

A

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

105
Q

Clinical features of trisomy 18 (Edward Syndrome)

A

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

106
Q

Clinical features of trisomy 13 (Patau syndrome)

A

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

107
Q

Genetics of Osteogenesis Imperfecta

A

Majority AD
AR (5-7%)
COL1A1, COL1A2, LEPRE1, or CRTAP

108
Q

Pathophysiology of Osteogenesis Imperfecta

A

Caused by structural or quantitative defects in type I collagen = primary componentof the extracellular matrix of bone and skin

109
Q

What is the classic triad of OI?

A

(1) Fragile bones
(2) Blue sclerae
(3) Early hearing loss

110
Q

Clinical features of OI type I

A
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

111
Q

Clinical features of OI type 2

A

LETHAL in perinatal period

112
Q

Clinical features of OI type 3

A
Second most severe
Progessive structural bone deformities
Fractures usually occur in utero
Macrocephaly
Triangular facies
Extreme short stature
113
Q

Clinical features of OI type 4

A

Severe, but not as bad as OI type 3
Normal sclerae
Recurrent fractures after ambulation, with resulting moderate bowing
Tooth abnormalities

114
Q

Clinical features of OI type 5/6

A

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

115
Q

Diagnosis of OI

A

Collagen biochemical studies using cultured dermal fibroblasts

DNA sequencing to identify mutations in COL1A1, COL1A2, LEPRE1, or CRTAP

116
Q

List 3 features of OI (other than fractures) (past SAQ)

A

-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

117
Q

Treatment of OI

A

PT for ambulation support
Ortho for fracture management
Bisphosphonates
GH may improve bone histology

118
Q

Recurrence risk of second child having OI in unaffected couple ?

A

5-7%

119
Q

Clinical features of OI type 7/8

A
Recessive form
Overlap types II and III but have distinct features:
White sclerae
Rhizomelia
Small to normal head circumference
120
Q

Most common anomaly associated with single umbilical artery

A

Renal abnormalities

121
Q

Clinical features of septo-optic dysplasia

A

Midline defects

  • Corpus callosum agenesis
  • Absent septum pallucidum
  • Optic nerve hypolasia
  • Small anterior pituitary
  • Panhypopituitarism to isolated deficiencies (GH deficiency, hypothyroidism or DI)
122
Q

Genetics of Rett’s syndrome

A

MECP2 gene

Almost exclusively females

123
Q

Clinical features of Rett’s syndrome

A
  • 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
124
Q

What is the recurrence risk of isolated cleft lip and palate?

A

4% recurrence risk

2.7% (unilateral), 5.4% (bilateral)

125
Q

What is the syndrome that causes AD CLP?

A

Van der Woude syndrome

126
Q

What percentage of infants with complete DiGeorge have CHARGE association?

A

1/3

Coloboma, genital hypoplasia and ear anomalies including deafness

127
Q

What test is important in patient with suspected Waardenburg?

A

Hearing test

128
Q

What is Amelogenesis imperfecta

A

Hereditary condition

Enamel defects of the primary and permanent teeth without evidence of systemic disorders

129
Q

List 3 types of chromosome tests

A

Karytope
FISH
Microarray-microdeletions/duplications

130
Q

What is molecular/DNA testing?

A

Sequences a gene
Detects SINGLE GENE disorders
(e.g. CFTR, FRAX for Fragile X, TSC1/TSC2, FBN1 for Marfans)

131
Q

Late complications of Turners syndrome

A
Low BMD
T2DM
Hyperlipidemia
HTN
IBD, Celiac
Infertility
132
Q

Most common cardiac lesion in DiGeorge

A

TOF

133
Q

What ongoing surveillance should you do in DiGeorge?

A
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

134
Q
NF-1 features by age
Infancy/preschool
School Age
Adolescence
Adulthood
A

Infancy/preschool

  • Plexiform neurofibroma
  • Tibial dysplasia
  • Development

School Age

  • Optic glioma
  • Lisch nodules
  • Short stature
  • HTN
  • Scoliosis

Adolescence
-Dermal neurofibromas

Adulthood

  • Malignancy
  • Osteopenia
135
Q

List 3 triple repeat disorders

A

Fragile X
Huntington
Congenital myotonic dystrophhy

136
Q

Components of Pierre RObin Sequence

A

Mandibular hypoplasia
Posteriorly displaced tongue
Cleft palate