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Flashcards in Syndromes Deck (74):
1

Fragile X genetics

trinucleotide repeat CGG in FMR1 region on X-chromosome --> PCR/southern blot looking at the number of repeats
Genetic anticipation
>200 copies = full mutation [5-44 normal, 44-54 grey zone, 55-200 = premutation carrier]
Female carrier frequency est 1:178

2

Fragile X features

large ears, long face, high arched palate, dental crowding
macro-orchadism (post-pubertal)
joint hyperlaxity (pes planus)
seizure 20%
macrocephaly (subtle)
MVP <3

3

Fragile X development outcomes

hyperactivity
sensory integration problems
intellectual disability (female IQ > male)
ASD
Enuresis

4

Fragile X health supervision

Eyes - strabismus, vision
ears - recurrent AOM, may need tubes to preserve hearing
cardiac - MVP (exam for murmur or click)
MSK - joint laxity
CNS - seizure risk
Development assessment

5

Fragile X Anticipatory guidance

Genetics referral
psychosocial
support groups
early intervention for PT, OT, SLP as required
Behavious (outburts, sexual issues etc)
Education (preschool, education needs, vocational training)

6

Fragile X DDx (x-linked [2] or similar features[1])

Usual ones: ADHD, LD, ODD, FASD, ASD
--> X-linked intellectual disability disorders: 1) Lujan-Fryns Syndrome (marfanoid habitus and macroorchidism) and
2) Atkin Syndrome (large ears, macroorchidism, and short stature)
--> Sotos Syndrome (Cerebral Gigantism): Overgrowth syndrome with features of macrocephaly, prominent forehead, prominent chin/mandible, coordination
dysfunction, and usually intellectual disability and difficult behavior.

7

Prader-Willi genetics

15q11 --> 75% paternal microdeletion
20% maternal uniparental disomy
Absence of the paternally inherited contribution of the PWS region of chromosome 15 leads to lack of the gene products and causes the findings of PWS
Methylation analysis + FISH

8

Prader-Willi features

Neonate: hypotonia, FTT, poor feeding
Pre-school: hyperphagia, dev delay
Bitemporal narrowing, almond eyes, tapering of digits

9

Prader-Willi associated medical conditions

Endo: hypothalamic insufficiency --> GH = short stature(eligible for replacement), primary adrenal insuf, hypothyroid
hyperphagia - obesity, OSA, T2DM, dyslipidemia
central sleep apnea
scoliosis (musc hypotonia)

10

Prader-Willi development outcomes

Gross motor delay (sit at 12 months, walk at 24)
poor coordination
language delay
intellect - IQ 60-70 (strength is visual-spacial, reading, weak in math and sequence processing)
tantrums, ADHD, OCD, psychosis, high pain tolerance

11

DDx for obesity/intellectual disability

Prader-Willi
Bardet-Biedl Syndrome (polydactyly, retinitis pigmentosa, cystic renal disease)
Cohen Syndrome (hypotonia, prominent central incisors, retinal dystrophy)
Alstrom Syndrome (cone-rod dystrophy, deafness, type 2 diabetes)
Sotos Syndrome

12

Prader-Willi health supervision newborn

confirm diagnosis
review feeding, hypotonia, need for NG
OSA
hypogonadism

13

Prader-Willi health supervision infancy

plot growth on growth curve
development assessment and early referral
vision and hearing (annual)
boys - undescended testes
dietitian - aggressive weight mgmt
assess GH
dentist - increased risk of caries
OSA - sleep study (esp before GH)

14

Prader-Willi health supervision childhood

Vision - annual
Thyroid q2-3 years or if symptomatic
Behaviour (hyperphagia)
Growth and development
scoliosis
Premature adrenarche
skin-picking (behavioural)
risk of psychosis when older

15

Angelman syndrome genetics

15q11
Missing maternal!
70% maternal microdeletion
10% UBE3A gene mutation (gene in this area)
5% paternal uniparental disomy (milder phenotype)
10% unknown
rest - imprinting
testing: DNA methylation is most sensitive single test, but DNA sequence analysis required to identify UBE3A mutations. Recurrence risk <1% for microdeletion
and pat. uniparental disomy. Recurrence risk as high as 50% for maternally inherited imprinting center defect or UBE3A mutation. (same as P-W)

16

Angelman syndrome features

"happy puppet"
psychomotor delay
seizures
acquired microcephaly
GDD
forward bend gait, arms held high bent at elbows
Severe intellectual disability
Good receptive language skills, but generally non-verbal
persistent social smile and bursts of laughter (as early as 10 weeks)
hyperactive
abnormal sleep cycle

17

Angelman syndrome health supervision

Hearing and vision
Adaptive equipment
early intervention by multi-D
Seizures - AED, neurology involvement
family support for hyperactivity and abn sleep cycle

18

Beckwith-Weidemann genetics

11p15 - dysregulation of imprinted genes
sometimes AD, most spontaneous loss of methylation centre for imprinting. Some paternal uniparental disomy (loss of mom)

19

Beckwith-Weidemann features at birth (8)

LGA
omphalocele or umbilical hernia
macroglossia,
facial nevus flammeus,
post. helical pits,
prominent eyes,
anterior ear lobe creases
HYPOGLYCEMIA + polycythemia

20

Beckwith-Weidemann medical conditions

Hypoglycemia
polycythemia
hypocalcemia
Dyslipidemia
hypothyroid
cardiomegaly (rare - HLHS, PFO, mild PS)
nephromegaly
risk of malignancy (embryonal tumours)

21

Beckwith-Weidemann malignancy risk and supervision

Wilm's, hepatoblastoma, neuroblastoma
AUS q3mo until age 8
AFP q6weeks until age 4

22

22q11.2 Deletion Syndrome Genetics

Usually sporadic mutation from normal parent
AD from affected parent
FISH

23

22q11.2 Deletion Syndrome features

Cardiac: TOF, VSD, interrupted aortic arch
facial: hypertelorism, long tubular nose, palate anomalies, velopharyngeal insuf
hypoCa! HypoPTH
Thymus aplasia - T-cell immunodef.
30% renal problems
Chronic AOM and sinusitis - with conductive hearing loss > SNHL
eyes: strabismus, posterior embryotoxin
Development: >90% delay, ASD 20%, communication disorder
Increased psych: bipolar, schizo, mood

24

22q11.2 Deletion Syndrome DDx

Cayler Cardiofacial Syndrome (asymmetric crying facies +conotruncal cardiac malformation): also 22q11.2 deletion
CHARGE Syndrome also features congenital heart disease, immunodeficiency,
hypocalcemia, and hearing loss.
Some overlap with oculo-auriculo-vertebral spectrum
(Goldenhar Syndrome), Kabuki Syndrome, Alagille Syndrome

25

22q11.2 Deletion Syndrome health supervision (8)

Cardiology evaluation
Endocrine evaluation
-->Calcium, hypoparathyroid studies
Renal ultrasound
Developmental evaluation
Early referral for Speech Therapy
Monitor for Hearing Loss
Immunology evaluation

26

Turner Syndrome Genetics

karyotype - 45XO (majority)
can also have mosaic 45X-/46XX*
*sometimes one of the mosaic X can have a structural defect

27

Turner Syndrome associated cardiac findings

Bicuspid aortic valve, CoA, HLHS with heart failure
LEFT heart lesions (vs. Noonans)

28

Turner Syndrome associated renal findings

>60%
horseshoe kidney, ectopic kidney, aplasia, double collecting system, UPJ obstruction

29

Turner Syndrome associated ENT findings

chronic AOM, conductive hearing loss

30

Turner Syndrome associated MSK findings

DDH (5-10%)
Scoliosis or kyphosis (10-20%)

31

Turner Syndrome associated endo findings

short stature - GH deficiency (replacement)
delayed puberty, infertility
menarche in 1-3%
obesity, dyslipidemia, hyperinsulinsm
thyroid

32

Turner Syndrome associated autoimmune findings

celiac, vitiligo, thyroiditis, IBD

33

Turner Syndrome associated derm findings

vitiligo
keloids
dysplasia

34

Turner Syndrome associated NEONATAL findings

Lymphedema of hands and feet, hydrops
nuchal webbing
broad chest with wide nipples
L cardiac defect

35

Turner Syndrome associated eye findings

strabismus, cataract, ptosis

36

Turner Syndrome development

Non-verbal learning disabilities, normal IQ
- visual-spacial, math, visual-motor
ADHD (24%)
depression, anxiety
Hearing loss - CHL from recurrent AOM, SNHL >6 years

37

Turner Syndrome health supervision

Cardiac: Initial evaluation and then yearly ECHO
o BP checks at all visits
Endocrine:
o Growth Hormone to increase stature
o Estrogen replacement therapy
Early treatment of scoliosis
Annual skin exams
Annual thyroid function
Monitor LH and FSH after age 10 years
School accommodations
Motherhood through adoption

38

Klinefelter Syndrome genetics

Karyotype - 47 XXY (mostly - some mosaic 46XY/47XXY)

39

Klinefelter Syndrome features

tall stature (long arm span)
gynecomastia
hypogonadism
hypercoagulable (DVT, PE risk)

40

Klinefelter Syndrome malignancy risk

breast CA (20x over XY male)
ALL, lymphoma (NH and Hodgkins)
bHCG secreting tumours (extragonadal germ cell tumours)

41

Klinefelter Syndrome endocrine features

infertility from azospermia
delayed puberty (low test, increased LH, FSH)
hypogonadism

42

Klinefelter Syndrome autoimmune disorders

SLE, RA, thyroid, T2DM

43

Klinefelter Syndrome developmental outcomes

Normal IQ
delayed expressive language
specific learning disabilities
ADHD
behaviour: shy, withdrawn, low maturity and self-esteem

44

Klinefelter Syndrome DDx

Kallman syndrome (hypogonadotropic with anosmia),
Prepubertal: milder form of Fragile X
ASD, hearing loss

45

Klinefelter Syndrome routine health supervision

Reassure regarding gender identity
Peds Endo: testosterone replacement IM or patch
o Begin age 11-12 yr.
o More masculine pubertal development; muscle mass
o Improves bone mineral density
o Improves self-esteem, mood and behavior
Plastic surgery available for gynecomastia
Monitor for male breast cancer
School accommodations/Early Intervention for language problems
Behavioral support
Klinefelter’s Syndrome Association, Inc.

46

NF1 genetics

Autosomal dominant mutations (90%) or whole gene deletions (5%) of NF1 gene at chromosome 17q11.2

47

NF1 Dx criteria

Two or more of the following:
Two or more neurofibromas or one plexiform neurofibroma
o 6 or more CALM >5mm in prepubertal
o 6 or more CALM >15mm postpubertal
Axillary or inguinal freckling (Crowe’s sign)
Optic nerve tumor
Two or more Lisch nodules (iris hamartoma)
Distinctive osseous lesion: sphenoid dysplasia or long-bone bowing with or without pseudoarthrosis
First degree relative with NF-1

48

NF1 cardiac associations

PS, CoA, CAD

49

NF1 routine health supervision

Developmental assessment/school support
MRI any suspected plexiform neurofibromas
Low threshold for Brain MRI
Manage scoliosis
Routine BP checks
Annual Peds Ophtho exams

50

Tuberous Sclerosis genetics

2 mutations: TSC1, TSC2 --> AD usually de novo

51

TS associated findings

cortical brain tubers --> seizures
subenpendymal nodules --> giant cell astocytoma
cardiac rhabdomyoma
derm: ash leaf, shagreen, periungual fibromas, ficial angiofibromas
retinal astrocytic hamartomas

52

TS development outcomes

intellectual disability (45-75%)
ASD (50%)
learning disability

53

TS routine screening

CT/MRI at diagnosis
Echocardiogram in infancy
Renal US at diagnosis
Peds Ophthalmology at diagnosis
Early Developmental Evaluation

54

Achondroplasia genetics

AD, FGFR3 gene
most commonly from sporadic mutation
If both parents have mutation then inheriting 2 mutations (homozygous) is lethal

55

Achondroplasia CNS

hydrocephalus - 5%, monitor HC
small foramen magnum - 10% fatal apnea before age 2
spinal stenosis (everyone has it)

56

Achondroplasia routine health supervision

Standardized linear growth charts
Environmental and adaptive modifications
--> Driving, reaching, etc
MRI or CT brain and C-spine after diagnosis during neonatal period or early infancy
--> Close monitoring of HC, risk of hydrocephalus
Sleep study
Audiology
Avoid poor infant positioning (<12months)
--> NO unsupported sitting, umbrella strollers, swings
Close neurologic monitoring with regular exams

57

Achondroplasia anesthetic risk

manipulation of the neck - risk of spinal cord compression bc of small FM
appropriate dose of meds for size
lack full extension of elbows sometimes - difficult IV
kyphosis, lumbar lordosis - avoid spinal anesthetic
all pregnant women with achondroplasia need c/s - pelvis too small
some have restrictive lung disease (5%)

58

Marfan Syndrome

AD, full penetrance, variable expressivity
FBN1 gene on chrom 15q21
Mutation detected in 90% of pts meeting clinical criteria

59

Marfan associated findings

Tall stature: incr arm span to height (>1.05), decr upper:lower segment (<0.85)
<3: aortic root dilatation, MVP/regurg
arachnodactyly
eyes: Ectopia lentis, myopia, cataracts, glaucoma, retinal detachment, exotropia/strabismus
Risk of spontaneous pneumo (apical blebs)
Connective tissue: Pectus (ex/car), pes planus, scoliosis, dural ectasia, jt hyperextensibility

60

Marfan Ddx

homocysteinuria
Kleinfelter
Elhers danlos
Stickler syndrome
Beals syndrome (congenital contractural arachnodactyly)
Loeys-Dietz ( dilated tortuous aorta, cleft palate or bifid uvula, hypertelorism, occasional craniosynostosis, arachnodactyly, often translucent skin )

61

Marfan routine health supervision

Cardiovascular
o Yearly echocardiography
o Beta-blockers reduce hemodynamic stress on aortic wall
o Surgical aortoplasty (aortic diameter > 5cm or smaller diameter but rapid progression of dilatation in very young children)
o Mitral and aortic valve replacement for progressive MI, AISBE prophylaxis essential
o Avoid competitive sports and isometric exercise
Ocular: Experienced Peds Ophthalmology is essential
o Lens dislocation may require surgical lens implantation
Progressive scoliosis: surgical stabilization
Severe pectus excavatum may limit cardiopulmonary function

62

Wilsons disease genetics and diagnosis

AR - defective Cu transport from liver into ceruloplasmin and biliary system
high serum/urine Cu, low ceruloplasmin
ATP7B gene on DNA sequence - once diagnosed screen all sibs bc they can be asymptomatic and is treatable

63

Wilsons disease associated findings

Lifelong neurologic impairment
o Drooling
o Tremors
Fulminant hepatic failure
Cirrhosis, portal hypertensions
Hemolytic crisis (can be fatal)
Cerebral and brain stem atrophy
White matter changes on brain MRI
Kayser-Fleischer Rings
Low serum ceruloplasmin

64

Wilsons disease development

Teens:
Deteriorating handwriting
Tremors
Clumsiness
Spasticity
Academic decline
Behavior disturbance

65

Wilsons psych symptoms

bipolar, depression, dysthymia, psychosis, schizo

66

Wilsons treatment

Early Diagnosis and treatment can prevent progression
Partner with Peds GI
Copper chelation therapy
o Penicillamine or triethylene tetramine dihydrochloride + oral zinc
Copper avoidance --> Shellfish, nuts, liver, chocolate

67

Long QTc Syndrome (3)

Congenital (+ FamHx 60%)
Romano-ward (less severe)
Jervell and Lange-Nielsen

68

Jervell and Lange-Nielsen syndrome

Long QTc, Ventricular tachyarrhythmias
profound hearing loss (SNHL)
AR
High risk of sudden cardiac death
mutation in cardiac potassium channel

69

Romano-Ward syndrome

Long QTc
familial history of sudden death, syncope
syncope, sz., palpitations with exercise or intense emotions
Screen family members, cardio ref, B-blockers, supervised swimming etc. like seizure kids

70

Noonans genetics

AD
Multiple mutations involved. 1/2 from PTPN11 gene

71

Noonans vs. Turners

Cardiac features are typically left-sided in Turner syndrome but right-sided in NS;
coarctation of the aorta and/or bicuspid aortic valve are more characteristic of Turner syndrome;
girls have gonadal dysgenesis in Turner syndrome; normal fertility in girls with NS.
Turner syndrome is attributable to loss of 1 sex chromosome.
NS behaviour more variable, more cognitive issues and LD

72

Noonans cardiac findings

Pulmonary valve stenosis
HCM
secundum AS
Partial AV canal defect

73

Noonans endo findings

Growth: 50-70% short stature - normal birth wt and length, then start to taper off
Bone age delay ~2years
puberty delayed with less of a growth spurt
thyroid Abs common, but hypothyroid not more common

74

Noonans heme findings

coagulation disorders: Factor XI def
low or defective Plt