Syndromes Flashcards
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
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
Fragile X development outcomes
hyperactivity sensory integration problems intellectual disability (female IQ > male) ASD Enuresis
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
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)
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.
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
Prader-Willi features
Neonate: hypotonia, FTT, poor feeding
Pre-school: hyperphagia, dev delay
Bitemporal narrowing, almond eyes, tapering of digits
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)
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
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
Prader-Willi health supervision newborn
confirm diagnosis
review feeding, hypotonia, need for NG
OSA
hypogonadism
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)
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
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)
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
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
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)
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
Beckwith-Weidemann medical conditions
Hypoglycemia polycythemia hypocalcemia Dyslipidemia hypothyroid cardiomegaly (rare - HLHS, PFO, mild PS) nephromegaly risk of malignancy (embryonal tumours)
Beckwith-Weidemann malignancy risk and supervision
Wilm’s, hepatoblastoma, neuroblastoma
AUS q3mo until age 8
AFP q6weeks until age 4
22q11.2 Deletion Syndrome Genetics
Usually sporadic mutation from normal parent
AD from affected parent
FISH
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
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
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
Turner Syndrome Genetics
karyotype - 45XO (majority)
can also have mosaic 45X-/46XX*
*sometimes one of the mosaic X can have a structural defect
Turner Syndrome associated cardiac findings
Bicuspid aortic valve, CoA, HLHS with heart failure
LEFT heart lesions (vs. Noonans)
Turner Syndrome associated renal findings
> 60%
horseshoe kidney, ectopic kidney, aplasia, double collecting system, UPJ obstruction
Turner Syndrome associated ENT findings
chronic AOM, conductive hearing loss
Turner Syndrome associated MSK findings
DDH (5-10%)
Scoliosis or kyphosis (10-20%)
Turner Syndrome associated endo findings
short stature - GH deficiency (replacement) delayed puberty, infertility menarche in 1-3% obesity, dyslipidemia, hyperinsulinsm thyroid
Turner Syndrome associated autoimmune findings
celiac, vitiligo, thyroiditis, IBD
Turner Syndrome associated derm findings
vitiligo
keloids
dysplasia
Turner Syndrome associated NEONATAL findings
Lymphedema of hands and feet, hydrops
nuchal webbing
broad chest with wide nipples
L cardiac defect
Turner Syndrome associated eye findings
strabismus, cataract, ptosis
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
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
Klinefelter Syndrome genetics
Karyotype - 47 XXY (mostly - some mosaic 46XY/47XXY)
Klinefelter Syndrome features
tall stature (long arm span)
gynecomastia
hypogonadism
hypercoagulable (DVT, PE risk)
Klinefelter Syndrome malignancy risk
breast CA (20x over XY male)
ALL, lymphoma (NH and Hodgkins)
bHCG secreting tumours (extragonadal germ cell tumours)
Klinefelter Syndrome endocrine features
infertility from azospermia
delayed puberty (low test, increased LH, FSH)
hypogonadism
Klinefelter Syndrome autoimmune disorders
SLE, RA, thyroid, T2DM
Klinefelter Syndrome developmental outcomes
Normal IQ delayed expressive language specific learning disabilities ADHD behaviour: shy, withdrawn, low maturity and self-esteem
Klinefelter Syndrome DDx
Kallman syndrome (hypogonadotropic with anosmia),
Prepubertal: milder form of Fragile X
ASD, hearing loss
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.
NF1 genetics
Autosomal dominant mutations (90%) or whole gene deletions (5%) of NF1 gene at chromosome 17q11.2
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
NF1 cardiac associations
PS, CoA, CAD
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
Tuberous Sclerosis genetics
2 mutations: TSC1, TSC2 –> AD usually de novo
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
TS development outcomes
intellectual disability (45-75%)
ASD (50%)
learning disability
TS routine screening
CT/MRI at diagnosis Echocardiogram in infancy Renal US at diagnosis Peds Ophthalmology at diagnosis Early Developmental Evaluation
Achondroplasia genetics
AD, FGFR3 gene
most commonly from sporadic mutation
If both parents have mutation then inheriting 2 mutations (homozygous) is lethal
Achondroplasia CNS
hydrocephalus - 5%, monitor HC
small foramen magnum - 10% fatal apnea before age 2
spinal stenosis (everyone has it)
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
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%)
Marfan Syndrome
AD, full penetrance, variable expressivity
FBN1 gene on chrom 15q21
Mutation detected in 90% of pts meeting clinical criteria
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
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 )
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
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
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
Wilsons disease development
Teens: Deteriorating handwriting Tremors Clumsiness Spasticity Academic decline Behavior disturbance
Wilsons psych symptoms
bipolar, depression, dysthymia, psychosis, schizo
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
Long QTc Syndrome (3)
Congenital (+ FamHx 60%)
Romano-ward (less severe)
Jervell and Lange-Nielsen
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
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
Noonans genetics
AD
Multiple mutations involved. 1/2 from PTPN11 gene
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
Noonans cardiac findings
Pulmonary valve stenosis
HCM
secundum AS
Partial AV canal defect
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
Noonans heme findings
coagulation disorders: Factor XI def
low or defective Plt
