Week 3: Peds & dysmorphology Flashcards
(27 cards)
Prader willi syndrome
-Imprinted disorder
-15q11.2-q13 deletion, mat UPD, pat imprinting due to deletion or epimutation
-70% deletion, ~25% maternal UPD
feeding issues (infancy), obesity, hypotonia, hypogonadism, cognitive/behavioral
-Neonatal hypotonina and poor feeding which evolves into hyperphagia in early childhood
-May see short stature, almond eyes, and brachydactyly, dev differences, hypogonadism, emotional dysregulation
Diagnosis
-1st tier: DNA methylation analysis and oligo-SNP combination array (OSA)
-Workup: endocrinology, diabetes screening, thyroid studies, eye exam, sleep study, hip ultrasound
-Feeding therapy, dev therapies, may need hormone treatment for precocious puberty and growth/sex hormone def, DM2, and hypothyroidism
-Diminished pain sensitivity may mask the presence of an infection or injury
Angelman syndrome
-Imprinting disorder
-15q11.2-q13
-Deletion of mat 15q11.2-q13 (most common ~70%), paternal UPD15q (5%), maternal imprinting defect of 15q11.2-q13 (4%), UBE3A mutation (>10% cases)
happy, ID/DD, gait ataxia, microcephaly, seizures
-Developmental differences, ataxia, pathologic happiness, abnormal food related behaviors, seizures, scoliosis
-Obesity, wide mouth, protruding tongue, light colored hair, hypopigmented skin (OCA2 gene located in 15q11.2-q13 region)
-“happy puppet”
Diagnosis
-1st tier: DNA methylation analysis
(can also use MLPA, CMA, UPD analysis and UB3A sequencing)
Workup: brain MRI, EEG. Eval by ophthal, neurology, feeding
Behavior modification, antiepileptics, augmentative communication
Beckwith-Wiedemann syndrome
-Imprinting disorder
-11p15.5
-imprinting defect at IC1&2 (55%), 20% UPD, 10% CDKN1C var, 10% micro del/dup
-Most common: loss of methylation at IC2 on mat chromo
-IC1: IGF2 and H19
-IC2: CDKN1C, KCNQ10T1, KCNQ1
omphalocele, Wilms tumor, macroglossia, macrosomia, neonatal hypoglycemia, body asymmetry
-May also see hepatoblasotma
Diagnosis
-1st tier: IC1 and IC2 methylation studies and CNV testing
Workup: abdominal US every 3 months until 4y, renal US from 4y-7y
Russell-Silver syndrome
-Imprinting disorder
-Chr7, Chr11
-Hypomethylation of ICR1 at 11p15.5, mat UPD7, mat dup of 11p15.5 or 7p, single gene mutations in IGF2, CDKN1C, PLAG2, HMGA2
Consider RSS in infants with combo: poor weight gain and short stature, but a normal head circumference
body asymmetry, triangular facies, 5th finger clinodactyly, relative macrocephaly @ birth, frontal bossing, micrognathia, short/small
Diagnosis
-1st tier: methylation analysis of 11p15.5 and testing for UPD7
-2nd tier: molecular testing
-Consider growth hormone therapy and nutritional supplementation
-Lower limb discrepancy >2cm requires intervention
Fragile X syndrome
-X-linked
-FMR1
Normal: 5-44
-Gray zone: 45-54
-Premutation: 55-200
-Affected: >200
->200 repeats causes hypermethylation of 5’ UTR and silencing of FMR1
Premutation carriers at risk for FXPOI and FXTAS
Dev differences, ASD, macroorchidism, long face and prominent forehead, large ears, connective tissue abnormailities
Diagnosis: FMR1 PCR testing or southern blot
Workup: dev, neuropsych, ophthal, ENT, cardio for baseline echo
Supportive therapies, avoid or start low dose psychotropic meds
Rett syndrome
-X-linked, male lethal
-MECP2
Progressive neurodev disorder associated with regression and development of stereotypic hand motions, behavioral concerns, loss of speech, bruxism, ataxia, tremors, acquired microcephaly, breathing abnormalities
Regression typically starts at 18m
Diagnosis
-Suspected clinically, confirmed molecularly
Workup: brain MRI and ECG (to assess for prolonged QTc). Evals by audiology, neuropsych, and pulmonology for breathing abnormalities
Trofinetide for improvement of Rett syndrome behaviors otherwise supportive care.
Coffin-Lowry syndrome
-X-linked dominant condition
-RPS6KA3
-Heterozygous females may be asymptomatic-symptomatic like males
stimulus induced drop attacks (~20%), ID, spasticity, seizures, hearing loss, hypotonia
Diagnosis: molecular testing
Menkes disease
-X-linked
-Gene: ATP7A
poor growth, kinky hair, sagging cheeks, skin laxity, hypotonia. Seizures begin 1-3 months of age
Other findings: subdural hematoma, cerebrovascular accidents
Workup: brain imaging, bladder US. Will see low serum copper and ceruloplasmin. May see abnormal serum and CSF catecholamine concentrations
Subcutaneous injections of copper histidine in early life improves survival and neurodevelopmental outcomes. Seizures management, dev services, and feeding therapy as indicated
MRI finding: “corkscrew” appearance of cerebral vessels
Joubert syndrome
-x-linked (OFD1), AR
->30 genes
DD, hypoplasia of cerebellar vermis and pathognomonic molar tooth sign, hypotonia, dysregulated breathing
Other: hepatic fibrosis, retinal disease, endocrine and skeletal anomalies, polydactyly. WIDE range of intellect.
Diagnosis: dx clinically in conjunction with brain MRI, dx can be confirmed molecularly
Workup: Brain MRI, sleep study, eye exam, renal/liver function tests, abdominal US, eval for GH def and pituitary anomalies
Bardet-Biedl syndrome
-AR
-BBS1 most commonly, others are BBS2, BBS10, BBS12, etc
postaxial polydactyly, DD, cone-rod dystrophy, central obesity, hypogonadism, olfactory dysfunction (anosmia), renal disease, GU anomalies
Central/truncal obesity develops in first year of life
Dx: established clinically and molecularly
Workup: renal US and echo, annual ophthal exam
Can use targeted therapy setmelanotide for obesity
Cornelia de Lange syndrome
-AD, XL
-NIBPL (most common ~80%)
growth restriction, microcephaly, synophrys, thick highly arched eyebrows, long eyelashes, short nasal bridge, radial ray anomalies, GERD, ID
Also: cardiac defects, GU anomalies, antibody def, hearing loss, seizures, myopia
CdLS-specific growth charts exist
Diagnosis: molecular sequencing including NIBPL
Workup: echo, renal US, CBC, immune profiling, eye and hearing evals, neuropsych, xrays for limb anomalies
Mowat-Wilson syndrome
-AD
-ZEB2 (majority) or deletion of 2q22.3 involving ZEB2 (15%)
-Truncating variants are most severe, full gene deletion causes worst epilepsy
CHD (esp. pulmonary stenosis), Hirschsprung dz, GU anomalies (esp. hypospadias), agenesis of corpus callosum (thus ID, epilepsy, microcephaly)
Often have happy demeanor, minimal speech, and wide gait that can look like Angelman syndrome
Facies: widely spaced eyes, broad eyebrows w/ medial flare, low-hanging columella, pointed chin, open-mouth expression, uplifted earlobes w/ central depression
No formal dx criteria but clinical dx is possible w/ facial features + another major symptom
mnemonics per other study group:
-You have to open your mouth a lot to say “wat” in Mowat.
-Mara Wilson would be friends with aliens since she had superpowers in that one movie, and Zeb is an alien-like name.
-Person mowing the lawn, then their heart starts hurting (heart defects, Hirsch), they die and their corpse collapses (corpus) and seizes.
Pitt-Hopkins syndrome
-AD
-Gene: TCF4
distinctive facial features, significant DD with moderate to severe ID, neurobehavioral/psych manifestations (e.g., stereotypic hand movements, ASD) , autonomic dysfunction (e.g., episodic hyperventilation, breath-holding while awake), most nonverbal
Love of music, frequent smiling and spontaneous laughter, stereotypic hand movements including hand wringing and flapping, bruxism
wide mouth with a full lower lip, widely spaced teeth, flared nostrils, a broad nasal bridge, a sharp, downturned nasal tip, and deep-set eyes that slant slightly upward
Most individuals nonverbal, but receptive language often stronger than expressive
Other common findings: sleep disturbances, seizures, constipation, severe myopia
Mnemonic:
“Few words, wide grin, breath stops again, hands spin”
-Few words: Minimal or absent speech
-Wide grin: Characteristic facial features (wide mouth), frequent smiling and spontaneous laughter
-Breath stops again: Recurrent hyperventilation and breath holding episodes
-Hands spin: Stereotypic hand movements (e.g., hand-wringing or repetitive motion)
Kabuki syndrome
-AD: KMTD2
-X-linked: KDM6A
long palpebral fissures, arched eyebrows, cupped ears, clefting, persistent fetal finger pads, hypotonia, frequent infections, DD, seizures
Isolated premature thelarche may occur in girls with Kabuki. Also hypermobility
Dx: clinically and/or molecularly
Workup: echo, renal US, immune workup
Intravenous immunoglobulin and growth hormone therapy may be considered
Phelan-McDermid syndrome
-AD
-SHANK3
-AKA 22q13.3 deletion syndrome, if terminal consider possibility of ring 22
ID, difficulties with or absent speech, DD, sleep disturbances, seizures, decreased pain perception, ASD
DD/ID (moderate to severe), sleep disturbances, absent/severely delayed speech, behavioral differences (not autism–mouthing/chewing objects, bruxism), neonatal hypotonia, ataxic/abnormal gait, decreased perception of pain, epilepsy, autism (60%), abnormal brain imaging (delayed myelination, agenesis of corpus callosum, ventriculomegaly, white matter atrophy or abnormality, large cisterna magna, arachnoid cyst), regression (~50%), malocclusion/widely spaced teeth, decreased perspiration/tendency to overheat, GERD, strabismus, vision problems, cardiac abnormalities, renal issues, lymphedema
Dysmorphic features: long eyelashes pointed chin, broad nose, wide nasal bridge, bulbous nose, malocclusion, periorbital fullness, large fleshy hands, abnormal ears, abnormal toenails-dysplastic, thin, flakey
CHARGE syndrome
-AD
-CHD7
C: coloboma
H: heart defect
A: choanal atresia
R: ID/restricted growth
G: Genital hypoplasia
E: ear anomalies
Dx: clinical findings, imaging, AND genetic testing
WOrkup: MRI of temporal bones to eval semicircular canals, cochlea, and cranial nerves. Echo, ECG, grwoth hormone levels, thyroid function tests, ca levels, renal/pelvis US
Pearl: cranial nerves most often affected are I (smell), VII (facial), VIII (hearing), and IX/X (sucking, swallowing, gut motility)
GLI3-related Pallister Hall syndrome
-AD
-GLI3 sequence variant, 25% de novo
Variable symptoms: hypothalamic hamartoma, polydactyly (meso or post), bifid epiglottis, can also have renal/GU/pulmonary anomalies
PH allelic with Greig cephalopolysyndactyly syndrome, but Greig has syndactyly and craniofacial features (vs PH has meso or post polydactyly)
Clinical dx possible if HH + mesoaxial polydactyly
Don’t remove HH unless it’s causing serious problems, monitor growth in case of precocious puberty
Thoughts from other study group:
-Hall = hypothalamic hamartoma (all H’s)
-Killian = more likely to kill you (more severe symptoms, die-aphragmatic hernia, the blood cells w/ tetrasomy tend to die out which makes those tests negative)
-Cat-eye is c22 while Killian is c12 bc cats have long lives (22 years)
-Although they have similar names, they’re so different that they don’t even have the same inheritance pattern (one is a whole extra chunk of chromosome + mosaic while the other is generic AD single-gene)
-Hall is the shorter name, therefore the simpler inheritance (GLI3 AD)
Rubinstein Taybi syndrome
-AD
-CREPBBP (more common), EP300
Short stature, poor growth, low-hanging columella, broad thumbs and great toes, ID, and ocular, auditory, renal, and cardiac anomalies
Obstructive sleep apnea common
Dx: established clinically, can confirm w molecular testing
Workup: eval for cardiac, renal, ophthal, neuropsych, neurology
Autosomal dominant polycystic kidney disease
-AD
-PKD1, PKD2
Most common form of PKD
Kidney cysts, bile duct cysts, hypertension, vascular aneurysms
~50% of patients develop kidney failure, aneurysms may rupture causing sudden death
PKD1: more severe, progresses to kidney failure faster than PKD2
Autosomal recessive polycystic kidney disease
-AR
-PKHD1
Much less common than AD PKD
Kidney cysts, bile duct cysts, hypertension
> 50% of patients develop kidney failure before 20y, in severe cases cysts cause renal failure before birth. Fetus can’t produce urine
–> potter sequence
Alport syndrome
-AD, AR, X-linked
-COL4A3, COL4A4, COL4A5
progressive renal disease causing isolated hematuria to renal failure. May see progressive hearing loss and eye concerns such as corneal erosions, maculopathy, anterior lenticonus
Males with XL alport syndrome should be evaluated for aortic dilation
Remember: can’t see, can’t pee, can’t hear a bee
Dx: confirmed with molecular testing of COL4 genes
Workup: urinalysis (may see proteinuria, hematuria), audiogram, ophthal exam
ACE-I or ARB meds to delay onset of severe renal disease, may require dialysis and kidney transplant
Cytinosis
Cystinuria
Hirschsprung disease
