Genetics and Dysmorphology Flashcards
22q11.2 deletion
What is it also known as
(aka: DiGeorge, velocardiofacial syndrome)
HYPOCALCEMIA, IMMUNE DEFICIENCY, KIDNEY abnormalities
hearing loss
congenital heart disease, palatal abnormalities
characteristic facial geatures, learning problems
Dx by fluorescence in situ hybridization analysis for submicroscopic deletion of chromosome 22, high-res karyotype, or chromosomal microarray
branchio-oto-renal syndrome (BOR)
mutations of EYA1 and SIX1
deafness
external ear deformities
lateral semicircular canal hypoplasia
brachial arch anomalies
renal malformations
Treacher Collins Syndrome
mandibular and zygomatic hypoplasia
coloboma of lower eyelids, absent lower eyelashes, external ear abnormalities, preauricular hair displacement onto cheekbones
CONDUCTIVE hearing loss (not SNHL)
3 genes: TCOF1, POLR1C, POLRID
Spinal Muscular Atrophy (types, onset, symptoms)
SMA 0: prenatal onset with infantile death
SMA I: onset <6 mo with lifespan >2 years
SMA II: onset 6-18 mo, 70% alive at 25 years of age
SMA III: onset >18 mo, normal lifespan
SMA IV: adulthood onset, normal lifespan
Gene: SMN1 or SMN2 (the more 2, the milder phenotype)
Types of Testing (8)
- Karyotype or 2. microarray: intellectual disability, autism, or multiple congenital anomalies
- Fluorescent in situ
- Hybridization Analysis
- Multigene panel testing
- Whole exome sequencing
- Specific (single) gene mutation analysis
- DNA methylation (Prader WIlli and Angelmann)
Spinal Muscular Atrophy (types, onset, symptoms)
SMA 0: prenatal onset with infantile death
SMA I: onset <6 mo with lifespan >2 years
SMA II: onset 6-18 mo, 70% alive at 25 years of age
SMA III: onset >18 mo, normal lifespan
SMA IV: adulthood onset, normal lifespan
Gene: SMN1 or SMN2 (the more 2, the milder phenotype)
+ tongue fasciculations
Endocrine abnormalities associated with Prader Willi
GH deficiency is universal
(and other HPA dysfunction like central hypothyroidism, OSA)
Prader Willi Syndrome
Characteristics and Dx
Global hypotonia
poor suck
hypogonadism
characteristic facial features (bitemporal narrowing of head, triangular mouth)
Global developmental delay
Behavior: compulsiveness, stubbornness, manipulative
HYPERPHAGIA, but feeding difficulties
Hypoplastic genitalia
SHORT stature
osteoporosis
small hands/feet, poor growth in early childhood
Almond-shaped eyes
Obesity
Dx: DNA methylation testing of parent specific imprinting (PWCR on Chromosome 15), also 2/2 inheriting 2 copies of chromosome 15 from mother
TFTs annual
Zellweger Syndrome
AR
Presentation: newborn period with global hypotonia, poor feeding, seizures, liver cysts w/ dysfunction, distinctive facies (flattened facies, large anterior fontanelle, broad nasal bridge, widely spaced sutures.)
Usually die in 1st year of life
Pancytopenia (what syndrome is it associated with?)
Fanconi Anemia
&
X-linked dyskeratosis congenita
Thrombocytopenia (what syndrome is it associated with?)
Wiskott-Aldrich syndrome
&
Thrombocytopenia absent radius syndrome
Hypercalcemia
Hypercalciuria
HYPOthyroidism
Williams Syndrome (triad)
+ supravalvular aortic stenosis
7q11.23
47,XYY
Expected sexual development/fertility, development, behavioral development, stature
- normal sexual and fertility
- Normal to mild delayed intelligence
- Behavior: impulsivity & hyperactivity
- TALL Stature
47,XYY
Expected sexual development/fertility, development, behavioral development, stature
- normal sexual and fertility
- Normal to v mild delayed intelligence
- learning/speech delay - Behavior: impulsivity & hyperactivity
- TALL Stature
- Bonus: cystic acne as adolescence
47,XXX
Expected sexual development/fertility, development, behavioral development, stature
triple X syndrome
TALL Stature (females)
Learning disabilities: usually normal (learning/speech)
Can have 10% seizures + kidney anomalies
Trisomy 13
microcephaly
microphthalmia
low-set ears
cleft lip and/or ppalate
holoprosencephaly
cutis aplasia (absence of skin)
polydactyly
clenched hands
cryptorchidism
renal anomalies
cardiac malformations
Trisomy 13
Patau Syndrome (1/16,000)
specific to trisomy 13:
cleft lip and/or palate
holoprosencephaly
cutis aplasia (absence of skin)
MIDLINE DEFECTS, HYPOTONIA, MICROPHTHALMIA (vs. tri 18)
others:
microcephaly
low-set ears
polydactyly
clenched hands
cryptorchidism
renal anomalies
cardiac malformations
Trisomy 18
features and how is it different/ similar to trisomy 13
Edwards Syndrome (1/5000)
Different: hypertonia, clenched fists, rocker-bottom feet, myomeningocele
Similarities to trisomy 13:
characteristic facial dysmorphology, prenatal and postnatal growth deficiency, renal and cardiac anomalies, severe intellectual disability, and nuchal thickening.
Dolichocephaly, external ear anomalies, micrognathia, short palpebral fissures, and small face.
5-10% of affected infants survive beyond the first year.
Non-inherited
NF2 eye exam findings
subcapsular lens opacity (rarely will progress to cataract)
NF1 eye exam findings
iris lisch nodules
colobomas are associated with ____
CHARGE
Heterochromia iridis is associated with ____ (4)
- Waardenburg syndrome
- Sturge-Weber Syndrome
- Parry-Romberg syndrome
- Horner syndrome
Shwachman-Diamond Syndrome
Exocrine Pancreatic Insufficiency (low elastase level), neutropenia, bone deformity, short stature, multiple infections
AR
If both parents have 1 copy of autosomal recessive trait, what’s the risk of kids getting the disease
25%
Which 3 diseases are X-linked dominant
- Incontinentia pigmenti
- Rett Syndrome
- Fragile X syndrome
MELAS
Mitochondrial Encephalomyopathy
Lactic Acidosis
Stroke-like episodes
- mitochondrial pattern of inheritence
Leigh Syndrome mode of inheritance
mitochondrial and AR inheritance
Uniparental disomy (UPD)
- what is it
- what syndromes are inherited this way
Patient inherits 2 copies from one parent’s chromosome (one parent’s is missing)
- Prader-Willi
- Angelman
- Beckwith-Wiedemann
Mode of inheritance for Friedreich Ataxia, Huntington, Fragile X
trinucleotide repeat expansion
Trisomy 21 physical presentation (7 systems)
- Face: epicanthal folds with up-slanting palpebral fissures, brushfield spots of iris, flat nasal bridge
- Neurologic: hypotonia
- Cardiovascular: conotruncal defects, AV canal defects
- GI: duodenal atresia, tracheoesophageal fistula, Hirschsprung, imperforate anus, Celiac
- Extremities: 5th finger clinodactyly, single transverse palmar creased, sandal gap toes
- Heme: Transent myeloproliferative disorder (10%), Lifetime risk of leukemia 1%
- Other: OSA, Obesity, Hearing loss in adulthood
Preventative health for trisomy 21 (5)
- CBC and TFT 6mo then 1yr and annually
- TTE
- XR cervical spine (if asymptomatic or getting intubated)
- Abd imaging if symptomatic
- Sleep study by 4 yo
Syndromes with craniosynostosis (3)
- Crouzon - (FGFR2)
- Pfeiffer Syndrome - (hearing loss, pollux/hallus varus +/- syndactyly)
- Apert Syndrome (prominent syndactyly, hearing loss)
Common clinical presentation of Crouzon
- Hypertelorism (large space between eyes)
- proptosis
- midface hypoplasia
- Cleft lip/pallate
- Beaked nose
- Prognathism
*normal intelligence and normal extremities)
Syndromes with PUBERTAL phenotypes (5)
- Turner
- Noonan
- Klinefelter
- Fragile X
- Prader-Willi
Turner Syndrome mode of inheritance
monosomy X (45 X)
NOT inherited
NOT associated with advanced materanal age
Noonan Syndrome mode of inheritance
Multiple gene mutations: PTPN11, SOS1, RAF1, RIT1) activation of RAS/MAPK cell signaling pathway (disrupts cell growth and division)
AD inheritance
Features of Noonan syndrome
- facial dysmorphology
- congenital heart defects
- short stature
- developmental delay
47,XXY
Development, stature, pubertal
Klinefelter
TALL stature (males)
Gynecomastia, microorchidism, micropenis, hypospadias
- Delayed puberty – needs testosterone replacement therapy if no spontaneous puberty, but usually normal
- Increased risk of testicular and breast cancer
Development: variable (speech, autism)
Turner sd physical manifestation (4 systems)
- Face: webbed neck, redundant nuchal skin, pos posterior hairline
- CV: shield chest with wide-spaced nipples, congenital heart defects (left-sided bicuspid aortic valve is common, coarctation of aorta)
- Extremities: congenital lymphedema (hands & feet), dysplastic nails, skeletal abnormalities (Short 4th 5th metacarpals, cubitus valgus, scoliosis, congenital hip dislocation)
- Other: short stature, renal abnl
Turner dx and other labs
Karyoptyping (FISH or array)
FSH & LH high, Estradiol Low
TFT
Imaging: TTE, renal bladder, Ophthalmology
Other: audiology
Turner
1. Stature
2. Puberty
3. Fertility
- Short (because of estrogen insufficiency, not because of premature menarchy)
- delayed
- infertile (streaked ovaries with premature ovarian failure)
Turner management/tx
- growth hormone
- Estrogen by 13yo if no spontaneous puberty
- DM (increased risk)
- Surveillance for hypothyroidism, celiac, IBD
Noonan how is it different from Turner
and what else
Down-slanting palpebral fissures
RIGHT-sided CV: pulm vein stenosis, atrial septal defect, hypertrophic cardiolmyopathy
- Face: webbed neck, low-set posteriorly rotated ears, hypertelorism, epicanthal folds, ptsosis, ocular anomalies
- CV: pectus carinatum, wide-spaced nipples
- GU: cryptoorchidism
- Heme: coagulopathy
- Extremities: lymphatic dysplasia, other, short stature
Noonan Dx
Labs: Multigene panel (PTPN11, SOS1, RAF1, RIT1)
CBC ,PT/PTT
Urinalysis
Imaging: TTE, renal US, XR chest/spine, MRI if symptomatic
Studies: ECG, ophtho eval, audiology
Noonan
1. Stature/growth
2. Puberty
3. development
- post-natal growth failure by 1 year of age
- normal puberty
- delays possible
Fragile X inheritance and genetic problem
XL dominant
trinucleotide CGG repeat expansion in FMR 1
<44 repeats = normal
Intermediate 45-54
Premutation 55-200
Full mutation 200+
Most common inherited intellectual disability
Fragile X
Fragile X physical manifestation
- Face: long narrow face, large ears, prominent jaw, tall forehead
- Neuro: Intellectual disability, speech delay, behavioral issues, fragile x- associated tremor ataxia syndrome (FXTAS), strabismus, seizures
- GU: Macroorchidism, extremities, pes planus, female carriers – premature ovarian failure
- CV: mitral valve prolapse
infertile
NF1 Inheritance
Autosomal dominance
Diagnostic criteria for NF1
2+ of the following:
- 6 hyperpigmented cafe-au-lait macules (5 mm in children, 15 mm postpuberty)
- 2+ neurofibromas or plexiform neurofibroma
- axillary or inguinal freckling (often appears in late childhood)
- optic glioma <10 yo
- 2+ lisch nodules (iris hamartomas, <20 years of age)
- Tibial pseudoarthrosis or sphenoid dysplasia
- 1st degree relative with NF1
If you think someone has NF1, what is the imaging and labs to get
- NF1 molecular testing
- MRI for detection and monitoring of internal neurofibromas over time, including signes of cerebrovascular disease
- Unidentified bright objects (UBOs) visualized in 50% of children with NF1
Monitoring and Tx for NF1
TUMORS
Ophtho: dx of optic glioma
Seizure treatment
Tumors: glioma and pheochromocytomas, jeuvenile myelomonocytic leukemia, breast cancer
Routine tumor surveillance
Scoliosis monitoring
Clinical diagnosis of NF2
One or more of the following:
1. Bilateral vestibular schwannomas
2. 1st degree relative with NF2 and unilateral schwanomma, glioma, neurofibroma, posterior subcapsular lenticular opacities
3. Unilateral schwannoma and any two of those listed previously
4. Multiple meningiomas and unilateral schwannoma or any two of the following: schwannoma, glioma, neurofibroma, cataract
Dx of NF2
NF2 molecular genetic testing
MRI/CT head
audiology eval
ophtho
Routine imaging in NF2: (what is it and how often)
Annual MRI >10 yo
Tuberous Sclerosis Complex can also be associated with what other disease
Polycystic kidney disease (PKD1)
Mode of inherritence of Tuberous sclerosis and NF2
AD
Clinical dx of tuberous sclerosis
Two or more of the following:
- > 3 hypopigmented macules (ash leaf spots)
- Shagreen patch (raised flesh colored patch on lower back) 50% of cases
- Facial angiofibromas ~4 yo (75%)
- Ungual fibromas (growth at the nail bed)
- Cortical tubers (80%)
- Subependymal giant cell astrocytomas (SEGAs, 10%)
- Lymphangioleiomyomatosis (LAM, 80% of females by age 40 years)
- Renal angiomyolipomas (70%)
- Cardiac rhabdo myomas (50%)
- Retinal hamartomas (40%)
Cognitive development of Tuberous sclerosis
Epilepsy (VERY COMMON)
1. ADHD
2. Cognitive impairment
3. Disruptive behavior
4. Anxiety
5. Depression
Surveillance for tuberous sclerosis
- Brain MRI (q3 years <25y if asymptomatic) for cortical tubers, radial glial bands, and subependymal nodules
1a. Chest CT every 5-10 yr in asympt females >18yo to monitor for LAM - EEG
- ECG
- TTE
- Renal bladder US
- Ophtho
Tx of Tuberous Sclerosis
mTOR inhibitor therapy – for progressing SEGAs
Vigabatrin for seizures
Skin findings of Incontinentia Pigmenti
- Blaschko line blistering rash in infancy,
- swirling macular hyperpigmentation in childhood
- Linear hypopigmentation in adulthood
Emergencies in patients with Incontinentia Pigmenti
Retinal detachment
Seizure
Mode of inheritance of Incontinentia Pigmenti
X-Linked Dominance
Mode of inheritance or Cause of Angelman Syndrome
Deletion of maternal segment of chromosome 15, or paternal UPD (only inheriting chromosome 15 from father).
Loss of function of UBE3A
Clinical presentation of Angelman Sd (Neuro, Movement, Personality)
Neuro:
1. Microcephaly
2. Seizure
3. Sleep disturbance
4. Cognitive impairment (non-verbal, developmental delay) 6-12mo
Movement:
1. Ataxia
2. Hypermotoric movements (arm tremors, jerky movements, clumsiness)
Personality:
1. Happy Demeanor, inappropriate laughter
2. Excitable, with hand-flapping
Lesch-Nyhan Sd, what is the main problem
Hyperuricemia
low HRPT enzyme activity
due to decreased Hypoxanthine-guanine phosphoribosyltransferase activity
How to test for Angelman Sd
methylation testing of 15q11.2-q13 region of chromosome 15
UBE3A molecular genetic testing
Meds to avoid in Angelman (3)
carba,azepine
Vigabatrin
Tiagabine
Mode of inheritance Lesh-Nyhan Sd
X-linked recessive
Clinical findings LNS
hypotonia, extrapyramidal and pyramidal involvement, developement delay
SELF-INJURIOUS BEHAVIOR
How to diagnose LNS
molecular sequencing
Management of LNS
allopurinol
baclofen
modalities to reduce self-injurious behaviors
Rett Sd mode of inheritance
X-linked dominant
Rett clinical presentation
Neuro
Microcephaly, seizure, stereotypies (hand-wringing), gait ataxia, bruxism, sleep disturbance, neuropsychiatric disturbance (agitation), developmentally normal until regression (~18 mo)
GI
Constipation, extremities, small hands/feet
Other
FTT, scoliosis
Diagnosis of Rett
MECP2 molecular genetic testing
Cardiac complication of Rett
Prolonged QTc
Williams Sd cause and manifestation
Deletion of chromosome 7 (~30 genes, ELN)
Abnormal elastin production –> CV and connective tissue problems
Williams Sd mode of inheritance
AD (but not typically inherited)
Williams Sd Face
“Elfin facies”
Broad forehead with bitemporal narrowing
Periorbital fullness
Malar hypoplasia
Long philtrum
Full lips with side mouth
Williams Sd Neurologic findings (3)
Stellate iris
Friendly – “cocktail party personality”
Intellectual disability
Williams Sd Cardiac manifestations
supravalvular aortic stenosis with or without coarctation
Other vascular abnormalities: pulmonary artery stenosis & renal artery stenosis
Williams Sd GI manifestations
hernias
rectal prolapse
Williams syndrome endo manifestations
hypothyroidism
HYPERcalcemia
How to test for Williams Sd
- Chromosomal Microarray (fluorescence in situ hybridization [FISH]
- Multiplex ligation-dependent probe amplification [MLPA]
- ELN Molecular genetic testing
Huntington Disease
- What’s the trinucleotide repeat problem
CAG
Huntington mode of inheritance
AD
Huntington mean age of onset
Survival after onset
35-44 yo
15-18 years after onset
Symptoms of Huntington
Motor:
- Early: involuntary movements, dystonia, chorea, speech
- Late: rigidity, bradykinesia, inability to walk/speak
Psychiatric (irritability, anxiety, depression)
Huntington treatment
Neuroleptic
Antiparkinsonian and psych agents
Mutation in Achondroplasia
FGFR3
Gly380Arg
Achondroplasia mode of inheritance
AD
>80% de novo mutation
Imaging for achondroplasia
skeletal survey
Baseline CT head to eval foramen magnum for stenosis
Other medical comorbidities of achondroplasia
recurrent otitis media, lordosis, kyphoscoliosis and hydrocephalus, hearing loss, monitor spinal stenosis in adults, sleep apnea
What to watch out for in sports for achondroplasia
contact sports, diving, gymanstics –> atlantoaxial instability
- also watch for intubation
Common cause of early death for achondroplasia (2)
respiratory insufficiency from small thorax and neurologic deficit from cervicomedullary junction compression
What is Arthrogryposis Multiplex Congenita (AMC)
multiple joint contractures that occur in neonates with congenital myasthenic syndromes (CMS) due to lack of in utero fetal movement.
Other manifestations of Arthrogryposis Multiplex congenita
neonatal hypotonia
ptosis
high arched palate
poor feeding
respiratoryinsufficiency (pulm hypoplasia, small thorax)
Does achondroplasia benefit from GH?
NO
Bell shaped chest, short ribs, shortened limbs, polydactyly. Diagnosis?
Jeune Asphyxiating Thoracic dystrophy (JATD)
How to diagnose jeune asphyxiating thoracic dystrophy and what’s the mode of inheritance
molecular genetic study” mutation in IFT80, TTC21B, DYNC2H1
AR
Marfan’s mutation
FBN1 –> fibrillin 1 is reduced
Marfan’s preventative measures
- yearly echo
- intermittent surveillance of aorta with CR or MRA in adolescence
Mode of inheritance Marfan
AD
Pharmacotherapy in Marfan
beta blocker and ACE for hemodynamic stress and remodeling
Sports in Marfan syndrome:
avoid contact sports (aortic dissection risk)
avoid positive pressure (wind instrument, scuba diving - risk of pneumothorax)
Long, narrow face, enophtalmos, Down-slanting palperal fissures, malar hypoplasia, micro/retrhognathia, high arched palate with dental crowding..
Marfan’s or Ehler danlos?
Marfan
Cardiovascular difference between Marfan and Ehler Danlos
Marfan: pectus excavatum or carinatum, aortic dilation/dissection, MVP
Ehler danlos:
aortic ROOT dilation (nonhypermobile)
MVP
Neurologic diff between Marfan and Ehler Danlos
BOTH: normal intelligence
Marfan: ectopia lentis, myopia
Ehler Danlos: hypotonia, delayed motor development
Extremity differences between Marfan and Ehler Danlos
Marfan: arachnodactyly, reduced elbow extension, positive wrist/thumb sign
Ehler danlos: joint hypermobility, easy dislocations/subluxations, cramping
Mutation in Ehlers-Danlos Syndrome
COL5A2 and COL5A1 – COLLAGEN production
Mode of inheritance Ehlers Danlos
Mostly AD
Can be AR
Types of Ehlers Danlos (III, IV, VI)
III: hypermobile
IV: vascular
VI: kyphoscoliotic
Which is the most dangerous type of Ehlers Danlos
Vascular (IV) can cause internal bleeding, stroke, peritoneal perforation, organ rupture, and shock
VACTRL
V vertebral
A anal atresia
C cardiac defect
TE tracheoesophageal fistula
R renal defects
L limb defects
CHARGE
C coloboma
H heart defect
A atresia choanae
R retardation
G genital anomalies
E ear anomalies
Macroglossia, unusual ear creases, hemihypertrophy, visceromegaly neonate born at 4500g with hypoglycemia. What is the dx and what are they at increased risk for?
Beckwith-Wiedemann
Wilms tumor (and other embryonal tumors like hepatoblastoma, neuroblastoma)
What is astrocytoma associated with?
NF1, tuberous sclerosis, melanoma-astrocytoma syndrome
Stickler syndrome
significant airway obstruction due to severe micrognathia, wide U-shaped cleft palate, and glossoptosis, high grade myopia, vitreous abnormalities, SNHL
Joint laxity, flat facies
Syndromes with pierre robin sequence
treacher collins
DiGeorge
Stickler
developmental delays, hypotonia, hearing loss, and a previously diagnosed generalized tonic-clonic seizure disorder. Her facies are remarkable for microcephaly, “Greek warrior” helmet nose, high anterior hairline with prominent glabella, hypertelorism, epicanthus, high-arched eyebrows, downturned mouth, small jaw, and small ears with bilateral ear pits. ASD. IUGR. Dx?
Wolf-Hirschhorn syndrome
4p deletion
5p deletion, small head, epicanthal folds, micrognathia, broad nasal bridge, hypertelorism, downward-slanting palpebral fissures, and moderate-to-severe intellectual disability. Dx?
Cri du Chat
small palpebral fissures, smooth philtrum, and a thin upper lip—in addition to failure to thrive and being small for gestational age
fetal alcohol syndrome
Mode of inheritance Duchenne muscular dystrophy
X-linked recessive
delayed achievement of motor milestones, calf pseudohypertrophy in early stages, and proximal muscle weakness that leads to wheelchair dependence by the age of 10 to 12 years. Dx?
Duchenne muscular dystrophy
Cardiomyopathy in Duchenne muscular dystrophy affect all men after age ___
18 yo
Female carriers of Duchenne Muscular Dystrophy has ___
mild muscle weakness and dilated cardiomyopathy
Endocrine abnormalities associated with Prader Willi
GH deficiency is universal
(and other HPA dysfunction like central hypothyroidism, OSA)
CTG repeats in DMPK
type 1 myotonic dystrophy
GAA repeats in FXN gene
Friedreich ataxia
CAG repeats in HTT
Huntington
CGG repeats in FMR1
Fragile X syndrome
Repeat cutoffs for fragile X syndrome
CGG in FMR1
Intermediate = 45-54 (easily transmitted by mother to offspring)
premutation = 55-200 (risk of developing tremor/ataxia, in females can have premature ovarian failure infertility, early menopause)
>200 = full mutation - males all affected
Decreased fetal movement, polyhydramnios, tented upper lip, hypotonia, bilateral club feet. Mother with droopy eyelids, cataracts, difficulty releasing grip after shaking hands, PPM placement. Dx?
myotonic dystrophy type 1 (congenital)
Best test for a neonate with multiple congenital anomalies that are not suggestive of a specific genetic syndrome
chromosomal microarray (deletion/duplications of genomic content across all chromosomes)
critically ill, small-for-gestational-age, female neonate with tetralogy of Fallot, cleft palate, and hypocalcemia
DiGeorge
22q11.2 deletion (evaluate with FISH)
Mode of inheritance of CF
autosomal recessive
