1 Peds Genetics Flashcards
What’s the real name for “brittle bone disease”?
Osteogenesis Imperfecta
What type of genetic disease is OI?
Autosomal dominant mostly
Some autosomal recessive subtypes
Majority of cases of OI involve mutations in what genes?
Alpha-1 and alpha-2 chains of TYPE I COLLAGEN (COLA1 or COLA2)
Which subtype of OI is the most common?
Type I
It’s mild. Sometimes you wouldn’t even know by looking at them that they’s got fucked up bones.
Which subtype of OI is the most severe?
Type II
Usually lethal in utero
How many other subtypes of OI are there?
Types III-IX: Moderate-severe with characteristics of everything in between
Key clinical features of osteogenesis imperfecta
Excessive/atypical fractures*** Short stature Bowlegs or other limb deformities Scoliosis/kyphosis*** (more common with Type III-IX, can lead to breathing difficulties) Basilar skull deformities —> spinal cord concerns BLUE SCLERAE****************** Hearing loss (progressive)*** Opalescent teeth*** Ligament and skin laxity
What are the dental findings in OI called?
Dentinogenesis imperfecta
Opalescent teeth
What is a common imaging modality for early diagnosis of OI?
Maternal U/S if severe
Fractures at various stages of healing that may be misdiagnosed as child abuse
Osteogenesis imperfecta
What are some hallmark imagining findings suggestive of OI?
Wormian bones (suture bones of skull)
Codfish vertebrae (vertebral bodies bi-concave from compression fractures)
Osteopenia
Why might you skip f/u xrays for a simple fracture in a kid with OI?
To minimize radiation exposure
How is OI usually diagnosed?
Often it’s a clinical diagnosis, especially if family history (unless you want to determine the specific subtype)
What does biochemical testing do for us in OI?
Helps evaluate structure and quality of type I collagen
Common lab findings in OI
Vitamin D, phosphorus, alkaline phosphates may be normal or elevated with recent fracture
HYPERCALCEMIA is common and relates to severity (b/c bones constantly being remodeled)
What is the main medicinal treatment for OI?
Bisphosphonates - Pamidronate (IV infusion every 3 months: 4 hours daily for 3 days)
Slows down bone reabsorption —> reduces fracture rates and increases bone density
Risks of hypocalcemia, OSTEONECROSIS OF THE JAW, and nephrotoxicity. But it’s helpful, I guess.
Marfan syndrome is a genetic mutation in …
Connective tissue protein FBN1 (fibrillin)
Autosomal dominant
Cardiac effects of Marfan syndrome
AORTIC ROOT DILATION/DISSECTION**
—> Aortic rupture risk
Mitral valve prolapse
What pulmonary condition are Marfan patients more predisposed to experience?
Spontaneous pneumothorax
What are the ophthalmologic effects of Marfan syndrome?
Myopia (nearsightedness)
Lens subluxation/dislocation
Musculoskeletal presentation of Marfan syndrome
Tall, thin with increased arm span/ht ratio
SCOLIOSIS
ARACHNODACTYLY (look for positive hand signs)
Pectus deformity
Hind foot valgus
Hyper mobile joints with laxity
Steinberg sign
Used for clinical evaluation of Marfan patients
Fold your thumb into the closed fist. Test is positive if the thumb tip extends from the palm of the hand.
Walker-Murdoch sign
Used for clinical evaluation of Marfan patients
Grip your wrist with your opposite hand. If thumb and fifth finger of the hand overlap with each other, this represents a positive test.
How is marfan diagnosed?
CVS or amniocentesis may detect defective gene
DNA testing
How do you evaluate a patient with Marfan?
ECHO/ECG to look for cardiac issues
Eye exam including slit lamp for lens dislocation
Radiographs: CXR, skeletal abnormalities
MRI/CT PRN
How do you manage patients with Marfan?
Involve specialists - Cardio, Ortho, Ophtho
Meds: Beta blocker (to take stress off the heart)
Strenuous activity restrictions
Possible surgery, if enlarged aorta, progressive scoliosis, chest deformity, eye problems
Where is the genetic defect in Prader-Willi Syndrome?
Affects long arm of Chromosome 15 - due to absence of PATERNAL gene expression
What is the primary cause of dysfunction in Prader-Willi Syndrome?
Hypothalamic or pituitary dysfunction —> primary central growth hormone deficiency
Expression of a gene depends on gender of parent donating the gene
Genetic imprinting
Uniparental disomy of Chromosome 15 leads to ______ if lose is paternal and _____ if loss if maternal
Paternal = Prader-Willi syndrome*** Maternal = Angelman syndrome
Which is more common - Prader-Willi or Angelman?
Prader-Willi - 75% of cases of chromosome 15 disomy
Angelman —> less distinct features, higher IQ, milder behavioral problems
PWS —> more likely to have autistic behaviors
Physical traits of PWS
Almond shaped eyes Triangular mouth Narrow forehead Short stature Small hands and feet Depigmentation (skin and eyes) Hypogonadism (typically sterile) Risk for osteoporosis
Social concerns for PWS
Developmental delay
Intellectual disability
Behavioral problems
Food seeking behavior
PWS in infants vs early childhood
Infants: profound HYPOTONIA —> feeding difficulties and FTT
Early childhood: HYPERPHAGIA and weight gain (binge eating)
Diagnosis of PWS is via…
Molecular genetic test —> Methylation analysis
Management of PWS
Limited 😔
Replace HGH and testosterone/estrogen Healthy diet/exercise Multidisciplinary therapies May consider group home Monitor for complications
Meds for hyperphagia generally not helpful
PWS complications
Type 2 DM Heart disease/stroke Sleep apnea Joint “wear and tear” Psychological component
Most common inherited intellectual disability
Fragile X
X-linked recessive disorder
Because Fragile X is X-linked, it has…
Higher incidence/severity in males
What is the Lyon hypothesis?
Because they have two X’s, variable expression due to X-activation (mosaicism) means they are typically ok in diseases like Fragile X
______% of x-linked recessive disorders are new mutations
90%
What clinical presentation is usually the reason boys end up being diagnosed with Fragile X?
Intellectual impairment —> genetic testing
Clinical presentation of Fragile X
Intellectual impairment Developmental delay (late language and motor delay) Autistic behaviors Poor ability to cope with transitions Hyperactivity Anxiety Behavior/tantrums Seizures
Physical characteristics of kids with Fragile X
Soft smooth skin
Microcephalic with prominent forehead/chin
Large ears and long, narrow face
MSK: joint laxity, hypotonia, pes Plano’s
Eye: Strabismus, blue iris
CV: Mitral valve prolapse (murmur)
Macro-orchid is after puberty
What is the specific gene that causes Fragile X?
CGG repeat in FMR1 gene (FragileX Mental Retardation Gene)
Pre-mutations (present slightly differently):
• Primary ovarian insufficiency (FXPOI)
• Tremor/ataxia syndrome (FXTAS)
How do you manage patients with Fragile X?
Multidisciplinary: med consults, various therapies, patient/parent ed
Echo
MRI and eval if seizures
GERD: meds, feeding therapy
PT, OT, Speech, individualized educ plan
What gene is affected in DiGeorge Syndrome?
22q11.2 defection
What is the inheritance pattern for DiGeorge Syndrome?
Autosomal dominant, but most often occurs randomly
Classic triad of SSx for DiGeorge Syndrome
Cardiac abnormalities
Hypoplastic thymus
Hypocalcemia
Subtypes of DiGeorge Syndrome is based upon …
Thymic hypoplasia and immune function
Can be partial or complete
How do cardiac symptoms present in DiGeorge Syndrome?
Can be asymptomatic with mild defects
More severe present with potential cyanosis, HF, FTT, and/or respiratory distress
Complete DiGeorge Syndrome is characterized by…
Complete absence of the thymus —> immunodeficiency
Why to DiGeorge patients end up with hypocalcemia?
Due to underdeveloped parathyroid
Besides the classic triad of SSx, what other potential concerns do DiGeorge patients have?
Craniofacial abnormalities (low set ears, wide set eyes, underdeveloped chin/small mouth, bulbous nose tip)
Palatial defects —> speech delay/difficulty
GU abnormalities
Recurrent infections/inflammatory diseases (b/c thymus hypoplasia)
Can also have skeletal concerns, developmental delay, and behavioral issues)
Dx of DiGeorge is based on…
Decreased CD3+ T cells and clinical findings
There are three different criteria for Dx (“Definitive”, “Probable”, “Possible”)
Initial evaluation of DiGeorge Syndrome should include…
Urgent echo (b/c of cardiac concerns)
Labs: CBC w/ diff, Ca and PO4
Renal U/S
CXR —> thymic shadow
How do you manage DiGeorge Syndrome?
Cardiac consult (observation v surgery)
Genetic consult for screening/counseling
Endocrine consult
Speech/feeding therapist
Behavioral/psychiatric counseling in adolescents
CAUTION with live vaccines
Isolation???
What is the prognosis for Complete DiGeorge?
Life expectancy in infant is less than 1 year without treatment
Thymic transplant if possible (if they do, they usually do quite well)
Hematopoietic stem cell transplant
Chromosomes with any number other than 46
Aneuploidies
Examples:
Klinefelter Syndrome
Turner Syndrome
Trisomy 13, 18, and 21
47, XXY
Klinefelter Syndrome
When does Klinefelter typically present?
POSTPUBERTAL
Infants and pre-pubertal boys typically have no obvious signs
Tall stature, narrow shoulders, long legs, microorchidism, gynecomastia, mild language delay/learning disabilities
What do labs look like in Klinefelter syndrome?
Testosterone low, FSH/LH elevated in adolescents (consider testosterone replacement)
Infertility eval: 50% may be able to father kids with assistance
45, XO
Turner Syndrome
1 in 2000 females
Can be result of mosaicism:
45,X / 46, XX
45,X / 46, XY with partial or complete deletion of Y
Turner patients have higher risk for …
X-linked recessive disorders such as hemophilia A/B
Short stature, low hairline, webbed neck, broad chest with wide spaced nipples, shield chest, pigmented nevi, average intellect
Turner Syndrome
Infants: lympedema in dorsum of hands and feet, CHD
Common cardiac findings in Turner Syndrome
COARCTATION OF THE AORTA (risk for aortic dissection)
Bicuspid AV (aortic stenosis)
HTN
MSK findings in Turner Syndrome
Cubits Valgus
Short 4th metacarpals
Madelung Deformity
GU findings in Turner Syndrome
STREAKED GONADS (underdeveloped)
Premature ovarian failure
Primary amenorrhea (small % can still get preggo)
HORSESHOE KIDNEY (or other renal malformations)
Management of Turner Syndrome
Multidisciplinary team
Infertility —> IVF with egg donation (pregnancy risky b/c of risk of aortic dissection)
Estrogen and cyclic progesterone therapy to stimulate puberty and assist with bone density
Monitor for gonadal malignancy (maybe prophylactic removal of gonads)
Counseling
What are the three trisomies that are possible?
Trisomy 13 = Patau Syndrome
Trisomy 18 = Edwards Syndrome
Trisomy 21 = Down Syndrome
Majority of which trisom(ies) die en utero?
Trisomy 13 and 18
Which trisomy results in midline craniofacial, eyes, forebrain?
Trisomy 13 (Patau)
Defect is prechordal mesoderm
Clinical features of Trisomy 13
Midline cleft lip and palate, sloping forehead, scalp defects, micro-ophthalmia, holoprosencephaly
MSK: HYPOtonia, clinodactyly, polydactyl, vertical talus
Severe intellectual disability, kidney defects, CHD, omphalocele
Prognosis for Trisomy 13
The worst
Majority die in utero
Affected infants usually die before 1 month of age and <5% survive beyond 6 months
Currently supportive care is recommended (“noninterventional paradigm”)
Clinical features of Trisomy 18 (Edwards)
Intrauterine growth restriction with low birth weight, low set ears, microcephalic, small jaw/mouth, prominent occipital
MSK: HYPERtonia/spasticity, overlapping digits, rocker bottom foot, short sternum
Horseshoe kidney
Airway obstruction
Omphalocele
CHD (VSD and PDA)
Prognosis for Trisomy 18
Majority die in utero
50% die within 2 weeks and only 5 % survive beyond 1 year
Most common chromosomal abnormality (1/600)
Trisomy 21 (Down)
Typical developmental delay in Down Syndrome is …
Twice the average age
Risk of Down Syndrome is increased with…
Advanced Maternal age
25 yo: 1/1350
35 yo: 1/350
45 yo: 1/35
Clinical features of Trisomy 21
Epicanthic folds, flat nasal bridge, folded low set ears, brachycephaly, brushfield spots (speckled iris), open mouth, protruding furrowed tongue, short neck with excessive skin, narrow palate, upslanting palpebral fissures
50% of Down Syndrome patients have…
CHD
Ex: AVSD, VSD, ASD, PDA, TOF
HEENT findings in Down Syndrome
Visual (cataracts, refractive errors)
Hearing (conductive loss with multiple infections)
Abnormal teeth
Pulmonary findings in Down Syndrome
Pulmonary HTN
Intermittent hypoxia
Obstructive sleep apnea
Recurrent PNA
GI findings in Down Syndrome
Duodenal atresia
Chronic constipation
Hirschprung Disease
Celiac
MSK findings in Down Syndrome
Short stature, HYPOtonia, joint laxity, short hands, transverse palmar crease (Simian line), space between 1st and 2nd toes
