Genetics Flashcards
Malformation
Abnormal tissue formation (e.g. renal agenesis, micrognathia, cleft palate, CHD)
Deformation
Associated with altered mechanical forces (extrinsic or intrinsic) on normal tissue (e.g. arthrogryposis from in utero constraints)
Disruption
Breakdown of normal tissue; destructive (e.g. amniotic bands, porencephaly, limb reduction from vascular anomalies)
Dysplasia
Abnormal organization of cellular formation into tissue; deregulation (e.g. hemangioma, ectodermal dysplasia)
Syndrome
Pattern of many primary malformations due to one etiology d/t ch abn, single gene d/o, or teratogen
Sequence
Primary defect with secondary effects (e.g. pierre robin sequence 2• to primary mandibular maldevelopment with secondary findings of micrognathia, cleft palate, and glossoptosis)
Mitochondria do
Can present at any age
S/s: lethargy, hypotonia, FTT, seizures, cardiomyopathy, hearing or visual deficits, movement do
Recurrence risk cardiac defect
1 previous child
2 previous children
1 previous -> 3-4% risk to next child
2 previous -> 10% risk to next child
Recurrence risk of cleft lip
1 previous child with unaffected parents
1 previous child with 1 affected parent
1 child & unaffected -> 4-5%
1 child & 1 affected -> 10%
Recurrence risk of cleft palate
1 previous child
1 previous -> 2-6%
Recurrence risk of club foot
1 previous child
1 previous child and 1 affected parent
1 previous -> 2-5%
1 previous and 1 parent -> 25%
Recurrence risk of Hirschsprungs
1 previous
1 previous child -> 3-5%
Recurrence risk of NTD
1 previous child
1 previous -> 3-5%
Recurrence risk of pyloric stenosis
Father
Mother
1 previous child
Father -> 5.5% son 2.4% daughter
Mother -> 19% son 7% daughter
1 previous child -> 3%
Recurrence risk of T21
Mother balanced translocation
Father balanced translocation
1 previous child & no translocation
Mother balanced translocation -> 10-15%
Father balanced translocation -> 5%
1 previous child & no translocation -> 1% unless AMA
Allele frequency calculations
p + q = 1 for allele frequency and then x100 for percent
p^2 + 2pq + q^2 = 1 where p^2 is AA, 2pq is Aa and q^2 is aa
For calculating prevalence, recessive and dominance, etc
Page 92 & 93 for examples
T13
Features
Patau syndrome
Midline abnormalities
Cardiac (vsd > pda)
Cutis aplasia
Narrow hyperconvex fingernails
Cleft lip, palate, small eyes
Holoprosencephaly
Persistent fetal Hb
Increased PMN with nuclear projections
T18
Clinical features
Triple screen
Edwards syndrome
Cardiac (vsd, pda > bicuspid Av, PS, CoA, TOF)
Clenched hands with overlapping
Small mouth
Short sternum
Triple screen: low bHCG, low unconj estradiol, low afp
T21
Clinical features
triple screen
94% complete trisomy
3-5% robertsonian translocation
2% mosaicism
Cardiac (endocardial cushion defect > vsd > pda > anomalous subclavian artery, mvp, AR)
Hyperflexibility of joints
Upslanting palpebeal fissures, flat nasal bridge, brushfield spots (speckled iris), short neck
Hypotonia
Tmd (can present in utero with hydrops)
Leukemia (15-20x compared to general population)
T21 postnatal eval
Echo
Red reflex (r/f catarct)
Mbss if issues feeding
Hearing screen
Carseat test if hypotonia
Cbc for tmd
Tsh
First year: referal to sleep medicine if c/f OSA, peds ophtho, repeat tsh at 6 & 12 mo then annual, hb at 1year
Cri du chat syndrome
Deletion 5p
Deleted portion is of paternal origin in 80%
CV: VSD, PDA, TOF
Facial: hypetelorism, downward slant palpebral fissures
Neuro: cat like cry, IQ, microcephaly, hypotonia
FTT
Deletion 13q syndrome
Thumb hypoplasia, colobomas, ^risk of retinoblastoma, microcephaly, high nasal bridge
Wolf Hirschhorn syndrome
Deletion 4p
High forehead, broad or beaked nose, hyperteleorism, low set simple ear with preauricular dimple, microcephaly, cranial asymmetry
Angelman syndrome
70% d/t 15q11-13 deletion - deleted maternal origin
20-30% d/t point mutation or other abn of maternal 15q11-13 region
Puppet like gait, elfine, seizures
22q11.2 microdeletion
Majority de novo
CATCH 22 - cardiac, abn facies, thymic hypoplasia, cleft palate, hypocalcemia
AD
Aortic arch abn, vsd, pda, tof
Deficient cellular immunity
Prader willi Syndrome
75% deletion of paternal origin 15q11-13
Small hands and feet, undescended testes, hypotonia
Test - methylation analysis
Ch analysis to assess recurrence risk
Can do FISH
Rubenstein Taybi syndrome
Majority sporadic
16p13.3
Cardiac, broad thumbs, broad first toe, downward palpebral fissures, hypoplastic maxilla, narrow palate, prominent or beaked nose, microcephaly
WAGR syndrome
11p13 microdeletion
Wilms tumor, aniridia, gu abn, IQ
Williams syndrome
7q11.23 deletion leads to deletion of elastin gene
Supravalvar subaortic stenosis > pps
Hypoplastic nails, prominent lips, stellate iris, IQ
Apert syndrome
Acrocephalosyndactyly
AD
Majority sporadic
Mut FGFR 2
Hypertelorism, midface hypoplasia, broad thumb and big toe, syndactyly, craniosynostosis
Crouzon syndrome
Craniofacial dystosis
AD
mut FGFR 2
Hypertelorism, maxillary hypoplasia, craniosynostosis, shallow orbits
Holt Oram syndrome
AD with variable expression
Cardiac: ASD, VSD, CoA, conduction defect
Upper limb defects, absent hypoplastic or abn shaped thumbs, narrow shoulders
Marfan syndrome
Abn fibrillin gene on 15q21.1
Noonan
Abn mapping of 12q22 region
Sporadic but can be AD
Dysplastic pulm valve, asd, cardiomyopathy
Pectus excavatum
Webbed neck
Abn coagulation pathway
Ddx for noonan
45 X/XY mosaic
Fetal hydantoin exposure
Fetal alcohol syndrome
Stickler syndrome
AD variable expression
Mut type II collagen on 12q13
Hereditary arthri-ophthalmopathy
Flat facies
Can be a/c pierre robin
Cataracts, retinal detachment, myopia, spondyliepiphyseal dysplasia (flat vertebrae with anterior wedging, poorly developed distal tibial epiphyses, flat femoral epiphyses)
Treacher collins syndrome
AD, variable expression
Manibulofacial dysostosis
May result from mut in TCOF1 gene (ch 5) => 1st and 2nd branchial arch maldevo
Lower eyelid coloboma, mandibular hypoplasia, dysmorphic ears, malar hypoplasia
Conductive hearing loss
Ellis-van Creveld syndrome
AR
Chondroectodermal dysplasia
Single atrium or ASD
short distal extremities, polydactyly
Narrow thorax
50% mortality in infancy d/t cardioresp difficulties
Fanconi pancytopenia syndrome
AR
^# of ch breaks in lymphocytes ans AF cells
Hyperpigmentation, radial and thumb hypoplasia, short stature
Pancytopenia (typically presents in childhood)
35% mortality and have ^ risk of AML
Meckel Gruber syndrome
AR
Cardiac defect, polydactyly, occipital encephalocele, cystic dysplastic kidneys
Range of phenotypic variability
Smith Lemli Opitz syndrome
AR
Defect in cholesterol synthesis
2nd and 3rd toe syndactyly, anteverted nostrils, cataracts, hypogenitalia, hypotonic in infancy to hypertonic
Prenatal diagnosis is possible (dec AF cholesterol)
Thrombocytopenia radial aplasia syndrome
AR
Low plt, eosinophilia, granulocytosis, anemia
Absent blt radii and ulnar abn
40% mortality because of hemorrhage early in infancy
Fryns syndrome
AR
CDH, ^risk of hirschsprung, duodenal atresia, imperforate anus
Dandy walker malformation, IQ low
Cloudy cornea, coarse facial features
Digital and nail hypoplasia
Menkes syndrome
X linked recessive
Kinky hair syndrome
Abn of copper transport leading to copper deficiency
Copper is a cofactor for many enzymes
Progressive cerebral deterioration, hypertonia, seizures
Majority death in early infancy
Charge syndrome and work up
Ch8q12 mut in CHD7 which alters chromatin
AD but majority de novo
Eval: echo, ophtho, otolaryngology, RBUS, hearing screen, CT temporal bones, karyotype
Need 4 mj or 3 mj & 3 minor
Cat eye syndrome
Extra part of ch 22 usually at 22q11 position
Cardiac, anal atresia, coloboma of iris
Cornelia de lange syndrome
Mut in 1 of 3 cohesin-associated genes
Vsd>tof
Micromelia, synophyrs, thin down turning upper lip, initial hypertonicity
Golderhar syndrome
Oculo-auriculo-vertebral spectrum or facio-auriculo-vertebral spectrum
Unknown etiology
1st and 2nd brachial arch abnormalities
Vsd>pda>tof>coa
Microtia, malar maxillary or mandibular hypoplasia, ear tags or pits, microphthalmia
Deafness with normal intelligence
Unilateral renal anomalies
Klippel Feil sequence
Unknown etiology
Early developmental defect of cervical vertebrae
Short neck, low hairline, limited rom of head, deafness
Can be a/c sprengel deformity (failure of scapula to descend)
Klippel Trenaunay Weber syndrome
Unknown etiology
Asymmetric limb hypertrophy
Vascular lesions
Poland sequence
Unknown etiology
Unilateral hypoplasia or absence of pectoralis muscle
Russel silver syndrome
Small triangular facies, micrognathia, short stature, congenital asymmetry of skeleton, 5th finger clinodactyly
VACTERL association
Increased risk in IDM
Can have VACTERL with H for hydrocephalus
Can have fanconi anemia
Dx of exclusion
3 major required
Those who meet criteria, 1/2 will have genetic abnormality and 1/2 will have isolates VACTERL
Evaluation for VACTERL
CXR, echo, RBUS, xray spine, spinal US, HUS, radiograph of extremities if visual abn, ophtho exam
Cbc (for overlapping abn)
Chromosomal analysis - microarray to exclude other causes
Ch breakage assay to assess for fanconi anemia
Trisomy 21 evaluation
Newborn: echo, red reflex, consider MBSS, cbc (for tmd), brainstem auditory evoked response or otoacoustic emission, ATT if hypotonic, TSH if NBS only tests fT4
First year: CBC annually starting at age 1, TSH at 6 and 12 months, sleep study if osa, cervical spine neutral position for procedures, ophthalmology eval by 6 months
Cri du chat syndrome
5p deletion syndrome (usually deleted portion is parental)
Hypertelorism, down slanting palpebral fissures, round face, epicanthal folds, strabismus, low ears
Mental deficiency, cat like cry (abn laryngeal development), microcephaly, hypotonia
30% have VSD, PDA, TOF
Deletion 13 q syndrome
Colobomas, risk retinoblastoma, hypertelorism, ptosis, high basal bridge, low set and malformed ears, micrognathia, microcephaly
Thumb hypoplasia, 5th finger clinodactyly, short big toe
Hypospadius, cryptorchidism
IUGR, mental deficiency
Deletion 4p syndrome (wolf hirschhorn syndrome)
Most de novo
High forehead, broad or beaked nose, hypertelorism, low set simple eat with preauricular simple, prominent glabella
Microcephaly, cranial asymmetry, hypotonia, seizures, cardiac abnormalities
Arachnodactyly a/c
Homocystinuria and Marian syndrome
Camptodactyly a/c
Trisomy 8
Isolated
Cleft lip &/or palate a/c
CHARGE association, DiGeorge, meckel gruber, Pierre Robin, smith Lemli opitz, trisomy 13, goldenhar, treacher collins
Clinidactyly a/c
Carpenter syndrome, Cornelia de Lange syndrome, deletion 13q, klinefelter, rubenstein taybi, t21, holt oram, prader willi
Coloboma a/c
Cat eye syndrome, charge, deletion 13q, treacher collins, t13
Cystic hygroma a/c
Noonan, Turner, t13,28,21
Ocular hypertelorism a/c
Apert, cat eye, cri du chat, crouzon, deletion 13q, DiGeorge, Noonan, t8, Turner
Hypotelorism a/c
Holoprosencephaly
Meckel gruber, Williams, t13
Limb hypertrophy a/c
Beckwith wiedemann and klippel trenauney Weber syndrome
Lip thick or prominent a/c
T8, WAGR, Williams
Hypogenitalia a/c
Carpenter, klinefelter, prader willi, SLO
Macroglossia is a/c
BWS, congenital hypothyroidism, t21
Micrognathia a/c
Cat eye, charge, Cornelia de Lange, deletion 13q, DiGeorge, marfan, Meckel gruber, mobius, Pierre Robin, russel silver, SLO, t8, t18, WAGR
Radial hypoplasia a/c
Fanconi, TAR, vacterl, Cornelia de Lange, holt oram, Poland, t13, t18
Syndactyly a/c
Apert, carpenter, CdL, isolated, Poland, SLO, t21, vacterl
