50 terms

Genetic Conditions I

Down syndrome inheritance/cause
Trisomy 21, mostly sporadic
risk increases with age
if Rob translocation risk is 1-3% if dad and 10-15% if mom (most common 14;21)
1-2% mosiac
3/4 error in miosis 1
(75% os SABs)
XYY inheritance/features
Sporadic, may be tall, ususally no dysmorphic features, increase risk for learning disablities, delays in speech and language, delayed motor skills, may also see hand tremors or involuntary movements and behavioral and emotional difficulties. Small % have ASD
Down syndrome common features
endocardial cushion - ASD, VSD
Upslanting palpebral fissures, epicanthal folds, brushfield sopts, Microcephaly, brachycephaly, flat nasal bridge, small dysplastic ears, hypotonia, short statue, short fingers, fifth finger clinodactyly, sandal gap, excess nuchal skin, single palmar crease, 12 % GI atresia, MR
Down syndrome increase risks
hearing loss, eye diesae hypothyroidism, acquired hip dislocation, Alzheimer in middle age
Increased risk for leukemia of 10-20 fold (<1% overall risk) in newborn period & betw 3-6 yrs
Trisomy 18 (Edwards) inheritance/cause
Sporadic in 80%
transloc in 20%
increase risk with maternal age
95% SAB
1:7500 incidence (liveborn)
Trisomy 18 (Edwards) common features
MR, FTT, severe heart malformations, hypertonia, prominent occiput, clenched fists, rocker-bottom feet

90% die by age 1, 80% female
Trisomy 13 (Patau) inheritance/cause
sporadic in 80%
20% unbalanced trans.
increase risk with maternal age
1:20,00,-25,000 live births
Trisomy 13 (Patau) common features
Growth retardation, severe MR, severe CNS malformations (holoprosencephaly), CL +/- CP, postaxial polydactyly, CHDs, clenched fists, rocker-bottom feet

50% die within first month
Klinefelter syndrome (XXY) inheritance/cause
Sporadic- 45% paternal M1, most maternal causes in M1
15% mosiac
increase risk with maternal age
1:1000 male births
Klinefelter syndrome (XXY) common features
Tall stature, infertile, hypogonadism, gynecomastia, learning difficulties (low verbal comprehension & ability), may have poor psychosocial adjustment
Turner syndrome (XO) inheritance/cause
Sporadic: 50% 45,X, 15% 45,X/46,XX, 10% other 45,X mosiacs, 15% 46,X,i(Xq)
maternal X present in 70%
NOT associated with increased maternal age
>99% SAB
Turner syndrome (XO) common features
Short stature, gonadal dysgenesis, coarctation of aorta, webbed neck, low posterior hairline, broad chest with widely spaced nipples, renal abn, avg/above avg intelligence, deficiency in spatial perception, perceptual motor organization or fine motor execution
Mole: Complete hydatidiform cause
Usually diploid, 46,XX, all paternal in origin, 23,X sperm fertilizes ovum that lacks nucleus then replicates
Mole: Complete hydatidiform features
Trophoblast hyperplasia, grossly disorganized or absent fetal tissue, fetus never present
Mole: Partial hydatidiform cause
Mostly diandric triploid
Mole: Partial hydatidiform features
Fetus present in early stages, but may not survive, nl & hydropic villi
Mole: Ovarian teratoma cause
Usually 46,XX, all of maternal origin
Mole: Ovarian teratoma features
Composed of multiple tissues, can contain hair, teeth, etc
Triploidy 69,XY inheritance/cause
Sporadic: 85% diandric (haploid egg + 2 sperm or haploid egg + diploid sperm)
15% digynic
(1 sperm + diploid egg)
Diandric Triploidy features
Well-grown fetus with proportionate or slightly small head size, large placenta with appearance of partial hydatidiform mole; usually dont survive to term
Digynic Triploidy features
Growth retarded fetus with microcephaly, small, fibrotic placenta, can survive to term
Pathognomonic for triploidy
3-4 syndactyly
Cri du Chat inheritance/cause
5p15- (microdeletion), sporadic (FISH or routine)
80% of cases are paternal del
10-15% chance of parent being translocation carrier
Cri du Chat features
Microcephaly, severe motor & mental retardation, round face, hypertelorism, micrognathia
Willliams syndrome inheritance/cause
7q11.2 (ELN), contiguous gene del (FISH)
Williams syndrome features
Hyperacustis; SUPRAVALVULAR AORTIC STENOSIS (75%); usually mild MR; characteristic facies (broad brow, bitemporal narrowness, periorbital fullness, short nose, full nasal tip, malar hypoplasia, long philtrum, FULL LIPS, wide mouth, malocclusion, small jaw, prominent earlobes); STELLATE/LACY IRIS PATTERN; strabismus; hoarse voice; strengths in auditory rote memory & language, extreme weakness in visuospatial construction; OVER-FRIENDLINESS, generalized anxiety, ADD
Wolf Hirschorn inheritance/cause
4p16.3-, sporadic, dels can vary in size (FISH)
Wolf Hirschorn features
Severe growth & mental retardation, microcephaly, "GREEK WARRIOR HELMET" face, CL +/- CP
Miller-Dieker syndrome inheritance/cause
17p13.3 (LIS1) continguous gene del (FISH)
Miller-Dieker syndrome features
LISSENCEPHALY, microcephaly, thickened cortex, furrowed forehead, short nose with upturned nares, prominent upper lip with thin vermilion border, small jaw, AGENESIS OF CORPUS CALLOSUM IN 90%; striking midline brain calcifications; MR, seizures
-prenatal polyhydramnios
Bloom syndrome inheritance/genetics
15q26 (BLM aka RECQL3)
common mut: 6bp isn/7bp del2281
Bloom syndrome etiology
-BLM protein is antirecombinase that suppresses sister chromatid exchanges during recombination
-Mutation leads to increased rate of sister chromatid exchanges, which leads to EXCESS CHROMOSOME BREAKAGE
Bloom syndrome features
growth deficiency, sun-sensitive "BUTTERFLY RASH", malar hypoplasia, nasal prominence, small mandible, dolichocephalic skull, hypersentivity to sunlight, highly susceptible to infection, nl intelligence in most, though may have learning disability; 20% CANCER RISK (half <age 20): non-Hodgkin lymphoma, acute leukemia, carcinomas of mouth, stomach, larynx, lung, esophagus, colon, skin, breast & cervix
Pallister-Hall syndrome features
Polydactyly, nail dysplasia, hypothalamic hamartomas, imperforate anus, treachae/laryngeal defects, renal abnormalities, pulmonary segmentation anomilies
-can be mild to severe
Pallister-Hall inheritance/genetics
GL13/7p13 (same as Greig cephalopolysyndactyly)
AD (seq sens 50%)
common muts: 2023delG, 2012delG
XP inheritance/genetics
7 genes (XPA-G), AR
XP etiology
Inability to repair genetic damage caused by UV exposure (defective nucleotide excision repair)
XP features
1000X RISK OF CUTANEOUS & OCULAR NEOPLASMS; median age of non-melanoma skin cancer onset is 10 yrs; Acute sunburn reaction on minimal UV exposure;
Neurologic impairment in 30%
Must avoid UV radiation!
Smith-Lemi-Opitz inheritance/genetics
DHCR7 (11q), AR
~65%-6 common mut
Smith-Lemi-Opitz etiology
abnormality in cholesterol metabolism resulting from deficiency of enzyme 7-dehydro-cholesterol reductase
Smith-Lemi-Opitz features
prenatal & postnatal growth retardation, microcephaly, moderate to severe mental retardation distinctive facial features, cleft palate, cardiac defects, underdeveloped external genitalia in males, post-axial polydactyly, & 2-3 toe syndactyly
Smith-Lemi-Opitz diagnosis
elevated serum concentration of 7-dehydrocholesterol (7-DHC) or an elevated 7-dehydrocholesterol: cholesterol ratio.
serum concentration of cholesterol usually low
Sequence analysis has 80% detection
On MSS: low uE3, hCG, and AFP
22q11.2 deletion syndrome inheritance/cause
AD (7%), sporadic (93%) (FISH-TUPLE probe)
Aberrant recombination between low copy repeated sequences/ unequal crossing over
22q11.2 deletion features
CHD (CONTRUNCAL - tet of Fallot, interrupted aortic arch, VSD, truncus arteriosus); palatal abnormalities - VPI, Cl/P; LD; immune deficiency; HYPOCALCEMIA; possible schizophrenia
Fanconi anemia inheritance/genetics
AR, multiple genes (at least 15) mostly FANC(A-n) but remember BRCA2 homos cause FA-D1
most common is FA-A caused by FANCA gene (60-70%), FA-C 2nd most (~14%)
AJ carrier freq 1:100
Fanconi anemia features
Aplastic anemia, bleeding, easy bruising, absent thumbs, bone marrow failure, skeletal deformaties, renal malformations, abnl skin pigmentation, CANCERS: AML, squamous cell cacinomas, head, neck, cervix, vulva, liver and esophageal tumors
Fanconi anemia etiology
-FANC proteins part of complex involved in DNA repair
-Mutations lead to progressive pancytopenia & CHROMOSOME BREAKAGE that worsens with exposure to alkylating agents
Fanconi anemia diagnosis
assessing levels of chromosome breakage
X-linked ichthyosis inheritance/genetics
Xp22.32/STS, del of STS and flanking region
AKA: STS deficiency
X-linked ichthyosis features
Onset by 6 mos; hypertrophic ichthyosis, esp. scalp, ears, neck & flexures; dark adherent skin scales; corneal opacities
-prolonged labor in mother