Genetic Conditions I

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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

HIGH PITCHED MEWING CRY in infancy
Microcephaly, severe motor & mental retardation, round face, hypertelorism, micrognathia

Willliams syndrome inheritance/cause

7q11.2 (ELN), contiguous gene del (FISH)
AD

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)
AD

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)
AR
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
XL
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

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