Genetics for the Sonographer - Home - KLINEFELTER SYNDROME 47, XXY • Seminiferous tubule dysgenesis

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  • Genetics for the Sonographer

    Jeffrey Kuller, MD Professor of Obstetrics and Gynecology

  • OUTLINE

    • Testing for aneuploidy • Increased maternal age • Previous aneuploid pregnancy

    • Hemoglobinopathies • Sickle cell disease

    • Evaluation of mental retardation (including Fragile X Syndrome)

    • Genetics of miscarriage • Recurrent pregnancy loss

  • INCREASED MATERNAL AGE

    •Risk for chromosomal abnormalities in the fetus increases with advancing maternal age • Etiology thought to be related to

    increased risk for a nondysjunctional event in the ovum

  • TESTING OPTIONS

    • Invasive testing • Amniocentesis • Chorionic villus sampling

    • Noninvasive testing • First trimester screening - Nuchal translucency

    combined with PAPP-A and b-hCG • Second trimester screening •Triple and Quad screening •Detailed ultrasound

  • RISK FOR ANEUPLOIDY

    •Risk depends on when data interpreted 35-year-old woman’s risk of having

    a fetus with Down syndrome: 1/270 @ second trimester 1/365 @ term

  • WHY AGE 35?

    Rate of detection approximately equal to rate of procedure-related loss

  • DOWN SYNDROME (Trisomy 21)

    •Most common chromosome abnormality in liveborns •Comprises approximately 1/2 of all

    chromosome abnormalities in liveborns • Always associated with mental

    retardation • 50% born with a congenital heart defect • Lowered live expectancy (age 35)

  • DOWN SYNDROME

    •Majority of pregnancies occur in younger women (80%) • 95% of cases due to Trisomy 21 • 5% of cases due to translocation Down

    syndrome Usually inherited from one of the parents who carries a “balanced” rearrangement

  • OTHER CHROMOSOME ABNORMALITIES ASSOCIATED WITH

    INCREASED MATERNAL AGE

    • Trisomy 18 • Trisomy 13 • 47, XXY (Klinefelter) • 47, XYY • 47, XXX

  • PATERNAL AGE

    • Few studies have demonstrated a slightly increased risk for chromosome abnormalities in pregnancies when father is > 55

    • Other reports have failed to confirm these findings

    • Advanced paternal age is associated with increased risk for new autosomal dominant mutations in offspring

  • PRIOR ANEUPLOIDY

    • The risk for a chromosome abnormality is a couple who have a previous child with a trisomy is approximately 1-2% •When the mother reaches age 35, the

    risk becomes the same as her age- related risk

  • PRIOR ANEUPLOIDY

    •Couple with previous conception with Trisomy 21 has risk for other aneuploid conceptions, not just Down syndrome • Thought to be due to the fact that the

    couple has increased predisposition to nondisjunction of any of the chromosomes in the egg or sperm

  • MONSOMY X (Turner Syndrome)

    • Shield chest •Cardiovascular defects (Coarctation or

    VSD) in 10 - 16% •Renal abnormalities in 38% •Wide carrying angle

  • MONSOMY X (Turner Syndrome)

    • Streak gonads with absent oocytes • Decreased adult height (141 - 146 cm) • Normal intellectual function but: •Verbal IQ > performance IQ •Cognitive defects (space-form blindness)

    • Hypoestrogenic • Short broad neck

  • KLINEFELTER SYNDROME 47, XXY

    • Seminiferous tubule dysgenesis • Decreased androgen production causes lack of normal

    secondary sexual development • Slightly taller than normal males • Scoliosis kyphosis, pectus abnormality more common than

    normal males • Increased breast tissue common and 20x rate of breast

    cancer as normal males • More likely to be mentally retarded or socially maladjusted • Personality described as passive, adapt poorly to new

    situations

  • 47, XYY

    • Patients usually have grossly normal testes and normal external genitalia •Mean testosterone levels normal • Tall stature, mental retardation,

    antisocial behavior are more common than in men with normal karyotypes • Likelihood of incarceration perhaps 1%

    (0.1% for normal males)

  • 47, XXX

    •Most normal phenotype •More likely to be mentally retarded •May experience delayed menarche or

    premature ovarian failure • Somatic anomalies not usually present

  • HEMOGLOBIN

    • Hemoglobin is a tetramer of 2 pairs of distinct globin chains

    • Hemoglobin A (normal adult hemoglobin): • 2 alpha chains • 2 beta chains

    • Each individual has: • 4 genes that code for alpha globin chains

    (chromosome 16) • 2 genes that code for beta globin chains

    (chromosome 11)

  • HEMOGLOBINOPATHIES

    • 5% of the world population are carriers for disorders of hemoglobin • Structural variants alter the hemoglobin

    molecule e.g. sickle cell anemia

    •Decreased production of one or more of the globin chains result it the thalassemias

  • SICKLE CELL ANEMIA

    •Currently the only genetic disorder allowing for direct diagnostic testing • Every person with sickle cell anemia

    has the same mutation (substitution of valine for glutamic acid at position 6 of the beta globin chain)

  • CARRIER TESTING FOR SICKLE CELL ANEMIA

    •Hb electrophoresis recommended for at risk individuals • Sickle prep is good screening test but

    can not distinguish heterozygote from homozygote or determine presence of Hb C

  • FRAGILE X SYNDROME

    •Most common inherited cause of mental retardation • Estimated frequency of •1/1100-1500 males •1/2000-3000 females

    • Inherited as X-linked dominant condition with incomplete penetrance

  • FRAGILE X SYNDROME Clincal Characteristics

    •Relatively large head circumference • Long face, prominent forehead, large

    ears, macro-orchidism •Hyperactive with speech characterized

    by perseverance repetition • Autistic behavior sometimes seen

  • TESTING FOR FRAGILE X SYNDROME

    • Associated with folate sensitive cytogenetically identifiable fragile site at band X q 27.3 • Fragile X gene (FMR-1) isolated in 1991 •Contains a region of unstable DNA with

    a (CGG) repeat sequence • Preferred diagnostic test is molecular

  • FMR-1 GENE

    • Normal variation in number of CGG repeats ranges from 6 - 45 copies

    • Small amplification (50 - 230 copies) represent premutations (not usually associated with clinical expression of phenotype)

    • Larger amplifications(> 230 copies) represent full mutations and are found in clinically affected males and females and some carrier females

  • FMR-1 PREMUTATIONS

    •Remain stable during spermatogenesis •Can amplify to full mutation in

    organogenesis • Female premutation carrier can

    therefore have clinically affected sons or daughters, but can also transmit the premutation in a stable form

  • PRENATAL DIAGNOSIS

    • Available by CVS or amniocentesis when mother identified as a carrier of premutation or full mutation • Testing performed cytogenetically and

    by DNA analysis since experience still limited in DNA analysis

  • UNDEFINED FAMILIAL MENTAL RETARDATION

    • Thorough 3 generation pedigree •Obtain medical records on affected

    individuals •Offer cytogenetic testing to rule out

    translocation/inversion and Fragile X testing

  • GENETIC ETIOLOGIES OF MISCARRIAGE

    •Chromosome abnormalities cause at least 50% of spontaneous abortions • Autosomal trisomies form the largest

    group of cytogenetically abnormal spontaneous abortions •Monsomy X is the single most common

    chromosome abnormality in spontaneous abortion

  • STRUCTURAL CHROMOSOME REARRANGEMENTS

    •Uncommon cause of spontaneous abortion • Implicated in recurrent miscarriage •Most common parental rearrangement

    is translocation

  • BALANCED TRANSLOCATIONS

    •Robertsonian •Reciprocal •While parents are phenotypically

    normal, the offspring may demonstrate unbalanced rearrangements such as chromosomal duplications or deletions

  • Genetic Science Learning Center: http://gslc.genetics.utah.edu/units/disorders/karyotype/robertsonian.cfm

    Robertsonian Translocation

  • Genetic Science Learning Center: http://gslc.genetics.utah.edu/units/disorders/karyotype/robertsonian.cfm

    Robertsonian Translocation

  • Genetic Science Learning Center: http://gslc.genetics.utah.edu/units/disorders/karyotype/robertsonian.cfm

    Robertsonian Translocation

  • RECURRENT PREGNANCY LOSS

    • In a summary of reports published prior to 1988, 3% of parents had chromosomal abnormalities • This is 6x the rate in the general

    population • Translocations and inversions most

    common rearrangement

  • WHEN TO KARYOTYPE PARENTS?

    • After 3 consecu