The Principles of Clinical Cytogenetics - Extra Materials - Springer

Prenatal Cytogenetics 307
to women who took these medications 3 months before and 1 month after conception. There is no
known increased risk for chromosome abnormalities, but if amniocentesis is being performed, it is
prudent to perform cytogenetic analysis on the specimen.
Women with Gestational Diabetes or Insulin-Dependent Diabetes Mellitus
It was thought in the past that women with gestational diabetes have a minimally increased risk of
having offspring with malformations. It is now known that some women classified as having gestational
diabetes are probably unrecognized insulin-dependent diabetics (251). Rosenn et al. (252) and
Schaefer et al. (253) evaluated glycemic thresholds as predictors for congenital malformations. Both
found that a fasting first-trimester blood glucose concentration of less than 120 mg/dL was associated
with no increased risk in malformations. Specifically, the risks for NTDs range from a 10-fold (254)
to a 20-fold (255) increased risk in infants of diabetic mothers. Because some centers offer amniocentesis
for detection of NTDs for this indication, cytogenetic analysis of the specimen would also be
prudent.
Advanced Paternal Age
A body of old literature in genetics suggests an increased risk of fetal chromosome abnormality
with advanced paternal age, but the most carefully constructed analyses do not support this association
(256–259). Advanced paternal age is not associated with fetal chromosome abnormalities. It is,
however, associated with a linearly increased risk of some autosomal dominant new mutations in the
offspring (260). In a policy statement on the subject, the American College of Medical Genetics
points out the fourfold to fivefold risk in offspring of men in their forties versus those of men in their
twenties. The relative increased risk for these defects is related to advanced age of the father for
autosomal dominant conditions and the maternal grandfather for X-linked conditions. Family histories
will not provide clues, as these types of mutations are sporadic. Examples of autosomal dominant
conditions associated with advanced paternal age include achondroplasia, neurofibromatosis, Marfan
syndrome, Treacher Collins syndrome, Waardenberg syndrome, thanatophoric dysplasia, osteogenesis
imperfecta, and Apert syndrome. Examples of X-linked conditions associated with increased
maternal grandfather’s age include fragile X syndrome (see Chapter 18), hemophilia A (factor VIII
deficiency), hemophilia B (factor IX deficiency), Duchenne muscular dystrophy, incontinentia
pigmenti, Hunter syndrome, Bruton agammaglobulinemia, and retinitis pigmentosa (261). The American
College of Medical Genetics acknowledges the risk but states that ultrasound examination is
usually of little benefit. Genetic counseling is indicated so the expectant couple can understand the
issues, and it is prudent to offer detailed fetal ultrasound examination in pregnancies involving men
40–45 years and older (261).
Special Issues
True Mosaicism and Pseudomosaicism
Mosaicism, or the presence of two or more cell lines in culture, is one of the most complex and
challenging issues in prenatal diagnosis. There are three levels of mosaicism in amniotic fluid and CVS
culture—levels I, II, and III. Level I is defined as a single-cell abnormality. Level II is defined as a
multiple-cell abnormality or (with an in situ culture method) a whole colony abnormality in one
culture not seen in any other cell cultures. Level III mosaicism is “true” mosaicism—the presence of
a second cell line in two or more independent cultures. The incidences of these in amniotic cell
cultures range from 2.5% to 7.1% for level I, 0.6–1.1% for level II, and 0.1–0.3% for level III mosaicism
(262–264).
The origin of the mosaic cell line cannot be determined without molecular studies. In general,
however, it appears that the majority of 45,X/46,XX cases occur after a normal disomic fertilization,
most mosaic trisomies are the result of postzygotic loss of the trisomic chromosome, and for trisomy
8, most cases are the result of somatic gain of the third chromosome 8 postzygotically (265).