The Principles of Clinical Cytogenetics - Extra Materials - Springer

Genetic Counseling 555
As previously noted, mosaicism can make the prognosis less clear. One example of this is 45,X/46,XY
mosaicism. The majority of prenatally diagnosed affected individuals, approximately 85–95%, are phenotypically
normal males externally. However, a range of phenotypes, from a female with Turner syndrome
to ambiguous genitalia to externally normal males, is possible. In phenotypic males, there can be variation
with respect to the size of the phallus, descent of the testes, and scrotal fusion. Hypospadius and other
nongenital abnormalities have also been noted. There is a risk, estimated to be approximately 27%, for
abnormal gonadal histology, which increases the risk for a gonadal tumor (gonadoblastoma). Therefore,
close follow-up to monitor for tumor development is warranted. The degree of mosaicism does not appear
to be a reliable predictor of the phenotype. Of note, the majority of cases of 45,X/46,XY mosaicism
diagnosed postnatally were associated with an abnormal phenotype. The reason for this discrepancy is that
the postnatally diagnosed cases reflect an ascertainment bias (41,42).
When an apparently balanced chromosome rearrangement is identified by CVS or amniocentesis,
the first step is to perform chromosome analysis on the parents. If one of the parents carries the same
rearrangement and is phenotypically normal, it is felt that the rearrangement is unlikely to confer a
significantly increased risk of abnormality. It is important to note that there are some mechanisms,
such as uniparental disomy (see Chapter 19), by which a balanced translocation inherited from a
phenotypically normal parent can be associated with an increased risk for abnormalities. These
mechanisms seem to be relatively uncommon (15). If the rearrangement is de novo, the risk assessment
becomes more difficult. It has been estimated that the risk for abnormality associated with a de
novo reciprocal translocation is approx 6.1%. The estimated risks for abnormality associated with a
de novo Robertsonian translocation or inversion are 3.7% and 9.4%, respectively (43). However, it
can be difficult, if not impossible, to predict specific abnormalities.
When a structural chromosome rearrangement is unbalanced, whether it is de novo or results from
the segregation of a balanced rearrangement in a carrier parent, the phenotype is likely to be abnormal.
Again, however, it is difficult to predict the specific abnormalities. Ultrasound examination and
a literature review might lend some information about the clinical picture.
The issue of confined placental mosaicism was introduced in the previous section regarding CVS,
as such mosaicism is more likely to be found at CVS than at amniocentesis (see also Chapter 12).
Mosaicism is not, however, always confined to the placenta. Mosaicism is classified as follows:
Level I mosaicism is defined as a single abnormal cell. This almost always represents a cultural artifact and,
in the vast majority of cases, is of no clinical significance to the pregnancy (15).
Level II mosaicism is defined as more than one cell with the same chromosome abnormality in one colony.
This type of mosaicism is, in the majority of cases, pseudomosaicism, which is the result of cultural
artifact (15). It is important to note that cultural artifact does not mean “laboratory error,” but is, rather,
an occasionally unavoidable result of growing cells in vitro.
Level III mosaicism is defined as two or more cells with the same chromosome abnormality in two or more
colonies. This finding is likely to represent true mosaicism and raises the level of concern that there is an
abnormal cell line in the fetus (15).
When mosaicism is identified prenatally, particularly level III mosaicism, follow-up testing, such as a
detailed ultrasound to evaluate the fetal anatomy and/or repeat chromosome analysis, via amniocentesis or
percutaneous umbilical blood sampling (PUBS, in which fetal blood is obtained from the umbilical cord
under ultrasound guidance), can be pursued. It is important to realize, however, that such testing is unlikely
to completely clarify the fetal karyotype. Again, the limitations of ultrasound in identifying certain
phenotypic abnormalities, such as mental retardation, must be made clear to the patient or couple. Furthermore,
a normal repeat chromosome analysis, although encouraging, does not guarantee the absence of an
abnormal cell line in the fetus. Likewise, an abnormal repeat chromosome analysis does not necessarily
mean that the abnormal cell line is present in the fetus. Genetic counseling to help the patient/couple
interpret this information is particularly important in such complex situations. If the pregnancy is terminated
or aborted spontaneously, chromosome analysis of a variety of fetal tissues should be considered. If
the pregnancy is carried to term, follow-up analysis of blood and/or skin might also be indicated.