Address correspondence to Robert Roger Lebel, MD, Genetics Services, 360 West Butterfield Road, Suite 245, Elmhurst, IL 60126-5068. Tel: 708-832-4363. Fax: 708-832-9580.

Department of Obstetrics and Gynecology, Elmhurst Memorial Hospital, Elmhurst, IL, £Genetics Services, Elmhurst, IL, §Department of Pediatrics, Christ Hospital, Palos Heights, IL

Synonyms: None.

Definition: Mosaicism for gonosomal aneuploidy.

Prevalence: Unknown, very rare.

Etiology: Nondysjunction.

Pathogenesis: Uncertain.

Associated anomalies: Variable, malformed external genitalia, short stature.

Differential diagnosis: By karyotype analysis.

Prognosis:Highly variable, depends on associated anomalies.

Recurrence risk: Undefined, empirically assessed at 1%.

Management: Depends on clinical presentation.

MESH Aneuploidy CDC 7588 ICD9 758.840

Introduction

Mosaicism 45,X/47,XYY is a rare prenatal and postnatal finding. Phenotypic manifestations are highly variable. We report this karyotype in one of a set of twins, discordant for gender, lost by spontaneous midtrimester miscarriage. We discuss the etiology of the mosaicism and of cell line inequality.

Case report

We observed 45,X/47,XYY mosaicism in a miscarried fetus. Pregnancy was complicated by delayed fertility and clomiphene therapy in a 34-year-old patient (35 at term). An early ultrasonogram (6 menstrual weeks) revealed three sacs, but one was irregular in shape and lacked an embryo. Apparently normal embryos were seen in the other two sacs; those developed normally up to an ultrasound examination at 18 weeks.

Two weeks later, the patient experienced vaginal bleeding while at work, and went home to rest. After several hours, she had a painless and precipitous delivery of a male fetus. Rushed to the hospital, she shortly delivered a girl. The fetuses were reported in an examination by a pathologist to be "without grossly discernible developmental defects", and to be discordant for sex (i.e., one normal male and one normal female); no internal examination was performed.

Karyotype analysis of fibroblasts from the phenotypic female delivered at the hospital revealed a normal female constitution (46,XX). Fibroblasts obtained from the male fetus delivered at home had a mosaic constitution: 45,X in 15 cells and 47,XYY in 85 cells.

Discussion

Definition

Mosaic chromosomal constitution 45,X/47,XYY has been reported rarely from fetuses, children and adults with a remarkably wide range of phenotypic expression (ranging from normal anatomy to Ullrich-Turner syndrome, to male pseudohermaphroditism) which does not correlate with relative percentages of the two cell lines in amniocytes, fibroblasts and lymphocytes¹.

Pathogenesis

Our observation supports the impression that this karyotype can be associated with a wide range of phenotypic expressions, although the lack of a proper autopsy limits our conclusions because we have no reliable anatomic details. Whether aneuploidy had a causative role in this pregnancy loss is dubious. Other causes of miscarriage are possible, and the karyotype has not per se been suspected of increasing the risk for pregnancy loss. The clinical history is consistent with "incompetent cervix", but that diagnosis was not supported by later clinical examination and testing.

The likely etiology for 45,X/47,XYY karyotype seems to be mitotic gonosomal nondisjunction at the first cell division of a 46,XY zygote; such has been appreciated since the early days of human karyotype analysis². An alternative hypothesis, chimeric fusion of embryos originating from one sperm lacking a gonosome and another with two Y chromosomes (zygotes 45,X and 47,XYY), is unlikely due to its complexity (three coincident unlikely events).

If the uneven ratio of the two cell lines truly represents the products of conception (i.e., not due to sampling error), there might have been nonrandom cellular death during early embryogenesis (selective against 45,X cells). In our case, moreover, it may be that monozygous twinning from the mosaic embryo took place with a very unequal distribution of the two cell lines, and that the early vanishing fetus was the one receiving mostly X-monosomic cells.

It is also credible, however, that the disproportion seen in this case and in previously reported cases could arise as a result of unequal distribution of the two cell lines into the fetal and placental poles at the time of implantation, as has been explored³, and that the early embryonic loss in our patient was coincidental.

Management

This interesting observation of a rare karyotype in a previously unreported clinical presentation (miscarriage of twins discordant for gender and for karyotype) does not simplify the vexing task of providing genetics counseling when prenatal testing reveals 45,X/ 47,XYY karyotype. Pettenati et al¹ provide a good discussion of that challenge. Clearly, the management option varies according to the other clinical findings besides the karyotype.

References

1. Pettenati MJ, Wheeler M, Bartlett DJ, et al: 45,X/47,XYY mosaicism: clinical discrepancy between prenatally and postnatally diagnosed cases. Am J Med Genet 39:42-47,1991.

2. Cooper HL, Kupperman HS, Rendon OR, et al: Sex-chromosome mosaicism of type XYY/XO. Ne Engl J Med 266:699-702, 1962.

3. McFadden DE, Kalousek DK: Confirmation of prenatal diagnosis of sex chromosome mosaicism. Am J Med Genet 32:495-497,1989.