Phenotypic effects of mosaicism for a 47,XXX cell line in Turner syndrome.(Letter to the Editor)

Turner syndrome, gonadal dysgenesis with sex chromosome abnormalities, occurs in approximately 1/3000 live-born females. Of females diagnosed with the condition, half are monosomic for the X chromosome. Among the rest, a multiplicity of chromosomal aberrations has been described. The more frequent are the presence of an isochromosome of the long arm of the X (i(Xq)) and ring X and mosaicism for two or more normal or abnormal cell lines (for example, 45,X/46,XX; 45,X/46,X,i(Xq); 45,X/46,XY). A small proportion (3-4%) (1,2) of subjects with Turner syndrome are mosaic for a triple X (47,XXX) cell line. The triple X syndrome in the nonmosaic state is associated with a decrement in intelligence from that expected based on parental and sib accomplishment, normal stature, and normal fertility. (3-8)

Is the prognosis for females with Turner syndrome mosaic for a triple X cell line substantially different from that for females with 45,X? Does the presence of a third, normal 46,XX cell line in some of these females predictably affect phenotype? Is the risk for mental retardation or the likelihood of preserved fertility or normal stature greater in this category of people than in those with 45,X or 45,X/46,XX alone?

I have reviewed our experience with 17 patients with Turner syndrome mosaic for a triple X cell line (11 with 45,X/47,XXX and six with 45,X/46,XX/47,XXX), and that of an additional 80 published case reports (t8 with 45,X/47,XXX and 62 with 45,X/46,XX/47,XXX). (1,9-64). These data are compared with those for the 227 girls and women with 45,X Turner syndrome and the 69 with 45,X/46,XX in our clinic database.

METHODS

Information gathered from medical records, direct examination, and self-report has been collected in a computer database as part of an ongoing, long term study of the natural history of Turner syndrome begun in 1977. (2,65,66) Subjects were ascertained through self-referral, advertisement, review of hospital records, and referral for diagnosis or management from paediatricians, obstetricians, perinatologists, endocrinologists, internists, and family practitioners.

All subjects have had karyotype confirmation of their clinical diagnosis. A minority has had two or more tissues analysed. In most of these, the two cell lines were amniotic fluid cells and confirmatory postnatal peripheral lymphocyte karyotyping.

I performed a search in PubMed using: Turner syndrome, sex chromosome, 47,XXX, triple X, and triple X females as search terms. I used the bibliographies from the citations generated to find case reports published before the inception of the electronic databases, as well as for any publications overlooked by the search strategy used. Reports in English, Italian, French, and Spanish were reviewed. I discarded any case reports without karyotype confirmation. Complete information was not available for all subjects. I analysed the results using the appropriate denominator for each feature.

RESULTS

Table 1 lists the ages and reasons for the diagnosis of Turner syndrome, comparing the subjects from our clinic population and those in the published reports to our clinic population with 45,X and 45,X/46,XX chromosome constitutions.

The women in the X/XX/XXX group described in the published reports were older than the subjects in the other groups. This is most likely because a significant proportion, one quarter, of these women were diagnosed in adult life, during evaluation of recurrent pregnancy loss. Among our clinic populations, prenatal diagnosis was a more common avenue of diagnosis than for the published cases. This reflects the nature of our clinic, which is a referral centre for such cases. We are less likely to be involved in the evaluation of recurrent pregnancy loss or fetal wastage and thus less likely to ascertain adult patients with Turner syndrome through this route.

Oedema is the primary reason for the diagnosis of Turner syndrome in infancy. Its absence as a clinical feature in the females with a triple XXX cell line constitutes a major difference between these subjects and those with 45,X or 45,X/46,XX. Although oedema in the newborn period was not recognised, in utero oedema most likely had been present, based on the presence of nuchal webbing in a similar proportion of the subjects with mosaicism for a 47,XXX cell line and those with monosomy X alone.

Approximately a third of patients with Thrner syndrome are diagnosed during evaluation for short stature. Among the published X/XX/XXX cases, short stature accounted for only 14% of diagnoses, despite the fact that almost two-thirds of the women were below the 3rd centile in height.

Tables 2 and 3 provide data regarding those features of Turner syndrome hypothesised most likely to be different in subjects with mosaicism for XXX: intellectual function, height, and fertility.

I did not try to establish the presence or absence of specific learning disabilities known to be associated with Turner syndrome, such as difficulties with spatial reasoning, processing, etc, (67-72) as there was inadequate information available for most of the published cases. Only frank mental retardation, as defined by a tested IQ below 70, inability to function…