Isodicentric Y chromosome in an Ullrich-Turner patient without virilization

INTRODUCTION

Y chromosomal material is occasionally observed in patients with Ullrich-Turner syndrome (UTS), usually as a mosaic presence of cells with structurally altered Y chromosome along with cells of 45,X karyotype. Depending on the relative dosage of Y chromosomal material, virilization or masculinization of patients may occur [Tuck-Muller et al., 1995].

The SRY gene (sex-determining region of the Y chromosome), a transcription factor on the short arm of the Y chromosome, is required for the undifferentiated gonads to develop into testes. The presence of this gene even in patients with XX karyotype leads to testis formation and masculinization [Nakagome et al., 1991]. Since a deletion in or severe mutation of the gene in a person with an XY karyotype causes a female phenotype, the gene is also called the testis determining factor (TDF) [Berta et al., 1990].

We report on an UTS patient without virilization in spite of the presence of Y derived marker chromosome and the SRY locus in 70% of her lymphocytes.

CLINICAL REPORT

Our patient, a 17-year-old young woman, presented with UTS and primary amenorrhea. Family history and perinatal history were unremarkable. She was born at term with age appropriate birth parameters. She has not had any significant disease. On examination, height was less than 3rd centile with weight above the 90th centile and normal head circumference. Except for capillary hemangiomas on the face, low occipital hairline, a high-arched palate and shield-like chest, no malformations or minor anomalies were noted. There was no sign of virilization. Thelarche and pubarche was appropriate for age (Tanner 4). Endocrine studies showed hypergonadotrophic hypogonadism, with a testosterone level of 3.0 nmol/L (normal value: below 2.6 nmol/L for females versus 9–32 nmol/L for males) suggesting lack of functional testicular tissue. Abdominal ultrasonography detected no gonads, but a hypoplastic uterus and normal vagina.

Routine G-, C-, and Q-banded chromosomal studies from lymphocyte culture showed mosaicism of 45,X/46,X, +mar. The tiny marker chromosome was present in about 70% of cells. By performing fluorescence in situ hybridization studies with the alpha-satellite specific fluorescent labeled probe (DYZ1, Oncor, Gaithersburg, MD), the marker was found to be of Y chromosomal origin, showing a centromere duplication. Using the Yq12 region specific probe with a control centromere probe (Y cocktail DYZ1/DYZ3, Oncor) we detected the deletion of this region: 45,X/46,X,idic(Y)(q11) (Fig. 1).

Concerning the lack of any masculinization or virilization in our patient, we analyzed the SRY gene by a PCR based method [Nakagome et al., 1991], and used the amelogenin gene [Nakahori et al., 1991] for control. We detected normal size of products. The critical region of the SRY gene [Berta et al., 1990] was sequenced showing no structural alterations (performed in the Universität Krankenhaus Eppendorf, Institut für Humangenetik, Hamburg, Germany).

Elective gonadal surgery was recently performed showing only connective tissue at the regular anatomical site of the gonads.

DISCUSSION

Partial deletion/duplication is one of the most common alterations of the Y chromosome presenting with a variable phenotype [Kosztolányi, 1988; Robinson et al., 1999]. In most cases, deletions with varying breakpoints of the Y chromosome along with a 45,X cell line mosaicism can be detected. Determining the presence of the SRY locus in these patients with UTS or UTS-like phenotype is essential for prognosis. It can predict the presence of testicular tissue in the abdominal cavity and it is associated with an increased risk for gonadoblastoma.

According to the extensive review of UTS with Y chromosome [Tuck-Muller et al., 1995], 17 of the 46 of those with dicentric Y chromosome secondary to a deletion on the long arm had no virilization/masculinization in spite of the hypothetical presence of short arm genes including SRY. In this review, the SRY locus was evaluated only in 2 patients [Tuck-Muller et al., 1995; Nanko et al., 1993], both having the gene with testicular tissue and virilization. In Nanko's patient there was no 45,X cell line present with the 46,Xdic(Y)(q11).

The cytogenetic findings in the patient of Fernandez et al. [1991] were similar to our results. They described virilization in their patient at the age of 14. In the patients of Henegariu et al. [1997] and Bergendi et al. [1997] a ring Y and a dicentric Y chromosome, respecitvely, were present with a 45,X cell line along with ambiguous genitalia and masculinization. Bukvic et al. [1996] described a phenotypic female with isodicentric Y and SRY positivity; however, the abnormal Y chromosome was present only in 5%of the cells. In the fifth study, no virilization has been described so far in a remarkable mosaicism including a 47,X,idic(Y)(q11),idic(Y) cell line with the SRY region present in lymphocytes and gonads [Jenderny et al., 1998].

The monozygotic twins described by Fujimoto et al. [1991] were of different gender in spite of the same underlying chromosomal abnormality; however, there was a difference in the ratio of cell lines and tissue mosaicism. Significant variation in tissue distribution of a Y-derived marker has been described in UTS mosaic patients [Petrusevka et al., 1996]. This could be a possible explanation also in our patient. Since UTS patients with dysgenetic gonads and with the presence of a part of the Y chromosome have a higher risk for gonadoblastoma [Verp and Simpson, 1987; Salo et al., 1995], elective surgery was performed in our patient showing only connective tissue at the regular anatomical site of the gonads.

Sexual differentiation is regulated by many different factors besides the SRY locus. Endocrine studies suggest the lack of any functional testicular tissue or Leydig cells in our patient. This can be secondary to mutations in other genes not evaluated in this study. However, the lack of virilization in many patients with isodicentric Y chromosome could also be the result of altered function of certain genes secondary to a position effect occurring in this relatively common structural anomaly.