Cytogenetic case report
Rare XXY/XX mosaicism in a phenotypic male with Klinefelter syndrome: case report

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Abstract

Klinefelter syndrome represents the most commonly found human sex chromosomal abnormality. It is characterized by small, firm testes with hyalinization of the seminiferous tubules, elevated gonadotropins and azoospermia. Males with Klinefelter syndrome may have a 47,XXY or a mosaic 47,XXY/46,XY constitutional karyotype and varying degrees of spermatogenic failure. Mosaicism 47,XXY/46,XX with clinical features suggestive of Klinefelter syndrome, is very rare and so far only 10 cases have been described in literature [1,2,5,8,10,15,22,23,25,44]. We report here a case of a mosaic 47,XXY/46,XX infertile male in whom detailed cytogenetic, histological and molecular studies were performed. Cytogenetic analysis revealed 80% and 50% mosaicism for the 46,XX cell line in blood lymphocytes and in skin fibroblasts, respectively, and the presence of 47,XXY cells only, in cultured testicular tissue. Testicular histopathology revealed atrophy of the testes with no spermatogenesis and absence of germ cells. Molecular analysis showed paternal inheritance of the extra X chromosome.

Introduction

Klinefelter syndrome represents the most commonly found human sex chromosomal abnormality with an incidence of one in 500 newborn males [12]. It is characterized by hypogonadism, gynecomastia, azoospermia or oligospermia, and increased levels of gonadotropins [34]. It is the most frequent cause of male infertility (4–6%) and it is observed in up to 11% of azoospermic and 0.7% of oligospermic men [6], [43]. Although most Klinefelter syndrome patients have a non-mosaic 47,XXY karyotype, a mosaic 47,XXY/46,XY karyotype is found in about 10% of cases [41]. The clinical features are variable and when a mosaic for a 46,XY cell line is present it is associated with a broad spectrum of fertility-associated problems, ranging from azoospermia to different grades of testicular insufficiency. In most cases, patients with no evidence of mosaicism are considered to be sterile. However, very few cases of naturally conceived offspring of proven paternity have been reported [20], [37]. Another small number of 47,XXY patients have sperm production that would allow them to benefit from assisted reproductive techniques such as testicular sperm extraction (TESE) or intracytoplasmic sperm injection (ICSI) to reproduce [7], [26]. However, recent studies have shown that the risk of producing pregnancies with sex as well as autosomal chromosomal abnormalities is significantly increased [7], [33], [35]. An increased number of 24,XX and 24,XY sperm cells in mosaic as well as non-mosaic Klinefelter patients compared with men without a chromosomal abnormality has been detected [42]. Higher frequencies of disomy 21 (6.2%) in 47,XXY spermatozoa compared to normal men (0.4%) have been reported [16].

For autosomal trisomies maternal errors predominate, accounting for 95% of cases [14]. The origin of the extra chromosome X in 47,XXY is more complicated and the percentage of cases reported in the literature in which non-disjunction has occurred in the father ranges from as low as 26%, to as high as 66% [9], [33], [36], [38]. There is no obvious increase in the age of the father among paternally derived cases [33]. Recent studies have shown that failure of the paternal X and Y-chromosomes to recombine in the XPYP pseudoautosomal region is the main cause of both 47,XMXPY and 47,XM XM Y cases [14].

Mosaicism 47,XXY/46,XX is extremely rare and has been reported in only five cases of individuals with features suggestive of Klinefelter syndrome [Table 1; [5], [10], [15], [23], [25], in four cases of true hermaphroditism [3], [24], [27], [39], in one case of ovarian hypoplasia [11] and in one patient with normal female phenotype [13]. The presence of a 46,XX cell line has also been reported in five other cases of patients with Klinefelter syndrome that have been mosaic for more than two different cell lines (Table 1 ; 2, 8, 22, 44). Only one 47,XXY/46,XX case has ever been reported in prenatal diagnosis and the pregnancy was electively terminated at 22 weeks [4].

A phenotypic male with Klinefelter syndrome and a 47,XXY/46,XX chromosomal constitution is presented, the first reported in the literature in who detailed cytogenetic, molecular and histopathological studies were performed. The rarity of XXY/XX mosaicism in comparison to XXY/XY, which is not infrequently encountered in Klinefelter patients will be discussed.

Section snippets

Case report

The patient, a 29-year-old man with male phenotype was referred to our unit with an indication of infertility. The patient received no medication. His height is 185 cm and his weight 86.2 kg. He had an eunuchoid habitus with long upper and lower extremities and disproportionally short trunk. Physical examination revealed bilaterally small firm testes with maximum diameter of each testis less than 10 mm suggestive of testicular atrophy. No signs of gynecomastia were observed and fat distribution

Results

The clinical phenotype of hypogonadal habitus with long extremities and short trunk as well as the endocrinological profile of our patient with elevated gonadotropins and low testosterone levels confirmed the presence of hypergonadotropic hypogonadism, consistent with the diagnosis of Klinefelter syndrome.

There were variable degrees of mosaicism for the 46,XX and 47,XXY cell lines in the three tissues evaluated. The highest number of 46,XX cells (80/100) was observed in the blood. The number of

Discussion

47,XXY/46,XX mosaic karyotype is rare and is associated with a broad spectrum of phenotypes such as Klinefelter syndrome (Table 1), true hermaphroditism [3], [24], [27], [39] or that of normal female [13]. Phenotypic variability in individuals with the same karyotype is often encountered in mosaicism involving the sex chromosomes [12]. For example, 45,X/46,XY mosaicism is associated with Turner syndrome, male phenotype with mixed gonadal dysgenesis, male pseudohermaphroditism, and apparently

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