Bourn Hall Clinic Bourn Cambridge CB3 7TR UK
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Abstract |
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Key words: azoospermia/sex-determining region Y/XX male syndrome
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Introduction |
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Through reporting this rare case and reviewing the current literature, the aim of this report is to highlight the value of karyotyping all males with congenital azoospermia or severe oligozoospermia who present for evaluation of infertility, since the phenotype does not always correlate with the presence or absence of Y sequences in the genome.
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Case report |
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Discussion |
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All males with discordant phenotype/sex chromosomal pattern are azoospermic due to absence of the long arm of the Y chromosome containing the azoospermia factor (AZF) gene, which is necessary for normal spermatogenesis (Tiepolo and Zuffardi, 1976; Grumbach and Conte, 1992
; Vogt et al., 1996
). The majority of cases have normal external genitalia, but 1015% of XX males shows various degrees of hypospadias (Lopez et al., 1995
). Molecular studies have detected Y chromosome material in 75% of XX males (Muller et al., 1987
), which explains their testicular development. On the other hand, many theories have been put forward to explain how patients who are Y-negative, as in this case, can have testes, despite complete absence of the Y chromosome. Researchers (Ferguson-Smith et al., 1990
; Vilain et al., 1994
) suggested the presence of other mutations (autosomal or X-linked) which could be responsible for testicular determination in the absence of Y sequences. The presence of hidden mosaicism with a Y-bearing cell line was proposed (Fechner et al., 1990
). More recently, the reporting of a Mexican family in which two siblings without genital ambiguities were SRY negative (Zenteno et al., 1997
), suggested that an inherited loss of function mutation in a gene participating in the sex-determining cascade could induce normal male sexual differentiation in the absence of SRY gene. This would strengthen what has been reported (Boucekkine et al., 1994
), that although the absence of Y-specific DNA generally results in incomplete musculinization, exceptions do occur. Another possibility for the aetiology of maleness in these cases is a downstream gene on the X chromosome in which expression is influenced by X inactivation (Kolon et al., 1998
). Lastly, it has been postulated that the sex reversal in these patient is due to a defect on a yet unidentified autosomal or X-linked sex-determining gene (Vernole et al., 2000
).
A total of 60% of true hermaphrodites have a 46,XX karyotype (Van Niekerk et al., 1981). Although the majority of 46,XX true hermaphrodites are negative for the Y-DNA sequence, including SRY gene (Ranie et al., 1989
; Pereira et al., 1991
; Sadi et al., 1996
), a minority could be positive (McElreavey et al., 1992
; Abbas et al., 1993
; Copelli et al., 1996
; Ramos et al., 1997
; Kojima et al., 1998
). Nevertheless, this diagnosis was unlikely in this patient because of the presence of normal male external genitalia, absence of gynaecomastia and no pelvic abnormality detected on examination. We therefore felt that there was no need for laparoscopy or laparotomy to exclude the presence of ovotestes, particularly since this patient became very upset when he was told about his condition. He refused an ultrasound scan, genetic counselling or psychiatric referral. Likewise Klinefelter's syndrome was unlikely because the arm span of the patient equalled his height and there was no Y chromosome, which is necessary for the diagnosis of Klinefelter's syndrome.
We conclude that the heterogeneous features of 46,XX male syndrome, together with its rarity, make it very easy to miss this syndrome in the differential diagnosis of phenotypic males with congenital azoospermia. Without karyotyping, these patients would be subjected to invasive procedures and the financial and psychological implications of these. Once the problem has been recognized, these individuals require gentle management (including regular follow-up for possible long-term androgen deficiency) and counselling through a cooperative interdisciplinary approach.
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Notes |
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References |
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Boucekkine, C., Toublane, J. E., Abbas, N. et al. (1994) Clinical and anatomical spectrum in XX sex reversed patients. Relationship to the presence of Y specific DNA-sequences. Clin. Endocrinol. (Oxf.), 6, 733742.
Copelli, S.B., Bergada, C., Billerbeck, A.E. et al. (1996) Molecular analysis of sex determination in sex-reversed and true hermaphroditism. Braz. J. Med. Biol. Res., 29, 743748.[ISI][Medline]
de la Chapelle, A. (1972) Analytic review: nature and origin of males with XX sex chromosomes. Am. J. Hum. Genet., 24, 71105.[ISI][Medline]
de la Chapelle, A. (1981) The aetiology of maleness in XX men. Hum. Genet., 58, 105116.[ISI][Medline]
Ferguson-Smith, M.A., Cook, A., Affara, N.A. et al. (1990) Genotypephenotype correlation in XX males and the bearing on current theories of sex determination. Hum. Genet., 84, 198202.[ISI][Medline]
Fechner, P.Y., Marcantonio, S.M., Jaswaney, V. et al. (1990) The role of the sex-determining region Y gene in the aetiology of 46,XX maleness. J. Clin. Endocrinol. Metab., 76, 690695.[Abstract]
Grumbach, M.M. and Conte, F.A. (1992) Disorders of sex differentiation. In Wilson, J.D. and Foster, D.W. (eds) Williams textbook of endocrinology. Saunders, Philadelphia, pp. 853951.
Kojima, Y., Hayashi, Y., Asai, N. et al. (1998) Detection of the sex-determining region of the Y chromosome in 46,XX true hermaphroditism. Urol. Int., 60, 235238.[ISI][Medline]
Kolon, T.F., Ferrer, F.A., McKenna, P.H. et al. (1998) Clinical and molecular analysis of XX sex reversed patients. J. Urol., 160, 11691172.[ISI][Medline]
Lopez, M., Torres, L., Mendez, J.P. et al. (1995) Clinical traits and molecular findings in 46, XX males. Clin. Genet., 48, 2934.[ISI][Medline]
McElreavey, K., Rappaport, R., Vilain, E. et al. (1992) A minority of 46,XX true hermaphrodites are positive for the Y-DNA sequence including SRY. Hum. Genet., 90, 121125.[ISI][Medline]
Muller, U., Donlon, T., Schmid, M. et al. (1986) Deletion mapping of the testis determining locus with DNA probes in 46,XX males and in 46,46XY and 46,X,dic(Y) females. Nucleic Acids Res., 14, 64896505.[Abstract]
Muller, U., Latt, S.A., Donlon, T. (1987) Y-specific DNA sequences in male patients with 46,XX and 47,XXX karyotypes. Am. J. Med. Genet., 28, 393.[ISI][Medline]
Nielsen, J. and Sillesen, I. (1975) Incidence of chromosome aberrations among 11 148 newborn children. Hum. Genet., 30, 112.
Page, D.C., Mosher, E., Simpson, E. et al. (1987) The sex determining region of the human Y chromosome encodes a finger protein. Cell, 51, 10911104.[ISI][Medline]
Pereira, E.T., de Almeida, J.C., Gunha, A.C. et al. (1991) Use of probes for ZFY, SRY, and the Y pseudoautosomal boundary in XX males, XX true hermaphrodites, and an XY female. J. Med. Genet., 28, 591595.[Abstract]
Ramos, E.S., Moreira-Filho, C.A., Vicente, Y.A. et al. (1997) SRY-negative true hermaphrodites and an XX male in two generations of the same family. Hum. Genet., 97, 596598.[ISI]
Ranie J., Robertson M.E., Malcolm, S. et al. (1989) Absence of Y specific DNA sequences in two siblings with 46XX hermaphroditism. Arch. Dis. Child., 64, 11851187.[Abstract]
Sadi, A.M., Toda, T., Kiyuna, M. et al. (1996) A true hermaphrodite with bilateral ovotestes: a case report. J. Obstet. Gynaecol. Res., 22, 247251.[Medline]
Sinclair, A.H. (1998) Human sex determination (review). J. Exp. Zool., 28, 501505.
Tiepolo, L. and Zuffardi, O. (1976) Localization of factors controlling spermatogenesis in the nonfluorescent portion of the human Y chromosome long arm. Hum. Genet., 34, 119124.[ISI][Medline]
Van Dyke, D.C., Hansom, J.W., Moor, J.W. et al. (1991) Clinical management issues in males with sex chromosomal mosaicism and discordant phenotype/sex chromosomal patterns. Clin. Pediatr. (Phil.), 30, 1521.[ISI][Medline]
Van Niekerk, W.A. and Retief, A.E. (1981) The gonads of human true hermaphrodites. Hum. Genet., 58, 105116.[ISI][Medline]
Vernole, P., Terrinoni, A., Didona B. et al. (2000) An SRY-negative XX male with Huriez syndrome. Clin. Genet., 57, 6166.[ISI][Medline]
Vilain, E., Le Fiblee, B., Morichon-Delvallez, N. et al. (1994) SRY- negative XX fetus with complete male phenotype. Lancet, 343, 240241.
Vogt, P.H., Edelmann, A., Kirsch, S. et al. (1996) Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum. Mol. Genet., 5, 933943.
Zenteno, J.C., Lopez, M., Vera, C. et al. (1997) Two SRY-negative XX male brothers without genital ambiguity. Hum. Genet., 100, 606610.[ISI][Medline]
Submitted on May 30, 2000; accepted on January 2, 2001.