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January 1998, Volume 48, Issue 1

Case Reports

46 XX Male: A Case of Sex Reversal Syndrome

Tasnim Ahsan  ( Department of Medicine, Jinnah Postgraduate Medical Centre, Karachi. )
Marium Saleem  ( Department of Medicine, Jinnah Postgraduate Medical Centre, Karachi. )
Asif Ahmed  ( Department of Medicine, Jinnah Postgraduate Medical Centre, Karachi. )
Merium Muzalfar  ( Department of Medicine, Jinnah Postgraduate Medical Centre, Karachi. )

Introduction

Sex reversal syndromes pose a serious clinical problem particularly when questions regarding sex re-assignment are raised in grown up patients. The expression of various degrees of phenotypic male gender in the absence of Y chromosome was truly perplexing until the identification of various testes determining genes and new ones continue to be identified. The presence of this male genetic material on the Xchromosome is the basis of this syndrome. One such case is being described.

Case Report

A 24 year old educated, unmarried man presented to the Endocrine Clinic, JPMC, complaining of gynaecomastia. He was shaving twice weekly and claimed to have morning erections regularly and a normal libido. He was the youngest of 4 male siblings. Another older brother was reported to have similar problems and had married twice without any children. Two other brothers were mamed with children and both had normal male attributes. He was short statured with a height of 165 ems. He had scanty facial hair and his skin was relatively fine. His voice remained unbroken and highpitched.Pubic and axillaiy hair showed normal distribution but were sparse, as was the body hair. Body contours were masculine. Penis and scrotum were well developed and normal in size. Testicles
were small and soft bilaterally. He had bilateral moderate gynaecomastia. The rest of the physical examination was normal. His gender identity was definitely male. Investigations showed alow testosterone at 1.8ng/ml (normal 2.0 - 8.1 ng/ml), FSH and LH were elevated at 35 mIU/ml and 21 mlU/ml (normal 1.0 - 12.0 mIU/ml and 2.0 - 12.0 mIU/ml respectively), suggesting primary hypogonadism, Thyroid function tests and serum prolactin level were normal. An ultrasound of the pelvis showed no evidence of uterus or ovaries but showed a normal sized prostate. Chromosomal analysis showed a female karyotype with 46 XX chromosomes. Inview of the well developed external genitalia chromosomal analysis was repeated which again showed 46 XX chromosomes. Semen analysis showed complete azoospermia. Testicular biopsy was not carried out. He was commenced on testosterone replacement therapy.

Discussion

46 XX males have beenweil described in literature with over 150 cases reported since 19641. These patients are similar phenotypically and endocnnologically to patients with classic Klinefelter’s syndrome except for slight differences, i.e., 47 XXY kaiyotype males, tend to be tall (mainly due to disproportionate leg length, which is present prepubertally but exacerbated after puberty), whereas patients with 46 XX karyotype tend to be short (mean height 168 cms), with normal skeletal proportions1,2. They also have a lower frequency of intellectual and psychosocial problems1,2. Unlike 47 XXY patients maternal age is not increased1. Postpubertally they have varying degrees of hypogonadism as in Kilnefelter’s syndrome with small testes andazoospermia1-3. The testicular histology is similar to that of 47, XXY males; decreased size and number of seminiferous tubules, absent germinal cells and peritubular and interstitial fibrosis. Leydig cells appear hyperplastic. In some cases the morphology is similar to germinal cell aplasia or intermediate with this disorder and seminiferous tubule dysgenesis1. The Y chromosome carries a gene(s) adjacentto the pseudoautosomalboundaty encoding the testis detennining factor. Once the testis develops in utero under the influence of testis detemüning gene (s), it produces the necessary hormones required for male phenotypic expression4. Complete male differentiation of the external genitalia and urogenital sinus occurs only if the androgenic stimulus is received during the critical period of development early in foetal life (8-12 weeks)5..The human testis determining gene(s) (SRY) has been isolated from a 35 kb region on the human Y chromosome. 46 XX males with genital abnormalities tend to lack evidence forY chromosome DNA and exhibit a greater prevalence and degree of gynaecomastia than their 46 XX male counterparts in whom a y to x translocation is present6. The presence of Y chromosome material on the paternally derived X chromosome is usually due to an abnormal X-Y interchange during the obligatory X-Y crossing over that occurs during male meiosis7. The theories put forward to explain sex reversal in 46 XX male patients include (1) loss of a Y chromosome early in embiyogenesis, (2) cryptic sex chromosome mosaicism with an undetected and/or circumscribed cell line containing a Y chromosome8, (3) translocation between a y and an x chromosome or autosome resulting in the presence of the testis determining gene (s) on an X chromosome or autosome, or (4) a mutation involving either an autosomal or X linked gene. Various studies have indicated that 80-90% of 46 XX males result from a Y to X translocation during meiosis5,7. 46 XX males who showed no evidence of Y specific DNA (mcluding SRY and ZFY probes), have been reported9. This suggests that testicular development in these males occurred in the absence of SRY gene (s). Phenotypic variation in 2 siblings with paternally derived SRY bearing chromosome has been described by N. Abbas et al10. One brother was a true hermophrodite and the other was a phenotypic male. This phenotypic variability can be explained by selective inactivation of one of the SRY bearing X chromosomes10. In view of the non availability of cytogenetic studies, it was not possible to determine the origin and the presence/absence of SRY gene (s) in the proband or the affected brother (who by all accounts seemed to be another similar case) or the parents of this case of genetic misadventure.

References

1. de Ia Chapelle, A. Analytic review: Nature and origin of males with XX sex chromosomes. Am. J. Hum. Genet., 1972;24:71-105.
2. de Ia Chapelle, A. The etiology of maleness in XX men. Hum. Genet.. 198 1;58:105-116.
3. Perez-Palacios, G., Medina, M., Ullao-Aguirre, A. et al. Gonadotropin dynamics in XX males. J. Clin. Endocrinol. Metab., 1981 ;53:254-257:
4. Goodfellow, P.N. and Darling, SM. Genetics of sex determination in man and mouse. Development, 1988;102:251-58.
5. Grumbach, MM. and Conte, F.A. Disorders of sex differentiation’ In Jean. D., Wilson, Daniel, W. Foster, ed. Williams Textbook of Endocrinology, 8th ed., USA, Saunders, 1992, p. 884.
6. Ferguson-Smith, MA., Cooke, A., Affara, NA. et al: Genotype- phenotype correlations in XX males and their bearing on current theories of sex determination. Hum. Genet, 1990;84:198-202.
7. Petit, C., dc-la Chapelle, A., Levilliers, J. et al. An abnormal XY interchange accounts for most but not all the cases of human XX maleness. Cell, 1987;49:595-602.
8. Miro, R., Cabellin, MR., Marsini, S. et al. Mosaicism in XX males. Hum. Genet., 1978;45:103-106.
9. Ferguson-Smith, M.A., Affara, N.A. and Briggs, H. The secret of sex. Lancet, 1990;ii:809-8 10.
10. Abbas, N., McElreavey, K., Leconiat, M. et al. Familial case of 46, XX male and 46, XX true hermaphrodite associated with a paternal derived SRY bearing X chromosome. CR. Acad. Sci., Paris, Sciences de Ia vie/Life Sci., 1 993;3 16:375-83.

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