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An Infertile Man with a 45x Karyotype
0022-5347 /88/1396-1316$02.00/0 Vol. 139, June Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1988 by The Williams & Wilkins Co.
AN INFERTILE MAN WITH A 45X KARYOTYPE YOSHIYUKI SAKAI, AKIMI OGAWA
AND
TAKASHI EHARA
From the Departments of Urology and Pathology, Shinshu University School of Medicine, Matsumoto, Japan
ABSTRACT
We describe an infertile man with normal secondary sexual characteristics and a 45X karyotype. Physical examination showed bilateral soft small testes and the semen contained no sperm. Serum testosterone, estrogen and gonadotropin levels were within normal range. Biopsy of the testis showed germinal aplasia. (J. Ural., 139: 1316-1317, 1988) Failure of spermatogenesis may be associated with chromosomal abnormalities. Patients with Klinefelter's syndrome, a common form of male infertility and hypogonadism, usually have an XXY sex chromosomal constitution and its variants have in common the presence of at least a Y chromosome. 1 Male sexual differentiation in the absence of a Y chromosome has been noted in rare entities of 46XX true hermaphrodites and 46XX male subjects 1• 2 in whom spermatogenesis is almost always impaired. A 45X karyotype associated with a male phenotype is extremely rare, with only 3 infant cases reported. 3- 5 We report on an infertile man with a 45X karyotype. CASE REPORT
A 27-year-old married man, an employee of a cigarette company, was referred to our hospital because of infertility. Medical and family history was noncontributory. He had no complaints in regard to sexual activities. The patient was 160 cm. tall and of normal intelligence. Physical examination was negative except for small (3 X 2 x 2 cm.) soft testes (fig. 1). Routine blood studies were normal. Semen analysis showed no sperm. Chromosomal studies on 33 cultured blood cells with G-banding and C-banding techniques revealed a 45X karyotype in all but 1 cell, which had a 44X chromosomal constitution (fig. 2). Serum hormonal data revealed testosterone 401 ng./ml. (normal 250 to 1,100), estrone 68.1 pg./ml. (normal 10 to 90), estradiol 30.5 pg./ml. (normal 10 to 40), estradiol less than 30 pg./ml. (normal), folliclestimulating hormone 20.1 mIU/ml. (normal 6.5 to 34.5) and luteinizing hormone 15.9 mIU/ ml. (normal 2 to 22). Vesiculography disclosed no anatomical or obstructive lesions in the seminal tract. Biopsy of the testis revealed that the seminiferous tubules were lined only by Sertoli cells and no germinal cells were present. Their basement membranes were slightly thickened, the vascular walls were hyalinized and there was no proliferation of Leydig cells in the interstitial tissue (fig. 3).
tubules and normal levels of serum gonadotropins are not consistent with Klinefelter's syndrome. A 45X karyotype usually is noted in female subjects with Turner's syndrome characterized by sexual infantilism, short stature and a variety of somatic anomalies. Male sexual differentiation rarely accompanies a 45X karyotype. Fraccaro and associates described a 6-year-old boy with a 45X karyotype. 3 The boy had penoscrotal hypospadias and mental retardation. Histology of the testes showed complete germinal aplasia but otherwise it was normal for age. LoCurto and associates reported on a 7-month-old child with normal male external genitalia and a 45X karyotype. 4 The child was mentally retarded and had signs of bone maldevelopment. The dermatoglyphic patterns were characteristic of Turner's syndrome. Histology of the testes was normal for age. Forabosco and associates described a 45X 5-month-old male infant who had some Turner-like stigmata. 5 Recently, Maeda and associates reported on a 21-month-old boy with a 45X/46XX mosaicism, who had an infantile testis and penoscrotal hypospadias. 7 Unlike these 45X male subjects, our patient was an adult and had neither hypospadias nor somatic anomalies characteristic of Turner's syndrome. The only findings were soft small testes with germinal aplasia. A boy with a 45X karyotype and germinal aplasia also has been described. 3 The chromosomal abnormality would account for this testicular lesion, although various etiologies cause germinal aplasia. In the 2, 45X male infants with histologically normal testes 4• 7 a similar testicular
DISCUSSION
The clinical features and histology of the testes in our patient are similar to those of the Sertoli-cell-only syndrome. This syndrome is characterized by a normal male phenotype with adequate virilization, absence of gynecomastia, small testes with normal consistency, and azoospermia with the seminiferous tubules containing Sertoli cells only and completely lacking the germinal epithelium.6 However, a 45X karyotype is not consistent with this syndrome, which always has a 46XY karyotype. Klinefelter's syndrome, a common form of male infertility and hypogonadism associated with chromosomal abnormality, also does not apply to the diagnosis of our patient. Not only a 45X karyotype but the absence of hyalinized seminiferous FIG. 1. External genitalia
Accepted for publication October 7, 1987. 1316
INFERTILE MAN WITH 45X KARYOTYPE
1317
--,-ll-·
FIG. 3. Biopsy of testis shows germinal aplasia. H & E, reduced from X380.
Fm. 2. Karyotype of blood cell is 45X
lesion could develop with the appearance of puberty, as occurs in Klinefelter's syndrome,' resulting in infertility in adulthood. Several explanations exist as to why the testes develop in the absence of a Y chromosome, including hidden sex chromosome mosaicism with an undetected cell line containing a Y chromosome, interchange or translocation between a Y and an X chromosome or an autosome, and a putative mutant autosomal gene that leads to differentiation of the testis.' H-Y antigen induces differentiation of the primitive gonad as a testis. The genes that code for H-Y antigen or regulate its expression normally are located in a Y chromosome. The fact that XX male subjects and XX true hermaphrodites are positive for Hy antigen, 8 and the case of 45X/46XX mosaicism positive for H-Y antigen 7 support the aforementioned hypotheses. Although H-Y antigen was not examined in our patient, it would have been positive and would have induced the development of the testes and normal male differentiation. The chromosomal analysis was performed by Dr. I. Yonemura, Department of Legal Medicine, Shinshu University School of Medicine. REFERENCES L Conte, F. A. and Grumbach, M. M.: Pathogenesis, classification, diagnosis, and treatment of anomalies of sex. In: Endocrinology.
2.
3.
4. 5.
6. 7.
8.
Edited by L. J. DeGroot, G. F. Cahill, Jr., W. D. Odell, L. Martini, J. T. Potts, Jr., D. H. Nelson, E. Steinberger and A. L Winegrad. New York: Grune & Stratton, vol. 3, chapt. 106, pp. 1317-1351, 1979. Raspa, R. W., Burbige, K. A. and Hensle, T. W.: The sex reversal syndrome (the XX male patient). J. Urol., 134: 152, 1985. Fraccaro, M., Lindsten, J., Klinger, H.P., Tiepolo, L., Bergstmnd, C. G., Herrlin, K. M., Livaditis, A., Pehrson, M. and Tillinger, K. G.: Cytogenetical and clinical investigations in four subjects with anomalies of sexual development. Ann. Hum. Genet., 29: 281, 1966. LoCurto, F., Pucci, E., Scappaticci, S., Scotta, S., Severi, F., Burgio, G. R. and Fraccaro, M.: XO and male phenotype. Amer. J. Dis. Child., 128: 90, 1974. Forabosco, A., Carratu, A., Assuma, M., De Pol, A., Dutrillaux, B. and Cheli, E.: Male with 45, X karyotype. Clin. Genet., 12: 97, 1977. del Castillo, E. B., Trabucco, A. and de la Baize, F. A.: Syndrome produced by absence of the germinal epithelium without impairment of the Sertoli or Leydig cells. J. Clin. Endocr., '1: 493, 1947. Maeda, 0., Nakamura, M., Namiki, M., Okuyama, A., Sonoda, T., Akiyama, T., Kurita, T. and Sakamoto, H.: 45X/46XX boy with hypospadias: case report. J. Urol., 135: 1249, 1986. Wachtel, S.S., Koo, G. C., Breg, W.R., Thaler, H. T., Dillard, G. M., Rosenthal, I. M., Dosik, H., Gerald, P. S., Saenger, P., New, M., Lieber, E. and Miller, 0. J.: Serologic detection of a Y-linked gene in XX males and in XX true hermaphrodites. New Engl. J. Med., 295: 750, 1976.
THE JOURNAL OF UROLOGY
Copyright© 1988 by The Williams & Wilkins Co.
AN INFERTILE MAN WITH A 45X KARYOTYPE YOSHIYUKI SAKAI, AKIMI OGAWA
AND
TAKASHI EHARA
From the Departments of Urology and Pathology, Shinshu University School of Medicine, Matsumoto, Japan
ABSTRACT
We describe an infertile man with normal secondary sexual characteristics and a 45X karyotype. Physical examination showed bilateral soft small testes and the semen contained no sperm. Serum testosterone, estrogen and gonadotropin levels were within normal range. Biopsy of the testis showed germinal aplasia. (J. Ural., 139: 1316-1317, 1988) Failure of spermatogenesis may be associated with chromosomal abnormalities. Patients with Klinefelter's syndrome, a common form of male infertility and hypogonadism, usually have an XXY sex chromosomal constitution and its variants have in common the presence of at least a Y chromosome. 1 Male sexual differentiation in the absence of a Y chromosome has been noted in rare entities of 46XX true hermaphrodites and 46XX male subjects 1• 2 in whom spermatogenesis is almost always impaired. A 45X karyotype associated with a male phenotype is extremely rare, with only 3 infant cases reported. 3- 5 We report on an infertile man with a 45X karyotype. CASE REPORT
A 27-year-old married man, an employee of a cigarette company, was referred to our hospital because of infertility. Medical and family history was noncontributory. He had no complaints in regard to sexual activities. The patient was 160 cm. tall and of normal intelligence. Physical examination was negative except for small (3 X 2 x 2 cm.) soft testes (fig. 1). Routine blood studies were normal. Semen analysis showed no sperm. Chromosomal studies on 33 cultured blood cells with G-banding and C-banding techniques revealed a 45X karyotype in all but 1 cell, which had a 44X chromosomal constitution (fig. 2). Serum hormonal data revealed testosterone 401 ng./ml. (normal 250 to 1,100), estrone 68.1 pg./ml. (normal 10 to 90), estradiol 30.5 pg./ml. (normal 10 to 40), estradiol less than 30 pg./ml. (normal), folliclestimulating hormone 20.1 mIU/ml. (normal 6.5 to 34.5) and luteinizing hormone 15.9 mIU/ ml. (normal 2 to 22). Vesiculography disclosed no anatomical or obstructive lesions in the seminal tract. Biopsy of the testis revealed that the seminiferous tubules were lined only by Sertoli cells and no germinal cells were present. Their basement membranes were slightly thickened, the vascular walls were hyalinized and there was no proliferation of Leydig cells in the interstitial tissue (fig. 3).
tubules and normal levels of serum gonadotropins are not consistent with Klinefelter's syndrome. A 45X karyotype usually is noted in female subjects with Turner's syndrome characterized by sexual infantilism, short stature and a variety of somatic anomalies. Male sexual differentiation rarely accompanies a 45X karyotype. Fraccaro and associates described a 6-year-old boy with a 45X karyotype. 3 The boy had penoscrotal hypospadias and mental retardation. Histology of the testes showed complete germinal aplasia but otherwise it was normal for age. LoCurto and associates reported on a 7-month-old child with normal male external genitalia and a 45X karyotype. 4 The child was mentally retarded and had signs of bone maldevelopment. The dermatoglyphic patterns were characteristic of Turner's syndrome. Histology of the testes was normal for age. Forabosco and associates described a 45X 5-month-old male infant who had some Turner-like stigmata. 5 Recently, Maeda and associates reported on a 21-month-old boy with a 45X/46XX mosaicism, who had an infantile testis and penoscrotal hypospadias. 7 Unlike these 45X male subjects, our patient was an adult and had neither hypospadias nor somatic anomalies characteristic of Turner's syndrome. The only findings were soft small testes with germinal aplasia. A boy with a 45X karyotype and germinal aplasia also has been described. 3 The chromosomal abnormality would account for this testicular lesion, although various etiologies cause germinal aplasia. In the 2, 45X male infants with histologically normal testes 4• 7 a similar testicular
DISCUSSION
The clinical features and histology of the testes in our patient are similar to those of the Sertoli-cell-only syndrome. This syndrome is characterized by a normal male phenotype with adequate virilization, absence of gynecomastia, small testes with normal consistency, and azoospermia with the seminiferous tubules containing Sertoli cells only and completely lacking the germinal epithelium.6 However, a 45X karyotype is not consistent with this syndrome, which always has a 46XY karyotype. Klinefelter's syndrome, a common form of male infertility and hypogonadism associated with chromosomal abnormality, also does not apply to the diagnosis of our patient. Not only a 45X karyotype but the absence of hyalinized seminiferous FIG. 1. External genitalia
Accepted for publication October 7, 1987. 1316
INFERTILE MAN WITH 45X KARYOTYPE
1317
--,-ll-·
FIG. 3. Biopsy of testis shows germinal aplasia. H & E, reduced from X380.
Fm. 2. Karyotype of blood cell is 45X
lesion could develop with the appearance of puberty, as occurs in Klinefelter's syndrome,' resulting in infertility in adulthood. Several explanations exist as to why the testes develop in the absence of a Y chromosome, including hidden sex chromosome mosaicism with an undetected cell line containing a Y chromosome, interchange or translocation between a Y and an X chromosome or an autosome, and a putative mutant autosomal gene that leads to differentiation of the testis.' H-Y antigen induces differentiation of the primitive gonad as a testis. The genes that code for H-Y antigen or regulate its expression normally are located in a Y chromosome. The fact that XX male subjects and XX true hermaphrodites are positive for Hy antigen, 8 and the case of 45X/46XX mosaicism positive for H-Y antigen 7 support the aforementioned hypotheses. Although H-Y antigen was not examined in our patient, it would have been positive and would have induced the development of the testes and normal male differentiation. The chromosomal analysis was performed by Dr. I. Yonemura, Department of Legal Medicine, Shinshu University School of Medicine. REFERENCES L Conte, F. A. and Grumbach, M. M.: Pathogenesis, classification, diagnosis, and treatment of anomalies of sex. In: Endocrinology.
2.
3.
4. 5.
6. 7.
8.
Edited by L. J. DeGroot, G. F. Cahill, Jr., W. D. Odell, L. Martini, J. T. Potts, Jr., D. H. Nelson, E. Steinberger and A. L Winegrad. New York: Grune & Stratton, vol. 3, chapt. 106, pp. 1317-1351, 1979. Raspa, R. W., Burbige, K. A. and Hensle, T. W.: The sex reversal syndrome (the XX male patient). J. Urol., 134: 152, 1985. Fraccaro, M., Lindsten, J., Klinger, H.P., Tiepolo, L., Bergstmnd, C. G., Herrlin, K. M., Livaditis, A., Pehrson, M. and Tillinger, K. G.: Cytogenetical and clinical investigations in four subjects with anomalies of sexual development. Ann. Hum. Genet., 29: 281, 1966. LoCurto, F., Pucci, E., Scappaticci, S., Scotta, S., Severi, F., Burgio, G. R. and Fraccaro, M.: XO and male phenotype. Amer. J. Dis. Child., 128: 90, 1974. Forabosco, A., Carratu, A., Assuma, M., De Pol, A., Dutrillaux, B. and Cheli, E.: Male with 45, X karyotype. Clin. Genet., 12: 97, 1977. del Castillo, E. B., Trabucco, A. and de la Baize, F. A.: Syndrome produced by absence of the germinal epithelium without impairment of the Sertoli or Leydig cells. J. Clin. Endocr., '1: 493, 1947. Maeda, 0., Nakamura, M., Namiki, M., Okuyama, A., Sonoda, T., Akiyama, T., Kurita, T. and Sakamoto, H.: 45X/46XX boy with hypospadias: case report. J. Urol., 135: 1249, 1986. Wachtel, S.S., Koo, G. C., Breg, W.R., Thaler, H. T., Dillard, G. M., Rosenthal, I. M., Dosik, H., Gerald, P. S., Saenger, P., New, M., Lieber, E. and Miller, 0. J.: Serologic detection of a Y-linked gene in XX males and in XX true hermaphrodites. New Engl. J. Med., 295: 750, 1976.