Case Report
Clinical Genetics 1990: 37: 69-73
Premature centromeric divisions and prominent telomeres in a patient with persistent Mullerian duct syndrome G. V. RANGNEKAR‘, B. M. LOYA‘,L. K. GOSWAMI’ and L. K. SENGUPTA’ ’Department of Surgery, Gandhi Medical College, Bhopal, and ’Department of Genetics, Bhopal University, Bhopal, India
A 35-year-old, rare male pseudohermaphrodite with inguinal hernia, testis, fallopian tube and uterus, symptoms referrable to persistent Mullerian duct syndrome, is described. The patient has a 46,XY karyotype in 50% of metaphases, while the remaining metaphases show premature cnetromeric divisions and hypoploid counts. Received I0 April, accepted f o r publication 27 July 1989 Key wordr: heterochromatin association in Mullerian duct syndrome; male pseudoherma-
phroditism; persistent Mullerian duct syndrome.
Male pseudohermaphroditism is a heterogeneous group including many different genetically determined abnormalities of variable nosology (Inhorn & Opitz 1968). Opitz et al. (1971) described four distinct genetic and clinical entities, viz. Swyer syndrome, the XY form of “pure gonadal dysgenesis or pure testicular dysgenesis: FTS (feminizing testes syndrome) or syndrome of Moms; incomplete feminizing testis syndrome (IFTS) or male external pseudohermaphroditism with secondary sexual development and breasts and, pseudovaginal perineoscrota1 hypospadias (PPSH).also known as masculinising male hermaphroditism. Subsequently many other clinical entities have been added and associations of aberrant chromosomal features have been described (see Borgaonkar 1984). The case we present here of a 35-year-old male falls into the category of Mullerian duct syndrome, a type of male pseudohermaphroditism (Campbell 1986). As far as
we know, this is the first report to record many premature centromeric divisions (PCD)and hypoploid counts in the lymphocyte cultures of a Mullerian duct syndrome patient.
Case Report
A 35-year-old male presented with a swelling in the right inguinal region which had typical features of indirect inguinal hernia. On examination, the right testis was found in the scrotum and was normal. The left testis was not present in the scrotum, nor palpable in the inguinal region. External genitalia were normal. The patient was a fully grown, otherwise normal male with beard, mamed, and able to perform intercourse normally. The breasts were of normal male size (Fig. 1). However he had no children and semen examination was azoos-
70
RANGNEKAR ET AL.
permic. Per rectal examination was normal and the prostate could be felt normally. He was operated for inguinal hernia on the right side, and on operation the uterus and right fallopian tube were found in the hernial sac (Fig. 2). On further exploration of the abdomen, the uterus could be traced up to the normal position of the cervix. The other (left) fallopian tube was also found, and adjacent to it was a right gonad which was thought to be atrophic, but on gross examination of a cut section, and also after biopsy, proved to be testis. Vas deferens was present on both sides. The uterus and fallopian tubes revealed lumena on cutting. A biopsy was also taken from the right gonad and was reported to be testicular tissue. Histologic
examination of the uterus revealed endometrium in the proliferative phase. Chromosome studies were made from the slides stained with Giemsa after conventional lymphocyte cultures in TC 199. More than 40 metaphases were photographed to yield the karyotype: the essential count (50%) revealed 46,XY, but there were occasional translocations. Since trypsin Giemsa banding could not be employed, it is very difficult to say whether it was the Y or 21 or 22 which had been involved in translocations. Nevertheless, 25% of metaphases exhibited 36-44 chromosomes only, while another 25% metaphases gave a clear picture of premature centromeric divisions (Fig. 3a & 3b). Some of the Giemsa-stained slides were also observed under fluorescent light in the Nikon fluorescence microscope, using a modified technique with green violet filters so as to yield standard repeatable pictures. As shown in Fig. 3c, the telomeric ends of the chromosomes have more sparkling fluorescence than the remaining parts. We wonder if this could be used for qualitative distinction of heterochromatic parts on the chromosomes. This needs exhaustive testing.
Discussion
Flg. 1. Photograph of patlent showing a fully grown male with beard, male breasts, apparently normal male body with external genitalia and right testis.
This case report emphasises the possibility that male intersex may be present with no external evidence of the anomaly. Such patients normally have hypospadias. However, the very unusual presentation of undescended testis with hernia may turn out to be due to male pseudohermaphroditism. The patient fulfils all the criteria of being a male except that he has the additional presence of internal female genitalia (fallopian tube and uterus; Fig. 1 & 2). This kind of male pseudohermaphroditism can result from defects in androgen syn-
I
MULLERIAN DUCT SYNDROME
71
no. 2 Photograph showing abdominal exploration. See uterus (u) covered with peritoneum (smooth), Rt. testis (1. white and bigger), left testis (white and small). fallopian tubes (1).
thesis, defects in androgen action, defects in Mullerian duct regression, and various uncertain causes. Persistent Mullerian duct syndrome results in normal penile development but, in addition, bilateral fallopian tubes, a uterus and an upper vagina and variable development of the vas deferens. The subjects commonly present with inguinal hernias that contain the uterus, and cryptorchidism is common. Most have uninformative family histories, but several pairs of siblings have been described in whom the condition must be inherited either as an autosomal recessive or as an X-linked recessive mutation (Sloan & Walsh 1976, Weiss & Kiefer 1978). Because the external genitalia are well developed and the patients masculinize normally at puberty, it is assumed that during the critical stage of embryonic sexual differentiation the fetal testes produced a normal amount of androgen.
However, Mullerian regression does not occur, possibly because of failure of fetal testis to produce Mullerian-inhibiting substance or because of failure of the tissues to respond to this hormone (Campbell 1986). Chromosome studies from lymphocyte cultures do not yield much information, except that the patient shows enough PCDs (premature centromeric divisions; Fig. 3A & B) which are known to result in azoospermia (Gabrron et al. 1986). Nearly 50% of metaphases show a normal male karyotype. Chromosomes of well-spread metaphases show prominent telomeric ends by unconventional fluorescence study. This is worth mentioning only because chromosome preparations under the same exposure do not yield such observation. In future, if the patient becomes co-operative, chromosome studies will be undertaken by banding methods, which may be quite useful.
72
RANGNEKAR ET AL.
B
Fig. 3A. Glemsa-stained metaphaae In lymphocyte cultures showing premature centromerlc divisions in a few chromosomes. 8 . Typical PCD in hypoplold metaphaae. C. Two metaphases stained wlth Qiemsa and viewed under modified technique wlth green-violet filters (unpublished) in fluorescent light show prominent telomeres. It is remarkable that under the same exposure and observation metaphase chromosomes of controlslpatients did not reveal such telomerlc prominence. Whether male pseudohermaphroditism is accompanied by activated heterochromatin areas needs to be surveyed in such patients by Cbanding.
MULLERIAN DUCT SYNDROME Acknowledgement
We are grateful to the Dean, Gandhi Medical College. Bhopal, for granting us permission to report this case. References Borgaonkar, D. S . (1984). Chromosomal Variation in Man. 4th Edit., New York, Alan R. Liss. Campbell, M. F. (1986). Urology, Vol. 2, 5th Edit. Philadelphia, W. B. Saunders, pp. 1836-1845. Gabrron, J., A. Jimenez & G. Glover (1986). Premature centromere division dominantly inherited in a subfertile family. Cytogenet. Cell Genet. 43, 69-71 Inhorn, S. L. & J. M. Opitz(1968). Abnormalities of sex development. In Endocrine Pathology, J.
73
B. M. Bloodworth (ed.). Baltimore, William & Wilkins. Opitz, J. M., J. L. Simpson, G . E. Sarto, R. L. Summit, M. New & J. German (1971). Pseudovaginal perineoscrotal hypospadias. Clin. Genet. 3, 1-26. Sloan, W. R. & P. C. Walsh (1976). Familial persistent Mullerian duct syndrome. J . Urol. 115, 459-461. Weiss, E. B. & J. H. Kiefer (1978). Persistent Mullerian duct syndrome in male identical twins. Pediatrics 61, 797-800. Address: Prof. H . K . Goswami Department of Genetics Bhopal University Bhopal, 462026 India
Clinical Genetics 1990: 37: 69-73
Premature centromeric divisions and prominent telomeres in a patient with persistent Mullerian duct syndrome G. V. RANGNEKAR‘, B. M. LOYA‘,L. K. GOSWAMI’ and L. K. SENGUPTA’ ’Department of Surgery, Gandhi Medical College, Bhopal, and ’Department of Genetics, Bhopal University, Bhopal, India
A 35-year-old, rare male pseudohermaphrodite with inguinal hernia, testis, fallopian tube and uterus, symptoms referrable to persistent Mullerian duct syndrome, is described. The patient has a 46,XY karyotype in 50% of metaphases, while the remaining metaphases show premature cnetromeric divisions and hypoploid counts. Received I0 April, accepted f o r publication 27 July 1989 Key wordr: heterochromatin association in Mullerian duct syndrome; male pseudoherma-
phroditism; persistent Mullerian duct syndrome.
Male pseudohermaphroditism is a heterogeneous group including many different genetically determined abnormalities of variable nosology (Inhorn & Opitz 1968). Opitz et al. (1971) described four distinct genetic and clinical entities, viz. Swyer syndrome, the XY form of “pure gonadal dysgenesis or pure testicular dysgenesis: FTS (feminizing testes syndrome) or syndrome of Moms; incomplete feminizing testis syndrome (IFTS) or male external pseudohermaphroditism with secondary sexual development and breasts and, pseudovaginal perineoscrota1 hypospadias (PPSH).also known as masculinising male hermaphroditism. Subsequently many other clinical entities have been added and associations of aberrant chromosomal features have been described (see Borgaonkar 1984). The case we present here of a 35-year-old male falls into the category of Mullerian duct syndrome, a type of male pseudohermaphroditism (Campbell 1986). As far as
we know, this is the first report to record many premature centromeric divisions (PCD)and hypoploid counts in the lymphocyte cultures of a Mullerian duct syndrome patient.
Case Report
A 35-year-old male presented with a swelling in the right inguinal region which had typical features of indirect inguinal hernia. On examination, the right testis was found in the scrotum and was normal. The left testis was not present in the scrotum, nor palpable in the inguinal region. External genitalia were normal. The patient was a fully grown, otherwise normal male with beard, mamed, and able to perform intercourse normally. The breasts were of normal male size (Fig. 1). However he had no children and semen examination was azoos-
70
RANGNEKAR ET AL.
permic. Per rectal examination was normal and the prostate could be felt normally. He was operated for inguinal hernia on the right side, and on operation the uterus and right fallopian tube were found in the hernial sac (Fig. 2). On further exploration of the abdomen, the uterus could be traced up to the normal position of the cervix. The other (left) fallopian tube was also found, and adjacent to it was a right gonad which was thought to be atrophic, but on gross examination of a cut section, and also after biopsy, proved to be testis. Vas deferens was present on both sides. The uterus and fallopian tubes revealed lumena on cutting. A biopsy was also taken from the right gonad and was reported to be testicular tissue. Histologic
examination of the uterus revealed endometrium in the proliferative phase. Chromosome studies were made from the slides stained with Giemsa after conventional lymphocyte cultures in TC 199. More than 40 metaphases were photographed to yield the karyotype: the essential count (50%) revealed 46,XY, but there were occasional translocations. Since trypsin Giemsa banding could not be employed, it is very difficult to say whether it was the Y or 21 or 22 which had been involved in translocations. Nevertheless, 25% of metaphases exhibited 36-44 chromosomes only, while another 25% metaphases gave a clear picture of premature centromeric divisions (Fig. 3a & 3b). Some of the Giemsa-stained slides were also observed under fluorescent light in the Nikon fluorescence microscope, using a modified technique with green violet filters so as to yield standard repeatable pictures. As shown in Fig. 3c, the telomeric ends of the chromosomes have more sparkling fluorescence than the remaining parts. We wonder if this could be used for qualitative distinction of heterochromatic parts on the chromosomes. This needs exhaustive testing.
Discussion
Flg. 1. Photograph of patlent showing a fully grown male with beard, male breasts, apparently normal male body with external genitalia and right testis.
This case report emphasises the possibility that male intersex may be present with no external evidence of the anomaly. Such patients normally have hypospadias. However, the very unusual presentation of undescended testis with hernia may turn out to be due to male pseudohermaphroditism. The patient fulfils all the criteria of being a male except that he has the additional presence of internal female genitalia (fallopian tube and uterus; Fig. 1 & 2). This kind of male pseudohermaphroditism can result from defects in androgen syn-
I
MULLERIAN DUCT SYNDROME
71
no. 2 Photograph showing abdominal exploration. See uterus (u) covered with peritoneum (smooth), Rt. testis (1. white and bigger), left testis (white and small). fallopian tubes (1).
thesis, defects in androgen action, defects in Mullerian duct regression, and various uncertain causes. Persistent Mullerian duct syndrome results in normal penile development but, in addition, bilateral fallopian tubes, a uterus and an upper vagina and variable development of the vas deferens. The subjects commonly present with inguinal hernias that contain the uterus, and cryptorchidism is common. Most have uninformative family histories, but several pairs of siblings have been described in whom the condition must be inherited either as an autosomal recessive or as an X-linked recessive mutation (Sloan & Walsh 1976, Weiss & Kiefer 1978). Because the external genitalia are well developed and the patients masculinize normally at puberty, it is assumed that during the critical stage of embryonic sexual differentiation the fetal testes produced a normal amount of androgen.
However, Mullerian regression does not occur, possibly because of failure of fetal testis to produce Mullerian-inhibiting substance or because of failure of the tissues to respond to this hormone (Campbell 1986). Chromosome studies from lymphocyte cultures do not yield much information, except that the patient shows enough PCDs (premature centromeric divisions; Fig. 3A & B) which are known to result in azoospermia (Gabrron et al. 1986). Nearly 50% of metaphases show a normal male karyotype. Chromosomes of well-spread metaphases show prominent telomeric ends by unconventional fluorescence study. This is worth mentioning only because chromosome preparations under the same exposure do not yield such observation. In future, if the patient becomes co-operative, chromosome studies will be undertaken by banding methods, which may be quite useful.
72
RANGNEKAR ET AL.
B
Fig. 3A. Glemsa-stained metaphaae In lymphocyte cultures showing premature centromerlc divisions in a few chromosomes. 8 . Typical PCD in hypoplold metaphaae. C. Two metaphases stained wlth Qiemsa and viewed under modified technique wlth green-violet filters (unpublished) in fluorescent light show prominent telomeres. It is remarkable that under the same exposure and observation metaphase chromosomes of controlslpatients did not reveal such telomerlc prominence. Whether male pseudohermaphroditism is accompanied by activated heterochromatin areas needs to be surveyed in such patients by Cbanding.
MULLERIAN DUCT SYNDROME Acknowledgement
We are grateful to the Dean, Gandhi Medical College. Bhopal, for granting us permission to report this case. References Borgaonkar, D. S . (1984). Chromosomal Variation in Man. 4th Edit., New York, Alan R. Liss. Campbell, M. F. (1986). Urology, Vol. 2, 5th Edit. Philadelphia, W. B. Saunders, pp. 1836-1845. Gabrron, J., A. Jimenez & G. Glover (1986). Premature centromere division dominantly inherited in a subfertile family. Cytogenet. Cell Genet. 43, 69-71 Inhorn, S. L. & J. M. Opitz(1968). Abnormalities of sex development. In Endocrine Pathology, J.
73
B. M. Bloodworth (ed.). Baltimore, William & Wilkins. Opitz, J. M., J. L. Simpson, G . E. Sarto, R. L. Summit, M. New & J. German (1971). Pseudovaginal perineoscrotal hypospadias. Clin. Genet. 3, 1-26. Sloan, W. R. & P. C. Walsh (1976). Familial persistent Mullerian duct syndrome. J . Urol. 115, 459-461. Weiss, E. B. & J. H. Kiefer (1978). Persistent Mullerian duct syndrome in male identical twins. Pediatrics 61, 797-800. Address: Prof. H . K . Goswami Department of Genetics Bhopal University Bhopal, 462026 India
