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Ambiguous Genitalia, Gonadoblastoma, Aniridia and Mental Retardation with Deletion of Chromosome 11
0022-534 7 /89/1425-1298$02.00/0 THE JOURNAL OF UROLOGY Copyright© 1989 by AMERICAN UROLOGICAL ASSOCIATION, !NC.
Vol. 142, November Printed in U.S.A.
AMBIGUOUS GENITALIA, GONADOBLASTOMA, ANIRIDIA AND MENTAL RETARDATION WITH DELETION OF CHROMOSOME 11 J. MARTINEZ-MORA,* L. AUDI, N. TORAN, R. ISNARD, A. CASTELLVI, M. PEREZ IRIBARNE J. EGOZCUE
AND
From the Department of Pediatric Surgery and Hormonal Laboratory, Hospital Germans Trias Pujol, Badalona, and Department of Pathology, Hospital Vall d'Hebro, and Department of Cell Biology, Autonomous University of Bellaterra, Barcelona, Spain
ABSTRACT
We describe a patient with ambiguous genitalia, gonadoblastoma, aniridia, mental retardation and 46XY, del (ll)(p13) karyotype. To our knowledge this association has been observed in only 2 patients to date. (J. Ural., 142: 1298-1300, 1989) The complex of Wilms tumor, aniridia, genitourinary abnormalities and mental retardation (WAGR complex) often is associated with a deletion or microdeletion of chromosome 11 [del(ll)(p13)]. 1 However, patients may have any combination of the different pathological findings included in the W AGR complex, that is presence or absence of genitourinary anomalies, presence or absence of Wilms tumor, presence or absence of the del(ll)(p13) anomaly and so forth. 2• 3 We report a case with ambiguous genitalia, gonadoblastoma, aniridia and mental retardation associated with the del(ll)(p13) chromosomal deletion. CASE REPORT
The propositus, the third child of a family without consanguinity, was seen at birth. The family tree is shown in figure 1. A brother of the mother and 1 of his 3 sons were mentally retarded. The patient had low set ears and ambigous genitalia with perineoscrotal hypospadias and a urogenital sinus (fig. 2). Genitography demonstrated a short common duct connecting a urethra, septate vagina and bicornuate uterus (fig. 3). No gonad was found on the left side. On the right side, an inguinal gonad was biopsied and corresponded to a testicle. 17-Ketosteroids were normal and congenital adrenal hyperplasia was ruled out. Ophthalmological examination revealed bilateral aniridia and glaucoma. The karyotype was 46XY. Since the penis was of normal size and the right gonad was a testis the patient was assigned a male sex. When the patient was 4 years old the presence of a bicornuate uterus was confirmed by laparotomy, and a large left gonadal tumor was excised and identified as a gonadoblastoma (fig. 4). The child was mentally retarded and speech was limited to monosyllables. Baseline testosterone was 17.1 ng./dl. (normal prepubertal 8 ± 5). After stimulation with human chorionic gonadotropin (1,500 units every 48 hours for 14 days) the value was 269 ng./dl. (normal stimulated 624 ± 249). Baseline androstenedione was 8.1 ng./dl. (normal prepuberty 21 ± 14) and after stimulation with human chorionic gonadotropin it was 13 ng./dl. (normal stimulated 38 ± 18). Denis-Browne urethroplasty was performed when he was 9 years old. When the patient was 14 years old baseline testosterone was 368 ng./dl., baseline androstenedione 75 ng./dl. and dehydroepiandrosterone 512 ng./dl. Luteinizing and follicle-stimulating hormone levels were elevated at 16 mlU/ml. (normal adult ~9) and 22.30 mIU/ml. (normal adult 2 to 10), respectively. When he was 15 years old a new chromosomal study with high resolution banding techniques 4 demonstrated the presence of a
deletion of the short arm of chromosome 11 [del(ll)(pter p13::p 11. 11 pter] (fig. 5). The karyotypes of the parents were normal. Presently, the patient is 16 years old. Weight is 48 kg. and height is 150 cm. He is completely blind. Pubertal development is normal, with normal virilization. DISCUSSION
The association of aniridia, gonadoblastoma and mental retardation with ambiguous genitalia has been reported previously in 3 patients. 5 • 6 Patient 1 had the Smith-Lemli-Opitz syndrome and intersexuality of the external genitalia. 5 In this patient 2 gonadoblastomas were resected and the karyotype was 46XY but at that time no further genetic studies were performed. Later, 2 patients were reported with aniridia, mental retardation, ambiguous genitalia and a deletion involving the short arm of chromosome 11. 6 A total of 3 patients, including ours, has been observed with ambiguous genitalia, aniridia, mental retardation, a 46XY karyotype and deletion of chromosome 11; none of them had Wilms tumor. We believe that our patient can be classified as having mixed gonadal dysgenesis because all signs of this syndrome were present, including ambiguous external genitalia, a vagina, bicornuate uterus and fallopian tube with gonadoblastoma on 1 side and a testicle on the other. In general, sex assignment of these patients depends on their age, size of the penis and psychosexual education. In newborns or infants with mixed gonadal dysgenesis the preferred sex assignment is female, taking into account the presence of a vagina and, generally, of a normal clitoris. If the penis is normal a male sex assignment should be considered. In children, management depends on the development of the external genitalia, especially the size of the penis, and also on the sex assignment at birth. If the sex is female clitoroplasty and vaginoplasty may be needed depending on the anatomy of the external genitalia. In male patients with hypospadias and corpora cavernosa of normal size the streak gonad or gonadoblastoma must be removed, and orchiopexy must be done if the histological status of the testis is normal; otherwise it also must be removed. Gonadoblastoma is a tumor with 2 or more types of cell clusters, including germ cells and stromal cells that sometimes appear as immature Sertoli or granulosa cells. Approximately 20% of all gonadoblastomas arise in streak gonads. This tumor is not a malignant neoplasm but its strong association with germinoma and other malignant tumors makes removal mandatory. There is general agreement that gonadectomy should be performed in cases of mixed gonadal dysgenesis because dysgenetic and streak gonads develop into gonadoblastomas in more than 30 to 50% of the cases before or during early adulthood. 7 •8
Accepted for publication April 26, 1989. * Requests for reprints: Department of Pediatric Surgery, Hospital Materno-Infantil "Germans Trias Pujol", Box 72, Badalona 08916, Barcelona, Spain. 1298
A.MB:!GUOUS GENITALIA, GONADOBLASTOMA, ANIRIDIA AND MENTAL RETARDATION
I
~
MENTAL RETARDATION.
Ill
CHROMOSOME STUDIES
/
l
1299
D
PROBAND
FIG. 1. Pedigree of family of propositus. There is no deletion of chromosome 11 in parents. Brother of mother and 1 of his sons are mentally retarded.
Fm. 4. Tubular structures show many cells with clear cytoplasm and prominent nucleus. No Leydig cells are seen in stroma. Calcification -is noted. H & E, reduced from X250.
11
11 p -
Fm. 5. Banded chromosomes 11 show de! (ll)(p13) anomaly
FIG. 2. Perineoscrotal hypospadias with urogenital sinus
absence of the different components of the WAGR complex is variable, since different pathological conditions can be found together or individually with or without deletion of chromosome 11. 2 • 3 • 9 Presently, the reason for this extreme variability is unknown, but it might depend on the size of the deletion, which may affect 1 or more genes in the chromosome and which can give rise to a visible or undetectable cytogenetic anomaly, as has been demonstrated in cases of retinoblastoma. 10• 11 On the other hand, the mechanisms of human male sexual development still are largely unknown, although presently it seems evident that such development depends on genes that may be present in the sex chromosomes and in some autosomes. 12 Thus, the short arm of chromosome 11 probably carries genes that are required for normal development of the iris, kidneys, male gonads and genitalia. 9 REFERENCES
FIG. 3. Genitography shows vaginal septum and bicornuate uterus
Since the karyotypes of the parents were normal, and no chromosomal reorganizations were observed, the deletion present in the patient must be considered as de novo. From a genetic viewpoint it should be noted that the presence or
1. Dallapiccola, B. and Forabosco, A.: Human microcytogenetics. Acta Med. Auxol., Hli: 5, 1987. 2. Turleau, C., de Grouchy, J., Dufier, J. L., Phuc, L. H., Schmelck, P. H., Rappaport, R., Nihoul-Fekete, C. and Diebold, N.: Aniridia, male pseudohermaphroditism, gonadoblastoma, mental retardation, and de! llpl3. Hum. Genet., 57: 300, 1981. 3. De Blois, M., Philip, T., Lenoir, G. M., Junien, C., Laurent, C. and Robert, J. M.: Etude cytogenetic en prometaphase de 13 cas de tumeur de Wilms sans aniridie. J. Genet. Hum., 31: 25, 1983. 4. Yunis, J. J.: High resolution of human chromosomes. Science, 191:
1300
MARTINEZ-MORA AND ASSOCIATES
1268, 1976. 5. Gracia, R., Nieto, J. A., Nistal, M., Iturriaga, R., Lledo, G., Barrio, R. and Lama, R.: Asociaci6n de aniridia con tumor embrionario no renal (gonadoblastoma) en niiio con sindrome de SmithLemli-Opitz. An. Esp. Ped., 9: 19, 1976. 6. Smith, A. C. M., Sujansky, E. and Riccardi, V. M.: Aniridia, mental retardation and genital abnormality in two patients with 46,XY, llp-. Birth Defects, 13: 257, 1977. 7. Davidoff, F. and Federman, D. D.: Mixed gonadal dysgenesis. Pediatrics, 52: 725, 1973. 8. Verp, M. S. and Simpson, J. L.: Abnormal sexual differentiation and neoplasia. Cancer Genet. Cytogent., 25: 191, 1987. 9. Francke, U., Holmes, L. B., Atkins, L. and Riccardi, V. M.: Aniri-
dia-Wilms' tumor association: evidence for specific deletion of llp13. Cytogenet. Cell Genet., 24: 185, 1979. 10. Cowell, J. K., Rutland, P., Hungerford, J. and Jay, M.: Deletion of chromosome region 13q14 is transmissible and does not always predispose to retinoblastoma. Hum. Genet., 80: 43, 1988. 11. Horsthemke, B., Greger, V., Barnert, H. J., Hopping, W. and Passarge, E.: Detection of submicroscopic deletions and a DNA polymorphism at the retinoblastoma locus. Hum. Genet., 76: 257, 1987. 12. Polani, P. E.: Abnormal sex development in man. Anomalies of sex-differentiating mechanisms. In: Mechanisms of Sex Differentiation in Animals and Man. Edited by C. R. Austin and R. G. Edwards. New York: Academic Press, chapt. 12, p. 549, 1981.
Vol. 142, November Printed in U.S.A.
AMBIGUOUS GENITALIA, GONADOBLASTOMA, ANIRIDIA AND MENTAL RETARDATION WITH DELETION OF CHROMOSOME 11 J. MARTINEZ-MORA,* L. AUDI, N. TORAN, R. ISNARD, A. CASTELLVI, M. PEREZ IRIBARNE J. EGOZCUE
AND
From the Department of Pediatric Surgery and Hormonal Laboratory, Hospital Germans Trias Pujol, Badalona, and Department of Pathology, Hospital Vall d'Hebro, and Department of Cell Biology, Autonomous University of Bellaterra, Barcelona, Spain
ABSTRACT
We describe a patient with ambiguous genitalia, gonadoblastoma, aniridia, mental retardation and 46XY, del (ll)(p13) karyotype. To our knowledge this association has been observed in only 2 patients to date. (J. Ural., 142: 1298-1300, 1989) The complex of Wilms tumor, aniridia, genitourinary abnormalities and mental retardation (WAGR complex) often is associated with a deletion or microdeletion of chromosome 11 [del(ll)(p13)]. 1 However, patients may have any combination of the different pathological findings included in the W AGR complex, that is presence or absence of genitourinary anomalies, presence or absence of Wilms tumor, presence or absence of the del(ll)(p13) anomaly and so forth. 2• 3 We report a case with ambiguous genitalia, gonadoblastoma, aniridia and mental retardation associated with the del(ll)(p13) chromosomal deletion. CASE REPORT
The propositus, the third child of a family without consanguinity, was seen at birth. The family tree is shown in figure 1. A brother of the mother and 1 of his 3 sons were mentally retarded. The patient had low set ears and ambigous genitalia with perineoscrotal hypospadias and a urogenital sinus (fig. 2). Genitography demonstrated a short common duct connecting a urethra, septate vagina and bicornuate uterus (fig. 3). No gonad was found on the left side. On the right side, an inguinal gonad was biopsied and corresponded to a testicle. 17-Ketosteroids were normal and congenital adrenal hyperplasia was ruled out. Ophthalmological examination revealed bilateral aniridia and glaucoma. The karyotype was 46XY. Since the penis was of normal size and the right gonad was a testis the patient was assigned a male sex. When the patient was 4 years old the presence of a bicornuate uterus was confirmed by laparotomy, and a large left gonadal tumor was excised and identified as a gonadoblastoma (fig. 4). The child was mentally retarded and speech was limited to monosyllables. Baseline testosterone was 17.1 ng./dl. (normal prepubertal 8 ± 5). After stimulation with human chorionic gonadotropin (1,500 units every 48 hours for 14 days) the value was 269 ng./dl. (normal stimulated 624 ± 249). Baseline androstenedione was 8.1 ng./dl. (normal prepuberty 21 ± 14) and after stimulation with human chorionic gonadotropin it was 13 ng./dl. (normal stimulated 38 ± 18). Denis-Browne urethroplasty was performed when he was 9 years old. When the patient was 14 years old baseline testosterone was 368 ng./dl., baseline androstenedione 75 ng./dl. and dehydroepiandrosterone 512 ng./dl. Luteinizing and follicle-stimulating hormone levels were elevated at 16 mlU/ml. (normal adult ~9) and 22.30 mIU/ml. (normal adult 2 to 10), respectively. When he was 15 years old a new chromosomal study with high resolution banding techniques 4 demonstrated the presence of a
deletion of the short arm of chromosome 11 [del(ll)(pter p13::p 11. 11 pter] (fig. 5). The karyotypes of the parents were normal. Presently, the patient is 16 years old. Weight is 48 kg. and height is 150 cm. He is completely blind. Pubertal development is normal, with normal virilization. DISCUSSION
The association of aniridia, gonadoblastoma and mental retardation with ambiguous genitalia has been reported previously in 3 patients. 5 • 6 Patient 1 had the Smith-Lemli-Opitz syndrome and intersexuality of the external genitalia. 5 In this patient 2 gonadoblastomas were resected and the karyotype was 46XY but at that time no further genetic studies were performed. Later, 2 patients were reported with aniridia, mental retardation, ambiguous genitalia and a deletion involving the short arm of chromosome 11. 6 A total of 3 patients, including ours, has been observed with ambiguous genitalia, aniridia, mental retardation, a 46XY karyotype and deletion of chromosome 11; none of them had Wilms tumor. We believe that our patient can be classified as having mixed gonadal dysgenesis because all signs of this syndrome were present, including ambiguous external genitalia, a vagina, bicornuate uterus and fallopian tube with gonadoblastoma on 1 side and a testicle on the other. In general, sex assignment of these patients depends on their age, size of the penis and psychosexual education. In newborns or infants with mixed gonadal dysgenesis the preferred sex assignment is female, taking into account the presence of a vagina and, generally, of a normal clitoris. If the penis is normal a male sex assignment should be considered. In children, management depends on the development of the external genitalia, especially the size of the penis, and also on the sex assignment at birth. If the sex is female clitoroplasty and vaginoplasty may be needed depending on the anatomy of the external genitalia. In male patients with hypospadias and corpora cavernosa of normal size the streak gonad or gonadoblastoma must be removed, and orchiopexy must be done if the histological status of the testis is normal; otherwise it also must be removed. Gonadoblastoma is a tumor with 2 or more types of cell clusters, including germ cells and stromal cells that sometimes appear as immature Sertoli or granulosa cells. Approximately 20% of all gonadoblastomas arise in streak gonads. This tumor is not a malignant neoplasm but its strong association with germinoma and other malignant tumors makes removal mandatory. There is general agreement that gonadectomy should be performed in cases of mixed gonadal dysgenesis because dysgenetic and streak gonads develop into gonadoblastomas in more than 30 to 50% of the cases before or during early adulthood. 7 •8
Accepted for publication April 26, 1989. * Requests for reprints: Department of Pediatric Surgery, Hospital Materno-Infantil "Germans Trias Pujol", Box 72, Badalona 08916, Barcelona, Spain. 1298
A.MB:!GUOUS GENITALIA, GONADOBLASTOMA, ANIRIDIA AND MENTAL RETARDATION
I
~
MENTAL RETARDATION.
Ill
CHROMOSOME STUDIES
/
l
1299
D
PROBAND
FIG. 1. Pedigree of family of propositus. There is no deletion of chromosome 11 in parents. Brother of mother and 1 of his sons are mentally retarded.
Fm. 4. Tubular structures show many cells with clear cytoplasm and prominent nucleus. No Leydig cells are seen in stroma. Calcification -is noted. H & E, reduced from X250.
11
11 p -
Fm. 5. Banded chromosomes 11 show de! (ll)(p13) anomaly
FIG. 2. Perineoscrotal hypospadias with urogenital sinus
absence of the different components of the WAGR complex is variable, since different pathological conditions can be found together or individually with or without deletion of chromosome 11. 2 • 3 • 9 Presently, the reason for this extreme variability is unknown, but it might depend on the size of the deletion, which may affect 1 or more genes in the chromosome and which can give rise to a visible or undetectable cytogenetic anomaly, as has been demonstrated in cases of retinoblastoma. 10• 11 On the other hand, the mechanisms of human male sexual development still are largely unknown, although presently it seems evident that such development depends on genes that may be present in the sex chromosomes and in some autosomes. 12 Thus, the short arm of chromosome 11 probably carries genes that are required for normal development of the iris, kidneys, male gonads and genitalia. 9 REFERENCES
FIG. 3. Genitography shows vaginal septum and bicornuate uterus
Since the karyotypes of the parents were normal, and no chromosomal reorganizations were observed, the deletion present in the patient must be considered as de novo. From a genetic viewpoint it should be noted that the presence or
1. Dallapiccola, B. and Forabosco, A.: Human microcytogenetics. Acta Med. Auxol., Hli: 5, 1987. 2. Turleau, C., de Grouchy, J., Dufier, J. L., Phuc, L. H., Schmelck, P. H., Rappaport, R., Nihoul-Fekete, C. and Diebold, N.: Aniridia, male pseudohermaphroditism, gonadoblastoma, mental retardation, and de! llpl3. Hum. Genet., 57: 300, 1981. 3. De Blois, M., Philip, T., Lenoir, G. M., Junien, C., Laurent, C. and Robert, J. M.: Etude cytogenetic en prometaphase de 13 cas de tumeur de Wilms sans aniridie. J. Genet. Hum., 31: 25, 1983. 4. Yunis, J. J.: High resolution of human chromosomes. Science, 191:
1300
MARTINEZ-MORA AND ASSOCIATES
1268, 1976. 5. Gracia, R., Nieto, J. A., Nistal, M., Iturriaga, R., Lledo, G., Barrio, R. and Lama, R.: Asociaci6n de aniridia con tumor embrionario no renal (gonadoblastoma) en niiio con sindrome de SmithLemli-Opitz. An. Esp. Ped., 9: 19, 1976. 6. Smith, A. C. M., Sujansky, E. and Riccardi, V. M.: Aniridia, mental retardation and genital abnormality in two patients with 46,XY, llp-. Birth Defects, 13: 257, 1977. 7. Davidoff, F. and Federman, D. D.: Mixed gonadal dysgenesis. Pediatrics, 52: 725, 1973. 8. Verp, M. S. and Simpson, J. L.: Abnormal sexual differentiation and neoplasia. Cancer Genet. Cytogent., 25: 191, 1987. 9. Francke, U., Holmes, L. B., Atkins, L. and Riccardi, V. M.: Aniri-
dia-Wilms' tumor association: evidence for specific deletion of llp13. Cytogenet. Cell Genet., 24: 185, 1979. 10. Cowell, J. K., Rutland, P., Hungerford, J. and Jay, M.: Deletion of chromosome region 13q14 is transmissible and does not always predispose to retinoblastoma. Hum. Genet., 80: 43, 1988. 11. Horsthemke, B., Greger, V., Barnert, H. J., Hopping, W. and Passarge, E.: Detection of submicroscopic deletions and a DNA polymorphism at the retinoblastoma locus. Hum. Genet., 76: 257, 1987. 12. Polani, P. E.: Abnormal sex development in man. Anomalies of sex-differentiating mechanisms. In: Mechanisms of Sex Differentiation in Animals and Man. Edited by C. R. Austin and R. G. Edwards. New York: Academic Press, chapt. 12, p. 549, 1981.