True agonadism: Report of a case analyzed with Y-specific DNA probes

American Journal of Medical Genetics 41:444-445 (1991)

Brief Clinical Report True Agonadism: Report of a Case Analyzed With Y-Specific DNA Probes Andrea T. Maciel-Guerra, Soltlnge B. Farah, Herald0 M. Garmes, Walter Pinto Jr., Joaquim M. Bustorff da Silva, Maria Teresa Baptista, Antonia Paula Marques-de-Faria, Gil Guerra Jr., and Maricilda P. de Mello Departamento de GenBtica Mddica (A.T.M., S.B.F., W.P.,AP.M.), Disciplina de Endocrinologia, Departamento de Clinica Mddica (H.M.G.,M.T.B.),Departamento de Cirurgia (J.M.B.S.),Departamento de Pediatria (G.G.),and Grupo Interdisciplinar de Estudo da Determinqcio e Diferenciqcio do Sex0 (A.T.M.,M.T.B., A.P.M., G.G.), Faculdade de C2ncias Me'dicas, and Centro de Engenhuria Genktica (MP.M.), Universidade Estadual de Campinas, Campinas, SP, Brazil We report on a 5-year-old girl with a male karyotype (46,XY), severe psychomotor and physical retardation, minor anomalies, and female external genitalia with a blindly ending vagina. She has normal adrenal function, prepubertal serum gonadotropin and testosterone levels, which did not rise after hCG stimulation. On abdominal exploration no gonads were found, and only mesonephric and Mullerian remnants. She was HY positive, and no deletion was detected in the Y chromosome using 5 different probes. Although a genetic defect is not excluded, pregnancy complications suggest an environmental insult to the developing testes.

true agonadism, testicular tissue must have been present a t some time during the embryonic development, since there is evidence for anti-Mullerian function and also for partial androgenic testicular function. It is likely to be confused with the Swyer syndrome (XY gonadal dysgenesis) [Swyer, 19551, which differs from the former in that there is normal differentiation of the external and internal genitalia. True agonadism, the syndrome of rudimentary testes, and bilateral anorchia represent related clinical entities due to regression of the fetal testes, in which the timing of testicular insult would be between 8 and 12 weeks of gestation, between 14 and 20 weeks, and after 20 weeks, respectively [Bergada et al., 1962; Clearly et al., 19771. Coexistenceof anorchia and true agonadism in the same sibship [Josso and Briard, 19801supports the hypothesis that both disorders are related and due to regression of KEY WORDS: embryonic testicular regresthe embryonic testes. sion, male pseudohermaphroCases of agonadism, rudimentary testes, and anditism, Y-specific DNA seorchia are mostly sporadic. However, autosomal recesquences sive inheritance of true agonadism is suggested by two kindreds with multiple sibs affected [Overzier and Linden, 1956; Park and Jones, 19701. INTRODUCTION As the explanation for the gonadal failure in these True agonadism is a rare form of male pseudoher- embryonic testicular regression syndromes is still a maphroditism first described by Overzier and Linden matter of discussion, we present here a case of true [19561. It is characterized by surgically verified absence agonadism which was analysed with Y-specific DNA of gonads in a 46,XY individual with female or slightly probes. ambiguous external genitalia (small phallus, underCLINICAL REPORT developed labia majora, and fusion of the labioscrotal folds) and absence of all but rudimentary Mullerian and N.M.M., a 5V4-year-oldgirl, was referred because of a Wolffian derivatives [Sarto and Opitz, 19731. Thus, in male karyotype (46,XY),detected during investigation of severe psychomotor retardation. She was the 2,600 g product of a term gestation to a 20Received for publication October 9,1990; revision received April year-old GlPO mother and a 27-year-old father. There 19, 1991. was no consanguinity, and the family history was unreAddress reprint requests to Dra. Andrea 'Ikevas Maciel-Guerra, markable. Pregnancy was complicated by severe hyperDepto. de Genetica MBdica, Faculdade de Cibncias MBdicas, Uniemesis, weight loss ( - 25 kg), infection of the urinary versidade Estadual de Campinas, Caixa Postal 6111,13.100 Camtract, anaemia, and 4 episodes of uterine bleeding. pinas SP,Brazil

0 1991 Wiley-Liss, Inc.

True Agonadism The patient was born by cesarian section, and neonatally she had generalized hypotonia, cyanosis, and feeding difficulties. At age 5V4 years she was obviously severely mentally retarded with length 94.5 cm, weight 11.3 Kg, and OFC 47.5 cm (all < 3rd centile). The patient was unable to walk and had no intelligible speech. She had minor anomalies with low anterior hairline, prominent glabella, apparently low-set and posteriorly angulated ears, bilateral clinodactily of the 5th finger and partial syndactyly of toes 2 and 3, and mild hirsutism. The external genitalia were female, with a blindly ending vagina. Laboratory investigation showed pre-pubertal serum gonadotropins (FSH, 23 mIU/ml; LH, 30 mIU/ml) and testosterone (< 30 ng/dl). There was no rise of testosterone after hCG stimulation. Results of determinations of cortisol, 17-alpha-OH-progesterone,dehydroepiandrosterone sulfate, and androstenedione were normal. The patient’s lymphocytes were able to absorb gw-16 monoclonal antibody, specific for HY antigen [Wachtel et al., 19841, as efficiently as those of normal control males. On exploration, no gross or microscopic evidence of gonadal tissue was found. Mesonephric remnants in the right adnexa and bilateral rudimentary Fallopian tubes were removed. The patient’s DNA was prepared from peripheral leukocytes and analysed by Southern blotting method with a panel of probes detecting 5 different intervals on the normal Y chromosome [Vergnaud et al., 19861, including the ZFY locus, TDF (pDP1007) [Page et al., 19871, Yp (pDP105) and centromere (pDP97) [Bernstein et al., 1987; Gal et al., 19871,euchromatic portion of the Yq (p Y-5) [Farah et al., unpublished data], and heterochromatin (pY3.4) [Lau et al., 19841. No deletion was detected in the patient’s Y chromosome using these probes.

DISCUSSION The clinical, endocrine, and cytogenetic data of the patient first suggested the diagnosis of XY gonadal dysgenesis. However, direct inspection by laparotomy and pathological findings failed to note gonadal tissue, and only remnants of Mullerian and Wolffian structures could be identified. Therefore, this is a case of true agonadism. In our patient, no deletion of the Y chromosome could be detected by use of 5 different probes. Although a genetic defect is not excluded, the extremely compli-

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cated pregnancy suggests the possibility of an environmental insult t o the embryonic testes. Teratogenic factors could also be responsible for the neurologic damage resulting in severe psychomotor retardation. Further studies on the clinical and molecular aspects of this rare disorder will certainly be useful to explain the underlying developmental process resulting in gonadal failure in the testicular regression syndromes.

ACKNOWLEDGMENTS We are grateful to Dr. Carlos Albert0 Moreira-Filho for HY antigen determination and to Mrs. Clarisa Ramos for technical assistance. We are also indebted to the Departamento de Anatomia Patolbgica, Faculdade de Ci6ncias MBdicas, UNICAMP. This work was supported with grants from FAPESP, CNPq, FAP-UNICAMP, and FINEP. REFERENCES Bergada C, Cleveland WW, Jones HW Jr, Wilkins L (1962):Variants of embryonic testicular dysgenesis: Bilateral anorchia and syndrome of rudimentary testes. Acta Endocrinol (Kbh) 40521-536. Bernstein R, Rosendorff J , Ramsay M, Pinto, MR, Page DC (1987): A unique dicentric X;Y translocation with Xq and Yp breakpoints: Cytogenetic and molecular studies. Am J Hum Genet 41:145-156. Clearly R, Caras J , Rosenfield RL, Young PCM (1977): Endocrine and metabolic studies in a patient with male pseudohermaphroditism and true agonadism. Am J Obstet Gynecol 128862-867. Gal A, Weber B, Neri G, Serra A, Miiller U, Schempp W, Page DC (1987):A 45,X male with Y-specific DNA translocated onto chromosome 15. Am J Hum Genet 40:477-488. Josso N, Briard ML (1980):Embryonic testicular regression syndrome: Variable phenotypic expression in siblings. J Pediatr 97:200-204. Lau YF, Huang JC, Dozy AM, Kan YW (1984):A rapid screening test for antenatal sex determination. Lancet 114-16 Overzier C, Linden H (1956): Echter Agonadismus (Anorchismus) bei Geschwistern. Gynaecologia 142:215-233. Page DC, Mosher R, Simpson EM, Fisher EM, Mardon G, Pollack J , McGillivra B, de la Chapelle A, Brown L (1987):The sex-determining region of the human Y chromosome encodes a finger protein. Cell 51:1091-1104. Park IJ, Jones HW (1970):Familial male pseudohermaphroditism with ambiguous external genitalia. Am J Obstet Gynecol 108:11971205. Sarto GE, Opitz JM (1973):The XY gonadal agenesis syndrome. J Med Genet 10:288-293. Swyer GIM (1955): Male pseudohermaphroditism: A hitherto undescribed form. Br Med J 2:709-721. Vergnaud G, Page DC, Simmler MC, Brown L, b u y e r F, Noel B, Botstein D, de la Chapelle A, Weissenbach J (1986):A deletion map of the human Y chromosome based on DNA hybridization. Am J Hum Genet 38:109-124. Wachtel GM, Wachtel SS, Nakamura D, Moreira-Filho CA, Brunner H, Koo GC (1984): H-Y antibodies recognize the H-Y transplantation antigen. Transplantation 37:8-13.