Tipar Cap coada final.qxd 1/22/2007 11:57 PM Page 465 Case report COMPLETE GONADAL DYSGENESIS WITH XY CHROMOSOMAL CONSTITUTION Dorina Stoicanescu *,1, Valerica Belengeanu 1, Dana Amzar 2, Cristina Popa 1, N. Hrubaru 3, Anca Rosianu 4 1 Medical Genetics Department, Victor Babes University of Medicine and Pharmacy Timisoara, Romania 2 Endocrinology Department, Victor Babes University of Medicine and Pharmacy Timisoara, Romania 3 Obstetrics and Gynecology Department, Bega Clinic, Victor Babes University of Medicine and Pharmacy Timisoara, Romania 4 Morphopathology Department, Victor Babes University of Medicine and Pharmacy Timisoara, Romania Abstract A 20-year-old woman was studied because of lack of spontaneous pubertal development and primary amenorrhea. At the moment of examination in the Medical Genetics Department she had normal height, sparse axillary and pubic hair, but breasts were well developed (she already had some estrogen therapy). She had normal but infantile external genitalia, normal vagina and small uterus. Laparoscopic investigation suggested the presence of gonadoblastoma in the dysgenetic gonads and histopathologic examination confirmed the diagnosis. The karyotype revealed a 46, XY chromosome constitution in lymphocytes, without structural defects of X or Y chromosomes. Because of the risk of malignancy, gonadectomy was performed. Key words: XY complete gonadal dysgenesis, 46,XY disorder of sex development, gonadoblastoma. INTRODUCTION Patients with the XY female type of gonadal dysgenesis appear to be normal females at birth, but they do not develop secondary sexual characteristics at puberty, have streak gonads and primary amenorrhea. A high incidence of neoplasia such as gonadoblastomas and germinomas in the gonads of these patients was noticed (1). The first step of sexual differentiation of a normal embryo having the X and Y chromosomes is the development of testes. This depends on a number of genes located on the sex chromosomes, but also on autosomes. If one of these genes is *Correspondence to: Dorina Stoicanescu, Medical Genetics Department, "Victor Babes"University of Medicine and Pharmacy, P-ta E. Murgu Nr. 2, Timisoara, Tel: 0256-204476. E-mail: dstoicanescu@yahoo.com Acta Endocrinologica (Buc), vol. II, no. 4, p. 465-470, 2006 465
Tipar Cap coada final.qxd 1/22/2007 11:57 PM Page 466 Dorina Stoicanescu et al. absent or does not function properly the testes will fail to develop. The presence of the SRY gene (sex-determining region of the Y chromosome) is absolutely necessary in the early stages of testicular formation. The embryo will thus develop as a male. In its absence, the fetal gonads will develop as ovaries. Mutations of SRY gene account for about 10-20% of cases with gonadal dysgenesis (Swyer syndrome), because without testes testosterone cannot be produced. Thus, the external genitalia do not virilizehttp://en.wikipedia.org/wiki/genitalia, so female genitalia will occur. Also the wolffian derivatives will fail to form. As antimullerian hormone is also missing mullerian derivatives will occur (2). At birth girls seem to be normal in all anatomic respects and before puberty there is usually no suspicion of a defect of the reproductive system. As these girls have streak gonads, at puberty secondary sexual characteristics do not occur, because of the inability of the streak gonads to produce sex hormones. Evaluation of the patient at this time usually reveals the presence of pubic hair, elevation of gonadotropins, which indicate that the pituitary is providing the signal for puberty, but the gonads are failing to respond (3). Evaluation must include chromosome analysis and imaging of the pelvis. The karyotype reveals the presence of X and Y chromosomes and the imaging shows the presence of a uterus but usually of no ovaries. Pelvic imaging, revealing the presence or absence of mullerian derivatives, is important for the differential diagnosis CASE REPORT We report the case of a female patient of 20 years old, who had menarche at 17 years, but it was induced with progesteron. Vaginal bleedings are present with contraceptive medication. At the moment of examination in the Medical Genetics Department she had normal stature (170 cm), sparse axillary and pubic hair (Tanner II), breasts were developed (Tanner III) (she already had some estrogen therapy). She had infantile but otherwise normal external genitalia, normal vagina but small uterus. The patient had no other anomalies. Gynecological examination revealed: exocervicitis, hypoplasic uterus, unpainful fallopian tubes. Genital ultrasonography revealed hypoplasia of the uterus (29.5/27/17mm) and gonads. The uterus had a homogeneous aspect and the endometrous was absent. A very small right gonad (12/14 mm) could be detected, but the left gonad could not be differentiated. Ultrasonography of the thyroid revealed hypoechogenicity, a volume of 7.38 ml, with a suspicion of autoimmune thyroiditis. Laboratory findings were positive for anti-thyroid peroxidase (TPO) antibody. High levels of antithyroid peroxidase antibodies (928 IU/ml) confirmed the diagnosis. Other laboratory findings: Serum levels of: Progesterone: 3.33 mmol/l 466
Tipar Cap coada final.qxd 1/22/2007 11:57 PM Page 467 XY female with gonadoblastroma and dysgenetic gonads Estradiol: 22.19 pmol/l Testosterone: 0.556 mmol/l FSH: 76.2 IU/l LH: 47.73 IU/l Laboratory investigations revealing very low levels of estradiol and high levels of FSH and LH in a patient with primary amenorrhea lead to the diagnosis of hypergonadotropic hypogonadism. Chromosome analysis performed from peripheral lymphocytes, using the standard GTG banding method, revealed the following karyotype: 46,XY (Fig.1). Figure1. Karyotype revealing the presence of the X and Y chromosomes. MRI revealed a small uterus, but no ovaries (Fig.2). The diagnosis of complete gonadal dysgenesis was based on the history of the patient, being evaluated for delayed puberty, her phenotype, elevation of gonadotropins that indicate in this patient that the pituitary is providing the signal for puberty but the gonads are failing to respond and also the cytogenetic analysis and imaging of the pelvis. Karyotype revealed the presence of the X and Y chromosomes and the MRI demonstrated the presence of a uterus but no ovaries. Gonads were removed because of the relatively high probability of malignant transformation known for patients with XY gonadal dysgenesis. Morphopathological examination: Macroscopic aspect: on the right part fallopian tube with a length of 3.5 cm and small ovary (1.3/0.5/0.4 cm); on the left two fragments were detected; one of 5 cm length, the fallopian tube and the other of 2.2/1.5/0.5 cm, possible ovary. Microscopic examination of both gonads revealed 467
Tipar Cap coada final.qxd 1/22/2007 11:58 PM Page 468 Dorina Stoicanescu et al. ovarian stroma with nests of small, round germinal cells devoid of mitotic activity and cells derived from the sex cords; the nests contain rounded hyaline bodies; large masses of calcified material within the nests (Figs. 3-5). The tumoral aspect suggests a gonadoblastoma. Few primordial follicles were seen. The fallopian tubes have prominent blood vessels. Figure 2. MRI reveals a small uterus. Ovarian structures were not found. Differential diagnosis include complete androgen insensitivity syndrome, Turner syndrome, partial X chromosome deletions, Frasier syndrome. The diagnosis of complete androgen insensitivity syndrome in individuals with a 46,XY karyotype is based on the following findings: undermasculinization of the external genitalia, normal testes with impaired spermatogenesis, absent or rudimentary mullerian structures, evidence of normal or increased synthesis of testosterone and normal conversion to dihydrotestosterone, normal or increased LH production by the pituitary gland. The androgen receptor gene is the only gene known to be associated with this syndrome. It is an X-linked recessive disorder, females are carriers. The diagnosis was excluded on the bases of laboratory and histopathological findings. Syndromes caused by numerical and structural abnormalities of the X chromosome were excluded on the bases of the phenotype and karyotype, which revealed the presence of the X and Y chromosome. Frasier syndrome, a condition characterized by the presence of the X and Y chromosomes, undermasculinized external genitalia that may range from ambiguous in appearance to normal-looking female genitalia, kidney disease and gonadal tumors, was also excluded, as the patient had normal renal function. 468
Tipar Cap coada final.qxd 1/22/2007 11:58 PM Page 469 XY female with gonadoblastroma and dysgenetic gonads DISCUSSION XY gonadal dysgenesis usually is diagnosed at puberty, when a seemingly healthy girl of normal stature lacks pubertal development. Gonadal failure is indicated by elevated levels of serum follicle-stimulating (FSH) and luteinizing hormone (LH) and a low plasma estradiol level. Pelvic ultrasound examination shows the presence of a small uterus. Clinical observations and segregation analysis indicate that XY gonadal dysgenesis is characterized by genetic heterogeneity. Chromosomal mosaicism may be the cause in some cases (4). The existence of 4 causes of XY gonadal dysgenesis was suggested (5): mutational suppression of H-Y structural genes by regulatory elements of the X chromosome or failure of an X-linked structural gene (in association with H-Y negative somatic cell phenotype); failure of H-Y antigen to engage its gonadal receptor (in association with the H-Y positive somatic cell phenotype); loss of the critical moiety of H-Y genes in deleted or translocated Y chromosome (in association with H-Y negative or intermediate somatic cell phenotype); and presence of XY-XO mosaicism. Mutations in several genes that regulate gonadal differentiation and testis determination are known now to be involved in the etiology of the disorder. In 10% to 15% of cases, complete 46,XY gonadal dysgenesis is caused either by a mutation in the SRY gene or by an Yp deletion of the pseudoautosomal junction region (6). In our case, molecular tests have not been performed. A small minority of patients with Swyer syndrome has some breast development and menstruation at the age of puberty, but this usually lasts for only a short time. This happens because the streak gonads sometimes begin to develop as ovaries. This is especially likely to happen in the form of Swyer syndrome caused by a gene defect on the X chromosome. However, in the absence of a second X chromosome, this ovarian tissue degenerates very rapidly, leading to what is normally called menopause, within a short time. The patient will still ultimately require hormone replacement. The most distinctive member of the group of tumors composed of a combination of germ cells and sex-cord stromal cells is gonadoblastoma (7-9). This tumor occurs in sexually abnormal individuals, most commonly affected by gonadal dysgenesis and carrying the Y chromosome (XY gonadal dysgenesis and XO/XY mosaicism) (10). Gonadoblastomas are bilateral in over one-third of cases. Most cases with gonadal dysgenesis are H-Y antigen negative. This observation supports the concept of causal heterogeneity of XY gonadal dysgenesis (11). Two main groups have been established: one H-Y antigen-positive that is more common, possibly due to gonad-specific receptor defects and the second H-Y antigen-negative, possibly due to mutation in the H-Y generating system, either of the structural gene (possible autosomal) or of a controlling gene (on the sex chromosomes). The H-Y antigen status may be of value in determining which 469
Tipar Cap coada final.qxd 1/22/2007 11:58 PM Page 470 Dorina Stoicanescu et al. patients are at risk for gonadoblastoma or dysgerminoma (12). More recently, the risk for gonadoblastoma has been associated with TSPY, a multicopy gene located in the GBY critical region (13). References 1. Gibbons B, Tan SY, Yo CC, et al. Risk of gonadoblastoma in female patients with Y chromosome abnormalities and dysgenetic gonads. J Paediatr Child Health 1999; 35:210 213. 2. Uehara S, Funato T, Yaegashi N, et al. SRY mutation and tumor formation on the gonads of XP pure gonadal dysgenesis patients. Cancer Genet Cytogenet 1999; 113:78 84. 3. Pozo J, Argente J: Ascertainment and treatment of delayed puberty. Horm Res 2003; 60 Suppl 3: 35-48. 4.Ropke A, Pelz A.-F., Volleth M., Schloer H. W., Morlot S.,Wieacker, P. F. Sex chromosomal mosaicism in the gonads of patients with gonadal dysgenesis, but normal female or male karyotypes in lymphocytes. American Journal of Obstetrics & Gynecology 2004; 190(4):1059-1062. 5. Wachtel, S. S. The genetics of intersexuality: clinical and theoretic perspectives. Obstet. Gynec. 1979; 54:671-685. 6. Kentaro M, Yoshiyuki K, Keiichi T, Shoichi S, Yutaro H Kenjiro K. Molecular evaluation of the SRY gene for gonads of patients with mixed gonadal dysgenesis. International Journal of Urology 2005; 12(7): 673-675. 7. Gitlay JC, Ausems MG, Van Seumeren L, et al. Short stature as the only presenting feature in a patient with an isodicentric (Y) (q 11.23) and gonadoblastoma. A clinical and molecular cytogenetic study. Eur J Pediatr 2001; 160:154 158. 8. Medina LRA, Merchan FI, Conde MAF, et al. Gonadoblastoma in Swyer syndrome. Acta Urol Esp 1997; 21:708 710. 9. Madiwale CV, Fernandes GC, Pandit AA, Kane SV. Gonadoblastoma with distinctly unusual pattern of yolk sac tumour overgrowth. Images in Pathology. 2003; 49(21):75-76. 10. Joki-Erkkila MM, Karikoski R, Rantala I, et al. Gonadoblastoma and dysgerminoma associated with XY gonadal dysgenesis in an adolescent with chronic renal failure: a case of Frasier syndrome. J Pediatr Adolesc Gynecol 2002; 15:145 149. 11. Zhao S, Kato N, Endoh Y, et al. Ovarian gonadoblastoma with mixed germ cell tumor in a woman with 46-XX karyotype and successful pregnancies. Pathol Int 2000; 50:332 335. 12. Gravholt CH, Fedder J, Naeraa RW, et al. Occurrence of gonadoblastoma in females with Turner syndrome and Y- chromosome material: a population study. J Clin Endocrinol Metab 2000; 85: 3199 3202. 13. Lau Y F. Gonadoblastoma, testicular and prostate cancers, and the TSPY gene. Am J Hum Genet April 1999; 64(4):921 927. 470