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CASE REPORT Swyer syndrome in a woman with pure 46,XY gonadal dysgenesis Maharjan Anita1, Min Jie2, Hong Li* Abstract Swyer syndrome or pure gonadal dysgenesis is a genetic aberration characterized by a 46,XY karyotype which are phenotypical females, with female genitalia at birth and normal Müllerian structures. The condition usually becomes apparent first in adolescence with delayed puberty and primary amenorrhea. This case report describes a 27 years old woman with primary amenorrhea and undeveloped breast. The patient had pure 46,XY gonadal dysgensis with hypoplastic uterus, estrogen treatment for amenorrhea, no neoplastic changes on the histopathology report. The patients with gonadal dysgenesis and 46, XY karyotype should be referred for bilateral gonadectomy because of the high risk of neoplastic transformation. Early diagnosis and treatment could help these patients have a normal sex life and carry a fetus in an immature uterus using donor oocytes and hormonal replacement.. Keywords: Swyer Syndrome, 46,XY pure gonadal dysgenesis, primary amenorrhea, dysgerminoma Address of Authors: Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University,Jiefang Road 238, Wuhan, Hubei, China. 1. [email protected], 008615072389065; 2. [email protected], 008615827649335 * Corresponding author [email protected], 008613995600099 Introduction Swyer syndrome or pure gonadal dysgenesis is a genetic aberration characterized by a 46, XY karyotype which are phenotypical females, with female genitalia at birth and normal Müllerian structures. Patients are generally diagnosed in adolescence with delayed pubertal development and most often with primary amenorrhea due to the fact that gonads have no hormonal or reproductive potential. [ 1 ] The psychosocial and reproductive implications of the condition require multidisciplinary management involving pubertal induction, psychosocial support and assisted reproductive technologies. In addition, streak gonads have 30% risk of development of gonadoblastoma and 50% to 60% risk of germ cell malignancies, mainly dysgerminoma. [ 2 ] Therefore, prophylactic gonadectomy is recommended once diagnosis is made. Management of Swyer syndrome is in line with other causes of ovarian failure and involves induction of puberty with estrogen to develop secondary sexual characteristics and long-term combined replacement therapy with estrogen and progesterone. [1] It has been hypothesized that women with Swyer syndrome have a particularly severe degree of estrogen deficiency and according to the definition they are completely devoid of any gonadal steroid production. Case report A 27-year old, single, Chinese female presented with a history of primary amenorrhea with pure gonadal dysgenesis was admitted to the hospital. The patient initially had primary amenorrhea, few pubic and axillary hair with undeveloped breast (Taner Stage II). She was treated with Climen (Estrogen estradiol valerate and cyproterone acetate) at the age of 20 after which menstruation started. Menstruation disappeared when she stopped pills. Later on, she continued her treatment and had menstruation till now with the regular cycle of 5 days intervals of 27-30 days. She had average height with undeveloped breast, normal vagina and cervix, no apparent somatic abnormalities and no clitoral enlargement or any evidence of virilization. Sonographic examination was performed which showed hypoplastic uterus with unremarkable ovaries. Karyotype studies were performed to confirm the diagnosis of pure 46, XY gonadal dysgenesis. Laboratory studies showed a serum FSH level of 68.05mIU/mL, LH level of 36.9305mIU/mL, T level of 47.88ng/dL which was within the normal range for women. retroverted uterus about 3cm×3cm×2cm with smooth surface was seen along with fallopian tubes on left and right side holding a piece of tissue (looked like streak gonads) measuring 2cm×2cm×1cm and 4cm×3cm×2cm respectively. Right side of gonad was covered by dense connective tissue of 1cm×2cm×1cm. Tissues were sent for frozen section which suspected a testis. Based on the agreement with the patient and her family, bilateral gonadectomy and salpingectomy were performed and sent for the pathological studies. Histopathological study of the left gonad revealed fibrous tissue whereas right gonad revealed the nodular distribution of atypical cells with translucent cytoplasm with fibrous tissue hyperplasia and infiltration of lymphocytes, which is illustrated by Figure 1. Similarly, histopathological study of the right dense connective tissue suspected short spindle cells of ovarian stroma with calcification. Immuno-histochemical report showed that the tumor cells for CD117 was positive as shown in Figure 2. Similarly, CD99 and P53 were also found positive but negative for PLAP, CK, inhibin, SMA, CD3, CD20 and CD21. Figure 1: The nodular distribution of atypical cells with fibrous tissue hyperplasia and infiltration of lymphocytes Laparoscopic gonadectomy was scheduled for the patient. During the operation, Figure 2: Tumor cells positive for CD117 Discussion The Swyer syndrome, 46,XY gonadal dysgenesis is a rare chromosomal defect seen in female phenotypic rare condition of sexual abnormality. [3 ] Patients are normally present with small or undeveloped breast but normal axillary and pubic hair. The external genitalia are phenotypically females, the upper part of the vagina and tubes are normal or reduced in size and the uterus is normal but undeveloped. [4] Patients suspected to suffer from Swyer syndrome are first subjected to laboratory testing for confirmation of the diagnosis. Early diagnosis is important for several reasons: firstly, because of the high risk of neoplastic transformation in the dysgenetic gonads; secondly, early institution of estrogen therapy for induction of puberty; thirdly, to allow adequate hormone replacement therapy to prevent osteoporosis. [5] Various karyotypes can be observed as 45,X, 46,XX, 46,XY, 45,X/46,XY, 47,XXY or more complex mosaïcisms. [6] The etiology of 46,XY gonadal dysgenesis is believed to be deletion of short arm of Y chromosome involving the sex determining region of Y (SRY) gene, mutation in other genes leading to inhibition of SRY function, or mutation of SRY itself. [3] In this case, the frozen section of the gonads suspected a testes and the diagnosis was done at the age of 27 .In order to avoid the risk of malignant transformation, bilateral gonadectomy and salpingectomy were carried out. In 2010, Negar et al. [1] hypothesized that chromosome Y contains a gonadoblastoma which is responsible for benign tumor, which may also develop bilaterally and coexist with other neoplasms such as dysgerminoma. Hence, the patients with gonadal dysgenesis and 46, XY karyotype should be referred for bilateral gonadectomy because of the high risk of neoplastic transformation. Therefore, females with Swyer syndrome required close follow up because of the high risk of neoplastic transformation in the dysgenetic gonads. In this case, after estrogen therapy patient had her first menstruation cycle but menstruation was disappeared when she stopped pills and the histopathology report also showed fibrous tissue. As dysgenetic gonads composed of only fibrous tissue; they do not exhibit hormonal function and gametogenesis or any structure that allow them to be identified as either ovaries or testicle. [4] Hence, an additional estrogen replacement therapy will be helpful for the development of secondary sexual characteristics and menstruation. [7 ] Presence of XY genotype and H-Y antigen does not affect the uterine and the endometrial response. There are a number of case reports of normal pregnancies and successful delivery in these patients with the help of artificial reproductive techniques (ART). [8,9,10] Thus, early diagnosis and treatment could help these patients have a normal sex life and carry a fetus in an immature uterus using donor oocytes and hormonal replacement. And after gonadectomy, long term estrogen therapy should be prescribed for its effect on vaginal epithelial, osteoporosis and cardiovascular system. Therefore, further studies should be performed to find the exact factors affecting the uterus size, amenorrhea and to improve the methods of inducing puberty in these patients. [1] References 1. 2. 3. 4. 5. Negar K, Saber G, Mahdi E. “Swyer syndrome in a woman with pure 46, XY gonadal dysgenesis and a hypoplastic uterus: a rare presentation.” Fertility and Sterility, 2010;93(1):267.e12-e14. Amie J.M. Hanlon, Rebecca M. Kimble. “Incidental Gonadal Tumors at the time of Gonadectomy in women with Swyer Syndrome: A Case Series.” Journal of Pediatric and Adolescent Gynecology, 2015;28 : 27-29. Patnayak R, Suresh V, Jena A et al. “Swyer Syndrome: A Case Report with Literature Review.” J Nepal Med Assoc; 2012:52(186):72-4. Da Silva Rios S., Mazzaro Monteiro I.C. et al. “A Case of Swyer Syndrome Associated with Advanced Gonadal Dysgerminoma Involving Long Survival.” Case Rep Oncol, 2015;8:179-184 . Azidah AK, Nik Hazlina NH, Aishah MN. “Swyer syndrome in a woman with pure 46, XY gonadal dysgenesis and a hypoplastic uterus.” Malaysian Family Physician, 2013;8(2): 58-61. 6. 7. 8. 9. 10. Carmen Capito, Marc-David Leclair, Alexis Arnaud et al. “46,XY pure gonadal dysgenesis: Clinical presentations and management of the tumor.” Journal of Pediatric Urology; 2011;7:72-75. Xue Du, XuHongZhang, YongMeiLi and YuKunHan. “46,XY female sex reversal syndrome with bilateral gonadoblastoma and dysgerminoma.” Experimental and Therapeutic Medicine, 2014:8:1102-1104. Maximilian Murtinger, Libor Hradecky, Dietmar Spitzer. Nicolas H. Zech. “Unexpected labor and successful twin birth to a pure dysgenetic women.” Arch Gynecol Obstet, 2013; 288:1425–1426. Ivan Tulic, Lidija Tulic, Jelena Micic. “Pregnancy in patient with Swyer syndrome.” Fertility and Sterility, 2011;95 (5):1789.e1–e2. Aziken M, Osaikhuwuomwan J, Osemwenkha A, Iribhogbe O, Orhue A. “Successful triplet pregnancy in an African with pure gonadal dysgenesis: A plus for assisted reproduction.” Asian Pacific Journal of Reproduction, 2015; 4(2): 166-168.