FERm.rrY AND STERILITY Copyright" 1981 The American Fertility Society
Vol. 35, No.3, March 1981 Printed in U.SA.
FAMILIAL 46,XX GONADAL DYSGENESIS
FATMA A. ALEEM, M.D., PH.D., F.A.C.O.G.* Department of Gynecology and Obstetrics, Montefiore Hospital and Medical Center, Bronx, New York 10467
Two sisters, ages 16 and 17, presented with secondary amenorrhea. In addition, primary ovarian failure, gonadal dysgenesis, and normal karyotypes were demonstrated. The most significant finding was a history of mumps, which they caught at the same time, 10 years before the onset of the amenorrhea. This disorder suggests that etiologic and environmental factors could prevail either in utero or during childhood. These patients are presented to emphasize the importance of considering gonadal dysgenesis as a differential diagnosis in patients with secondary amenorrhea, especially when the menstrual life has been a short one. Fertil Stern 35:317, 1981
Streak gonads are usually seen in Turner's syndrome, a disorder that occurs sporadically, and is accompanied by a number of congenital and sex chromosome abnormalities. 1 - s Streak gonads, identical with those observed in Turner's syndrome, have also been reported in phenotypic females who lack both somatic anomalies and chromosomal abnormalities. 4 ,5 The recent availability of immunoreactive gonadotropins and the expanded use of the laparoscope have enabled the identification of increasing numbers of cytogenetically and phenotypically normal patients with hypergonadotropism and primary ovarian failure. The etiology is diverse, and familial instances do occur. 5 McDonough et al. 5 reported that, among 82 patients with hypergonadotropic amenorrhea, 30 had normal 46,XX or 46,XY karyotypes as well as normal stature. They assumed that many such patients are incorrectly reported, and it is therefore conceivable that this group may be larger than is apparent from the literature. 6 The presence of multiple affected siblings directs the study of the precise contribution of environmental factors (intrauterine and extra-
uterine) to ovarian failure in a patient with a normal karyotype. 6 CASE REPORTS
Two sisters, ages 16 and 17, with normal stature and well-developed secondary sexual characteristics, had developed abrupt secondary amenorrhea. The mother, a 34-year-old well-developed para 2-0-0-2 female, had a history of normal menarche at age 12. Her menstrual periods were always regular, she did not have a fertility problem, and there was no history of drug intake during the two pregnancies. There was no consanguineous relationship between the two parents.
Patient 1 History. L. Y. was a 17-year-old black female with abrupt secondary amenorrhea and hot flashes of 1 year's duration. According to the history provided by the mother the patient had contracted mumps at age 7, but we could not document this in medical records. Thelarche and pubarche had occurred at ages 11 and 12, respectively. Menarche had occurred at age 13. She had had regular periods with cramps, every 28 days, lasting 3 to 4 days. Four months before her menses abruptly ceased, she contracted chickenpox. Shortly after the amenorrhea started, she developed hypopigmented skin lesions on the face, back, chest, and
Received April 21, 1980; revised August 11, 1980; revised and accepted October 29, 1980. *Reprint requests: Fatma A. Aleem, M.D., Ph.D., Department of Gynecology and Obstetrics, Montefiore Hospital and Medical Center, 111 East 210th Street, Bronx, New York 10467.
limbs, which had been diagnosed by a dermatologist as postinflammatory hypopigmentation. The patient then noticed a milky discharge from her breasts which occurred when her nipples were pressed. She was 64 inches tall and weighed 106 pounds. Hypopigmented macules with dry scaly papules were observed over her face, arms, chest, and back. The patient's breast development was complete. With gentle pressure, galactorrhea was noticed in both breasts. The external genitalia were normal, the vaginal mucosa was smooth, and the cervix and uterus were slightly smaller than normal. The adnexa were not palpable. Laboratory Studies. Laboratory studies revealed the following data: The serum folliclestimulating hormone (FSH) level was 380 mIUlml (normal range for the follicular phase is 5 to 20 mIU/mI). The serum luteinizing hormone (LH) level was 315 mIU/ml (normal range for the follicular phase is 2 to 30 mIUlmI). The serum estradiol concentration was 1.5 ng/100 ml (normal follicular phase level is 3 to 10 ng/100 mI). Serum prolactin concentrations were 11.3 ng/ml and 10 ng/ml on two different occasions. Thyroid and adrenal functions were normal. Skull x-rays showed evidence of asymmetry of the sella turcica with deepening of the floor on the right. Polytomography revealed asymmetric enlargement of the sella with deepening of the floor anterior andjust to the right of the midline with thinning of the cortex. Cytogenetic studies were X-chromatin-positive and revealed a karyotype in peripheral blood leukocytes of 46,XX (counting 56 cells). The patient did not respond to oral progesterone. At laparoscopy, the tubes were normal and the uterus was slightly smaller than normal. The right ovary was streak. The left ovary was normal in shape but was much smaller than normal and had a 3-mm cyst which was biopsied along with adjacent ovarian tissue and tissue from the streak ovary. Pathologic examination revealed a streak right ovary with dense fibrous connective tissue and foci of ovarian stroma. Pathologic examination of the left ovary revealed a corpus albicans and fibrous ovarian stroma (Fig. 1). Immunologic studies indicated the absence of serum antibodies. The indirect immunofluorescence technique was carried out on the ovarian tissue and on the serum of the patient against normal ovarian tissue and against serum from a control subject. Using goat antihuman immunoglobulin, the immunofluorescence study revealed the absence of ovarian antibodies. The patient was put on replacement therapy and responded with regular monthly bleeding. In addition, the serum
FSH level decreased to 105 mIU/ml and the serum LH level decreased to 119 mIU/mi.
History. The younger sister of patient 1 was a 16-year-old black female who presented with amenorrhea of 2 years' duration. Menarche had occurred at age 13 and she had had irregular, painless menstrual periods until age 14, when her menstrual periods abruptly ceased. The patient had had normal thelarche and pubarche with normal development except for mild obesity dating from childhood. According to the history obtained from the mother, the patient contracted mumps at 6 years of age, during the time of her sister's mumps infection. She was 62% inches tall and weighed 138 pounds, with normal development. The breast tissues were slightly atrophic, with no galactorrhea or masses. The pelvic exam. ination revealed normal external genitalia, smooth vaginal mucosa, and slightly smaller than normal cervix and uterus. The adnexa were not palpable. Laboratory Studies. Laboratory studies revealed the following data: The serum FSH level was 294 mIUlml and the serum LH level was 266 mIU/mi. The serum estradiol level was 2.2 ng/lOO ml and the serum prolactin concentration was 5 ng/ml. Thyroid and adrenal functions were normal. Cytogenetic studies were X-chromatinpositive and revealed a karyotype of 46,XX (counting of 56 cells). Immunologic studies were negative. The patient did not respond to oral progesterone. At laparoscopy, the tubes were normal. The uterus was slightly smaller than normal. The right ovary was streak, and the left was fibrous and much smaller than normal. Pathologic examination of a biopsy specimen of the right ovary
FIG. 1. A segment of the left ovary (patient 1) with a form of hyalinized tissue suggestive of a corpus albicans.
FAMILIAL 46,XX GONADAL DYSGENESIS
Vol. 35, No.3
FIG. 2. A segment of the right ovary (patient 2) consisting of dense, fibrous, connective tissue and thick-walled blood vessels.
(Fig. 2) revealed dense, fibrous, connective tissue and thick-walled blood vessels. No ovarian tissue was seen. The left ovarian biopsy revealed fibrous ovarian stroma, but no ova were seen. The patient responded to replacement therapy by having monthly bleeding. The serum FSH level decreased to 128 mIU/ml and the serum LH level decreased to 62 mIUlml. DISCUSSION
It is apparent from this presentation that these two sisters had secondary amenorrhea with ovarian failure and streak gonads or pure gonadal dysgenesis, despite normal 46,XX karyotypes. The only possible explanation for the galactorrhea and the abnormal radiologic findings in the sella turcica of the older sister is pituitary enlargement resulting from end-organ failure, as reported by Danziger et al. 7 The familial nature of this disorder is in keeping with the sporadic reports in the literature of chromosomally normal dysgenesis. 8 More than 130 such individuals have been described in the literature since XX gonadal dysgenesis was first-recognized in 1960. According to Simpson et al.,8 there are at least 13 known familial aggregates of the disorder. In the reported cases of XX gonadal dysgenesis with familial aggregation, affected family members have been siblings. 9 In several instances, parents of the affected siblings have been consanguineous, which suggests an autosomal recessive mode of inheritance. 10 , 11 Since the parents of our presented patients were not consanguineous, the defect is most likely due to heterogeneous factors, which may include an environmental factor. In these
cases, both sisters had contracted mumps in childhood. In the literature, three patients with oligomenorrhea and infertility associated with mumps have been reported, which also implicates in. fectious-infiltrating diseases as etiologic factors in ovarian failure: 12 In addition, the histologic findings in the ovaries of those three patients resembled the fibrosed ovaries of our two patients. Although the exact etiology of ovarian failure after mumps infection is still not clear, several studies have indicated that it may be related to a disturbance of follicular function. 13 An increased incidence of infertility has also been reported in patients with a history of mumps. Most of these patients were infected between 7 and 12 years of age, when the ovary is initiating its function. However, ovarian failure is not necessarily related to the severity of the infection. 13 Over environmental factors, which are rarely involved, include systemic conditions such as ~-thalassemia and mucocopolysaccharidosis. These may account for sufficient infiltration to the ovary to produce ovarian failure. 6 It is also highly suggestive that ovarian failure frequently occurs with adrenal and thyroid hypofunction 14 , 15 as well as with autoimmune disease. This could not be documented in our patients because all immunologic tests were negative and their thyroid and adrenal functions were normal. An additional etiologic factor could be the ovarian insensitivity syndrome or "Savage syndrome," 16 which is due to a receptor defect. The ovarian morphology of this syndrome is characteristic of the existence of an intact follicular apparatus, missing from the ovaries of our patients. The familial nature of this disorder suggests an autosomal recessive inheritance, which is consistent with the analysis by Simpson 17 of families with more than one member who had XX gonadal dysgenesis. In conclusion, familial gonadal dysgenesis with a normal karyotype is a multifaceted defect in which immune, congenital, and environmental factors may playa role. Our two patients probably were exposed to the same etiologic factor. We speculate that the mumps they contracted during childhood was probably the main etiologic factor.
Acknowledgments. The author acknowledges the cooperation of the Cytogenetic Laboratory, Kennedy Center, Albert Einstein College of Medicine, and the Department of Pathology, Montefiore Hospital and Medical Center, for carrying out the karyotyping and the immunologic study of these patients.
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Gynecol 54:544,1979 Goldberg M, Scully A, Solomon I, Steinbach H: Gonadal dysgenesis in phenotypic female subjects with cytogenetic studies in fifty-three. Am J Med 45:529, 1968 Jones H, Turner H, Ferguson-Smith M: Turner syndrome and phenotype. Lancet 1:1155, 1966 Espiner E, Veale A, Sands V, Fitzgerald P: Familial syndrome of streak gonads and normal male karyotype in five phenotypic females. N Engl J Med 283:6, 1970 McDonough PG, ByrdJR, Tho PT, Mahesh VB: Phenotypic and cytogenetic findings in eighty-two patients with ovarian failure-changing trends. Fertil Steril 28:638, 1977 McDonough P: Amenorrhea-etiologic approach to diagnosis. In Modern Trends in Infertility and Conception Control, Vol 1, Edited by EE Wallach, RD Kempers. Baltimore, Williams & Wilkins Co, 1979, p 119 Danziger J, Wallace S, Handel S, Samaan N: The sella turcica in primary end organ failure. Radiology 131:111, 1979 SimpsonJ, Christakos A, Horwith M, Silverman F: Gonadal dysgenesis in individuals with apparently normal chromosomal complements: tabulation of cases and compilation of genetic data. Birth Defects 7:215, 1971 Simpson J: Gonadal dysgenesis and sex chromosomal abnormalities-phenotypic and karyotypic correlations.
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In Genetic Mechanism of Sexual Development, Edited by I Porter. New York, Academic Press, 1978, p 365 Simpson J: Gonadal dysgenesis. In Disorders of Sexual Differentiation, Edited by J Simpson. New York, Academic Press, 1976, p 243 Smith A, Frazer I, Noel M: Three siblings with premature gonadal failure. Fertil Steril 32:528, 1979 MorrisenJ, GivensJ, WiserW, Fish S: Mumps oophoritis: a case of premature menopause. Fertil Steril26:655, 1975 Prinz W, Taubert H: Mumps in pubescent females and its effect on later reproductive function. Gynecology 167:23, 1969 Moraes-Ruehsen M, Blizzard R, Garcia-Bunuel R, Jones G: Autoimmunity and ovarian failure. Am J Obstet Gynecol 112:693, 1972 Vazquez A, Kenny F: Ovarian failure and antiovarian antibodies in association with hypoparathyroidism, moniliasis, and Addison's and Hashimoto's diseases. Obstet Gynecol 41:414, 1973 Jones G, Moraes-Ruehsen M: A new syndrome of amenorrhea in association with hypergonadotropism and apparently normal ovarian follicular apparatus. Am J Obstet Gynecol 104:5!n, 1969 Simpson J: Genetic aspects of reproductive failure: deficiencies of oocyte number (gonadal dysgenesis) and abnormalities of oogenesis (spontaneous abortion). In The Infertile Woman. Chicago, Year Book Medical Publishers, 1979, p 293