American Journal of Medical Genetics 55:38-42 (1995)

Mediastinal Teratorna and Precocious Puberty in a Boy With Mosaic Klinefelter Syndrome

Ajanta N. Derenoncourt, M. Castro-Magana, and Kenneth Lee Jones Department of Pediatrics, University of California in San Diego, La Jolla, California (K.L. J., A.N.D.), and Winthrop University Hospital, Mineola, New York fM.C.-M)

We describe a boy who developed pre- cocious puberty resulting from chorionic gonadotropin produced by a mediastinal germ cell tumor. Following tumor removal he began spontaneous precocious sexual de- velopment which was treated and then ar- rested spontaneously. Investigation of this arrested puberty established that he had Klinefelter syndrome (KS) mosaicism. He represents the first instance of KS mo- saicism reported with a mediastinal germ cell tumor, a neoplasm commonly reported in males with a 47,XXY karyotype. We rec- ommend that all males with KS and early sexual development or with “normal” tes- ticular growth be screened with measure- ment of germ cell tumor markers including p-subunit of human chorionic gonadotropin and a-fetoprotein.

KEY WORDS: puberty, GnRH, HCG, hypo- gonadism, primary medias- tinal germ cell tumor

@ 1995 Wiley-Liss, Inc.

INTRODUCTION Individuals with the Klinefelter syndrome (KS) usu-

ally have delayed or absent secondary sexual develop- ment [Leonard et al., 19791. We describe a boy who developed precocious puberty, initially resulting from chorionic gonadotropin (HCG) secretion by a germ cell neoplasm. After removal of the tumor this develop- ment progressed spontaneously as a consequence of androgen-induced maturation of his hypothalamus. Eventually his sexual development arrested leading to investigation and the diagnosis of hypogonadal hypo- gonadism and karyotypic identification of mosaic KS.

This report is the first description in a male with KS mosaicism of a mediastinal teratoma, a tumor rela-

Received for publication March 9, 1994; revision received August 1, 1994.

Address reprint requests t o Kenneth Lee Jones, M.D., Division of Endocrinology, Department of Pediatrics, UCSD School of Medi- cine, 0609-c, La Jolla, CA 92093-0609.

0 1995 Wiley-Liss, Inc.

tively frequently associated with a 47,XXY karyotype. In addition to this boy’s unusual and instructive clini- cal course, the report illustrates the importance of assessing P-HCG, the specific HCG subunit, in KS individuals with precocious sexual development.

CLINICAL REPORT The patient was initially seen at age 9Y1z years

for a swelling over his left lower chest. At that time he had had signs of secondary sexual development for 6 months, including accelerated growth in height and weight gain and the appearance of sexual hair, acne, and genital growth. His general health had been good, and he had no central nervous system or visual symptoms.

On physical examination he was a normal appearing boy who was physically mature for his stated age. He was tall at 142 cm (50th centile for 11 years) and his weight of 32 kg was at the 50th centile for chrono- logical age. His physical findings were unremarkable except for the swelling over his left chest. His genitalia were at Tanner Stage I1 and his pubic hair was at Tanner Stage 111. The left testis had a maximum dia- meter of 3.0 cm and the right measured 3.5 cm.

A chest radiograph, done to evaluate the chest wall lesion, showed a large, lobular mediastinal mass which contained calcification and extended into the right lung field. A CT scan of the chest further defined the mass in the right anterior mediastinum (Fig. 1). In view of the location of the mass and the sexual precocity, a func- tioning teratoma was suspected. Serum markers for germ cell neoplasms [Vogelzang, 19821 were elevated with p-HCG measuring 59 mIU/ml (normal <6.7 mIU/ml) and a-fetoprotein 416 ng/ml (normal 0-15 ng/ml). His serum testosterone was in pubertal ranges at 997 ng/dl (normal for a late pubertal or adult male) and his skeletal age was more than 3 years advanced at 13 years (Table I).

A gonadotropin releasing hormone (GnRH) stimula- tion study evoked no appreciable rise in follicle stimu- lating hormone (FSH) or luteinizing hormone (LH) con- firming that the pubertal changes were not the result of hypothalamic/pituitary activation [Castro-Magana et al., 19851. The combination of sexual development, elevated serum tumor markers, and a suppressed gonadotropin response t o GnRH strongly suggested

Mosaic Klinefelter Syndrome 39

Fig. 1. operatively.

This CT scan of the chest shows the right anterior mediastinal mass as it appeared pre-

that the mediastinal mass was a functioning germ cell tumor.

The mass was removed, but a small amount of tissue invading the mediastinum in the subcarinal region was not resectable. Histologically the tumor was classified as a benign, mature teratoma with multiple well differ- entiated tissue present (Fig. 2). Postoperative imaging studies of the mediastinum identified no residual tumor, evaluation for metastases revealed none, and the tumor markers fell to normal ranges within weeks of surgery. At the recommendation of the Institutional Tumor Board a three course chemotherapy regimen was carried out without complication.

The patient's serum testosterone fell from the preop- erative level of nearly 1000 to 190 ngldl 2 weeks after surgery (Table I). He was then retested with GnRH and showed a pubertal response [Roth et al., 19721. With his advanced bone age, pubertal testosterone concentra- tions, and pubertal gonadotropin response, he was started on daily GnRH agonist subcutaneously and then changed to intramuscular depot GnRH agonist [Kappy et al., 19893 at a dose of 7.5 mg every month to suppress his puberty. This therapy produced a decrease in testicular size from a maximum diameter of 3.5 to 2.5 cm. over a 4-month period. The GnRH agonist ther- apy was continued for 14 months with no further

TABLE I. Clinical and Laboratory Information* ~ ~ - ~~ ~

11/88 (preop) 11/88 (postop) 5/89 6/90 10/90 4/92 8/92 ~ -

Age in years 9Y12 - 1OYiz 117'12 11Yn 13Yu 13/12 Bone age in years 13 - - 13 - 14 - P-HCG (mIU/ml) 59 < 10 - 1.8 - 3.2 - a-Fetoprotein (ng/ml) 417 18 <5 - - <4.8 - Testosterone (ng/dl) 997 190 150 420 200 145 190 FSH (mIU/ml) 4 . 3 <1.3 2.2 18.0 24.2 18.8 19.3 LH (mIU/ml) 40 <2.2 c2.0 10.1 <2.0 4.1 4.2

* Normal testosterone values in males are as follows: prepubertal <3-10, early adolescence 18-150, in late adolescence 350-970. Normal FSH and LH values in males are, repectively, prepubertal 11-3.2, early adolescence 2-7, late adolescence 1-8, and prepubertal < 1 4 , early adolescence <1-5, late adoles- cence 4.5-11.

40 Derenoncourt et al.

Fig. 2. Photomicrograph of the histology of the teratoma. An epidermal cyst with mature squamous cell differentiation and sloughing within the cyst can be seen. There is also loose mesenchyme and com- pact mesenchyme surrounding respiratory mucosa.

advancement in skeletal maturation. His growth did slow significantly, and at age 1171~ years the agonist was discontinued. Three months later his testes had again increased to a maximum diameter of 3.5 cm and his serum testosterone had increased from a nadir of 150 to 420 ngldl. Gonadotropins were also in puber- tal ranges with an FSH of 18 mIUlml and an LH of 10.1 mIU/ml.

TABLE 11. GnRH Stimulation Test Results

0 min 20 min 40 min 60 min

Preop

FSH LH (mIU/ml) (mIU/ml)

<1.3 15.2 <1.3 15.3 <1.3 15.1 <1.3 14.4

-

Postop (16 days)

FSH LH (mIU/ml) (mIU/ml)

<1.3 <2.2 5.3 38 9.2 49.2 9.8 47.1

~-

This progression had ceased by his next visit 3 months later. Examination showed no further increase in testicular size, his serum testosterone had fallen to 200 ngldl, and his FSH was increasing. At age 133/12 years, 25 months after discontinuation of GnRH ago- nist, his serum testosterone was low at 145 ngldl, there was no additional testicular growth, and he had begun to develop gynecomastia. Chromosomal analysis was performed and showed a 46,XY147,XXY pattern, diag- nostic of Klinefelter mosaicism.

DISCUSSION This boy’s clinical presentation makes several impor-

tant points. He represents the first individual described with Klinefelter mosaicism with a primary mediastinal terotomdgerm cell tumor (PMGCT), a condition re- ported most frequently in males with a 47,XXY karyo- type. It also demonstrates that in KS the testes are capable of generating normal adult serum testosterone

Mosaic Klinefelter Syndrome 41

Finally the question is raised as to whether pubertal development in individuals with KS should always be monitored with measurements of P-HCG. It is difficult to answer this question as there is no direct study of the incidence of germ cell tumors in individuals with KS. One could argue that the increased incidence, cal- culated in one case to be 50-fold, is evidence enough. However, KS is the most common sex chromosome abnormality occurring in humans, reported at 1 per 576 male births [Nielsen and Wholert, 19901, or more than 3Y2 times more frequent than chromosome anomalies of the Ullrich-Turner syndrome. If one uses the likely in- flated estimate of the incidence of germ cell tumors at 2-3/100,000 males (Waterhouse, 1981) and the increase in KS as 50-fold, also possibly increased by ascertain- ment bias, the incidence in KS would be 1.5/1,000. Given this low incidence and the variability of age of onset, screening with P-HCG would be problematic. In view of this, we would recommend P-HCG screening of all KS individuals with early puberty or in those with evidence of “normal” testicular size or testosterone gen- eration. All others should be monitored carefully on a clinical basis for any symptoms or signs which may indicate the presence of germ cell tumors.

ACKNOWLEDGMENTS The views expressed in this case report are those of

the authors and do not reflect the official policy or posi- tion of the Department of the Navy, Department of Defense, nor the U.S. Government. The data were presented in part at the annual meeting of the Western Society for Pediatric Research in February 1993.

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concentrations when driven by high concentrations of HCG. Finally it raises the question of whether all indi- viduals with KS should be screened for HCG secretion when they begin pubertal development.

It is well documented that KS is represented by a wide range of phenotypes, which may in part be due to different karyotypic forms, with poly X and poly X / poly Y forms [Leonard et al., 19791. Most KS individu- als have a 47,XXY chromosome pattern. The most com- mon variant, 46,XY/47,XXY mosaicism, found in this boy, occurs in 10% of reported cases [Gordon et al., 19721. Men with this karyotype occasionally have seemingly normal sexual development, exhibit no signs of gonadal failure until the fourth or fifth decades of life, and, rarely, are fertile [Gordon et al., 1972; Leonard et al., 1979; Gabrilove et al., 19791.

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Testicular size in KS is usually small [Ahmad et al., 19711, but the testes of this boy responded to elevated HCG concentrations with increased size and testos- terone secretion sufficient to produce pubertal develop- ment, as might have been predicted since many of the prepubertal KS patients previously described with germ cell tumors had precocious sexual development [Pierson et al., 1975; Dannon et al., 1979; Floret et al., 1979; Chaussain et al., 1980; Beasley et al., 1987; Hasle et al., 19921. It has been established that basal plasma testosterone levels and those generated in response to short HCG stimulation overlap in men with 47,XXY KS and in normal men [Leonard et al., 19791. This rela- tively normal pattern of testosterone secretion may be even more likely in males with mosaicism [Gordon et al., 19721 and in younger individuals [Gabrilove et al., 19791.

42 Derenoncourt et al.

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