Precocious Puberty due to an hCG-secreting tumor in Klinefelter syndrome Sasigarn A. Bowden¹, Carlos R Suarez² and John A. Germak¹ ¹Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio ²Department of Pediatrics, School of Medicine, University of Louisville, Louisville, Kentucky Approximately 4% of boys with precocious puberty have hCG-producing tumors. The most common hCG-secreting tumor causing precocious puberty is hepatoblastoma, while the remainder are germ cell tumors in various locations. Germ cell tumors occur rarely in children and do not always present as precocious puberty. Germ cell tumors of the mediastinum comprise only 4% of all germ cell tumors in children and adolescents. It has been estimated that 8% or perhaps as high as 20% of male patients with a primary mediastinal germ cell tumor (PMGCT) have Klinefelter syndrome (KS), suggesting the need for chromosome analysis in all patients with PMGCT. Individuals with Klinefelter syndrome (KS) usually have delayed or absent secondary sexual development. We described a boy who developed precocious puberty due to a hCG-secreting primary mediastinal germ cell tumor. This finding led to the diagnosis of Klinefelter syndrome in this patient. In reported cases of PMGCT associated with KS, mean age at diagnosis was 17 years, compared to 29 years (range 2-67) in patients with PMGCT without KS. Most individuals with PMGCT are diagnosed by chest X-ray because of chest symptoms. The reported cases of precocious puberty as a presentation of PMGCT in the age group less than 10 are only a few. DISCUSSION A 7-1/2 year-old boy presented with precocious puberty that developed over 6 months including rapid growth spurt (height 25th%75th%), deepening voice, penile enlargement, facial hair and Tanner III pubic hair. Testes were firm and 4 cc in volume. Bone age was normal at 8 years. Hormone studies revealed suppressed LH (<0.05 mIU/ml at baseline without response to GnRH) and FSH (baseline <0.3 mIU/ml with peak response to 0.95 mIU/ml after GnRH). Serum testosterone was 509 ng/dL (normal <10). 17-OH progesterone (119 ng/dL), DHEA (34 ng/dL) and cortisol (5.3 ug/dL) were normal. Serum hCG (124 IU/L) and α-fetoprotein (30 ug/L) were elevated. CT scan of the brain and ultrasound of the liver, adrenal, and testes were normal. Chest X-ray revealed a mediastinal mass and chest CT showed a 6 x 6 cm anterior mediastinal mass with calcification. The mediastinal mass was surgically removed. Histological examination confirmed a germ cell tumor with more mature cells. Because the tumor was encapsulated and completely resected, he did not receive chemotherapy or radiotherapy. A karyotype revealed Klinefelter syndrome, 47,XXY. Cytogenetic study of the tumor showed 48,XXY,+21. Serum hCG and testosterone decreased to normal within 2 days after surgery. Close follow up over 3 years has shown no tumor recurrence. Serum hCG, AFP and chest CT have remained normal. hCG-producing tumors are found in approximately 4% of boys with precocious puberty that is due to stimulation of Leydig cell testosterone secretion by hCG. The presence of small testes despite advancing pubertal signs in this patient is concordant with this mechanism. This case confirms the association of primary mediastinal germ cell tumor (PMGCT) and Klinefelter syndrome (KS). It also illustrates the importance of obtaining a karyotype when PMGCT is diagnosed. This case also demonstrates that in KS the testes are capable of generating normal adult testosterone levels when driven by high concentrations of hCG. Most patients with PMGCT present with chest symptoms diagnosed after the second decade. Only a few reported cases of PMGCT and KS were diagnosed at a young age in association with precocious puberty. ABSTRACT A 7.5 year-old Caucasian boy was evaluated for precocious puberty of 6 months duration. He was noticed to have a rapid growth spurt and to have grown taller than his 8 year-old brother. His height shifted from 25th% to 75th% within 6 months. (see growth chart) There was history of deepening of voice. Parents also noted enlargement of his penis with frequent erections and development of pubic hair. Mother’s height was 157.5 cm and father’s 171.5 cm, giving him a mid-parental height of 171.5 cm (15th%). On physical exam, his height was 129.3 cm (75th%), and weight 26.1 kg (65th%). He had a small amount of hair over the upper lip, but no facial acne. There was no skin hyperpigmentation. Examination of the genitalia showed Tanner III pubic hair. The penis was 10 cm long. The testes were 4 ml in volume bilaterally. They were firm and smooth, and had a uniform consistency. The rest of the history and physical examination were noncontributory. CLINICAL REPORT Chest X ray (at Dx) CXR Post surgery Diagnosis: Precocious puberty due to hCG-producing germ cell tumor at anterior mediastinum. This finding led to diagnosis of Klinefelter syndrome. Patient subsequently had surgical removal of the mediastinal mass. Histologic examination confirms germ cell tumor, with more mature cells. Because the tumor was encapsulated and completely resected, he did not receive chemotherapy. Cytogenetic study of the tumor specimen: 48,XXY,+21. Serum hCG and testosterone levels decreased to normal levels within 2 days after surgery. Close follow up over 3 years has shown no evidence of recurrence. Repeat hCG and AFP levels as well as Chest CT during follow up are normal. CLINICAL COURSE: Bone age (Greulich and Pyle) was normal at 8 years. Thyroid function test was normal. Baseline FSH 0.24 mIU/mL, LH <0.5 mIU/mL (ICMA) Testosterone was elevated at 509 ng/dL. 17-OH Progesterone 119 ng/dL. (normal prepubertal range is 3-90 ng/dL) DHEA 34 ng/dL Cortisol 5.3 ug/dL Serum hCG was elevated at 124 IU/L (normal is undetectable) α fetoprotein was elevated at 30. Brain CT : normal Ultrasound of liver, adrenal, and testes were normal. Chest X-ray: mediastinal mass (see picture) Chest CT: 6 x 6 cm anterior mediastinal mass with calcification. Chromosome study: 47,XXY LAB INVESTIGATIONS: . The presence of small testes discordant with the degree of pubertal development suggest peripheral precocious puberty. hCG-producing tumors cause precocious puberty in boys by stimulation of Leydig cell testosterone secretion by hCG, without maturation of the hypothalamic-pituitary-testicular axis. This case confirms the association of primary mediastinal germ cell tumor and Klinefelter syndrome. It also illustrates the importance of obtaining a karyotype when PMGCT is diagnosed. This case also demonstrates that in KS the testes are capable of generating normal adult testosterone levels when driven by high concentrations of hCG. SUMMARY Growth Chart