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00019616-200409000-00006ReportThe EndocrinologistThe Endocrinologist© 2004 Lippincott Williams & Wilkins, Inc.14September 2004 p 261-264Nongerminomatous Germ Cell Tumor of the Pineal Gland Causing Gonadotropin-Independent Precocious Puberty in a Child With 47, XYY KaryotypeA Clinical and Radiographic Case ReviewCase ReportKhan, Asjad MD*; Price, Donald MD†; Castro-Magaña, Mariano MD, FACE*; Angulo, Moris MD*; Cañas, J Atilio MD, FACE*From the *Department of Pediatrics, Division of Pediatric Endocrinology and the †Department of Radiology, Winthrop University Hospital, State University of New York at Stony Brook School of Medicine, Mineola, New York.Reprints: J. Atilio Canas, MD, FACE., Pediatric Endocrinology, Nemours Children’s Clinic, 807 Children’s Way, Jacksonville, FL 32207. E-mail: [email protected] 3-year and 11-months-old boy presented with a 9-month history of increasing penile enlargement, pubic hair, deepening of the voice, and rapid growth. The erect penile length was 14 cm with bilateral testicular volume of 3 mL. Laboratory evaluation revealed suppressed follicle-stimulating hormone and luteinizing hormone, elevated total testosterone (259 ng/dL), elevated alpha feto-protein (AFP 79 ng/mL), rapidly increasing β-human chorionic gonadotropin (β-hCG 14–399 mIU/mL) over 2 weeks, and a karyotype revealed 47, XYY. Radiographic evaluation revealed a 1.5-cm mixed solid/cystic mass in the pineal gland. Chemotherapy was initiated to attempt to normalize the tumor markers (AFP and β-hCG). This is the first report of a nongerminomatous germ cell tumor (NGGCT) in a 47, XYY karyotype male. Tumor markers (hCG and AFP) should be included in the workup of adult males with 47, XYY as they are in children with precocious puberty.Sandberg et al described the 47, XYY karyotype in 1961.1 Robinson et al2 reported that the presence of an extra Y chromosome is found in approximately 1 in 1000 male births. Fryns et al3 found 50 male patients with an XYY karyotype out of 98,725 males and females that had chromosomal testing. Males with 47, XYY chromosomal constitution are common and probably blend into the general population as normal individuals, but the true incidence of this karyotype is not known. The most frequently described clinical features during childhood are tall stature, impulsive behavior, and learning disabilities. Overvirilization and aggressive behavior are frequently observed in adults; however, precocious puberty has not been reported during childhood. Unlike individuals with 47, XXY, precocious puberty caused by germ cell tumors (GCTs) has not previously been described in 47, XYY.4–6 We describe the first reported case of nongerminomatous germ cell tumor (NGGCT) of the pineal gland in a patient with 47, XYY karyotype causing precocious puberty.CASE REPORTA 3-year and 11-months-old boy presented to our office for the evaluation of rapid development of pubic hair and deepening voice. The parents also reported that he was “taller than his 8-year-old brother.” On physical examination, the patient’s height was 117.8 cm (±3.22 standard deviation [SD]) and his weight was 24.1 kg (±2.51 SD). The patient had a deep and hoarse voice. He was noted to have acne, epicanthal folds, a high arched palate, and a long flat philtrum. He had fine hairs above his upper lip. The genital examination revealed an erect penile length of 14 cm with 3- to 4-mL testicular volume bilaterally. Pubic hair was found to be Tanner stage III, whereas axillary hair was Tanner stage II. The rest of the examination, including neurologic evaluation, was appropriate for age.Initial blood work revealed normal thyroid hormones, 17 OH progesterone (111 ng/dL), 11-deoxycortisol (90 ng/dL), DHEA (34 ng/dL), and androstenedione (28 ng/dL). His luteinizing hormone (LH; <0.02 IU/L) and follicle-stimulating hormone (FSH; 0.64 IU/L) levels were suppressed. However, serum testosterone (259 ng/dL) and free testosterone (72.9 pg/mL) were elevated. Serum level of β-hCG was initially found to be 14 mIU/mL. β-hCG measured weekly increased rapidly to 81 mIU/mL after 1 week and to 399 mIU/mL after 2 weeks. A serum AFP was 79 ng/mL 1 week after presentation. Karyotype revealed 47, XYY in all 20 HPA-simulated metaphases counted. A lumbar puncture done 2 weeks after presentation showed elevated spinal fluid levels of β-hCG (554 mIU/mL) and AFP (44 ng/mL); no malignant cells were found however. His bone age was 7 years, whereas the chronologic age was 3 years 11 months.An ultrasound of the testes, abdomen, and pelvis did not reveal any abnormalities. A computed tomography (CT) scan of the chest, abdomen, and pelvis, with and without contrast, was normal. A magnetic resonance image (MRI) of the abdomen and pelvis was negative for any metastatic lesions. A positron emission tomography scan did not show any hypermetabolic areas. A pre- and postcontrast MRI of the head revealed a 1.5-cm mixed solid/cystic lesion in the area of the pineal gland (Fig. 1A, B). Metastases were not found on radiographic studies.JOURNAL/endst/04.03/00019616-200409000-00006/figure1-6/v/2021-02-17T201744Z/r/image-png (A) Sagittal T1-weighted image of pineal region. Pineal mass between open black and open white arrows. The high signal at the anterosuperior part of the mass may be fat or blood. Q, quadrigeminal plate; T, thalamus; white arrowhead, aqueduct of Sylvius. (B) Sagittal T1-weighted image with intravenous gadolinium–DTPA enhancement. The pineal mass is irregularly shaped and enhances with contrast. One of several areas of cyst formation in the lesion is visible as a nonenhancing are (black arrowhead). Q, quadrigeminal plate; T, thalamus; V, internal cerebral vein.The patient was scheduled to receive 4 cycles of high-dose chemotherapy with carboplatin, Cytoxan, and etoposide based on the Second International CNS GCT study group protocol.7 The need for radiotherapy and/or surgical resection was to be evaluated depending on the degree of radiographic residual and the response of the central nervous system tumor markers. The use of high-dose chemotherapy with stem cell rescue was to be used in the event of an incomplete normalization of tumor markers. Delayed surgical resection was considered to be the best chance for a cure.DISCUSSIONGerm cell tumors account for approximately 3% of malignancies during childhood and adolescence.8 They are presumably derived form primordial germ cells that can occur within the gonad or in extragonadal sites. Extragonadal germ cell tumors (EGGCTs) represent approximately 5% to 10% of adult GCTs but account for almost two thirds of germ cell tumors in the pediatric age group. EGGCTs are primarily divided in germinomas and nongerminomas. Germinomas originate from the primordial germ cells, demonstrate no histologic differentiation, and are malignant but have a relatively benign prognosis as a result of their unique radiosensitivity. Nongerminomatous germ cell tumors (NGGCTs), on the other hand, originate from differentiated embryonic (embryonal carcinoma, mature or immature teratomas) or extraembryonic tissue (choriocarcinoma, yolk sac or endodermal sinus tumor), or a mixture of these, and have a varying degree of malignancy with relatively poor prognosis (Fig. 2). The most common sites for EGGCTs in children are along the midline, anterior mediastinum (50–70%), retroperitoneum (30–50%), pineal gland (5%), and sacrococcygeal region (<5%). These tumors can also be found in the neck, stomach, liver, prostate, and vagina.9JOURNAL/endst/04.03/00019616-200409000-00006/figure2-6/v/2021-02-17T201744Z/r/image-tiff Classification of germ cell tumors.Controversy remains regarding the origin of EGGCTs with the classic theory suggesting that germ cells migrate from the extraembryonic yolk sac into the embryo through the midline dorsal mesentery between the fourth and sixth week of gestation.10 Failure of some of these cells to reach their gonadal destination may allow them to become involved in the stream of lateral mesoderm and eventually multiply in sites foreign to their proper environment.11 Others argue that germ cells transformed in the testicle can undergo reverse migration to ectopic regions capable of supporting their growth in organs such as the thymus and the pineal gland.12Malignant transformation of germ cells is the result of a multistep process of genetic changes and has recently been reviewed by Houldsworth.13 Molecular genetic studies performed on tumor specimens are providing insight into the mechanisms implicated in anaplasia of the germ cells. Gain of genetic material derived from chromosomes 1–8, 12–14q, 17–18q, 20, 21, and X have all been documented in microdissected intratubular germ cell neoplastic lesions.13 A high frequency of genetic alterations in a single locus INK4a/ARF has been demonstrated in many types of tumors.14 This locus has 2 promoters and encodes 2 completely different proteins, p16INK4a and p14ARF. By acting as an inhibitor of cyclin-dependent kinases, the p16INK4a protein decreases the phosphorylation of retinoblastoma protein and results in cell cycle arrest at G1.15 The other encoded protein, p14ARF, interacts with mdm2 and stimulates the degradation of mdm2 protein.16 The mdm2 sequesters p53 and inhibits its function as G1-S checkpoint controller and apoptosis inducer. Recently, the balance between these 2 important tumor-suppressor factors, p53-mdm2, was shown to be disrupted in intracranial GCTs.17 Mutations in the INK4a/ARF gene have been reported in 71% of intracranial GCTs, resulting in accumulation and functional impairment of p53. This abnormality was reported in 90% of germinomatous and 55% of NGGCTs examined.18Intracranial NGGCTs arise primarily in the pineal region (68%), anterior third ventricle (suprasellar and intrasellar), posterior third ventricle, and rarely in the fourth ventricle.19 They account for 0.1% to 6.4% of all central nervous system malignancies in Western countries and become symptomatic primarily in male children and young adults.20 Patients presenting with pineal lesions often show symptoms of hydrocephalus (47%) or Parinaud’s syndrome (34%), which is caused by compression of the quadrigeminal plate and gives failure of upward gaze, papillary dilatation, and nystagmus retractorius.19 Less common symptoms include obtundation (26%), pyramidal signs (21%), ataxia (19%), diabetes insipidus (18%), and hypopituitarism (19%), and sexual precocity most commonly associated with choriocarcinomas (55%).19 Elevated levels of tumor markers in the cerebrospinal fluid are most specific in making the diagnosis of NGGCTs. However, up to 10% of germinomas can secrete hCG at low levels because of the presence of syncytiotrophoblasts.21,22 hCG is predominant in choriocarcinomas and embryonal cell carcinomas. Alpha-fetoprotein (AFP) is associated with endodermal sinus tumors (yolk sac), embryonal carcinomas, and immature teratomas. MRI with and without gadolinium is the neuroimaging test of choice. Intratumoral calcifications, however, especially in small lesions, may be better seen with CT.23,24 Imaging should include screening the craniospinal axis for cerebrospinal fluid dissemination and metastasis.There is considerable disagreement with the treatment of germ cell tumors, especially intracranial GCTs.8,9,25–30 Some authorities prefer to have neurosurgical biopsy/resection and results of histology before starting chemotherapy and/or radiotherapy (RT),29,31 whereas others recommend delayed surgical resection after initial chemotherapy and/or RT.25,32 Because of the deleterious effects of RT on the immature nervous system and the possibility of central nervous system spread from surgical intervention, investigators have used chemotherapeutic strategies that either reduce or eliminate RT.7,27,32 There have been reports of good response of germ cell tumors to treatment with platinum-based chemotherapeutic agents in combination with etoposide.33It is well known that patients with gonadal dysgenesis have a 30% chance of developing gonadoblastomas,34 an in situ form of germ cell tumor with the ability to transform most commonly into dysgerminoma (50% of cases) but also yolk sac tumors, immature teratomas, or choriocarcinomas.35 The risk of tumor development in gonadal dysgenesis and intersex patients with a Y chromosome is 10% at age 20 and 19% at age 30 years.35 Disorders of sexual differentiation include 45, X/46, XY mosaicism, androgen insensitivity syndrome, and 46, XY/iso(p) Y mosaicism. Most authors recommend gonadectomy in these children in the presence of any portion of a Y chromosome, the presumed risk factor. To our knowledge, however, the few malignancies reported in patients with 47, XYY karyotype have been of mesodermal origin (myeloid and lymphoid malignancies ALL and AML).36–38Others and our group have reported the occurrence of GCTs in patients with 47, XXY4,6,8,39,40 or mosaic Klinefelter’s syndrome.5 This case represents the first reported case in a 47, XYY individual. Chromosome analysis and tumor markers should always be included in the workup of gonadotropin-independent precocity and also in adult males with 47, XYY.CONCLUSIONWe describe the first reported case of NGGCT of the pineal gland in a patient with 47, XYY karyotype presenting with precocious puberty. Precocity was caused by production of β-hCG by the neoplastic germ cells. Elevated levels of AFP in the cerebrospinal fluid indicate the presence of yolk sac elements that characterize this tumor as embryonal carcinoma. Because markers were found preoperatively and surgery for these tumors is rarely curative, high-dose chemotherapy was instituted before pathologic examination. MRI features of the tumor pre- and postchemotherapy, close follow up of serum and cerebrospinal fluid markers, and an extensive search for distal metastases are key components in the management of these patients.REFERENCES1.Sandberg AA KG, Ishihara T. Hauschka TS. An XYY human male. Lancet. 1961;2:971–972.[Context Link]2.Robinson DO, Jacobs PA. The origin of the extra Y chromosome in males with a 47,XYY karyotype. Hum Mol Genet. 1999;8:2205–2209.[Context Link][CrossRef][Medline Link]3.Fryns JP, Kleczkowska A, Kubien E, et al. XYY syndrome and other Y chromosome polysomies. Mental status and psychosocial functioning. 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