Precocious puberty due to human chorionic gonadotropin secreting germinoma.

This study aims to report a rare case of precocious puberty (PP) due to a human chorionic gonadotropin (hCG)-producing germinoma located in the suprasellar region. A 10-year-old male patient presented with sexual precocity, headache, drowsiness, loss of appetite, and papilledema. Significant acceleration of bone age in relation to chronological age, high serum total testosterone levels, and hypopituitarism (unresponsiveness to stimulation test) were observed. Magnetic resonance imaging (MRI) of the brain showed a large suprasellar tumor and triventricular dilatation. High hCG levels were found in both blood and cerebrospinal fluid. Hormone replacement therapy and transcranial surgery associated with radiotherapy were performed, with complete regression of sexual characteristics and normal laboratory tests post-operatively. Clinical and laboratory findings, in addition to MRI scans, led to the diagnosis of an hCG-producing tumor and PP, which represents a rare report in the literature.

Introduction

Intracranial germ cell tumors (GCTs) are rare neoplasms that typically arise in the pineal and suprasellar regions. They account for 0.5-3% of all pediatric tumors of the central nervous system (CNS),[1] germinomas being the most common histological type. Although the production of tumor-associated human chorionic gonadotropin (hCG) by a germinoma is a rare occurrence, it may lead to precocious puberty (PP) due to it's structural and functional similarity to luteinizing hormone (LH).

We report a case of hCG-producing tumor located in the suprasellar region and associated with sexual precocity.

Case Report

A 10-year-old male patient was brought to our department with premature pubarche and onset of facial acne at the age of 8 years and increase in penis size at the age of 9 years. Concomitantly, he had a progressive, gradually worsening holocranial headache associated with drowsiness and loss of appetite. The patient denied deterioration of vision. Previously, he was a healthy patient, born by spontaneous vaginal delivery at term weighing 3510 g and measuring 50 cm. He was breastfed for 3 months and had normal neuropsychomotor development. The patient had no family history of endocrine disorders, sexual precocity, or consanguinity. The mother's and father's self-reported height was 155 cm and 175 cm respectively. Physical examination revealed height of 148 cm (90-95th percentile), weight of 39 kg (75-90th percentile), blood pressure of 90/60 mmHg, heart rate of 60 beats per minute, facial acne, abdominal fat deposition in the periumbilical region, bilateral, symmetrical and prepubertal sized (3 mL) testes within the scrotum, 8-cm long penis, and Tanner stage P3-G2. Papilledema was detected on fundoscopy.

Magnetic resonance imaging (MRI) of the brain showed a large, hyperintense tumor in the suprasellar region, with hypodense areas inside the tumor, which was located in the anterior third ventricle, measuring 3 cm in the largest diameter and causing triventricular dilatation [Figure 1]. Radiographs of the hands and wrists revealed significant acceleration of bone age (BA) in relation to chronological age (CA) (BA: 13 years; CA: 10 years and 8 months; standard deviation: 10 months). MRI of the abdomen yielded normal results. Laboratory tests revealed that the values for serum glucose, albumin, calcium, sodium, potassium, renal function, and liver function were within the normal limits. Hormonal tests showed increased hCG levels in both blood and cerebrospinal fluid (CSF), increased total testosterone levels, and hypopituitarism (unresponsiveness to gonadorelin stimulation test) [Table 1]. The results of tumor marker tests are also described in Table 1.

Figure 1

Large, hyperintense suprasellar tumor, with hypodense areas inside, located in the anterior third ventricle, measuring 3 cm in the largest diameter (arrows) and causing triventricular dilatation

Table 1

Results from hormonal tests and tumor marker tests

The patient was diagnosed with an hCG- and testosterone-producing tumor associated with hypopituitarism and intracranial hypertension. Hormone replacement therapy was initiated with levothyroxine and hydrocortisone, and transcranial surgery was performed. Anatomopathologic examination confirmed the diagnosis of germinoma []Figure 2]. Radiotherapy was performed after surgical resection of the tumor. The patient showed complete regression of sexual characteristics and acne, with normal laboratory tests post-operatively.

Figure 2

Uniform large tumor cells with large nuclei, prominent nucleoli, and abundant glycogen-rich cytoplasm are noted among reactive inflammatory cells and bands of connective tissue, supporting the diagnosis of germinoma

Discussion

PP is defined as the presence of signs of puberty before the age of 8 years in girls and 9 years in boys.[2] PP is more frequently found in girls, with a female-to-male ratio of 12.3:1.[3] It is important that PP be properly investigated in boys because, unlike girls, the onset of idiopathic PP is uncommon among boys, having an organic cause in most cases. Gonadotropin-independent PP (GIPP) results from an increased secretion of sex hormones, regardless of the maturation of the hypothalamic–pituitary–gonadal axis. hCG-producing tumors,[4] including gonadal and extragonadal GCTs may lead to GIPP.[5] In the present case, which reported premature pubarche, increased penis size and small testicular size compared to the overall pubertal development, high testosterone levels associated with suppressed LH and follicle-stimulating hormone (FSH) levels and an unresponsiveness to a GnRH analog-stimulation test confirmed the diagnosis of GIPP.

GCTs account for 3-11% of all childhood tumors in the United States and Western Europe, whereas in Japan they account for 12.5-16% of the cases.[6] Among the GCTs, germinomas are the most common of the histological type (41%).[7] Extragonadal GCTs often occur in the pineal and suprasellar regions, as in the case described here. The clinical presentation of suprasellar GCTs may include panhypopituitarism, diabetes insipidus, and visual disturbances, with a long pre-diagnosis period, generally longer than 1 year. In the present case, the effects of tumor compression led to hypopituitarism and manifestations of intracranial hypertension, such as headache and papilledema.

Data from the literature have demonstrated the presence of hCG and its subunits in tumor cells of different origins, including CNS neoplasms.[8] According to reports on hCG-producing germinomas, including a Japanese series of 111 cases of intracranial GCTs, these tumors account for 18% of all germinomas.[9] It is known that these lesions have a worse prognosis compared to non-secretory germinomas, with a higher recurrence rate[9] and shorter survival.[10] However, detection of hCG is not a marker of metastasis or tumor size, and its presence often indicates the activity of syncytiotrophoblastic elements within the tumor.[7] Both serum and CSF hCG measurements in our patient were well above the normal limits, a finding that, together with the MRI scans, is consistent with the diagnosis of an hCG-producing tumor, which after biopsy was classified as a germinoma. Increased stature, advanced BA, presence of pubic hair and acne, and early genital development were caused by the increase in serum testosterone levels. hCG is structurally similar to LH, and excessive increases may stimulate the leydig cells of the testes to produce testosterone. As a result, the patient also showed pituitary-axis suppression, with reduced levels of gonadotropic hormones. Reduced FSH levels may explain the lack of correlation between testicular growth and other sexual characteristics presented by the patient, since testicular maturation depends upon this hormone.

Characteristics on computed tomography or MRI images often do not provide sufficient information for a histological diagnosis. Therefore, given the diversity of the tumor subtypes found in the suprasellar region, obtaining adequate biopsy specimens is of paramount importance. For this purpose, open surgery is preferable, as performed in this case, and the histological examination should define the approach that will be used.[910]