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Male LH-Independent Sexual Precocity in a 3.5-Year-Old Boy Caused by a Somatic Activating Mutation of the LH Receptor in a Leydig Cell Tumor

Department of Hematology/Oncology and Endocrinology, University Children’s Hospital (A.R.-U., H.T.W., K.S.-O., S.T., B.P.H.), 45122 Essen, Germany; University Children’s Hospital (U.M.), 44791 Bochum, Germany; Department of Veterinary Anatomy, Justus Liebig University (M.B.), 35392 Giessen, Germany; and Department of Radiology, University Hospital (J.S.), 45122 Essen, Germany

Address all correspondence and requests for reprints to: Dr. Annette Richter-Unruh, Department of Hematology/Oncology and Endocrinology, University Children’s Hospital Hufelandstrasse 55, 45122 Essen, Germany. E-mail: . annette.richter-unruh{at}uni-essen.de

Abstract

We describe the clinical features of severe sexual precocity in a 3.5-yr-old boy. Hormonal evaluation showed LH-independent T hypersecretion. Initial examination of the adrenals and testes revealed no evidence of congenital adrenal hyperplasia, hCG- or androgen-secreting tumors, or McCune-Albright syndrome. In the coding sequence of the LH receptor gene no activating mutation was found. Spironolactone (5.7 mg/kg·d) and testolactone (40 mg/kg·d) were unsuccessful in suppressing the elevated concentration of T. To further determine the origin of the elevated serum T, a selective venous sampling procedure was planned. However before the sampling procedure, high resolution ultrasound examination showed a small tumor in the left testis, which was removed. Histology proved the tumor to be a Leydig cell adenoma. Sequencing of the tumor LH receptor gene revealed a heterozygous mutation in exon 11 encoding a replacement of aspartic acid at position 578 with histidine, which has been shown to be a constitutively activating mutation.

These findings indicate that in male patients with gonadotropin-independent sexual precocity, the presence of small testicular Leydig cell tumors harboring a somatic mutation of the LH receptor gene should be considered.

GONADOTROPIN-INDEPENDENT sexual precocity in the male is frequently associated with activating mutations of the human LH receptor gene (1, 2, 3, 4). These autosomal dominant gain of function mutations of the LH receptor lead to signs of sexual development usually before the age of 4 yr (4, 5). To date, only 15 LH receptor mutations, all located in exon 11, have been reported (6). None of the 10 European patients with familial male-limited sexual precocity caused by LH receptor gene mutations had the Asp⁵⁷⁸Gly mutation, which is responsible for the vast majority of cases reported from the U.S. (7). Recently, Leydig cell adenomas of 3 boys were shown to display a new activating mutation at the same position (Asp⁵⁷⁸His) (8). Leydig cell adenomas are the most prevalent hormone-producing tumors of the testis and account for 1–3% of all testicular tumors (9, 10). Although Leydig cell adenomas are benign in most cases, 10% become malignant in adults (11).

Sexual precocity in Leydig cell adenomas is due to gonadotropin-independent T secretion. The signs of sexual development tend to appear later in boys with Leydig cell tumors than in boys with familial male-limited sexual precocity; signs appear for the latter between the age of 5–9 yr (10). We now describe a boy with the clinical features of sexual precocity before the age of 4 yr in whom a somatic mutation of the LH receptor gene was detected.

Case Report

At the age of 3.5 yr our patient presented with pubarche and enlargement of the penis (penile length, 8 cm; >2.5 SD score), but a prepubertal testicular volume (2 ml right side, 3 ml left side). Skeletal maturation was typical for a 6-yr-old boy. There was no history of external androgen exposure. Family history of precocious puberty was negative. Endocrine evaluation revealed LH-independent (basal LH, <0.1 U/liter; basal FSH, 0.1 U/liter; after GnRH stimulation: maximum LH, 0.7 U/liter after 30 min; maximum FSH, 1.1 U/liter after 60 min) hypersecretion of T (299 ng/dl; normal, <20 ng/dl). Clinical examination, hormonal analysis in blood and in urine collected over 24 h, and ultrasound examinations of the adrenals showed no evidence of congenital adrenal hyperplasia or hCG- or androgen-secreting tumors. McCune-Albright syndrome was excluded by the absence of cafe-au-lait lesions and a negative bone scan. Repeated ultrasound examinations using the ATL Apogee 800 Plus system (Long Mont, CO) and the Siemens Sonoline SI-400 system (Erlangen, Germany) failed to demonstrate a testicular tumor; however, no color-coded sonography was performed at that time. Generally, the boy’s phenotype was compatible with the presence of an activating mutation in the LH receptor gene, but blood samples showed no DNA alteration in exon 11.

Therapy with spironolactone (5.7 mg/kg·d) and testolactone (40 mg/kg·d) was initiated, but did not result in a decrease in the elevated T levels or a remittance of symptoms. To further determine the origin of the elevated serum T levels, a selective venous sampling procedure was planned, but was not performed. Immediately before catheterization, high resolution ultrasound examination using Acuson Sequoia equipment (Mountain View, CA) showed a small tumor in the left testis (Fig. 1). Histological examination showed the tumor to be a well vascularized Leydig cell adenoma (Fig. 2).

View larger version (81K): [in this window] [in a new window]   Figure 1. Ultrasound of the left testis (longitudinal scan, linear array, 8 MHz, Acuson Sequoia). A, Hypoechoic mass at the lower pole of testis, 1 cm in diameter, indicated by +. B, Color-coded sonography showing a focal hyperperfusion only within the tumor mass. The brighter the color, the faster the blood flow. Red and blue indicate the different directions of the blood flow.

View larger version (160K): [in this window] [in a new window]   Figure 2. Leydig cell tumor consisting of Leydig cells showing a distinct tumor pattern of vascularity (). Primary magnification, x40.

Materials and Methods

The patient’s parents were informed about all diagnostic steps and gave their written consent for the necessary surgery, tumor removal, and analysis of tumor tissue.

After surgery, tumor material was frozen at -80 C. Genomic DNA was extracted from the tumor as well as from peripheral blood cells (QIAGEN, Hilden, Germany). Exons 1–10 and two overlapping fragments of exon 11 of the LH receptor gene were amplified by PCR using primers and conditions previously described (7, 12). The presence and length of the fragments were checked on agarose gels, purified with the High Pure PCR Purification Kit (Roche, Mannheim, Germany) and sequenced using the Thermo Sequenase Dye Terminator Cycle Sequencing Kit for PCR fragments (Amersham Pharmacia Biotech, Little Chalfont, UK).

Results

Genomic DNA extracted from blood samples revealed a heterozygous T to A alteration at nucleotide 337, resulting in an tyrosine to asparagine change at codon 113 in exon 4 (Tyr¹¹³Asn; Fig. 3). In exon 11 of the LH receptor gene no alteration could be identified.

View larger version (32K): [in this window] [in a new window]   Figure 3. Genomic sequence analysis of exon 4 in blood. Left, Patient with heterozygous DNA change at position 113 (blood) (Tyr113Asn). Right, Control.

View larger version (25K): [in this window] [in a new window]   Figure 4. Genomic sequence analysis of exon 11 from tumor (left) and blood (right) of our patient presenting the heterozygous Asp578His mutation only in the tumor.

Gonadotropin-independent sexual precocity in males represents a group of heterogeneous disorders including hCG- or androgen-producing tumors, McCune-Albright syndrome (13), various forms of congenital adrenal hyperplasia (14), as well as true familial male precocious puberty (1, 2, 3). In testicular Leydig cells, LH or its analog, hCG, bind to the LH receptor. This reaction initiates a signal via G proteins and adenylyl cyclase that results in T production. Activating mutations in the LH receptor gene may stimulate this cascade in the absence of LH or hCG. Despite careful evaluation, it is sometimes difficult to establish a cause for the high serum levels of T in boys with sexual precocity. An overview of the differential diagnosis of precocious puberty in boys was given by Brunner and Otten (15).

Early puberty is associated with an early increase in growth and skeletal maturation, a severely compromised adult height, and emotional disorders. When treatment of the underlying cause is impossible, inhibition of the biosynthesis of T may be attempted using ketokonazole. Testolactone, which inhibits conversion of androgen to estrogen, and spironolactone, which blocks the action of androgens, may also be administered (16, 17). In some patients a selective venous sampling should considered to determine the origin of the high serum T levels. This method requires an experienced investigator.

We present a patient with the clinical features of sexual precocity before the age of 4 yr. Repeated ultrasound examinations using standard ultrasound devices failed to detect a testicular tumor. However, another ultrasound examination using the high resolution system provided by Acuson Sequoia equipment revealed a small hypoechoic tumor of the left testis. Additional color-coded sonography showed a marked hypervascularity of the tumor. The better delineation of the tumor by Acuson system is probably due to the coherent image formation resulting in superior image resolution. Conventional ultrasound systems are beamformer-based and display only the amplitude of acoustic signal. Unlike conventional systems, coherent image formation scans with a 512 digital processing channel to acquire and encode both phase and amplitude data, resulting in images based on the full echo information with increased spatial and temporal resolution. The time elapsed between examinations using the two differing ultrasound devices was short (31 d), making the possibility of a rapidly growing tumor unlikely. We therefore recommend the use of high resolution ultrasound examination to detect testicular tumors at an early stage.

Our patient presented asymmetry of testicular volume (2 and 3 ml). Our results show that in a case of an asymmetric enlargement of the testes in young boys with idiopathic gonadotropin-independent sexual precocity, a testicular tumor should be considered. In boys with familial male-limited gonadotropin-independent precocious puberty, signs of sexual development usually appear before the age of 4 yr. Patients with Leydig cell tumors, however, present these signs at a later age, typically between the age of 5–9 yr. Furthermore, we prove here that the presence of Leydig cell adenomas is also possible in boys younger than 4 yr of age. Based on these results, boys with idiopathic gonadotropin- independent sexual precocity should receive a long-term follow-up including ultrasound examinations using a high resolution system of the testes at any age and at each examination to exclude that Leydig cell adenomas have developed.

The coupling of most LH receptor proteins to G proteins involves the sixth transmembrane domain and its flanking third intracellular loop (18). In accordance with these findings, 11 of the 15 activating mutations of the LH receptor have been identified in this region (6). Therefore, the sixth transmembrane domain and its flanking third intracellular loop encoded by exon 11 are hot spots for activating mutations of the LH receptor gene, although amino acid changes have also been found in other transmembrane segments (6). No activating mutations have been identified in exons 1–10, which encode the signal peptide and the extracellular domain of the LH receptor. When mutations in exon 11 are absent, it is unlikely that exons 1–10 are the cause of idiopathic gonadotropin-independent sexual precocity (7); other causes should be investigated. However, the TSH receptor, which belongs to the same family of G protein-coupled receptors as FSH and LH, showed activating mutations in the exons for hormone binding (exon 1–10) (19). This indicates that activating mutations in exons 1–10 in the LH receptor gene cannot be completely excluded, although they may be rare (20). Therefore, the whole coding sequence of the LH receptor gene may be sequenced when after extensive diagnostics no cause of the idiopathic gonadotropin-independent sexual precocity is found.

In our search for LH receptor genomic changes, we found a heterogeneous DNA alteration in exon 4 (Tyr¹¹³Asn) in samples of our patient’s blood and tumor. In addition we found a somatic mutation at position 578 (Asp⁵⁷⁸His). As this is a constitutively activating mutation, as described by Liu et al. (8), this explains the phenotype of our patient. Liu et al. (8) showed that the main feature that distinguishes the Asp⁵⁷⁸His mutation from LH receptor mutations associated with FMPP is its ability to activate not only the stimulatory G protein-coupled receptor, but also the phospholipase C pathway of signal transduction. Whether this downstream pathway is also a mitogenic stimulus remains unclear, as activating mutations of the G_s protein can also lead to the development of adenomas (15, 21). Liu et al. (8) described the same somatic mutation in exon 11 in Leydig cell adenomas from 3 unrelated boys. Exon 4 of the LH receptor gene was not investigated in these boys. It might be interesting to verify whether there is a correlation between the DNA alteration in exon 4 (Tyr¹¹³Asn) and the Asp⁵⁷⁸His mutation in exon 11, because we cannot exclude that Tyr¹¹³Asn contributes to the early onset of symptoms in our patient. Analyzing more young patients with Leydig cell adenomas may provide a correlation between Tyr¹¹³Asn and Asp⁵⁷⁸His. We suppose that the heterozygous alteration in exon 4 is most likely to be a rare polymorphism and did not study the functional effect of Tyr¹¹³Asn substitution in the extracellular domain on hormone binding and cAMP formation at this time. As the residue of interest in exon 4 is not conserved among other species (rat, mouse) and other members of the glycoprotein hormone receptor family, we do not expect a special role for this nucleotide. Furthermore, the polymorphism was found in both blood and tumor material. The fact that T levels returned to normal prepubertal concentrations after tumor removal is not compatible with a role for the polymorphism for LH-independent T production. Finally, we screened more than 140 DNA samples from normal subjects by direct sequencing for this nucleotide exchange without a similar DNA change (results not shown).

Sex hormones are known to stimulate the growth of cancer cells (22) and have been proposed as a factor influencing the risk of malignant changes in case of perinatal exposure (23, 24, 25). Early exposure to prolonged and elevated concentrations of T occurs in familial male-limited gonadotropin-independent precocious puberty patients. Thus, these patients may be predisposed to develop testicular tumors. A number of studies have shown that constitutive activation of the signal transduction pathway of the G protein-coupled receptor, resulting from mutations of either the receptor or the G protein-coupled receptor, may lead to neoplasia (13, 26, 27). Recently, a 10-yr-old boy with precocious puberty due to activating mutations in the gene encoding the LH receptor has been reported who developed Leydig cell nodules (28). A case of a testicular seminoma in a familial male-limited gonadotropin-independent precocious puberty patient with the activating mutation Asp⁵⁷⁸Gly was reported in 1998 (29). Also, gonadotropin-independent sexual precocity in a 9-yr-old boy with nodular interstitial cell hyperplasia was described in 1981 (30); unfortunately, molecular analysis of the LH receptor gene was not available then. Although no studies have been reported on this, we speculate that prolonged elevated levels of T due to the activating mutation, with onset during infancy, could have predisposed the patients to the development of testicular tumors. Although patients with male-limited gonadotropin-independent precocious puberty have no developmental problems after puberty, we advise that in these patients regularly scheduled testicular examinations include the use of high resolution ultrasound equipment.

In conclusion, our findings indicate that in males with idiopathic gonadotropin-independent sexual precocity the presence of small testicular Leydig cell tumors harboring a somatic mutation of the LH receptor gene should be considered even at very young age.

Acknowledgments

Footnotes

This work was supported by the IFORES-Program of the Faculty of Medicine, University of Essen, Essen, Germany (to A.R.-U.).

Received April 12, 2001.

Accepted November 26, 2001.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Richter-Unruh, A. Articles by Hauffa, B. P. Search for Related Content PubMed PubMed Citation Articles by Richter-Unruh, A. Articles by Hauffa, B. P.