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

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 x d) and testolactone (40 mg/kg x 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.

Fetal but not adult Leydig cells are susceptible to adenoma formation in response to persistently high hCG level: a study on hCG overexpressing transgenic mice

“…In humans, a specific activating mutation of the Lhcgr, D578H, was found to lead to the formation of LC adenomas (Liu et al, 1999;Richter-Unruh et al, 2002). Whether such adenomas are derived from fetalor adult-type LCs remains unknown.…”

“…Although the regression of fetal LCs in man starts normally already in fetal life (Chemes, 1996;Habert et al, 2001), we do not know how an activating Lhcgr mutation affects their lifespan. Nevertheless, the hCG þ mice provide a phenocopy of the human activating mutation of Lhcgr presenting with prepubertal LC adenomas and testotoxicosis (Liu et al, 1999;Richter-Unruh et al, 2002). Another phenotypic feature of the activating Lhcgr mutations is precocious puberty in boys between 1 and 4 years of age (Themmen and Huhtaniemi, 2000).…”

“…Activating Lhcgr mutations are associated with LC hyperplasia (Themmen and Huhtaniemi, 2000), but LC adenomas have only been found in connection with a particular activating Lhcgr mutation, D578 H (Liu et al, 1999;Richter-Unruh et al, 2002). In vitro studies on this mutated receptor have shown that besides cAMP, it constitutively also activates the inositol phosphate and MAPK signaling cascades (Liu et al, 1999;Hirakawa et al, 2002).…”

What have gonadotrophin overexpressing transgenic mice taught us about gonadal function?

“…In agreement with previous studies, based on long-term LH/hCG treatments in vivo (Risbridger et al 1982, Gaytan et al 1994, these mice developed focal Leydig cell hyperplasia/hypertrophy, but failed to promote testicular tumours. This was intriguing, since in humans, a specific activating mutation of the LHR (Asp 578 His) is associated with Leydig cell adenomas (Liu et al 1999, Richter-Unruh et al 2002. Interestingly, recent studies in young hCGab þ mice demonstrated postnatally clear Leydig cell adenomas of foetal Leydig cell origin, but these tumours disappeared at puberty .…”

Constitutively active luteinizing hormone receptors: Consequences of in vivo expression

“…Females with the activating mutations do not have an apparent phenotype. A particularly potent activating somatic mutation (D578H) has been identified in boys with testicular adenomas wherein the mutation is limited to the adenoma and not the surrounding normal tissue (Liu et al, 1999;Canto et al, 2001;Richter-Unruh et al, 2002).…”