Unexpected mosaicism of R201H-GNAS1 mutant-bearing cells in the testes underlie macro-orchidism without sexual precocity in McCune–Albright syndrome

Abstract

McCune-Albright syndrome (MAS), usually presenting with polyostotic bone dysplasia, café-au-lait skin lesions and sexual precocity, results from a somatic activating mutation of the GNAS1 gene, which encodes the Gs-alpha protein involved in signalling of several G-protein-coupled receptors. The clinical spectrum depends on tissue distribution of mutant-bearing cells. Sexual precocity has been ascribed to the occurrence of a mutant GNAS1 allele in the gonadal anlage, from which all somatic cells of the differentiated gonads arise. In boys, precocious activation of Leydig cell androgen secretion results in pubertal spermatogenesis, leading to testicular enlargement, and in the development of secondary sex characteristics. However, sexual precocity is rare in MAS males while isolated testicular enlargement is frequently observed. We recently reported the case of a boy with macro-orchidism and signs of Sertoli cell hyperactivity but no signs of hyperandrogenism, which was unexpected since Gs-alpha is functional in both Sertoli and Leydig cells. To understand its pathophysiology, we microdissected an available testicular biopsy to separate Sertoli from Leydig cells. The R201H-GNAS1 allele was present only in Sertoli cells, resulting in isolated Sertoli cell hyperfunction, evidenced by increased AMH expression and cell hyperplasia leading to prepubertal macro-orchidism, with no signs of Leydig cell activation. The different early embryologic origin of precursors contributing to Sertoli and Leydig cell lineages may underlie the differential existence of the mutated GNAS1 gene. Lack of occurrence of the mutation in Leydig cells may explain why sexual precocity is rarely observed in boys with MAS.

Regulation of spermatogenesis in McCune–Albright syndrome: lessons from a 15-year follow-up.

“…However, macroorchidism was not associated with manifestations of hyperandrogenism, probably due to an autonomous hyperfunction of Sertoli cells, with no activation of Leydig cells. In fact, it has been recently demonstrated that GNAS1 allele mutation may be present only in Sertoli cells (18), resulting in isolated Sertoli cell hyperfunction (15). In the present case, on the contrary, clinical, biochemical, and histological findings altogether suggest an isolated Leydig cell hyperfunction, with no premature activation of Sertoli cells.…”

Compensatory function of the remaining testis is dissociated in boys and adolescents with monorchidism

“…Therefore, serum AMH is a widely accepted biomarker of testicular activity during childhood (30,31,32,33,34,35,36). Furthermore, serum AMH has been postulated as a surrogate marker for the mass of functional Sertoli cells in patients with gonadal dysgenesis (37), hypogonadotropic hypogonadism (14,38) and Sertoli cell hyperplasia (39,40). In the present work, the significant correlation between testicular volume and AMH suggested that AMH levels reflect the degree of compensatory hypertrophy in prepubertal patients with monorchidism.…”

Unusual Phenotypical Variations in a Boy with McCune-Albright Syndrome

“…His elevated levels of IB and AMH are considered to be a marker of Sertoli cell activation which could account for the macroorchidism [25]. …”

“…While we did not analyze this patient’s testicular tissue, we previously studied and reported the case of a boy with MAS and macroorchidism with hyperfunction of Sertoli cells [25] similarly suggested by high levels of IB and AMH. In the first reported case, testicular biopsy and molecular study revealed isolated Sertoli cell hyperplasia, mosaic activation of the G s α gene in Sertoli cells and no Leydig cell maturation.…”