Precocious Puberty, Male-Limited

A number sign (#) is used with this entry because of evidence that male-limited precocious puberty can be caused by constitutively activating mutations in the luteinizing hormone receptor gene (LHCGR; 152790).

See 139320.0019 for testotoxicosis in paradoxical combination with pseudohypoparathyroidism type Ia, due to a specific mutation in the GNAS1 gene.

Description

Familial male precocious puberty is a gonadotropin-independent disorder that is inherited in an autosomal dominant, male-limited pattern. Affected males generally exhibit signs of puberty by age 4 years (Shenker et al., 1993).

Nomenclature

Rosenthal et al. (1983) suggested the term 'familial testotoxicosis' for this disorder, in analogy to thyrotoxicosis.

Clinical Features

Schedewie et al. (1981) and Rosenthal et al. (1983) described a syndrome of sexual precocity in boys, characterized by a sex-limited autosomal dominant inheritance pattern and extremely rapid virilization. In this syndrome, in contrast to 'true' precocious puberty, increased gonadal testosterone secretion appears to be gonadotropin-independent because both basal and gonadotropin-releasing hormone-induced secretion of luteinizing hormone (LH; 152780) is low whether measured by radioimmunoassay or bioassay and there are no suppressive effects of potent gonadotropin-releasing hormone analogs. Schedewie et al. (1981) studied 2 brothers; one, aged 3 years, showed advanced spermatogenesis on testis biopsy. Of the 4 patients described by Rosenthal et al. (1983), 3 were adopted and 1 had a history of sexual precocity in the maternal grandfather. One was born of a pregnancy complicated by hyperthyroidism treated with prophylthiouracil. They mentioned preliminary studies of a family with 24 affected males over 6 generations.

Reiter et al. (1984) had an opportunity to define the natural history of the disorder on the basis of affected males in 3 consecutive generations. The grandfather, aged 59, began precocious sexual development at about 1 year of age, was 165 cm tall, had 4 brothers and 4 sisters who were all normal, and had had 3 children of whom the oldest was affected (the father of the proband grandson). The proband's father, aged 28, had onset of sexual precocity at age 1 year, prompting adrenal exploration (with normal findings) at age 18 months. He was 154.4 cm tall, well muscled and well virilized, had normal-sized penis and very small, soft testes, and showed reduced sperm count but had fathered 3 children in less than 5 years. The proband presented at 12 months of age with a 2-month history of accelerated growth velocity, deepening voice, pubic hair, axillary odor, and striking enlargement of the penis. Bone age was 2 and 2/3 years. Testosterone levels in all 3 subjects were very high. (In this family, the grandfather's condition may have been the result of new mutation. Since his 2 normal children were girls and the 2 normal children of his affected son were girls, a Y-linked mutation cannot be excluded.)

Gondos et al. (1985) reviewed the testicular changes found in biopsy specimens. In all cases, Leydig cells showed nuclear and cytoplasmic features characteristic of fully differentiated steroidogenic cells.

Manasco et al. (1991) found that the plasma of boys with familial male precocious puberty contains a novel stimulator of testicular testosterone production. They demonstrated the testis-stimulating factor by a bioassay using adult male cynomolgus monkeys. The factor was inactive in a rodent system.

Lim and Low (1994) reported testotoxicosis in a Chinese father and son. Both had early sexual development. In both, testicular volume was only 6 ml despite fully developed secondary sexual characteristics. Both had adult testosterone concentrations but a suppressed gonadotropin response to gonadotropin-releasing hormone.

Clinical Management

Laue et al. (1989) reasoned that because the pubertal growth spread in boys appears to be mediated by both androgens and estrogens, blockade of both androgen action and estrogen synthesis would normalize the growth of boys with this disorder. In studies of 9 boys from 8 families they found that neither spironolactone, an antiandrogen, nor testolactone, an inhibitor of androgen-to-estrogen conversion, had any effect when given alone. However, a combination of the 2, given for at least 6 months, restored both the growth rate and the rate of bone maturation to normal prepubertal levels and controlled acne, spontaneous erections, and aggressive behavior.

Molecular Genetics

Shenker et al. (1993) noted that testosterone production and Leydig cell hyperplasia occur in the context of prepubertal levels of luteinizing hormone. Since the LH receptor is a member of the family of G protein-coupled receptors, they hypothesized that male-limited precocious puberty might be due to a mutant receptor that is activated in the presence of little or no agonist. In testing their hypothesis, they identified a mutation in the LHCGR gene (D578G; 152790.0001) in affected individuals from 8 different families. COS-7 cells expressing the mutant LH receptor exhibited markedly increased cyclic AMP production in the absence of agonist, suggesting that autonomous Leydig cell activity in this disorder is caused by a constitutively activated LH receptor. This is an example of constitutive activation of a stimulatory G protein comparable to that in the McCune-Albright syndrome (174800) and in hyperfunctioning thyroid adenoma (152790.0002).

Martin et al. (1998) reported a 35-year-old man, previously diagnosed with familial male-limited precocious puberty (FMPP) and in whom heterozygosity for the dominant gain-of-function D578G mutation in the LHCGR gene was identified, who was subsequently found to have a testicular seminoma. The authors stated that this represented the first case of a testicular germ cell tumor described in an FMPP patient, raising the possibility of a potentially harmful effect of prolonged increased concentrations of sex hormones, with onset early in life, upon the cellular components of the testes.

Liu et al. (1999) described 3 unrelated boys with precocious puberty and Leydig cell adenomas containing a somatic activating mutation of the LHCGR gene (D578H; 152790.0019). Canto et al. (2002) reported 2 additional unrelated boys with gonadotropin-independent hypersecretion of testosterone due to Leydig cell adenomas; the same heterozygous D578H mutation was found in DNA from the tumors from both patients, but not from the adjacent normal tissue or blood leukocytes.

Leschek et al. (2001) reported a boy diagnosed with gonadotropin-independent precocious puberty at 4 years of age, in whom they identified a constitutively activating missense mutation in the LHCGR gene (D564G; 152790.0029) in peripheral blood leukocytes. At 10.8 years of age, ultrasound examination to quantitate testicular volume revealed a right testicular mass, and at the time of surgery for excisional biopsy, 2 masses were found and removed. Histologic examination of the masses showed nodular Leydig cell hyperplasia surrounded by normal-appearing seminiferous tubules with spermatogenesis; DNA from tumor tissue revealed the same D564G mutation that was present in peripheral blood leukocytes. Leschek et al. (2001) noted that in another FMPP family known to carry the D564G mutation (Wu et al., 2000), none of the members had Leydig cell nodules to date. Leschek et al. (2001) stated that the only previously reported testicular mass in FMPP was a seminoma (Martin et al., 1998), and suggested that LH receptor activation may be a predisposing factor in the development of testicular tumors.

History

This disorder was reported by Stone (1852) in a 4-year-old boy named Theodore. It was noted that 'the father presented extreme precocity, having experienced his first sexual indulgence at the age of 8 years. He informed us that between the ages of 10 and 13 years he was a 'better man' than he had ever been since. Delicacy forbids my detailing his prowess at that early age.'