ESPE Abstracts

Introduction: Familial male-limited precocious puberty (or testotoxicosis) is a very rare genetic disorder with autosomal dominant transmission that causes gonadotropin-independent precocious puberty due to mutations activating the lutropin-chorionic gonadotropin receptor (LHCGR), which lead to elevated testosterone levels and suppressed gonadotropins. The age of onset is between 2-5 years essentially with penis and testes enlargement, linear growth acceleration, progressive bone age advancement and growth of pubic hair. Premature epiphyseal fusion results in reduced adult stature. Current treatment consists of a combination therapy with nonsteroidal antiandrogen agents and aromatase inhibitors.

Case presentation: A 4-years and 6-months-old male came to our clinic for appearance of pubic hair for months. Familiarity for precocious puberty (paternal line). The growth curves documented a progressive acceleration of staturoponderal growth from 2-years-old (50th to 95th percentile). On physical examination: herculean appearance, presence of café-au-lait spot on right flank, increased penis size, testicles 6-8 cc bilaterally, dark curly pubic hair. No headache or visual changes. There was tall stature (+3.39 SD) and advancement of bone maturation (7.9 years). GnRH test was performed which documented peripheral precocious puberty (elevated testosterone values with suppressed basal and post-stimulus gonadotropin levels). Thyroid function, serum and urinary electrolytes, 17-OH-P, ACTH, cortisol, PRL, alpha-fetoprotein and beta-HCG were normal. Testicular ultrasonography didn’t show morpho-structural changes. Head MRI and adrenal ultrasound were negative. Excluding tumor causes, genetic investigation showed a c.1193T>C mutation of the LHCGR gene in heterozygosity, confirming the diagnosis of testotoxicosis. In contrast, molecular investigation for McCune-Albright syndrome was negative. After starting antiandrogenic therapy (ketoconazole) associated with cyproterone acetate, the child presented a significant reduction in testosterone levels (from 355 ng/dl to 14 ng/ml during the first year of follow-up). However, after 1 year of treatment, because of the onset of iatrogenic adrenal insufficiency, the therapy was modified with the combination of letrozole and spironolactone. At 6.6 years-old GnRH test documented activation of the pituitary-gonadal axis with diagnosis of central precocious puberty. Therefore, therapy with GnRH analogs was initiated.

Conclusions: Male peripheral precocious puberty is a very rare condition. After excluding neoplastic causes and congenital adrenal hyperplasia from 21-OH deficiency, rarer causes such as McCune-Albright syndrome or testotoxicosis should be considered. Testotoxicosis should be treated early with antiandrogenic drugs to mitigate the effect of testosterone on stature and bone maturation. Therapeutic management, however, requires the use of off-label drugs that may lead to side effects. Close clinical-auxological and laboratory follow-up appears essential.