Familial peripheral male-limited precocious puberty (ORPHA:3000)
Familial male limited precocious puberty (FMPP) is a gonadotropin-independent familial form of male-limited precocious puberty, generally presenting between 2-5 years of age as accelerated growth, early development of secondary sexual characteristics and reduced adult height.
Epidemiology
FMPP is a very rare condition; prevalence is less than 1/1,000,000.
Clinical description
FMPP presents in boys from 2-5 years of age with precocious signs of puberty including growth acceleration, penile enlargement, acne, pubic hair and facial hair. Spontaneous erection and masturbatory behavior are commonly observed. Testicular volume is moderately increased, in contrast to central precocious puberty (see this term) where testicular volume is markedly enlarged, similar to normal puberty. Presentation is variable, even between siblings, but most untreated patients have been reported to have premature epiphyseal fusion resulting in a compromised adult height. Aggressive behavior and social exclusion may occur. Mild oligospermia has been reported in some adults, but most individuals retain fertility. An increased risk of attention-deficit hyperactivity disorder (ADHD) has been observed.
Etiology
FMPP is caused by an activating mutation of the Lutropin-Choriogonadotropic Hormone Receptor gene (LHCGR, 2p21) which leads to increased levels of sex steroids in the context of low luteinizing hormone. This receptor's chronic activation leads to precocious testosterone production by Leydig cells. No effect is observed in female carriers due to the dual luteinizing hormone (LH)/ follicle stimulating hormone (FSH) signal necessary to promote ovarian stimulation.
Diagnostic methods
Patients display increased serum testosterone levels (typically 3- 20 nmol/l) and decreased secretion of gonadotropins, even after stimulation with luteinizing hormone-releasing hormone (LHRH). Radiological examination reveals skeletal maturation. Diagnosis is confirmed by genetic testing identifying activating mutations in the LHCGR gene.
Differential diagnosis
Differential diagnoses include other causes of precocious puberty associated with low levels of gonadotropins such as adrenal tumors, testicular Leydig cell tumors (ruled out by testicular ultrasound since they can be of small size), human chorionic gonadotropin (HCG)-secreting tumors, congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, CAH due to 11-beta-hydroxylase deficiency, central precocious puberty (with detectable LH levels that can be stimulated by gonadotropin-releasing hormone (GnRH) or GnRH agonists) (see these terms), and occult exposure to androgens.
Antenatal diagnosis
Prenatal genetic screening is feasible when a proband has been identified.
Genetic counseling
Transmission is autosomal dominant. Mothers may act as silent carriers, with each son having a 50% risk of displaying FMPP.
Management and treatment
Treatment consists in reducing hyperandrogenism in children (sexual maturation, stature). Two options have been proposed. The first one consists of administrating the androgen antagonist bicalutamide (12.5-100 mg/d) together with aromatase inhibitors such as anastrozole (1 mg/d) or letrozole (2.5 mg/d) to normalize the growth rates until adult height has been reached. The second option consists of administrating androgen biosynthesis inhibitors such as ketoconazole (15 mg/kg/d) that result in a decrease in testosterone levels. In both cases, the treatments may be supplemented by GnRH therapy if central (gonadotropin-dependent) precocious puberty develops. Psychological counseling is needed to help the patient and family adjust to the stimulative effects of high androgen levels.
Prognosis
Prognosis is good; with treatment most patients reach an appropriate adult height. The disease does not seem to have any consequence during adulthood but this is based on limited clinical reports.

                            Last update: 
                            February 2014


                            - Expert reviewer(s): 
                            Pr Jean-Claude CAREL