· Familial male-limited precocious puberty (FMPP) is a rare disorder characterized by early onset gonadotropin-independent precocious puberty. This report presents an extremely rare case of FMPP with an activating mutation of the LHCGR gene in a Korean boy who presented with precocious pubertal development at 16 months of age and a positive familial history of precocious puberty.

Familial male-limited precocious puberty (FMPP; OMIM #176410) is a very rare cause of gonadotropin-independent precocious puberty and is exclusively expressed in males. FMPP is caused by activating mutations of the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) gene that are inherited in an autosomal dominant manner. This results in excessive testosterone production by the Leydig cells despite low luteinizing hormone (LH) and follicular stimulating hormone (FSH) levels. This activating mutation in LHCGR affects only males because activation of the LH receptor alone is sufficient to stimulate steroidogenesis in Leydig cells. In females, co-activation of the FSH receptor is definitely required to stimulate granulosa cells to synthesize aromatase, which converts androgens produced by the thecal cells to estradiol, but the precise underlying mechanism remains elusive [1,2].

In affected males, early signs of precocious puberty usually appear at 2–4 years of age [1,3]. Rapid growth and bone age advancement result from the conversion of androgens to estrogens by the enzyme aromatase. Without treatment, rapidly progressive precocious puberty and accelerated skeletal maturation result in compromised final adult height [4]. Diagnosis of FMPP is confirmed by identifying an activating mutation in the LHCGR gene. The goals of treatment are to suppress pubertal progression by reducing the effects of testosterone and to increase final adult height by inhibiting the aromatization of testosterone to estrogen [3-5].

In this report, we describe a boy with a familial history of precocious puberty confirmed by a mutation of the LHCGR gene. To the best of our knowledge, this is the first case of genetically confirmed FMPP in a Korean boy. Written informed consent for publication of this report was obtained from the patient's parents.

A 16-month-old boy was brought to our outpatient clinic with complaints of premature pubic hair development, acne, and accelerated linear growth, which was observed by the patient's parents at the age of 12 months. The patient was born at 37+2 weeks of gestation by cesarean section with a birth weight of 2.45 kg (-1.7 standard deviation score [SDS]). The patient was the first baby of fraternal twins and had a healthy twin sister. The patient's grandfather and father had a history of precocious puberty and profound short stature (height of grandfather and father: 148 cm and 158 cm, respectively). Upon physical examination, the patient's height and weight were 83 cm (+1.2 SDS) and 14.3 kg (+2.8 SDS), respectively. The testicular volume was 2 mL bilaterally, and pubic hair development was appropriate for Tanner stage II (Fig. 1). The stretched penile length was 7 cm (>2 SDS). The patient had an oily face with acneiform eruptions without any dysmorphic features, gynecomastia, or palpable abdominal masses. Cafeau-lait spots and hyperpigmentation were not observed. The patient's bone age was estimated by the Greulich-Pyle method [6] and was significantly advanced to 4 years of age.

Laboratory findings showed extremely high serum testosterone (5.74 ng/mL [appropriate for Tanner IV–V]; normal range, <0.05 ng/mL), suppressed LH (<0.07 mIU/mL; normal range, 0.02–0.15 ng/mL), normal serum level of FSH (0.56 mIU/mL; normal range, 0.38–1.11 mIU/mL), slightly elevated α-fetoprotein (14.1 ng/mL; normal range, 0–10 ng/mL), and normal serum level of β-human chorionic gonadotropin (<0.2 mIU/mL, normal range, <5 mIU/mL). Adrenocorticotropic hormone (25.4 pg/mL; normal range, 10–60 pg/mL), cortisol (10.44 μug/dL; normal range, 3–21 μug/dL), 17-hydroxyprogesterone (1.96 ng/mL; normal range, 0.03–9 ng/mL), androstenedione (<0.3 ng/mL; 0.08-0.5 ng/mL), and dehydroepiandrosterone sulfate (19.1 μg/dL; 5–57 μg/dL) were all within the normal infant range. A gonadotropinreleasing hormone (GnRH) stimulation test did not stimulate gonadotropin (peak LH and FSH, 0.52 and 6.69 mIU/mL, respectively). Magnetic resonance imaging of the brain and ultrasonography of the scrotum and adrenal gland were all normal. Mutation analysis of the LHCGR gene identified a heterozygous mutation, c.1730 C>T (p.Thr577Ileu), which was previously reported in a patient with FMPP [7]. Familial genotyping confirmed a normal genotype from the mother, but the same pathogenic variant of LHCGR was identified from the father. The patient was finally diagnosed with FMPP based on clinical, laboratory, and genetic findings.

A combination of antiandrogen treatment with bicalutamide (25 mg/day) and aromatase inhibition with anastrozole (1 mg/day) was initiated [8], and the patient was followed up every 1–3 months. Serum LH and FSH levels were maintained within prepubertal ranges during the follow-up period (Table 1). Despite persistently elevated testosterone level (6.79–8.85 ng/mL, Table 1), pubertal progression was sufficiently suppressed, showing a decreased stretched penile length to 6 cm, pubic hair to Tanner stage I, and resolved acneiform eruptions. The patient's growth velocity decreased from 2.1 cm/mo to 14 cm/10 mo (Fig. 2). At 27 months of age, the patient's bone age, as estimated by the Greulich-Pyle method, was 4.8 years. No specific side effects were observed, and aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels were all normal (Table 1).

Written informed consent was obtained from the patient's parents to publish this case report.

In this report, we describe an extremely rare case of FMPP with a mutation of the LHCGR gene in a Korean boy who presented with precocious puberty at 16 months of age and a family history of precocious puberty through 3 generations. To our knowledge, this is the first case of genetically confirmed FMPP in Korea.

LHCGR is a member of a subfamily of G protein-coupled receptors characterized by a large N-terminal extracellular domain containing several leucine-rich repeats. The gene comprises 11 exons, spanning approximately 80 kb, mapped on chromosome 2p16.3 [2]. The gain-of-function mutation of LHCGR causes FMPP with autosomal dominant inheritance, whereas the loss-of-function mutation results in Leydig cell hypoplasia with hypergonadotropic hypogonadism of males or 46, XY disorder of sex development. The mutations are inherited in an autosomal recessive manner (OMIM *152790).

FMPP is one of the rarest causes of peripheral precocious puberty, exclusively affecting males. It was first described in 1981 by Schedewie et al. [1] in 2 brothers with rapid virilization, increased bone age, and advanced spermatogenesis. Variable clinical features of precocious puberty and advanced bone age were observed in subsequent reports [8-16]. The characteristics and pathogenic variants of patients with FMPP in recent case reports are summarized in Table 2. The onset age of symptoms ranged from 6 months to 6.6 years, and only 2 patients were younger than the patient in the present case [8,11]. Among the 7 unrelated patients who underwent parental genotyping, mutations were inherited from 3 affected fathers and 3 asymptomatic carrier mothers, and 1 patient had a de novo mutation (Table 2).

The mutation spectrum of the LHCGR gene causing FMPP is heterogeneous; however, activating mutations that were identified in boys with FMPP, including that in our case, are primarily located in exon 11, which encodes transmembrane helices [17]. An activating mutation either disrupts the inactive state or stabilizes the active-state conformation of the LHCGR protein, resulting in persistently elevated LHCGR signal transduction in testicular Leydig cells, with excessive testosterone production [2].

The therapeutic goals of FMPP are to suppress pubertal progression and to delay epiphyseal fusion to increase final adult height [3]. Virilization can be abated by reducing the peripheral effects of testosterone on the androgen receptor or inhibiting testosterone synthesis. Epiphyseal fusion can be delayed by inhibiting the conversion of testosterone to estrogen or by blocking the action of estrogens at the epiphyses. Longacting GnRH agonists were the primary treatment before the discovery of the molecular mechanism of FMPP; such agonists were ineffective as they could not suppress the action of elevated testosterone [18]. After the pathophysiology was better understood, antiandrogen drugs, such as medroxyprogesterone acetate, cyproterone, and ketoconazole, were used. These medications decreased testosterone secretion, growth velocity, and skeletal maturation but showed limited efficacy in improving final height. In addition, ketoconazole showed serious side effects, including hepatotoxicity and adrenal suppression [3,9]. A therapeutic regimen that combines spironolactone (a weak antiandrogen) and testolactone (an aromatase inhibitor) with deslorelin (a long-acting GnRH analog) at the onset of central precocious puberty has been shown to normalize the growth rate and bone maturation and to improve predicted height in boys with FMPP [19,20]. Most recent studies have demonstrated that the combination of bicalutamide (an antiandrogen) and anastrozole (a third-generation aromatase inhibitor) has shown better height outcomes than previous reports [4,9,10]. This combination treatment showed better potential for the preservation of final adult height than treatment with either agent alone [5]. Our patient also received this combination treatment and showed an impressive clinical response in pubertal progression, growth velocity, and skeletal maturation without any side effects.

Treatment regimens have evolved over the years, but there is no consensus regarding optimal treatment. Testosterone is not a good indicator for treatment efficacy, and clinical and auxological parameters are more important. Long-term follow-up that focuses on the auxological parameters rather than biochemical profiles is required. In our patient, treatment efficacy was monitored by physical examination and bone age progression. Bicalutamide and anastrozole may interfere with normal sex steroid profiles. However, information on the longterm effects on testicular function, lipid profiles, and bone mineral accrual of this therapeutic combination is limited, and further research is required [9].

In conclusion, we described a case of FMPP in a Korean boy that was confirmed by identifying an LHCGR gene mutation. FMPP appears to be exceptionally rare or underrecognized in the Korean population. It should be considered in the differential diagnosis of peripheral precocious puberty, particularly when the family history of precocious puberty is limited to male family members.