Gonadotropin-Independent
Precocious Puberty in Boys
(LHCGR)

Precocious puberty is defined as the premature appearance of secondary sexual characteristics in young children, accompanied by an increase in growth rate and premature skeletal maturation (reviewed in 1, 2). The loss of synchronization between physical maturation and emotional and intellectual development can lead to psychosocial problems for affected children. In addition, the accelerated skeletal maturation often results in reduced adult height due to premature closure of epiphyseal junctions. In many cases, treatment options are available to halt or even reverse precocious pubertal development; choice of the most effective therapy, however, may depend on knowledge of the underlying cause.

Precocious puberty is classified into two types: The more common central or true precocious puberty is caused by a premature increase in gonadotropin secretion, while the rarer gonadotropin-independent precocious puberty or precocious pseudopuberty is due to a gonadotropin-independent premature elevation in gonadal or adrenal sex steroid hormones. In boys, the causes of gonadotropin-independent precocious puberty include autosomal dominant gain-of-function mutations in LHCGR, the gene for the shared receptor for human chorionic gonadotropin (hCG) and luteinizing hormone (LH) (3, 4). LHCGR-related precocious puberty is known as testitoxicosis, or, since it is expressed only in males, familial male-limited precocious puberty (FMPP).

Genetic testing for FMPP-associated gain-of-function mutations in LHCGR can allow definitive diagnosis of FMPP, helping to select the most appropriate therapy for arresting precocious pubertal development. In addition, family testing can enable early identification of boys predisposed to developing FMPP, allowing timely intervention.

Causes of Gonadotropin-Independent Precocious Puberty in Boys

Normally, puberty is triggered by initiation of the pulsatile release of gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH acts on the pituitary to stimulate the release of the gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH). In the male, LH signals the Leydig cells in the testes to begin production of androgens, which then drive the development of the male secondary sex characteristics. Extraglandular aromatization of testosterone gives rise to estrogen, which is believed to be responsible for the pubertal growth spurt and closure of the epiphyseal junctions in bones (5). While the majority of testosterone is synthesized in Leydig cells, biosynthesis of the testosterone precursor androstenedione occurs in both Leydig cells and the zona reticularis of the adrenal cortex, which also produces small amounts of testosterone.

Gonadotropin-independent precocious puberty is due to exogenous sex steroid exposure or to LH-independent synthesis of testosterone or overproduction of adrenal androgens (6).

Gonadotropin-Independent Testosterone Synthesis

Familial Male-Limited Precocious Puberty
Familial male-limited precocious puberty is caused by LH-independent activation of testosterone production in Leydig cells (3, 4). Normally, testosterone synthesis is stimulated by binding of LH to the luteinizing hormone chorionic gonadotropin receptor (LHCGR) expressed on Leydig cells. LHCGR belongs to the family of G-protein coupled seven-transmembrane-domain proteins. Binding of LH to LHCGR activates an intracellular G protein, which initiates a series of further reactions, ultimately leading to testosterone biosynthesis.

G Proteins

G proteins are membrane-associated heterotrimers composed of an alpha, a beta, and a gamma subunit (7). The alpha subunit binds guanine nucleotides and displays GTPase activity. In a G protein coupled to an unbound receptor, the alpha subunit is occupied by a GDP molecule. Ligand binding to the receptor triggers exchange of GDP for GTP, allowing the GTP-bound alpha subunit to dissociate from the beta-gamma dimer. Both the GTP-bound alpha subunit and the free beta-gamma dimer then serve various effector functions. The G protein associated with LHCGR belongs to the Gs class, which activates adenylyl cyclase, promoting synthesis of the second messenger cAMP.

FMPP-associated gain-of-function mutations in LHCGR allow the receptor molecule to activate the receptor-coupled Gs protein and trigger testosterone synthesis in the absence of agonist binding (8). FMPP-associated mutations typically are missense mutations and cluster in the transmembrane domains, especially in the sixth, and in the third cytoplasmic loop. Of note, most activating mutations do not abolish the ability of LHCGR to respond to stimulation by hCG.

For reasons that are not entirely clear, FMPP-associated mutations in LHCGR do not seem to cause any phenotype in females (9, 10). In contrast, loss-of-function mutations in LHCGR lead to hypogonadism in both males and females (11, 12).

Leydig Cell Adenomas
Leydig cell adenomas are the most frequent form of hormone-producing testicular tumors (13, 14). In several cases, a somatic gain-of-function mutation in LHCGR, leading to testosterone overproduction, has been detected in Leydig cell adenomas (15-17).

McCune-Albright Syndrome
McCune-Albright Syndrome is due to somatic gain-of-function mutations in the alpha subunit of Gs proteins normally activated by ligand binding to G-coupled cell-surface receptors such as LHCGR (18, 19). Constitutive activation of the Gs protein decouples synthesis of gonadal steroid hormones from regulation through the LHCGR receptor, leading to precocious puberty. McCune-Albright Syndrome affects predominantly girls, but can also occur in boys.

Germ Cell Tumors
Gonadal or extragonadal germ cell tumors have been associated with secretion of hCG, which can stimulate LHCGR and thus lead to testosterone production (20).

Overproduction of Adrenal Androgens

Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia (CAH) is due to overstimulation of the adrenals by adrenocorticotropic hormone (ACTH) released in response to low plasma cortisol concentrations (21). This cortisol deficiency can be caused by loss-of-function mutation in any one of several enzymes involved in cortisol synthesis. Depending on the enzymatic block, precursors of cortisol may be shunted into the synthesis of adrenal androgens. The resulting overproduction of adrenal androgens can lead to virilization, presenting as ambiguous genitalia in females and precocious puberty in males.

Adrenal Tumors
Adrenal tumors can lead to overproduction of adrenal androgens and, in young boys, to precocious puberty (22).

Clinical Presentation of FMPP

Most boys with FMPP present at age two to three, with an increase in penis size, bilateral enlargement of the testes, appearance of pubic hair, and rapid bone growth. Characteristically, the increase in testicular volume is slightly less than expected from the degree of sexual maturation (2). Bone age is usually advanced over the chronological age by several years (23). Left untreated, FMPP is associated with rapid virilization, tall stature in boys, and below average height in adult men. Post-pubertal development and fertility are typically little affected.

It has been suggested that FMPP may predispose individuals to testicular tumors (8, 24)

Diagnosis of FMPP

Diagnosis of precocious puberty in boys is based on the appearance of secondary sexual characteristics and advanced bone age before age nine. Detection of pubertal or adult concentrations of testosterone in the presence of prepubertal concentrations of gonadotropins indicates gonadotropin-independent precocious puberty (1, 2). This finding can be confirmed by showing lack of gonadotropin increase in response to administration of gonadotropin-releasing hormone.

FMPP is indicated by onset of pubertal development before age four, with an increase in testicular volume that is slightly less than expected from the overall stage of pubertal development. A clear family history of male-limited precocious puberty can confirm a diagnosis of FMPP. In absence of an obvious family history, exclusion of other common causes of gonadotropin-independent precious puberty is necessary, requiring numerous biochemical and imaging studies. CAH can be excluded on biochemical grounds, since it leads to an elevation in the levels of certain cortisol precursors. In addition, CAH is characterized by a relative lack in testicular enlargement. Virilizing adrenal tumors are associated with increased concentrations of adrenal androgens and may be detected by adrenal imaging. Testicular tumors often lead to asymmetric enlargement of the testes. While they may be palpable, testicular tumors can be more reliably detected through ultrasonography.

Genetic testing can allow a definitive diagnosis of FMPP based on a single blood draw (8). In families known to be affected with FMPP, genetic testing can identify female carriers of the disease and permit a diagnosis of FMPP in male infants before they become symptomatic.

Treatment of FMPP

Treatment of gonadotropin-independent precocious puberty depends on the underlying cause. While CAH is managed with cortisol replacement and tumors are typically excised, FMPP can be treated with ketoconazole (25, 26), an inhibitor of testosterone biosynthesis, or combined therapy with spironolactone, an antiandrogen, and testolactone, an inhibitor of androgen-to-estrogen conversion (27, 28). Both treatments may induce central precocious puberty, which can be controlled with long-acting GnRH analogues. Ketoconazole may be associated with hepatotoxicity in a dose-dependent manner (29)

Genetics of FMPP

Inheritance of FMPP is autosomal dominant and male-limited. Similar to the inheritance pattern seen with X-linked diseases, females act as carriers of FMPP-associated mutations in LHCGR. However, in contrast to X-linked diseases, FMPP can be male-to-male inherited. Most FMPP-related mutations in LHCGR seem to be inherited; sporadic mutations were reported in 12 to 33% of patients (30, 31). The majority of cases of FMPP in the US are due to an aspartate to glycine mutation at position 578 in LHCGR that has not been found in European or Brazilian patients (30-32). Severity of FMPP cannot be easily predicted from the genotype, as phenotypic variability has been observed within families. However, an aspartate to tyrosine mutation at position 578 appears to be associated with very early onset of pubertal development.

Genetic Testing for FMPP

The Male Precocious Puberty (LHCGR) Evaluation detects mutations in LHCGR and can allow a definitive diagnosis of FMPP, helping to choose the most appropriate treatment for arresting pubertal development. Genetic testing for FMPP can also identify asymptomatic female carriers of an FMPP-associated mutation in LHCGR and detect a predisposition for developing FMPP in male infants.

How Is Genetic Testing for FMPP Performed?

DNA for sequencing is obtained from leukocytes present in a small blood sample. The coding sequences of LHCGR are amplified in a highly specific manner through a polymerase chain reaction (PCR), and all PCR products are fully sequenced. Sequencing results are interpreted, and a detailed result report is sent to the patient’s physician.

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