Last updated:
12/10/2024
Years published: 2024
NORD gratefully acknowledges Ellen Leschek, MD, Program Director, National Institutes of Health, National Institute of Diabetes, Digestive and Kidney Diseases, Division of Diabetes, Endocrinology and Metabolic Diseases, for the preparation of this report.
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Summary
Familial male-limited precocious puberty (FMPP) is a rare genetic condition characterized by the onset of puberty by about 3 years of age in affected males.1
Signs and symptoms of FMPP can include penis enlargement, pubic and underarm hair, adult body odor, acne, height growth acceleration, advanced bone age, excess muscular development and impulsivity and aggressive physical/sexual behavior. Testes are slightly enlarged, but small for the extent of masculinization (male sexual development).2
FMPP is caused by a change (variant) in the luteinizing hormone receptor (LHR) gene, which results in continuous release of testosterone from the Leydig cells in the testes. FMPP follows an autosomal dominant inheritance pattern.3
The diagnosis of FMPP is suspected based on the signs and symptoms and/or a positive family history. Family history may not be obvious if the gene variant was inherited from a long line of females or if the variant is sporadic. At diagnosis, affected male children typically have high blood testosterone. However, the other hormones that are elevated in boys experiencing normal puberty (luteinizing hormone [LH] and follicle stimulating hormone [FSH]) are low.4 Genetic testing can confirm the presence of a LHR variant.
There is no cure for FMPP, but diagnosis allows for appropriate treatment, monitoring and genetic counseling.
Normal male puberty typically starts with an increase in testicular size at approximately 9 years of age or later. This is usually followed by pubic and underarm (axillary) hair growth, penis (phallus) enlargement, adult body odor, acne and an increased rate of growth.
FMPP usually begins between 1 and 3 years with premature signs and symptoms of puberty due to too much testosterone circulating in the blood as well as excessive estrogen. The extra estrogen is due to conversion of testosterone to estrogen by aromatase, an enzyme that is present in some body tissues. The onset, progression and severity of FMPP signs and symptoms can vary from person to person and even within families.3
The signs and symptoms of FMPP may include3:
When normal puberty begins, the hypothalamus in the brain releases gonadotropin-releasing hormone (GnRH), which stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH) into the bloodstream. When LH reaches the testes, it binds to the luteinizing hormone receptor (LHR) on the Ledig cells of the testes, prompting them to produce testosterone.
FMPP is caused by an activating variant in the LHR gene5. Many different activating variants of this gene have been reported. When there is an activating variant in the LHR gene, the LHR behaves as though there is always LH in the circulation. The result is continuous release of testosterone from the Leydig cells of the testes. The testosterone causes early development of male characteristics (masculinization). Also, some testosterone gets converted to estrogen by an enzyme (aromatase) found in some body tissues. Testosterone and estrogen cause rapid height growth and aging of the growth plates of the bones.
FMPP follows a dominant pattern of inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is needed to produce the disease. The gene variant can be inherited from either parent or can be due to a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. Males who have the gene variant will have FMPP. Females who have the gene variant do not have any medical issues, but they are able to pass the variant to their children (50% risk for each pregnancy).
FMPP is a rare disorder. There are probably fewer than 1,000 people in the U.S. with FMPP.6 Many activating variants have been identified in the LHR gene. In the U.S., the most common variant is substitution of the amino acid glycine for aspartic at position 578.7 This variant is less common in FMPP individuals in Europe, suggesting the possibility that many FMPP males in the U.S. descended from a small number of affected males.
The diagnosis of FMPP should be strongly suspected in a male child if there are signs and symptoms of precocious puberty, such as masculinization and rapid height growth and/or a family history of FMPP. LH and FSH blood levels are typically in the prepubertal range in the early years. Blood testosterone is characteristically elevated, and X-ray of the left hand and wrist shows that the bone age is advanced compared to chronological age. If there is no family history of FMPP, it is important to measure the hormones that can be produced by germ cell tumors, hCG and alpha-fetoprotein (AFP). If hCG and AFP are normal, sequencing of the LHR gene should be performed to look for a gene variant that causes FMPP.
The primary reasons to treat FMPP in childhood are to: (1) suppress pubertal hormones to prevent rapid early masculinization (pubic hair, axillary hair, phallic enlargement, acne, body odor, muscular body build, etc.) and (2) prevent early closure of the growth plates of the bones, which can decrease adult height.3
While there are no FDA-approved therapies for FMPP, two treatment approaches are used. The first is ketoconazole, an oral drug that blocks the production of some hormones in the body, including testosterone.11-13 Sometimes ketoconazole causes liver damage (regardless of dose).1 Ketoconazole can also decrease the body’s production of cortisol, a hormone that is important in regulating the body’s response to stress. Reduction in cortisol release can be life-threatening. The second approach involves a combination of an oral drug to block the effects of testosterone (spironolactone or bicalutamide) and another oral medication to prevent an enzyme in the body from changing the testosterone to estrogen (anastrozole or letrozole). The combination has shown better outcomes for preserving final adult height. Early real (central) puberty typically occurs in boys with FMPP and injectable gonadotropin releasing hormone (GnRH) is added to the treatment regimen when this occurs.1,3,4,15
Studies show that the newer combination treatments not only slow puberty but also allow them to grow normally. Some affected people get better without side effects.4
The hormonal issues caused by FMPP are managed by pediatric endocrinologists. Many boys with FMPP have attention-deficit/hyperactivity disorder (ADHD), requiring treatment with medication and/or therapy.16 They can also have physically and sexually aggressive behavior, particularly before treatment is initiated.3 For these reasons, inclusion of a mental health specialist on the care team is beneficial for boys with FMPP.
Genetic counseling should be provided for males with FMPP and females with a family history of FMPP who are of child-bearing age and planning to have children. It is beneficial to know if a male child will be affected so that treatment can be started early.
Males with FMPP have a 50% chance of passing the gene variant on each time they have a child. If the child is male and inherits the gene variant, he will develop FMPP. If the child is female, she will have a 50% chance of inheriting the gene variant, which she can then pass on to her children. If a female has a family history of FMPP, she can have genetic testing to determine if she is a carrier of the gene variant. If a father has FMPP or a mother is a carrier of a FMPP gene variant, blood can be obtained from the baby at birth or early in life to determine if they have a LHR variant. Alternatively, if the baby is a boy, the parents can work closely with the pediatrician to monitor the baby for signs and symptoms of FMPP and a testosterone level can be drawn at 12-18 months to assess the child for FMPP. If the baby is a girl, testing is not necessary until she is of child-bearing age and is planning to have children.
There is currently one natural history study underway for children with excess androgen, including boys with FMPP.17 This study is evaluating individuals with genetic causes of too much androgen (including testosterone) to better understand its effects.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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