LHCGR

At least 17 LHCGR gene mutations have been identified in boys and men with familial male-limited precocious puberty. These mutations replace single protein building blocks (amino acids) in the luteinizing hormone/chorionic gonadotropin receptor. The mutations cause the receptor to be constantly turned on (constitutively activated), even when not attached (bound) to luteinizing hormone or chorionic gonadotropin. Researchers suggest that the change in amino acid sequence may lead to constitutive activation by changing the shape or other properties of the receptor.

In males, the overactive receptor causes the Leydig cells to produce an excess of testosterone, leading to familial male-limited precocious puberty. Affected boys begin exhibiting the signs of puberty, such as genital growth and pubic hair, between the ages of 2 and 5. The overactive receptor has no apparent effect on females.

LHCGR gene mutations that cause Leydig cell hypoplasia disrupt luteinizing hormone/chorionic gonadotropin receptor function, impeding the body's ability to react to these hormones. In males, the mutations result in poorly developed or absent Leydig cells and impaired production of testosterone. A lack of testosterone interferes with the development of male reproductive organs before birth and the changes that appear at puberty.

Mutations that prevent the production of any functional receptor protein cause more severe signs and symptoms of Leydig cell hypoplasia. Affected individuals with a typical male chromosome pattern (46,XY) have female external genitalia and small testes that are undescended, which means they are abnormally located in the pelvis, abdomen, or groin. Severely affected individuals do not develop secondary sex characteristics, such as increased body hair, at puberty.

LHCGR gene mutations that allow some receptor protein function cause milder signs and symptoms of Leydig cell hypoplasia. Affected males may have a range of genital abnormalities, including a small penis (micropenis), the opening of the urethra on the underside of the penis (hypospadias), or a scrotum divided into two lobes (bifid scrotum). Because of these abnormalities, the external genitalia may not look clearly male or clearly female.

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Although people who are genetically female (with two X chromosomes in each cell) may inherit mutations in both copies of the LHCGR gene that disrupt luteinizing hormone/chorionic gonadotropin receptor function, they do not have Leydig cell hypoplasia because they do not have Leydig cells. Females with the same LHCGR gene mutations that cause Leydig cell hypoplasia in males have normal female genitalia and normal breast and pubic hair development, but they may begin menstruation later than usual (after age 16) and have irregular menstrual periods. These mutations also prevent ovulation, leading to an inability to have children (infertility).