Growth hormone insensitivity (GHI) is a group of extremely rare genetic disorders in which the body is unable to use the growth hormone that it produces. GHI can be caused by mutations in the growth hormone receptor (GHR) gene or mutations in genes involved in the action pathway within the cell after the growth hormone binds to its receptor, preventing the production of insulin-like growth factor (IGF-1), the substance responsible for the growth effects of growth hormone. Even more rarely, children with GH gene deletion who have been treated with recombinant GH develop antibodies that block GH binding to its receptor. Affected children fail to grow normally.

Children with GHRD who are treated with IGF-1 before puberty have improved growth, but, unlike children with GH deficiency given recombinant GH treatment, they do not have normal growth restored. Treatment for these conditions is only effective while the growing bones are still open, i.e. before the completion of adolescence. IGF-I insensitivity due to IGF-I receptor mutation mimics GHI, but results in less severe growth deficiency and is somewhat responsive to treatment with recombinant GH.

GHI is characterized by short stature and delayed bone age, as well as normal or high levels of circulating GH. Other common symptoms are delayed onset of puberty, prominent forehead, low blood sugar and obesity in adulthood. Except for an extremely rare form of GHI, where the gene for IGF-I is defective, brain development is normal, apparently because IGF-I can be made during fetal life without GH stimulation in the other conditions. Some, but definitely not all, patients with the less rare condition of IGF-I receptor deficiency may have mild intellectual impairment.

Laron and colleagues in Israel, first reported the condition in 1966, based on observations that began in 1958, and have continued to the present. The molecular basis for the syndrome he described, genetic mutation of the GHR in some of the Israeli patients was initially described in 1989, and since then over 40 different mutations of this protein have been identified by many investigators. The other genetic defects in the action pathway of GH after its binding to the GHR and associated with varying effects of IGF-I deficiency have been described in the past 15 years.

Laron syndrome is caused by mutations in the GHR gene. This gene provides instructions for making a protein called the growth hormone receptor. The receptor is present on the outer membrane of cells throughout the body, particularly liver cells. As its name suggests, the growth hormone receptor attaches (binds) to growth hormone; the two proteins fit together like a key in a lock. When growth hormone is bound to its receptor, it triggers signaling that stimulates the growth and division of cells. This signaling also leads to the production, primarily by liver cells, of another important growth-promoting hormone called insulin-like growth factor I (IGF-I).

Growth hormone and IGF-I have a wide variety of effects on the growth and function of many parts of the body. For example, these hormones stimulate the growth and division of cells called chondrocytes, which play a critical role in producing new bone tissue. Growth hormone and IGF-I also influence metabolism, including how the body uses and stores carbohydrates, proteins, and fats from food.

Mutations in the GHR gene impair the receptor's ability to bind to growth hormone or to trigger signaling within cells. As a result, even when growth hormone is available, cells are unable to respond by producing IGF-I and stimulating growth and division. The cells' inability to react to growth hormone, which is described as growth hormone insensitivity, disrupts the normal growth and function of many different tissues. Short stature results when growth hormone cannot adequately stimulate the growth of bones. Changes in metabolism caused by insensitivity to growth hormone and the resulting shortage of IGF-I cause many of the other features of the condition, including obesity.

Researchers are working to determine how mutations in the GHR gene may protect people with Laron syndrome from developing cancer and type 2 diabetes. Studies suggest that insensitivity to growth hormone may help prevent the uncontrolled growth and division of cells that can lead to the development of cancerous tumors. Growth hormone insensitivity also appears to alter how the body responds to insulin, which is a hormone that regulates blood sugar levels. Resistance to the effects of insulin is a major risk factor for type 2 diabetes. People with Laron syndrome have the opposite situation, an increased sensitivity to insulin, which likely helps explain their reduced risk of this common disease.