NORD gratefully acknowledges Arlan L. Rosenbloom, MD, Adjunct Distinguished Service Professor Emeritus, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida, for assistance in the preparation of this report.
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 growth hormone binds to its receptor, preventing production of insulin-like growth factor (IGF-1), the substance responsible for the growth effects of growth hormone. Even more rarely, children with a 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 in infancy and early childhood, 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 GHRD in 1966, based on observations that began in 1958, and have continued to the present. The molecular basis for the syndrome they described, a mutation of the GHR gene in some of the Israeli patients was initially described in 1989, and since then over 60 different mutations in the gene for this protein has been identified by many investigators. Mutations in genes in the action pathway of GH after it’s binding to the GHR and associated with varying effects of IGF-I deficiency have been described in the past 15 years.
There is a wide range of effects depending on the gene mutations involved (see Causes section). The very few individuals with IGF-I gene mutation have severe intellectual disability and intrauterine growth failure, with deafness and micrognathia. GHRD results in severe growth failure without deleterious effects on intrauterine growth or brain development, and the mutation of STAT5b, responsible for an important activator protein, has similar growth effects but is also associated with severe impairment of immunocompetence. The IGFALS mutation, affecting an important stabilizing component of the circulating IGF-I, while associated with very low circulating IGF levels, has only modest effects on growth.
GHI is characterized by severe but proportionate short stature as a result of growth failure that begins at birth. Along with growth retardation, there are delays in tooth eruption. There is also disproportion between the growth of the skull and face, a saddle nose and deep-set eyes. Sexual development is moderately delayed in both genders. In females with these disorders, the onset of menses usually takes place between 16 to 19 years of age. Hands and feet are smaller than normal, in proportion to overall body size. A high-pitched voice may also be present and obesity is common in the adults, especially women.
High circulating levels of GH are found in the children but may not be obvious without stimulation tests in the adults. A high percentage of young patients have low blood sugar levels (hypoglycemia) that can be associated with seizures in some very young children. Recently, researchers have found that a population of individuals with GHRD in Ecuador (where approximately 1/3 of the world’s population of GHRD has been identified) had absence of cancer and diabetes with molecular evidence of protection from aging changes in their DNA. This may be due to a protective effect from the low IGF-I levels, and in the case of absence of diabetes despite obesity, due to absence of counter-regulation effects of GH.
GHI is inherited as an autosomal recessive genetic disorder and caused by mutation of the GHR gene or mutations in the genes involved in the action pathway within the cell after GH binds to its receptor, including STAT5b, IGF-1, and IGFALS.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Worldwide, only about 300 cases of GHI due to GHRD have been reported. The ethnic background for most (90%) of the reported cases is known. About 65% of patients have Middle Eastern ancestry and a group of Ecuadorian conversos. (Conversos are Jews who converted to Christianity in Spain during the Inquisition, some of whom migrated to the New World) Subsequently, marriage among close relatives made the disorder more common among the descendants of these groups. STAT5b, IGF-1 and IGFALS mutations have been reported in only a few families.
A diagnosis of GHI is usually made when failure to grow is accompanied by the typical facial appearance and central chubbiness that suggests GH deficiency, but with the finding of elevated GH levels.
The orphan drug mecasermin rinfabate (recombinant IGF-I) has been approved for children whose growth failure is due to GHRD or GH inactivating antibodies. For more information contact:
Basking Ridge, NJ
Treatment of GHI with recombinant human GH is not effective because the body cannot utilize the hormone to grow. Recombinant IGF-I therapy is associated with a risk of hypoglycemia which can be prevented by feeding. Fortunately, long-term effects of hypoglycemia have not been seen.
Genetic counseling is recommended for patients and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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For information about clinical trials sponsored by private sources, contact:
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Arlan L. Rosenbloom, MD
Adjunct Distinguished Service Professor Emeritus
Department of Pediatrics
University of Florida College of Medicine
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