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NORD is very grateful to 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 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.
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 STAT5b mutation has similar growth effects but is also associated with severe immunocompetence impairment. The IGFALS mutation, while resulting in 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 females.
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.
GHI is inherited as an autosomal recessive genetic disorder and caused by mutation of the GH receptor 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.
Autosomal recessive inherited diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Defects occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives 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 defective gene and, therefore, 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 and be genetically normal for that particular trait is 25%. The risk for most recessive conditions is the same for males and females.
All individuals carry a few abnormal genes. 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 250 cases of GHI due to GHRD have been reported. The ethnic background for most (90%) of the reported cases is known. About 65% of cases involve persons of 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.
Symptoms of the following disorders can be similar to those of GHI. Comparisons may be useful for a differential diagnosis:
In addition to the genetic forms of GHI, failure to have a normal growth response despite adequate GH production is characteristic of a number of conditions including chronic illness, undernutrition, kidney disease, liver disease, and congenital syndromes. These conditions are often referred to as secondary GHI.
Coffin-Siris syndrome is a disorder of unknown cause. It is present at birth and affects both sexes. It is chiefly characterized by feeding problems, frequent respiratory infections, and growth deficiencies. (For more information on this disorder, choose "Coffin-Siris" as your search term in the Rare Disease Database.)
Cockayne syndrome is a progressive disorder which manifests itself during the second year of life. It is characterized by a hypersensitivity to sunlight and growth retardation. (For more information on this disorder, choose "Cockayne" as your search term in the Rare Disease Database.)
Growth hormone deficiency (GHD), in its most severe form, is very similar to primary GHI, the main difference being that in children with GHI, a high level of GH is present in the blood and the administration of recombinant GH does not result in normalization of growth.
The cause of GHD is often unknown, but genetic defects have been described in the receptor for GH releasing hormone from the brain and in the GH molecule, as well as in factors that lead to other hormone deficiencies along with GH. It can be treated fairly easily and reliably with injections of recombinant human GH. (For more information on this disorder, choose "growth hormone deficiency" as your search term in the Rare Disease Database.)
Hydrocephalus can be confused with GHI due to GHRD in infancy because of the prominence of the forehead, presence of sclera (white) above the iris of the eye, the so-called "setting sun sign", the small face relative to the skull, and the prominence of scalp veins. However, rapid head growth is not occurring as it is in hydrocephalus. (For more information on this disorder, choose "Hydrocephalus" as your search term in the Rare Disease Database.)
There are many disorders that can cause short stature. For more information on those disorders choose "short stature" as your search term in the Rare Disease Database or contact the Human Growth Foundation or the Short Stature Foundation noted in the resources section of this report.
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 Increlex (recombinant IGF-I) has been approved for children whose growth failure is due to GHRD or GH inactivating antibodies. For more information, please contact:
2000 Sierra Point Parkway, Suite 400
Brisbane, CA 94005
Phone: (650) 624-2900
Fax: (650) 624-4940
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:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Contact for additional information about growth hormone insensitivity:
Arlan L. Rosenbloom, MD
Adjunct Distinguished Service Professor Emeritus
Department of Pediatrics
University of Florida College of Medicine
PO Box 8126
Gaithersburg, MD 20898-8126
Phone #: 301-251-4925
800 #: 888-205-2311
Home page: http://rarediseases.info.nih.gov/GARD/
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Home page: http://www.hgfound.org/
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Home page: http://www.magicfoundation.org
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Rosenbloom AL, Guevara-Aguirre J. Growth Hormone Resistance. Emedicine. http://emedicine.medscape.com/article/922902-overview accessed. Updated April 18, 2012. Accessed July 17, 2012.
Zvi Laron, MD: The man behind Laron syndrome. Endocrine Today. http://www.healio.com/endocrinology/news/print/endocrine-today/%7B3D0E1CEB-3309-4899-84F7-C12033B7C82E%7D/Zvi-Laron-MD-The-man-behind-Laron-syndrome. July 2010. Accessed July 17, 2012.
Report last updated: 2012/07/18 00:00:00 GMT+0