Última actualización:
August 01, 2016
Años publicados: 1990, 1992, 1995, 2003, 2005, 2011, 2012, 2016
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.
Summary
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.
Introduction
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.
Treatment
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:
Ipsen Biopharmaceuticals
Basking Ridge, NJ
https://increlex.com/patient-patient-product-information.asp
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
Email: [email protected]
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Arlan L. Rosenbloom, MD
Adjunct Distinguished Service Professor Emeritus
Department of Pediatrics
University of Florida College of Medicine
Gainesville, Florida
[email protected]
TEXTBOOKS
Rosenbloom AL. Growth hormone insensitivity syndrome. In: Radovick S, ed. Pediatric Endocrinology: A Practical Clinical Guide. 2nd ed. New York, NY: Springer Science 2013: page 29-54.
Allan DB, Rose SR, Reiter EO. Normal growth and growth disorders In: Kappy MS, Allen DB, Geffner M, eds. Principles and Practice of Pediatric Endocrinology. Springfield, IL: Charles C Thomas; 2005:77-211.
Rosenbloom AL, Connor EL. Hypopituitarism and other disorders of the growth hormone (GH)-insulin like growth factor-I (IGF-I) axis. In: Lifshitz F, ed. Pediatric Endocrinology. Vol. 2. 5th ed, New York, NY: Informa Healthcare; 2007:65-100.
JOURNAL ARTICLES
Guevara-Aguirre J, Rosenbloom AL. Obesity, diabetes, and cancer: insight into the relationship from a cohort with growth hormone receptor deficiency. Diabetologia. 2015;58:37-42.
Guevara Aguirre J, Rosenbloom AL, Balasubramaniam P, Teran E, Guevara Aguirre M, Guevara C,Procel P, Alfaras I, De Cabo R, Di Biase S, Narvaez L, Saavedra, J, Longo VD. Absent GH counterregulation due to GH receptor deficiency with obesity and enhanced insulin sensitivity.J Clin Endocrinol Metab. 2015;100:2589-2596.
Guevara-Aguirre, J, Balasubramanian P, Guevara-Aguirre M, et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. 2011;3(70):70ra13. https://www.ncbi.nlm.nih.gov/pubmed/21325617
David A, Hwa V, Metherell LA, et al. Evidence for a continuum of genetic, phenotypic, and biochemical abnormalities in children with growth hormone insensitivity. Endocr Rev. 2011;32:472-97.
Rosenbloom AL. Mecasermin (recombinant human insulin like growth factor-I). Adv Therapy. 2009;26:40-54.
Rosenbloom AL. The physiology of human growth: a review. Reviews in Endocrinology. 2008;36-48.
Rosenfeld RG, Belgorosky A, Camacho-Hubner C, Savage MO, Wit JM, Hwa V. Defects in growth hormone receptor signaling. Trends Endocrinol Metab. 2007;18:134-141.
Walenkamp MJ, van der Kamp HJ, Pereira AM, Kant SG, van Duyvenvoorde HA, Kruithof MF. A variable degree of intrauterine and postnatal growth retardation in a family with a missense mutation in the insulin-like growth factor I receptor. J Clin Endocrinol Metab. 2006;91:3062-3070.
Kornreich L, Horev G, Schwarz M, Karmazyn B, Laron Z. Laron syndrome abnormalities: spinal stenosis, os odontoideum, degenerative changes in atlanto-odontoid joint, and small oropharynx. AJNR Am J Neuroradiol. 2002;23(4):625-31.
Laron Z, Pertzelan A, Mannheimer S. Genetic pituitary dwarfism with high serum concentration of growth hormone — a new inborn error of metabolism? Isr J Med Sci. 1966;2:152-155.
INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Laron Syndrome. Entry No: 262500. Last Update 07/14/2016.. Available at: https://omim.org/entry/262500 Accessed August 1, 2016.
Rosenbloom AL, Guevara-Aguirre J. Growth Hormone Resistance. Medscape. Last Update September 15, 2015. https://emedicine.medscape.com/article/922902-overview Accessed August 1, 2016.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Growth Hormone Insensitivity With Immunodeficiency. Entry No: 245590. Last Update 10/20/2010.. Available at: https://omim.org/entry/245590 Accessed August 1, 2016.
Zvi Laron, MD: The man behind Laron syndrome. Endocrine Today. July 2010. https://www.healio.com/endocrinology/news/print/endocrine-today/%7B3D0E1CEB-3309-4899-84F7-C12033B7C82E%7D/Zvi-Laron-MD-The-man-behind-Laron-syndrome Accessed August 1, 2016.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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