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Complete GH Insensitivity (OMIM 262500)

المؤلف:  Wass, J. A. H., Arlt, W., & Semple, R. K. (Eds.).

المصدر:  Oxford Textbook of Endocrinology and Diabetes

الجزء والصفحة:  3rd edition , p1118

2026-09-24

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 Defects in GHR cause variable degrees of insensitivity to GH. The classical form of GHI, also known as Laron syndrome, is characterized by severe short stature observed during childhood (height SDS usually < – 4) associated with dysmorphic features also presented in patients with complete congenital GH deficiency (craniofacial disproportion with a relatively small face, depressed nasal bridge, high- pitched voice, truncal obesity, and micropenis). The adult height of non- treated patients is around 40 centimetres or more below the population mean. These patients have very low levels of IGF- 1, IGFBP- 3, ALS, and GHBP, but elevated basal and stimulated GH levels. This condition is inherited in an autosomal recessive pattern, usually involving consanguineous parents or families from inbred communities.

Important insights on longevity of patients with complete GHI have been published in recent years. Despite obesity and a decrease in lean body mass due to a lifetime without GH action, these patients are protected from diabetes and cancer and have a longevity similar to controls. In a similar manner, GHI animal models demonstrate an improvement of insulin sensitivity over time and extension of lifespan.

Since the first description of homozygous defects in GHR causing complete GHI, more than 70 pathogenic variants in this gene have been identified, involving several types of mutations: gross deletions (6%); non- synonymous single nucleotide variants (41%) or premature stop codons (20%); small deletions causing a frameshift (14%); and nucleotide changes that directly affect the splicing process (19%). The majority of these mutations are located in exons that encode the extracellular domain of GHR (exons 4 to 7). The missense mutations usually disrupt the binding sites for GH and/ or impair the transport of the receptor to the plasma membrane. Usually the diagnosis of these patients is not difficult and molecular studies add little additional information to the clinical assessment.