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The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
Orpha Number: 181393
Growth hormone insensitivity syndrome (GHIS) is a group of diseases characterized by marked short stature associated with normal or elevated growth hormone (GH) concentrations, which fail to respond to exogenous GH administration. GHIS comprises growth delay due to IGF-1 deficiency, growth delay due to IGF-1 resistance, Laron syndrome, short stature due to STAT5b deficiency and primary acid-labile subunit (ALS) deficiency (see these terms).
A few cases of IGF-1 deficiency, IGF-1 resistance, STAT5B and ALS deficiencies, and more than 250 cases of Laron syndrome have been reported in the literature so far. Males and females are equally affected.
Intrauterine growth and birth size are usually subnormal. Postnatal growth is slowed. Facial dysmorphism is common and includes microcephaly, thin upper and everted lower lips and small chin. Disproportional growth, delayed motor development and delayed puberty have been described in some cases and relative obesity may occur in young adults. Intellectual development varies from normal intelligence to intellectual deficiency. Despite sharing short stature and the classical biochemical features of GH insensitivity, affected individuals present heterogeneous clinical features depending on the genetic condition. Immune deficiency has been described in some cases of STAT5b deficiency. Hearing loss has been described in some cases of IGF-1 deficiency.
GHIS is due to mutations in the growth hormone receptor ( GHR ) gene (Laron syndrome) or to post receptor defects due to mutations in the IGF-1 (IGF-1 deficiency and IGF-1 resistance), IGFALS (short stature due to primary ALS deficiency) or STAT5B genes (STAT5b deficiency). Transmission is autosomal recessive.
The diagnosis is based on clinical and biological findings. Hormonal tests reveal normal or high serum concentrations of GH. IGF-1 and growth hormone binding protein (GHBP) levels depend on the disease-causing mutations. IGF-1 levels are low in cases ofGHR defects, STAT5b, IGF-1 and ALS deficiencies, and high in cases of IGF-1 resistance. GHBP levels are low in cases of mutations in the extracellular domain of GHR and normal in cases of mutations in the intracellular domain of GHR or post receptor defects. IGF-BP 3 levels are low in cases of GHR, STAT5b, and ALS deficiencies, normal in cases of IGF-1 deficiency. ALS levels are low in cases of ALS deficiencies. Genetic tests should be performed to make a precise etiological diagnosis.
The differential diagnosis should include secondary IGF-1 deficiency due to nutritional problems or chronic pediatric diseases.
Genetic counseling should be proposed to parents of an affected individual before any further pregnancy, informing them of the risks and the available diagnostic methods.
Management and treatment
Management aims at improving growth and, except for IGF-1 resistance, includes treatment with daily subcutaneous injections of mecasermin, a recombinant human IGF-1, and diet with adequate caloric intake. In August 2005, mecasermin was granted EC orphan drug designation. Growth hormone treatment may partially improve growth in cases of IGF-1 resistance. There is no treatment that cures or prevents the disease.
With age, osteoporosis can become apparent. Patients may develop obesity, hypercholesterolemia, insulin resistance, glucose intolerance and even type II diabetes.
Visit the Orphanet disease page for more resources.
Source: GARD Last updated on 05-01-20
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