Diseases title

Laron syndrome )

Orpha Number: 633
Complete growth hormone insensitivity, GH receptor deficiency, Growth hormone receptor deficiency, Laron-type dwarfism, Primary GH insensitivity, Primary GH resistance, Primary growth hormone insensitivity, Primary growth hormone resistance, Short stature due to growth hormone resistance

Laron syndrome is a congenital disorder characterized by marked short stature associated with normal or high serum growth hormone (GH) and low serum insulin-like growth factor-1 (IGF-I) levels which fail to rise after exogenous GH administration. The disease has been described in more than 250 cases and is more frequent in Semitic or Mediterranean populations. Males and females are equally affected. Intrauterine growth and birth size are usually normal. Postnatal growth is slowed and generally disproportional with delayed bone age; adult stature ranges from -3 to -12 SD. Motor development is delayed because of diminished muscle mass. Newborns often present with hypoglycemia and a micropenis. Puberty is often delayed. Facial dysmorphism is common and includes protruding and high forehead, shallow orbits, hypoplastic nasal bridge and small chin. Sparse hair may be observed in infancy. Relative obesity, delayed tooth eruption, high-pitched voice, thin bones and skin, and decreased sweating are often present. Patients occasionally have blue sclera and hip degeneration. The disease is due to mutations in the GHR gene (5p14-p12). Mutations affecting the extracellular domain of the growth hormone receptor result in low growth hormone binding protein levels (GHBP, structurally identical to the extracellular domain of GHR) and defective IGF-I production. Transmission is autosomal recessive. A Laron syndrome-like phenotype has been described which is associated with immunodeficiency and is due to gene dysfunction of the signal transducer and activator of transcription 5b (STAT5b deficiency; see this term). A mutation in STAT5B has also been observed in a patient suffering from typical Laron syndrome. Diagnosis is based on clinical and biological findings. Hormonal tests reveal normal or increased level of GH and low IGF-1 levels, which fail to rise after exogenous GH administration. GHBP levels are low in cases with mutations in the extracellular domain of the GHR and normal in cases with mutations in the intracellular domain. Genetic tests should be performed to make a precise etiological diagnosis. The differential diagnosis should include severe growth hormone deficiency (GHD) and growth delay due to IGF-I resistance (see this term), as well as secondary IGF-I deficiency mostly 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 aims at improving growth and includes treatment with daily subcutaneous injections of mecasermin, recombinant human IGF-I, and diet with adequate caloric intake. Frequent feeding is necessary in order to avoid hypoglycemia. In August 2005, mecasermin was granted EC orphan drug designation. There is no treatment that cures or prevents the disease. Prognosis seems good but with age, patients may develop obesity, hypercholesterolemia and have increased risk of fractures due to osteopenia.
source: Orphanet