Laron syndrome

Called the Laron syndrome, also known as primary GH insensitivity, GH receptor deficiency, short stature by growth hormone resistance, primary growth hormone insensitivity or growth hormone receptor deficiency is a very rare, autosomal recessive disease characterized by mainly a short stature manifests in affected patients.

Frequency

The Laron syndrome is an extremely rare inherited disorder. About 200 to 300 cases have been reported worldwide.

Clinical features and diagnosis

Patients with Laron syndrome have an innate resistance to growth hormone. Due to a genetic defect in the somatotropin receptor ( GHR, growth hormone receptor ) somatotropin (GH, growth hormone ) can not activate the expression of insulin- like growth factor 1 (IGF -I, insulin- like growth factor I).

Short stature, facial deformities, trunk emphasized obesity, later onset of puberty and recurrent hypoglycemia are typical of the Laron syndrome. In plasma, there are extremely low levels of IGF -1 and significantly increased values ​​for somatotropin. Somatotropin -binding protein ( GHBP ), the soluble isoform of the GHR is either greatly reduced or completely absent in the plasma or function.

Children have an increased susceptibility to infection.

The strongly reduced secretion of IGF- I causes not only short stature. Patients with Laron syndrome have a substantially reduced probability of developing cancer, acne, and diabetes mellitus. Also, the aging takes place slowly. An Ecuadorian population in the province of Loja 99 patients with Laron syndrome has been medically monitored 22 years. In this group, a non-lethal malignancy and no cases of diabetes mellitus was observed in this period. In the control group, however, the prevalence of cancer in 17% and for diabetes at 5 %. These epidemiological data lead to speculation as to whether slowed by an artificial lowering of IGF -1 levels, aging and the likelihood of developing cancer can be reduced.

Dwarf mice also exhibit a deficit in GHR and have a significantly higher life expectancy than the wild type.

Genetics

The GHR gene, encodes the somatotropin receptor is located in the human chromosome 5 p13 -p12 gene locus, the gene consists of 638 amino acids and is membrane bound. The mutations in the GHR can be either the binding of GH to the extracellular domain ( ectodomain ) prohibit or receptor dimerization after docking of the somatotropin block. Both these factors mean that the cells of the patients express only very low levels of IGF-1.

The defects in the GHR gene, which can lead to Laron syndrome, are heterogeneous and include gene deletions and nonsense, missense, frameshift and splice -site mutations, as well as repetitive CpG dinucleotide substitutions, all essentially the extracellular domains of GHR concern. In total, over 30 different GHR - inactivating mutations were found.

In an Ecuadorian population of Spanish descent with little genetic exchange through inbreeding in humans is found in exon 6 homozygous substitution of a single nucleotide.

Treatment and Prognosis

1986 biotechnologically produced IGF-I ( rhIGF-I, recombinant human IGF-I) is available in sufficient quantities, so that in order from Laron syndrome affected children can be treated. The prognosis is - even without treatment - favorable. Patients can, apart from the daily disabilities, limited, lead a short stature, a largely normal life.

First description

The Laron syndrome was established in 1966 by a working group led by the Israeli Zvi Laron Kinderendokrinologen (* 1927) first described. According to him, the disease was named. The clinical studies began in 1958, however, a group short stature children who had high levels of growth hormone in serum. Thereafter, the cause of the disease has been identified as the molecular defect in the growth hormone receptor ( somatotropin receptor).