User:Dmil3422/Laron Syndrome

Laron syndrome, or Laron-type dwarfism, is an autosomal recessive disorder characterized by an insensitivity to growth hormone (GH), usually caused by a mutant growth hormone receptor. It causes a short stature and an increased sensitivity to insulin which means that diabetes mellitus type 2 is less likely to develop, and possibly cancer as well. It can be treated with injections of recombinant IGF-1.

Presentation
The principal feature of Laron syndrome is abnormally short stature (dwarfism). Physical symptoms include: prominent forehead, depressed nasal bridge, underdevelopment of mandible, truncal obesity, and micropenis in males. The breasts of females reach normal size, and in some are large in relation to body size. It has been suggested that hyperprolactinemia may contribute to the enlarged breast size. Seizures are frequently seen secondary to hypoglycemia. Some genetic variations decrease intellectual capacity. Laron syndrome patients also do not develop acne, except temporarily during treatment with IGF-1 (if performed).

In 2011, it was reported that people with this syndrome in the Ecuadorian villages are resistant to cancer and diabetes and are somewhat protected against aging. This is consistent with findings in mice with a defective growth hormone receptor gene.

Pathophysiology


Molecular genetic investigations have shown that this disorder is mainly associated with mutations in the gene for the growth hormone receptor (GHR). These can result in defective hormone binding to the ectodomain or reduced efficiency of dimerization of the receptor after hormone occupancy. There are exceptionally low levels of insulin-like growth factor (IGF-1) and its principal carrier protein, insulin-like growth factor binding protein 3.

A related condition involving postreceptor insensitivity to growth hormone has been associated with STAT5B.

Diagnosis
Laron syndrome can be diagnosed through biochemical analyses: basal GH levels are abnormally increased, while IGF-1 is low. When a GHRH test is performed, IGF-1 fails to increase. GHBP (growth hormone binding protein) levels are low in cases with mutations in the extracellular domain of the GH receptor and normal in cases with mutations in the intracellular domain. Genetic tests should be performed to make a precise etiological diagnosis.

Treatment
Administration of GH has no effect on IGF-1 production, therefore treatment is mainly by biosynthetic IGF-1. IGF-1 must be taken before puberty to be effective.

The drug product Increlex (mecasermin), developed by the company Tercica, purchased by Ipsen, was approved by the US Food and Drug Administration in August 2005 for replacing IGF-1 in patients who are deficient.

IPLEX (Mecasermin rinfabate) is composed of recombinant human IGF-1 (rhIGF-1) and its binding protein IGFBP-3. It was approved by the U.S. Food and Drug Administration (FDA) in 2005 for treatment of primary IGF-1 deficiency or GH gene deletion. Side effects from IPLEX are hypoglycemia. IPLEX's manufacturing company, Insmed, after selling its protein production facility, can no longer develop proteins, thus can no longer manufacture IPLEX as of a statement released in July 2009.

Prognosis
People with Laron syndrome have strikingly low rates of cancer and diabetes, although they appear to be at increased risk of accidental death due to their stature.

Incidence
The majority of reported cases of Laron syndrome have been in people with Semitic origins, almost all of them being Jews or assimilated descendants of Jews.

Numerous Laron syndrome patients are found in Israel among the country's diverse Jewish population composed of Jews from around the world, as well as patients outside Israel originally from communities of the Jewish diaspora, such as Egypt and Iraq. There is also a disproportionate number of sufferers found in remote villages in Ecuador who are descended from colonial-era Jewish-origin New Christian conversos (Sephardi Jews who themselves, or whose forebears, had been compelled to convert to Catholicism back in Spain) who had covertly migrated to Ecuador during the Spanish Conquest despite the Spanish Crown's prohibition of their emigration to its colonies and territories as a result of the Inquisition.

Other patients include people of other Semitic non-Jewish origins, including from Saudi Arabia.

Eponym
It is named after Zvi Laron, the Israeli researcher who, with A. Pertzelan and S. Mannheimer, first reported the condition in 1966, based upon observations which began in 1958.

Resistance to GH was first reported by Laron in 1966. Since then, severe resistance to GH, characterized by grossly impaired growth despite normal levels of GH in serum, has been termed Laron syndrome.

Homo floresiensis
Recent publications have proposed that Homo floresiensis represented a population with widespread Laron syndrome. This is only one of several competing hypotheses, and has received criticism as insufficient to explain the "range features observed in H. floresiensis".