Laron syndrome

Source: Wikipedia, the free encyclopedia.

Laron syndrome
Other namesgenetic pituitary dwarfism (1966), Laron dwarfism (1973), Laron-type dwarfism (1984), growth hormone insensitivity (1994), hereditary somatomedin deficiency, growth hormone receptor deficiency (GHRD)(1999)
IGF-1, Mecasermin[3]
Frequency1–9 / 1,000,000 (approximately 250 known cases worldwide) [4][5]

Laron syndrome (LS), also known as growth hormone insensitivity or growth hormone receptor deficiency (GHRD), is an

insulin-like growth factor 1 (IGF-1; somatomedin-C) production in response to growth hormone (GH; hGH; somatotropin).[6] It is usually caused by inherited growth hormone receptor (GHR) mutations.[2][6]

Affected individuals classically present with

craniofacial abnormalities, micropenis, low blood sugar, and low serum IGF-1 despite elevated basal serum GH.[7][5][8]

LS is a very rare condition with a total of 250 known individuals worldwide.[4][5] The genetic origins of these individuals have been traced back to Mediterranean, South Asian, and Semitic ancestors, with the latter group comprising the majority of cases.[5] Molecular genetic testing for growth hormone receptor gene mutations confirms the diagnosis of LS, but clinical evaluation may include laboratory analysis of basal GH, IGF-1 and IGFBP levels, GH stimulation testing, and/or GH trial therapy.

People with LS are unresponsive to growth hormone therapy; the disease is instead treated mainly with recombinant IGF-1, Mecasermin.[3]

Evidence has suggested that people with Laron syndrome have a reduced risk of developing cancer and

diabetes mellitus type II, with a significantly reduced incidence and delayed age of onset of these diseases compared to their unaffected relatives.[9][10] The molecular mechanisms of increased longevity and protection from age-related disease among people with LS is an area of active investigation.[11]

Presentation

Physical features

LS is recognized as being part of a spectrum of conditions that affect the

tall stature.[1][12]

In addition to short stature, other characteristic physical symptoms of LS include: prominent forehead, depressed

Seizures are frequently seen secondary to hypoglycemia. Some genetic variations decrease intellectual capacity.[15] Laron syndrome patients also do not develop acne, except temporarily during treatment with IGF-1 (if performed).[9]

Pathophysiology

inheritance
.
Impact of insulin/IGF-1 signaling in Laron syndrome (A) and Western diet (B) on FoxO-mediated gene regulation and associated pathologies. GHR*, growth hormone receptor loss of function mutation in Laron syndrome; GIP, glucose-dependent insulinotropic polypeptide, a whey protein-induced incretin, which stimulates β-cell proliferation and insulin secretion; PRL, prolactin; PRL secretion is induced by serotoninergic hypothalamic signaling; Trp, tryptophan, and Leu, leucine, essential amino acids enriched in the whey protein α-lactalbumin; Trp via serotonin synthesis stimulates pituitary GH and PRL secretion and Leu stimulates β-cell proliferation and insulin secretion.

Under normal circumstances in humans, growth hormone (GH) is released in a pulsatile fashion from cells known as

protein synthesis.[16] Obesity and increased adipose tissue, especially visceral fat, results in reduced GH secretion.[16] There is a natural age-related decline in the GHRH-stimulated release of GH.[16]

Growth hormone receptor mutations

Molecular genetic investigations have shown that LS is mainly associated with autosomal recessive mutations in the gene for the growth hormone receptor (GHR).[6][17] These can result in defective hormone binding to the ectodomain or reduced efficiency of dimerization of the receptor after hormone occupancy.[18]

LS is generally classified as "primary" GH insensitivity, which is distinguished from "secondary" GH insensitivity.

diabetes mellitus.[5][6] A GHR mutation that results in only partial insensitivity to GH can manifest as a form of idiopathic short stature.[2][8]

STAT5B

A related condition involving postreceptor insensitivity to growth hormone has been associated with STAT5B.[19]

Diagnosis

LS should be suspected in children or adults with distinctive physical features listed above, extremely elevated serum hGH concentrations despite low serum IGF-1 levels.[14] A failure of IGF-1 to increase in response to exogenous hGH (IGF-1 stimulation test) is diagnostic for LS.[14] The gold standard for confirming a diagnosis of LS is to perform a genetic analysis with PCR to identify the precise molecular defect in the GH receptor gene.[14] Other laboratory abnormalities include GHBP (growth hormone binding protein) levels being low in cases with mutations in the extracellular domain of the GH receptor and normal in cases with mutations in the intracellular domain. Low serum levels of IGFBP are non-diagnostic for LS.[14]

Treatment

Administration of

recombinant GH has no effect on IGF-1 production, therefore it is ineffective for the treatment of Laron syndrome.[20] Instead, it is treated mainly by recombinant IGF-1.[21] IGF-1 must be taken before puberty to be effective.[22][medical citation needed
]

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.[23]

IPLEX (Mecasermin rinfabate) is composed of recombinant human

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.[24][25] 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.[26]

Legal battle for access to Medicine in Ecuador

In Ecuador, despite having the highest number of Laron syndrome cases in the world, affected children lacked proper treatment. In 2010 and 2014, a group of parents, led by Santiago Vasco Morales, filed lawsuits requesting the Ecuadorian government to provide the necessary comprehensive treatment. However, due to the lack of response and non-compliance with court rulings, the parents sought assistance from the Inter-American Commission on Human Rights (IACHR). Only after an admissibility report was issued by the IACHR on April 24, 2020 [27] did the Ecuadorian state begin administering the treatment. Unfortunately, many patients who needed IGF-1 treatment were unable to benefit from it, as they reached adulthood without receiving this essential medication. This was due to the unjustified refusal of the Ecuadorian state to provide such treatment for more than a decade.[28]

Prognosis

Cancer and diabetes

It has been reported that people with LS in Ecuador are resistant to cancer and diabetes and are somewhat protected against aging.[29][30][31] This is consistent with findings in mice with a defective growth hormone receptor gene.[22] Among the approximately 100 individuals in this population, there were no reported cases of diabetes and one case of cancer.[32]

A 2019 study of individuals with

healthspan, with resistance to cancer and attenuated effects of aging, but neither patients with LS nor IGHD experienced an increase in their overall lifespan.[33]

Incidence

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. The original "Israeli cohort" of patients referred to Zvi Laron and colleagues beginning in 1958 consisted of 64 patients as of 2009, including 4 deceased patients.[1] The countries of origin of these patients include Israel, Palestine, Jordan, Lebanon, Iran, Malta, Italy, Argentina, Ecuador, and Peru.[1]

A disproportionate number of people with the condition are found in remote villages in the

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.[29][22][5][2][34]

Other patients include people of other Semitic non-Jewish origins, including from Saudi Arabia, Japan, and China.[1]

Homo floresiensis

Recent publications have proposed that

Pygmies of Central Africa.[38]

History

Israeli and Palestinian ancestry with distinct physical characteristics resembling hypopituitarism.[1][6] However, researchers noticed that these people had high serum GH levels, which are expected to be low in patients with hypopituitarism.[1] Successive studies carried out over the subsequent 20 years by Laron and colleagues revealed an absence of IGF-1 release in response to exogenous hGH and an absence of GH binding to liver cell membranes in this group of patients.[1] The results of these studies provided clear evidence that the pathogenicity of the disease was the result of GH receptor failure in the liver.[1]

See also

  • Hypothalamic–pituitary–somatic axis

References

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  23. ^ "Increlex (mecasermin)". Centerwatch.com. Retrieved 21 November 2014.
  24. ^ Kemp SF. "Mecasermin rinfabate". Thomson Reuters. Retrieved 5 March 2011.
  25. ^ Meyer R. "Approval letter (Mecasermin rinfabate)" (PDF). FDA. Retrieved 5 March 2011.
  26. ^ "Insmed Provides Update on Supply of IPLEX(TM)". Retrieved 25 August 2017.
  27. ^ "Report No. 75/20 - Petition 1011-11 - Report on Admissibility" (PDF). www.oas.org. Archived from the original (PDF) on 20 October 2020. Retrieved 9 June 2023.
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External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Laron_syndrome&oldid=1227026868"