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Laron syndrome

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Laron syndrome

Laron syndrome
Classification and external resources
ICD-10 E34.3
ICD-9 259.4
OMIM 262500 245590
DiseasesDB 7262
eMedicine ped/1277
MeSH D046150

Laron syndrome, or Laron-type dwarfism, is an autosomal recessive disorder characterized by an insensitivity to growth hormone (GH), caused by a variant of the growth hormone receptor. It causes short stature and a resistance to diabetes and cancer.

Eponym

It is named after Zvi Laron, the Israeli researcher who, with A. Pertzelan and S. Mannheimer, first reported the condition in 1966,[1][2] based upon observations which began in 1958.[3]

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.

Pathophysiology

Laron syndrome has an autosomal recessive pattern of inheritance.

Molecular genetic investigations have shown that this disorder is mainly associated with mutations in the gene for the GH receptor. 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.[4]

Clinical characteristics

The principal feature of Laron syndrome is abnormally short stature (dwarfism). Physical symptoms include: prominent forehead, depressed nasal bridge, underdevelopment of mandible, truncal obesity[5] and a very small penis. Seizures are frequently seen secondary to hypoglycemia. Some genetic variations decrease intellectual capacity.[6]

The majority of reported cases have been of Arabic or Semitic origin, with numerous patients in Israel, Saudi Arabia, Egypt, Iraq, and remote villages in Ecuador with Sephardic roots.[7][8]

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.[7][9][10] This is consistent with findings in mice with a defective growth hormone receptor gene.[8]

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.[8] The drug product Increlex (mecasermin), developed by the company Tercica, now Genentech, was approved by the US Food and Drug Administration in August 2005 for replacing IGF-1 in patients who are deficient.[11]

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.[12][13] Side effects from IPLEX are hypoglycemia.

IPLEX's manufacturing company, Insmed, can no longer develop proteins and can no longer manufacture IPLEX as of a statement released in January 2012.

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.[8][9]

Homo floresiensis

Recent publications have proposed that Homo floresiensis represented a population with widespread Laron syndrome.[14][15] This hypothesis has received criticism and is unconfirmed.

References

  1. ^ synd/2825 at Who Named It?
  2. ^ Laron Z, Pertzelan A, Mannheimer S (1966). "Genetic pituitary dwarfism with high serum concentration of growth hormone—a new inborn error of metabolism?". Isr. J. Med. Sci. 2 (2): 152–5.  
  3. ^ Laron Z (2004). "Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958–2003". J. Clin. Endocrinol. Metab. 89 (3): 1031–44.  
  4. ^ Hwa V, Camacho-Hübner C, Little BM, et al. (2007). "Growth hormone insensitivity and severe short stature in siblings: a novel mutation at the exon 13-intron 13 junction of the STAT5b gene". Horm. Res. 68 (5): 218–24.  
  5. ^ Laron Z, Ginsberg S, Lilos P, Arbiv M, Vaisman N (2006). "Body composition in untreated adult patients with Laron syndrome (primary GH insensitivity)". Clin. Endocrinol. (Oxf) 65 (1): 114–7.  
  6. ^ Shevah O, Kornreich L, Galatzer A, Laron Z (2005). "The intellectual capacity of patients with Laron syndrome (LS) differs with various molecular defects of the growth hormone receptor gene. Correlation with CNS abnormalities". Horm. Metab. Res. 37 (12): 757–60.  
  7. ^ a b Guevara-Aguirre, J; Balasubramanian, P; Guevara-Aguirre, M; Wei, M; Madia, F; Cheng, CW; Hwang, D; Martin-Montalvo, A et al. (2011). "Growth Hormone Receptor Deficiency Is Associated with a Major Reduction in Pro-Aging Signaling, Cancer, and Diabetes in Humans". Science Translational Medicine 3 (70): 70ra13.  
  8. ^ a b c d Wade, Nicholas (17 February 2011). "Ecuadorean Villagers May Hold Secret to Longevity".  
  9. ^ a b Bai, Nina. "Defective Growth Gene in Rare Dwarfism Disorder Stunts Cancer and Diabetes".  
  10. ^ Winerman, Lea. "Study: Dwarfism Gene May Offer Protection From Cancer, Diabetes".  
  11. ^ "Increlex (mecasermin)". Centerwatch.com. Retrieved 21 Nov 2014. 
  12. ^ Kemp, S.F. "Mecasermin rinfabate". Thomson Reuters. Retrieved 5 March 2011. 
  13. ^ Meyer, Robert. "Approval letter (Mecasermin rinfabate)". FDA. Retrieved 5 March 2011. 
  14. ^ Hershkovitz I, Kornreich L, Laron Z (2007). "Comparative skeletal features between Homo floresiensis and patients with primary growth hormone insensitivity (Laron syndrome)". Am. J. Phys. Anthropol. 134 (2): 198–208.  
  15. ^ Culotta E (2007). "Paleoanthropology. The fellowship of the hobbit". Science 317 (5839): 740–742.  

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