Laron's syndrome

from Wikipedia, the free encyclopedia
Classification according to ICD-10
E34.3 Short stature, not elsewhere classified;
Laron type
ICD-10 online (WHO version 2019)

The Laron syndrome , also known as primary GH insensitivity , GH receptor deficiency , short stature due to growth hormone resistance , primary growth hormone insensitivity or growth hormone receptor deficiency called, is a rare, autosomal - recessive inherited disease that primarily by manifested a short stature in the affected patients.

frequency

Laron's syndrome is an extremely rare hereditary disease. Around 200 to 300 cases have been described worldwide so far.

Clinical picture and diagnostics

The signaling pathways in patients with Laron syndrome (left) compared to the signaling pathways in “healthy” people with a Western diet.

Patients with Laron's syndrome have a congenital lack of functional receptors for the growth hormone somatotropin. Due to a genetic defect in the somatotropin receptor (GHR, growth hormone receptor ), the somatotropin (GH, growth hormone ) cannot activate the expression of the insulin-like growth factor 1 (IGF-I, insulin-like growth factor I ).

Short stature, facial deformities , trunk-dominated obesity , late onset of puberty and recurrent hypoglycaemia are typical for Laron syndrome. In plasma extremely low levels found for the IGF-1 and significantly elevated levels of somatotropin. Somatotropin-binding protein (GHBP), the soluble isoform of GHR, is either severely depleted in plasma or completely absent or inoperable.

Children are more susceptible to infection.

The greatly reduced release of IGF-I not only causes short stature. Patients with Laron syndrome have a significantly reduced chance of developing cancer , acne and diabetes mellitus . Even the aging takes place slowly. An Ecuadorian population in the province of Loja of 99 patients with Laron syndrome was medically monitored for 22 years. One non-lethal malignancy and no case of diabetes mellitus were observed in this group during this period . In the control group, however, the prevalence for cancer was 17% and for diabetes 5%. These epidemiological data lead to speculation as to whether artificially lowering IGF-1 levels could slow aging and reduce the likelihood of developing cancer.

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

genetics

The GHR - gene , which for the growth hormone receptor encoded , is located in humans on chromosome 5 , locus p13-p12. The gene product consists of 638 amino acids and is membrane-bound . The mutations in the GHR can either prevent the binding of GH to the extracellular domain (ectodomain) or block the dimerization of the receptor after the somatotropin has docked. Both of these factors mean that the cells of the affected patients express only very small amounts of IGF-1.

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

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

Treatment and prognosis

Since 1986, biotechnologically produced IGF-I (rhIGF-I, recombinant human IGF-I) has been available in sufficient quantities so that children affected by Laron syndrome can be treated with it. The prognosis is favorable - even without treatment. Apart from the daily handicaps caused by short stature, patients can lead a largely normal life.

Initial description

Laron's syndrome was first described in 1966 by a working group led by the Israeli child endocrinologist Zvi Laron (* 1927). The disease was named after him. The clinical investigations began as early as 1958 on a group of small children who had high levels of growth hormones in the serum. Then the cause of the disease was identified as a molecular defect in the growth hormone receptor (somatotropin receptor).

See also

further reading

Specialist literature

Popular science articles

Individual evidence

  1. ^ Laron syndrome. In: Orphanet (Rare Disease Database).
  2. ↑ a b c d e Y. Zhou, BC Xu, HG Maheshwari, L. He, M. Reed, M. Lozykowski, S. Okada, L. Cataldo, K. Coschigamo, TE Wagner, G. Baumann, JJ Kopchick: A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor / binding protein gene (the Laron mouse). (PDF; 318 kB) In: Proceedings of the National Academy of Sciences Volume 94, Number 24, November 1997, pp. 13215-13220, ISSN  0027-8424 . PMID 9371826 . PMC 24289 (free full text).
  3. ↑ P. Altmeyer: Entry of Laron's syndrome in the encyclopedia of dermatology, venereology, allergology, environmental medicine , Springer-Verlag Berlin Heidelberg, online version
  4. ↑ RG Rosenfeld, AL Rosenbloom, J. Guevara-Aguirre: Growth hormone (GH) insensitivity due to primary GH receptor deficiency. In: Endocrine reviews Volume 15, Number 3, June 1994, pp. 369-390, ISSN  0163-769X . PMID 8076588 . (Review).
  5. ↑ a b M. Leslie: Genetics and disease. Growth defect blocks cancer and diabetes. In: Science Volume 331, Number 6019, February 2011, p. 837, ISSN  1095-9203 . doi: 10.1126 / science.331.6019.837 . PMID 21330503 .
  6. ↑ BC Melnik, SM John, G. Schmitz: Over-stimulation of insulin / IGF-1 signaling by western diet may promote diseases of civilization: lessons learned from laron syndrome. In: Nutrition & metabolism Volume 8, 2011, p. 41, ISSN  1743-7075 . doi: 10.1186 / 1743-7075-8-41 . PMID 21699736 . ( Open access )
  7. ↑ J. Guevara-Aguirre, P. Balasubramanian, M. Guevara-Aguirre, M. Wei, F. Madia, CW Cheng, D. Hwang, A. Martin-Montalvo, J. Saavedra, S. Ingles, R. de Cabo , P. Cohen, VD Longo: Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. In: Science Translational Medicine Volume 3, Number 70, February 2011, p. 70ra13, ISSN  1946-6242 . doi: 10.1126 / scitranslmed.3001845 . PMID 21325617 .
  8. ↑ R. Steuerman, O. Shevah, Z. Laron: Congenital IGF1 deficiency Tends to confer protection against post-natal development of malignancies. In: European Journal of Endocrinology / European Federation of Endocrine Societies Volume 164, Number 4, April 2011, pp. 485-489, ISSN  1479-683X . doi: 10.1530 / EJE-10-0859 . PMID 21292919 .
  9. ↑ EJ Gallagher, D. LeRoith: Is growth hormone resistance / IGF-1 reduction good for you? In: Cell Metabolism Volume 13, Number 4, April 2011, pp. 355-356, ISSN  1932-7420 . doi: 10.1016 / j.cmet.2011.03.003 . PMID 21459318 .
  10. ^ A. Bartke: Life Extension in the Dwarf Mouse. In: Handbook of Models for Human Aging. PM Conn (editor), Academic Press, 2006, ISBN 0-12-369391-8 , pp. 403-413, limited preview in Google Book Search
  11. ^ Laron syndrome.  In: Online Mendelian Inheritance in Man . (English)
  12. ↑ UniProt P10912
  13. ↑ JA Phillips: Molecular biology of growth hormone receptor dysfunction. In: Acta paediatrica Volume 383, September 1992, pp. 127-131, ISSN  0803-5326 . PMID 1458007 . (Review).
  14. ↑ PJ Godowski, DW Leung, LR Meacham, JP Galgani, R. Hellmiss, R. Keret, PS Rotwein, JS Parks, Z. Laron, WI Wood: Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron-type dwarfism. In: Proceedings of the National Academy of Sciences Volume 86, Number 20, October 1989, pp. 8083-8087, ISSN  0027-8424 . PMID 2813379 . PMC 298219 (free full text).
  15. ↑ ML Sobrier, F. Dastot, P. Duquesnoy, N. Kandemir, N. Yordam, M. Goossens, S. Amselem: Nine novel growth hormone receptor gene mutations in patients with Laron syndrome. In: The Journal of clinical endocrinology and metabolism Volume 82, Number 2, February 1997, pp. 435-437, ISSN  0021-972X . PMID 9024232 .
  16. ↑ J. Guevara-Aguirre, AL Rosenbloom, MA Vaccarello, PJ Fielder, A. de la Vega, FB Diamond, RG Rosenfeld: Growth hormone receptor deficiency (Laron syndrome): clinical and genetic characteristics. In: Acta paediatrica Scandinavica Volume 377, 1991, pp. 96-103, ISSN  0300-8843 . PMID 1785320 . (Review).
  17. ^ A b Z. Laron: Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958-2003. In: The Journal of clinical endocrinology and metabolism Volume 89, Number 3, March 2004, pp. 1031-1044, ISSN  0021-972X . PMID 15001582 .
  18. ↑ Z. Laron, A. Pertzelan, S. Mannheimer: Genetic pituitary dwarfism with high serum concentration of growth hormone-a new inborn error of metabolism? In: Israel journal of medical sciences Volume 2, Number 2, 1966 Mar-Apr, pp. 152-155, ISSN  0021-2180 . PMID 5916640 .

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