Leopard syndrome pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]
Overview
Leopard syndrome is most commonly caused by missense mutations in the PTPN11 gene. It has also been associated with other gene mutations such as RAF1 and BRAF.
Pathophysiology
Genetics
Although genes PTPN11, RAF1, and BRAF are the genes known to be associated with LEOPARD syndrome, it is most commonly caused by missense mutations in the PTPN11 gene. The mutations cause a loss of catalytic activity of the SHP2 protein (the gene product of the PTPN11 gene located at chromosome 12q22-qter), which is a previously unrecognized behavior for this class of mutations.[1] This interferes with growth factor and related signalling. While further research confirms this mechanism,[2][3] Genetic heterogeneity recently confirmed by the identification of RAF1 gene mutations in two out of six PTPN11 mutation negative LEOPARD syndrome patients.[4] Additional research is needed to determine how this relates to all of the observed effects of LEOPARD syndrome.
Associated Conditions
Noonan syndrome and neurofibromatosis 1 have a great similarity in presentations with LEOPARD, which make the diagnosis difficult and mostly based on genetic testing. Laboratory studies should include molecular analysis of the PTPN11 and RAF1 genes. In a study of 10 infants with clinical indications of LEOPARD syndrome prior to their first birthday, 8 (80%) patients were confirmed to have the suspected mutation. An additional patient, with the suspected mutation was subsequently found to have NF1, following evaluation of the mother.[5] There are 5 identified allelic variants responsible for LEOPARD syndrome. Which seems to be a unique familial mutation, in that all other variants are caused by transition errors, rather than transversion.
Microscopic Pathology
On histological examination of the lentigines there is pigment accumulation in the dermis as well as the deeper layers of epidermis. There is an increase in melanocytic density owing to corrugation of the dermoepidermal junction. There are no naevus cells and the rete ridges are prominent.[6]
References
- ↑ Tartaglia M, Martinelli S, Stella L; et al. (2006). "Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease". Am. J. Hum. Genet. 78 (2): 279–90. doi:10.1086/499925. PMID 16358218.
- ↑ Hanna N, Montagner A, Lee WH; et al. (2006). "Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1". FEBS Lett. 580 (10): 2477–82. doi:10.1016/j.febslet.2006.03.088. PMID 16638574.
- ↑ Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG (2006). "PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects". J. Biol. Chem. 281 (10): 6785–92. doi:10.1074/jbc.M513068200. PMID 16377799.
- ↑ Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S; et al. (2007). "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy". Nat Genet. 39 (8): 1007–12. doi:10.1038/ng2073. PMID 17603483.
- ↑ Digilio MC, Sarkozy A, de Zorzi A; et al. (2006). "LEOPARD syndrome: clinical diagnosis in the first year of life". Am. J. Med. Genet. A. 140 (7): 740–6. doi:10.1002/ajmg.a.31156. PMID 16523510.
- ↑ Coppin BD, Temple IK (1997). "Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis)". J Med Genet. 34 (7): 582–6. PMC 1051000. PMID 9222968.