LEOPARD syndrome: Clinical aspects and molecular pathogenesis

A. Sarkozy, M. C. Digilio, G. Zampino, B. Dallapiccola, M. Tartaglia, B. D. Gelb

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

LEOPARD syndrome (LS) is an autosomal dominant disorder for which the acronymic name denotes major clinical characteristics including lentigines, facial dysmorphism, heart defects, cryptorchidism, short stature and sensorineural deafness. Café-au-lait spots are common in LS and tend to appear earlier in life than the lentigines. The features of LS overlap closely with those observed in Noonan syndrome (NS) and distinguishing the two in infants and young children before lentigines emerge can be challenging. LS, like NS, arises from dysregulated RAS/mitogenactivated protein kinase (MAPK) signaling. Mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP-2, are found in roughly 90% of LS patients. Ten missense mutations have been reported, two (Y279C and T468M) being most common. LS-associated SHP-2 mutant proteins have impaired phosphatase activity, contrasting notably with the gain-of-function SHP-2 mutants associated with NS. Mutations in a second LS gene, RAF1, account for an additional 3% of cases. The RAF1 protein is a serine/ threonine kinase that is part of the RAS-MAPK cascade. RAF1 is basally inactive and, when activated, activates the MAPK kinases, MEK1 and 2. The two LS-associated RAF1 mutations engender gain-of-function effects and one of the alleles has also been observed in patients with NS as well. Considering both disorders, RAF1 mutations associate strongly with the development of HCM. In sum, LS, like the phenotypically similar NS, arises from dysregulated RAS-MAPK signaling. While biochemical differences between their alleles exist, a fuller explanation of their respective disease pathogenesis awaits elucidation.

Original languageEnglish
Title of host publicationMonographs in Human Genetics
Pages55-65
Number of pages11
Volume17
DOIs
Publication statusPublished - 2009

Publication series

NameMonographs in Human Genetics
Volume17
ISSN (Print)00770876
ISSN (Electronic)16623835

ASJC Scopus subject areas

  • Genetics(clinical)

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    Sarkozy, A., Digilio, M. C., Zampino, G., Dallapiccola, B., Tartaglia, M., & Gelb, B. D. (2009). LEOPARD syndrome: Clinical aspects and molecular pathogenesis. In Monographs in Human Genetics (Vol. 17, pp. 55-65). (Monographs in Human Genetics; Vol. 17). https://doi.org/10.1159/000164839