ONLINE MUTATION REPORT Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome

M ultiple lentigines LEOPARD syndrome (MIM 151100) is an autosomal dominant multiple congenital anomaly syndrome, with high penetrance and markedly variable expression. The acronym LEOPARD was coined by Gorlin et al. in 1971 as a mnemonic of the major features of this disorder: multiple lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. It is also known as cardiocutaneous syndrome, Moynahan syndrome, lentiginosis profuse, and progressive cardiomyopathic lentiginosis. 4 Voron et al. proposed some diagnostic criteria for multiple lentigines LEOPARD syndrome. More than 100 cases have been described, and one review has been published. 6 Multiple lentigines LEOPARD syndrome shares many features with Noonan syndrome (MIM 163950), in which lentigines and deafness usually are not present. About 40% of patients with Noonan syndrome have missense mutations in the PTPN11 gene, which encodes for the protein tyrosine phosphatase SHP2. Multiple lentigines LEOPARD syndrome has proved to be allelic to Noonan syndrome, 16 with two recurrent PTPN11 mutations in exons 7 (Tyr279Cys) and 12 (Thr468Met). Recently, we reported a novel PTPN11 mutation (Gln506Pro) in a unique patient with multiple lentigines LEOPARD syndrome, which suggests that mutations other than Tyr279Cys and Thr468Met could be found in these patients. As PTPN11 mutations in multiple lentigines LEOPARD syndrome and Noonan syndrome are exclusive to these conditions, the distinctive manifestations of these disorders likely result from different molecular mechanisms. For instance, as commented in a recent report, the cardiac phenotypes in patients with Noonan syndrome and those with multiple lentigines LEOPARD syndrome with PTPN11 mutations are rather dissimilar, with pulmonary valve stenosis prevailing in the former and hypertrophic cardiomyopathy in the latter. We examined the PTPN11 gene in a consecutive series of 30 patients with multiple lentigines LEOPARD syndrome, including 16 new patients. We report the full spectrum of molecular defects of these patients and describe the clinical features related to PTPN11 gene mutations.