Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene

Multiple-lentigines (ML)/LEOPARD (multiple (l) under bar entigines, (e) under bar lectrocardiographic-conduction abnormalities, (o) under bar cular hypertelorism, (p) under bar ulmonary stenosis, (a) under bar bnormal genitalia, (r) under bar etardation of growth, and sensorineural (d) under bar eafness) syndrome is an autosomal dominant condition-characterized by lentigines and cafe' au lait spots, facial anomalies, cardiac defects-that shares several clinical features with Noonan syndrome (NS). We screened nine patients with ML/LEOPARD syndrome (including a mother-daughter pair) and two children with NS who had multiple cafe' au lait spots, for mutations in the NS gene, PTPN11, and found, in 10 of 11 patients, one of two new missense mutations, in exon 7 or exon 12. Both mutations affect the PTPN11 phosphotyrosine phosphatase domain, which is involved in <30% of the NS PTPN11 mutations. The study demonstrates that ML/LEOPARD syndrome and NS are allelic disorders. The detected mutations suggest that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the ML/LEOPARD-syndrome subtype of NS.