PTPN11 gene analysis in 74 Brazilian patients with Noonan syndrome or Noonan-like phenotype.

Mutations in the PTPN11 gene are known to cause a large fraction of the cases of Noonan syndrome. The objective of this study was to determine the PTPN11 gene mutation rate in a cohort of clinically well-characterized Brazilian patients with Noonan or Noonan-like syndromes and to study the genotype-phenotype correlation. Fifty probands with Noonan syndrome ascertained according to well-established diagnostic criteria, 3 with LEOPARD syndrome, 5 with Noonan-like/multiple giant cell lesion syndrome, and 3 with neurofibromatosis/ Noonan were enrolled in this study. Mutational analysis was performed using denaturing high-performance liquid chromatography (DHPLC) followed by sequencing of amplicons with an aberrant elution profile. We detected missense mutations in the PTPN11 gene in 21 probands with Noonan syndrome (42%), in all 3 patients with LEOPARD syndrome, and in 1 case with Noonan-like/multiple giant cell lesion syndrome. One patient with neurofibromatosis-Noonan syndrome had a mutation in both the PTPN11 and NF1 genes. The only anomalies that reached statistical significance when comparing probands with and without mutations were the hematological abnormalities. Our data confirms that Noonan syndrome is a genetically heterogeneous disorder, with mutations in the PTPN11 gene responsible for roughly 50% of the cases. A definitive genotype-phenotype correlation has not been established, but the T73I mutation seems to predispose to a myeloproliferative disorder. Regarding Noonan-like syndromes, mutation of the PTPN11 gene is the main causal factor in LEOPARD syndrome, and it also plays a role in neurofibromatosis-Noonan syndrome. Noonan- like/multiple giant cell lesion syndrome, part of the spectrum of Noonan syndrome, is also heterogeneous.