High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation.
Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.
Rojnueangnit, K; Xie, J; Gomes, A; Sharp, A; Callens, T; Chen, Y; Liu, Y; Cochran, M; Abbott, M-A; Atkin, J; Babovic-Vuksanovic, D; Barnett, CP; Crenshaw, M; Bartholomew, DW; Basel, L; Bellus, G; Ben-Shachar, S; Bialer, MG; Bick, D; Blumberg, B; Cortes, F; David, KL; Destree, A; Duat-Rodriguez, A; Earl, D; Escobar, L; Eswara, M; Ezquieta, B; Frayling, IM; Frydman, M; Gardner, K; Gripp, KW; Hernández-Chico, C; Heyrman, K; Ibrahim, J; Janssens, S; Keena, BA; Llano-Rivas, I; Leppig, K; McDonald, M; Misra, VK; Mulbury, J; Narayanan, V; Orenstein, N; Galvin-Parton, P; Pedro, H; Pivnick, EK; Powell, CM; Randolph, L; Raskin, S; Rosell, J; Rubin, K; Seashore, M; Schaaf, CP; Scheuerle, A; Schultz, M; Schorry, E; Schnur, R; Siqveland, E; Tkachuk, A; Tonsgard, J; Upadhyaya, M; Verma, IC; Wallace, S; Williams, C; Zackai, E; Zonana, J; Lazaro, C; Claes, K; Korf, B; Martin, Y; Legius, E; Messiaen, L
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