TY - JOUR
T1 - Noonan syndrome
T2 - Comparing mutation-positive with mutation-negative dutch patients
AU - Croonen, E. A.
AU - Nillesen, W.
AU - Schrander, C.
AU - Jongmans, M.
AU - Scheffer, H.
AU - Noordam, C.
AU - Draaisma, J. M T
AU - Van Der Burgt, I.
AU - Yntema, H. G.
PY - 2013/6/1
Y1 - 2013/6/1
N2 - Noonan syndrome (NS) is an autosomal dominant disorder characterized by facial dysmorphisms, short stature and congenital heart defects. The disorder is genetically heterogeneous and shows clinical overlap with other RASopathies. These syndromes are caused by mutations in a variety of genes leading to dysregulation of the RAS-MAPK pathway: PTPN11, KRAS, SOS1, RAF1, CBL, SHOC2, NRAS, BRAF, MAP2K1, MAP2K2, HRAS, NF1 and SPRED1. In this study, we conduct a genotype-phenotype analysis of 33 patients with a clinical diagnosis of NS without a PTPN11 mutation. Mutation analysis of the genes involved in RASopathies was performed, except for NF1 and SPRED1. In 14 (42%) NS patients, a mutation was found, 7 (21%) had a mutation in SOS1, 3 (9%) in RAF1 and 1 (3%) in KRAS, MAP2K2, BRAF and SHOC2 each. The phenotype of these mutation-positive cases corresponded to that described in the literature. In the cases with a BRAF and MAP2K2 mutation, the diagnosis cardio-facio-cutaneous syndrome was made. The patient with the SHOC2 mutation had features compatible with 'Noonan-like syndrome with loose anagen hair'. Three major clinical features of NS - a typical face, short stature and a pulmonary valve stenosis - were less frequently present in the group without a mutation. Missense mutations in genes encoding proteins of the RAS-MAPK pathway cause NS. The 3 major clinical features of NS were less frequently present in the mutation-negative patients, which stresses the importance of the syndrome-specific symptoms of the face, heart and short stature in NS. However, all mutation-negative cases met the NS criteria, indicating that the involvement of novel genes is to be expected.
AB - Noonan syndrome (NS) is an autosomal dominant disorder characterized by facial dysmorphisms, short stature and congenital heart defects. The disorder is genetically heterogeneous and shows clinical overlap with other RASopathies. These syndromes are caused by mutations in a variety of genes leading to dysregulation of the RAS-MAPK pathway: PTPN11, KRAS, SOS1, RAF1, CBL, SHOC2, NRAS, BRAF, MAP2K1, MAP2K2, HRAS, NF1 and SPRED1. In this study, we conduct a genotype-phenotype analysis of 33 patients with a clinical diagnosis of NS without a PTPN11 mutation. Mutation analysis of the genes involved in RASopathies was performed, except for NF1 and SPRED1. In 14 (42%) NS patients, a mutation was found, 7 (21%) had a mutation in SOS1, 3 (9%) in RAF1 and 1 (3%) in KRAS, MAP2K2, BRAF and SHOC2 each. The phenotype of these mutation-positive cases corresponded to that described in the literature. In the cases with a BRAF and MAP2K2 mutation, the diagnosis cardio-facio-cutaneous syndrome was made. The patient with the SHOC2 mutation had features compatible with 'Noonan-like syndrome with loose anagen hair'. Three major clinical features of NS - a typical face, short stature and a pulmonary valve stenosis - were less frequently present in the group without a mutation. Missense mutations in genes encoding proteins of the RAS-MAPK pathway cause NS. The 3 major clinical features of NS were less frequently present in the mutation-negative patients, which stresses the importance of the syndrome-specific symptoms of the face, heart and short stature in NS. However, all mutation-negative cases met the NS criteria, indicating that the involvement of novel genes is to be expected.
KW - Congenital heart defects
KW - Facial characteristics
KW - Noonan syndrome
KW - RAS-MAPK pathway
KW - RASopathies
UR - http://www.scopus.com/inward/record.url?scp=84880006609&partnerID=8YFLogxK
U2 - 10.1159/000350686
DO - 10.1159/000350686
M3 - Article
AN - SCOPUS:84880006609
SN - 1661-8769
VL - 4
SP - 227
EP - 234
JO - Molecular Syndromology
JF - Molecular Syndromology
IS - 5
ER -