A new mutation in the C-SH2 domain of PTPN11 causes Noonan syndrome with multiple giant cell lesions.
Noonan syndrome (NS), an autosomal dominant multisystem disorder, is caused by the dysregulation of the RAS-MAPK pathway and is characterized by short stature, heart defects, pectus excavatum, webbed neck, learning problems, cryptorchidism and facial dysmorphism. We here present the clinical and molecular characterization of a family with NS and multiple giant cell lesions (MGCLs). The proband is a 12-year-old girl with NS and MGCL. Her mother shows typical NS without MGCL. Whole-exome sequencing of the girl, her mother and her healthy maternal grand parents revealed a previously unobserved mutation in exon 5 of the PTPN11 gene (c.598 A>T; p.N200Y), transmitted from the mother to the proband. As no other modification in the RAS-MAPK pathway genes as related to Rasopathies was detected in the proband, this report demonstrates for the first time that a unique mutation affecting this, otherwise unaffected signaling route, can cause both NS and NS/MGCL in the same family. This observation further confirms that NS/MGCL is not a distinct entity but rather that MGCL represents a rare complication of NS. Moreover, the localization of the p.N200Y mutation suggests an alternative molecular mechanism for the excessive phosphatase activity of the PTPN11-encoded protein.
Plateforme GENOMAX, Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, Centre de Recherche d'Immunologie et d'Hématologie. Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
Raphael
R
Carapito
Plateforme GENOMAX, Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, Centre de Recherche d'Immunologie et d'Hématologie. Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
Nicodème
N
Paul
Plateforme GENOMAX, Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, Centre de Recherche d'Immunologie et d'Hématologie. Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
Meiggie
M
Untrau
Plateforme GENOMAX, Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, Centre de Recherche d'Immunologie et d'Hématologie. Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
Louise
L
Ott
1] Service d'Hématologie et Oncologie Pédiatrique, CHU Nantes, Nantes, France [2] INSERM, UMR 957, Nantes, France.
Nadège
N
Corradini
Service de Pédiatrie, CHU Nantes, Nantes, France.
Sylvaine
S
Poignant
Service d'Orthopédie Pédiatrique, CHU Nantes, Nantes, France.
Loïc
L
Geffroy
Service de Pédiatrie, CHU Nantes, Nantes, France.
Emmanuelle
E
Caldagues
1] INSERM, UMR 957, Nantes, France [2] Service d'Anatomie Pathologique, CHU Nantes, Nantes, France.
Marie-Françoise
MF
Heymann
Service d'Anatomie Pathologique, CHU Nantes, Nantes, France.
Elisabeth
E
Cassagnau
1] INSERM, UMR 957, Nantes, France [2] Service de Génétique Médicale, CHU Nantes, Nantes, France.
Bertrand
B
Isidor
Plateforme GENOMAX, Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, Centre de Recherche d'Immunologie et d'Hématologie. Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
Seiamak
S
Bahram
D001706:Biopsy; D002648:Child; D004252:DNA Mutational Analysis; D059472:Exome; D019066:Facies; D005260:Female; D015726:Giant Cells / Q000473:pathology*; D006801:Humans; D008297:Male; D009154:Mutation; D009634:Noonan Syndrome / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000737:chemistry / Q000235:genetics*; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D018909:src Homology Domains / Q000235:genetics*
D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11