title: Two cases of Noonan syndrome with severe respiratory and gastroenteral involvement and the SOS1 mutation F623I.
abstract: Noonan syndrome (NS) is an autosomal dominant, inherited disorder characterized by facial dysmorphism, congenital heart defects, and reduced postnatal growth. Dysregulated RAS-MAPK signalling is the common molecular basis for NS, a genetically heterogeneous disease. Germline mutations in genes encoding small GTPases of the RAS family (KRAS and NRAS), modulators of RAS function (PTPN11, SOS1 and SHOC2) or downstream signal transducers (RAF1) are causative for NS. SOS1 is the second major gene for NS after PTPN11. Compared to patients with mutations in other genes, SOS1 mutation-positive individuals in general tend to have a more favorable outcome, with less short stature and cognitive impairment. We describe two unrelated patients with NS carrying the same heterozygous SOS1 missense mutation (c.1867T > A/p.F623I). The phenotype of both patients is remarkable as they show uncommon clinical features such as pulmonary lymphangiectasis, congenital pleural effusions, severe feeding problems, and laryngomalacia. These findings may be related to the specific mutation present in our two patients, or be part of the SOS1 phenotype. Detailed clinical assessment of large cohorts of patients with NS and SOS1 mutation is required to clarify this initial observation.
authors.affiliation: SC Genetica Medica, Ospedale Materno Infantile IRCCS Burlo Garofolo, Trieste, Italy. fabretto@burlo.trieste.it
authors.forename: Antonella
authors.initials: A
authors.lastname: Fabretto
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kutsche
authors.forename: May-Britt
authors.initials: MB
authors.lastname: Harmsen
authors.forename: Sergio
authors.initials: S
authors.lastname: Demarini
authors.forename: Paolo
authors.initials: P
authors.lastname: Gasparini
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Fertz
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
mesh_terms: D002675:Child, Preschool; D011905:Genes, ras; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D009634:Noonan Syndrome / Q000235:genetics*; D010641:Phenotype; D020837:SOS1 Protein / Q000235:genetics*
chemical_list: D020837:SOS1 Protein