title: SOS1 frameshift mutations cause pure mucosal neuroma syndrome, a clinical phenotype distinct from multiple endocrine neoplasia type 2B.
abstract: BACKGROUND
  Mucosal neuromas, thickened corneal nerves and marfanoid body habitus are characteristic phenotypic features of multiple endocrine neoplasia type 2B (MEN2B) and often provide an early clue to the diagnosis of the syndrome. Rarely, patients present with typical physical features of MEN2B but without associated endocrinopathies (medullary thyroid carcinoma or pheochromocytoma) or a RET gene mutation; this clinical presentation is thought to represent a distinct condition termed 'pure mucosal neuroma syndrome'.
  
  
  METHODS
  Exome sequencing was performed in two unrelated probands with mucosal neuromas, thickened corneal nerves and marfanoid body habitus, but no MEN2B-associated endocrinopathy or RET gene mutation. Sanger sequencing was performed to confirm mutations detected by exome sequencing and to test in family members and 3 additional unrelated index patients with mucosal neuromas or thickened corneal nerves.
  
  
  RESULTS
  A heterozygous SOS1 gene frameshift mutation (c.3266dup or c.3248dup) was identified in each proband. Sanger sequencing showed that proband 1 inherited the c.3266dup mutation from his affected mother, while the c.3248dup mutation had arisen de novo in proband 2. Sanger sequencing also identified one further novel SOS1 mutation (c.3254dup) in one of the 3 additional index patients.
  
  
  CONCLUSIONS
  Our results demonstrate the existence of pure mucosal neuroma syndrome as a clinical entity distinct from MEN2B that can now be diagnosed by genetic testing.
authors.affiliation: Department of Molecular Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
authors.forename: Martina
authors.initials: M
authors.lastname: Owens
authors.affiliation: Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Kivuva
authors.affiliation: Department of Ophthalmology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Quinn
authors.affiliation: Northern Genetics Service, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Caswell
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Hana
authors.initials: H
authors.lastname: Lango Allen
authors.affiliation: Department of Diabetes and Endocrinology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
authors.forename: Bijay
authors.initials: B
authors.lastname: Vaidya
authors.affiliation: Department of Molecular Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.|Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D059472:Exome / Q000235:genetics; D005192:Family Health; D005260:Female; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D009061:Mouth Mucosa / Q000378:metabolism* / Q000473:pathology; D009062:Mouth Neoplasms / Q000175:diagnosis / Q000235:genetics*; D018814:Multiple Endocrine Neoplasia Type 2b / Q000175:diagnosis / Q000235:genetics; D009463:Neuroma / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020837:SOS1 Protein / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D013577:Syndrome
chemical_list: D020837:SOS1 Protein