Novel mutations of NFIX gene causing Marshall-Smith syndrome or Sotos-like syndrome: one gene, two phenotypes

Pediatr Res. 2015 Nov;78(5):533-9. doi: 10.1038/pr.2015.135. Epub 2015 Jul 22.


Background: Only 15 point mutations in NFIX gene have been reported so far, nine of them cause the Marshall-Smith syndrome (MSS) and the remaining mutations lead to an overgrowth disorder with a less severe phenotype, defined as Sotos-like.

Methods: The clinical findings in three patients with MSS and two patients with a Sotos-like phenotype are presented. Analysis of the NFIX gene was performed both by conventional or next-generation sequencing.

Results: Five de novo mutations in NFIX gene were identified, four of them not previously reported. Two frameshift mutations and a donor-splice one caused MSS, while two missense mutations in the DNA binding/dimerisation domain entailed an overgrowth syndrome with some clinical features resembling Sotos syndrome, accompanied by a marfanoid habitus, very low BMI, long narrow face, or arachnodactyly.

Conclusion: Marshall-Smith mutations are scattered through exons 6-10 of NFIX gene, while most point mutations causing an overgrowth syndrome are clustered in exon 2. Clinical features of this overgrowth syndrome may well be considered an intermediate phenotype between Sotos and Marfan syndromes.

Publication types

  • Case Reports

MeSH terms

  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / genetics*
  • Amino Acid Sequence
  • Base Sequence
  • Bone Diseases, Developmental / diagnosis
  • Bone Diseases, Developmental / genetics*
  • Child
  • Child, Preschool
  • Craniofacial Abnormalities / diagnosis
  • Craniofacial Abnormalities / genetics*
  • DNA Mutational Analysis / methods
  • Exons
  • Fatal Outcome
  • Female
  • Genetic Association Studies
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Molecular Sequence Data
  • Mutation*
  • NFI Transcription Factors / genetics*
  • Phenotype
  • Septo-Optic Dysplasia / diagnosis
  • Septo-Optic Dysplasia / genetics*
  • Sotos Syndrome / diagnosis
  • Sotos Syndrome / genetics*
  • Young Adult


  • Genetic Markers
  • NFI Transcription Factors
  • NFIX protein, human

Supplementary concepts

  • Marshall-Smith syndrome