Gain-of-function pathogenic variants in SMAD4 are associated with neoplasia in Myhre syndrome

Am J Med Genet A. 2020 Feb;182(2):328-337. doi: 10.1002/ajmg.a.61430. Epub 2019 Dec 14.


Myhre syndrome is an increasingly diagnosed rare syndrome that is caused by one of two specific heterozygous gain-of-function pathogenic variants in SMAD4. The phenotype includes short stature, characteristic facial appearance, hearing loss, laryngotracheal stenosis, arthritis, skeletal abnormalities, learning and social challenges, distinctive cardiovascular defects, and a striking fibroproliferative response in the ear canals, airways, and serosal cavities (peritoneum, pleura, pericardium). Confirmation of the clinical diagnosis is usually prompted by the characteristic appearance with developmental delay and autistic-like behavior using targeted gene sequencing or by whole exome sequencing. We describe six patients (two not previously reported) with molecularly confirmed Myhre syndrome and neoplasia. Loss-of-function pathogenic variants in SMAD4 cause juvenile polyposis syndrome and we hypothesize that the gain-of-function pathogenic variants observed in Myhre syndrome may contribute to neoplasia in the patients reported herein. The frequency of neoplasia (9.8%, 6/61) in this series (two new, four reported patients) and endometrial cancer (8.8%, 3/34, mean age 40 years) in patients with Myhre syndrome, raises the possibility of cancer susceptibility in these patients. We alert clinicians to the possibility of detecting this syndrome when cancer screening panels are used. We propose that patients with Myhre syndrome are more susceptible to neoplasia, encourage increased awareness, and suggest enhanced clinical monitoring.

Keywords: SMAD4 pathogenic variants; Myhre syndrome; cancer; endometrial carcinoma; oncogene; transforming growth factor-beta signaling.

MeSH terms

  • Adult
  • Cryptorchidism / complications
  • Cryptorchidism / genetics*
  • Cryptorchidism / pathology
  • Endometrial Neoplasms / complications
  • Endometrial Neoplasms / genetics*
  • Endometrial Neoplasms / pathology
  • Exome Sequencing
  • Facies
  • Female
  • Gain of Function Mutation / genetics
  • Growth Disorders / complications
  • Growth Disorders / genetics*
  • Growth Disorders / pathology
  • Hand Deformities, Congenital / complications
  • Hand Deformities, Congenital / genetics*
  • Hand Deformities, Congenital / pathology
  • Heterozygote
  • Humans
  • Intellectual Disability / complications
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Male
  • Middle Aged
  • Mutation / genetics
  • Neoplasms / complications
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Phenotype
  • Smad4 Protein / genetics*
  • Transforming Growth Factor beta / genetics


  • SMAD4 protein, human
  • Smad4 Protein
  • Transforming Growth Factor beta

Supplementary concepts

  • Growth mental deficiency syndrome of Myhre