Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families

Am J Med Genet A. 2023 Jul;191(7):1900-1910. doi: 10.1002/ajmg.a.63226. Epub 2023 May 14.


Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation.

Keywords: Jansen-de Vries syndrome; PPM1D; cyclic vomiting; developmental delay; hypersocial personality.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Developmental Disabilities / diagnosis
  • Developmental Disabilities / genetics
  • Female
  • Humans
  • Infant
  • Intellectual Disability* / diagnosis
  • Intellectual Disability* / genetics
  • Intellectual Disability* / pathology
  • Male
  • Middle Aged
  • Neurodevelopmental Disorders* / diagnosis
  • Neurodevelopmental Disorders* / epidemiology
  • Neurodevelopmental Disorders* / genetics
  • Phenotype
  • Protein Phosphatase 2C / genetics
  • Retrospective Studies
  • Vomiting
  • Young Adult


  • PPM1D protein, human
  • Protein Phosphatase 2C