Epigenetic Causes of Overgrowth Syndromes

J Clin Endocrinol Metab. 2024 Jan 18;109(2):312-320. doi: 10.1210/clinem/dgad420.


Human overgrowth disorders are characterized by excessive prenatal and/or postnatal growth of various tissues. These disorders often present with tall stature, macrocephaly, and/or abdominal organomegaly and are sometimes associated with additional phenotypic abnormalities such as intellectual disability and increased cancer risk. As the genetic etiology of these disorders have been elucidated, a surprising pattern has emerged. Multiple monogenic overgrowth syndromes result from variants in epigenetic regulators: variants in histone methyltransferases NSD1 and EZH2 cause Sotos syndrome and Weaver syndrome, respectively, variants in DNA methyltransferase DNMT3A cause Tatton-Brown-Rahman syndrome, and variants in chromatin remodeler CHD8 cause an autism spectrum disorder with overgrowth. In addition, very recently, a variant in histone reader protein SPIN4 was identified in a new X-linked overgrowth disorder. In this review, we discuss the genetics of these overgrowth disorders and explore possible common underlying mechanisms by which epigenetic pathways regulate human body size.

Keywords: WNT signaling; epigenetic modifications; histone; methylation; tall stature.

Publication types

  • Review

MeSH terms

  • Abnormalities, Multiple* / genetics
  • Autism Spectrum Disorder*
  • Epigenesis, Genetic
  • Histone Methyltransferases / genetics
  • Humans
  • Intellectual Disability* / genetics
  • Syndrome


  • Histone Methyltransferases