Unexplained regression in Down syndrome: 35 cases from an international Down syndrome database

Stephanie L. Santoro, Sheila Cannon, George Capone, Cathy Franklin, Sarah J. Hart, Victoria Hobensack, Priya S. Kishnani, Eric A. Macklin, Kandamurugu Manickam, Andrew McCormick, Patricia Nash, Nicolas M. Oreskovic, Vasiliki Patsiogiannis, Katherine Steingass, Amy Torres, Diletta Valentini, Kishore Vellody, Brian G. Skotko

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Purpose: An entity of regression in Down syndrome (DS) exists that affects adolescents and young adults and differs from autism spectrum disorder and Alzheimer disease. Methods: Since 2017, an international consortium of DS clinics assembled a database of patients with unexplained regression and age- and sex-matched controls. Standardized data on clinical symptoms and tiered medical evaluations were collected. Elements of the proposed definition of unexplained regression in DS were analyzed by paired comparisons between regression cases and matched controls. Results: We identified 35 patients with DS and unexplained regression, with a mean age at regression of 17.5 years. Diagnostic features differed substantially between regression cases and matched controls (p < 0.001 for all but externalizing behaviors). Patients with regression had four times as many mental health concerns (p < 0.001), six times as many stressors (p < 0.001), and seven times as many depressive symptoms (p < 0.001). Tiered medical evaluation most often identified abnormalities in vitamin D 25-OH levels, polysomnograms, thyroid peroxidase antibodies, and celiac screens. Analysis of the subset of patients with nondiagnostic medical evaluations reinforced the proposed definition. Conclusions: Our case–control evidence supports a proposed definition of unexplained regression in Down syndrome. Establishing this clinical definition supports future research and investigation of an underlying mechanism.

Original languageEnglish (US)
Pages (from-to)767-776
Number of pages10
JournalGenetics in Medicine
Issue number4
StatePublished - Apr 1 2020


  • Down syndrome
  • Down syndrome disintegrative disorder
  • regression
  • trisomy 21

ASJC Scopus subject areas

  • Genetics(clinical)


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