Nosology and inheritance pattern(s) of joint hypermobility syndrome and Ehlers-Danlos syndrome, hypermobility type: a study of intrafamilial and interfamilial variability in 23 Italian pedigrees

Am J Med Genet A. 2014 Dec;164A(12):3010-20. doi: 10.1002/ajmg.a.36805. Epub 2014 Oct 22.


Joint hypermobility syndrome (JHS) and Ehlers-Danlos syndrome, hypermobility type (EDS-HT) are two markedly overlapping heritable connective tissue disorders. The cumulative frequency of JHS and EDS-HT seems high, but their recognition remains an exclusion diagnosis based on different sets of diagnostic criteria. Although proposed by a panel of experts, clinical identity between JHS and EDS-HT is still a matter of debate due to unknown molecular basis. We present 23 families with three or more individuals with a diagnosis of JHS and/or EDS-HT. Rough data from the 82 individuals were used to assess the frequency of major and minor criteria, as well as selected additional features. A series of statistical tools were applied to assess intrafamilial and interfamilial variability, emphasizing intergenerational, and intersex differences. This study demonstrates marked heterogeneity within and between families in terms of agreement of available diagnostic criteria. In 21 pedigrees affected individuals belong to two or three phenotypic sub-categories among JHS, EDS-HT, and JHS + EDS-HT overlap. Intergenerational analysis depicts a progressive shifting, also within the same pedigree, from EDS-HT in childhood, to JHS + EDS-HT in early adulthood and JHS later in life. Female-male ratio is 2.1:1, which results lower than previously observed in unselected patients' cohorts. In these pedigrees, JHS, EDS-HT, and JHS + EDS-HT segregate as a single dominant trait with complete penetrance, variable expressivity, and a markedly evolving phenotype. This study represents a formal demonstration that EDS-HT and JHS contitute the same clinical entity, and likely share the same genetic background, at least, in familial cases.

Keywords: Ehlers-Danlos syndrome; autosomal dominant; classification; diagnosis; joint hypermobility; nosology; penetrance; variability.

MeSH terms

  • Diagnosis, Differential
  • Ehlers-Danlos Syndrome / classification
  • Ehlers-Danlos Syndrome / epidemiology*
  • Ehlers-Danlos Syndrome / genetics*
  • Female
  • Humans
  • Inheritance Patterns / genetics*
  • Italy / epidemiology
  • Joint Instability / classification
  • Joint Instability / epidemiology*
  • Joint Instability / genetics*
  • Male
  • Pedigree
  • Phenotype*
  • Surveys and Questionnaires