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

Abstract

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.

Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes

“…EDS, and particularly JHS/ hEDS, predominantly affects women, with a relative prevalence of about 70%. 2 Our cohort was relatively small and composed of all women except for one man. Therefore, despite the finding of SFN in all patients, we cannot exclude sex-related differences.…”

“…1 More recently, segregation studies introduced and demonstrated the overlap between hEDS and the joint hypermobility syndrome (JHS). 2 The diagnosis of EDS is confirmed by molecular tools in most types except JHS/hEDS, which remains a clinical diagnosis based on available criteria. 3 Pain is common in various EDS types, particularly JHS/hEDS, 4 and its pathogenesis is mostly unknown.…”

“…The coexistence of burning sensation, paresthesias, allodynia, cramps, and diffuse myalgia has suggested a neuropathic component that was recently investigated in 44 patients using a questionnaire study. 5 Compression and axonal neuropathies could be more common in EDS 2 and have a role in hyperalgesia associated with JHS/hEDS. 6 Some pain features in patients with EDS suggest the involvement of small nerve fibers that has never been investigated before.…”

Anesthetic Management of a Patient With Ehlers-Danlos Syndrome

“…3 In the present case, EDS-HT, also called ''EDS type III,'' mimics joint hypermobility syndrome. 4,5 EDS-HT and joint hypermobility syndrome are clinically overlapping connective tissue disorders featuring generalized joint hypermobility, muscloskeletal pain, and minor skin features. 6 EDS-HT and joint hypermobility syndrome may constitute the same clinical entity and likely share the same genetic background, at least in familial cases.…”

“…Investigations into their relationship are still ongoing. 2,4 In classic EDS, the causative genes are COL5A1 and A2, COL1A1 and A2, COL3A1, PLOD1, and ADAMTS2, while the causative gene of EDS-HT has not been mapped so far. 2 In EDS-HT, the hereditary form is thought to be autosomal dominant, and the female:male ratio is about 2:1.…”