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.

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.

Castori M ，Dordoni C ，Valiante M ，Sperduti I ，Ritelli M ，Morlino S ，Chiarelli N ，Celletti C ，Venturini M ，Camerota F ，Calzavara-Pinton P ，Grammatico P ，Colombi M ... -  《-》

Differential diagnosis and diagnostic flow chart of joint hypermobility syndrome/ehlers-danlos syndrome hypermobility type compared to other heritable connective tissue disorders.

Joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT) is an evolving and protean disorder mostly recognized by generalized joint hypermobility and without a defined molecular basis. JHS/EDS-HT also presents with other connective tissue features affecting a variety of structures and organs, such as skin, eye, bone, and internal organs. However, most of these signs are present in variable combinations and severity in many other heritable connective tissue disorders. Accordingly, JHS/EDS-HT is an "exclusion" diagnosis which needs the absence of any consistent feature indicative of other partially overlapping connective tissue disorders. While both Villefranche and Brighton criteria include such an exclusion as a mandatory item, a systematic approach for reaching a stringent clinical diagnosis of JHS/EDS-HT is still lacking. The absence of a consensus on the diagnostic approach to JHS/EDS-HT concerning its clinical boundaries with similar conditions contribute to limit our actual understanding of the pathologic and molecular bases of this disorder. In this review, we revise the differential diagnosis of JHS/EDS-HT with those heritable connective tissue disorders which show a significant overlap with the former and mostly include EDS classic, vascular and kyphoscoliotic types, osteogenesis imperfecta, Marfan syndrome, Loeys-Dietz syndrome, arterial tortuosity syndrome, and lateral meningocele syndrome. A diagnostic flow chart is also offered with the attempt to support the less experienced clinician in stringently recognizing JHS/EDS-HT and stimulate the debate in the scientific community for both management and research purposes.

Colombi M ，Dordoni C ，Chiarelli N ，Ritelli M ... -  《-》

Spectrum of mucocutaneous manifestations in 277 patients with joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type.

Cutaneous manifestations are a diagnostic criterion of Ehlers-Danlos syndrome, hypermobility type (EDS-HT) and joint hypermobility syndrome (JHS). These two conditions, originally considered different disorders, are now accepted as clinically indistinguishable and often segregate as a single-familial trait. EDS-HT and JHS are still exclusion diagnoses not supported by any specific laboratory test. Accuracy of clinical diagnosis is, therefore, crucial for appropriate patients' classification and management, but it is actually hampered by the low consistency of many applied criteria including the cutaneous one. We report on mucocutaneous findings in 277 patients with JHS/EDS-HT with both sexes and various ages. Sixteen objective and five anamnestic items were selected and ascertained in two specialized outpatient clinics. Feature rates were compared by sex and age by a series of statistical tools. Data were also used for a multivariate correspondence analysis with the attempt to identify non-causal associations of features depicting recognizable phenotypic clusters. Our findings identified a few differences between sexes and thus indicated an attenuated sexual dimorphism for mucocutaneous features in JHS/EDS-HT. Ten features showed significantly distinct rates at different ages and this evidence corroborated the concept of an evolving phenotype in JHS/EDS-HT also affecting the skin. Multivariate correspondence analysis identified three relatively discrete phenotypic profiles, which may represent the cutaneous counterparts of the three disease phases previously proposed for JHS/EDS-HT. These findings could be used for revising the cutaneous criterion in a future consensus for the clinical diagnosis of JHS/EDS-HT.

Castori M ，Dordoni C ，Morlino S ，Sperduti I ，Ritelli M ，Valiante M ，Chiarelli N ，Zanca A ，Celletti C ，Venturini M ，Camerota F ，Calzavara-Pinton P ，Grammatico P ，Colombi M ... -  《-》

Refining patterns of joint hypermobility, habitus, and orthopedic traits in joint hypermobility syndrome and Ehlers-Danlos syndrome, hypermobility type.

Joint hypermobility syndrome (JHS) and Ehlers-Danlos syndrome, hypermobility type (EDS-HT) are two overlapping heritable disorders (JHS/EDS-HT) recognized by separated sets of diagnostic criteria and still lack a confirmatory test. This descriptive research was aimed at better characterizing the clinical phenotype of JHS/EDS-HT with focus on available diagnostic criteria, and in order to propose novel features and assessment strategies. One hundred and eighty-nine (163 females, 26 males; age: 2-73 years) patients from two Italian reference centers were investigated for Beighton score, range of motion in 21 additional joints, rate and sites of dislocations and sprains, recurrent soft-tissue injuries, tendon and muscle ruptures, body mass index, arm span/height ratio, wrist and thumb signs, and 12 additional orthopedic features. Rough rates were compared by age, sex, and handedness with a series of parametric and non-parametric tools. Multiple correspondence analysis was carried out for possible co-segregations of features. Beighton score and hypermobility at other joints were influenced by age at diagnosis. Rate and sites of joint instability complications did not vary according to age at diagnosis except for soft-tissue injuries. No major difference was registered by sex and dominant versus non-dominant body side. At multiple correspondence analysis, selected features tend to co-segregate in a dichotomous distribution. Dolichostenomelia and arachnodactyly segregated independently. This study pointed out a more protean musculoskeletal phenotype than previously considered according to available diagnostic criteria for JHS/EDS-HT. Our findings corroborated the need for a re-thinking of JHS/EDS-HT on clinical grounds in order to find better therapeutic and research strategies. © 2017 Wiley Periodicals, Inc.

Morlino S ，Dordoni C ，Sperduti I ，Venturini M ，Celletti C ，Camerota F ，Colombi M ，Castori M ... -  《-》

Knowledge, assessment, and management of adults with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type among Flemish physiotherapists.

Physiotherapy plays a fundamental role in managing adults with the joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT). However, it is a challenge for both the patient and the physiotherapist as the condition is poorly understood and treatment for JHS/EDS-HT is currently undefined. Insight into current practice is, therefore, necessary in order to establish baseline knowledge in this area and in the long term to improve the standard of patient care. Therefore, the purpose of this study was to evaluate current physiotherapists' knowledge of JHS/EDS-HT and to gain insight into current physiotherapy practice with emphasis on assessment, management, and treatment efficacy. Three hundred twenty-five Flemish physiotherapists participated in the study by filling out electronically a modified version of the "Hypermobility and Hypermobility Syndrome Questionnaire" (HHQ), which covered theoretical constructs such as general knowledge, assessment, management, and learning in relation to generalized joint hypermobility and JHS/EDS-HT. The results show that physiotherapists report a low level of confidence with regard to assessment and management of JHS/EDS-HT. Knowledge of hypermobility and JHS/EDS-HT is weak, especially regarding the features associated with JHS/EDS-HT. Many treatment approaches are used by physiotherapists with the majority showing preference for education, reassurance, muscle strengthening, proprioceptive and core stability training. Almost all approaches were perceived as being clinically effective by the physiotherapists, highlighting a lack of consensus. In conclusion, this study in Flemish physiotherapists confirms that JHS/EDS-HT is under-recognized, not well known and deemed difficult to treat. Further education is required and sought by the physiotherapists surveyed, and future research is needed.

Rombaut L ，Deane J ，Simmonds J ，De Wandele I ，De Paepe A ，Malfait F ，Calders P ... -  《-》