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 ... -  《-》

The neuromuscular differential diagnosis of joint hypermobility.

Joint hypermobility is the defining feature of various inherited connective tissue disorders such as Marfan syndrome and various types of Ehlers-Danlos syndrome and these will generally be the first conditions to be considered by geneticists and pediatricians in the differential diagnosis of a patient presenting with such findings. However, several congenital and adult-onset inherited myopathies also present with joint hypermobility in the context of often only mild-to-moderate muscle weakness and should, therefore, be included in the differential diagnosis of joint hypermobility. In fact, on the molecular level disorders within both groups represent different ends of the same spectrum of inherited extracellular matrix (ECM) disorders. In this review we will summarize the measures of joint hypermobility, illustrate molecular mechanisms these groups of disorders have in common, and subsequently discuss the clinical features of: 1) the most common connective tissue disorders with myopathic or other neuromuscular features: Ehlers-Danlos syndrome, Marfan syndrome and Loeys-Dietz syndrome; 2) myopathy and connective tissue overlap disorders (muscle extracellular matrix (ECM) disorders), including collagen VI related dystrophies and FKBP14 related kyphoscoliotic type of Ehlers-Danlos syndrome; and 3) various (congenital) myopathies with prominent joint hypermobility including RYR1- and SEPN1-related myopathy. The aim of this review is to assist clinical geneticists and other clinicians with recognition of these disorders.

Donkervoort S ，Bonnemann CG ，Loeys B ，Jungbluth H ，Voermans NC ... -  《-》

Generalized joint hypermobility, joint hypermobility syndrome and Ehlers-Danlos syndrome, hypermobility type.

This issue of the American Journal of Medical Genetics Seminar Series Part C is dedicated to generalized joint hypermobility (gJHM), joint hypermobility syndrome (JHS), and Ehlers-Danlos syndrome, hypermobility type (EDS-HT). gJHM is the best known clinical manifestation of inherited defects of the connective tissue. On the other side, JHS and EDS-HT are actually considered one and the same from a clinical perspective by most practitioners and researchers (i.e., JHS/EDS-HT), and their molecular basis remains unknown. For decades, "non-syndromic" gJHM and JHS/EDS-HT have been thought to be simple clinical curiosities or an asset for the "affected" individual. In recent years, the attention on these partially overlapping phenotypes has increased, as they are now recognized risk factors for a series of non-communicable diseases and long-term disabilities. This series consists of 10 papers focused on three main topics, namely (i) assessment and differential diagnosis of children and adults with gJHM, (ii) systematic presentation of selected key non-articular manifestations of JHS/EDS-HT and actual perception of physiotherapy as the best therapeutic resource for this condition, and (iii) exploration of the available knowledge relating "congenital laxity of tissues" to various dysfunctions of the nervous system during development and adulthood. The contributors hope that this collection raises attention to this fascinating field of knowledge, which seems to have ramifications in virtually all medical disciplines.

Castori M ，Colombi M 《-》

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 ... -  《-》