The genetic basis of the joint hypermobility syndromes

Abstract

Rheumatologists have long considered that joint hypermobility is inherited. The familial aggregation is striking and the pattern of inheritance strongly points to an autosomal dominant mode. The first comprehensive description of symptomatic joint hypermobility in the rheumatological literature is attributed to Kirk, Ansell and Bywaters in 1967 [1]. They coined the term ‘hypermobility syndrome’ (HMS). Later, the recognition of the relatively benign prognosis of the HMS in terms of life-threatening complications led to the use of the term ‘benign joint hypermobility syndrome’ (BJHS) or latterly, the ‘joint hypermobility syndrome’ (JHS). Early workers believed that joint hypermobility merely represented the upper end of a Gaussian distribution of the range of normal physiological movement [2]. Later it became apparent that connective tissues other than joints, such as skin, bone and eye, participated in the connective tissue fragility seen in JHS. These clinical signs of connective tissue fragility are usually most prominent in the different forms of heritable disorders of connective tissue (HDCTs) such as Marfan syndrome (MFS), osteogenesis imperfecta (OI) and the Ehlers–Danlos syndromes (EDS). Marfan syndrome is an autosomal dominant disorder characterized by aortic dilatation, ectopia lentis, marfanoid habitus and mild to moderate joint hypermobility [3]. Osteogenesis imperfecta, another autosomal dominant HDCT, is mainly characterized by varying degrees of bone fragility, blue sclerae, short stature and mild joint hypermobility. The EDS comprise a clinically and genetically heterogeneous group of connective tissue diseases of which the principal clinical features are joint hypermobility, skin hyperextensibility, delayed wound healing with atrophic scarring and generalized connective tissue fragility [4]. There exists, however, a phenotypic overlap between these forms of HDCT. The marfanoid habitus (Table 1) for instance was once considered to be pathognomonic for MFS. This notion is no longer tenable. Marfanoid habitus can be seen in a host of HDCTs, as illustrated in Table 2. Similarly, the blue sclerae, once thought to occur only in OI are now considered to have a wider relevance as a non-specific pointer to collagen deficiency. Skin hyperextensibility (and associated bruising, delayed healing and atrophic scarring) originally identified exclusively with EDS, is also recognized in MFS [3]. Although brittle bones were initially considered to feature only in OI, a reduction in bone mineral density detected by Dual energy x-ray absorptiometry (DEXA) scanning has been demonstrated in both EDS [5] and MFS [6]. With recognition of the presence of mild fragility of connective tissues other than the joints in patients with JHS, it became evident that JHS is itself an under-recognized form of an HDCT. Patients with JHS can present mild expression of marfanoid habitus (Table 2), osteoporosis, blue sclerae, skin hyperextensibility, atrophic scarring or easy bruising [7, 8] (Table 3). Since these features can also be present in the most common form of EDS, the hypermobility type (or former type III), it seems increasingly likely that JHS is, if not identical, indistinguishable from the hypermobility type of EDS [9].