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F. Malfait, A. J. Hakim, A. De Paepe, R. Grahame, The genetic basis of the joint hypermobility syndromes, Rheumatology, Volume 45, Issue 5, May 2006, Pages 502–507, https://doi.org/10.1093/rheumatology/kei268
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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].
Arachnodactily (Steinberg + wrist signs) |
Scoliosis |
Pectus excavatum/carinatum |
Span:height ratio ≥1.03 |
Crown/pubis:pubis/floor ratio <0.89 |
Hand:height ratio >11% |
Foot:height ratio >15% |
Arachnodactily (Steinberg + wrist signs) |
Scoliosis |
Pectus excavatum/carinatum |
Span:height ratio ≥1.03 |
Crown/pubis:pubis/floor ratio <0.89 |
Hand:height ratio >11% |
Foot:height ratio >15% |
Arachnodactily (Steinberg + wrist signs) |
Scoliosis |
Pectus excavatum/carinatum |
Span:height ratio ≥1.03 |
Crown/pubis:pubis/floor ratio <0.89 |
Hand:height ratio >11% |
Foot:height ratio >15% |
Arachnodactily (Steinberg + wrist signs) |
Scoliosis |
Pectus excavatum/carinatum |
Span:height ratio ≥1.03 |
Crown/pubis:pubis/floor ratio <0.89 |
Hand:height ratio >11% |
Foot:height ratio >15% |
Congenital contractural arachnodactily |
Familial thoracic aortic aneurysm |
Familial aortic dissection |
Familial ectopia lentis |
Familial Marfan-like habitus |
Mass phenotype |
Familial mitral valve prolapse |
Stickler syndrome |
Shprintzen–Goldberg syndrome |
Homocystinuria |
EDS, kyphoscoliotic type (EDS type VI) |
(Benign) joint hypermobility syndrome |
Congenital contractural arachnodactily |
Familial thoracic aortic aneurysm |
Familial aortic dissection |
Familial ectopia lentis |
Familial Marfan-like habitus |
Mass phenotype |
Familial mitral valve prolapse |
Stickler syndrome |
Shprintzen–Goldberg syndrome |
Homocystinuria |
EDS, kyphoscoliotic type (EDS type VI) |
(Benign) joint hypermobility syndrome |
Congenital contractural arachnodactily |
Familial thoracic aortic aneurysm |
Familial aortic dissection |
Familial ectopia lentis |
Familial Marfan-like habitus |
Mass phenotype |
Familial mitral valve prolapse |
Stickler syndrome |
Shprintzen–Goldberg syndrome |
Homocystinuria |
EDS, kyphoscoliotic type (EDS type VI) |
(Benign) joint hypermobility syndrome |
Congenital contractural arachnodactily |
Familial thoracic aortic aneurysm |
Familial aortic dissection |
Familial ectopia lentis |
Familial Marfan-like habitus |
Mass phenotype |
Familial mitral valve prolapse |
Stickler syndrome |
Shprintzen–Goldberg syndrome |
Homocystinuria |
EDS, kyphoscoliotic type (EDS type VI) |
(Benign) joint hypermobility syndrome |
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].
Classification of disease
Clinical scientists, epidemiologists and geneticists have hitherto attempted to define clinical patterns of disease in their quest for reliable systems for classification and diagnosis. In the field of the HDCTs, the first attempt to produce sets of consensus-derived criteria was the Berlin nosology of 1986 [10], which aimed at covering the whole range of HDCTs. With the advent of molecular genetics, the Berlin nosology fell rapidly out of date and revised criteria for MFS (the Ghent criteria) [11] and EDS (the Villefranche criteria) [12] emerged in 1996 and 1998, respectively, to be followed by the validated 1998 Brighton criteria for JHS in 2000 [13]. Such sets of criteria are useful in defining cohorts of patients for research studies, but represent poor substitutes for precise laboratory tools capable of identifying specific genetic causes of disease.
The genetics of the HDCTs
To date, the genetic basis of joint hypermobility remains largely unknown. Study of the HDCTs, such as EDS, MFS and OI, can give important insights into the mechanisms underlying joint hypermobility, since joint hypermobility is a prominent feature in all of these syndromes, albeit to a variable degree. The connective tissue matrix consists of fibrillary collagens, fibrillins, elastins and proteoglycans, and together these structural components provide the unique mechanical properties of the joint capsule and the surrounding ligaments and tendons. Joint hypermobility can be present in a mild form in MFS, caused by mutations in the fibrillin-1 gene, and in OI, caused by mutations in the genes encoding type I collagen, quantitatively the most important member of the family of fibrillary collagens. Joint hypermobility is, however, most prominent in the different subtypes of the EDS, and EDS patients are hence good models for the study of the genetic mechanisms underlying joint hypermobility.
The Villefranche classification for EDS recognizes six subtypes, based on the severity of the clinical features, the underlying biochemical and genetic defect and the pattern of inheritance [12]. Besides these recognized subtypes there are, however, many rare unclassified variants, the molecular basis of which is often unknown. Joint hypermobility is, to a varying degree, a cardinal feature in all subtypes of EDS. Mutations in genes encoding fibrillary collagens or collagen-modifying enzymes have been identified in most forms of EDS, but the molecular defect underlying the most frequent form of EDS, the hypermobility type, and the related phenotype of JHS remains at present largely unknown.
Reports of genetic studies in patients and/or families with EDS, hypermobility type, or with JHS are scarce. In analogy with the other EDS subtypes, genes encoding collagens and collagen-modifying enzymes have been considered as candidate genes for these conditions. Narcisi et al. [14] identified a mis-sense mutation in the COL3A1 gene, encoding type III collagen, in a family with features reminiscent of EDS, hypermobility type. Normally, mutations in this gene result in the vascular type of EDS. This form is characterized by extensive bruising and vascular fragility, with risk of premature death from vascular or bowel rupture. No other mutations in COL3A1 have been identified since in EDS, hypermobility type, and it is possible that the affected members of the reported family had a late onset of their vascular problems. One study investigated the segregation of collagen genes in two families with JHS. This study excluded the COL3A1, COL5A2 and COL6A3 genes as the causative genes for the condition, and there was no indication for strong linkage to the COL1A1 and COL1A2 genes [15]. In another study, no association could be found between particular length variants in COL2A1 and joint hypermobility [16].
Recently, mutations in a non-collagenous molecule, tenascin-X, have been identified in a subset of patients with EDS, hypermobility type, and JHS [17]. Tenascin-X is a large extracellular matrix glycoprotein, belonging to the family of tenascins. Complete absence of tenascin-X was initially identified in patients with a phenotype reminiscent of classic EDS, characterized by skin hyperextensibility, joint hypermobility, easy bruising and tissue fragility, but without the atrophic scarring, typical for classic EDS [18]. Subsequently it was shown that all obligate heterozygous carriers had reduced levels of serum tenascin-X. Approximately half of these individuals (45%) suffered from generalized joint hypermobility, often associated with joint (sub)luxation and chronic musculoskeletal pain. Interestingly most of these individuals were women, whereas none of the heterozygous men were hypermobile [17]. These findings are in accordance with the higher prevalence of EDS, hypermobility type, and JHS among women. Together these findings suggest that haploinsufficiency of tenascin-X plays a role in the pathogenesis of joint hypermobility, but factors such as gender and modifying genes possibly affect hypermobility. However, haploinsufficiency of tenascin-X can account for only a small subset of patients with joint hypermobility, as it was detected in only 5–10% of series of patients with EDS, hypermobility type, or JHS [17]. The identification of mutations in tenascin-X is, however, an important model in the study of the genetic basis of EDS and joint hypermobility. It is the first example of mutations in a gene encoding a protein other than a collagen or a collagen-modifying enzyme in this group of conditions. It suggests ways to study the basis of joint hypermobility, and it also suggests that mutations in genes for other non-collagenous proteins could result in either EDS or joint hypermobility.
Joint hypermobility is also an important feature in most EDS subtypes, other than the hypermobility type, and in many EDS-like phenotypes that cannot be classified in one of the six recognized subtypes. Unravelling the genetic basis underlying these phenotypes can also provide important insights in the molecular basis of joint hypermobility.
For example, mutations in the genes encoding type I collagen (COL1A1 and COL1A2) play an important role in the pathogenesis of joint hypermobility. Mutations in these genes are generally associated with OI, a heritable disorder of connective tissue, characterized by brittle bones. Patients with OI also frequently suffer from mild joint hypermobility. A special group of mutations in collagen type I are mutations leading to partial or complete skipping of exon 6 in the COL1A1 or COL1A2 gene, resulting in a deficient processing of the N-terminal propeptide of the α1 or the α2 chain of collagen type I. These mutations are observed in a rare form of EDS, the arthrochalasis type, characterized by profound joint hyperlaxity, congenital dislocation of the hip, osteopenia and characteristic structural abnormalities of the collagen fibrils [19]. Recently we identified a patient with a phenotype that shows overlap between OI and EDS, with mild joint hypermobility, recurrent joint dislocations, mild skin hyperextensibility, osteopenia and blue sclerae. Molecular testing revealed skipping of exon 7 of the COL1A2 gene, leading to delayed processing of the N-propeptide of the α2-chain of type I collagen (unpublished data). A small number of mutations at the N-terminal end of the helical region of α2(I) have also been reported [20–24]. These patients all show a combination of EDS and OI symptoms. Similarly it was shown that exon-skipping mutations and glycine substitutions in the same region of the α1(I) chain also result in an overlap phenotype between OI/EDS, with severe joint hypermobility as one of the most striking features. It was shown that these mutations prevent or delay the removal of the procollagen N-propeptide [25]. Overall these findings suggest that interference with the processing of the N-propeptide of either α-chain of type I collagen is responsible for EDS-like symptoms, with joint hypermobility as one of its major complications. Joint hypermobility was also the presenting and cardinal feature in a young patient in whom a homozygous mutation in the COL1A2 gene was identified. This mutation led to the introduction of a premature termination codon further down in the gene and ‘nonsense-mediated RNA decay’ of the mutant transcripts, resulting in a total absence of the α2 chain of collagen type I. Total lack of α2(I) has only been described in six other patients, all of them presenting joint laxity [26–29]. As adults these patients are at risk of aortic and mitral valve insufficiency, and hence this form was recognized as a new subtype of EDS, the cardiac valvular subtype [30].
Exceptionally, mutations in COL1A1 cause the classic subtype of EDS (EDS type I and type II) [31], but more often this subtype results from mutations in the genes encoding collagen type V (COL5A1 and COL5A2). Collagen type V is a quantitatively minor fibrillary collagen that interacts with type I collagen during fibrillogenesis and regulates fibril diameter [32]. Mutations in type V collagen interact with the fibrillogenesis and result in fibrils that have a strikingly disrupted shape and diameter on electron micrographs [33]. Classic EDS is characterized by soft and velvety skin, abnormal scar formation and marked joint hypermobility. The joint hypermobility is usually generalized, affecting both large and small joints, and it can range in severity from mild to severe, with major articular complications such as habitual subluxation and dislocation of the joints. At birth, uni- or bilateral dislocation of the hip may be present. Some adult individuals may suffer from chronic musculoskeletal pain, despite normal radiographs. In approximately one third of patients, the disease is caused by a mutation leading to a non-functional COL5A1 allele (‘COL5A1 null-allele’), resulting in haploinsufficiency of type V collagen. In a smaller proportion of patients, a structural mutation in COL5A1 or COL5A2, resulting in the production of a functionally defective type V collagen protein, is responsible for the phenotype. Together, mutations in the collagen type V genes can be identified in approximately half of the patients with classic EDS. In the other half, the genetic basis of the phenotype is still largely unknown [34]. No genotype–phenotype correlations can be made so far, but a large inter- and intra-familial variability in severity is seen. In this respect it is important to note that a clinical overlap may exist between the mild form of classic EDS (EDS type II) and the hypermobility type. This is illustrated by two pedigrees with classic EDS, where the affected children presented with a ‘full-blown’ classic EDS phenotype, while the affected parent only showed some mild and localized joint hypermobility, and no overt skin hyperextensibility or scarring, suggesting the diagnosis of EDS, hypermobility type, or JHS, rather than classic EDS. Surprisingly, molecular testing showed the presence of a non-functional COL5A1 allele in the affected children and the affected parent in both pedigrees (authors’ observations). These examples show that classic EDS may be mild with only some localized joint hypermobility as a presenting feature, and that the possibility of a COL5A1 null allele should be considered in patients presenting with joint hypermobility.
Except for the EDS, OI and Marfan syndrome, joint hypermobility may be the presenting feature in some other rare genetic conditions. Pseudo-achondroplasia (PSACH), for example, is an autosomal dominant disorder characterized by short stature, short extremities and ligamentous laxity, which is usually most prominent in the hands and fingers. The mobility at the elbows may, however, be restricted and flexion contractures may develop at the hips. Premature osteoarthritis, especially in the hips and knees, is common. This relatively mild condition is caused by mutations in the gene encoding COMP, cartilage oligomeric matrix protein [35]. This is a large pentameric glycoprotein, present in the extracellular matrix of the chondrocytes, in tendon and in ligaments, where it interacts with collagen type I and type II [36].
Joint hyperlaxity and multiple congenital joint dislocations of hips, elbows and knees are the main features of the Larsen syndrome. Other symptoms of this condition include characteristic facial appearance (with a flat face, prominent forehead, widely spaced eyes and a depressed nasal bridge), abnormal hands with short metacarpals and cylindrical fingers, cleft palate or uvula, equinovarus deformity of the foot, dental abnormalities and cardiovascular lesions. Recently, heterozygous mutations were reported in two families in the gene encoding filamin B, a cytoplasmic protein that appears to be involved in vertebral segmentation, joint formation and enchondral ossification [37]. Another Larsen syndrome locus, LAR1, was mapped earlier to chromosome 3p [38].
Distal joint hyperextensibility, especially of the wrist and ankles, in combination with proximal contractures and generalized muscle weakness, is the hallmark of the severe congenital muscular dystrophy, known as Ullrich disease or scleroatonic muscular dystrophy [39]. The finding of the excessive distal laxity is striking and often raises EDS as a diagnostic consideration. The condition is caused by recessive mutations in the genes encoding type VI collagen, specifically COL6A2 and COL6A3 [40], but can also be the result of heterozygous mutations in the COL6A1, COL6A2 or COL6A3 genes [41, 42].
Other candidate genes
Studies in transgenic mice have suggested few other candidate genes for joint hypermobility so far. Various members of an expanding family of secreted proteoglycans, the ‘small leucine-rich proteoglycans’ (SLRPs), have been shown to interact directly with fibrillar collagens, thereby modulating fibril formation, growth and morphology in vitro. Their importance in regulating fibrillogenesis has become clear from studies of SLRP-deficient mice, some of which have phenotypes resembling EDS. For example, lumican and fibromodulin are two members of this family that regulate the assembly of collagens into higher-order fibrils in connective tissues. Mice deficient in both of these proteoglycans manifest severe joint hyperlaxity and age-dependent osteoarthritis. Fibromodulin deficiency alone results in a significant reduction in tendon strength, while the tendon stiffness is further reduced with lumican deficiency in a dose-dependent way [43]. Also mice deficient in decorin, dermatopontin or mimecan show features reminiscent of EDS, such as skin hyperextensibility and ultrastructural changes in collagen fibril diameter, but no human examples have been documented for these different mouse models [44–46]. Sztrolovics et al. [47] studied the coding sequences of human decorin, biglycan and fibromodulin in patients with EDS, hypermobility type, but did not detect any mutations. At present it remains an open question to what extent mutations in SLRPs or still other candidate molecules account for EDS, hypermobility type, or JHS in humans.
Guidance for diagnostic biochemical and molecular testing in patients with joint hypermobility
When a patient presents in the clinic with joint hypermobility, a clinical evaluation is mandatory in order to exclude other signs of connective tissue fragility and a family history; in particular, clinical signs indicative of the more serious forms of EDS should be sought (Table 3). The presence of marked skin hyperextensibility, atrophic scarring and prominent bruising is suggestive for the classic form of EDS (formerly, EDS type I/II), whereas a history of congenital hip dislocation is the hallmark for the arthrochalasis subtype. Extensive bruising and/or a family history of vascular or intestinal rupture or sudden death is highly suspicious for the vascular subtype of EDS. A medical history of several fractures upon minimal trauma, short stature and blue sclerae are suggestive of OI. When moderate joint hypermobility is associated with a marfanoid habitus (tall and slender build, arachnodactyly) coupled with a history of ectopia lentis and/or aortic dilatation or aneurysm, MFS should be strongly suspected. The same combination without such ocular or cardiac involvement will point in the majority of cases to EDS hypermobility type (or JHS) with marfanoid habitus. Other characteristic features and clinical symptoms may point to the diagnosis of PSACH, Larsen syndrome, Ullrich muscular dystrophy or still other conditions where joint hypermobility plays a prominent role.
When the presence of EDS, OI or MFS is suspected, additional morphological, biochemical and/or molecular analyses are available to confirm the diagnosis. Molecular analysis of the fibrillin-1 gene in case of suspected MFS can be performed on genomic DNA extracted from leucocytes (blood sample). In the case of suspected EDS or OI, a skin biopsy should be taken in order to perform biochemical analysis of collagens type I, III and V. Depending on the clinical and biochemical evaluation, further molecular analysis can be performed on DNA extracted from the cultured fibroblasts. This approach helps to identify the genetic defect underlying joint hypermobility in patients with some of the well-known subtypes of EDS, such as the classic, vascular and arthrochalasis subtype, as well as in some rare and unclassified variants, such as the OI/EDS overlap phenotype and the cardiac vascular phenotype. In these patients, elucidation of the biochemical and/or molecular defect underlying their phenotype may help to confirm their specific subtype of EDS, as this is not always straightforward from the clinical examination. This may have important implications for genetic counselling, management and preventive therapy, and provides the possibility of pre-natal or pre-implantation diagnosis. Biochemical analysis of the fibrillary collagens and mutation analysis of the respective genes is, however, normal in the majority of patients who present with EDS, hypermobility type, or JHS. For the clinician, certainly in the UK, the various laboratory-based diagnostic investigations referred to in this review, with the exception of FBN1 mutation analysis, through the Genetic Testing Network, are currently a luxury that is, at best, hard to come by and, at worst, unavailable.
Summary
The HDCTs present the clinician with a wide variety of signs, symptoms and complications, many of which overlap to a certain extent between conditions. On the whole, the rarer forms of these conditions may be identified clinically by the striking degree to which they manifest particular phenotypes, and the genetic abnormalities and inheritance patterns of these conditions is well understood. For the common variants, EDS, hypermobility type, and JHS, the genetics is poorly understood. A combination of factors is likely in these conditions and is a focus of further research.
The authors have declared no conflicts of interest.
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Author notes
Centre for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium and 1Centre for Rheumatology, University College Hospital, London W1T 4NJ, UK.
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