The clinical assessment of the joint laxity syndrome is not difficult but examiners should be trained in order to ensure the reliability of the exam. Our group has developed a two-day training course with the support of a CD [ 20 ].

Brighton criteria, taken from Grahame R, et al. 2000 [ 19 ]. JHS is diagnosed if the patient presents 2 major criteria, 1 major and 2 minor criteria, or 4 minor criteria. 2 minor criteria will be enough when there is a first-degree relative with the syndrome clearly diagnosed. JHS is excluded by the presence of the Marfan or the Ehlers–Danlos Syndrome. The first major criterion and the first minor one exclude each other, as do the second major and the second minor.

In 2010 Grahame [ 19 ] developed the Brighton criteria to replace the Beighton criteria for the joint hypermobility syndrome (JHS). According to these criteria, the syndrome diagnosis is made taking into account the Beighton score and also some other clinical manifestations associated with hypermobility. As it could be expected, the correlation between them is very high. They are seldom used outside of rheumatology. The main sets of criteria are included in Table 2 .

In 1992, the Hospital del Mar criteria ( Table 1) compiled all the items included in the most clinically used criteria. This new scale showed consistent indicators of reliability, internal consistency, and predictive validity and provided evidence for using different scores according to age and gender [ 18 ].

There are several sets of criteria that show minimal variations from the original proposed by Rotés, although new self-assessment questionnaires have been recently added to the assessment methods of JHS [ 16 , 17 ]. A review paper of all the available criteria showed a high degree of agreement among all of them [ 18 ]; a more comprehensive set of 10 criteria obtained by cluster analysis was also proposed. However, the most often used are the “Beighton criteria” converted to a nine point clinical scale by which subjects with a score ≥ 4 are considered as having JH. The condition is characterized through the examination of five body areas, each one receiving a separate score of hyperextension: fifth fingers, thumbs, elbows, knees, and trunk (see Figure 1) .

Clinical features in JHS can be articular or extra-articular and are always related to the connective tissue. Among the best known articular features of JHS are arthralgia, lumbalgia, soft-tissue rheumatism (e.g., epicondylitis, tenosynovitis, bursitis), recurrent dislocations, childhood scoliosis, or rheumatoid arthritis [ 13 , 14 ]. Among the best-known extra-articular features of JHS are hernias, varicose veins, “easy bruising”, keloids, uterine or rectal prolapse, spontaneous pneumothorax, fibromyalgia, dysautonomia, and some other conditions also linked to panic disorder as asthma, mitral valve prolapse, thyroid dysfunction, or irritable bowel syndrome [ 14 , 15 ].

JHS is an inherited connective tissue disorder associated with a generalized collagen laxity and characterized by an increase of active or passive joint mobility in the absence of another rheumatologic disease. JHS has an estimated prevalence in the general population ranging between 10%–20%, and is one of the hereditary disorders of the connective tissue, which include other conditions such as Ehlers–Danlos syndrome, Marfan syndrome, and ostogenesis imperfecta [ 10 ]. In fact, there is an overlap with the Ehlers– Danlos type III. This condition has an autosomal dominant pattern and twin studies showed that genetics accounts for at least 70% of the phenotype variance rather than environmental factors such as training. JHS is more common in childhood and tends to decline when aging. The prevalence is higher in females and probably there are ethnic differences, which suggest genetic variations. JHS is also associated with musculoskeletal dysfunctions, possibly resulting from a glycoprotein deficiency and genetic alterations affecting the formation of collagen, which would explain tissue looseness, prolapsed organs, visceroptoses, pneumothorax, and vulnerability to trauma in these patients.

In 1973, after an epidemiological study by Beighton et al. [ 8 ] using both joint laxity and joint mobility, the syndrome gained general interest in rheumatology and by then, renamed joint hypermobility (JH), began to be studied in a broader way as a separate entity [ 9 ]. Later on, the seminal work of Rodney Grahame was very important to get the Joint Hypermobility Syndrome (JHS) revisited among rheumatologists. He has produced three editions of the Beighton book [ 10 ] as well as other books about the topic and also has boosted clinical research on it [ 11 , 12 ]. Another prominent author who has provided insightful clinical descriptions of the JHS is Dr J. Bravo [ 13 ].

The condition was described for the first time about 60 years ago when it was properly identified and associated to pathology of the musculoskeletal system [ 4 ]. The original name proposed by Rotés was 'Joint Laxity' (Laxité Articulaire) and it was published in a French journal (Revue du Rhumatisme). In 1964, Carter and Wilkinson, also using the name of joint laxity (JL), published a relevant paper in which they proposed some diagnostic criteria [ 7 ].

In order to clarify the terminology all along this chapter, we shall use indistinctly Joint Laxity (the original name) and Joint Hypermobility (the given name). Although the second is more often used in English publications, it in fact refers to a rather unspecific consequence (increased mobility), whereas hyperlaxity refers more correctly to the intrinsic mechanism (increased laxity of fibers).

3.2. Comorbidity data between anxiety and JHS

Empirical history of the clinical relationship between anxiety disorders and JHS started with a case-control study conducted by our group in 1993, with rheumatologic outpatients with JHS [21]. Diagnoses of panic disorder, agoraphobia, and simple phobia were significantly more frequent among hypermobile patients. There were no significant differences in the diagnoses of generalized anxiety disorder, dysthymia, or major depressive disorder. Around 70% of rheumatologic patients with JHS had some kind of anxiety disorder. However, this only occurred in 22% of controls, a usual figure in chronic patient samples. Cases were 10 times more likely to suffer from anxiety than controls. Specifically, agoraphobia and panic disorders were, respectively, 5 and 7 times more likely (Table 3).

% JHS % Non-

JHS Age-Sex Adjust. Odds Ratio 95 % C. I. Any Anxiety D. 69,3 22,0 10.69 4.80–23.81 Panic D. 34.2 6.8 6.96 2.31–20.91 Panic & Agora. 24.6 5.1 6.40 1.82–22.43 Simple Phobia 29.8 8.5 5.77 2.05–16.24 Agoraphobia 37.7 11.9 5.08 2.06–12.49 General.Anx. 10.5 5.1 2.49 0.65–9.45 Major Depress. 14.9 3.4 4.51 0.99–20.56 Dysthymic D. 7.9 5.1 2.15 0.53–8.65 Table 3. Lifetime psychiatric disorders in JHS cases (n=114) and non-JHS controls (n=59) seen at an outpatient rheumatological unit, from Bulbena A, et al. 1993 [21].

For a subsequent second study, conducted to support this hypermobility-anxiety association, outpatients with new diagnoses of panic disorder and/or agoraphobia were examined, as well as nonanxious psychiatric and nonpsychiatric outpatients as control groups [22]. Results showed that JHS was present in almost 70% of anxiety cases, versus slightly over 10% of controls. This meant that cases with panic disorders and/or agoraphobia were 17 times more likely to suffer from JHS. Conclusions were valid for women [OR=23.7; CI95% 10.6–52.9] but also for men [OR=10.5; CI95% 3.0–36.3].

Lumley et al. [23] evaluated the psychosocial functioning in patients suffering from Ehlers–Danlos Syndrome (JHS is considered EDS type III). The sample was selected from an outpatient research clinic and the results showed that EDS type III group had higher scores on anxiety, depression, and interpersonal sensitivity as well as higher scores in the symptomatology checklist and the pain scales.

Other lines of research studied possible specific somatotype characteristics in patients with panic disorder/agoraphobia [24]. Cases with panic and/or agoraphobia from an outpatient mental health clinic were compared to psychiatric and medical controls matched by age and gender. Within the entire sample, the asthenic somatotype was associated with higher JH scores. Interestingly enough, the prevalence of asthenic somatotype was at the same time significantly higher in the panic/agoraphobia group (33.3%) compared to the psychiatric (19.2%) and the medical (18.7%) controls. The authors finally concluded that the relationship between panic disorder and asthenic somatotype might be mediated through JHS.

These results were confirmed by another study carried out by the same group in 2014 [25]. They included 60 patients with Panic and Agoraphobia and 60 controls. The authors found that cases and controls differed in the percentage of ectomorphic subjects: 38.3% of cases and 13.3% of controls were categorized as ectomorphic [χ 2=8.5, df=1, p=0.004]. In order to explore the characteristics associated with the ectomorphic somatotype, the two groups were collapsed into one, and ectomorphic and nonectomorphic subjects were compared. The ectomorphic group was younger and showed significantly more hypermobility of joints and more prevalence of panic and agoraphobia. Differences in sex, intake of antidepressants, marital status, educational degree, and labour situation were minor and statistically nonsignificant (Table 4). To further clarify the relative value of previously mentioned variables in relation to somatotype, a logistic regression model was constructed with the ectomorphic somatotype as dependent variable and as independent variables, sex, age, and JH. Only the last one was independently associated with the ectomorphic somatotype [OR=3.25, 95% CI: 1.35–7.8, p=0.008]. Therefore, after adjusting for age and sex, ectomorphic somatotype was independently related to JH status (the more hypermobile, the more likely to be ectomorphic).

Characteristics Ectomorphic group (n=31) Nonectomorphic group (n=89) χ2 / t p Female 54.8 48.3 0.17 .677 Age 29.2 32.2 1.98 .050 Antidepressants 41.9 30.3 0.92 .338 Single 67.7 51.7 1.80 .180 High educated 22.6 43.8 3.53 .060 Employed 93.5 97.8 0.29 .588 Panic 64.5 41.6 3.98 .046 Agoraphobia 64.5 32.6 8.43 .004 JH status 45.2 20.2 6.09 .014 Table 4. Comparison of subjects with and without ectomorphic somatotype (according to the Heath-Carter method). All characteristics are expressed in %, except age expressed in mean (S.D.).

Later on, this association was studied in the general population. A two-phase cross-sectional epidemiological study was carried out in a rural town in order to establish lifetime risk for anxiety and affective disorders in subjects affected with JHS. A sample of 1,305 individuals was examined at baseline and over 500 were subsequently subjected to follow-up in a two-stage epidemiological study. Hypermobile patients were six times more likely to suffer from agoraphobia (OR 5.9; CI 95% 3 to 11.7), eight times more likely to suffer from social phobia (OR 7.8; CI 95% 2.4 to 24.8), and eight times more likely to suffer from panic disorder (OR 8.2, CI 95% 3.4 to 19.7) than non-JHS patients. Results were valid for males and females. No differences were found for other anxiety disorders or mood disorders [26].

In the same sample of general population, it was also found that hypermobiles had significantly higher scores in fear and phobia scales, strenghtening the hypothesis that intensity of fears is greater in subjects with JHS [27]. We assessed fear intensity and frequency using a modified version of the Fear Survey Schedule (FSS-III). When the groups with and without joint hypermobility were compared, the mean total scores for both genders were significantly higher for the hypermobile group. These results showed that the association of JHS and phobic anxiety is sustained for intense fears and might represent a susceptibility factor for these anxiety conditions.

The same design was replicated in 2011 in a sample of 150 nonclinical students [28]. Severe fears and daily consumption of cigarettes, alcohol, coffee, and chocolate were compared with the hypermobility scores. We found significant differences when comparing severe fears between the groups with and without hypermobility (7.6 vs. 11; p = 0.001). The frequency of chocolate intake was also significantly higher among subjects with joint hypermobility (31.2% vs. 51.2%; p = 0.038). No significant differences were found regarding cigarette (19.5% vs. 19.3%), alcohol (36.6% vs. 34.9%), and coffee (46.3% vs. 35.8%) consumption. These patterns of consumption may, therefore, be interpreted as self-treatment attempts of subsyndromal anxiety in hypermobile subjects.

In 2004, our group also assessed a nonclinical sample of subjects employed in the same company (N=526) [29]. Subjects with JHS had significantly higher scores in STAI trait anxiety [female average: 16.5 vs. 11; p<0.001] [male average: 13 vs. 11; p<0.03]. STAI state anxiety scores were also higher among hypermobile subjects, although not significantly (Figure 2).

Joint hypermobility has also been assessed in relation to psychoactive substances. Baeza-Velasco [30] designed a cross sectional study in college students to assess the use of alcohol and tobacco. The odds of being assessed with JH were greater in those who consumed tobacco and alcohol. Women with JH had higher levels of state anxiety and used emotion-focused coping (i.e., efforts to regulate affect) more than any other coping strategies to deal with stress.

The first structural neuroimaging study on the association was published in 2012 evaluating regional cerebral grey matter in regards to hypermobility status in 72 healthy volunteers [31]. Interestingly enough, bilateral amygdala volume was higher in the hypermobile group. Their findings linked hypermobility to the structural integrity of a brain center implicated in normal and abnormal emotions and physiological responses.

In 2005, we studied schizophrenic outpatients (N=124) with the hypothesis that anxiety disorders mediated by JHS were not symptoms but an independent comorbid entity in schizophrenic patients [32, 33]. Joint Hypermobility was noticeably more likely among panic disorder/phobia-clustered schizophrenic patients than among the noncomorbid group (OR = 9.35; IC = 95% [3.85–22.73]; p<0.0001). The cluster panic disorder/phobia had higher scores in fear scales and schizophrenia positive symptom scales. We are now performing a voxel-based morphometric study in order to examine brain structure, comparing magnetic resonance images of 20 schizophrenic-anxious patients and 20 schizophrenic patients. The preliminary results indicated gray matter volume differences in the schizophrenic-anxiety group in the dorsolateral prefrontal cortex related to the interaction between both conditions. Our findings suggest that the schizophrenic-anxiety group is characterized by specific neural abnormalities that cannot be explained by the presence of schizophrenia or anxiety, but by their conjunction, and this might result in a certain symptomatology [34].

The relationship between social phobia and height was studied through a cross sectional study to explore the frequency of social phobia as well as a heritable disorder of the connective tissue (HDCT) in tall people [35]. One hundred and fifty eight subjects with heights greater than 180 cm in females and 190 cm in males were included in the study; social phobia and HDCT were highly prevalent in tall subjects. JHS was associated with greater prevalence of social phobia symptoms.

The association between anxiety disorders and JHS was also assessed in a sample of university students from Chile [36]. Fifty university students with JH and 50 controls were selected to participate in this case control study. The JH group had higher use of antidepressants and anxiolytics compared to the controls. They also exhibited greater anxiety background, anxiety symptoms, and psychosomatic complaints. A similar study was carried out by Baeza-Velasco et al. in a group of undergraduates in a French university [37]. The aim of the study was to explore the Joint Hypermobility Syndrome (JHS) in the university students and also to assess a possible relationship between this collagen condition and certain psychological variables. Three hundred and sixty five undergraduates from a French University were included in the study and the researchers found that JH was present in almost 40% of the sample and it was also associated with higher levels of somatosensory amplification as well as higher scores in depression and general anxiety in females.

After a number of significant cross-sectional studies we conducted a prospective incidence analysis that assesses whether JHS could be a risk factor in developing anxiety conditions [38]. We sought to determine the cumulative incidence of anxiety disorders in a cohort of young subjects recruited from the general population who had not developed any type of anxiety condition up to the moment; consequently a scheduled 15-year follow-up covering subjects from late adolescence to adulthood was planned. The total population sample was 1,305 subjects, and in order to observe the development of anxiety disorders during the 15-year study period, only the lower age segment (at that time subjects aged between 16 and 20) included in the town’s municipal registry was invited to participate. We sought to describe the occurrence of new cases of anxiety disorders during the study period, therefore the exclusion criterion for the study was having already had an anxiety disorder at baseline examination. At baseline, 158 subjects were screened for participation in the study, and after the 15-year follow-up the final sample comprised 137 subjects (86.7% retention rate). Results showed that cumulative incidence of panic/agoraphobia at follow-up was significantly higher for the JHS group (41.4%) than for the control group (1.9%) with relative risk of 22.3 (CI 95% 4.6–108.7), p<0.0001, (NNT 3, CI 95% 2.9–2.3). Incidence of social phobia (RR=6.52; CI 95% 1.7–24.2; p<0.001) and simple phobia (RR=3.31; CI 95% 1.1–9.6; p=0.02) was also significantly higher for the JHS group (Table 5). Moreover, anxiolytic drug use was nearly fourfold higher among JHS subjects compared to non-JHS.

Total Sample

n = 137 JHS Status JHS present

n = 29 JHS absent

n = 108 RR 95% CI P n % n % Anxiety Disorders Panic/Agoraphobia 12 41.4 2 1.9 22.3 (4.6 to 108.7) 0.0001*** Social Phobia 7 24.1 4 3.7 6.5 (1.7 to 24.2) 0.001* Simple Phobia 8 27.6 9 8.3 3.3 (1.1 to 9.6) 0.02* GAD 7 24.1 9 8.3 2.9 (0.97 to 8.62) 0.14 ns Other Disorders Depression/Dysthymia 7 24.1 7 6.48 3.7 (1.2 to 11.7) 0.15 ns Table 5. Incident cases and relative risk after 15 years of follow-up according to JHS status. Taken from Bulbena A, et al. 2011 [38]. JHS, Joint Hypermobility Syndrome according to Beighton criteria assessed at baseline.

GAD, Generalized Anxiety Disorder

Statistical significance: * p<0.05, ** p<0.001, *** p<0.0001, ns: non significant.



Nevertheless, some studies failed to find a significant correlation between panic disorder and JH. The study by Benjamin et al. was carried out in Israel on 101 patients with patient disorder and 39 controls [39]. The authors also attempted to examine the possible association between reactivity to carbon dioxide and JH. The rate of JH did not differ between the cases and controls neither between JH and carbon dioxide responses. However they used the crude number of hyperlax joints instead of the scoring method, which carries the cutoff point to the extreme of the distribution and therefore is not fully comparable to the rest of studies. On the other hand, the instruments used to assess anxiety in these patients (the self-rating scale of the National Institute of Mental Health, DSM IV panic symptoms scores and 100mm visual analogue scales of anxiety) are uncommon and could explain the results of the study.

Gulpek et al. designed a study to test the association between JHS and panic disorder and also to determine whether mitral valve prolapse (MVP) accounts for or changes this association [40]. The sample consisted of 115 subjects that were divided in 3 groups. The first group (n=42) included patients with PD and MVP, the second group (n=35) consisted of patients with PD and without MVP and the third group (n=38) had patients with MVP and no psychiatric diagnosis. No significant differences were found in prevalence or severity of JH between groups according to Beighton criteria scoring. However, JH was present in 59.5% of the panic disorder patients with mitral valve prolapse, and 52.6% of the control subjects. Compared to other studies, the prevalence of JH in the control group was never found as high as in this study. Since the prevalence of JH was higher in patients with PD and MVP (59.5%), authors suggested that MVP affects the prevalence of JH in PD. The prevalence of panic disorder was also higher in the JH compared to controls.

Another research group from Turkey studied the relationship between thorax deformity, anxiety, and joint hypermobility. Fifty-two males with thorax deformity and 40 healthy controls from a general outpatient medical clinic were selected to participate in the study [41]. Twenty patients (40%) from the cases group met criteria for JH and those subjects had significantly higher scores in the anxiety scales, particularly in panic disorder. All the cases (with and without JH) had higher anxiety scores compared to controls.

Ercolani and his team designed a study to assess the psychological features of the joint hypermobility syndrome [42]. They recruited 30 JH subjects and two control groups; 25 healthy subjects and 30 fibromyalgia patients. JH group showed significant psychological distress and increased frequency and intensity of somatic symptoms compared to both control groups. A work from another Spanish group [43] has shown again a high prevalence of JHS (61.8%) among panic subjects compared with 10.9% in the healthy control group and 9% in the psychiatric control group. Interestingly, these authors found an intermediate figure among subjects suffering from fibromyalgia (25.4%).

One recent study provided insight about the importance of autonomic symptoms the hypermobility type of Ehlers–Danlos syndrome (EDS) [44]. They included 80 patients with EDS JH, as well as 11 patients with classical EDS (cEDS), seven with vascular EDS (vEDS), 38 with Fibromyalgia and 43 healthy controls. The total autonomic symptom burden was higher in EDS JH (57.9 ± 21.57) than in the other groups but comparable to FM (53.8 ± 19.85). They concluded that joint hypermobility and neuropathy may play a role in the development of autonomic symptoms. In the same line of research, another study described the lived experience of EDS JH and the impact of the symptoms in the daily functioning [45]. The most frequent physical symptoms were joint pain (99%), hypermobility (99%), and limb pain (91%). They also reported a high frequency of other conditions including chronic fatigue (82%), anxiety (73%), depression (69%), and fibromyalgia (42%). These studies are summarized in Table 6.