Hypermobility Syndrome

Abstract

Hypermobility is defined as an abnormally increased range of joint motion due to excessive laxity of the constraining soft tissues. Although it usually is a benign clinical finding that has few serious implications, it should raise the clinician’s level of concern for the presence of an underlying disorder, particularly one involving the connective tissue. In addition, its association with joint symptoms makes hypermobility an important clinical finding in children who have musculoskeletal complaints.In theory, the distinction between hypermobility and the upper limit of normal mobility is arbitrary because joint motion varies within the general population. In practice,however, it is not difficult to distinguish hypermobility from the generally accepted clinical norm in the majority of children. Hypermobility may be localized, involving one or several joints, or generalized, involving a number of joints throughout the body. Although excessive joint laxity is a prominent feature of many systemic disorders, it occurs more commonly in isolation.Hypermobility syndrome is the term used to describe otherwise healthy individuals who exhibit generalized hypermobility associated with musculoskeletal complaints. The term was coined in 1967 by Kirk and colleagues, who reported the occurrence of rheumatic symptoms in a group of hypermobile children who had no connective tissue disorders or other forms of systemic disease. Some clinicians prefer the term benign joint hypermobility syndrome to distinguish affected individuals from those manifesting hypermobility as part of a more serious disorder. Because hypermobility syndrome has a strong genetic component, it also has been called familial joint hypermobility.Generalized hypermobility in the absence of systemic disease is a common condition that has a prevalence of 4% to 13% in the general population. This probably is an underestimate of the true frequency because many people who have hypermobility do not develop joint symptoms or seek medical attention. Moreover, the prevalence of hypermobility varies markedly with age,gender, and ethnicity of the study population. It is well known that children have relatively loose joints compared with adults; this normal joint laxity diminishes rapidly during late childhood or early adolescence and more slowly through adulthood. The age-related decline in joint mobility has been attributed to progressive biochemical changes in collagen structure that result in stiffening of the connective tissue components of joints. At any given age, females have a greater degree of joint laxity. Hypermobility also varies dramatically among ethnic groups, occurring more commonly in persons of African, Asian, and Middle Eastern descent. Within these ethnic groups, the pattern of age- and gender-related variation is maintained.Researchers investigating the prevalence of hypermobility syndrome often have examined patients in rheumatology clinics, where they are referred for evaluation of musculoskeletal complaints. Systematic examination of these individuals for evidence of generalized hypermobility in the absence of systemic disease has yielded prevalence figures for hypermobility syndrome of 2% to 5%, with a relative predominance of young girls. As with generalized hypermobility, these figures probably underestimate the true prevalence of the syndrome because many individuals do not seek medical evaluation for mild and intermittent musculoskeletal symptoms. In the subset of patients who have episodic and unexplained joint pain,the prevalence of hypermobility syndrome may be significantly higher. Gedalia and colleagues found generalized hypermobility in 66% of school children who had recurrent arthritis or arthralgia of unknown etiology. Although arthritis usually is not considered a feature of hypermobility syndrome, these data suggest an increased prevalence of this condition in children who present with intermittent musculoskeletal complaints.The primary conditions that can involve hypermobility are listed in Table 1. Generalized hypermobility is a prominent feature of hereditary connective tissue disorders,including Marfan syndrome, Ehlers-Danlos syndrome, and osteogenesis imperfecta. In the marfanoid hypermobility syndrome, generalized hypermobility is present in combination with the typical skeletal manifestations and skin hyperelasticity of Marfan syndrome, but the ocular and cardiovascular manifestations are absent. Hypermobility often is found in metabolic diseases such as homocystinuria and hyperlysinemia, chromosomal disorders such as Down syndrome, and a variety of familial and sporadic genetic syndromes. Joint laxity may be associated with orthopedic abnormalities,including congenital hip dysplasia and recurrent dislocations of the shoulder and patella. Hypermobility may be acquired in neurologic conditions,such as polio and tabes dorsalis, and in rheumatologic diseases. Although hypermobility can develop in juvenile rheumatoid arthritis, limitation of joint motion is much more likely. Familial asymptomatic hypermobility is a term used to describe contortionists, who demonstrate significant generalized joint laxity but do not develop joint symptoms. Finally, it is important to distinguish true joint hypermobility from apparent hypermobility, which occurs in the context of muscular hypotonia.Although the precise etiology of hypermobility syndrome is unknown, it clearly has a strong genetic component. Affected first-degree relatives are identified in as many as 50% of cases. An autosomal dominant pattern of inheritance is most common, although autosomal recessive and X-linked transmission also have been documented.The predominance of affected females who have hypermobility syndrome has fueled speculation about the role of gender-related factors in the development and expression of the condition. Some clinicians have observed phenotypic differences, including variations in location, nature, and severity of joint symptoms, between affected males and females from the same family. The relative contribution of environmental influences, such as estrogen, or X-linked genetic factors is not understood.There are questions about whether hypermobility syndrome represents the upper end of normal variation in joint mobility or it reflects a mild disorder of connective tissue. In support of the latter view, stigmata of generalized connective tissue involvement,including marfanoid habitus, high-arched palate, skin striae, hyperelastic or thin skin, varicose veins, and spinal abnormalities, have been observed in some patients who have hypermobility syndrome. Additional studies have documented an increased incidence of mitral valve prolapse in hypermobile individuals, but this association has been controversial.Biochemical and molecular research has supported the classification of hypermobility syndrome as a connective tissue disorder. Collagen analysis of skin samples from patients who have hypermobility syndrome has demonstrated alterations in the normal ratios of collagen subtypes and abnormalities of the microscopic connective tissue structure. In 1996, the British Society for Rheumatology reported the identification of mutations in fibrillin genes in several families who had hypermobility syndrome.Despite intensive speculation, the pathogenesis of generalized joint laxity in hypermobility syndrome remains unclear. It appears likely that normal joint development and function require the interaction of a number of genes coding for the structure and assembly of joint-related connective tissue proteins. Although hypermobility syndrome may result from one or more mutations in such genes,the importance of pathogenetic classification is a problem of semantics rather than a clinically relevant issue for the general pediatrician.The pathogenesis of joint complaints in patients who have hypermobility syndrome may be understood best by considering the basic structure of a joint. The extent of joint mobility is determined by the strength and flexibility of surrounding soft tissues, including the joint capsule, ligaments, tendons,muscles, subcutaneous tissue, and skin. It has been hypothesized that excessive joint laxity leads to inappropriate wear and tear on joint surfaces and surrounding soft tissues, resulting in symptoms referable to these tissues. The clinical observation of increased symptoms related to excessive use of hypermobile joints lends further support to this hypothesis. Recent studies also have demonstrated reduced proprioceptive sensation in the joints of patients who have hypermobility syndrome. Such findings have led to speculation that impaired sensory feedback contributes to excessive joint trauma in affected individuals.Children who have hypermobility syndrome may present with a variety of musculoskeletal complaints. The most common symptom is joint pain, which often develops after physical activities or sports during which the affected joint(s)is/are used repeatedly. Pain may be localized in one or several joints or it may be generalized and symmetric. Although pain most commonly involves the knee, any joint, including those of the spine, can be affected. The pain usually is self-limited in duration, but it can recur with activity. Less commonly, children may experience joint stiffness, myalgias, muscle cramps,and nonarticular limb pain. Although brief episodes of joint swelling can occur in hypermobility syndrome, they are uncommon and should prompt consideration of an alternative diagnosis. In some cases, the onset of symptoms is preceded by a recent growth spurt, and affected females often report premenstrual exacerbations. Because symptoms typically are related to activity, they tend to occur later in the day. In contrast to arthritic disorders, morning stiffness is an uncommon finding in children who have hypermobility syndrome. Instead, they may awaken at night with complaints of joint or extremity pain, especially following an active day. Frequently,affected children will have a family history of similar complaints or“double-jointedness” in childhood among first-degree relatives. In addition to relatively nonspecific musculoskeletal complaints, some patients may have an associated history of congenital hip dysplasia, recurrent joint dislocations or subluxations, ligament or tendon rupture, easy bruising,fibromyalgia, or temporomandibular joint dysfunction.In addition to the primary finding of generalized joint hypermobility, physical examination may reveal pain upon joint manipulation and, in unusual cases, mild degrees of effusion. Signs of active inflammation, including significant tenderness,swelling, redness, warmth, and fever, are absent. If such findings are present, they suggest another diagnosis.Examination of patients who have hypermobility syndrome also may reveal extra-articular abnormalities that are more typical of serious connective tissue disorders. Such findings can include pes planus, scoliosis, lordosis, genu valgum, lateral patellar displacement, marfanoid habitus, high-arched palate, skin striae, thin skin,and varicose veins. Although most affected children do not have cardiovascular findings, a subset of patients may have evidence of mitral valve prolapse (MVP). As noted previously, the association of MVP with hypermobility syndrome is controversial. Although early studies indicated an increased incidence of MVP in affected patients, more recent investigations that used stricter echocardiographic criteria for the diagnosis of MVP have questioned this association. However, serious cardiovascular abnormalities are seen with some connective tissue disorders that also manifest hypermobility. For this reason, any hypermobile child who has suspicious cardiac symptoms or physical findings requires further evaluation by a cardiologist.The key to making the diagnosis of hypermobility syndrome lies in accurate assessment of the child for evidence of generalized joint laxity. This is accomplished with five simple clinical maneuvers that require no special equipment and can be performed by any general physician in 30 to 60 seconds (Figs. 1–5Figure 1Figure 2Figure 3Figure 4Figure 5). The father of the 3-year-old girl shown in the figures is similarly affected, illustrating that hypermobility syndrome can be seen at any age. It should be noted that joint laxity in patients who have hypermobility syndrome is virtually always symmetric, except in the presence of other musculoskeletal abnormalities that might limit joint motion. In addition, some consider hyperextension of all fingers, not just the fifth finger, as the physical finding to examine in hypermobility syndrome.Developed by Carter and Wilkinson and later modified by Beighton for large population studies, this examination has become the most widely accepted screen for detecting generalized hypermobility. It correlates well with more quantitative,instrument-dependent methods. Patients are scored on a 9-point scale, with 1 point awarded for each hypermobile site. The points then are summed to give a total or “Beighton score” (Fig. 6). A Beighton score of 4 or more points usually is considered indicative of generalized hypermobility.Because there is considerable clinical overlap between hypermobility syndrome and heritable disorders of connective tissue, specific diagnostic criteria have been developed by the British Society for Rheumatology (Table 2). In addition to findings of generalized hypermobility and musculoskeletal symptoms, a number of less commonly associated features have been incorporated into these criteria.Although hypermobility syndrome is a relatively common condition, it is a diagnosis of exclusion. Exclusion of more serious infectious, inflammatory, and autoimmune disorders presenting with painful or swollen joints can be aided by appropriate laboratory studies, including complete blood count,erythrocyte sedimentation rate (ESR), rheumatoid factor, antinuclear antibody (ANA) titer, and levels of serum immune globulin and complement. Such tests usually are not indicated in children who have hypermobility syndrome, and results are normal when the tests are performed. Abnormalities in any of these tests, such as leukocytosis, increased ESR, or a positive ANA titer, suggest an alternative diagnosis. If there is joint effusion,aspiration of the joint fluid will reveal a noninflammatory pattern in patients who have hypermobility syndrome.As outlined in Table 1, the differential diagnosis of hypermobility includes a wide variety of genetic and acquired disorders, and it is important to consider each of these possibilities when evaluating a patient who presents with generalized joint laxity. Differentiating hypermobility syndrome from more serious disorders of connective tissue is a particularly common diagnostic dilemma. Further, asymptomatic hypermobility may be detected frequently on routine physical examination, prompting the possibility of an undiagnosed connective tissue disease. For these reasons, it is critical for the clinician to recognize the distinguishing features of inherited connective tissue disorders in hypermobile children.Ehlers-Danlos syndrome (EDS) refers to a group of connective tissue disorders that shares the features of joint hypermobility and skin abnormalities. The skin findings may range from softness, thinness, or hyperelasticity to extreme fragility with easy bruisability and abnormal scar formation. There are ten subtypes of EDS, which differ in terms of severity of joint and skin findings, involvement of other tissues, and mode of inheritance. Specific molecular defects in collagen or enzymes involved in connective tissue formation have been identified in several EDS subtypes.The majority of EDS cases are represented by types I, II, and III. The most severe joint laxity is seen in EDS type I; affected patients have significant hypermobility, often accompanied by pain, effusion, and dislocation. Children who have this condition may experience congenital hip dislocation,clubfeet, or delayed ambulation due to joint symptoms and leg instability. Associated skin findings include soft, extensible skin with a velvety texture, easy bruising, and formation of thin “cigarette paper”scars when injured. EDS type II is similar to but less severe than EDS type I. Both disorders are caused by defects in type V collagen and inherited in an autosomal dominant fashion. Autosomal recessive cases of EDS type II,caused by other collagen defects, have been reported but are rare. EDS type III is similar to type I with respect to joint involvement, but skin abnormalities usually are limited to an abnormally soft and velvety texture. For this reason, EDS type III often is confused with hypermobility syndrome,which generally is believed to have few or no skin changes. From a practical standpoint, however, the clinical differences are minimal, and the two disorders should be managed similarly. EDS type III is transmitted in an autosomal dominant fashion, and the precise molecular defect is unknown.Of the less frequent subtypes of EDS, the most important to recognize is EDS type IV. Although joint and skin abnormalities are usually mild, affected individuals have a markedly increased risk of potentially fatal spontaneous rupture of the arteries and hollow organs, such as the colon. Women who have EDS type IV may experience uterine rupture during pregnancy. This autosomal dominant disorder is caused by defective type III collagen. Of note, a revised EDS clinical classification system has been proposed.Marfan syndrome is an autosomal dominant disorder characterized by a tall, thin body habitus (marfanoid habitus), long extremities, elongated fingers (arachnodactyly), ocular abnormalities (myopia, lens dislocation),and generalized joint hypermobility. It is caused by mutations in the fibrillin-1 gene on chromosome 15. Fibrillin is an essential glycoprotein component of elastic connective tissue. Recognition of this disorder is critical because patients are predisposed to life-threatening aneurysms and dissections of the aorta as well as aortic valve regurgitation and mitral valve prolapse. Because of the serious nature of Marfan syndrome, any child suspected of having this condition should undergo genetic, cardiologic, and ophthalmologic evaluation. As part of this evaluation, plasma amino acids should be analyzed to exclude the presence of homocystinuria, a metabolic disorder in which there is excessive accumulation of homocystine. In most cases, this results from deficient activity of the enzyme cystathionine synthetase. Clinically, homocystinuria is very similar to Marfan syndrome with respect to body habitus, lens dislocation, and generalized joint hypermobility. However, patients who have homocystinuria may have mental retardation and are at significantly increased risk of arterial thrombosis.Osteogenesis imperfecta, an autosomal dominant disorder of collagen, is characterized by thin blue sclerae, excessive joint mobility, and bone fragility, often resulting in multiple fractures and bony deformities. The disorder is highly variable, frequently arises from a sporadic mutation, and includes both lethal and nonlethal forms. Lethal forms involve severe bone fragility that is incompatible with life. The nonlethal varieties may be more subtle in clinical presentation, with complications related to fractures, joint instability, short stature, and progressive spinal deformity. The latter problem may lead to cardiorespiratory compromise, and effective surgical correction is difficult because of bone fragility. In adulthood, progressive otosclerosis often results in deafness.Stickler syndrome is an autosomal dominant disorder that is characterized by hypermobility, typical facial features (malar hypoplasia with depressed nasal bridge and epicanthal folds),Robin sequence (micrognathia, glossoptosis, and cleft palate), early-onset arthritis, severe myopia, and sensorineural hearing loss. Affected infants often experience respiratory problems related to Robin sequence, and children may develop arthritis before adolescence. Severe myopia and an increased risk of retinal detachment necessitate frequent ophthalmologic evaluation.Williams syndrome is another autosomal dominant disorder featuring hypermobility. However, joint laxity is observed primarily in childhood; older affected individuals may develop joint contractures. These patients also manifest short stature, characteristic facial appearance, hoarse voice, developmental delay with an outgoing “cocktail party” personality, and occasional hypercalcemia. Patients may have congenital cardiovascular disease, most commonly supravalvular aortic stenosis, and are predisposed to develop other vascular stenoses. Recently,this syndrome has been found to arise from deletions in the long arm of chromosome 7, which always includes the region of the elastin gene. Definitive diagnosis is possible by molecular testing.After more serious disorders are excluded and hypermobility syndrome is diagnosed,clinical management is straightforward. First and foremost, the child and his or her family should be reassured that hypermobility syndrome is a relatively common and benign condition that does not have the potentially disabling or life-threatening sequelae of other rheumatologic or connective tissue disorders. Such reassurance may prove particularly helpful to the parents of children who have a history of nonspecific and recurrent musculoskeletal complaints.For acute symptoms, patients should be advised to use non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen as needed. A bedtime dose of a longer acting NSAID, such as naproxen, may benefit children who have nocturnal symptoms. Because the pathogenesis of joint complaints in hypermobility syndrome is not related to inflammation, the effectiveness of NSAIDs for symptoms other than pain has been disputed. Moderate or severe symptoms may necessitate rest or abstention from activities that aggravate joint complaints. Physical therapy and hydrotherapy can provide additional relief of acute symptoms.Chronic management of this condition typically involves several strategies,including explanation of the nature of hypermobility syndrome and the association between excessive joint movement and development of symptoms. Patients should be advised to identify activities that precipitate symptoms and to modify their lifestyles accordingly. Vigorous and repetitive activities, as performed during certain sports or hobbies, may underlie the symptoms and should be targeted as potential aggravating factors. The use of NSAIDs or acetaminophen prior to such activities can help to control associated symptoms and facilitate participation. In some cases, affected children may require a physician’s excuse to avoid exacerbating symptoms during physical education classes at school.Despite the importance of avoiding excessive activity, a diagnosis of hypermobility syndrome should not be used to encourage inactivity. Rather, it is generally accepted that moderate exercise is extremely beneficial by maximizing muscle support around hypermobile joints. Swimming is advocated for improving general muscle tone, and specific strengthening exercises may help to increase muscular support in particularly symptomatic areas. Because the knee is the joint involved most commonly, quadriceps exercises can be especially helpful. Instruction of children in joint protection techniques also may prove beneficial. For example, children who have hyperextensible knees are encouraged to stand with their knees slightly flexed, while those who have unstable ankles may benefit from the use of an ankle aircast. Finally,patients who have significant symptoms or extreme degrees of joint hypermobility should be encouraged to avoid all sports, hobbies, or careers involving physical activities that may result in chronic and excessive joint stress.Because joints tend to stiffen with age, the natural history of hypermobility syndrome is typically one of improvement, with progressively lessening degrees of joint laxity and associated musculoskeletal symptoms. Many affected children outgrow their symptoms during adolescence or adulthood, and women may experience fewer symptoms following menopause.Although hypermobility syndrome is a relatively benign condition, some potentially significant sequelae have been reported to occur with increased frequency in affected patients. Studies of hypermobile football players and ballet dancers have noted an increased frequency of ruptured ligaments, joint dislocations, and other orthopedic injuries. Affected individuals may be predisposed to fractures, and scoliosis may result from hypermobility of the spine. Some clinicians have observed hernias as well as uterine and rectal prolapse with increased frequency in adults who have hypermobility syndrome.Finally, it has been speculated that children who have hypermobility syndrome are at increased risk of developing premature degenerative osteoarthritis as adults. A specific pattern of progression that involves onset of osteoarthritis in the fourth to fifth decade, followed by eventual chondrocalcinosis within affected joints, has been described by some clinicians. However, much of the evidence for this association has been anecdotal, and it remains an issue of considerable debate. It generally is agreed that only long-term prospective studies of patients who have hypermobility syndrome will provide the needed insight into the natural history and prognosis of this common and often unrecognized condition.