Hypermobility Syndromes and Chronic Pain in Children

This article goes into great detail outlining the consequences of hypermobility syndromes in children, causing chronic pain, significant disability, and a reduction in quality of life.

When flexibility is not necessarily a virtue: a review of hypermobility syndromes and chronic or recurrent musculoskeletal pain in children – 2015 Oct – free full-text PMC4596461

Chronic or recurrent musculoskeletal pain is a common complaint in children.

Among the most common causes for this problem are different conditions associated with hypermobility  

Pediatricians and allied professionals should be well aware of the characteristics of the different syndromes associated with hypermobility and facilitate early recognition and appropriate management

In this review we provide information on

• Benign Joint Hypermobility Syndrome,
• Ehlers-Danlos Syndrome,
• Marfan Syndrome,
• Loeys-Dietz syndrome and
• Stickler syndrome,

and discuss their characteristics and clinical management.

Introduction

A wide variety of non-inflammatory conditions may cause musculoskeletal pain in the pediatric age, and the most common causes seen by paediatric rheumatologists include conditions associated with hypermobility.

Hypermobility may have a significant impact on quality of life of affected children and their parents, even in the milder forms.

All physicians and allied professionals that may be involved in the care of children with musculoskeletal complaints should therefore be well trained to recognize hypermobility and to run the differential diagnosis between the various clinical entities associated with it.

A critical approach to a child with hypermobility is crucial to correctly identify the underlying cause and avoid time/money- consuming investigations.

In this paper we review different etiologies of musculoskeletal pain associated with hypermobility, including some genetic disorders, and discuss the clinical approach in these children.

Review

Benign joint hypermobility syndrome (BJHS)

Children with hypermobile joints by definition display a range of movement that is considered excessive, taking into consideration the age, gender and ethnic background of the individual.

It is estimated that at least 10–15 % of normal children have hypermobile joints and the term joint hypermobility syndrome (JHS) is reserved to the cases of joint hypermobility associated with symptoms with no other causes found for them

JHS can be associated with hereditary connective tissue disorders, and the term “Benign” is used in contrast to more serious and potentially complicated or life-threatening musculoskeletal syndromes such as some forms of Ehlers-Danlos syndrome (EDS), Marfan syndrome, and Loeys-Dietz syndrome.

Even if BJHS is very common, this condition is largely under-recognized by primary care physicians and often poorly managed.

Symptoms frequently start in childhood and continue into adult life.

For the majority of individuals joint hypermobility may be of no consequence, and what brings a proportion of subjects to develop BJHS is not fully understood. BJHS seems to be transmitted by an autosomal pattern, and first-degree relatives with the disorders can be identified in many cases.

Joint pain is thought to be caused by excessive movement, increasing stress on joint surfaces, ligaments and adjacent structures.

Other factors may contribute to the development of the syndrome, such as

• poor proprioception,
• autonomic dysfunctions and
• fatigue secondary to poor sleep

The predominant presenting complaint is pain,
which may be widespread and debilitating

The pain typically starts during or after activity.

The most common affected sites are the lower limbs after walking (for example walking to and from school).

Children usually report excess fatigue, handwriting difficulties or ‘clicking or cracking’ joints

Occasionally episodes of joint swelling lasting hours to days, joint dislocations, or more commonly subluxations with spontaneous reduction are reported.

Back-pain is also a common complaint because the lumbar spine is one of the most mobile sections of the vertebral column and the excessive movements may lead to pain in hypermobile subjects.

Chronic pain results in a reduced exercise tolerance and can negatively impact patients’ life.

A significant proportion of subjects progressively quit sports and other physical activities. In addition, pain amplification is a common feature in these cases

BJHS has been considered to cause only musculoskeletal symptoms for many years, but there is now mounting evidence that many other extra-skeletal manifestations may occur.

These symptoms arise usually after the third decade of life, but have been described in adolescents, and may be due to connective tissue abnormalities, linking BJHS and other hereditary disorders of connective tissues, namely Ehlers-Danlos syndrome type III.

These include

• functional and anatomic gastrointestinal tract abnormalities (constipation, bloating, diarrhea, hiatal hernias),
• autonomic dysfunctions (postural tachycardia syndrome, palpitations, orthostatic intolerance, headache, fatigue) and
• skin abnormalities (easy bruising, striae)

Some of these symptoms are overlapping with those observed in Juvenile Fibromyalgia (JFM), and indeed there are few reports describing high incidence of BJHS in children with JFM.

Furthermore, children who have both JFM and BJHS may exhibit lower tender-points thresholds and a greater number of tender-points compared to children with JFM but no benign joint hypermobility

The management of individuals with BJHS can be very challenging and there are no evidence-based management strategies currently available

Acute pain episodes are commonly managed using taping, bracing or splinting or with non-steroidal anti-inflammatory drugs as needed

Physical therapy is of the outmost importance, and encouraging an active lifestyle may improve function and enhance quality of life

As general principles, strengthening exercises focused on muscles around hypermobile joints may help to enhance joint support throughout movement and reduce pain; closed chain exercises may enhance proprioceptive feedback and optimize muscle action

Proprioception may be improved also by coordination and balance exercises.

Physical therapy should also encompass a generalized exercise programme, addressing cardio-respiratory, musculoskeletal and neurological aspects of movement with the aim to reduce deconditioning

As already mentioned, the Health Related Quality of Life in children with hypermobility and their parents may be worse than that of healthy controls and this may well be secondary to the presence of chronic pain and fatigue, that act as stressors in everyday life.

This is an important aspect to consider for physicians approaching a child with BJHS, that should not underestimate the burden of this condition, often interpreted as benign and not worth any intervention.

Ehlers-Danlos Syndromes (EDSs)

EDSs comprise a very heterogeneous group of heritable disorders of connective tissue

The increased flexibility and fragility of the soft connective tissues result in a wide range of changes in the skin, ligaments, joints, blood vessels and internal organs

The connective tissue fragility follows abnormalities in the expression or structure of the fibrillar collagen types I, III and V, as well as enzymatic abnormalities in the post-translational modification and processing of these collagens.

Mutations in the COL5A1 and COL5A2 genes, encoding the α1- and the α2-chains of type V collagen, respectively, are found in approximately 50 % of individuals with the classic type of EDS.

Mutations in TNX-B, encoding for Tenascin X, in approximately 5 % of patients with the hypermobility type, while vascular EDS is caused by heterozygous mutations in the COL3A1 gene, encoding type III collagen.

The clinical spectrum of EDSs varies from mild skin and joint hyperlaxity to severe physical disability and life-threatening vascular complications.

Even if the hypermobility is asymptomatic, this condition can result in childhood in congenital club foot, pes planus and joint effusions. In young adulthood the classic subtype can be complicated by repetitive subluxations and dislocations either spontaneously or after minimal trauma

Patients usually report chronic and recurrent pain that is difficult to treat and premature osteoarthritis is a major concern.

One of the most typical features is the skin hyper-extensibility, which means that the skin stretches easily but snaps back after release. The skin is often smooth and velvety to the touch

For pediatric rheumatologists, a real diagnostic challenge is represented by the hypermobility subtype of EDS (EDS-HT), which is by far the most common subtype. The genetic basis of EDS-Hybermobile is largely unknown and a reliable diagnostic test for this EDS subtype is lacking

It is still a matter of debate if EDS-HT and BJHS really represents two different diseases or if they should be reviewed as a spectrum of a single entity, sharing common genetic bases and showing considerable variability in clinical presentation, between as well as within families.

The management of children with Ehlers-Danlos syndromes requires a multidisciplinary approach.

Children with pronounced skin fragility should be advised to avoid contact sports and to wear protective pads or bandages in order to prevent bruises and hematomas

Cutaneous stitches should be left in place twice as long as usual, and additional fixation of adjacent skin with adhesive tape can help to prevent stretching of the scar.

Patients with mitral valve prolapse and regurgitation require antibiotic prophylaxis for bacterial endocarditis. A baseline echocardiogram with aortic diameters measurement is recommended before 10 years of age, with follow-up studies timed according to whether an abnormal measurement is found

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For the vascular and vascular-like types of EDS, some prophylactic measures are of particular importance. Invasive vascular procedures such as arteriography and catheterization should also be avoided because of the risk for life-threatening vascular rupture. Surgical interventions are generally discouraged because of increased vascular fragility, and conservative therapy is recommended

Marfan Syndrome (MS)

MS is an hereditary autosomal dominant, multisystem disorder of connective tissue with extensive clinical variability. It is a relatively common condition, with approximately 1 in 5000 people affected

It is caused by defects in FBN1, the gene that codes for the protein fibrillin, although patients with mutations in other genes, including TGFBR1 and TGFBR2, have also been rarely reported

Cardinal features involve the ocular, musculoskeletal, and cardiovascular systems. Skeletal system involvement in Marfan syndrome is characterized by bony overgrowth; such overgrowth may be noticeable at birth or can develop in young children and results in disproportional long limbs

Marfan patients have been reported to have reduced bone mass and muscle mass, compared to healthy controls. All this skeletal abnormalities may account for the very high incidence of severe daily pain that Marfan patients report

Joint laxity may be significant in young MS patients and can lead to ligament injury, dislocations, chronic joint pain and degenerative arthritis

Diagnosis and management require a multidisciplinary approach by geneticists, cardiologists, orthopedic surgeons and ophthalmologists with experience in this field.

Loeys-Dietz syndrome (LDS)

LDS is a recently described rare autosomal dominant connective tissue disorder characterized by a severe and widespread arterial involvement since childhood.

The disorder is most often caused by heterozygous mutations in TGF-β receptors TGFBR1 and TGFBR2

The classification depends on the presence or absence of craniofacial features (hypertelorism, bifid uvula and cleft palate). Affected individuals show generalized arterial abnormalities, ascending aneurysms and rapidly progressive aortic aneurysm

LDS diagnostic criteria have not been defined and confirmatory genetic testing is required. Management of LDS involves regular cardiology follow-up to establish the extent of vascular involvement, early surgical intervention, genetic counseling and monitoring in pregnancy

Stickler syndrome (SS)

SS is a multisystem connective tissue disorder that can affect the eye, craniofacies, inner ear, skeleton, and joints

Stickler syndrome has been associated with mutations of COL2A1, which encodes for the alpha-1 chain of type II collagen, COL11A1 gene, which encodes for the alpha-1 chain of type XI collagen, and COLL11A2 gene.

Based on the vitreous abnormalities Stickler syndrome is classified as Type 1 (“membranous”; characterized by a persistence of vestigial vitreous gel in the retrolental space) and the rare Type 2 (“beaded”, characterized by sparse and irregularly thickened bundles throughout the vitreous cavity).

A non-progressive myopia is common. Craniofacial findings may include a flat facial profile, telecanthus and epicanthal folds, micrognathia and cleft palate. Hearing impairment, especially sensorineural deafness for high tones, is common but the overall sensorineural hearing loss in type I Stickler syndrome is typically mild and not significantly progressive

Conclusions

Musculoskeletal pain is one of the more common complaints in the pediatric population.

It is common for parents of affected children to seek a pediatric evaluation, and commonly these children are referred to a rheumatologist.

Among the leading non-inflammatory causes of joint pain seen by pediatric rheumatologists are those associated with hypermobility.

The musculoskeletal complaints are typical of non-inflammatory conditions, with the onset of pain that is typically exacerbated by exercise and is usually a late afternoon/evening pain, without the typical signs and symptoms of inflammatory arthropathies, such as joint swelling or morning stiffness

Inflammatory markers are invariably within normal limits.

Many other clinical manifestations may enrich the clinical picture, based on the underlying cause.

The presence of chronic pain secondary to hypermobility may have a profound impact on patients’ quality of life, leading to a high burden for patients, families and the health care system

Moreover, the genetic syndromes depicted in this review may have early and late severe complications.

Pediatricians, and specifically pediatric rheumatologists, should therefore keep a high index of suspicion for early recognition of hypermobility-associated syndromes.