Review Article: Hypermobility syndromes and chronic or recurrent MSK pain in children (Oct 2015)

By Marco Cattalini, Raju Khubchandani, and Rolando Cimaz
(Dr. Raju Khubchandani is a Pediatric Rheumatologist at the Department of Paediatrics, Jaslok Hospital and Research Centre, Mumbai, India)

Abstract

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.

Pediatr Rheumatol Online J. 2015; 13: 40.
Published online 2015 Oct 6. 
PMCID: PMC4596461
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Excerpts relevant to HEDS:

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. The prevalence of JHS is not known with precision, given the lack of studies of large cohorts. Sperotto et al., conducted a cross sectional study in a cohort of healthy schoolchildren, aged 8–13 years from the province of Padua, Italy, and found that BJHS occurred in the 13,2 % of the 289 children evaluated []. 
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. The pathophysiology of benign joint hypermobility is unclear. Hypermobility is more common in childhood and adolescence, in females, and in some ethnicities, and it tends to lessen during adulthood. Still, polyarticular hypermobility may be present in up to 30 % of males and 40 % of females during early adulthood []. 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. Variable penetrance is generally observed []. With the exception of a minority of patients, who show a deficiency of tenascin X, no abnormality in collagen or related proteins has been identified as a cause for BJHS []. 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. Heavy school bags are often an aggravating feature. 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. This 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 “Beighton score” (derived from the original one by Carter and Wilkinson) is commonly used to diagnose hypermobility. Hypermobility is present if 4 out of 9 points are scored. When this score is applied to normal children, a large proportion of the population is hypermobile (Table 1, Figs. 1,22,22 and and3).3and3).3). This reflects the fact that, as already discussed, connective tissue structures may be looser and joints hypermobile in childhood, especially compared to adults. For these reasons it may be better to consider a Beighton score of 5 or more positive []. The Beighton score has been incorporated into a more comprehensive set of criteria called the Brighton Criteria (Table 2), which take into account the possible multisystemic nature of this condition. Although these criteria have not been formally validated in a pediatric population, they have been used in some studies on children with 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. However reassurance and a multi-disciplinary training program are the mainstays of long term management. 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 [].

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In "Ehlers-Danlos Syndromes (EDSs)", the authors write:

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 []. According to the Villefranche classification, the major diagnostic criteria are generalized joint hypermobility and presence of typical skin manifestations. However, these features are usually more subtle than in the classic type of EDS but these criteria are nevertheless helpful to differentiate this form of EDS from the more common “Benign joint hypermobility syndrome (BJHS)” []. 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. 
Joint hypermobility is typically limited to the small joints of the hands in the vascular subtype. This subtype has the worst prognosis because of a high rate of spontaneous arterial rupture usually in the third or the fourth decade of life. Unlike other EDS types, the skin is not hyper-extensible, but rather thin and translucent, showing a visible venous pattern over the chest, abdomen and extremities. Excessive bruising is the most common sign and is often the presenting complaint, especially in children. Other early manifestations include premature rupture of the membranes, congenital clubfoot or congenital hip dislocation, inguinal hernia, and severe varicosities. The facial and cutaneous features may be very subtle or even absent []. If there is a strong clinical suspicion of vascular EDS, direct DNA analysis is mandatory, even in the absence of an abnormal biochemical abnormality. 
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. In children physio-therapeutic support is important. Acetaminophen should be preferred over NSAIDs for joint pain and thus minimizing the risk of easy bruising due to platelet disfunction. For the same reason COX-2 inhibitors may be an option, although no studies have been published on their use in EDS. 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. A useful resource for these measurements is parameterz.blogspot.in. 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 [,].