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* Department of Pediatric Physical Therapy, University Medical Center, Wilhelmina Children’s Hospital, Utrecht, The Netherlands
Julius Center for Health Sciences and Primary Care, University Medical Center, Wilhelmina Children’s Hospital, Utrecht, The Netherlands
Department of Pediatrics, University Medical Center, Wilhelmina Children’s Hospital, Utrecht, The Netherlands
|| Department of Pediatric Orthopedics, University Medical Center, Wilhelmina Children’s Hospital, Utrecht, The Netherlands
¶ Department of Medical Genetics, University Hospital Groningen, Groningen, The Netherlands
# Gaubius Laboratory; TNO Prevention and Health, Leiden, The Netherlands
** Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Methods. Nineteen children who attended the Children’s Hospital of the University Medical Center Utrecht for generalized hypomobility of the joints (mean age: 11.6; standard deviation: 2.7), in combination with musculoskeletal complaints or abnormal walking as primary complaints (symptomatic generalized hypomobility [SGH]), were compared with an age-matched reference group of 284 healthy children with normal mobility of the joints. Anthropometrics, range of joint motion, muscle strength, exercise tolerance, motor development, quantitative ultrasound measurements of bone, and degradation products of collagen in urine were studied. Collagen modifications were determined in skin biopsies of 3 children and in hypertrophic scar tissue of another child, all with SGH.
Results. The range of joint motion was significantly decreased in almost all joints of all 19 children and after adjustment for age, gender, body weight, and height, significantly lower than that of the reference group (–108.3 degrees; 95% confidence interval [CI]: –136.9 to –79.8). Quantitative ultrasound measurements as well as urinary pyridinoline cross-link levels were, after adjustment for possible confounders, significantly lower in SGH children (broad-band ultrasound attenuation: –9.6 dB/MHz [95% CI: –17.4 to –1.9]; speed of sound: –25.0 m/s [95% CI: –39.7 to –10.3]; hydroxylysylpyridinoline: –50.1 µmol/mmol [95% CI: –87.6 to –12.6], lysylpyridinoline: –21.3 µmol/mmol [95% CI: –34.0 to –8.6]). An increased amount of pyridinoline cross-links per collagen molecule was observed in skin and hypertrophic scar tissue, in combination with increased amounts of collagen.
Conclusion. SGH in children is considered a new clinical entity with specific clinical characteristics and might be related to an increased stiffness of connective tissue as a result of higher amounts of collagen with increased cross-linking.
Key Words: joint hypomobility • collagen • functional ability • quantitative ultrasound measurements • musculoskeletal complaints • habitual toe-walking
Abbreviations: SGH, symptomatic generalized hypomobility • SD, standard deviation • CI, confidence interval • QUS, quantitative ultrasound • Hyp, hydroxyproline • Pro, proline • Hyl, hydroxylysine • HP, hydroxylysylpyridinoline • LP, lysylpyridinoline • TLH, telopeptide lysyl hydroxylase
Population studies revealed that interindividual variation in joint mobility fits into the Gaussian distribution and that the amount of joint mobility in children is inversely related to age.1,2 Joint hypermobility or ligamental laxity, at 1 end of this distribution, has been recognized and described as a separate entity.3–6 Most individuals with loose joints experience no ill effects and enjoy a symptom-free life. In fact, it is an advantage in certain professions, such as ballet dancers, gymnasts, and musicians.7,8 However, when generalized hypermobility becomes symptomatic, the "benign joint hypermobility syndrome" is diagnosed, provided that the patients do not show signs of any rheumatic, neurologic, skeletal, or metabolic diseases.3,9–13 The prevalence of generalized joint hypermobility in children and adults varies between 10% and 25% and is related to age, gender, and race, whereas symptomatic joint hypermobility is seen in adults 
3.3% among women and 0.6% among men.5,6,14 The term "benign" is used because of the favorable prognosis of this syndrome by comparison with other, more serious connective tissue disorders associated with hypermobility (eg, Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta).3,4
Remarkably, joint hypomobility, at the other end of the distribution, with or without specific musculoskeletal complaints and other systemic effects, has never been described in the literature as a separate entity. The cause of hypomobility is probably an increased stiffness of the joint ligaments. As the biomechanical properties of ligaments are mainly determined by the collagen network, the molecular defect involved in the pathogenesis of hypomobility may reside within these proteins.
We report on clinical and osseal features as well as some biochemical characteristics of collagen I in children who attended our clinic with generalized hypomobility of the joints, musculoskeletal complaints, or abnormal walking in the absence of a known rheumatic, neurologic, skeletal, or metabolic disorder (symptomatic generalized hypomobility [SGH]). Our aim was to assess whether the reduced range of joint motion in these children was associated with specific changes in other tissues that contain collagen I or with specific changes in the quality or the quantity of collagen I degradation products.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The reference group consisted of 117 healthy primary school prepubertal pupils and 167 healthy secondary school adolescents from the city of Zeist, the Netherlands (mean age [standard deviation (SD)] total reference group: 12.8 (3.3) years; boys/girls: 118/166).15 In this reference group, no children with past or present signs of any rheumatic, neurologic, skeletal, metabolic, or collagen disease or a reported delay in motor performance were included (reported in the patient’s medical history). Skin collagen data of the 3 children were compared with skin data from 10 healthy white individuals, encompassing a large age range (19–72 years). The Medical Ethics Committee of the Wilhelmina Children’s Hospital (University Medical Center Utrecht) approved this study, and informed consent was obtained from all parents.
Measurements
Body height and weight were measured in a standardized manner without shoes and heavy clothing to the nearest cm and 100 g, respectively.16 The active range of joint motion of the shoulder (anteflexion), elbow (flexion and extension), wrist (palmar and dorsal extension), hip (flexion and extension), knee (flexion and extension), and ankle (plantar and dorsal extension) was measured bilaterally to the nearest 5 degrees with a standard 2-legged 360-degree goniometer, using the "anatomic landmark" method.17 Children were asked to actively stretch or bend the joint maximally without interference by the investigator. Children were not allowed to help the ipsilateral muscles by the use of contralateral limbs. No significant differences were found between the left and the right extremities; therefore, the mean range of joint motion was calculated. Total range of joint motion was a summing up of all of the measurements. Preceding the present study, a reliability study regarding range of joint motion was performed. All of the joints of 16 healthy children were independently measured (first author and 4 trained physical therapists), and the Pearson correlation coefficient between the assessors’ measurements was .69 (P = .003). The mean difference between 2 measurements in these children was 2.4 degrees (SD: 4.6), indicating that 95% confidence interval (CI) was <9.2 degrees, which we found acceptable for measuring range of joint motion.
Muscle strength of the abductors of the shoulder, flexors of the hip, and dorsal extensors of the ankle joint as well as strength of grip were measured bilaterally with a handheld myometer.18 Measurements were performed consecutively 3 times, and the highest value was registered. Total muscle strength motion was a summing up of all measurements.
In the children with SGH, exercise tolerance was measured using an incremental treadmill protocol according to Bruce et al,19,20 with normative values for age and gender for the Dutch population.20 Motor performance was measured using the Movement Assessment Battery for Children, with normative age-related scores for the total motor development and subscales for manual dexterity, ball skills, and static and dynamic balance.21 A parental questionnaire provided information concerning the child’s health status, the possible presence of familial hypomobility of the joints, the presence of exercise-induced pain or complaints in the musculoskeletal system, and the presence of (familial) habitual walking on the toes. Exercise-induced pain and complaints was defined when children were not able to participate or should stop sports-leisure activities because of increasing pain in calf and periarticular knee and hip muscles. After sport activities, they complained for several days of pain in these muscles. Habitual toe-walking was defined as bilateral symmetric toe-walking with extensive limitation in dorsiflexion of the ankle joint without known cause.
Quantitative ultrasound (QUS) measurement was performed as a noninvasive method for assessing bone quantity and bone stiffness.22–24 Measurements of the right os calcis were performed with a Sahara ultrasound device (Hologic QDR 4500; Hologic Inc, Waltham, MA) measuring broad-band ultrasound attenuation (dB/MHz) and speed of sound (m/s). Acoustic phantoms, provided by the manufacturer, were scanned daily and showed no drift over the time span of the study.
Urine specimens (spot samples) and skin biopsies were hydrolyzed overnight in 6 M HCl in Teflon-sealed glass tubes. Amino acid analyses (hydroxyproline [Hyp], proline [Pro], and hydroxylysine [Hyl]) and cross-link analysis (hydroxylysylpyridinoline [HP] and lysylpyridinoline [LP]) of the tissue hydrolysates were conducted as described previously.25 The quantities of cross-links and Hyl were expressed as the number of residues per collagen molecule (mol/mol collagen), assuming 300 Hyp residues per triple helix. Hyp in the urine hydrolysates was derivatized with 9-fluorenylmethyl chloroformate and quantified with high-performance liquid chromatography.25,26 Finally, HP and LP levels in urine hydrolysates were determined using a high-performance liquid chromatography system equipped with on-line sample purification on CC31 cellulose using a Prospekt solid-phase extractor.
Central estimators were calculated as means (standard error of the mean) or medians (minimum, maximum) when appropriate. The data were analyzed using linear regression with a group indicator as independent variable. Results are presented as linear regression coefficients of the group indicator representing mean group differences with their corresponding 95% CIs. The same models were used to adjust for possible confounding factors. Statistical significance was considered to have been reached when 95% CIs did not include the null value.
Role of the Funding Source
The sponsor for analysis of urine specimens (The Royal Dutch Society for Physiotherapy) was not involved in the study design, collection, analysis, and interpretation of data or in the writing of the manuscript and in the decision to submit the paper for publication.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Urinary cross-link levels (HP, LP), after adjustment of possible confounders such as age, gender, body height, and weight, were significantly lower in the children with SGH compared with the control subjects (Table 4). In the unaffected skin of the 3 children who had SGH and were operated on, substantial amounts of pyridinoline (HP and LP) cross-links (0.073 ± 0.03 residues/collagen molecule) were present, compared with the skin data from the 10 healthy white individuals (3.6 times lower [0.020 ± 0.01]; Table 5). In the hypertrophic scar tissue of the 16-year-old girl, 0.526 pyridinoline residues/collagen molecule were found. This is approximately twice as much as the mean values reported for hypertrophic scar tissue or keloid and 20-fold higher than normal skin (Table 5). The data of the skin of the 10 healthy white individuals (19–72 years of age) did not show age-related changes and were similar to values reported for skin of younger subjects (7–15 years).27 The number of Hyl residues in the triple helix of the collagen molecule was 16.2 ± 2.1 (normal skin range: 16.7 ± 0.6; Table 5). The ratio of Hyp to Pro (a measure of the ratio of collagenous to noncollagenous proteins) was 0.647 ± 0.033 (normal range: 0.598 ± 0.020; Table 5), indicating that there was an increased amount of collagen in the skin of the patients. The amount of Hyl residues (27.6/collagen molecule) and the Hyp/Pro ratio (0.734) in the hypertrophic scar was, as expected, elevated compared with normal skin; unfortunately, these parameters have never been measured in hypertrophic scar tissue.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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We found in these children a decrease in QUS parameters of bone, a lower amount of collagen degradation products in the urine, and an increase of cross-links per collagen molecule and total collagen content in skin biopsies. The associated exercise-induced pain is probably caused by a relative overuse of musculotendinogenous structures adjacent to the stiff joints.
The incidence of habitual (idiopathic) toe-walking is reported to be 24%, and the cause remains unknown.30 In our opinion, decreased range of joint motion in the ankle and knee joints, resulting in habitual toe-walking, may be an indicator of systemic stiffness of the joints. The range of joint motion is determined by the interaction between the extra-articular (neurologic system, muscles) and the intra-articular structures.31 In children with SGH, no evidence of a primary neurologic cause was found. The primary cause of systemic decrease in range of joint motion is likely to be an increased stiffness of joint ligaments and musculotendinogenous structures. As the biomechanical properties of these structures are mainly determined by the collagen network, the molecular defect involved in the pathogenesis of hypomobility may reside within this network. It is interesting that defects in the collagen network of adults with symptomatic generalized joint hypermobility, the possible counterpart of SGH, have been reported.9
With the Contompasis semiquantitative scoring system for range of joint motion, hypomobility also can be measured.32 We did not choose to use this scoring system, because only information concerning the thumb (opposition), fifth metacarpophalangeal joint (dorsiflexion), elbow (hyperextension), knee (hyperextension), spine (flexion), and ankle joint (dorsiflexion) can be obtained. Therefore, we measured agonistic and antagonistic movements of all joints of upper and lower extremities, which provided more detailed information concerning the possible systemic derangement. In the future, a scoring system should be developed for differentiation between normal and abnormal range of joint motion. Until now, we have suggest that local joint hypomobility is present when range of joint motion in that particular joint is lower than –1 SD of the control group. When local joint hypomobility is present in more joints of lower and upper extremities, we would suggest generalized joint hypomobility to be present.
In the present study, we found a decrease in QUS parameters. In general, long-standing immobility may have strong effects on bone and muscle, resulting in a decrease in quantitative bone ultrasound characteristics.33 Children with SGH participated well in society, and no long-term immobility was present. In addition, no increased bone remodeling was observed; on the contrary, decreased levels of collagen degradation products in urine were found.
Although this is a cross-sectional study, we speculate that children with SGH might have more complaints during growth spurts (eg, puberty). When body weight increases (eg, puberty) in habitual toe-walking, the plantigrade position in the ankle joint might become possible, although without a normal gait pattern. Parents who also were hypomobile reported that exercise-induced complaints did not materially change in adolescence and adulthood.
The collagen cross-link data of the SGH skin biopsies and the hypertrophic scar tissue seem to be indicative of an abnormality in collagen processing. Pyridinoline cross-links can be formed only when the lysine in the collagen telopeptides is converted into Hyl. The latter reaction is catalyzed by the enzyme telopeptide lysyl hydroxylase (TLH).34 Unfortunately, the gene for this enzyme has not yet been cloned, and the enzyme has not been purified, and no test is available to measure its activity. However, pyridinoline cross-links point to the presence of TLH. In normal postnatal human skin, lysyl hydroxylation of the telopeptides is close to 0, resulting in very low or undetectable pyridinoline levels. In the skin biopsies of children with SGH, significant amounts of HP and LP were found, indicating that hydroxylation of lysine of the telopeptides occurred. We believe that in children with symptomatic joint hypomobility, an abnormally high expression of TLH is seen. As can be concluded from the pyridinoline levels, TLH is upregulated in fibrotic tissues and scars.34 In the hypertrophic scar of the 16-year-old girl, large amounts of pyridinolines were found, levels that were twice as high as in hypertrophic scars, again indicating an upregulation of TLH.35 Pyridinoline cross-links are involved in the irreversible collagen deposition in fibrosis, indicating that collagen cross-linked by pyridinolines shows a lower rate of degradation than collagen that contains cross-links derived from a telopeptide lysine.36,37 The increased amount of collagen in the skin of children with SGH is in line with this statement: the higher pyridinoline levels prohibit collagen degradation. In this context, it is of interest that 5 children with SGH had broadened, hypertrophic scar tissue after anamnestically reported minimal trauma. Also noteworthy is the relatively low amount of collagen degradation products seen in the urine of children with generalized joint hypomobility. One would actually expect this when collagen is more heavily cross-linked with pyridinolines. As these degradation products are mainly derived from bone collagen,38 collagen that normally shows a relatively low lysyl hydroxylation level of the telopeptides, TLH may not be upregulated in skin alone. It therefore is reasonable to assume that the upregulation of TLH is of a more systemic nature, ie, several connective tissues (eg, bone and probably also ligaments and musculotendinogenous structures) are involved. More research is indicated to provide insight into the prevalence of SGH in children and adults and to provide insight into the possible related defects in collagen metabolism
In conclusion, children with SGH present a characteristic clinical presentation that may be caused by changes in collagen metabolism, possibly as a result of an increased hydroxylation of lysine residues in the collagen telopeptides as a result of an upregulation of TLH.
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ACKNOWLEDGMENTS |
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We thank the participating children with symptomatic joint hypomobility and their parents and the children from the primary schools "Het Spoor" and "Openbare Montessori School" (Zeist, the Netherlands) and the secondary school "De Breul" (Zeist, the Netherlands), who served as the reference group. L. Hokke, A.A. Nijenhuis, M.J. Vis, and P.J. Wetselaar, physical therapy students, are gratefully acknowledged for their support in the conduct of the study.
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FOOTNOTES |
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Reprint requests to (R.H.H.E.) Department of Pediatric Physical Therapy, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Rm KB 02.056.0, PO Box 85090, 3508 AB Utrecht, The Netherlands. E-mail: R.Engelbert{at}wkz.azu.nl
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REFERENCES |
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