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Section II: Original Articles: Pediatrics

Orthopaedic Manifestations of Ehlers-Danlos Syndrome

Stanitski, Deborah F. MD*; Nadjarian, Richard MD, MPH**; Stanitski, Carl L. MD*; Bawle, Erwati MD**; Tsipouras, Petros MD

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Clinical Orthopaedics and Related Research: July 2000 - Volume 376 - Issue - p 213-221
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Abstract

Ehlers-Danlos syndrome is a heritable disorder of connective tissue characterized by abnormal collagen synthesis and cross-linking.9 Among all connective tissue disorders, Ehlers-Danlos syndrome is thought to be the most prevalent.9

The first detailed description of Ehlers-Danlos syndrome was made in 1892 by Tschernogobow,11,12 who stressed an interconnection among the core symptoms: skin fragility, joint hypermobility, and molluscoid pseudotumors of bony prominences as an overall manifestation of a "fundamental and generalized inadequacy of connective tissue," and his name is still used in Russia to designate the disorder. Ehlers, a Danish dermatologist presented a case of the disorder in 1901.7 Danlos, a French dermatologist, discussed several cases in 1908, and both authors agreed about the cardinal features of the disease.6 At the urging of Weber in 1936,13 the joint eponym was accepted and popularized.

This interpretation of signs and symptoms in making a clinical diagnosis has essentially remained unchanged throughout the years. Contemporary investigators such as McKusick9 define the cardinal manifestations of Ehlers-Danlos syndrome as hyperextensible skin with a soft, velvety, doughy texture, dystrophic scarring, easy bruising, joint hypermobility, and connective tissue fragility. Although these are the primary manifestations of Ehlers-Danlos syndrome, secondary manifestations such as vascular and colonic ruptures and ocular or dental complications and platelet abnormalities distinguish the subcategories of the disease.

Currently, nine subcategories exist: Types I to VIII and Type X. Each type is based on its inheritance pattern, secondary manifestations, and degrees of phenotypic variation. Even with tissue typing, almost half of patients with Ehlers-Danlos syndrome cannot be classified with certainty into one of these nine categories.1

Ehlers-Danlos syndrome Types I (gravis) and II (mitis) share an autosomal dominant inheritance and show the cardinal manifestations to a severe and moderate degree, respectively.9 Joint laxity and hypermobility are prominent findings. Skin hyperextensibility and tissue fragility are distinguishing features of these types.

Ehlers-Danlos syndrome Type III (hypermobile type), like Types I and II, has autosomal dominant inheritance but has marked articular hypermobility, moderate dermal hyperextensibility, and minimal scarring.

Ehlers-Danlos syndrome Type IV (vascular type) has a heterogeneous inheritance pattern, with variable manifestations, including joint hypermobility limited to the digits; pale, translucent skin with visible venous patterns without hyperextensibility; and hyperpigmentation or scarring.1,9 Other distinguishing characteristics of Type IV are a predisposition toward severe bruising and vascular and colonic ruptures.9

Ehlers-Danlos syndrome Type V (X-linked type) presents with an X-linked inheritance pattern, with the cardinal manifestations apparent in moderate degree. It is differentiated by its pattern of inheritance.14

Ehlers-Danlos syndrome Type VI (ocularscoliotic type) is an autosomal recessive type, with severe cardinal manifestations, similar to those of Ehlers-Danlos syndrome Type I. Ocular complications and spinal malalignment are reportedly the distinguishing features of this type.14

Ehlers-Danlos syndrome Type VII (arthrochalasis multiplex congenita) presents with a heterogeneous inheritance pattern and marked joint laxity associated with multiple dislocations. Short stature and mandibular micrognathia are other hallmarks of this type.14

Ehlers-Danlos syndrome Type VIII (periodontitis type) shows an autosomal dominant inheritant pattern. Periodontitis, gingival recession, and early tooth loss are distinguishing features.4,14

Ehlers-Danlos syndrome Type X (fibronectin abnormality) is transmitted in an autosomal recessive fashion. Cardinal manifestations are present, but the skin texture is normal. Other expressions include striae distensae, petechiae, and a platelet aggregation defect.2,14 As opposed to a collagen defect, fibronectin abnormality seems to be the principle cause of Ehlers-Danlos syndrome Type X.

With the exception of the report of Ainsworth and Aulicino,1 which was based on a mailed questionnaire survey and without clinical evaluation, the orthopaedic clinical literature on Ehlers-Danlos syndrome is limited, comprised primarily of case reports and series with small numbers of patients.3,4,8 The musculoskeletal manifestations of Ehlers-Danlos syndrome focus around joint instability and secondary inflammation, diminished function, and reported symptoms associated with spinal malalignment. Historically, Types I, III, VI, and VII are associated with major orthopaedic problems. Ehlers-Danlos syndrome Types VI and VII are extremely rare. Because of the rarity of the other types, the current study focuses on the orthopaedic aspects associated with Types I to IV.

The purpose of this article is to report the results of clinical evaluation of a large number of affected patients to more clearly delineate the nature, risk, and prevalence of functional, clinical musculoskeletal problems in those patients. This clinical report is not designed to be a review of surgical indications and outcomes or a review of collagen biochemistry or the basic science involved in Ehlers-Danlos syndrome research.

MATERIALS AND METHODS

Physicians and other healthcare providers, working with the Ehlers-Danlos National Foundation, organized a learning conference on Ehlers-Danlos syndrome. The 93 conference participants with Ehlers-Danlos syndrome or suspected of having same were sent questionnaires before the meeting and were asked to bring the completed questionnaires to the conference. Physicians from the departments of psychiatry, ophthalmology, orthopaedics, and genetics examined the participants. Physicians from the departments of gynecology and urology also examined the female participants. Members of the department of radiology provided radiologic evaluation.

Of the original 93 participants, 60 (64.5%) had definite diagnoses of Ehlers-Danlos syndrome by family history, prior collagen typing, or both, and were considered appropriate participants for the study. Most of the remaining 33 patients had diagnoses of joint hypermobility syndrome (previously designated as Ehlers-Danlos syndrome Type IX) and were not included in the study.

The patient questionnaire provided information concerning family history; prior orthopaedic surgical procedures; reports of joint pain, swelling, dislocation, or back and neck pain; and a functional assessment of activities of daily living using standard occupational therapy parameters.

Study participants were evaluated in terms of activities of daily living functional ability using the following criteria: walking, stair climbing, use of assistive devices, and reported upper extremity use for activities of daily living including functional grip strength.

The questionnaire subdivided walking ability into five categories: inability to walk (wheelchair bound), household ambulation, ability to walk less than 1 block, ability to walk 3 to 6 blocks, and unlimited walking ability. Patient's abilities were recategorized as ones with either unlimited walking ability or some degree of limitation.

Stair climbing ability was subdivided into five categories: unable to climb stairs, able to climb one stair at a time, able to climb with use of the banister, some other method of climbing other than one step over another, and able to climb one step over another. Patients were recategorized as either having the ability to climb one step over another (normal) or being limited to some degree.

Upper extremity function was subdivided into six categories: inability to use the arm, minimal activity only, light housework, most housework, slight restrictions only, and normal activities. For the purposes of this study, patient upper extremity function was recategorized as either normal or less than normal. Patients were questioned about their frequency of dropping objects as a functional measure of hand strength.

Levels of functional dependence were gauged by use of assistive devices, including wheelchairs, walkers, crutches, canes, shoe orthotics, splints, and other orthotics.

The prevalence of prior orthopaedic surgical procedures was assessed. Surgical histories were categorized according to operative location. Multiple surgical procedures on the same area in the same patient were counted as a single site. No data were gathered concerning preoperative indications, contraindications, or outcome quality because these were not purposes of the study.

An occupational and a physical therapist and members of the Wayne State University Department of Orthopaedic Surgery conducted musculoskeletal examinations. These examinations included assessment of stance, gait, joint ranges of motion (ROM), gross motor strength and grip strength measured by Jamar Dynamometer, and pinch strength measured by Preston Pinch Gauge with dominant and nondominant hand side-to-side comparisons expressed as a percentage.

If patients had clinical evidence of truncal asymmetry or a positive Adam's forward bend test, erect posteroanterior and lateral thoracolumbar spine radiographs were taken. Curve direction, location, and magnitude were recorded. Curves from 10° to 19° were rated as minimal; 20° to 29°, mild; 30° to 49°, moderate; and greater than 50°, severe. Sagittal plane abnormalities were also assessed.

Findings were recorded on a standardized form to document joint ROM, spinal alignment, grip strength, and other criteria.5,8

Patient data were organized into a database, and statistical analysis was done using analysis of variance (ANOVA) and contingency table analysis (chi square).

RESULTS

Of the 60 study participants determined to have true Ehlers-Danlos syndrome: 13 (22%) had Type I, nine (15%) had Type II, 30 (50%) had Type III, six (10%) had Type IV, one (1.5%) had Type VI, and one (1.5%) had Type VIII. Because of the limited number of patients with Types VI and VIII disorders (two), they were not included in the descriptive or statistical portions of the study. Thus, the current study reports data on 58 patients with Types I through IV Ehlers-Danlos syndrome.

Table 1 summarizes the demographic data by Ehlers-Danlos syndrome type.

TABLE 1
TABLE 1:
General Demographics Among Ehlers-Danlos Syndrome Types

Physical examination showed that all of these patients had joint ROM greater than published normal values.5 When means of joint motion data were compared among Ehlers-Danlos syndrome types, most of the differences were not significant. Comparisons that did approach a significance of probability less than 0.05 included hip abduction, prone hip external rotation, and forearm supination.

Analysis of orthopaedic signs and symptoms associated with Ehlers-Danlos syndrome was focused on five areas: scoliosis, back and neck pain, joint pain, joint swelling, and joint instability. Table 2 presents the prevalence of orthopaedic symptoms among the four Ehlers-Danlos syndrome types. Two subcategories were created as a way of assessing the frequency and intensity of the back pain described. Patients reporting back or neck pain more than two times per week were considered to have frequent pain. In addition, patients responding that back and neck pain had resulted in inactivity were considered to have intense pain. These subcategories of back and neck pain are presented in Table 3.

TABLE 2
TABLE 2:
Prevalence of Orthopaedic Symptoms Among Ehlers-Danlos Syndrome Types
TABLE 3
TABLE 3:
Breakdown of Back and Neck Pain Among Ehlers-Danlos Types

Thirty of the 58 (51.7%) patients had clinical and radiographic evidence of scoliosis. Curves were thoracic in 46.7%, thoracolumbar in 16.7%, and lumbar in 36.6% of cases. Minimal curves were seen in 53.4%, (average, 22°); moderate curves in 23.3%, (average, 35.8°), and no patient had a severe curve requiring surgery (> 50°). Of the patients with scoliosis, Type I represented 26.7%; Type II, 6.6%; Type III, 56.7%; and Type IV, 10%. Of the patients with documented Ehlers-Danlos syndrome, Type I had the highest percentage of patients with scoliosis (61.5%), followed by Types III (56.7%), IV (50%), and II, (22.2%). Type I curves were minimal or mild in 87.5%, and Type III curves were minimal or mild in 71%. Neither group had any patient with a severe curve. Ten percent of the patients with scoliosis (three of 30) had radiographic evidence of either an L5-S1 Grade 1 spondylolisthesis (two) or retrolisthesis (one).

Of the patients with scoliosis, 82% had enough back or neck pain to cause limitations of activities. Of all of the patients who stopped their activity because of back and neck pain, 39% had scoliosis exceeding 10°. Of the remaining patients without spinal deformity, nearly 71% reported equally intense back or neck pain. Scoliosis did not statistically influence the severity of subjective back pain complaints in these patients.

Most of the patients with Ehlers-Danlos syndrome in this study reported joint pain (88%; 50 of 58), swelling (51.7%; 30 of 58), or dislocation (72%; 42 of 50). Patients with Types II and III reported the most frequent problems with joint pain. Among the four types, there were no significant differences in history of joint dislocation and swelling.

The questionnaire response revealed that 26% (15 of 58) of respondents reported hip dislocations. At examination, all respondents with hip dislocations had snapping of the iliotibial band over the greater trochanter as opposed to true hip instability. This problem was habitual and voluntary in numerous patients.

The walking data stratified against Ehlers-Danlos syndrome type is seen in Table 4. Type III Ehlers-Danlos syndrome was the most functionally debilitating, with 83% of those affected having some degree of ambulatory limitation. Overall, 61% (35 of 58) of all patients with Ehlers-Danlos syndrome studied were limited to some degree in their ability to walk.

TABLE 4
TABLE 4:
Functional Ability Stratified by Ehlers-Danlos Syndrome Type

Table 4 shows stair climbing data stratified against Ehlers-Danlos syndrome type. Type III Ehlers-Danlos syndrome caused the greatest limitations, with 63% of those afflicted having problems climbing stairs. Overall, 51% (30 of 58) of all patients with Ehlers-Danlos syndrome in the series were limited to some degree in their ability to climb stairs.

Patients with Type III syndrome were the most affected group relative to upper extremity function, with 83% easily dropping objects (Table 4). Sixty-four percent (37 of 58) of patients with Ehlers-Danlos syndrome said they easily dropped objects, implying problems with functional hand strength. Fifty of the 58 patients consented to have objective grip and pinch strength assessments. In general, if grip strength was diminished, pinch strength also was reduced for any specific patient. Patients with Type III syndrome had the widest range of grip strength (46.6%-100%) and pinch strength (40%-100%) ratio comparisons. The 27 patients with Type III syndrome had the highest average grip percentage (dominant-nondominant similarity) and the lowest average pinch percentage. The reverse was true of the six patients with Type IV syndrome tested. Most (92%) of patients with Type III syndrome reported less than normal upper extremity function. Overall, 73% (42 of 58) of patients with Ehlers-Danlos syndrome claimed less than normal upper extremity function (Table 4).

Use of assistive devices was common among patients with all types of Ehlers-Danlos syndrome, particularly among those with Types II (78%) and III (77%) (Table 4). Overall, 69% (40 of 58) of patients with Ehlers-Danlos syndrome used assistive devices, indicating functional limitations. Total number of orthopaedic surgeries, surgeries categorized by area, and number of surgeries per patient, stratified by Ehlers-Danlos syndrome type, are seen in Table 5. Overall, 46.6% (27 of 58) of participants with Ehlers-Danlos syndrome had orthopaedic surgical procedures. Among Ehlers-Danlos syndrome types studied, 57% (17 of 30) of participants with Type III, but only 17% (one of six) of participants with Type IV syndrome had surgery. Surgery of the knee was the most common type, with 22.4% (13 of 58) of patients having undergone some type of knee surgery, representing 48% of patients who had an orthopaedic surgical procedure. Spine surgery was uncommon and was reported by 12% (seven of 58) of all participants with Ehlers-Danlos syndrome and reflected 26% (n = 27) of those participants who had some form of orthopaedic surgery. Data on other surgical procedures and their respective breakdowns by Ehlers-Danlos syndrome type are listed in Table 5. Although no patients with one type of Ehlers-Danlos syndrome had a significantly higher rate of orthopaedic surgical procedure, patients with Type III Ehlers-Danlos syndrome had the highest frequency of orthopaedic surgery, with an average of 1.17 surgeries per patient and 2.06 sites of surgery per patient. The average number of operations per person for all Ehlers-Danlos syndrome types was 0.88, and the average number of surgery sites per patient was 1.89.

TABLE 5
TABLE 5:
Orthopaedic Surgeries Among Ehlers-Danlos Syndrome Types

The available data were not intended to allow an analysis to clarify surgical indications, effectiveness, and outcomes of performed procedures.

DISCUSSION

The current article presents the largest reported clinical series of patients with Ehlers-Danlos syndrome in whom specific functional objective and subjective analyses were performed relative to Ehlers-Danlos syndrome type. Ainsworth and Aulicino's report1 was based on a return mail questionnaire with 72% return rate from 210 patients in the Ehlers-Danlos National Foundation. In contrast to their review, which had a self-described Ehlers-Danlos syndrome type documentation in 65% of cases, all of the current patients had documentation of Ehlers-Danlos syndrome type, and those without a definitive Ehlers-Danlos syndrome diagnosis were eliminated from the study. All patients in the current review had clinical evaluation in addition to a standardized questionnaire and, when indicated, radiographic assessment.

The study data reflect an inherent bias because the patients assessed were voluntary attendees at a national Ehlers-Danlos Syndrome Foundation educational symposium for patients and families. Some of the patients included in this study were also reported by Ainsworth and Aulicino.1 Patients at this meeting may overrepresent specific types: for example, those who were more functional and those with the interest, social, and fiscal means to attend the conference. The gender data (female:male = 11:1) may be such a reflection because most previously reported prevalence information for the disorder has a male preponderance. The current study was able to categorize only five males (9%) with Ehlers-Danlos syndrome Types I to IV. Slightly more than half of all patients with Ehlers-Danlos syndrome knew of a relative with the disease. A similar percentage were either students or housewives, and 7% reported being unemployed. The clinical functional data obtained reflect, in large measure, the major represented segment, Type III, which accounted for 50% of the attendees with documented Ehlers-Danlos syndrome.

Levels of function in terms of walking ability, stair climbing, functional hand strength, use of assistive devices, upper extremity function, and reports of pain were compared among Ehlers-Danlos syndrome types. Differences in joint pain were significant (p < 0.015) among types, with a greater proportion of patients with Type III disorder reporting pain (100%, n = 30) as compared with those with Types I (69%, n = 13), II (89%, n = 9), and IV (67%, n = 6). Similar chronic pain data have been reported by Sacheti et al.10 Functional differences between the types were not significant for stair climbing ability or use of assistive devices. Comparisons in walking ability, functional hand strength, and upper extremity function all produced significant results.

Abnormal walking was experienced by 60% (35 of 58) of patients with Ehlers-Danlos syndrome. Individuals with Type III disorder were found to have a significantly (p < 0.006) higher percentage of abnormal ambulation (83%, n = 30) compared with Types I (33%, n = 13), II (44%, n = 9), and IV (33%, n = 6). The current data are similar to that in Ainsworth and Aulicino's1 study, which reported 40% crutch or wheelchair use in their cases.

Functional hand strength was also a problem for patients with Ehlers-Danlos syndrome. Sixty-four percent claimed to drop objects easily. Individuals with Type III disorder had a significantly (p < .02) higher percentage of reduced hand function (83%) than did those with Types I (38%), II (50%), and IV (40%). Patients with Type III syndrome grip side to side comparisons were the most consistent and reflect bilateral compromise. Pinch strength in patients with Type III syndrome seemed to be less affected bilaterally. Possible causes such as pain, joint instability, excessive joint motion, or weakness could not be defined by the data obtained.

Abnormal levels of upper extremity function were experienced by 73% of participants with Ehlers-Danlos syndrome. Individuals with Type III disorder experienced a significantly (p < 0.02) higher percentage (92%) of reduced upper extremity function than did their counterparts with Types I (56%), II (50%), and IV (33%).

Back pain and scoliosis were assessed to determine whether the scoliosis seen in patients with Ehlers-Danlos syndrome was associated with debilitating pain. The variable used to assess debilitation was activity modification because of back pain. Overall, 60.8% (35 of 58) of those with back pain experienced a level debilitating enough to cause inactivity. This finding is in sharp contrast to the data of Beighton and Horan,4 who found only six of 100 patients with Ehlers-Danlos syndrome who reported troublesome backache. They did not specifically address the issue of scoliosis. No significant correlation was established in the current patients between back pain and scoliosis, suggesting that scoliosis in patients with Ehlers-Danlos syndrome may not be the cause of change of activity related to back pain. The scoliosis seen in the current patient cohort was minimal or mild in most cases (76.7%), and no patient had a severe curve. Lumbar spine scoliotic curve deformity was seen in 53.3% of the patients with scoliosis.

In the current review, patients with Type III syndrome represented the highest percentage of patients with scoliosis, a frequency also seen in a previous report, which did not define location, direction, or curve magnitude.1

The significant number of patients (26%) reporting hip dislocations actually were experiencing snapping of the iliotibial band over the greater trochanter and not femoral and acetabular instability. This finding is consistent with the data of Beighton and Horan,4 who reported only one patient (of 100) with Ehlers-Danlos syndrome with a true dislocated hip secondary to a fall.

A significant number (35.5%) of conference participants were eliminated from the study because they did not meet the criteria for a diagnosis of Ehlers-Danlos syndrome. Most of these had the diagnosis of joint laxity syndrome, previously diagnosed as Ehlers-Danlos syndrome Type IX. This category has been dropped from the Ehlers-Danlos syndrome classification because these patients lack the change in skin texture and hyperextensibility, tissue fragility, wound healing problems, and joint instability seen as the cardinal manifestations associated with true Ehlers-Danlos syndrome.

Surgical indications and outcomes could not be assessed in these patients because of lack of specific information regarding their procedures. Additional study of orthopaedic surgical indications and efficacy in patients with Ehlers-Danlos syndrome is necessary to delineate the role of such procedures in the management of this disorder.

The results suggest that among the patients reviewed in this study, Ehlers-Danlos syndrome Type III was the most functionally debilitating form of this syndrome. This is in contrast to McKusick's9 statement that, although the orthopaedic complications associated with Type III are common, he thought the overall condition relatively harmless. The authors of the current study found that symptoms associated with Ehlers-Danlos syndrome Type III were more likely to lead to surgery, and patients with Type III disorder experienced a higher incidence of pain and lower level of function. These findings are more in line with those reported by Ainsworth and Aulicino,1 who also found that 37 patients (25.3% of the total reviewed) with Type III disorder reported significant problems with grip strength, fine motor skills, and functional activities of daily living. Sacheti et al10 also found a major incidence of debilitating chronic pain in this group of patients. The reasons for diminished function in patients with Type III syndrome appear to be related to a combination of joint pain, instability, and muscle weakness, an uncommon triad in the other types reviewed.

References

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