REVIEW URRENT C OPINION
Orthopedic aspects of collagen disorders Lauren E. LaMont and Shevaun M. Doyle
Purpose of review The purpose of this article is to provide the pediatrician with a review of disorders that have the orthopedic manifestation of joint hypermobility. Hypermobility, also termed ligamentous laxity, may present in different parts of the body at different times throughout childhood and adolescence. It may be symptomatic or incidentally found on the physical examination. Many conditions that cause joint hypermobility resolve with nonoperative management, but occasionally operative intervention is required for the best patient outcome. Recent findings In addition, hypermobility may be associated with collagen disorders that affect vital organ systems. Recognition of hypermobility combined with a thorough patient evaluation may be the initial opportunity for the pediatrician to uncover disease that may be managed promptly. Summary Heightened awareness of subtle hypermobility or symptomatic joint laxity on physical examination facilitates optimal management and favorable outcomes in children with this condition. Keywords hypermobility, ligamentous laxity, Marfan syndrome
INTRODUCTION Joint hypermobility and laxity are common findings in normal children, but can be associated with a variety of specific disorders and syndromes. Joint laxity peaks in childhood and gradually decreases with age. Although hypermobility can be a normal physical finding, it is important to fully evaluate the hypermobile patient with musculoskeletal complaints for associated syndromes. In the asymptomatic patient, laxity is associated with other syndromic features and can lead to a clinical diagnosis. Here we describe the spectrum of physical findings that can be associated with hypermobility and laxity on examination, the classification of these findings, and the necessity for further evaluation. These diagnoses can range from conditions as profound as Down syndrome to those as inconspicuous as benign generalized ligamentous laxity [1,2]. In the evaluation of the hypermobile child, clinicians must understand the associated syndromes and the implications for musculoskeletal injury. Hypermobile patients have increased joint range of motion and will often describe themselves as being ’double-jointed’. A small subset of patients will have laxity or hypermobility that is associated with a heritable connective tissue disorder. These disorders include osteogenesis imperfecta, Loeys– Dietz, Marfan, and Ehlers–Danlos syndromes.
Knowledge of concomitant findings is essential to initiate an appropriate work-up. Hypermobility can also be part of an isolated syndrome known as benign generalized ligamentous laxity. Benign generalized ligamentous laxity is a hypermobility syndrome that has been well defined, but is often undetected [3]. Diagnosis of this syndrome, as opposed to physiologic laxity, has implications for musculoskeletal pain later in life. Chronic pain and fibromyalgia have also been linked to hypermobility, but are uncommon in children [4].
HISTORY When a patient presents with a specific musculoskeletal complaint or is noted incidentally to have increased joint range of motion on physical examination, a complete musculoskeletal examination should be performed. It is important to note the chronicity of complaint as well as a history of other Hospital for Special Surgery, New York, New York, USA Correspondence to Shevaun M. Doyle, MD, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA. Tel: +1 646 797 8816; fax: +1 646 797 8836; e-mail: [email protected] Curr Opin Pediatr 2014, 26:79–84 DOI:10.1097/MOP.0000000000000035
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KEY POINTS It is important to fully evaluate the hypermobile patient with musculoskeletal complaints for associated syndromes. Hypermobility may be associated with collagen disorders that affect vital organ systems. Recognition of hypermobility combined with a thorough patient evaluation may be the initial opportunity for the pediatrician to uncover disease that may be managed promptly.
joint complaints. The rate of occurrence should also be noted to determine whether patients have had frequent sprains, strains, or fractures in the past. The patient’s activity level and any limitations imposed by joint pain help to establish the severity of the complaint. Patients with benign joint laxity are at increased risk for injury with physical activity, and intensity of sports participation may lead to increased musculoskeletal complaints. Beyond the musculoskeletal system, many other systems may be affected. Questions regarding frequent bruising or spontaneous hemarthroses are important. The integumentary system is often affected and concerns about scarring are not uncommon in certain collagen disorders. The gastrointestinal system may also be affected and a higher incidence of hiatal hernias has been seen in patients with hypermobility [5].
PHYSICAL EXAMINATION When hypermobility is identified on physical examination, a thorough joint evaluation is necessary to differentiate between pathologic and physiologic joint laxity. In addition to the musculoskeletal system, it is important to note any other abnormalities that may suggest a syndrome associated with a collagen disorder. On initial examination, the patient’s general appearance should be noted. Tall stature, a thin body habitus, and arachnodactyly are associated with Marfan syndrome. A thorough integumentary examination can identify bruising or abnormal scars. Skin should also be assessed for hyperelasticity as is seen in Ehlers–Danlos syndrome and other collagen disorders [6,7]. Ophthalmic gross examination may reveal a bluish hue to the sclera; this may be evident in patients with osteogenesis imperfecta, Ehlers–Danlos syndrome, and even generalized joint laxity. Ptosis of the eyelid should also be noted for its association with collagen disorders and hypermobility syndromes [8]. Dislocated lenses, as seen in 80
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Marfan syndrome, will only be evident on slit-lamp examination. A level of suspicion of the syndrome is warranted before referral to an ophthalmologist. Hearing loss, noted on a screening examination, may be identified in patients with osteogenesis imperfecta [9]. Additionally, dental examination may reveal dentinogenesis imperfecta, which aids in diagnosis of osteogenesis imperfecta. In patients affected with collagen disorders such as Marfan syndrome, cardiopulmonary complications carry the greatest risk of morbidity and mortality. Aortic root dilatation is one of the manifestations of disease that may be asymptomatic and undetectable on physical examination [10]. For that reason, further imaging studies are necessary for patients meeting the criteria for diagnosis, so that appropriate medical or surgical intervention can be implemented [11]. Finally, a thorough appendicular and axial skeletal examination ultimately will determine the diagnosis of hypermobility. The commonly used Beighton–Horan criteria evaluate hypermobility on the basis of knee, elbow, spine, and finger range of motion. The Adams forward bend test should be performed in all patients to assess for spinal curvature and truncal rotation. Examination of the spine may reveal scoliosis, which often is seen in patients with ligamentous laxity. In scoliosis screening, ligamentous laxity has been associated with increased truncal rotation [12]. Examination of bilateral shoulders, elbows, wrists, digits, hips, knees, and ankles should be performed to determine range of motion, stability, and tenderness. The degree of mobility and laxity seen in these joints will determine the diagnosis and the need for intervention. Attention particularly to hyperextensibility of the knee, elbow, and digits is the key to diagnosis. Joint effusions also may be seen in patients with hypermobility, as traumatic hemarthroses have been reported in patients with Ehlers–Danlos syndrome [13].
CLASSIFICATION The first classification system to describe hypermobility was by Carter and Wilkinson [14]. They described generalized joint laxity in school children and found that it affected 7% of otherwise physically normal children. At this time, the syndrome of hypermobility was not appreciated and the significance of laxity was thought to be predisposed for congenital hip dislocation in boys [14]. Beighton and Horan [15] further modified and re-named this classification in 1969 (Fig. 1). The Beighton–Horan criteria were established from clinical findings in 100 patients with Ehlers–Danlos syndrome. The Volume 26 Number 1 February 2014
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Orthopedic aspects of collagen disorders LaMont and Doyle
The Beighton-Horan criteria for generalized hypermobility Joint exam Passive hypertension of the small finger (bilateral)
Points 2
Criteria for + sign >90°
Passive thumb apposition to forearm (bilateral)
2
Thumb touch forearm
Elbow hyperextension (bilateral)
2
>10°
Knee hyperextension (bilateral)
2
>10°
Standing trunk flexion with knees fully extended
1
Palms flat on floor
FIGURE 1. Review of the Beighton–Horan criteria.
score is graded on knee, elbow, and small finger hyperextensibility, ability to touch thumb to volar forearm, and truncal flexibility (Fig. 2a and b). The
(a)
score is a nine-point system based on the extensibility of a specific joint. A score of above 6 suggests hypermobility. Hypermobility can also be graded by the Brighton criteria that distinguish major and minor criteria for hypermobility. However, the Beighton criteria continue to be used commonly and have been shown to have good to excellent intrarater and interrater reliability [16].
WORK-UP A more invasive work-up should be performed based on physical examination findings. Patients with collagen disorders may have mild bleeding tendencies [17 ]. Patients with findings consistent with laxity and complaints of easy bruisability should have a complete blood count to rule out blood clotting disorders. Additional hemostatic laboratory tests, such as von Willebrand factor, may be performed in patients with a bleeding concern, as there is an increased incidence of mucocutaneous bleeding disorders in patients with symptomatic joint hypermobility. These serum markers also should be obtained when a child with joint laxity is undergoing any invasive procedure. Radiographic imaging unveils malalignment in the axial and appendicular skeleton. Patients with truncal rotation detected on the Adams forward bend test should undergo a scoliosis series to evaluate overall alignment. Similarly, other lax joints or long bones that demonstrate abnormalities such as excess varus, valgus, procurvatum, or recurvatum should be imaged to identify bony versus soft tissue abnormalities. When a collagen disorder, such as Marfan syndrome or Loeys–Dietz syndrome, is uncovered, patients need to be counseled about the predisposition to an aortic aneurysm or dissection. For &&
(b)
FIGURE 2. (a) Demonstration of hypermobility in the left wrist. The thumb is apposed easily to the volar forearm without any discomfort to the patient. (b) Demonstration of hyperextension of the left elbow.
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patients with Marfan syndrome, the American Heart Association recommends an echocardiogram at the time of diagnosis. For patients with Loeys–Dietz syndrome, complete aortic and cerebrovascular to pelvis vascular imaging is advised.
GENETIC TESTING In a patient with a clinical examination consistent with a collagen disorder, genetic testing may help confirm the diagnosis and mutation. Some patients may know a family member with a mutation that already has been identified. The major collagen disorders are inherited in an autosomal dominant fashion. Marfan syndrome is associated with a fibrillin 1 mutation, and Loeys–Dietz is associated with a mutation in transforming growth factor-beta receptor. Genetic testing may not always be essential for diagnosis. Ritelli et al. [18 ] demonstrated that the diagnosis of classic Ehlers–Danlos syndrome could be made on patients with three major criteria of the Villefranche nosology as well as the existence of affected relatives. For the small number of patients who had several minor signs, with or without a family history, genetic testing identified the COL5A1 or COL5A2 gene to confirm diagnosis of Ehlers–Danlos syndrome. These genetic tests involved DNA sequencing that had been purified from whole blood samples. In patients with multiple atraumatic or low energy mechanism fractures, once child abuse has been ruled out, genetic testing is used to identify the COL1A1 and COL1A2 genes to substantiate the diagnosis of osteogenesis imperfecta.
FIGURE 3. Depiction of pes planus (flat feet), a clinical feature of patients with Marfan syndrome.
&
SPECIFIC DISORDERS WITH HYPERMOBILITY AND INTERVENTIONS Joint dislocation or subluxation can occur in patients with benign generalized ligamentous laxity; therefore, these conditions must be anticipated and treated expediently. Stabilizing procedures, however, are fraught with complications due to the quality of the underlying soft tissue. After dislocation, the first line of treatment consists of a period of immobilization followed by a focused rehabilitation program. For example, a shoulder dislocation in a patient with ligamentous laxity should be managed nonoperatively unless there is a recurrence [19]. Once nonoperative management fails, open or arthroscopic stabilization procedures may be performed. Although joint pain may or may not be present initially, patients may still be affected in the long term. Comparison of knee function in 10-year-olds and adults with generalized hypermobility showed 82
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only the adults had clinically impaired knee function [20]. In children with symptomatic joint laxity, Engelbert et al. [21] demonstrated decreased maximal exercise capacity. Marfan syndrome is associated with several specific musculoskeletal abnormalities, including scoliosis, arachnodactyly, protrusio acetabuli, pes planovalgus, pectus excavatum, and ligamentous laxity, which can lead to recurrent dislocations (Fig. 3). In childhood and adolescence, scoliosis often is detected prior to diagnosis of Marfan syndrome and requires operative management. Bracing has not been shown to be as effective as it is in adolescent idiopathic scoliosis (AIS); significant and progressive curves are indications for instrumentation and fusion [22]. Marfan patients require more fusion levels and more re-operations, and are at greater risk of complications compared with AIS patients [23]. Musculoskeletal complaints in patients with Ehlers–Danlos vary in presentation, but there is significant joint laxity and scoliosis. Joint laxity is more commonly symptomatic in patients with Ehlers–Danlos syndrome, as is general musculoskeletal pain [24 ]. Although little literature exists on management of spinal fusion in Ehlers–Danlos, there is a very high rate of complications with posterior spinal fusion [25]. Any surgical intervention comes with a high risk of wound complications due to the fragility of skin and poor healing. The collagen disorder most recognized for significant orthopedic issues is osteogenesis imperfecta. Multiple fractures occur over the course of childhood, the number of which vary, based on the specific mutation. As a result of multiple fragility &&
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(a)
(b)
FIGURE 5. (a) An anteroposterior view of both knees in a child with Down syndrome. (b) The Merchant view of both knees in a child with Down syndrome.
dislocations; patellofemoral instability is a common issue (Fig. 5a and b). Other disorders that afflict patients with Down syndrome include hallux valgus, pes planus, atlantoaxial subluxation, slipped capital femoral epiphysis, and hip subluxation/dislocation [25]. Patellar and hip instability may affect the ambulatory status of these patients. Surgical stabilization of the patella can improve function in patients with severe disability [26].
CONCLUSION
FIGURE 4. Posteroanterior radiograph of a child with osteogenesis imperfecta and scoliosis.
fractures, long bone bowing may develop over time. Other orthopedic anomalies include scoliosis (Fig. 4), vertebral abnormalities, and basilar invagination. The generalized ligamentous laxity and hypotonia seen in Down syndrome can lead to joint
Ligamentous laxity is common in childhood, but can be present in multiple collagen disorders. It may manifest in different parts of the body at different times throughout childhood and adolescence. Patients may present to their physicians with or without symptoms of hypermobility or they may present with other entities such as scoliosis or fracture. It is important that the evaluation includes a thorough musculoskeletal examination. The finding of joint hypermobility may tip the examiner to the detection of a collagen disorder such as Marfan syndrome, Ehlers–Danlos disease, or osteogenesis imperfecta: disorders that affect vital organ systems that may require ancillary testing to optimize the patient’s long-term health and well being. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Caird MS, Wills BP, Dormans JP. Down syndrome in children: the role of the orthopaedic surgeon. J Am Acad Orthop Surg 2006; 14:610–619. 2. Finsterbush A, Pogrund H. The hypermobility syndrome. Musculoskeletal complaints in 100 consecutive cases of generalized joint hypermobility. Clin Orthop Relat Res 1982; 168:124–127. 3. Kirk JA, Ansell BM, Bywaters EG. The hypermobility syndrome. Musculoskeletal complaints associated with generalized joint hypermobility. Ann Rheum Dis 1967; 26:419–425. 4. Grahame R. Pain, distress and joint hyperlaxity. Joint Bone Spine 2000; 67:157–163. 5. Al-Rawi ZS, Al-Dubaikel KY, Al-Sikafi H. Joint mobility in people with hiatus hernia. Rheumatology (Oxford) 2004; 43:574–576. 6. Holbrook KA, Byers PH. Skin is a window on heritable disorders of connective tissue. Am J Med Genet 1989; 34:105–121. 7. Remvig L, Duhn PH, Ullman S, et al. Skin extensibility and consistency in patients with Ehlers-Danlos syndrome and benign joint hypermobility syndrome. Scand J Rheumatol 2009; 38:227–230. 8. Wolf JM, Cameron KL, Owens BD. Impact of joint laxity and hypermobility on the musculoskeletal system. J Am Acad Orthop Surg 2011; 19:463–471. 9. Makizumi Y, Kashio A, Sakamoto T, et al. Cochlear implantation in a patient with osteogenesis imperfecta. Auris Nasus Larynx 2013; 40:510–513. 10. Callewaert B, Malfait F, Loeys B, De Paepe A. Ehlers-Danlos syndromes and Marfan syndrome. Best Pract Res Clin Rheumatol 2008; 22:165–189. 11. Nataf P, Lansac E. Dilation of the thoracic aorta: medical and surgical management. Heart 2006; 92:1345–1352. 12. Erkula G, Kiter AE, Kilic BA, et al. The relation of joint laxity and trunk rotation. J Pediatr Orthop B 2005; 14:38–41. 13. Giordano P, Del Vecchio GC, Scaraggi R, et al. Hemarthrosis due to a rare cause of hemorrhagic diathesis: Ehlers-Danlos syndrome. Pediatr Hematol Oncol 2008; 25:205–209. 14. Carter C, Wilkinson J. Persistent joint laxity and congenital dislocation of the hip. J Bone Joint Surg Br 1964; 46:40–45.
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15. Beighton P, Horan F. Orthopaedic aspects of the Ehlers-Danlos syndrome. J Bone Joint Surg Br 1969; 51:444–453. 16. Boyle KL, Witt P, Riegger-Krugh C. Intrarater and interrater reliability of the Beighton and Horan Joint Mobility Index. J Athl Train 2003; 38:281–285. 17. Jackson SC, Odiaman L, Card RT, et al. Suspected collagen disorders in the && bleeding disorder clinic: a case-control study. Haemophilia 2013; 19:246– 250. This article stresses the importance of recognizing clinical hypermobility to uncover a potential cause/contributor to a bleeding disorder. 18. Ritelli M, Dordoni C, Venturini M, et al. Clinical and molecular characterization & of 40 patients with classic Ehlers-Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations. Orphanet J Rare Dis 2013; 8:1172–1178. This article identifies two specific genes that are found in patients with classic Ehlers–Danlos syndrome. 19. Schenk TJ, Brems JJ. Multidirectional instability of the shoulder: pathophysiology, diagnosis, and management. J Am Acad Orthop Surg 1998; 6:65– 72. 20. Juul-Kristensen B, Hansen H, Simonsen EB, et al. Knee function in 10-year-old children and adults with generalised joint hypermobility. Knee 2012; 19:773– 778. 21. Engelbert RH, van Bergen M, Henneken T, et al. Exercise tolerance in children and adolescents with musculoskeletal pain in joint hypermobility and joint hypomobility syndrome. Pediatrics 2006; 118:e690–e696. 22. Robins PR, Moe JH, Winter RB. Scoliosis in Marfan’s syndrome. Its characteristics and results of treatment in thirty-five patients. J Bone Joint Surg Am 1975; 57:358–368. 23. Gjolaj JP, Sponseller PD, Shah SA, et al. Spinal deformity correction in Marfan syndrome versus adolescent idiopathic scoliosis: learning from the differences. Spine (Phila Pa 1976) 2012; 37:1558–1565. 24. Shirley ED, Demaio M, Bodurtha J. Ehlers-Danlos syndrome in orthopaedics: && etiology, diagnosis, and treatment implications. Sports Health 2012; 4:394– 403. This article provides mainstream awareness of Ehlers–Danlos syndrome for multidisciplinary healthcare specialties. 25. Diamond LS, Lynne D, Sigman B. Orthopedic disorders in patients with Down’s syndrome. Orthop Clin North Am 1981; 12:57–71. 26. Bettuzzi C, Lampasi M, Magnani M, Donzelli O. Surgical treatment of patellar dislocation in children with Down syndrome: a 3- to 11-year follow-up study. Knee Surg Sports Traumatol Arthrosc 2009; 17:334–340.
Volume 26 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Orthopedic aspects of collagen disorders Lauren E. LaMont and Shevaun M. Doyle
Purpose of review The purpose of this article is to provide the pediatrician with a review of disorders that have the orthopedic manifestation of joint hypermobility. Hypermobility, also termed ligamentous laxity, may present in different parts of the body at different times throughout childhood and adolescence. It may be symptomatic or incidentally found on the physical examination. Many conditions that cause joint hypermobility resolve with nonoperative management, but occasionally operative intervention is required for the best patient outcome. Recent findings In addition, hypermobility may be associated with collagen disorders that affect vital organ systems. Recognition of hypermobility combined with a thorough patient evaluation may be the initial opportunity for the pediatrician to uncover disease that may be managed promptly. Summary Heightened awareness of subtle hypermobility or symptomatic joint laxity on physical examination facilitates optimal management and favorable outcomes in children with this condition. Keywords hypermobility, ligamentous laxity, Marfan syndrome
INTRODUCTION Joint hypermobility and laxity are common findings in normal children, but can be associated with a variety of specific disorders and syndromes. Joint laxity peaks in childhood and gradually decreases with age. Although hypermobility can be a normal physical finding, it is important to fully evaluate the hypermobile patient with musculoskeletal complaints for associated syndromes. In the asymptomatic patient, laxity is associated with other syndromic features and can lead to a clinical diagnosis. Here we describe the spectrum of physical findings that can be associated with hypermobility and laxity on examination, the classification of these findings, and the necessity for further evaluation. These diagnoses can range from conditions as profound as Down syndrome to those as inconspicuous as benign generalized ligamentous laxity [1,2]. In the evaluation of the hypermobile child, clinicians must understand the associated syndromes and the implications for musculoskeletal injury. Hypermobile patients have increased joint range of motion and will often describe themselves as being ’double-jointed’. A small subset of patients will have laxity or hypermobility that is associated with a heritable connective tissue disorder. These disorders include osteogenesis imperfecta, Loeys– Dietz, Marfan, and Ehlers–Danlos syndromes.
Knowledge of concomitant findings is essential to initiate an appropriate work-up. Hypermobility can also be part of an isolated syndrome known as benign generalized ligamentous laxity. Benign generalized ligamentous laxity is a hypermobility syndrome that has been well defined, but is often undetected [3]. Diagnosis of this syndrome, as opposed to physiologic laxity, has implications for musculoskeletal pain later in life. Chronic pain and fibromyalgia have also been linked to hypermobility, but are uncommon in children [4].
HISTORY When a patient presents with a specific musculoskeletal complaint or is noted incidentally to have increased joint range of motion on physical examination, a complete musculoskeletal examination should be performed. It is important to note the chronicity of complaint as well as a history of other Hospital for Special Surgery, New York, New York, USA Correspondence to Shevaun M. Doyle, MD, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA. Tel: +1 646 797 8816; fax: +1 646 797 8836; e-mail: [email protected] Curr Opin Pediatr 2014, 26:79–84 DOI:10.1097/MOP.0000000000000035
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Orthopedics
KEY POINTS It is important to fully evaluate the hypermobile patient with musculoskeletal complaints for associated syndromes. Hypermobility may be associated with collagen disorders that affect vital organ systems. Recognition of hypermobility combined with a thorough patient evaluation may be the initial opportunity for the pediatrician to uncover disease that may be managed promptly.
joint complaints. The rate of occurrence should also be noted to determine whether patients have had frequent sprains, strains, or fractures in the past. The patient’s activity level and any limitations imposed by joint pain help to establish the severity of the complaint. Patients with benign joint laxity are at increased risk for injury with physical activity, and intensity of sports participation may lead to increased musculoskeletal complaints. Beyond the musculoskeletal system, many other systems may be affected. Questions regarding frequent bruising or spontaneous hemarthroses are important. The integumentary system is often affected and concerns about scarring are not uncommon in certain collagen disorders. The gastrointestinal system may also be affected and a higher incidence of hiatal hernias has been seen in patients with hypermobility [5].
PHYSICAL EXAMINATION When hypermobility is identified on physical examination, a thorough joint evaluation is necessary to differentiate between pathologic and physiologic joint laxity. In addition to the musculoskeletal system, it is important to note any other abnormalities that may suggest a syndrome associated with a collagen disorder. On initial examination, the patient’s general appearance should be noted. Tall stature, a thin body habitus, and arachnodactyly are associated with Marfan syndrome. A thorough integumentary examination can identify bruising or abnormal scars. Skin should also be assessed for hyperelasticity as is seen in Ehlers–Danlos syndrome and other collagen disorders [6,7]. Ophthalmic gross examination may reveal a bluish hue to the sclera; this may be evident in patients with osteogenesis imperfecta, Ehlers–Danlos syndrome, and even generalized joint laxity. Ptosis of the eyelid should also be noted for its association with collagen disorders and hypermobility syndromes [8]. Dislocated lenses, as seen in 80
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Marfan syndrome, will only be evident on slit-lamp examination. A level of suspicion of the syndrome is warranted before referral to an ophthalmologist. Hearing loss, noted on a screening examination, may be identified in patients with osteogenesis imperfecta [9]. Additionally, dental examination may reveal dentinogenesis imperfecta, which aids in diagnosis of osteogenesis imperfecta. In patients affected with collagen disorders such as Marfan syndrome, cardiopulmonary complications carry the greatest risk of morbidity and mortality. Aortic root dilatation is one of the manifestations of disease that may be asymptomatic and undetectable on physical examination [10]. For that reason, further imaging studies are necessary for patients meeting the criteria for diagnosis, so that appropriate medical or surgical intervention can be implemented [11]. Finally, a thorough appendicular and axial skeletal examination ultimately will determine the diagnosis of hypermobility. The commonly used Beighton–Horan criteria evaluate hypermobility on the basis of knee, elbow, spine, and finger range of motion. The Adams forward bend test should be performed in all patients to assess for spinal curvature and truncal rotation. Examination of the spine may reveal scoliosis, which often is seen in patients with ligamentous laxity. In scoliosis screening, ligamentous laxity has been associated with increased truncal rotation [12]. Examination of bilateral shoulders, elbows, wrists, digits, hips, knees, and ankles should be performed to determine range of motion, stability, and tenderness. The degree of mobility and laxity seen in these joints will determine the diagnosis and the need for intervention. Attention particularly to hyperextensibility of the knee, elbow, and digits is the key to diagnosis. Joint effusions also may be seen in patients with hypermobility, as traumatic hemarthroses have been reported in patients with Ehlers–Danlos syndrome [13].
CLASSIFICATION The first classification system to describe hypermobility was by Carter and Wilkinson [14]. They described generalized joint laxity in school children and found that it affected 7% of otherwise physically normal children. At this time, the syndrome of hypermobility was not appreciated and the significance of laxity was thought to be predisposed for congenital hip dislocation in boys [14]. Beighton and Horan [15] further modified and re-named this classification in 1969 (Fig. 1). The Beighton–Horan criteria were established from clinical findings in 100 patients with Ehlers–Danlos syndrome. The Volume 26 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Orthopedic aspects of collagen disorders LaMont and Doyle
The Beighton-Horan criteria for generalized hypermobility Joint exam Passive hypertension of the small finger (bilateral)
Points 2
Criteria for + sign >90°
Passive thumb apposition to forearm (bilateral)
2
Thumb touch forearm
Elbow hyperextension (bilateral)
2
>10°
Knee hyperextension (bilateral)
2
>10°
Standing trunk flexion with knees fully extended
1
Palms flat on floor
FIGURE 1. Review of the Beighton–Horan criteria.
score is graded on knee, elbow, and small finger hyperextensibility, ability to touch thumb to volar forearm, and truncal flexibility (Fig. 2a and b). The
(a)
score is a nine-point system based on the extensibility of a specific joint. A score of above 6 suggests hypermobility. Hypermobility can also be graded by the Brighton criteria that distinguish major and minor criteria for hypermobility. However, the Beighton criteria continue to be used commonly and have been shown to have good to excellent intrarater and interrater reliability [16].
WORK-UP A more invasive work-up should be performed based on physical examination findings. Patients with collagen disorders may have mild bleeding tendencies [17 ]. Patients with findings consistent with laxity and complaints of easy bruisability should have a complete blood count to rule out blood clotting disorders. Additional hemostatic laboratory tests, such as von Willebrand factor, may be performed in patients with a bleeding concern, as there is an increased incidence of mucocutaneous bleeding disorders in patients with symptomatic joint hypermobility. These serum markers also should be obtained when a child with joint laxity is undergoing any invasive procedure. Radiographic imaging unveils malalignment in the axial and appendicular skeleton. Patients with truncal rotation detected on the Adams forward bend test should undergo a scoliosis series to evaluate overall alignment. Similarly, other lax joints or long bones that demonstrate abnormalities such as excess varus, valgus, procurvatum, or recurvatum should be imaged to identify bony versus soft tissue abnormalities. When a collagen disorder, such as Marfan syndrome or Loeys–Dietz syndrome, is uncovered, patients need to be counseled about the predisposition to an aortic aneurysm or dissection. For &&
(b)
FIGURE 2. (a) Demonstration of hypermobility in the left wrist. The thumb is apposed easily to the volar forearm without any discomfort to the patient. (b) Demonstration of hyperextension of the left elbow.
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patients with Marfan syndrome, the American Heart Association recommends an echocardiogram at the time of diagnosis. For patients with Loeys–Dietz syndrome, complete aortic and cerebrovascular to pelvis vascular imaging is advised.
GENETIC TESTING In a patient with a clinical examination consistent with a collagen disorder, genetic testing may help confirm the diagnosis and mutation. Some patients may know a family member with a mutation that already has been identified. The major collagen disorders are inherited in an autosomal dominant fashion. Marfan syndrome is associated with a fibrillin 1 mutation, and Loeys–Dietz is associated with a mutation in transforming growth factor-beta receptor. Genetic testing may not always be essential for diagnosis. Ritelli et al. [18 ] demonstrated that the diagnosis of classic Ehlers–Danlos syndrome could be made on patients with three major criteria of the Villefranche nosology as well as the existence of affected relatives. For the small number of patients who had several minor signs, with or without a family history, genetic testing identified the COL5A1 or COL5A2 gene to confirm diagnosis of Ehlers–Danlos syndrome. These genetic tests involved DNA sequencing that had been purified from whole blood samples. In patients with multiple atraumatic or low energy mechanism fractures, once child abuse has been ruled out, genetic testing is used to identify the COL1A1 and COL1A2 genes to substantiate the diagnosis of osteogenesis imperfecta.
FIGURE 3. Depiction of pes planus (flat feet), a clinical feature of patients with Marfan syndrome.
&
SPECIFIC DISORDERS WITH HYPERMOBILITY AND INTERVENTIONS Joint dislocation or subluxation can occur in patients with benign generalized ligamentous laxity; therefore, these conditions must be anticipated and treated expediently. Stabilizing procedures, however, are fraught with complications due to the quality of the underlying soft tissue. After dislocation, the first line of treatment consists of a period of immobilization followed by a focused rehabilitation program. For example, a shoulder dislocation in a patient with ligamentous laxity should be managed nonoperatively unless there is a recurrence [19]. Once nonoperative management fails, open or arthroscopic stabilization procedures may be performed. Although joint pain may or may not be present initially, patients may still be affected in the long term. Comparison of knee function in 10-year-olds and adults with generalized hypermobility showed 82
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only the adults had clinically impaired knee function [20]. In children with symptomatic joint laxity, Engelbert et al. [21] demonstrated decreased maximal exercise capacity. Marfan syndrome is associated with several specific musculoskeletal abnormalities, including scoliosis, arachnodactyly, protrusio acetabuli, pes planovalgus, pectus excavatum, and ligamentous laxity, which can lead to recurrent dislocations (Fig. 3). In childhood and adolescence, scoliosis often is detected prior to diagnosis of Marfan syndrome and requires operative management. Bracing has not been shown to be as effective as it is in adolescent idiopathic scoliosis (AIS); significant and progressive curves are indications for instrumentation and fusion [22]. Marfan patients require more fusion levels and more re-operations, and are at greater risk of complications compared with AIS patients [23]. Musculoskeletal complaints in patients with Ehlers–Danlos vary in presentation, but there is significant joint laxity and scoliosis. Joint laxity is more commonly symptomatic in patients with Ehlers–Danlos syndrome, as is general musculoskeletal pain [24 ]. Although little literature exists on management of spinal fusion in Ehlers–Danlos, there is a very high rate of complications with posterior spinal fusion [25]. Any surgical intervention comes with a high risk of wound complications due to the fragility of skin and poor healing. The collagen disorder most recognized for significant orthopedic issues is osteogenesis imperfecta. Multiple fractures occur over the course of childhood, the number of which vary, based on the specific mutation. As a result of multiple fragility &&
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Orthopedic aspects of collagen disorders LaMont and Doyle
(a)
(b)
FIGURE 5. (a) An anteroposterior view of both knees in a child with Down syndrome. (b) The Merchant view of both knees in a child with Down syndrome.
dislocations; patellofemoral instability is a common issue (Fig. 5a and b). Other disorders that afflict patients with Down syndrome include hallux valgus, pes planus, atlantoaxial subluxation, slipped capital femoral epiphysis, and hip subluxation/dislocation [25]. Patellar and hip instability may affect the ambulatory status of these patients. Surgical stabilization of the patella can improve function in patients with severe disability [26].
CONCLUSION
FIGURE 4. Posteroanterior radiograph of a child with osteogenesis imperfecta and scoliosis.
fractures, long bone bowing may develop over time. Other orthopedic anomalies include scoliosis (Fig. 4), vertebral abnormalities, and basilar invagination. The generalized ligamentous laxity and hypotonia seen in Down syndrome can lead to joint
Ligamentous laxity is common in childhood, but can be present in multiple collagen disorders. It may manifest in different parts of the body at different times throughout childhood and adolescence. Patients may present to their physicians with or without symptoms of hypermobility or they may present with other entities such as scoliosis or fracture. It is important that the evaluation includes a thorough musculoskeletal examination. The finding of joint hypermobility may tip the examiner to the detection of a collagen disorder such as Marfan syndrome, Ehlers–Danlos disease, or osteogenesis imperfecta: disorders that affect vital organ systems that may require ancillary testing to optimize the patient’s long-term health and well being. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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Orthopedics
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Caird MS, Wills BP, Dormans JP. Down syndrome in children: the role of the orthopaedic surgeon. J Am Acad Orthop Surg 2006; 14:610–619. 2. Finsterbush A, Pogrund H. The hypermobility syndrome. Musculoskeletal complaints in 100 consecutive cases of generalized joint hypermobility. Clin Orthop Relat Res 1982; 168:124–127. 3. Kirk JA, Ansell BM, Bywaters EG. The hypermobility syndrome. Musculoskeletal complaints associated with generalized joint hypermobility. Ann Rheum Dis 1967; 26:419–425. 4. Grahame R. Pain, distress and joint hyperlaxity. Joint Bone Spine 2000; 67:157–163. 5. Al-Rawi ZS, Al-Dubaikel KY, Al-Sikafi H. Joint mobility in people with hiatus hernia. Rheumatology (Oxford) 2004; 43:574–576. 6. Holbrook KA, Byers PH. Skin is a window on heritable disorders of connective tissue. Am J Med Genet 1989; 34:105–121. 7. Remvig L, Duhn PH, Ullman S, et al. Skin extensibility and consistency in patients with Ehlers-Danlos syndrome and benign joint hypermobility syndrome. Scand J Rheumatol 2009; 38:227–230. 8. Wolf JM, Cameron KL, Owens BD. Impact of joint laxity and hypermobility on the musculoskeletal system. J Am Acad Orthop Surg 2011; 19:463–471. 9. Makizumi Y, Kashio A, Sakamoto T, et al. Cochlear implantation in a patient with osteogenesis imperfecta. Auris Nasus Larynx 2013; 40:510–513. 10. Callewaert B, Malfait F, Loeys B, De Paepe A. Ehlers-Danlos syndromes and Marfan syndrome. Best Pract Res Clin Rheumatol 2008; 22:165–189. 11. Nataf P, Lansac E. Dilation of the thoracic aorta: medical and surgical management. Heart 2006; 92:1345–1352. 12. Erkula G, Kiter AE, Kilic BA, et al. The relation of joint laxity and trunk rotation. J Pediatr Orthop B 2005; 14:38–41. 13. Giordano P, Del Vecchio GC, Scaraggi R, et al. Hemarthrosis due to a rare cause of hemorrhagic diathesis: Ehlers-Danlos syndrome. Pediatr Hematol Oncol 2008; 25:205–209. 14. Carter C, Wilkinson J. Persistent joint laxity and congenital dislocation of the hip. J Bone Joint Surg Br 1964; 46:40–45.
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15. Beighton P, Horan F. Orthopaedic aspects of the Ehlers-Danlos syndrome. J Bone Joint Surg Br 1969; 51:444–453. 16. Boyle KL, Witt P, Riegger-Krugh C. Intrarater and interrater reliability of the Beighton and Horan Joint Mobility Index. J Athl Train 2003; 38:281–285. 17. Jackson SC, Odiaman L, Card RT, et al. Suspected collagen disorders in the && bleeding disorder clinic: a case-control study. Haemophilia 2013; 19:246– 250. This article stresses the importance of recognizing clinical hypermobility to uncover a potential cause/contributor to a bleeding disorder. 18. Ritelli M, Dordoni C, Venturini M, et al. Clinical and molecular characterization & of 40 patients with classic Ehlers-Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations. Orphanet J Rare Dis 2013; 8:1172–1178. This article identifies two specific genes that are found in patients with classic Ehlers–Danlos syndrome. 19. Schenk TJ, Brems JJ. Multidirectional instability of the shoulder: pathophysiology, diagnosis, and management. J Am Acad Orthop Surg 1998; 6:65– 72. 20. Juul-Kristensen B, Hansen H, Simonsen EB, et al. Knee function in 10-year-old children and adults with generalised joint hypermobility. Knee 2012; 19:773– 778. 21. Engelbert RH, van Bergen M, Henneken T, et al. Exercise tolerance in children and adolescents with musculoskeletal pain in joint hypermobility and joint hypomobility syndrome. Pediatrics 2006; 118:e690–e696. 22. Robins PR, Moe JH, Winter RB. Scoliosis in Marfan’s syndrome. Its characteristics and results of treatment in thirty-five patients. J Bone Joint Surg Am 1975; 57:358–368. 23. Gjolaj JP, Sponseller PD, Shah SA, et al. Spinal deformity correction in Marfan syndrome versus adolescent idiopathic scoliosis: learning from the differences. Spine (Phila Pa 1976) 2012; 37:1558–1565. 24. Shirley ED, Demaio M, Bodurtha J. Ehlers-Danlos syndrome in orthopaedics: && etiology, diagnosis, and treatment implications. Sports Health 2012; 4:394– 403. This article provides mainstream awareness of Ehlers–Danlos syndrome for multidisciplinary healthcare specialties. 25. Diamond LS, Lynne D, Sigman B. Orthopedic disorders in patients with Down’s syndrome. Orthop Clin North Am 1981; 12:57–71. 26. Bettuzzi C, Lampasi M, Magnani M, Donzelli O. Surgical treatment of patellar dislocation in children with Down syndrome: a 3- to 11-year follow-up study. Knee Surg Sports Traumatol Arthrosc 2009; 17:334–340.
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