Heterotopic ossi \201 cation Heterotopic ossi \201 cation (HO) is the abnormal formation of true bone within extraskeletal soft tissues and is the more rational term for a group of conditions previously referred to as myositis ossi \201 cans. See Figure 14.14. \200 HO can be, though is not always, triggered by trauma, can occur after panniculitis or assoc iated with certain pastimes (e.g. Rider \200\231s bones \200\223 HO in hip adductors; Shoo ter \200\231s bones \200\223 HO in the deltoid muscle). There is a strong association betw een spinal cord injury and HO (twice as likely in male patients). HO is rare in children <1 0 years, occurs in all races and at any site; often starts as a painful mass and may requir e differentiation from malignancy. Although HO can, in theory, complicate trauma and neu- r al injury in many, there may be a propensity in rare cases to develop spontaneous lesions ( myositis ossi \201 - cans nontraumatica). HO originates from osteoprogenitor cells lying i n soft- tissue \200\223 possible muscle septae or fascia. The process, which starts with s pindle cell proliferation takes about 6 weeks to develop established bone. Lesions evolve m edially, so although they start in soft-tissue, they even- tually lesions merge with the sk eleton. The condition is discriminated from the very rare AD \201 brodysplasia ossi- \201 cans progressiva (FOP) where bone is relentlessly and extensively formed in soft-tissu es through adolescence into adulthood. In FOP families there is linkage to 2q23 \200\223 24 , where there is a mutation in the activin A receptor type 1A (ACVR1) gene - a BMP type 1 r eceptor. ACVR1 is a critical regulator of BMP signaling in endochondral bone formation duri ng embryogenesis. Figure 14.14 Established heterotopic ossi \201 cation in upper arm: contiguous with diaphy sis (two lesions) and one just above lateral epicondyle (patient with myositis ossi \201 c ans nontraumatic. Resources Osteopetrosis web site: a self-funded voluntary \200\230sign post \200\231 site. Available at: http://www.osteopetrosis.org/. Also see UK based organization: http://www.os teopetrosis.co.uk See comprehensive open access article by Beighton PH, Hamersma H, Brunkow ME. Available at: www.ncbi.nlm. nih.gov/books/bv.fcgi?rid=gene.chapter.sost MHE coalition: www.familyvillage.wisc.edu/ lib_mhe.htm \200\223 a site for patients and their families. Also, a useful site listing current research and medical/scienti \201 c information. Avail able at: www.mheresearchfoundation. org/homepage.html. See also the excellent, comprehensiv e article by Schmale GA. Available at: www.ncbi.nlm.nih. gov/books/bv.fcgi?rid=gene.chapter .ext. Patient resources The Melorheostosis Society: www.melorheostosis.com/ Melorheostosis UK: ww w.melo.eu.com MISCELLANEOUS BONE DISEASES 2 436 References Azouz EM, Greenspan A. Melorheostosis. Orphanet encyclopedia 2005. Available at: www.orpha.net/data/patho/GB/ uk-Melorheostosis.pdf. Wallace SE, Wilcox WR. Camurati \200\223Engelmann Disease. Available at: http://www.genetests.org/pro \201 les/ced/index.html Whyte MP. Sclerosing bone disorders. In: Favus MJ (ed.) Primer on the metabolic bone diseas es and disorders of mineral metabolism, 6th edn. Washington DC: ASBMR, 2006:398 \200\223414 . Shore EM, Xu M, Feldman GJ, et al. A recurrent mutation in the BMP type I receptor ACVR1 ca uses inherited and sporadic \201 bro- dysplasia ossi \201 cans progressiva. Nat Genet 20 06; 38: 525 \200\2237. 437 Chapter 15 Hereditary diseases of connective tissue Marfan syndrome 438 Ehlers \200\223Danlos syndrome 440 Joint hypermobility syndrome 442 MARFAN SYNDROME 438 Marfan syndrome TGF-B has been demonstrated in the cardiac valve disease of \201 brillin de \201 cient m ice. De \201 nition An inherited disorder of connective tissue initially described by Marfan in 1896 and recently shown to be due to defects in the \201 brillin gene (FBN-1). The \201 brillin-2 gene on chromosome 5 has 80% homol- ogy with \201 brillin-1 and muta tions are associated with cases of congenital contractural arachnodactyly. Classi \201 cation criteria Criteria for the diagnosis of Marfan syndrome have been propos ed \200\223 the Ghent nosology (De Paepe et al., 1996). Epidemiology Clinical features Key features on history \200 Presentation is often with tall stature (>95th centile), in combination with disproportiona tely long limbs and arachnodactylyl. There may be a family history of tall stature, arachno dac- tylyl, severe myopia, and sudden cardiac death. Myopia is common and may be severe due to increased axial length of the ocular globe. Table 15.1 The Ghent nosology for Marfan syndrome Skeletal system ( \211 4 required to be present) \200 Pectus carinatum. Pectus excavatum. Key features on examination Skeletal \200 Span to height ratio >1.05. Wrist and thumb signs. Typical skeletal features include scoliosis, pectus excava- tum or carinatum, high arched p alate, ligamentous laxity, and \202 at feet. Bone mineral density on DXA is reduced. Scoliosis > 20 . Elbow extension <170 . Pes planus. Protrusio acetabulae. Ocular Slit lamp examination is required to detect the typical upward subluxation of the le ns, which is present in about 60% of cases. This occurs bilaterally. Dura Lumbosacral ectasia demonstrated on CT or MRI. Ocular Cardiovascular The most common cardiovascular features are mitral valve prolapse and dilata tion of the ascending aorta, with devel- opment of mitral or aortic regurgitation. Dilatati on of the aorta starts at the sinus of valsalva and is symmetrical. Aortic rupture or disse ction may occur. General investigations \200 Ectopia lentis. Cardiovascular \200 Dilatation of ascending aorta involving at least the sinuses of valsalva. Dissection of ascending aorta. Pedigree \200 Routine hematological, biochemical and serological tests are all normal. Echocardiographic assessme437nt of aortic root and arch dilatation is necessary. Mutation screening of all 65 exons of the FBN-1 gene is available using genomic DNA extracted from leucocytes and can d etect the majority of mutations. First degree relative with Marfan syndrome. Presence of FBN-1 mutation. For index case: diagnosis requires major criteria in at least two different organ systems and involvement of a third organ system. For relative of an index case: major criterion in one system and involvement of a second or gan system. \200 The incidence of Marfan syndrome is 1 in 20 000 and it is one of the more common inherited disorders of con- nective tissues. There is no known gender, racial, or geographical in \202 uence on incidence. Inheritance is autosomal dominant. 25% of cases arise as a result of new mutations. Imaging Plain radiographs of limbs, skull, spine, and chest. Differential diagnosis The Mar fanoid habitus is no longer considered patho- gnomic for Marfan syndrome and can be found i n a number of other conditions (see Tables 15.2, 3). \200 \200 Etiology Marfan syndrome is due to a mutation in the \201 brillin-1 gene on chromosome 15 q21.1. Fibrillin-1 has a high degree of homology with the latent TGF-B binding proteins. Th e TGF-B family of cytokines are secreted as large latent complexes which are sequestered in the extracellular ma- trix, which may then play a role in regulation of TGF-B activity. Mu tations in the gene coding for the type II TGF-B receptor replicate the classical Marfan ph enotype. The current notion is that the features of Marfan syndrome are acquired postnatall y as a result of failed regulation of TGF-B by the extracellular matrix. Increased activity of Homocystinuria has similar musculoskeletal and ocular manifestations, but the lens dislocat es downwards. Homocystine may be detected in the urine. Congenital contractural arachnodact yly has similar skeletal features, but there are no ocular or cardiovascular abnormalities. The contractures improve with age. Marfanoid hypermobility syndrome has no ocular or cardi ovascular abnormalities, but the skin and joints are more hyperextensible than in Marfan sy ndrome. In EDS types I, II, and III valvular defects may be present, but joint laxity is mo re severe and skeletal proportions are normal. CHAPTER 15 Hereditary diseases of connective tissue 439 should be performed electively when the aortic root diameter reaches about 50 mm. Pregnancy is high risk in patients with moderate aortic dilatation. Orthopedic surgery to correct or prevent further progression of scoliosis should be considered when the angle >45 . Table 15.2 Features of the Marfanoid habitus Arachnodactyly. Span to height \211 1.05. Crown/pubis:pubis/ \202 oor ratio <0.89. Hand:height ratio >11%. Foot:height ratio >15%. Follow-up \200 Scoliosis. Patients should be managed in centers with appropriate cardiological, ophthalmology, and or thopedic expertise. Annual echocardiography and electrocardiography should be performed to monitor aortic dilatation and consideration of surgery should begin at 45 mm with more freq uent echocardiography. Annual ophthalmology assessment, 6-monthly orthopedic assessment of these at risk of sco- liosis and intervention when the scoliosis exceeds 45 . Pectus carinatum. Pectus excavatum. Table 15.3 Conditions in which the Marfanoid habitus is found \200 Congenital contractural arachnodactyly. Familial thoracic aortic aneurysm (Loeys-Dietz). Resources Patient organizations National Marfan Foundation. www.marfan.org Familial aortic dissection. Familial ectopia lentis. Familial Marfan-like habitus. Others OMIM 154700: www.ncbi.nlm.nih.gov/omim/ Mass phenotype. Familial mitral valve prolapse. ICD-10 coding Q87.4 Stickler syndrome. Marfan syndrome Shprintzen \200\223Goldberg syndrome. References Bird HA. Lessons from Marfan \200\231s syndrome. Rheumatology 2007; Homocystinuria. 46: 902 \200\2233. EDS, kyphoscoliotic Type (EDS type VI). DePaepe A, Devereux RB, Dietz HC, et al. Revised criteria for the Benign joint hypermobility syndrome. Marfan syndrome. Am J Med Genet 1996; 62: 417 \200\22326. Mizuguchi T, Collod-Beroud G, Akiyama T, et al. Heterozygous TGFBR2 mutations in the Marfan syndrome. Nat Genet 2005; 37: 275 \200\22381. Prognosis \200 Life expectancy was previously reduced by 30 \200\22340% due to sudden cardiac death, but p rograms of regular echocardiography to assess aortic root diameter has improved life expect ancy to around 50 \200\22370 years. Post-cardiac surgery prognosis is 88% at 5 years. Ng CM, Cheng A, Myers LA, et al. TGF-B dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J Clin Invest 2004; 114: 1586 \200\22392. Pereiria L, DAlession M, Ramirez F, et al. Genomic organization of eh sequence coding for \201 brillin, the defective gene product in Marfan syndrome. Hum Mol Genet 1999; 10: 99 \200\223117. Patient advice \200 Sakai LY,Keene DR, Engvall E. Fibrillin, a new 350-kD glycoprotein, is a component of extra cellular micro \201 brils. J Cell Biol 1986; 103: 2499 \200\223509. Inherited condition of connective tissue with autosomal dominant pattern of inheritance. Mu ltisystem involving joints, eyes, and heart. Risk of aortic dissection and aortic regurgita tion. Neccessity for regular echocardiography and electrocar- diography to monitor aortic r oot size. Possible need for cardiac surgery. Risk of pregnancy. Cardiac status. \200 See also Joint hypermobility syndrome Ehlers \200\223Danlos syndrome Osteogenesis imperfect a p. 442 p. 440 p. 398 Treatment \200 Tight control of blood pressure reduces the risk of aortic dilatation. Surgical repair of b oth the aortic arch and aortic root EHLERS \200\223DANLOS SYNDROME 440 Ehlers \200\223Danlos syndrome De \201 nition The Ehlers \200\223Danlos Syndrome (EDS) is a group of inherited defects in collagen types I, III, and V. They are clinically het- erogeneous, but characterized by sk in fragility, ligamentous laxity, spinal deformity, vascular fragility, and rarely retinal detachment Classi \201 cation criteria The Villefranche classi \201 cation scheme recogni zes subtypes based on clinical features, and underlying biochemical and genetic defect (Tab le 15.4). Clinical features Key features on history Articular/periarticular Joint laxity: this may be pronounced. When presenting in adult life, there is often a history joint laxity at school , and being relatively good at gymnastics or acrobatics. History of recurrent joint disloca tions. Cutaneous \200 \200 \200 History of soft, thin, hyperextensible skin. Scar healing. Bruising. Table 15.4 Classi \201 cation of Ehlers-Danlos syndrome Familial history Joint laxity, poor wound healing or bruising. Name Type OMIM Inheritance Key features on examination Skeletal Joint hypermobility as assessed using the Beighton sca le. Classical gravis I 130 000 AD Classical mitis II 130 010 AD Hypermobility III 130 020 AD Cutaneous \200 \200 Vascular IV 130 050 AD Hyperextensible skin. Poor wound healing with thin atrophic scars. X-linked V 305 200 XL Kyphoscoliosis VI 225 400 AR Key features of the types of EDS \200 Arthrochalasia VIIA 130 060 AD Type I EDS (previously the gravis form) is characterized by velvety and hyperextensible ski n, marked joint laxity, thin atrophic scars and easy bruising. Type II EDS (previously miti s form) is a less severe form of Type I, but early osteoarthritis may develop. Type III EDS is associated with recurrent joint dislocation and osteoarthritis. Scars heal normally. Th is type overlaps with the joint hyper mobility syndrome. Type IV EDS is the severest form a nd has a poor prognosis. Complications include arterial rupture, colon or uterine rupture. The facies are characteristic with large eyes, thin nose and lips. There is marked bruising , the skin appears aged and there is joint hyperextensibility. Type V has similar features to Type II, but has X-linked inheritance. Type VI is characterized by scoliosis, ocular fra gility, soft extensible skin and hypermobility. Type VII presents with recurrent joint disl ocation, joint laxity, short stature, and skin bruising. Type VIII is characterized by gene ralized periodontitis, with soft extensible skin, easy bruising, and hypermobility. Type X presents with mild joint hypermobility, easy bruising, and abnormal platelet aggregation. VIIB 130 060 AD Dermatospraxis VIIC 225 410 AR Periodontitis VIII 130 080 AD Fibronectin de \201 cient X 225 310 AR. OMIM = On-line Mendelian inheritance in man (www.ncbi.nlm.nih.gov/ omim/). AD = autosomal d ominant; AR=autosomal recessive. XL = X-linked. Epidemiology The incidence varies depending on type, the most severe vascular type IV EDS o ccurs in less than 1:100 000 births. The classic EDS type I is estimated to occur 1:20 000 people. Etiology \200 Type III collagen is a homotrimer encoded on chromo- some 2q31. The constituent A1 (III) ch ains share with type I collagen the same arrangement of exons and Gly-X-Y repeats. The clas sic type of EDS (subtypes I and II) are usually caused by mutations in genes encoding colla gen type V (COL5A1 and COL5A2). These mutations interfere with \201 brillogenesis and res ult in disrupted \201 brils, which can be seen on electron microscopy. This only accounts for 30% of cases of classical EDS. Type IV EDS results from defects in structure or synthe sis of type III collagen. Type VI is due to defects in lysyl hydroxylase. Type VII EDS has defects of the processing of N-terminal peptide of type I collagen, which results in abnorm al \201 bril formation. The mutations cause skipping of exon 6 which contains the N-prote inase cleavage site or the N-terminal proteinase itself. Type X is due to defects in \201 bronectin. Tenascin-X is an extracellular matrix protein, mutations in gene for which resu lt in a clinical phenotype similar to classic EDS. Diagnosis Biochemical studies of collagens types I, III, V using \201 bro- blasts are req uired to establish the diagnosis. Molecular analysis of COL1A1, COL1A2, COL3A1, COL5A1, COL 5A2, genes are required to con \201 rm the diagnosis. \200 Differential diagnosis \200 The features of EDS overlap with other collagen disor- ders Marfan syndrome, osteogenesis i mperfecta, and benign joint hypermobility syndrome. The \201 rst two are rare, but the th ird is common. Establishment of the precise type of EDS may be dif \201 cult solely on cli nical grounds, but it is important to exclude type IV because of its serious manifestations . \200 CHAPTER 15 Hereditary diseases of connective tissue 441 \201 broblast collagen synthesis, thereby further weakening tendons and other collagen co ntaining tissues. Surgical sutures may tear through weak skin leading to dehiscence. Conven tional analgesics and NSAIDs may be helpful in the short term, but less so in the long term . Self-help is important and patients need to recognize that the precise cause of widesprea d pain may be dif \201 cult to establish. Physiotherapy with joint stabilization exercise can reduce pain and reduce excessive movement. Retinal detachment and premature osteoarthritis should lead to consideration of Stickler \200\231s syndrome as an abnor- mality of collagen I. Prognosis \200 \200 This depends on type. Type IV has the poorest prognosis because of arterial, bowel, or uter ine rupture. The milder forms are associ- ated with a normal life expectancy. Patient advice \200 Resources Patient organizations Ehlers-Danlos National Foundation (www.ednf.org/) EDS is due to an inherited defect of collagen. Most types are inherited in a autosomal domi nant manner, with 50% of children being affected. Sports that hyperextend or otherwise stre ss joints should be avoided. Patients especially those with type IV need to be educated to inform all physicians of their condition. Skin is often fragile and care should be given to surgical procedures. Patients are often relatively resistant to local anesthetics for reas ons, which are unclear; this leads to anxiety on the part of the patient and a label of sen sitive \200\231 patient being given. Others OMIM www.ncbi.nlm.nih.gov/sites/entrez, see Table 15.1. ICD-10 coding Q79.6 Ehlers \200\223Danlos syndrome References Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syn dromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and E hlers-Danlos Support Group (UK). Am J Med Genet 1998; 77: 31 \200\2237. Treatment There are no randomized controlled trials of treatment in EDS. \200 Malfait F, Hakim A, de Paepe A, Grahame R. The genetic basis of the joint hypermobility syn dromes. Rheumatology 2006; 45: 502 \200\2237. See also Marfan syndrome Joint hypermobility syndrome Osteogenesis imperfect Treatment of presenting soft tissue or articular lesions using conventional approaches, suc h as rest, ice, elevation, physiotherapy, local steroid injections, and surgery. Corticoste roid injection with a depot preparation should be avoided where possible because they inhib it p. 438 p. 442 p. 444 JOINT HYPERMOBILITY SYNDROME 442 Joint hypermobility syndrome De \201 nition Joint hypermobility syndrome (JHS) is the occurrence of musculoskeletal sym ptoms in hypermobile subjects in the absence of demonstrable systemic rheumatological disea se. Epidemiology \200 Generalized ligamentous laxity occurs in up to 10% of the general population. The majority of people are asymptomatic. Hypermobility generally decreases throughout life. Women are mo re \202 exible than men. There is a greater range of joint mobility in Asians than sub-Sa haran Africans who are also more mobile than white Caucasians. There is an occupational ass ociation with ballet dancers, musicians, gymnasts, and acrobats due to the require- ment fo r great \202 exibility. \200 \200 \200 Classi \201 cation criteria Joint hypermobility is assessed using the nine point Beigh- to n hypermobility scale (Table 15.5). However, this ignores other joints that may be hypermob ile. Table 15.5 Nine-point Beighton scoring system for joint hypermobility Scoring 1 point each side \200 Etiology The genetic basis of JHS is unknown. Genes encoding col- lagens and collagen-modif ying enzymes are considered to be good candidate genes. Mutations in the non-collagenous te nascin-X gene have been found in small number of patients with JHS. Complete absence of ten ascin-X results in a phenotype reminiscent of the classic type of EDS. The heterozygotes ha ve reduced levels of tenascin-X and about half have generalized joint hypermobility. This s uggest that haploinsuf \201 ciency of tenascin-X may account for a small proportion (5 \200\22310%) of patients with JHS. Passive dorsi \202 exion of the \201 fth MCP joint to 90 . Apposition of the thumb to t he \202 exor aspect of the forearm. Hyperextension of the elbow beyond 0 . Hyperextensio n of the knee beyond 0 . Scoring 1 point \200 Forward \202 exion of the trunk placing hands \202 at on the \202 oor with knees exte nded Maximum score = 9 Mutations in genes encoding COL1A1 and COL1A2 also have a role in the development of hyperm obility, although typically they are responsible for osteogenesis imperfecta. Adapted from Beighton et al. (1973). Criteria for the diagnosis of the hypermobility syndro me have been proposed. Clinical features Key features in history Articular/periarticular \200 Table 15.6 1998 Brighton revised diagnostic criteria for the benign joint hypermobility syn drome Presentation is with traction injuries at enthesis, synovitis, tenosynovitis, bursitis, cho ndromalacia patellae, rotator cuff lesions. Joint instability with recurrent dislocation or subluxation especially shoulder, patella, MCP, and TMJ joints. Chronic low grade inflammat ory synovitis with a traumatic background. Major criteria \200 A Beighton score >4/9 (either currently or historical). Arthralgia for > 3 months in 4 or m ore joint. Minor criteria \200 A Beighton score of 1, 2, or 3/9 (0, 1, 2, 3, if aged >50 years). Arthralgia (>3 months) in 1 \200\223 3 joints or back pain (>3 months), spondylosis, spondylolysis/spondyolisthesis. Dislocation/subluxation in more than one joint or in one joint on more than one occasion. Soft tissue rheumatism - \211 3 lesions (e.g. epicondylitis, tenosynovitis, bursitis). Mar fanoid habitus: (tall, slim, span > height, upper segment: lower segment <0.89 and arachnod actyly). Abnormal skin: striae, hyperextensibility, thin skin, papyraceous scarring. Eye si gns: drooping eyelids or myopia or antimongoloid slant. Varicose veins, hernia, uterine, or rectal prolapse. Cutaneous \200 \200 History of soft, thin, hyperextensible skin. Striae may develop at puberty, and are signi \201 cant if not the result of pregnancy or obesity. Skeletal A history of stress fractures of metatarsals, \201 bula, pars in- terarticularis in the lumbar spine and vertebral bodies is common Key features on examination Skeletal \200 Joint hypermobility that should be assessed using the Beighton hypermobility scale. Other j oints may be hypermobile, which are not assessed in the scale. Joint instability may result in medial arch collapse in the foot. Absence of evidence of progressive in \202 ammatory arthritis. Myofascial trigger spots may be present. Joint hypermobility syndrome is diagnosed in the presence of: - 2 major criteria OR - 1 maj or and 2 minor criteria OR - 4 minor criteria Two minor criteria will suf \201 ce in the p resence of an unequivocally affected \201 rst degree relative. JHS is excluded by the pre sence of Marfan \200\231s syndrome or EDS (other than type III \200\223 hypermobility type ). NB Major criteria 1 and minor 1 are mutually exclusive as are major 2 and minor 2. Adapt ed from Grahame et al. (2000). \200 Cutaneous \200 \200 Soft, thin, hyperextensible skin. Striae. CHAPTER 15 Hereditary diseases of connective tissue 443 Treatment \200 \200 Neurophysiological \200 \200 \200 Impairment of joint proprioception. Relative lack of ef \201 cacy of topical local anesthe tics. Dysautonomia. Devise and individual treatment plan. Treat soft tissue conditions in conventional style wi th rest, physiotherapy, local steroid injections, and surgery as needed. Depot injection sh ould be avoided as these preparations can further weaken soft tissues. Care should be taken with surgery, especially in those with fragile skin because of the risks of wound dehiscen ce. Physiotherapy employing a variety of techniques \200\223 passive mobilization, exercis es, traction, joint stabilization, and proprioceptive enhancement. Analgesia using NSAIDs o r analgesics may useful in the short term. General investigations \200 The acute phase response (ESR and CRP), and autoanti- body pro \201 le are both normal or negative unless there is coincidental disease. DXA scanning reveals generalized osteopaenia . Differential diagnosis \200 JHS must be distinguished from more severe disorders of connective tissue such as Marfan sy ndrome, Ehlers Danlos syndrome type IV and osteogenesis imperfecta. There are a number of o verlapping clinical features. EDS IV has a readily recognizable clinical phenotype, but the other types of EDS may be dif \201 cult to distinguish. The presence of skin hyperextensi bility and bruising is suggestive of classic EDS (Types I and II); a history of congenital hip dislocation is suggestive of the arthrocha- lasis subtype of EDS. A history of bone fra gility, short stature, and blue sclerae is suggestive of osteogenesis imperfecta. The prese nce of the Marfanoid habitus together with cardiovascular or ocular involvement suggests Ma rfan syndrome. Resources Patient organizations Joint Hypermobility syndrome association: www.hypermobility .org ICD-10 coding M35.7 Hypermobility syndrome References Beighton PH, Solomon L, Soskolne C. Articular mobility in African populations. Ann Rheum Dis 1973; 32: 413 \200\22317. Grahame R, Bird HA, Child A, et al. British Society for Rheumatology Special Interest Group on Heritable Disorders of Connective Tissue Disease. The revised (Brighton 1998) criteria for the diagnosis of BJHS. J Rheumatol 2000; 27: 1777 \200\2239. Prognosis JHS is benign as life-threatening complications are not a feature. Kirk JH, Ansell B, Bywaters EGH. The hypermobility syndrome. Ann Rheum Dis 1967; 26: 425. Pathology Skin biopsies from hypermobile subjects show abnormali- ties of in the structure of collagen bundles. Malfait F, Hakim AJ, De Paepe A, Grahame R. The genetic basis of the joint hypermobility sy ndromes. Rheumatology 2006; 45: 502 \200\2237. See also Marfan syndrome Ehlers \200\223Danlos syndrome Osteogenesis imperfect Patient advice \200 p. 438 p. 440 p. 428 Reassure patients that they do not have a more serious rheumatic disease (e.g. in \202 amm atory arthritis) and that they do have a recognized condition. Advice about appropriate lev els of exercise. This page intentionally left blank 445 Chapter 16 Musculoskeletal infection Practical approach to a hot swollen joint 446 Septic arthritis 448 Gonococcal arthritis 452 Osteomyelitis 454 Soft tissue infection 458 Rheumatic fever 462 Brucellosis 464 Lyme disea se 466 Viral arthritis 468 Mycobacterial infection 472 Fungal infection 476 PRACTICAL APPROACH TO A HOT SWOLLEN JOINT 446 Practical approach to a hot swollen joint De \201 nition A patient presenting with a hot swollen joint requires emergency assessment and treatment, as the major cause of avoidable morbidity is untreated sepsis. Polarizing light microscopy should always be performed to look for crystals. Other investigations Blood cultures These should always be taken in cases of suspected seps is. Epidemiology Risk Factors for septic joint \200 \200 \200 \200 \200 \200 \200 \200 Full blood count An FBC with differential white count should always be per- formed. The abs ence of raised neutrophil count does not exclude sepsis, especially if previous antibiotics have been given. Pre-existing joint disease. Prosthetic joints. Low socioeconomic status. IV drug abuse. Alc ohol abuse. Diabetes mellitus. Recent intra-articular steroid injections. Ulcerated skin. Acute phase response Absence of a raised ESR or CRP does not exclude sepsis. The CRP and ES R may be a guide to response to treatment. Biochemistry \200 Serum uric acid is of no diagnostic value in the diagnosis of acute gout or sepsis. Renal a nd liver function should be measured, as evidence of renal or hepatic dysfunction is indica tive of a worse prognosis. Clinical features Key features on history \200 A septic joint usual presents with <2 weeks duration of symptoms. Any joint may be affected ; hip and knee are probably the most common. In up to 22% of cases more than one joint may be affected. The presence or absence of fever is not a reliable indica- tor of infection. R isk factors for sepsis. Previous history of gout or pseudogout. History of trauma. Clotting INR if the patient is anticoagulated, although anticoagula- tion is not a contrain dication for joint aspiration. If INR is elevated above 3.5, then consideration should be g iven to correcting the INR before joint aspiration. \200 \200 Imaging Plain radiographs Plain X-rays of the infected are of no value in the diagnosis of acute infection. They may, however, show chondrocalcino- sis suggestive of pyrophosphate ar thropathy. They are useful as a baseline against which future \201 lms can be evaluated. Key features on examination \200 The joint is hot, swollen, and tender with a reduced range of movement. Overlying erythema without a joint effusion is suggestive of cellulitis. Evidence of swelling in either the su pra- or infra patellar region is suggestive of bursitis. Look for portals of infection. A g outy joint is exquisitely tender and red. A tophus may be present overlying the joint. Toph i may be present elsewhere, e.g. ears, elbows, toes, and \201 ngers. Bone scintigraphy This will show an infected joint as a hot joint, but is unable to disting uish this from other in \202 ammatory process. \200 \200 MRI This is most useful in late untreated cases where there is a possibility of underlying bone damage or osteomyelitis. Treatment Antibiotic treatment for joint sepsis This should be in accordance with local gui delines follow- ing advice from a local microbiologist. There is little high quality eviden ce as to the choice and length of treatment. Treatment should be initiated empirically and then modi- \201 ed when results are available. Differential diagnosis The hot swollen joint must always be considered septic in the absenc e of a de \201 nite alternative diagnosis. \200 \200 \200 \200 \200 \200 Sepsis. In \202 ammatory arthritis. Crystal arthritis (due to both gout and CPPDD). Haemar throsis. Trauma. Bursitis/cellulitis. Likely organisms are Staph. aureus or streptococci; therefore, initial antibiotic choice sh ould re \202 ect this, espe- cially if there are no risk factors for atypical organisms. In the elderly or immunocompromised patient, Gram- negative organisms are more likely. MRSA should be considered in high risk patients. Conventionally, IV antibiotics are given f or 2 weeks and General investigations Synovial \202 uid examination Synovial \202 uid should be aspira ted, sent for Gram stain and cultured prior to starting antibiotics. Anticoagulation is not a contraindication to joint aspiration. then orally for 4 weeks. Joint drainage Pus should be removed from an infected joint either by needle aspiration or arthroscopically. Repeated joint lavage may be required. A prosthetic joint with suspected infection should al- ways be referred to an orthopedic surgeon. CHAPTER 16 Musculoskeletal infection 447 References Jordan KM, Cameron JS, Snaith M, Zhang W, Doherty M, Seckl J, Hingorani A, Jaque s R, Nuki G on behalf of the British Society for Rheumatology and British Health Profession als in Rheumatology Standards, Guidelines and Audit Working Group (SGAWG). British Society for Rheumatology and British Health Professionals in Rheumatology Guideline for the Managem ent of Gout. Rheumatology, 2007; 46: 1372 \200\2234. Other conditions Crystal arthritis \200 Aspirate joint and consider injection of intra-articular corticosteroids. Use NSAIDs or col chicine as appropriate. In \202 ammatory arthritis Aspirate joint and consider intra-articular corticosteroids. Us e NSAIDs and oral/intramuscular steroids as necessary. Treat underlying in \202 ammatory a rthritis. Mathews C, Field M, Jones A, et al. BSR, BHPR, BOA, RCGP and BSAC guidelines for the manage ment of the hot swollen joint in adults. Rheumatology 2006; 45: 1039 \200\22341. Haemarthrosis Aspirate joint arthroscopically to dryness. Investigate for causes of bleedin g if no history of trauma. See also Synovial \202 uid analysis Bacterial infections Crystal arthritis Resources Guidelines BSR, BHPR, BOA, RCGP and BSAC. Guidelines for the Man- agement of the Hot Swollen Joint in Adults. BSR and BHPR. Guidelines for the Management of Gout. SEPTIC ARTHRITIS 448 Septic arthritis De \201 nition Septic arthritis is a pyogenic infection within a joint, and is a medical e mergency with an associated mortality and morbidity. Prompt diagnosis and appropriate treat ment are imperative to limit cartilage destruction, and to preserve a good functional outco me. Immunode \201 ciency virus (HIV) infection should be con- sidered in intravenous drug abus ers. Pre-existing joint disease: the risk of haematogenous spread is increased due to incre ased blood \202 ow into abnormal joints. Co-morbidities: diabetes, malignancy, chronic or gan fail- ure, e.g. established renal or liver disease, skin disease. Prosthetic joints. Classi \201 cation Classi \201 cation is usually on the basis of the causative organ- ism . Staphylococcus aureus is the commonest organism isolated in septic arthritis. Staphylococcus aureus immunopathology \200 Staph. aureus septic arthritis causes the most severe joint destruction because of the rang e of extracellular toxins and degradative enzymes produced by this par- ticular organism. S ome strains are encapsulated, which aids the virulence of the organism. Staphylococcal adhe sions, expressed on the bacterial surface, enable the organism to adhere to and invade host tissue, and facilitate penetration of joints. Soft tissue infection is much more likely to be caused by staphylo- coccal strains without the ability to express adhesin. Some toxins, named superantigens, are responsible for the release of cytokines, such as tumor necrosis factor and interferon gamma, which result in fever, hypotension, and the features of severe systemic sepsis. The immune response of the host is also central to the severity of presen tation of infection. T cell action, which occurs in the adaptive immune response, aggravate s the damage caused by joint sepsis, and elimination of T cell activity reduces mortality a nd joint damage. B cell deple- tion appears to have no effect on outcome following septic a rthritis. The innate immune system protects against infection by staphylococci, and the sev erity of infection is more marked in hosts in which there are complement de \201 ciencies. Epidemiology Incidence \200 Septic arthritis is relatively rare and is estimated at 6 per 100 000 per year in developed countries, with those under 15 and over 55 representing the highest risk groups. Septic ar thritis is more likely to occur in individuals with pre-existing joint disease, e.g. prosth etic joints or in \202 am- matory arthritis. In patients with rheumatoid arthritis, the in cidence is estimated to be around 70 per 100 000 per annum. Common causative organisms Gram positive septic arthritis \200 Gram positive cocci cause 50 \200\22370% of bacterial septic arthritis with Staph. aureus, S. epidermidis, and strepto- cocci (pyogenes, group B and G) the most commonly isolated org anisms. In contrast, Group C Streptococci, pneumococci, and Gram positive bacilli are more rarely implicated. Gram negative septic arthritis \200 Gram negative infection is most commonly caused by Neisseria species, with N. gonorrheoa an d N. meningitides the most common agents. Haemophilus in \202 uenzae, previously a commonl y impli- cated pathogen in pediatric infection, is less frequently seen since the introduct ion of the HIB (Haemophilus in \202 uenzae type b) vaccine. Gram negative rods cause less than 20% of septic arthri- tis, with E. coli, Proteus mirabilis, Klebsiella, and entero- ba cter the most commonly implicated organisms in this group. Pseudomonas aeruginosa infection is rare and usually found in the elderly. Less than 1% of septic arthritis is caused by an aerobic bacteria. Clinical features High clinical suspicion allows early diagnosis. Key features in the history \200 There is usually sudden onset of severe pain and swell- ing, with functional disability. Pa tients usually, but not always, feel systemically unwell. There may be a history of recent/ continuing distant infection. Rigors occur in patients with fever, but may also be a featur e of crystal arthritis. The age of the patient is relevant as extremities of age make septi c arthritis more likely. There may be a history of pre-existing joint disease. Recent instr umentation, e.g. arthroscopy or joint aspira- tion and injection should be established. Imm unosuppressive therapies, such as glucocorticoid therapy, are important risk factors. Antic oagulation is not a risk factor for infection, but it is important to check clotting prior to joint aspiration in those patients who are anticoagulated. Recent antibiotic treatment s hould be established as iso- lation of the causative organism is more dif \201 cult in thi s setting. Polyarticular infection occurs in up to 22% of cases. \200 Risk factors for septic arthritis \200 \200 \200 \200 Age: the extremes of ages are more susceptible. Gender: similar incidence is seen in men an d women Distal infection: septic arthritis most usually arises from haematogenous spread fr om a distal focus. Instrumentation: sepsis following joint aspiration or arthroscopy is rar e and is estimated at 1 in 15 000 to 1 in 50 000. Immunosuppression: for example, with gluc ocorticoids. Alcoholism. Intravenous drug abuse: the puncture site is the portal of entry f or organisms, and is most commonly contami- nated with Staph. aureus. Underlying concomitan t Human \200 \200 CHAPTER 16 Musculoskeletal infection 449 Useful tips \200 Some patients have no fever and a subacute onset, making diagnosis more challenging. Polyar ticular sepsis is rare and is usually found in patients with predisposing factors. Cellulitis may co-exist, and iatrogenic septic arthritis may occur as a result of inserting a needle through infected skin. In this situation, the diagnosis of septic arthritis may n eed to be made pragmatically on the basis of clinical \201 ndings. If \202 uid cannot b e aspirated from a potentially septic joint, consider asking another experienced doctor, or request- ing an ultrasound-guided aspiration. If a patient is anticoagulated with warfarin , an urgent INR should be checked, and anticoagulation reversal considered if the INR is gr eater than 3.5. An icepack will induce vasoconstriction and may reduce the risk of haemarth rosis. Key features on examination \200 