ROD features on undecalci \201 ed bone biopsy Acknowledgements With thanks to Dr Brian Camilleri, Consultant Nephrolo- gist, for his impo rtant contribution on the text. ROD subtype Histomorphometry/features Osteitis \201 brosa High bone turnover Markedly increased remodeling activity Resources Guidelines For physicians, guidelines on managing renal bone disease and other Adynamic bone disease Low bone turnover Decreased remodeling activity and osteoid surfaces aspects of CKD are at www.renal.org. Osteomalacia Low bone turnover Decreased remodeling activity Increased osteoid surfaces ICD-10 codes N25.0 Renal osteodystrophy N25.8 SHPT of renal origin Mixed Patchy areas of osteitis \201 brosa Increased osteoid References Cunningham J, Sprague S. Osteoporosis in chronic kidney disease. Am J Kidney Dis 2004; 43: 566 \200\22371. Treatment Osteoporosis risk in patients with CKD 1 or 2 and early CKD 3 should be managed r outinely. EBPG Expert Group on Renal Transplantation. European best prac- tice guidelines for renal t ransplantation. Section IV: long-term management of the transplant recipient. Bone disease. Nephrol Dial Transplant 2002; 17(Suppl 4): 43 \200\2238. Management of metabolic abnormalities in CKD3 \200 Elder G. Pathophysiology and recent advances in renal osteodys- When GFR is <60 ml/min iPTH should be measured and if elevated 25-OHD checked (NKF, 2002). 25-OHD de \201 ciency is common and is a risk for severe hyperparathyroidism in CKD. If 25 -OHD is insuf \201 cient (<75 nmol/l), supplemental vitamin-D3 and calcium can be given wi th advice to increase skin exposure to the sun. 25-OHD de \201 ciency (<25 nmol/l) is ofte n associated with osteomalacia bone and muscle lesions, and high dose 25-OHD repletion then may be needed. trophy. J Bone Min Res 2002; 17: 2094 \200\22315 Martin KJ, Ziyad Al-A, Gonzalez EA. Renal osteodystrophy. In: Favus MJ (ed.) Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 6th edn. Washington DC: ASBMR, 2006:359 \200\22366. Moe S, Dreuke T, Cunningham J, et al. De \201 nition, evaluation, and classi \201 cation of renal osteodystrophy: a position statement from kidney disease: improving global outcome s (KDIGO). Kidney Int 2006; 69: 1945 \200\22353. NKF. National Kidney Foundation K/DOQI clinical practice guide- lines for chronic kidney di sease: evaluation, classi \201 cation, and strati \201 cation. Am J Kidney Dis 2002; 39(S uppl 2): S1 \200\223246. Ramsey-Goldman R, Dunn JE, Dunlop DD, et al. Increased risk of fracture in patients receivi ng solid organ transplants. J Bone Miner Res 1999; 14: 456 \200\22363. Management of SHPT in ROD In CKD 4 and 5 key components of management are to: \200 Reduce phosphate retention by restricting dietary phos- phate, using frequent dialysis and phosphate binders (e.g. sevalamer). Optimize PTH levels by judicious use of active vitamin- D analogs (e.g. 1A-calcidol, calcitriol or paricalcitol). Consider calcimimetics (e.g. Cina calcet), which increase the sensitivity of the PTH gland calcium-sensing recep- tor thereby reducing PTH release. OSTEOGENESIS IMPERFECTA 428 Osteogenesis imperfecta Osteogenesis imperfecta (OI) is a rare autosomal domi- nant inherited disorder of connectiv e tissue characterized by bone fragility and fracture. Forms are chie \202 y due to abnormalities in Type 1 collagen and clinically varied \200\223 from a lethal phenotype an d mild forms that may only manifest as osteoporosis in adults. Classi \201 cation of OI by type OI type Clinical features Inheritance I Normal stature. Little or no deformity. Blue sclerae. Hearing loss in 50% AD II Lethal in the perinatal period AD III Progressive deformity. Short stature. Sclerae vary. DI common. Hearing loss common AD/AR (rare) IV Mild to moderate bone deformity. Variable short stature. DI common. Occasional hearing loss . Sclerae vary. AD AD, gene unknown V Phenotypically the same as IV but also triad of hypertrophic callus formation, dense metaph yseal bands, interosseous membrane ossi \201 cation. Normal Type 1 collagen Phenotypically the same as IV. iALP. Fish scale appearance of bone under microscope Phenotypically the sa me as IV. Found only in small Quebecois community. Blue sclerae. Rhizomelia. Moderate to se vere bone disease. VI Unknown VII AR, gene at 3p22-24.1 AD=autosomal dominant; AR=autosomal recessive; DI=dentinogenesis imperfecta. Classi \201 cation Broadly in keeping with general features associated with recognized phe notypes there are varying degrees of growth de \201 ciency, dentinogenesis imperfecta, hea ring loss, macrocephaly, blue sclerae, scoliosis, barrel chest, and hypermobility. OI is co nventionally described according to Sillence. \200 Some features are common to all OI types: \202 at mid-face, bluish sclerae, yellow or opa lescent teeth, relative macro- cephaly, barrel chest and pectus excavatum, joint laxity. Type I OI \200 Mildest form of OI. Fractures occur postnatally often when child starts to mobilize, but in cidence of fracture decrease after puberty. Occasionally, presents in early middle age as \200\230early osteoporosis \200\231. Hearing loss can occur \200\223 often late in childho od or early adulthood. Growth de \201 ciency, long bone deformity, and dentino- genesis im perfecta are unusual. Sillence described 4 types according to clinical features. Three further types have been ad ded though these have been described on the basis of additional non-clinical parameters. Ty pes IV \200\223VI appear to have normal type 1 collagen. Epidemiology OI is rare. Reliable \201 gures of prevalence and incidence don \200\231t ex ist. Both males and females are affected. Cases, families, and disease clusters in small et hnically restricted groups have been described from across the world. Type II OI \200 Generally lethal in the peri-natal period. Birth often premature and are small for gestatio nal age. There are major skeletal deformities and demise usually follows respiratory insuf \201 ciency. Type III OI \200 Etiology and pathophysiology \200 >90% of OI patients have abnormalities in type 1 collagen. Types V \200\223VI do not have t ype 1 collagen mutations. Type 1 OI is due to reduced synthesis of structurally normal type 1 collagen and have an increase in type 3: type 1 collagen ratio. In types II \200\223IV a mixture of normal and abnormal collagen is synthesized. With rare exceptions the structura l defects are either glycine substitutions or an in-frame deletion from alternate exon spli cing. Defects in collagen chains impair helix folding and expose chains to enzymes for long er thus chains become excessively modi \201 ed. Recessive forms of OI are probably caused by parenteral mosaicism for a dominantly inherited mutation. Severe type with progressive deformity. Fractures occur very commonly. Bones deform from no rmal muscle ten- sion. Extreme growth de \201 ciency and scoliosis common. Type III is com patible with full life span, although respira- tory insuf \201 ciency and cor pulmonale ca n occur in middle age. Respiratory problems frequently complicate and com- promise long-ter m health. \200 Type IV OI \200 Moderately severe. Diagnosis can be at birth although often not until becomes mobile or eve n starts school. Typically several fractures a year occur though decrease after puberty. Fi nal stature is small and children may be responsive to growth hormone. Compatible with norm al life-span. Radiographically, there is osteoporosis and many develop scoliosis and verteb ral fractures. Clinical features OI can present at different ages thus its differential diagno- sis varies dependently (see below). A positive family history is absent because mutations occur de no vo. CHAPTER 14 Bone diseases 429 Cancellous bone volume and cortical width are always decreased \200\223 under polarized li ght the lamellae are thin- ner and less smooth than in controls. Mineral apposition rates a re normal. OI/EDS subtype A discrete subtype of OI may exist, where there are fea- tures suggestive al so of Ehlers \200\223Danlos syndrome (EDS). Joint laxity/hypermobility is prominent. Type V \200\223VII Recent subtypes of OI indistinguishable from Type IV OI have been propos ed on the basis of having distinguishing radiology and/or bone histology. Differential diagnosis Depends on the time of presentation. \200 Prenatally: severe type II or III may be dif \201 cult to distin- guish from achondrogenes is type 1. In neonates: infantile hypophosphatasia \200\223 low ALP in the latter usually distinguishes. In toddlers and older children non-accidental injury is often considered the cause of recurrent fractures. In the pre-pubertal child age 9 \200\22311 years idiopathic juve- nile osteoporosis (IJO; see \200\230Osteoporosis in children \200\231) In adults: ca uses of osteoporosis. Investigations Serum biochemistry is normal though sometime ALP is elevated after a fractur e. Imaging \200 In all types of OI: generalized osteopaenia. Long bones have thin cortices and a gracile ap pearance. Long bones of the arm are less affected than those of the leg. In severe OI, long bones are bowed, have modeling deformities, metaphyseal \202 aring, and a popcorn appear - ance at metaphyses. Vertebral fractures are common and affect thoracolum- bar segments \201 rst. Skull radiographs can show platybasia in types III and IV. In this situation surv eillance for brain stem features and myelopathy is prudent, and imaging with MRI sometimes necessary. L1-L4 1.6 1.1 1.2 1.0 D M B 0.8 Bone densitometry DXA evaluation shows low BMD for age. Notably DXA can aid diagnosis in mi lder OI forms in adults. Generally, OI severity correlates inversely with Z-score. 0.6 0.1 Bone histomorphometry \200 0.2 Usually defects in modeling are obvious. There is thick- ening of trabeculae. 15 10 11 12 13 14 Age Figure 14.12 Changes in BMD (+12% from baseline) in a woman with mild OI and fragility frac tures (at age <40y) with serial pami- dronate injections (30mg once every 4 months) Treatment Physical therapy and rehabilitation are key interventions. Physiotherapy should b egin in infancy and be undertaken by specialist physiotherapists cognisant with the aims an d objectives of managing OI, and it \200\231s complications. Orthopedic care \200 Involved orthopedic surgeons should be experienced in managing OI. Preventive surgery is of ten necessary. Fractures should not be allowed to heal without reduc- tion as function may be lost if deformity occurs. Long bones require \201 xation with an intramedullary rod wi th the smallest diameter to avoid cortical atrophy. Surveillance for associated features \200 Abnormal pulmonary function, particularly poor thoracic excursion, respiratory infections, and cor pulmonale are should be monitored for and managed early. Hearing loss and cord comp ression at the skull base can occur and can be monitored for. A radiograph showing platybas ia at an early stage might denote those at risk of high cervical cord lesions. Recombinant human GH Figure 14.11 OI, girl aged 12 years. Left: despite an intramedullary (Shef \201 eld) rod i nserted as prevention against fracture, a shaft frac- ture has occurred. Right: the fractur e has worsened and rod bends (radiograph on day of surgery). Note extendable lower part of rod has not fully extended with growth as intended and distal femur striations correspondin g to cycles of intravenous pamidronate. OSTEOGENESIS IMPERFECTA 430 Severe growth de \201 ciency associated with OI can be treated with rhGH. Most type I OI a nd 50% type IV OI respond to rhGH. Type I OI children can respond to reach normal height. ICD-10 codes Q78.0 Osteogenesis imperfecta References Glorieux FH, Rauch F, Plotkin H, Ward L, Travers R. Type V osteo- genesis imperf ecta: a new form of brittle bone disease. J Bone Miner Res 2000; 15: 1650 \200\2238. Bisphosphonates \200 RCTs in children with moderately severe OI suggest that IV bisphosphonates have therapeutic potential (ses also Plate 26) Bisphosphonate therapy increases BMD, iliac trabecular bone volume, and cortical width in the short-term, but effects on cortical bone may not be as ob vious as on trabecular bone. Fracture prevention data in the long- term are not conclusive. The optimum duration of treatment with IV bisphospho- nates in children and adults is unkn own. Both oral and IV bisphosphonates have been used suc- cessfully to increase BMD in mild er forms of OI particu- larly in adults. Long-term fracture prevention studies have not yet been completed. Glorieux FH, Ward LM, Rauch F, Lalic L, Roughley PJ, Travers R. Osteogenesis imperfecta typ e VI: a form of brittle bone disease with a mineralization defect. J Bone Miner Res 2000; 1 7: 12 \200\22318. Kuivaniemi H, Tromp G, Prockop DJ. Mutations in \201 brillar collagens and network forming collagen cause a spectrum of diseases of bone, cartilage and blood vess els. Human Mutat 1997; 9: 300 \200\22315. Marini JC. Osteogenesis Imperfecta. In: Favus MJ (ed.) Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism 6th edn. Wa shington DC: ASBMR, 2006: 418 \200\22321. Rauch F, Travers R, Plotkin H, Glorieux FH. The effects of intrave- nous pamidronate on the bone tissue of children and adolescents with osteogenesis imperfecta. J Clin Invest 2002; 110: 1293 \200\2239 Sakkers R, Kok D, Engelbert R, et al. Skeletal effects and functional outcome with olpadron ate in children with osteogenesis imper- fecta. A 2y randomized placebo-controlled study. L ancet 2004; 363: 1427 \200\22331. Resources Patient and physician resources The OI Foundation is a repository of advice and i nforma- tion for patients, physicians and therapists: www.oif. org. A similar UK-based orga nization is www. brittlebone.org. See excellent and comprehensive (open access) article by Steiner RD, Pepin MG and Byers PH. Available at: www. ncbi.nlm.nih.gov/books/bv.fcgi?rid=ge ne. chapter.oi. Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteo- genesis imperfecta. J Med Genet 1979; 16: 101 \200\22316. Ward LM, Rauch F, Travers R, et al. Osteogenesis imperfecta type VII: an autosomal recessiv e form of brittle bone disease. Bone 2002; 31: 12 \200\22318. This page intentionally left blank MISCELLANEOUS BONE DISEASES 1 432 Miscellaneous bone diseases 1 Fibrous dysplasia (FD) A congenital non-inherited disorder usually diagnosed in childhood. Normal bone and bone marrow are replaced by highly vascular \201 brous tissue and pre-ost eoblastic cells. \200 Etiology \200\223 somatic mutations in the cAMP regulating protein GsA, which is coded for by the GNAS gene. Children present with skeletal pain. FD can vary from a single lesion (monostotic) or involve multiple sites (poly- ostotic). FD can affect skull, spine, and long bones. FD frequently is associated with hyperpigmentation (caf -au lait spots) and hyperfunctioning endocrinopa- thies (e.g. growth hormone excess, hyperthyr oidism, Cushing \200\231s). FD in combination with these features is termed McCune-Albright syndrome. FD can be associated with fractures, limb length discrep- ancy, and long bone de formity. FD lesions are characteristic on radiographs and bone scintigraphy is useful for s taging disease, and in determin- ing response to bisphosphonates. Hypophosphataemia and exc ess FGF-23 are associated features. Markers of bone turnover are increased. Pain can persis t into adulthood and, generally, pain is often poorly addressed. Patients bene \201 t from NSAIDs. Intravenous bisphosphonates have shown consistent ef \201 cacy in reducing pain, although there is some debate whether lesions change radiographically and long-term skeleta l complications can be prevented. Current theories of aetiopathogenesis focus on the pos- sibility of enhanced exposure of pe ripheral tissues to vascular endothelial growth factor (VEGF) or COX2- derived PGE2. Bone s cintigraphy shows bone lesions but patterns are not speci \201 c. CT chest can determine c ause of HPOA. A role for bisphosphonates in HOA management has been suggested, and clinical responses to pamidronate have been reported in both primary and secondary HOA. Bene \201 cial effects of octreotide have been reported in two cases of refractory secondary HOA. Fibrogenesis imperfecta ossium (FIO) Rare bone disease of unknown etiology characterized by diffuse coarse trabeculation \200\223 mixed sclerosis and lysis, which needs to be discri minated from Paget \200\231s Disease of Bone (see p. 418) and axial osteomalacia. \200 \200 Sporadic condition with no known genetic factors. Presents during middle age or later with bone pain usu- ally in proximal distribution. Fractures occur. Many cases exhibit rapid det erioration and progressive disability. Patients have marked bony tenderness. In early disea se, radiographs show osteopaenia, but later show abnormal trabeculation (dense \201 sh-ne t) with blur- ring between trabecular and cortical bone. FIO is distinguished from PDB by a lack of bone expan- sion and cortical bone appearances. In FIO cortices are thin and often not visible. Cortex in PDB is usually highly visible and often thickened. ALP is increased , but calcium, phosphate, and PTH nor- mal unless there is coincident hypovitaminosis-D. Hi stopathology: aberrant collagen structure lacking bire- fringence on polarized light micros copy. Electron micro- scopy shows collagen fibrils are thin and \200\230tangled \200\231; abnormal mineralization; thick osteoid seams. In some, but not all reported cases there may be an association with paraproteinaemia. No proven effective treatment in all reported cas es. Pulse melphalan (e.g. 4 \200\2236 mg bd daily) and prednisolone 0.25 mg/day for 5 days/ month and continuous calcitriol 0.25 \200\2230.5 g/day has facilitated long-term survival in one case and been reported \200\230successful \200\231 in another. Hypertrophic osteoarthropathy (HOA) Primary HOA (pachydermal periostitis) Autosomal dominan t condition of unclear etiology caus- ing clubbing, hyperhydrosis, skin thickening (especia lly of the head termed cutis vertices gyrata), arthralgias, and periostitis affecting mainl y distal limb bones. \200 Affects men > women and blacks > whites. Onset typi- cally in adolescence. Peripheries can enlarge and appear \200\230acromegalic \200\231. Radiographs: periosteal thickening and ra gged whisker- ing of proliferative bone. Distinguished from secondary HOA (smooth undulatin g perisosteal thickening). Joint contractures and neurovascular compression from osteoscler otic lesions can require surgical intervention. \200 Secondary HO (90% of all HOA cases) Secondary causes of HPOA are pulmonary (HPOA), pleu- ral, cardiac, abdominal, and miscellan eous. Pleural causes include pleural \201 broma and mesothelioma. \200 Cyanotic heart disease with a right-to-left shunt is the only cardiac cause described. Pulm onary causes: bronchogenic carcinoma; tuberculo- sis; pulmonary abscesses; blastomycosis; b ronchiectasis; emphysema; and Pneumocystis carinii infection in AIDS, Hodgkin disease, meta stases, or cystic \201 brosis. Abdominal causes: liver cirrhosis, IBD, amoebic and bacill ary dysentery, polyposis, gastrointestinal tract neoplasms, lymphoma, Whipple \200\231s and biliary atresia. Digital clubbing is common. Initially, \201 bro-elastic tissue in the n ailbed thickens. Then \202 uctuation, striations, shininess and increased curvature of th e nail follows. Articular features occur in 30 \200\22340% of patients and are often the pr esenting features. Figure 14.13 FIO. Coarse \200\230fishnet \200\231 trabecular pattern. Note: no bone expans ion and absence of cortical features in pelvis CHAPTER 14 Bone diseases 433 Osteonecrosis (ischaemic necrosis) Regional vascular changes can cause bone ischaemia that, if suf \201 ciently severe will cause bone cell death. Conse- quently, if resorption of d ead tissue is compromised during skeletal repair then fracture can occur owing to focal bon e weakness. See also pp. 168 \200\223171. Common sites of osteonecrosis and osteochondritis Adult skeleton \200 \200 \200 \200 Osteochondritis dissecans (K nig). Osteochondritis of lunate (Kienb ck). Proximal carpal scaphoid. Femoral or humeral head and fractured talus. Major causes of osteonecrosis \200 Endocrine/metabolic: \200 \200 \200 \200 \200 Storage diseases (e.g. Gaucher \200 \231s disease). Haemoglobinopathies. Trauma, dysbaria. HIV infection. Radiotherapy. Idiopat hic. Growing skeleton \200 \200 \200 \200 \200 \200 \200 \200 alcohol abuse, pancreatitis; glucocorticoid therapy; Cushing \200\231s syndrome, phaeochrom ocytoma; Gout; Osteomalacia. LCPD femoral head. Slipped femoral epiphysis. Osgood Schlatter (tibial tuberosity osteochon drosis). Navicular osteochondrosis (K hler). Medial tibial condyle osteochondrosis (Blount ). Os calcis osteochrondrosis (Sever). Second metatarsal head osteochondrosis (Freiberg). P rimary vertebral ossi \201 cation center osteochondrosis (Calv ). Secondar y ver tebr al ossification center (Scheuermann \200\231s). Humeral capitellum osteochondrosis (Pinner). \200 \200 \200 \200 \200 Legg \200\223Calv \200\223Perthes disease (LCPD) Idiopathic osteonecrosis of capital femo ral epiphysis in children. It is common, complex, and controversial. \200 Mostly reported in patients receiving bisphosphonates for bone cancer, typically in those w ho have had radio- therapy of head and/or neck. Incidence may also relate to the presence o f poor oral health and may be triggered by dental work. The lesions can be persistent, ofte n slow and sometimes impossible to heal, and can lead to recurrent infections. It is pruden t to avoid intravenous bisphosphonates in those with poor oral health or delay treatment un til after necessary dental work has been completed. Typically affects ages 2 \200\22312 years, mean age 7 years. Mainly boys. Etiology is unkno wn. Interruption of blood \202 ow at this site may be caused by raised intracapsular pres sure, syno- vitis, venous thrombosis, or increased blood viscosity. Extensive femoral head involvement is invariable. The growth plate becomes ischaemic. Cartilage survives however. Reparative processes can succeed though if fracture occurs there is pain. Leg growth can be affected and the growth plate can fuse prematurely. Children with LCPD typically limp with pain, have reduced hip motion, and can develop permanent con- tractures if not addressed. Radiographs: should request AP and \200\230frogs legs \200\231 views. MR: often helpful to stage lesion. Prognosis depends on the degree to which the femoral head deforms and extent of epiphyseal involvement. Treatment usually conservative: analgesia, physiotherapy, monit oring for femoral head displacement. Surgical intervention is required for correction of fe mo- ral head deformity. Resources See explanation of the disease for patients at www. mayoclinic.com/health/fibrous -dysplasia/. See also, the Fibrous Dysplasia Foundation: www. fibrousdysplasia.org. References Chapurlat R, Delmas PD, Liens D. Long-term effects of intravenous pamidronate in \201 brous dysplasia of bone. J Bone Miner Res 2002; 10: 1746 \200\22352. Kelly MH, Brillante B, Collins MT. Pain in \201 brous dysplasia of bone: age-related chan ges and the anatomical distribution of skeletal lesions. Osteoporos Int 2008; 19: 57 \200 \22363. Skeletal sites prone to osteonecrosis LCPD illustrates how subchondral bone is especially p rone to osteonecrosis. The pathogenesis of interrupted blood \202 ow is poorly understood though. Process has been linked to numbers of adipocytes within medullary space com- press ing sinusoids. Kozal KR, Milne GL, Morrow JD, Cuiffo BP. Hypertrophic osteoar- thropathy pathogenesis: a c ase highlighting the potential role for cyclo-oxygenase-2-derived prostaglandin E2. Nature Clin Practice Rheumatol 2006; 2(8): 452 \200\2236. Matucci-Cerinic M, Lott T, Jajic IVO, Pignone A, Bussani C, Cagnoni M. The clinical spectru m of pachydermoperiostitis (primary hypertrophic osteoarthropathy). Medicine 1991; 79: 208 \200\22314. Osteochondroses Refers to atraumatic ischaemic necrosis that typically affects an ossi \201 cation (growth) center. The extent and se- verity of lesions is variable. See also cha pters on anatomy and regional musculoskeletal lesions. Pazianas M, Miller P, Blumentals WA, Bernal M, Kothawala P. A review of the literature on o steonecrosis of the jaw in patients with oste- oporosis treated with oral bisphosphonates: prevalence, risk fac- tors, and clinical characteristics. Clin Ther 2007; 29: 1548 \200\223 58. Swan CH, Shah K, Brewer DB, Cooke WT. Fibrogenesis imperfecta ossium. Q J Med 1976; 45: 233 \200\22353. Osteonecrosis of the jaw Ralphs JR, Stamp TCB, Dopping-Hepenstal PJC, Ali SY. Ultrastructural features of the osteoi d of patients with \201 brogenesis imperfecta ossium. Bone 1989; 10: 243 \200\2239. Recently described in patients receiving intravenous bisphosphonates, notably Zoledronate a nd pamidronate. MISCELLANEOUS BONE DISEASES 2 434 Miscellaneous bone diseases 2 Sclerosing bone disorders Many conditions cause either localized or general sclerosis of bo ne. The major ones are listed below. Low dose GCs can reduce symptoms but bisphospho- nates can increase pain. There is some int erest in the therapeutic potential of losartan, which may have in vivo anti-TGFB effects. Pycnodysostosis About 100 cases from 50 families described. AR inheri- tance. May have affe cted Henri Toulouse-Lautrec. \200 Disorders characterized by bone sclerosis \200 Dysostoses: osteopetrosis, melorheostosis, progres- sive diaphyseal dysplasia, endosteal hy perostosis, pycnodysostosis, osteopathia striata, osteopoikilosis. Metabolic: carbonic anhy drase II de \201 ciency, hepatitis C associated sclerosis, \202 uorosis, LRP5 activation (high bone mass phenotype), renal osteodystrophy (see p. 426), X-linked hypophosphataemia (see p. 424). Other: axial osteomalacia, FIO (see p. 432), Erdheim Chester disease, hypertr ophic osteoarthropathy (p. 432), Paget \200\231s (see p. 418), sarcoid (see p. 510), mastoc ytosis, leukemia, lymphoma, myeloma, osteonecrosis (see p. 433), sickle cell disease, bone metastases (e.g. prostate), previous radiotherapy. Impaired collagen degradation a consistent feature. Recent studies point to deactivating mu tation in cathepsin K gene. Low GH and IGF-1 levels have been described. Global prevalence though rare; particularly well reported in Japan. Presents with short stature, dysmorphic f eatures. Shares many radiographic features with ADO. No con- sistent abnormal laboratory ab normalities. There is no known speci \201 c treatment. \200 \200 Endosteal hyperostosis (EH) Originally Van Buchem described a condition termed \200\230hyp erostosis corticalis generalisata \200\231 in 1955. There are now two main types of EH reco gnized: Osteopetrosis Autosomal dominant (AD) form relatively benign and the recessive (AR) form invariably letha l in infants (not dis- cussed here). There is diversity in clinical features and some heter ogeneity in genotypes. \200 Van Buchem disease Rare AR condition described in adults and children caused by 52 kb delet ion downstream enhancer of SOST, which encodes for sclerostin \200\223 a peptide, which pr omotes osteo- blast apoptosis, binds to LRP5/6 and antagonizes canonical Wnt signaling. \200 All forms develop through a speci \201 c defect in osteoclast mediated bone resorption. Th ere are 2 main adult forms: Type 1 AD osteopetrosis (ADO) is high bone mass phenotype with LRP5 activa- tion. Type 2 ADO is Albers \200\223Schonberg disease which has been associated with mutations in CLCN7 (a chloride channel gene). In adult disease radiographic changes h ave begun in childhood: symmetrical increase in bone mass; skull base sclerosis and vertebr al end-plate thickening; \200\230bone-in- bone \200\231 appearance to vertebrae; alternati ng sclerotic/ lucent bands in iliac/long bones. Fractures. Features: facial palsies; hearin g de \201 cit; slipped capital epi- physis; carpal tunnel syndrome. Bone biochemistry norm al. Elevation in acid phos- phatase. Histopathology diagnostic. In adults treatment is supp ortive (in children bone mar- row transplant has improved some patients). Features: progressive asymmetrical jaw enlargement, cranial neural foraminae narrowing (fac ial nerve palsy, optic atrophy, deafness etc); tender long bones; \206\221ALP. Endosteal c ortical thickening is dense and homogenous; sclerotic skull, mandible, pelvis, and ribs. No known treatment. Surgery to relieve cranial nerve entrapment can be considered. Sclerosteosis Cortical hyperostosis with syndactyly. AR condition occur- ring primarily in Afrikaners or others of Dutch ancestry. Patients have a shortened life expectancy. \200 Enhanced osteoblast activity owing to deactivating lesions in SOST gene. Features: patients generally tall ( \200\230gigantism \200\231); cranial nerve palsies; square mandible; rais ed intracranial pres- sure; headache; syndactyly; \201 nger nail dysplasia. Normal radiog raphs in early childhood. Radiographic features similar to Van Buchem disease otherwise. No speci \201 c treatment available. Progressive diaphyseal dysplasia (PDD) AD condition (mutations in TGFB1 gene). Also known a s Camurati \200\223Engelman disease. \200 Presents in children with limping or waddling gait, leg pain, muscle wasting, and reduced e xtremity fat. If severe can cause enlarged head, proptosis, thin limbs. Features: cranial n erve palsies, skeletal tenderness, enlarged liver/spleen. Although progressive, severity is variable and clinical course unpredictable. Remission of symptoms can occur. Radiographs t ypically show smooth symmetrical hyper- ostosis of long bone diaphyses. Lesions show on bon e scintigraphy. Bone biochemistry is normal. ALP sometimes elevated. Melorheostosis Sporadic condition probably due to segmentary embryonic defect. Unknown etio logy. \200 Presents in childhood often with bone pain and stiffness or soft-tissue abnormalities ( \201 bromas, \201 brolipomas, lin- ear melorheostotic scleroderma, hypertrichosis, capil- lary haemangiomas, lymphangiectasias). Lesions appear typically in sclero/myotomes. Bone l esions: dense irregular, eccentric hyperostoses often in lower > upper limbs. Lesions are v ascular, show intensely on bone scans, progress in childhood, but change is variable in adu lts. CHAPTER 14 Bone diseases 435 Bone pain can persist due to subperiosteal new bone. Marrow \201 brosis can occur. Radiol ogically, lesions have been likened to hardened wax dripping down a candle. No speci \201 c treatment. Affected joints can deform requir- ing surgical correction of contractures. Disorders of hyperostosis/heterotopic bone Abnormal bone can arise from the skeleton (e.g. HME) or can form as a result of signals, which trigger mesenchymal tissue to form bone in p eriskeletal soft tissue. Hereditary multiple hyperostosis (HME) Also termed \200\230diaphyseal aclasia \200\231, th is is an AD condition caused by various mutations in exostosin genes 1 or 2. \200 Characterized by the development of bony protuber- ances mainly located on the long bones. Three HME loci have been mapped to chromosomes 8q24 (EXT1), 11p11-13 (EXT2), and 19p (EXT3) . The EXT1 and EXT2 genes encode glycosyltransferases involved in synthesis of heparan sulf ate proteoglycans. Exostoses can impair growth if near the growth plate, cause limb deformi ties, increase the risk of osteoarthritis in adjacent joints and interfere with nerve funct ion. The most severe forms of the disease and malignant transformation of exostoses to chon drosarcomas were associated with EXT1 mutations. Surgery to excise hyperostoses can be help ful. Surveillance for malignant change is important. 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