The condition is associated with bone, renal, GI, and neuromuscular complications. Bony pro blems can be seen on plain radiographs and range from mild subperiosteal bone resorption to full osteitis \201 brosa cystica with bone cysts, \200\234brown tumors, \200\235 bone r esorption of the distal phalanges and clavicles, patchy osteosclerosis (classic \200\234ru gger (rugby) jersey \200\235 spine), and multiple lytic lesions of the skull. These changes may often, however, be nonspeci \201 c. Renal stones are a common complication. GI manifestations include peptic ulceration and pancreatitis. The myopathy of primary PT is rare and more often a syn drome of fatigue and weakness is seen. \200 Primary HPT is diagnosed by assaying PTH leve ls. The assays are sensitive and able to distinguish between nonparathyroid tumor secreting PTH and parathyroid hormone. PARATHYROID DISEASE AND RELATED DISORDERS 461 Treatment \200 Medical management includes adequate rehydration and avoidance of high cal cium intake. Clinical trials with calcimimetic agents (stimulate calcium receptors with con sequent inhibition of PTH secretion) and in particular cinacalcet hydrochloride are ongoing and may be effective in primary HPT. At the time of writing, cinacalcet has received FDA a pproval for the treatment of secondary HPT in patients with chronic kidney disease. Some individuals (especially the elderly) have physiological mild elevation of PTH due to vitamin D de \201 ciency with normal calcium levels. Vitamin D sho uld be replaced and the serum calcium and PTH levels monitored after 8 \200\22310 weeks. Parathyroidectomy should be offered to individuals with moderate- to-high serum calcium and /or symptoms and complications of the condition, the latter regardless of whether serum cal cium levels are \200\234borderline \200\235 raised or not. US imaging, thallium/technetium scans, MR and CT are all useful ways of establishing the position of an adenoma. However, exploration by an experienced surgeon is equally effective. Secondary and tertiary hyperparathyroidism Secondary hyperparathyroidism occurs as a conseq uence of abnormalities in serum calcium and homeostatic \200\234sensing \200\235 of calciu m levels. With time, PTH secretion becomes autonomous and the abnormality is then called te rtiary hyperparathyroidism. This is most often seen in conditions such as end-organ renal d isease and vitamin D resistance. Calcimimetics may have an important role to play in contro lling secondary HPT but at present parathyroidectomy is the best treatment option. Vitamin D replacement to lower PTH secretion does not appear to be effective in patients with other wise normal vitamin D levels. Familial hypocalciuric hypercalcemia (FHH) or familial benign hypercalcemia (FBH) \200 Th is condition is common but most often asymptomatic. It is inherited as an autosomal dominan t with high penetrance. Radiographs, PTH, and renal function are usually normal. Although p arathyroid gland hyperplasia occurs, parathyroidectomy is invariably unsuccessful at loweri ng serum calcium levels. The two indications for parathyroidectomy are neonatal severe hyperparathyroidism and adult relapsing pancreatitis. Use of diuretics, estrogens, or phosphate to regulate serum calciu m has been unsuccessful. Patients should, therefore, be followed without intervention unles s complications arise. In pregnancy the three situations to be aware of are: asymptomatic hypercalcemia in the affected offspring of a carrier \200 severe neonatal hy percalcemia in affected offspring of an unaffected mother (intrauterine secondary hyperpara thyroidism, which usually resolves spontaneously) hypocalcemia in the unaffected offspring of an affected mother (fetal parathyroid suppression). CHAPTER 16 Metabolic bone diseases 462 Familial hyperparathyroid syndromes Up to 10% of cases of hyperparathyroidism may have a he reditary syn- drome. The most common of these is multiple endocrine neoplasia (MEN). Type I , autosomal dominant and equal in both sexes, is associated with pancreatic and pituitary a denomas, and adrenal hyperplasia. Type IIA, autosomal dominant Sipple \200\231s disease, is characterized by pheochromocy- tomas and medullary carcinoma of the thyroid. Parathyroid hormone resistant syndromes \200 Pseudohypoparathyroidism (PHP) occurs as a r esult of resistance to PTH by target tissues. The biochemical consequences are hypocalcemia , hyperphosphatemia, and elevated PTH. Cyclic AMP (cAMP) mediates many actions of PTH. Administration of bioactive PTH to normal i ndividuals leads to increased urinary excretion of cAMP. The abnormal response to this test in individuals with PHP classi \201 es them either type I \200\224no increase in urine cA MP with bioactive PTH \200\224or type II \200\224normal increase in urine cAMP but abnormal phosphate handling. The net effect is features similar to those of hypoparathyroidism of any cause (such as con genital parathyroid absence, or surgical removal). Common symptoms include: neuromuscular irritability (due to associated hypocalcaemia) \200 muscle cramps \200 ps eudopapilledema \200 extrapyramidal signs \200 mental retardation \200 cataracts \200 coarse hair/alopecia \200 abnormal dentition \200 personality disturbance. PHP type Ia (Albright \200\231s hereditary osteodystrophy (AHO)) manifests as short stature, round facies, obesity, brachydactyly, and subcutaneous ossi \201 cation. Albright observed that some individuals have these features without PHP. The term pseudops eudohypoparathyroidism was coined. This group has a normal serum calcium and PTH/ cAMP test . Cases with PHP type I but who lack features of AHO are classi \201 ed type Ib. They often have the skeletal abnormalities seen in cases of hypoparathyroidism. In type II PHP there is a normal cAMP response but an abnormal phosphate response in the kidney. The mainstay of therapy is the maintenance of serum calcium and phosphate levels. The complication of calcium and vitamin D supplements is the increase d risk of renal stones due to hypercalciuria. One gram a day of calcium is recommended and products rich in phosphate (e.g., dairy foods) should be avoided. Hydroxyvitamin D suppleme nts are valuable but serum calcium and phosphate levels should be checked weekly for 4 \200 \2236 weeks up to steady state and then every 3 \200\2236 months. PARATHYROID DISEASE AND RELATED DISORDERS 463 Renal osteodystrophy \200 The kidneys regulate calcium/phosphate balance, are a target organ for PTH, and produce 1,25-dihydroxyvitamin D (calcitriol). Renal osteodystrophy is th e net effect on bone that occurs due to derangement of calcium homeostasis in chronic renal failure. Renal bone disease is classi \201 ed as \200\230high turnover \200\231 or \200 \230low turnover \200\231 depending on whether serum PTH levels are high or low/normal resp ectively. Low turnover, adynamic osteodystrophy, is related to excess bone aluminum deposit ion in dialysis patients and is also seen in diabetes mellitus and corticosteroid therapy a nd as part of aging. Hyperphosphatemia, hypocalcemia, impaired calcitriol production, and skeletal resistance to PTH all contribute to secondary HPT in chronic renal failure. Serum PTH varies too widely in the condition to be useful in assessing treatment. Serum alkaline phosphatase is increas ed and is a useful marker though it does not distinguish between high and low turnover stat es. The clinical manifestations of renal osteodystrophy are shown in Table 16.10. Table 16.10 The clinical manifestations of renal osteodystrophy Clinical feature Comment Bone pain Common Skeletal deformity Common. Affects appendicular and axial skeleton Children: onset <3 years, rachitic; onset <10 years, bowing of long bones, widened metaphys es, pseudoclubbing, slipped epiphyses Adults: lumbar scoliosis, kyphosis, distorted thorax Growth retardation Proximal muscle weakness Ectopic calci \201 cation Soft-tissues. Visceral. Vascular \200\224if severe,individuals may develop ischemic necrosi s CHAPTER 16 Metabolic bone diseases 464 The management of renal osteodystrophy \200 Good dietary control of phosphate can maintai n normal calcium levels, but low-phosphate diets are often unacceptable and normal phosphat e levels are best achieved with binding agents, e.g., calcium carbonate or calcium acetate. Small doses of calcitriol (vitamin D) may help to lower serum PTH levels. Some individuals may be sensitive to calcitriol and serum calcium levels may increase. Most patients require doses of 0.25 \200\2230.5 g daily; children may require higher doses. Parathyroidectomy is indicated in persistent symptomatic hypercalcemia, ectopic calci \201 cation, and severe bone pain. Ectopic calci \201 cation and ossi \201 cation \200 Ectopic calci \201 cation can aris e from any one of a number of causes of hypercalcemia or hyperphosphatemia. These include renal failure, hyperparathyroidism, an d sarcoidosis. Dystrophic calci \201 cation is also a feature of SScl (see Chapter 12), DM (see Chapter 13), and p calcinosis. Ectopic ossi \201 cation can be seen posttrauma and following myositis. It is also a feature of several rare conditions including pseudo- hypoparathyroidism and my ositis ossi \201 cans progressiva. Early signs of muscle ossi \201 cation are best detect ed with MR scanning. Later ossi \201 cation it easily visible on plain radiographs. Treatm ent is dif \201 cult but includes physiotherapy to maintain suppleness and possibly hepari ns or bisphosphonates to halt bone formation. This page intentionally left blank CHAPTER 16 Metabolic bone diseases 466 Paget \200\231s disease of bone \200 Paget \200\231s disease is a chronic disorder of acc elerated bone resorption and formation resulting in deformity in size and shape of bone as well as fragility despite apparent \200\234thickening \200\235 of bone. The condition is common (about 5% of the population over the age of 55) in the United Kingd om, the United States, Australia, and New Zealand, with a male to female ratio of 3:2. It i s uncommon in Asia, and non-White races. Very little is known of the molecular basis of Paget \200\231s disease. There is evidence to suggest that it may be triggered by exposure to a slow virus. Paramyxovirus antigens found in bone cells, and compatible with measles, respiratory syncytial virus, and canine distemper have all been implicated. The clinical features of Paget \200\231s disease are shown in Table 16.11. Diagnosis and treatment \200 Serum alkaline phosphatase, a measure of bone formation, is the most useful marker and may be elevated as much as 30 times above normal. Occasionally, in limited Paget \200\231s, the enzyme is normal. This should not be a deterrent to treatin g painful lesions. The differential diagnosis of increased bone alkaline phosphatase includ es metastatic bone disease, osteomalacia, hyperparathyroidism, and hyperphosphatasia. Urine hydroxyproline excretion is also increased. Hydroxyproline is a breakdown product of collagen and a marker of bone resorption. Other markers of bone turnover are available but most remain experimental and are not needed for the diagnosis and treatment of Paget \200 \231s disease. There is a wide variation in radiographic appearance of the condition but the main features are sclerosis, bone expansion, and coarse, disorganized, trabecular bone. Isotope bone scanning is a sensitive investigation for de \201 ning the extent of lesions. Many rare hereditary dysplastic conditions are associated with bone sclerosis. These includ e osteopetrosis, Engelmann \200\231s disease, and pycnodysostosis. These conditions are bey ond the scope of this book. Sclerosis is also a feature of many other conditions including metabolic disease ( \202 uorosis, hypervitaminosis D, parathyroid disease, renal osteodyst rophy), malignancy (lymphoma, myeloma, skeletal metastases), infection, sarcoidosis, and tu berous sclerosis. Thermographic improvement and pain reduction are correlated with effective treatment of Pag et \200\231s; thermographic observations probably demonstrate a decline in bone and perioss eous blood \202 ow after treatment. There are several indications for treatment of Paget \200\231s disease: pain arising from pagetic sites \200 deforming disease \200 skull disease \200 compli cations: progressive neurological syndrome, fractures, hypercalcemia, high-output cardiac f ailure, serum alkaline phosphatase (over twice upper normal). PAGET \200\231S DISEASE OF BONE 467 Table 16.11 Clinical features of Paget \200\231s disease of bone Clinical feature Details Pain Deep, boring pain, possibly correlated to blood \202 ow Bone expansion and deformity Hands or feet 10% of cases Pelvis 75% Lumbar spine 50% of cases Femur 35% of cases Sacrum 35% of cases Skull 35% of cases Tibia 30% of cases Radius 15% of cases Fractures Heat Neurological syndromes Deafness (sensorineural or conductive) Tinnitus Headache Brainstem/cerebellar compression Spinal cord/root compression Cranial nerve entrapment High-output cardiac failure Rare \200\224occurs when > 40% of the skeleton is involved Malignant osteosarcoma Seen in 0.1% of cases, esp. if disease present for > 10 years Immobilization hypercalcemia Serum calcium levels are nearly always normal Gout Retinal angioid streaks Pagetic and related osteoarthritic pain may be reduced by simple analgesics but pure Pagetic bone pain responds poorly to this. In most cases now, the choic e of treatment falls between bisphosphonates and calcitonin. These drugs are discussed in t he Osteoporosis section at the beginning of this chapter. Etidronate may be given for 6 months at a dose of 5 mg/kg/day. Vitamin D supplements may minimize the mineralization defects that can occur with even low doses of etidronate. Oral tiludronate 400 mg daily for 3 months has been FDA approved for t he treatment of Paget \200\231s disease. IV pamidronate may also be used and many in curren t practice offer a single dose infusion of 30 \200\22390 mg (depending on renal function) t o symptomatic patients, with follow-up and measurement of CHAPTER 16 Metabolic bone diseases 468 serum alkaline phosphatase after 3 months. Transient \202 ulike symptoms of fever, myalgi a, and arthralgia often occur after the \201 rst dose of IV pamidronate. Risedronate may also be given at 30 mg daily for one month. SQ or IM calcitonin may also be used in Paget \200\231s disease. The disadvantages are common symptoms of nausea and diarrhea, relapse on therapy, and expense. Nasal spray calcitonin may be useful but the therapeutic effect is weaker than with bisphos phonates. Typical dosing for salmon calcitonin would be a 10 IU test dose followed by 50 \200\223100 IU daily, reducing to 50 IU 2 \200\2233 times per week once a symptomatic respo nse is achieved (usually after 4 \200\2238 weeks). If there has been no symptomatic respons e after 3 months, calcitonin therapy should be stopped. There is no consensus about whether or when to treat Pagetic joints per se prior to joint replacement. This page intentionally left blank CHAPTER 16 Metabolic bone diseases 470 Miscellaneous diseases of bone Osteochondritis and osteonecrosis \200 The osteochondroses are a heterogeneous group of disorders, de \201 ned by their radiological appearances. In a few instances, radiological osteochondritis may be an incidental \201 nding, not associated with symptoms and may represent a normal develop mental variant. Usually, however, it is painful, occurs in the growing skeleton between the ages of 3 \200\22316 years, and is more frequent in men and in the peripheral skeleton. So me cases are due to infarction (osteonecrosis) of subchondral bone. For others the etiology is unknown. Osteonecrosis (synonyms: avascular necrosis, ischemic necrosis, aseptic necrosis) can occur at several sites and is associated with as many eponyms (see Ta ble 16.12). Bone infarction and subsequent pain occurs in susceptible areas because of limi ted collateral circulation and low perfusion pressure, e.g., in the femoral head. First, bo ne and adjacent marrow becomes necrotic. Granulation tissue then advances into the dead bon e, which is resorbed. Osteoblasts then lay down new osteoid. Advanced osteonecrosis leads t o secondary osteoarthritis, severe disability, and eventually the need for joint replacemen t. In the acute phase, core decompressive surgery may help preserve the joint, although som e patients may require total joint replacement. Etiological factors for osteonecrosis include trauma, sepsis, radiation, thermal, and elect rical injury. Caisson \200\231s disease is an obliterative endarteritis of the femoral head caused by expanding nitrogen gas in divers who decompress too quickly. Hematological cause s include hemophilia, coagulopathies, and hemoglobinopathies. Endocrine causes include Cush ing \200\231s syndrome and glucocorticoid use (high dose >60 mg/day over a period of months ). There is an increased susceptibility to the condition in several rheumatic conditions in cluding RA (Chapter 5), SLE (Chapter 10), SScl (Chapter 13), and vasculitis (Chapter 15). F inally, a miscellaneous group of associations with osteonecrosis include bisphosphonate the rapy, alcohol abuse, organ transplantation, dialysis, HIV infection, pancreatitis, chronic liver disease, hypertriglyceridemia, and pregnancy. Osteonecrosis complicates 20% of cases of intracapsular hip fracture. \200 Fat embolism m ay account for some cases, e.g., in alcoholism and Cushing \200\231s disease. Asymptomatic osteonecrosis in SLE may be as high as 35% (it is symptomatic in 5 \200\22310%). Osteonecrosis is diagnosed and classi \201 ed radiologically: (Arlet and Ficat classi \201 cation): I = normal; II = osteoporosis, cysts, sclerosis giving mottled appearance; III = subchondral bone collapse; IV = abnormal bone contour and joint space los s. Bone scintigraphy, CT, and MR are more sensitive. MR can identify early changes in bone marrow before bone necrosis and has greatest speci \201 city once bone changes occur. \200 Legg \200\223Calv \200\223 Perthes \200\231 disease is osteonecrosis of the femora l epiphysis and occurs in children from 3 to 8 years old, and affects boys more than girls (ratio 4:1). It is bilateral in 10 \200\22320% of cases. Symptoms MISCELLANEOUS DISEASES OF BONE 471 Table 16.12 The osteochondroses Skeletal area Disease eponym Mechanism Upper limb Basal phalanges Thiemann Trauma Second metacarpal head Mauclaire Trauma Lunate Kienbock Osteonecrosis Carpal navicular Prieser Trauma Humeral capitellum Panner Trauma/ osteonecrosis Lower limb Second metatarsal base Freiberg Osteonecrosis Fifth metatarsal base Iselin Trauma Tarsal navicular K hler ?Trauma/normal variant Talus Diaz Trauma-related Calcaneal Sever Traction apophysitis* Apophysis of tibial tubercle Osgood \200\223 Schlatter Traction apophysitis* Proximal tibia Blount \200\223 Inferior patella pole Sinding \200\223Larsen- Johansson Traction apophysitis* Femoral epiphysis Legg \200\223Calv \200\223 Perthes Osteonecrosis Axial skeleton Vertebral epiphysis Scheuermann Repeated trauma Due to repetitive overloading of tendons, usually from sports. include an insidious onset of limp and pain in the groin or referred to the knee/thigh whic h is relieved by rest. Limitation of hip internal rotation and abduction (due to adductor s pasm) is typical. Leg length inequality suggests bone collapse. There may be spontaneous re solution, especially in younger patients, in whom conservative management is indicated. Osgood \200\223Schlatter \200\231s disease is probably due to repetitive trauma at the site of patellar tendon insertion into the tibial tubercle, typically in athletic adole scents, especially young men aged 14 \200\22316 years. Pain on exercise usually eases with rest. The diagnosis is made clinically and on demonstrating an enlarged fragmented tibial t ubercle on a lateral view radiograph. Bilateral knee views helps to distinguish normal from abnormal. CHAPTER 16 Metabolic bone diseases 472 Scheuermann \200\231s disease, though not consistently de \201 ned, is thought to be a ver tebral epiphyseal osteochondritis that occurs in adolescence. Although it can be an inciden tal radiographic \201 nding, it is also associated with diffuse spinal pain that is more likely to be present if the osteochondritis is thoracolumbar (25%) rather than thoracic (75 %) and the child is an athlete or very active. It can present with painless dorsal kyphosis with compensatory lumbar lordosis and lateral spine radiographs show irregularity of verte bral end-plates, anterior vertebral wedging, and kyphosis. Sinding \200\223Larsen \200\223Johansson \200\231s disease occurs as a consequence of over- loading of the patella at its secondary center of ossi \201 cation producing a traction a pophysitis at the patella lower pole. Though not exclusive to the group, it is a typical sp orts-related injury in adolescent athletes who jump, e.g., high-jump, basketball. Treatment is with simple analgesia or NSAIDs, and rest. K hler \200\231s disease is osteonecrosis of the tarsal navicular. Changes may represent a developmental variation in ossi \201 cation and it presents with a painful limp. Weight bearing is more comfortable on the outside of the foot and the navicular is tender. Freiberg \200\231s disease, osteonecrosis of the metatarsal (usually the second) head follo wing trauma, is most common in adolescent women. Pain is localized and worse on weight bear ing, and swelling may be detectable. Osteochondritis dissecans \200 This is usually a solitary lesion of the medial femoral co ndyle. A fragment of articular cartilage and subchondral bone becomes demarcated and may fo rm an intra-articular loose body. The cause is unknown but may be due to abnormal ossi \201 cation or trauma. Similar features may occasionally be seen at the elbow, hip, and tal us. The condition is seen most often in male adolescents. Symptoms are mainly acute onset pain, an effusion, and limited movement of the joint. Plain radiographs will show a well-circumscribed, sclerotic lesion. \200 In young patient s before skeletal maturity there is a good chance of healing. After the epiphyses have clos ed, however, there is more risk of a loose body and secondary osteoarthritis. Arthroscopy c an assist in assessing the degree of damage and removing loose bodies. Surgery ranges from drilling the lesion in situ to encourage healing, to bone osteochondral allografts. Osteoid osteoma \200 This is a benign osteoid-forming tumor that can be an elusive cause of bone pain, radiculopathy, or arthritis in children and adults. It is uncommon and accoun ts for 10% of benign bone neoplasia. It is 2 \200\2233 times more common in men than women and the incidence is highest in the second and third decades of life. More than two-thirds of lesions occur in long bones and especially the femur and tibia. Pain is the primary symptom and may be referred. \200 The typical lesion is seen on plain radiography as an isolated, well- de \201 ned area of sclerosis with a radiolucent nidus often containing MISCELLANEOUS DISEASES OF BONE 473 speckles of calcium. Isotope bone scanning is a sensitive method of isolating a lesion and CT is valuable for localizing the nidus before surgical resection. Most individuals will respond, in part, to aspirin or NSAIDs. Provided the nidus is completely resected, surgery is curative. Fibrous dysplasia \200 This condition manifests as sporadic isolated or multifocal \201 brous bone cysts and occurs most often in the second to third decade of life in isolated (mono-os totic) disease, and before the age of 10 years in multifocal (polyostotic) disease. McCune-Albright syndrome is a triad of \201 brous dysplasia, hyper- pigmented \200\234 c af -au-lait \200\235 patches, and endocrine abnormalities. Laboratory tests are usually normal. \200 There is no speci \201 c treatment. Some lesio ns regress. Fractures heal in the normal way. Girls with McCune \200\223Albright-associated precocious puberty may respond to the aromatase inhibitor testolactone. CHAPTER 16 Metabolic bone diseases 474 Molecular abnormalities of collagen and \201 brillin \200 Collagen and \201 brillin a re major connective tissue proteins with important mechanical functions. This section will deal brie \202 y with osteogenesis imper fecta, Ehlers-Danlos syndrome, and Marfan syndrome. There are a number of types of collagen and a number of gene mutations leading to subtypes of collagen diseases. In this respect we will focus only on c ommon aspects of these uncommon conditions, although the reader should be aware that joint hypermobility syndrome (akin to Ehlers-Danlos hypermobility type) is probably far more comm on than most clinicians realize, and therefore, it is underdiagnosed. Osteogenesis imperfecta (OI) \200 OI (also known as brittle bone disease) is a spectrum o f conditions ranging from stillbirth to asymptomatic signs. The pathogenesis centers around abnormalitie s of type I collagen that is found not only in bone but also ligaments, teeth, sclerae, and skin. Ligament laxity, joint hypermobility, easy bruising, and poor dentition are common features . The differences between the four types of OI are shown in Table 16.13. Generalized osteopenia, deformity, and fractures are common bone and radiographic \201 ndings. The differential diagnosis in children includes juvenile os teoporosis, Cushing \200\231s disease, and homocystinuria. \200 There is no effective med ical therapy for OI. Patients may need surgery in late childhood/adulthood for deformities, and good dental hygiene. Children may present with multiple injuries that lead the clinician to consider child-abuse as a source for these \200\224absolute care must be taken in ensuring neither OI or anothe r collagen disorder is present before considering further action. Marfan syndrome \200 Marfan syndrome is characterized by long extremities (span/height ra tio >1.03), long \201 ngers and feet (arachnodactyly) with a hand/ height ratio >11% and hand/foot ratio >15%, tall stature (with upper segment/lower segment ratio <0.89), pectus d eformity of the chest wall (increasing risk of chest infections), high-arched palate, mandi bular hypoplasia, lens dislocations and myopia, and joint laxity. There is a predisposition to mitral valve prolapse and acute aortic root rupture. All patie nts should have an echocardiogram and thoracic CT/ MR to assess the aortic valve and arch. Beta-blockade has long been used to decrease the rate of aortic dilatation and improve long-term survival. However, there are little data to support this a pproach. MOLECULAR ABNORMALITIES OF COLLAGEN AND FIBRILLIN 475 In mouse models, losartan has been demonstrated to be an effective therapy through transforming growth factor- B antagonism, and may be an important advance i n the treatment of this disease. It is an autosomal dominant condition with complete penetrance and prevalence of 1 in 25,000. Table 16.13 Clinical and biochemical abnormalities in OI Type Clinical features Inheritance Defect Autosomal dominant Decreased production of type I procollagen I Normal bone growth. Normal dentition. Hearing loss in 50%. Blue sclera II Lethal. Stillbirths Autosomal dominant. Rearrangement of collagen IA/2A genes Autosomal reces- sive (rare) III Often deformed growth at birth and worsens. Poor dentition common. Hearing loss common. May have blue sclera Autosomal dominant or recessive Mutations in alpha-1 and alpha-2 collagen chains IV Often bone deformity and short stature. Poor dentition common. Hearing loss uncommon. Norma l sclera. Autosomal dominant Mutations in the alpha-2 chains A subgroup similar to Marfan syndrome but without vascular fragility exists. The condition is called congenital contractural arachnodactyly. \200 Numerous gene mutations have been found for both conditions, both linked to abnormalities of the protein \201 brillin type I and II. The main aim of follow-up and assessment of these individuals is the early detection and referral of cardiac valve and aortic disease. Musculoskeletal sympt oms should be managed in much the same way as outlined in the section below on joint hyperm obility syndrome. Ehlers \200\223Danlos syndrome \200 This is a clinically heterogeneous condition characte rized by skin fragility, ligament laxity, short stature, spinal deformity, vascular fragili ty, and (rarely) retinal detachment. 1 Retinal detachment and a history of early onset OA s hould lead the clinician to consider the CHAPTER 16 Metabolic bone diseases 476 diagnosis of Stickler \200\231s syndrome, which is often associated with a defect in the co llagen 2A1 (COL2A1) gene. There are at least nine genetic subtypes of Ehlers \200\223Danlos syndrome (EDS), of which at least \201 ve have de \201 ned biochemical abnormalities. The classi \201 cation, ge netic abnormalities and clinical features of EDS are shown in Table 16.14. Various inherita nce patterns are found dependent on the subtype of EDS. Hypermobility type EDS is the most common of these conditions and probably synonymous with JHS (see text below). Clinicians should be very sure they have con \201 dently excluded vascular (type IV) EDS as this is associated with signi \201 cant mortality. Therapy for these conditions centers on graded exercise and joint and skin protection. Some individuals require joint splints. Spinal deformity may need bracing or surgery and retina l disease requires ophthalmic expertise. Vascular rupture is a major concern in vascular type (type IV). This may occur even in the absence of documented aneurysms. This risk should always be taken into account during surge ry or pregnancy, indeed as should tissue fragility in general for all subtypes. Tissue vulnerability should always be at the forefront of planning any surgical intervention. Patients are often also resistant to local anesthetics \200\224the cause unclear. Failing to recognize this phenomenon can lead the clinician to inadvertently accus e the patient of being \200\234sensitive \200\235 or anxious without realizing that they t ruly do not get a full effect from the anesthetic. Dif \201 culties may arise during pregnancy \200\224patients may get additional joint pain from increased body weight, early rupture of membranes and premature birth, cervical incom petence and spontaneous abortion, excessive tissue trauma during delivery, and musculoskele tal complications in the post-natal period due to lifting and caring for the newborn. The diagnosis is primarily clinical. Genetic testing can be done by looking for abnormalities of collagen types I, III, and V, although these tests may not be widely available. A skin biopsy is required. Benign joint hypermobility syndrome (BJHS) \200 Joint hypermobility can be associated wit h a multisystem clinical picture and may be associated with diffuse chronic pain and fatigue. \200 Hypermobility i s usually considered present if a person satis \201 es four or more maneuvers in the nine- point Beighton hypermobility score (see Table 16.15). BJHS is excluded in the presence of Marfan syndrome or Ehlers \200\223 Danlos syndrome (exc luding hypermobility (Type III)). It may be synonymous with EDS hypermobility type. The revised (Brighton 1998) criteria for BJHS are shown in Table 16.16. BJHS is diagnosed i n the presence of two major, one major and two minor, or four minor criteria. Two minor cri teria will suf \201 ce where there is an unequivocally affected \201 rst-degree relative . The criteria serve to demonstrate the range of clinical \201 ndings in the condition. MOLECULAR ABNORMALITIES OF COLLAGEN AND FIBRILLIN 477 Table 16.14 Clinical features and genetics of EDS Type Inheritance Genetic defect Common Clinical picture Hyper-lax skin. Profound bruising and scarring Classical (type I and II) AD Abnormal pro-alpha 1 and 2 encoded by COL5A1 and A2 gene Hypermobility (Type III) AD Not known. ? Tenascin X insuf \201 ciency See BJHS, Table 16.16 Vascular (Type IV) AD Abnormal pro-alpha 1 encoded by COL3A1 gene Characteristic facies \200\224wide spaced eyes, lobeless ears. Vascular rupture Kyphoscoliosis (Type VI) AR De \201 ciency of lysyl hydroxylase Severe hypotonia. Scoliosis. Scleral fragility Atherochalasia (Type VII subtype) AD Abnormal pro-alpha 1 and 2 encoded by COL1A1 and A2 Severe dislocations. Skin laxity. Bruising. Hypotonia Dermatospraxis (Type VII subtype) AR De \201 ciency of procollagen 1 peptidase Severe, sagging skin. Bruising. Hernias Rare forms: X-linked (Type V) X-linked ? Milder version of Classical type Periodontal (Type VIII) AD ? Classical with gum fragility Type X ?AR ? Milder version of classical type with platelet aggregation AD-autosomal dominant; AR-autosomal recessive CHAPTER 16 Metabolic bone diseases 478 Treatment of hypermobility syndrome \200 Although hypermobility diminishes with age, the symptoms tend to continue and may worsen. It is important to remember that older patients may have been previously more mobile and that the Beighton score may not be an appropriate measure. A his tory of joint laxity should be sought. \200 Hypermobility extends beyond the joints highl ighted in the Beighton scale. The clinician should look at the \201 ngers, shoulders, nec k, hips, patellofemoral joint, and skin laxity. Analgesics are often unhelpful for chronic pain but have their place for the treatment of a cute symptoms. Pain and fatigue cause signi \201 cant morbidity. Joint stabilizing exercises with particular reference to core stability, posture and propri oception are bene \201 cial, as may be advice on avoiding overuse injuries and practical w ays of managing day-to-day activities. A global approach to joint stability and function, a s opposed to just treating regional symptoms, is effective. Pain management should be considered in chronic pain cases. This might include for example, cognitive behavioral therapy and the process is similar to that used in \201 bromyalgia (see Chapter 18). \200 The role of serotonergic/noradrenergic agents in these patients is unclear. In part there may be effective control of depression, however, there may also be d irect analgesic properties to these agents. Neuroleptic agents for neuropathic pain have not been studied in this group of patients. Ho wever, gabapentin or pregabalin and other similar agents may have a role. Table 16.15 Beighton hypermobility rating Subject has the ability to: Right Left 1. Passively dorsi \202 ex the \201 fth metacarpophalangeal joint to (cid:2) 90 1 1 2. Oppose the thumb to the volar aspect of the ipsilateral Forearm 1 1 3. Hyperextend the elbow (cid:2) 10 1 1 4. Hyperextend the knee (cid:2) 10 1 1 5. Place hands \202 at on the \202 oor without bending the knees 1 Possible total score 9 MOLECULAR ABNORMALITIES OF COLLAGEN AND FIBRILLIN 479 Table 16.16 The Brighton (1998) criteria for benign joint hypermobility syndrome Major criteria A Beighton score of 4 out of 9 or greater (current or historical) Arthralgias for > 3 months in four or more joints Minor criteria A Beighton score of 1, 2, or 3 out of 9 Arthralgias in one to three joints or back pain, either for longer than 3 months, spondylos is/spondylolisthesis Dislocation/subluxation in > one joint, or one joint on > one occasion Soft tissue rheumatism in three or more sites Marfanoid habitus Abnormal skin: striae, hyperextensibility, papyraceous scars Eye signs: drooping eyelids, myopia, Varicose veins, hernias, uterine/rectal prolapse Rare chondrodysplasias and storage disorders There are >150 distinctive chondrodysplasias r epresenting autosomal dominant, recessive, and X-linked patterns of inheritance. The \201 rst identi- \201 ed mutations were found in the collagen 2A1 gene, and are associated wi th premature osteoarthrosis. Such conditions include achondrogenesis, Kniest syndrome, spon dyloepiphyseal dysplasia, and the Stickler syndrome. Clinical features in the latter three conditions include premature joint destruction, joint/bone deformity, short stature, and pr ogressive myopia (with or without retinal detachment). Stickler syndrome patients are also prone to hernias and cardiac valvular and conduction disorders. Storage diseases associated with progressive skeletal dysplasia include: Mucopolysaccharidoses, e.g., Hurler, Hunter, Scheie \200 Mucolipidoses \200 Sphingolipi doses \200 Gaucher \200\231s disease \200 Fabry \200\231s disease. The detail and compl exities of these conditions is beyond the scope of this book. This page intentionally left blank 481 Chapter 17 Infection and rheumatic disease Introduction 482 Pyogenic nongonococcal and gonococcal arthritides 486 Pyogenic nongonococc al & gonococcal arthritides 488 Mycobacterium tuberculosis 490 Osteomyelitis 492 Lyme disea se 494 Rheumatic fever 496 CHAPTER 17 Infection and rheumatic disease 482 Introduction Infectious agents have been linked directly and indirectly (through organ- ism -speci \201 c and autoimmune responses) to a number of acute and chronic in \202 ammatory rheumatic diseases. This chapter will introduce some exam- ples of in \202 ammatory mecha nisms (see Table 17.1) and infectious agents (see Table 17.2) linked to rheumatic disease, and then discuss septic arthri- tis, osteomyelitis, Lyme disease, and rheumatic fever. Table 17.1 Pathogenesis of rheumatic disease associated with infection In \202 ammatory process Basic process Example Susceptibility Local infection at musculoskeletal sites Infection. Tissue in \202 ammation and direct damage Pyogenic septic arthritis Structural damage to joint replacement Diabetes, complement and immunoglobulin de \201 cie ncies Pathogen and pathogen-speci \201 c immune response Infection and organism-speci \201 c response. Immune response to intact organismor fragmen ts, probable immune complex- mediated tissue injury Syndromes associated with viral hepatitis, e.g., Sj gren \200\231s syndrome Not generally established Pathogens, immuneresponse, and auto immunity i. Cross-reactive immune response Rheumatic fever Rheumatoid arthritis Juvenile idiopathic arthritis Systemic lupus erythemat osus Certain MHC class I and II genes Receptor genes MHC class I and II genes T-cell receptor ge nes ii. Infection inferred but not established autoreactivity I N T R O D U C T O N I 4 8 3 CHAPTER 17 Infection and rheumatic disease 484 Table 17.2 Selected pathogens associated with arthritis Class Examples Disorder Bacteria Staphylococcus and Streptococcus Non-gonococcal arthritis Septic monoarthritis Osteomyelitis Neisseria spp Gonococcal arthritis Brucella Septic monoarthritis Spondylarthropathy Chlamydia Reactive (formerly, Reiter \200\231s) Mycobacteria M. tuberculosis Osteomyelitis Spinal disease Monoarthropathy Atypical mycobacteria M. avium complex M. malmoense Septic arthritis in immunosuppressed patients Spirochete Borrelia burgdorferi Lyme disease Viruses Parvovirus B19 Fifth disease Rubella Polyarthropathy Hepatitis B Polyarteritis nodosa Hepatitis C Cryoglobulinemia Sj gren \200\231s syndrome HIV Polyarthralgia and myopathy Vasculitis Sicca syndrome Protozoa Toxoplasma Polyarthritis Giardia Oligoarthritis Small-vessel vasculitis Trypanosoma Myopathy Helminths Toxocara