Many nonrheumatic systemic disorders cause musculoskeletal signs or symptoms, most commonly arthralgia, arthritis, myalgia, or bone pain. Sometimes these are trivial; however, occasionally they are the presentations of the underlying disease. This chapter outlines some systemic disorders that may present in the guise of a rheumatic disease. Rheumatic manifestations of malignancies are discussed in Chapter 50 . It is not our intent to describe comprehensively the clinical and laboratory manifestations or management of such disorders, which can be found in standard textbooks dealing with the specific diseases.
Disorders Related to Vitamin Deficiency or Excess
A number of disorders in which there is a deficiency or excess of certain vitamins result in signs or symptoms that suggest a rheumatic disease.
Rickets and Osteomalacia
Rickets and osteomalacia are diseases associated with defective ossification of bone matrix. Rickets is a disease of the physis, and occurs only in children. Osteomalacia is a disease affecting the other sites of bone formation and occurs in both children and adults. Rickets has many causes, which can be identified as being either calcipenic (mostly related to deficiency of the active form of vitamin D [1,25-dihydroxyvitamin D 3 ] or calcium deficiency), or phosphopenic (mostly resulting from renal wasting of phosphate) ( Table 45-1 ).
|TYPE||CAUSE OR BIOCHEMICAL ABNORMALITY|
|Vitamin D deficiency||Exclusion from light or insufficient dietary vitamin D|
|Calcium deficiency||Impaired calcium absorption in celiac disease, inflammatory bowel disease, scleroderma, or liver disease|
|Vitamin D resistance||Impaired parathormone-dependent proximal renal tubular reabsorption of phosphate|
|Vitamin D dependence|
|Type 1||Defect in renal 1-α-hydroxylase|
|Type 2||End-organ unresponsiveness to 1, 25-dihydroxyvitamin D 3|
|Hypophosphatasia||Decreased serum alkaline phosphatase|
Most cases of rickets worldwide result from exclusion from the sun for social or cultural reasons, or from insufficient dietary intake of vitamin D. Vitamin D–deficiency rickets is seldom encountered in developed countries, but may occur in infantile and adolescent forms in the rest of the world. It may also develop in the presence of sufficient dietary vitamin D, when there is impaired absorption because of celiac disease, inflammatory bowel disease, scleroderma, or liver disease. Maternal vitamin D insufficiency can influence fetal bone development as early as 19 weeks’ gestation. Some types (i.e., hypophosphatemic rickets and rickets associated with hypophosphatasia) are associated with defective mineralization and are classified as osteochondrodysplasias, as discussed in Chapter 53 . Disorders such as cystinosis that result in renal tubular acidosis, may present as rickets with pain in the joints and metaphyseal enlargement ( Fig. 45-1 ). Administration of some anticonvulsant medications interferes with vitamin D metabolism and, in children deprived of sunlight, may also be a cause.
The normal source of vitamin D 3 in humans is the skin in which ultraviolet rays of sunlight convert 7-dehydrocholesterol into the vitamin prohormone. This compound is subsequently transformed to the 25-hydroxy form in the liver and then to active 1,25-dihydroxyvitamin in the kidney ( Fig. 45-2 ). A deficiency of 1,25-dihydroxyvitamin D 3 may result from a nutritional deficiency, from hepatic failure to convert vitamin D to 25-hydroxyvitamin D, or from failure of the kidney to convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D 3 .
Hypophosphatemic vitamin D–resistant rickets, when expressed in infancy, leads to short stature, bowing of the legs, and ectopic calcification. This disorder is inherited as an X-linked recessive or autosomal dominant trait, although sporadic cases occur. The basic defect is impaired parathormone-dependent proximal renal tubular reabsorption of phosphate. A low serum phosphate concentration with a normal calcium level is characteristic.
Type I vitamin D–dependent rickets is an autosomal recessive defect in renal 1-α–hydroxylase that results in failure of hydroxylation of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D 3 . The onset of typical features of rickets occurs before the age of 2 years. Type II vitamin D–dependent rickets is rare and characterized by defective intracellular interaction between 1,25-dihydroxyvitamin D 3 and its receptor. Symptoms of rickets begin in early infancy. Alopecia and absence of eyelashes occur frequently in this disorder.
Hypophosphatasia, a rare autosomal recessive disorder caused by a mutation in the gene for tissue-nonspecific alkaline phosphatase (TNSALP), presents in infancy as severe rickets and fractures. Band keratopathy, proptosis, and papilledema develop. There may be early loss of teeth. Chondrocalcinosis and pseudogout may be associated features. There is a marked depression in the concentration of serum alkaline phosphatase. Treatment with nonsteroidal antiinflammatory drugs may lead to symptomatic improvement. Recent reports have noted an association between hypophosphatasia and chronic recurrent multifocal osteomyelitis (chronic nonbacterial osteomyelitis) in at least four children.
The child with rickets presents with joint pain and tenderness over the bones. Rickets can occasionally mimic inflammatory arthritis. Bowing of the long bones and splaying of the rib cage are characteristic features. Proximal muscle weakness, particularly of the lower extremities, is occasionally prominent. Defective bone growth results from suppression of calcification and maturation of epiphyseal cartilage. The result is a wide, frayed, irregular zone of uncalcified osteoid at the epiphyseal line—the rachitic metaphysis ( Fig. 45-3 ).
Ascorbic acid (vitamin C) is required for the formation of normal collagen and chondroitin sulfate. Vitamin C is neither synthesized nor stored in the body, and in the malnourished child a deficiency of dietary vitamin C may lead to scurvy with poor collagen synthesis and intradermal, gingival, and subperiosteal hemorrhage. Subperiosteal hemorrhage results in severe bone pain in the arms and legs; the child, usually an infant, assumes the flexed posture of pseudoparalysis and is irritable when picked up. Synovitis is rare, but hemarthroses may occur. In severe cases “scorbutic beads,” resulting from subluxation of the sternum at the costochondral junctions, may be visible on physical examination. Radiographs demonstrate subperiosteal new bone apposition. Treatment with oral or parenteral vitamin C results in definite improvement within 2 weeks.
A large number of physiological functions, organogenesis, and embryogenesis are affected by vitamin A and the derivative retinoids. Excess intake of vitamin A or retinoids causes pain in the extremities, irritability, apathy, alopecia, and delayed growth. Cortical hyperostosis (e.g., metatarsal bones, ulnas, spine) is a typical radiographic finding. Abnormal epiphyseal growth and periosteal new bone apposition occur occasionally.
Disorders Related to Environmental Factors
An endemic progressive osteoarthropathy primarily affecting children between the ages of 5 and 15 years, has a prevalence of 1% to 2% in affected areas of Tibet, northwestern China, northeastern Russia, and North Korea. It is unassociated with systemic or visceral manifestations. The etiology is uncertain, but it may result from Fusarium mycotoxins in fungus-infected grain or from selenium or iodine deficiency. Experimental animals fed grain infected with Fusarium species develop a similar form of epiphyseal dysplasia. There is depletion of aggregating proteoglycan (aggrecan), which results in an epiphyseal dysplasia from a zonal necrosis of chondrocytes of the epiphyses and metaphyses. These abnormalities increase in severity as long as the child lives in the endemic area and eats foods made with the contaminated grain. Excessive amounts of iron in the water and diet may contribute further to the polyarthritis. A genetic influence has been proposed in humans and in a murine model. Differences in gene expression by osteoarthritis cartilage and cartilage from adults with Kashin–Beck disease imply different pathogenic mechanisms.
Kashin–Beck disease causes symmetric polyarthritis and progressive enlargement and limitation of motion involving multiple joints (i.e., elbows, interphalangeal joints, wrists, knees, and ankles). In the school-age child, morning stiffness, aching, and muscle weakness are the initial symptoms. Joint effusions and laboratory indices of inflammation are absent early in the disease. The eventual dwarfing, epiphyseal deformity, and short digits resemble those encountered in the lysosomal storage diseases. Radiographic findings include irregular erosions of the small bones of the hands and feet. Treatment with selenium may be beneficial. Although iodine supplementation may be important, iodine deficiency is not thought to be a causative factor.
Mseleni Joint Disease
Mseleni joint disease is a chronic polyarthritis that affects a large proportion of the Tsonga population of the Mseleni area of northern Zululand on the eastern seaboard of South Africa. Onset of joint pain in childhood or adolescence is the first symptom of the disease. Restriction of movement and limitation of mobility develop at a variable rate. Mild stunting of growth is common, and a few patients develop severe dwarfing ( Table 45-2 ). The life span is not shortened. Characteristic radiographic abnormalities include irregularity of the surface, density, and shape of the epiphyses that progresses to a secondary osteoarthritis; in the hips, which bear the brunt of the disease, protrusio acetabuli occurs in females ( Fig. 45-4 ). Short metacarpals, ulna, and radius, and a deformity of the distal end of the ulna are also present. The diagnosis is usually obvious in the geographic and racial context, but the clinical presentation may suggest cretinism, brucellosis, hemochromatosis, alkaptonuria, and Legg–Calvé–Perthes disease at different stages of its development. Hips, knees, and ankles are the predominant sites of involvement in 66% of women, 25% of men, 7% of girls, and 4% of boys. Hands, wrists, shoulders, and elbows are less commonly affected. Neither a genetic nor an environmental cause has been identified. Handigodu, an idiopathic familial arthropathy found in a small area of southern India, closely resembles Mseleni joint disease, both clinically and radiographically.
|CHARACTERISTIC||MSELENI JOINT DISEASE||KASHIN–BECK DISEASE|
|First noted||6 yr to adult||6-10 yr|
|Inherited||Probably not||Probably not|
|Sex ratio||More females||More males|
|Stunting of growth||Slight to severe||Moderate|
|Posture||Lumbar lordosis, genu valgum||Lumbar lordosis, neck extended, knees flexed|
|Radiology||Fragmented epiphyses, flared metaphyses, brachymetacarpia, protrusio acetabuli, platyspondyly||Dysplastic interphalangeal, wrist, knee, ankle joints intraarticular loose bodies|
Fluorosis is endemic in certain areas of the world, particularly Asia and Africa, and results in chronic rheumatic symptoms in children. High levels of fluoride may occur naturally in the water supply or may result from pollution. Radiologically identified skeletal fluorosis was reported in 8% of children living in households with indoor coal-burning stoves in southern China, and in 4.4% of children in an area of Tanzania with high water fluoride content. Dental fluorosis is an early sign of toxicity. Knee pain is often an early symptom, followed by limb, hand, or characteristic spinal abnormalities that suggest a chronic inflammatory arthropathy. Radiographs demonstrate increased bone density and later show calcification of the spinal ligaments, intervertebral disks, and entheses. Cord compression can result from narrowing of the spinal canal. There is a marked periosteal reaction in the long bones.
Abnormalities of Uric Acid Metabolism
The term gout refers to a group of disorders characterized by hyperuricemia and deposition of monosodium urate monohydrate crystals in tissues. Its major clinical manifestations include an acute monoarthritis, most commonly in the first metatarsophalangeal joint; chronic erosive arthritis associated with subcutaneous periarticular deposits of urate (tophi); and nephrolithiasis, often leading to chronic renal failure.
Serum urate levels increase normally at puberty, particularly in males, from approximately 3.5 mg/dL (0.21 mmol/L) in childhood to an upper limit of 7 mg/dL (0.42 mmol/L) in adult males, and 6 mg/dL (0.36 mmol/L) in adult females. Above these concentrations, the serum becomes saturated with urate.
Gout may result from increased production or decreased excretion of uric acid ( Box 45-1 ). Diagnosis is confirmed by demonstration with compensated polarized light microscopy of negatively birefringent, needle-shaped monosodium urate crystals in synovial fluid ( Fig. 45-5 ). Ultrasound, magnetic resonance imaging, and dual-energy CT have also been used to demonstrate urate in tophi. Treatment of the acute attack with nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin, or with colchicine, is usually effective. Short-term corticosteroids may be needed. After the acute episode has subsided, allopurinol is the drug of choice for prevention of recurrences.
Increased Uric Acid Production
Becker syndrome (phosphoribosyl pyrophosphate synthetase superactivity)
Glycogenosis type I (glucose-6-phosphate dehydrogenase deficiency)
Decreased Uric Acid Excretion
Reduced glomerular filtration rate
Reduced fractional urate excretion
Sickle cell anemia
Increased levels of organic acids
Type I glycogen storage disease
Maple syrup urine disease
Salicylates (low dose)
Gouty arthropathy is rare in children. Treadwell identified 66 patients younger than 20 years who were reported between 1769 and 1960 and added two additional cases. In many early publications, the exact diagnosis is in doubt. The onset of gouty arthritis in a 14-year-old boy as a result of chronic compensated hemolysis of unknown cause has been described. Yarom and colleagues reported two children with marked hyperuricemia, mild renal failure, and acute, episodic, painful swelling of one joint, often the first metatarsophalangeal joint, knee, ankle, elbow, or a proximal interphalangeal joint of the hand. The authors have seen two unrelated boys with gout presenting as polyarthritis. Gout has also been reported in children with glycogen storage disease, malignancy, renal failure, and in an adolescent with juvenile idiopathic arthritis (JIA). Typical radiographic changes in a teenage boy are shown in Fig 45-6 .
An exceptionally large group of children and youth with juvenile gout has been reported in Taiwan. Juvenile gout accounted for 543 patients, 1.9% of all patients with the disease, and occurred in children as young as 8 years of age; 97% were male. Although greater than one half of the patients had a paternal history of gout, there is as yet no genetic explanation for this disease or for the uniquely high prevalence of gout in this age group in Taiwan.
The Lesch–Nyhan syndrome, first described in 1967 as an X-linked recessive disorder of uric acid metabolism and central nervous system dysfunction, results from a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) resulting in an overproduction of uric acid and uric aciduria. ( Table 45-3 ). There is a range of clinical phenotypes, the most severe of which is characterized by developmental delay, choreoathetosis, and spasticity beginning in the first year of life. These abnormalities progress, and by 2 to 4 years of age, the child develops self-mutilation (lips, fingers). With rare exceptions, affected boys do not develop acute gouty arthritis, at least not until the adolescent or adult years. Severity of the disorder is determined by the degree of HPRT deficiency resulting from unique mutations in each family. Variants of Lesch–Nyhan syndrome have much less neurologic disease, but more frequent gout and nephrolithiasis and its complications. Lesch–Nyhan variants have been called the Kelley–Seegmiller syndrome , although Torres et al present arguments against the appropriateness of this eponym.
|Clinical characteristics||Progressive development of choreoathetosis, spasticity, and mental retardation with self-mutilation|
|Biochemical defect||Deficiency of hypoxanthine-guanine phosphoribosyltransferase|
|Laboratory findings||Hyperuricemia and uric acid crystalluria|
Treatment with allopurinol, which blocks the conversion of xanthine and hypoxanthine to uric acid, effectively prevents the rheumatic complaints but does not alter the central nervous system disease, for which there is no effective therapy.
Phosphoribosyl Pyrophosphate Synthetase Superactivity
An X-linked mutation resulting in excessive activity of phosphoribosyl pyrophosphate synthetase (PPRPS), the enzyme that converts ribose-5-phosphate to PP-ribose-phosphate, results in increased purine production and is a rare cause of gout in children and young adults, sometimes with neurologic deficits and sensorineural deafness. Allopurinol effectively controls this disorder.
Glycogen storage disease type I (von Gierke disease) may be associated with the onset of gouty arthritis or tendinitis in childhood. Children with this disorder are stunted and have marked hepatomegaly, progressive mental retardation, abnormalities of platelet function, and hypoglycemia. Hyperuricemia results from increased catabolism of adenosine triphosphate and decreased urate excretion. Other types of glycogen storage disease and other metabolic disorders may have musculoskeletal manifestations, especially myopathy.
Calcium Pyrophosphate Deposition Disease
Crystals of calcium pyrophosphate dihydrate (CPPD) in synovial fluid and joint structures are associated with a chronic inflammatory and degenerative joint disease (pseudogout ). The wrists, knees, shoulders, and ankles are most commonly affected. Synovial fluid CPPD crystals are positively birefringent when viewed through a compensated polarized light microscope and are shorter than urate crystals. The disease occurs almost exclusively in older adults. It has rarely been noted in adolescence. Chondrocalcinosis, is a term that refers to the radiologic appearance of CPPD crystals in hyaline cartilage and fibrocartilage. Radiographs demonstrate linear calcifications in the menisci of the knee and in other cartilaginous structures, such as the triangular cartilage of the wrist. In descriptions of familial chondrocalcinosis, however, there have been rare reports of adolescents in whom the disorder presented as an acute, self-limited polyarthritis, often precipitated by exercise or trauma. The characteristics of the clinical disease have varied, however, depending on the kindred, age at onset, severity, and the presence of an associated osteoarthritis or chondrodysplasia.
Ochronosis (alkaptonuria) is an autosomal recessive defect in homogentisic acid oxidase resulting in the accumulation of homogentisic acid in tissues, pigmentation of cartilage (e.g., ears, sclerae, heart valves), calcification and ossification of the intervertebral disks, accelerated osteoporosis and osteoarthritis, and vascular disease. Black urine or staining of the diapers is often the sign that prompts referral of the child with this metabolic defect. Arthritis related to ochronosis has not been reported in children.
Defects in lipoprotein metabolism are associated with a high risk of premature atherosclerosis, coronary artery disease, and musculoskeletal abnormalities. Articular and tendinous swelling accompany essential familial hypercholesterolemia and hypertriglyceridemia; both of these conditions are autosomal dominant traits. In type II hyperlipoproteinemia (familial hypercholesterolemia), the Achilles, patellar, and extensor tendons of the hands are the principal locations of xanthomata. These lesions are associated with recurrent episodes of an acute migratory polyarthritis. In type IV hyperlipoproteinemia (hypertriglyceridemia), the hands, knees, and ankles are primarily affected by mild chronic or migratory oligoarthritis. The onset is often acute, and fever and an elevated white blood cell count may occur. The arthritis is self-limited but may be misdiagnosed as acute rheumatic fever, especially if the tendon xanthomata are mistaken for nodules.
Xanthomata of the tendons also occur in sitosterolemia, a syndrome resulting from accumulation of sterols derived from vegetable sources. The xanthomata initially appear in childhood and usually involve the extensor tendons of the hands and, later, the patellar, Achilles, and plantar tendons. Plasma sterol levels are elevated, and cholesterol levels may be increased.
In the sphingolipidoses, lipid accumulates in cells as a result of specific enzyme deficiencies. Of the many different sphingolipidoses, three have prominent musculoskeletal signs and symptoms ( Table 45-4 ). Farber lipogranulomatosis is an autosomal recessive disorder marked in the neonatal period by a hoarse cry and irritability. Painful red masses develop along tendon sheaths and over pressure points, as well as around the joints, especially the wrists, small joints of the hands and feet, elbows, knees, and ankles. Nodules have also been described in conjunctivae, ears, and nares. Epiglottal and laryngeal swelling results in repeated pulmonary infections, leading to death by about 2 years of age. Delayed motor development and mental retardation are prominent. The basic process underlying this disease is the cytoplasmic accumulation of a glycolipid ceramide in fibroblasts, histiocytes, macrophages, and neurons, attributable to a deficiency of lysosomal acid ceramidase. The central nervous system, retina, respiratory tract, heart, liver, spleen, lymph nodes, synovium, and bone are all affected to various degrees. Radiographic changes in the skeleton consist of osteoporosis, juxtaarticular erosions, and disruption of the normal trabecular pattern.
|Farber disease||AR||Painful red masses along tendons at wrists, elbows, knees, and ankles|
|Gaucher disease||AR||Osteoporosis with pathological fractures of femur and vertebrae|
|Fabry disease||XR||Recurrent fever and severe distal arthritis with burning pain; rash|
In Gaucher disease, an autosomal recessive disorder, glucocerebroside accumulates in the reticuloendothelial cells of the bone marrow, spleen, liver, lymph nodes, and viscera as a result of deficiency of glucocerebrosidase. Hepatosplenomegaly and pathological fractures of the femur or vertebrae suggest the diagnosis. Premature osteoarthritis of weight-bearing joints is an important feature of the juvenile form of this disease. One of the diagnostic hallmarks of Gaucher disease is widening of the distal femur. Characteristic areas of rarefaction and osteoporosis are visible in the peripheral and axial skeleton, including the skull.
Fabry disease is characterized by the progressive accumulation of birefringent deposits of triglycosylceramide in the endothelial, perithelial, and smooth muscle cells of blood vessels, and in ganglion and perineural cells of the autonomic nervous system. The disease results from an X-linked recessive deficiency of α-galactosidase A, resulting in the intralysosomal accumulation of glycosphingolipids. The disease most often becomes evident in boys around 6 years of age and in girls one or two years later. Children often present with chronic pain and recurrent episodes of fever and severe burning pain in the extremities, particularly the hands and feet, diarrhea or abdominal pain, hypohidrosis, and heat and cold intolerance. Osteoporosis and osteonecrosis may occur especially in weight-bearing joints such as the hips. A typical rash consisting of purple papules, angiokeratoma corporis diffusum universale, accompanies the other features of Fabry disease. Enzyme activity may be assayed in skin fibroblasts and leukocytes. Female heterozygotes may develop milder forms of this disorder. Renal, cardiac, or cerebral disease leads to death in the mid-adult years in untreated patients. Recombinant α-galactosidase enzyme replacement therapy and renal allograft transplantation, if renal failure has developed, correct the metabolic defect. A diagnostic algorithm has been suggested. A number of other rare disorders present in a manner similar to that of the diseases discussed earlier, but they have not been clearly identified as involving a lysosomal degradative enzyme. One such entity, multicentric reticulohistiocytosis, or lipoid dermatoarthritis, is a rare, mutilating, symmetric polyarthritis. An important diagnostic clue is the presence of clear histiocytic cutaneous nodules ( Fig. 45-7 ). Stiffness and contractures appear early, and the joints (with a predilection for the interphalangeal and metacarpophalangeal joints) are swollen and tender. Biopsy of the lesions of the skin, mucous membranes, or synovium demonstrates lipid-laden histiocytes and foamy multinucleated giant cells. Most described cases have been in adults and are not familial. The disease has been associated with a number of autoimmune disorders and malignancies.