Chronic Musculoskeletal Pain in Children: Part I. Initial Evaluation

JENNIFER L. JUNNILA; VICTORIA W. CARTWRIGHT

JENNIFER L. JUNNILA, M.D., M.P.H., AND VICTORIA W. CARTWRIGHT, M.D., M.S.

Am Fam Physician. 2006;74(1):115-122

This is part I of a two-part article on musculoskeletal pain in children. Part II, “Rheumatic Causes,” will appear in the July 15, 2006, issue of AFP.

Author disclosure: Nothing to disclose.

Musculoskeletal pain can be difficult for children to characterize. Primary care physicians must determine whether the pain may be caused by a systemic disease. Change in activity, constitutional symptoms such as fevers and fatigue, or abnormal examination findings without obvious etiology should raise suspicion for rheumatic disease. A complete physical examination should be performed to look for extra-articular signs of rheumatic disease, focusing on but not limited to the affected areas. A logical and consistent approach to diagnosis is recommended, with judicious use of laboratory and radiologic testing. Complete blood count and erythrocyte sedimentation rate measurement are useful if rheumatic disease is suspected. Other rheumatologic tests (e.g., antinuclear antibody) have a low pretest probability in the primary care setting and must be interpreted cautiously. Plain radiography can exclude fractures or malignancy; computed tomography and magnetic resonance imaging are more sensitive in detecting joint inflammation. Family physicians should refer children to a subspecialist when the diagnosis is in question or subspecialty treatment is required. Part II of this series discusses rheumatic diseases that present primarily with musculoskeletal pain in children, including juvenile arthritis, the spondyloarthropathies, acute rheumatic fever, Henoch-Schönlein purpura, and systemic lupus erythematosus.

Musculoskeletal pain during childhood is common; in population surveys, 16 percent of school-age children reported limb pain.¹ Musculoskeletal pain can be difficult for children to characterize and can cause children and parents great anxiety. Although the cause of acute musculoskeletal pain in children usually is obvious, the cause of chronic musculoskeletal pain or pain that has associated systemic symptoms can be more difficult to determine. The term “growing pains” may be applied mistakenly to children who have a serious rheumatic or malignant disease. Children who have unusual symptoms or abnormal findings on physical examination should be evaluated carefully.

A logical and consistent approach to diagnosis is necessary to treat the pain and its cause effectively and to avoid the long-term complications of untreated disease. This article, part I of a two-part series, outlines a primary care approach to evaluating and diagnosing the child with musculoskeletal pain who may have a rheumatic illness. Part II² discusses common rheumatic causes of musculoskeletal pain in children, as well as treatment and referral recommendations. Nonrheumatic causes of musculoskeletal pain are much more common than rheumatic causes. An exhaustive list of the many possible causes of musculoskeletal pain in children is beyond the scope of this series but should be considered when screening for underlying disease in children with joint complaints.

Clinical recommendation	Evidence rating	References
CBC and ESR tests are recommended for children with chronic joint pain to help exclude infection and malignancy.	C	¹⁶
The ANA and rheumatoid factor tests have a low positive predictive value in the primary care setting and are not recommended for routine use in the initial diagnosis of joint pain.	C	^{23,25,26,28,30}
Plain radiography should be the first radiologic study used. However, radiographs are typically more useful in excluding certain conditions (e.g., malignancy) than in making a positive diagnosis of arthritis.	C	^20,33

Approach to the Child with Musculoskeletal Pain

A suggested approach to the child with musculoskeletal pain is provided in Figure 1. Key characteristics for distinguishing between benign and serious causes of musculoskeletal pain are listed in Table 1.³

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HISTORICAL FACTORS

Musculoskeletal disorders have multiple etiologies,⁴ and the history and physical examination greatly aid in narrowing the differential diagnosis.^5,6 For example, mechanical joint pain is more likely to be acute, to involve point tenderness, and to be worse at the end of the day or with overuse, whereas inflammatory joint pain generally is less well defined or described as “stiff,” is worse in the mornings,⁷ and feels better with use.

The family physician must first determine the specific location of the pain. Pain localized to areas other than the joint may be related to connective tissue or muscle involvement.⁸ The possibility of referred pain, such as hip disease with associated groin or knee pain, should be considered. The joint distribution and the number of joints involved will help organize the evaluation.^9,10 For example, arthritis in only one joint may be caused by pauciarticular juvenile arthritis, septic arthritis, or a seronegative spondyloarthropathy. Inflammatory diseases such as polyarticular juvenile rheumatoid arthritis, mixed connective tissue disease, and systemic lupus erythematosus usually cause symmetric arthritis affecting multiple joints.^5,11

The next step is to determine whether the process is inflammatory. Prolonged morning stiffness, swelling, and constitutional symptoms (e.g., fever, weight loss, fatigue) suggest inflammatory processes such as arthritis or vasculitis. Other historical descriptors include alleviating and aggravating factors and frequency and duration of pain. Rapid onset of pain suggests trauma, sepsis, hemarthrosis, or malignancy. Onset of pain over several days suggests infectious or reactive arthritis. The physician should be concerned if a child limits daily activities.

Finally, the physician should search for extra-articular symptoms that would be helpful in making the diagnosis. Characteristic rashes accompany several rheumatic causes of musculoskeletal pain: parents may notice the malar rash of systemic lupus erythematosus or the heliotrope rash of juvenile dermatomyositis.^8,12–14 Classic clinical scenarios may further indicate a systemic disease: the arthritis and rash of Henoch-Schönlein purpura typically follow an upper respiratory tract infection, whereas reactive arthritis typically follows a genitourinary or gastrointestinal tract infection. A painful red eye may accompany the spondyloarthropathies.

PHYSICAL EXAMINATION

A complete physical examination may disclose additional clinical signs that point toward a diagnosis. A general appearance of well-being is reassuring regarding multiorgan involvement; however, a child with only one or two joints affected by arthritis may appear well overall. Lymphadenopathy or hepatosplenomegaly can be associated with malignancy and inflammatory diseases such as systemic lupus erythematosus. Rashes are characteristic in patients with acute rheumatic fever, Henoch-Schönlein purpura, and the systemic form of juvenile arthritis. Gottron’s papules—erythematous plaques overlying extensor surfaces of knuckles—are pathognomonic for juvenile dermatomyositis.^8,14,15 A comprehensive examination will help exclude infectious, traumatic, and oncologic etiologies of musculoskeletal complaints.^16,17

The musculoskeletal examination may demonstrate arthritis or myositis. Specific findings of arthritis include warmth, swelling, loss of range of motion, and guarding of the joint. Although these are classic inflammatory signs, they may be minimal or difficult to detect even in juvenile arthritis. Muscle mass and strength also should be evaluated. Long-standing arthritis may have associated bony enlargement or muscle atrophy.^18,19 Proximal muscle weakness is present in juvenile dermatomyositis and can be subtle without performing formal strength testing of axial muscles. Focal tenderness or abnormalities may suggest orthopedic or oncologic²⁰ etiologies rather than inflammatory causes.

FOLLOW-UP

Many rheumatic clinical entities tend to develop over weeks or months (Table 1).³ Close follow-up to determine the child’s clinical course therefore is recommended. Resolution of symptoms and continued absence of worrisome features can reassure the child and family that a chronic inflammatory disease is not present; conversely, additional signs and symptoms noted at a follow-up visit may direct further evaluation or referrals, if warranted.

Adjunctive Tests

Laboratory tests and radiologic studies may help to support a diagnosis in a child with a high likelihood of inflammatory musculoskeletal illness and may exclude worrisome diagnoses such as infection and malignancy. The need for adjunctive tests is determined by the child’s clinical features. Selected tests used in the diagnosis of musculoskeletal pain are listed in Table 2.^{4,13,16,17,20–34}

Test*	Condition associated with positive or abnormal results	Diagnostic capabilities	When test should be conducted
Laboratory
CBC	Leukocytosis or thrombocytosis: inflammation, infection Cytopenias: SLE,²¹ malignancy¹⁶	White blood cell count typically is normal in children with juvenile RA and in 66 percent of children with leukemia^17,22 Elevated white blood cell count and platelets are seen with infection and in inflammatory conditions such as systemic onset juvenile RA	Initial evaluation of chronic joint pain or clinical suspicion of SLE to check for cytopenias
ESR	Inflammation, infection	Discordant ESR and platelet count worrisome for malignancy¹⁶ Can be normal with arthritis²³ Can be elevated with infection, juvenile RA, and SLE but cannot discriminate between different etiologies of inflammation	Initial evaluation of chronic joint pain or pain out of proportion to clinical findings
ANA	SLE, vasculitis, juvenile RA	Positive in approximately 10 to 40 percent of healthy children²⁴ Titers greater than 1:320 more likely to be true-positive for inflammatory diseases²⁵ Higher risk for iritis in ANA-positive juvenile RA²⁶	In a patient with juvenile RA to recommend frequency of iritis screening or when high clinical suspicion for SLE (see Table 3)
Rheumatoid factor	Juvenile RA	Approximately 70 percent sensitivity and 82 percent specificity for RA^27–29 Low positive predictive value in primary care setting	To assist in diagnosis of juvenile RA, SLE, or mixed connective tissue disease, usually after referral
Anti–double-stranded DNA	SLE	Positive in 73 percent of children with SLE²¹	To quantify disease activity in patients with confirmed diagnosis
HLA-B27 genotype	Spondyloarthropathy	Genetic marker rare in blacks but present in 7 to 10 percent of non-Latino whites and in up to 50 percent in other ethnicities³⁰ 86 percent sensitivity and 96 percent specificity for spondyloarthropathy³¹	To classify arthritis, usually after referral.
HLA-B27 genotype	Spondyloarthropathy		Consider use if family history of psoriasis, inflammatory bowel disease, arthritis and back pain, or spondyloarthropathy
Radiology
Plain radiography	Bone tumors,^16,20 fractures, chronic osteomyelitis	Normal findings in juvenile RA or early osteomyelitis Abnormal in only 44 percent of patients with leukemia³²	Initial evaluation of patient with significant joint or bone pain
MRI, CT	Periarticular inflammation, tumors, cartilage abnormalities⁴	More sensitive than plain film radiographs in detecting malignancy and inflammatory conditions such as sacroiliitis^20,33 Intravenous gadolinium enhancement helps detect inflammation	When joint examination is equivocal or difficult (e.g., in temporomandibular or hip joints)
Echocardiography	Pericardial fluid in patients with systemic juvenile RA and pericardial friction rub Evaluation for carditis in acute rheumatic fever Evaluation for pericarditis in SLE	Diagnostic procedure of choice for detecting pericarditis or carditis	In patients with fever, rash, and arthritis³⁴
Echocardiography			In patients who have SLE with cardiac symptoms

LABORATORY TESTS

Rheumatologic laboratory tests can confirm a clinically suspected diagnosis for the cause of musculoskeletal pain in children but are not diagnostic in themselves. If a serious rheumatic cause is suspected, the family physician should use laboratory tests judiciously and interpret them in the context of the child’s clinical presentation. History and physical examination findings help determine whether laboratory tests are needed. A normal complete blood count (CBC) and erythrocyte sedimentation rate (ESR) and a negative antinuclear antibody (ANA) test result reduces the likelihood of infection, cancer, and systemic lupus erythematosus (Table 2^{4,13,16,17,20–34}).^13,16,17 The ANA must be interpreted according to the patient’s pretest probability of rheumatic disease. In the primary care setting this usually is low, so most positive results are false-positive (Table 3).³⁵

ANA titer	Positive likelihood ratio*	Likelihood of disease (%)
ANA titer	Positive likelihood ratio*	Primary care setting†	Specialty setting‡
> 1:1280	9.9	17.0	81
1:640	2.2	4.2	49
1:320	1.1	2.1	32
1:160	0.8	1.6	26
1:80	0.8	1.6	26
1:40	0.7	1.4	23
1:20	0.4	0.8	15

The use of an arthritis or rheumatoid panel is not recommended because this can lead to false-positive results, unnecessary expense, and patient worry; each test is best used in the appropriate clinical setting. Some laboratory tests, such as the human leukocyte antigen B27 (HLA-B27) and rheumatoid factor, may help determine prognosis in rheumatic disease but cannot be used to make a diagnosis and therefore are most useful in the specialist setting. The tests most useful in the primary care setting include the CBC (to detect inflammation or cytopenias), ESR (a sensitive but not specific marker of inflammation), and ANA (with clinical suspicion for systemic lupus erythematosus).

RADIOLOGIC STUDIES

A worrisome history, atypical or systemic symptoms, or abnormal physical findings in a child with musculoskeletal pain warrant use of radiologic studies. Normal plain radiographs can be reassuring regarding fracture and some malignancies, such as bony lesions.^20,32,36 However, certain cancers (e.g., leukemia, lymphoma) do not have characteristic radiographic abnormalities, and most children with malignancy therefore will not have abnormal radiographs.^17,22,32

Various modalities may help identify the extent of musculoskeletal disease or exclude other causes of joint complaints. Magnetic resonance imaging (MRI) has the greatest sensitivity for inflammatory processes^20,37 but is time-consuming and costly and should be used judiciously. Computed tomography or MRI may be helpful to characterize the anatomy when the location of the affected joint makes physical examination difficult (e.g., in the hip or temporomandibular joints).^37,38 Echocardiography is useful in acute rheumatic fever to detect carditis and valvular lesions³⁴ and in systemic onset juvenile rheumatoid arthritis or systemic lupus erythematosus to detect pericarditis.

Other Considerations

Several conditions are useful to note because they illustrate how a thorough history and detailed physical examination with adjunctive laboratory and radiologic tests can identify the diagnosis. These are malignancy, benign nocturnal limb pains, and benign hypermobility syndrome.

MALIGNANCY

Physicians must be alert to the possibility of malignancy as the cause of musculoskeletal pain in children. Cancer occurs in about one in 6,400 children annually, and acute lymphoblastic leukemia, the most common leukemia, has an annual incidence of one to five per 100,000.³⁹ Patients with other types of cancers also may present with nonspecific complaints such as fever and bone or joint pain.⁴⁰ Additionally, malignant musculoskeletal tumors account for 5 to 10 percent of malignant neoplasms of childhood; the most common of these lesions are osteosarcoma, Ewing’s sarcoma, and rhabdomyosarcoma.⁴¹

Cancer should be considered in a child who has pain out of proportion to clinical findings, or suggestive laboratory or radiologic test results. Pain is the most common presenting symptom of malignancy,^16,20 with swelling and reactive arthritis over the involved bone occurring a few weeks or months after onset of pain. Children with fevers, weight loss, and abnormalities on laboratory evaluation may already have metastases. Tumors may be indicated on plain radiographs by abnormalities such as periosteal elevation, cortical destruction with a “moth-eaten” appearance, and an apparent soft tissue mass.³² A bone scan may localize involved areas, and computed tomography or MRI may further delineate the lesion. Steroids are contraindicated until malignancy has been excluded in children who appear ill and have joint pain or swelling.

BENIGN NOCTURNAL LIMB PAINS OF CHILDHOOD

Benign nocturnal limb pains of childhood (formerly known as “growing pains”) are cramping pains of the thigh, shin, and calf; they affect approximately 35 percent of children four to six years of age, although they may occur up to age 19.⁴¹ The exact pathophysiology of the pain is unknown: it is not associated with the pubertal growth spurt but theoretically may be associated with growth in general.⁴² The pain typically occurs in the evening or at night, may awaken the child from sleep, and disappears by morning. Benign nocturnal limb pains are not associated with a limp.

The classic clinical presentation in the absence of other inflammatory or chronic signs and symptoms should reinforce the benign nature of this entity. Physical examination of the child is normal. No further diagnostic testing is necessary in the absence of worrisome complaints or anatomic abnormalities. Parents should be reassured that there are no long-term sequelae.

BENIGN HYPERMOBILITY SYNDROME

Benign hypermobility syndrome occurs typically in young girls before or during adolescence. Patients with this condition present with musculoskeletal pain associated with generalized hypermobility of joints but no associated congenital syndrome. The prevalence of this condition is estimated to range from 8 to 20 percent.^1,43 Connective tissue diseases such as Marfan syndrome and Ehlers-Danlos syndrome should be considered. Various criteria for hypermobility exist,¹ including evaluation of mobility of the thumb onto the forearm; degree of hyperextension of the metacarpals, elbows, and knees; and the ability to place the palms on the floor with knees straight.

Hypermobility is diagnosed with reassuring history and specific physical examination findings. Close follow-up and review of the child’s complaints and physical examination findings usually will direct further referral or reassurance. Children with hypermobility syndrome should be reassured of the benign nature of their condition. If symptoms are significant enough to interfere with activities, the child may need to alter physical activity temporarily or receive formal physical therapy. Prolonged pain symptoms should prompt review of any applicable athletic program and evaluation for other diagnoses.

Sherry DD, Malleson PN. Nonrheumatic musculoskeletal pain, and idiopathic musculoskeletal pain syndromes. In: Cassidy JT, Petty RE, eds. Textbook of Pediatric Rheumatology. 4th ed. Philadelphia, Pa.: Saunders, 2001: 362–81.

Junnila JL, Cartwright VW. Chronic musculoskeletal pain in children. Part II: Rheumatologic causes. Am Fam Physician [In press].

Malleson PN, Beauchamp RD. Rheumatology: 16. Diagnosing musculoskeletal pain in children. CMAJ. 2001;165:183-8.

Kasper MJ, Robbins L, Root L, Peterson MG, Allegrante JP. A musculoskeletal outreach screening, treatment, and education program for urban minority children. Arthritis Care Res. 1993;6:126-33.

Brewer EJ, Bass J, Baum J, Cassidy JT, Fink C, Jacobs J, et al. Current proposed revision of JRA criteria. JRA Criteria Subcommittee of the Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association section of the Arthritis Foundation. Arthritis Rheum. 1977;20(suppl 2):195-9.

Manners PJ, Diepeveen DA. Prevalence of juvenile chronic arthritis in a population of 12-year-old children in urban Australia. Pediatrics. 1996;98:84-90.

Calabro JJ, Marchesano JM. The early natural history of juvenile rheumatoid arthritis. A 10-year follow-up study of 100 cases. Med Clin North Am. 1968;52:567-91.

Pachman LM, Hayford JR, Chung A, Daugherty CA, Pallansch MA, Fink CW, et al. Juvenile dermatomyositis at diagnosis: clinical characteristics of 79 children. J Rheumatol. 1998;25:1198-204.

Cassidy JT, Levinson JE, Bass JC, Baum J, Brewer EJ, Fink CW, et al. A study of classification criteria for a diagnosis of juvenile rheumatoid arthritis. Arthritis Rheum. 1986;29:274-81.

Huppertz HI, Bentas W, Haubitz I, Girschick HJ, Ganser G, Thon A, et al. Diagnosis of paediatric Lyme arthritis using a clinical score. Eur J Pediatr. 1998;157:304-8.

Ramos-Niembro F, Alarcon-Segovia D, Hernandez-Ortiz J. Articular manifestations of mixed connective tissue disease. Arthritis Rheum. 1979;22:43-51.

Yell JA, Mbuagbaw J, Burge SM. Cutaneous manifestations of systemic lupus erythematosus. Br J Dermatol. 1996;135:355-62.

Takei S, Maeno N, Shigemori M, Imanaka H, Mori H, Nerome Y, et al. Clinical features of Japanese children and adolescents with systemic lupus erythematosus: results of a 1980–1994 survey. Acta Paediatr Jpn. 1997;39:250-6.

Shehata R, al-Mayouf S, al-Dalaan A, al-Mazaid A, al-Balaa S, Bahabri S. Juvenile dermatomyositis: clinical profile and disease course in 25 patients. Clin Exp Rheumatol. 1999;17:115-8.

Guidelines for the diagnosis of rheumatic fever. Jones Criteria, 1992 update. Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association [Published correction appears in JAMA 1993;269:476]. JAMA. 1992;268:2069-73.

Cabral DA, Tucker LB. Malignancies in children who initially present with rheumatic complaints. J Pediatr. 1999;134:53-7.

Trapani S, Grisolia F, Simonini G, Calabri GB, Falcini F. Incidence of occult cancer in children presenting with musculoskeletal symptoms: a 10-year survey in a pediatric rheumatology unit. Semin Arthritis Rheum. 2000;29:348-59.

Sherry DD, Stein LD, Reed AM, Schanberg LE, Kredich DW. Prevention of leg length discrepancy in young children with pauciarticular juvenile rheumatoid arthritis by treatment with intraarticular steroids. Arthritis Rheum. 1999;42:2330-4.

Vostrejs M, Hollister JR. Muscle atrophy and leg length discrepancies in pauciarticular juvenile rheumatoid arthritis. Am J Dis Child. 1988;142:343-5.

Mehlman CT, Crawford AH, McMath JA. Pediatric vertebral and spinal cord tumors: a retrospective study of musculoskeletal aspects of presentation, treatment, and complications. Orthopedics. 1999;22:49-56.

Ferraz MB, Goldenberg J, Hilario MO, Bastos WA, Oliveira SK, Azevedo EC, et al. Evaluation of the 1982 ARA lupus criteria data set in pediatric patients. Committees of Pediatric Rheumatology of the Brazilian Society of Pediatrics and the Brazilian Society of Rheumatology. Clin Exp Rheumatol. 1994;12:83-7.

Tuten HR, Gabos PG, Kumar SJ, Harter GD. The limping child: a manifestation of acute leukemia. J Pediatr Orthop. 1998;18:625-9.

Gardner GC, Kadel NJ. Ordering and interpreting rheumatologic laboratory tests. J Am Acad Orthop Surg. 2003;11:60-7.

Malleson PN, Mackinnon MJ, Sailer-Hoeck M. What to do with a positive ANA test? Pediatr Rheumatol online journal, May–June 2004. Accessed February 3, 2006, at: www.pedrheumonlinejournal.org/may-june/ANA.htm.

McGhee JL, Kickingbird LM, Jarvis JN. Clinical utility of antinuclear antibody tests in children. BMC Pediatr. 2004;4:13.

American Academy of Pediatrics Section on Rheumatology and Section on Ophthalmology: Guidelines for ophthalmologic examinations in children with juvenile rheumatoid arthritis. Pediatrics. 1993;92:295-6.

Bas S, Genevay S, Meyer O, Gabay C. Anticyclic citrullinated peptide antibodies, IgM and IgA rheumatoid factors in the diagnosis and prognosis of rheumatoid arthritis. Rheumatology. 2003;42:677-80.

Bas S, Perneger TV, Seitz M, Tiercy JM, Roux-Lombard P, Guerne PA. Diagnostic tests for rheumatoid arthritis: comparison of anti-cyclic citrullinated peptide antibodies, anti-keratin antibodies and IgM rheumatoid factors. Rheumatology. 2002;41:809-14.

Hoffman IE, Peene I, Pottel H, Union A, Hulstaert F, Meheus L, et al. Diagnostic performance and predictive value of rheumatoid factor, anti-citrullinated peptide antibodies, and the HLA shared epitope for diagnosis of rheumatoid arthritis. Clin Chem. 2005;51:261-3.

Gran JT, Husby G. HLA-B27 and spondyloarthropathy: value for early diagnosis?. J Med Genet. 1995;32:497-501.

Prakash S, Mehra NK, Bhargava S, Malaviya AN. HLAB27 related “unclassifiable” seronegative spondyloarthropathies. Ann Rheum Dis. 1983;42:640-3.

Rogalsky RJ, Black GB, Reed MH. Orthopaedic manifestations of leukemia in children. J Bone Joint Surg Am. 1986;68:494-501.

Battafarano DF, West SG, Rak KM, Fortenbery EJ, Chantelois AE. Comparison of bone scan, computed tomography, and magnetic resonance imaging in the diagnosis of active sacroiliitis. Semin Arthritis Rheum. 1993;23:161-76.

Lanna CC, Tonelli E, Barros MV, Goulart EM, Mota CC. Subclinical rheumatic valvitis: a long-term follow-up. Cardiol Young. 2003;13:431-8.

Malleson PN, Sailer M, Mackinnon MJ. Usefulness of antinuclear antibody testing to screen for rheumatic diseases. Arch Dis Child. 1997;77:299-304.

Trueworthy RC, Templeton KJ. Malignant bone tumors presenting as musculoskeletal pain. Pediatr Ann. 2002;31:355-9.

Kuseler A, Pedersen TK, Gelineck J, Herlin T. A 2 year follow up study of enhanced magnetic resonance imaging and clinical examination of the temporomandibular joint in children with juvenile idiopathic arthritis. J Rheumatol. 2005;32:162-9.

Argyropoulou MI, Fanis SL, Xenakis T, Efremidis SC, Siamopoulou A. The role of MRI in the evaluation of hip joint disease in clinical subtypes of juvenile idiopathic arthritis. Br J Radiol. 2002;75:229-33.

Steliarova-Foucher E, Stiller C, Kaatsch P, Berrino F, Coebergh JW, Lacour B, et al. Geographical patterns and time trends of cancer incidence and survival among children and adolescents in Europe since the 1970s (the ACCIS project): an epidemiological study. Lancet. 2004;364:2097-105.

Redaelli A, Laskin BL, Stephens JM, Botteman MG, Pashos CL. A systematic literature review of the clinical and epidemiological burden of acute lymphoblastic leukaemia (ALL). Eur J Cancer Care. 2005;14:53-62.

Evans AM, Scutter SD. Prevalence of “growing pains” in young children. J Pediatr. 2004;145:255-8.

Noonan KJ, Farnum CE, Leiferman EM, Lampl M, Markel MD, Wilsman NJ. Growing pains: are they due to increased growth during recumbency as documented in a lamb model?. J Pediatr Orthop. 2004;24:726-31.

Grahame R, Bird H. British consultant rheumatologists’ perceptions about the hypermobility syndrome: a national survey. Rheumatology. 2001;40:559-62.