AAOS Comprehensive Orthopaedic Review

Section 3 - Pediatrics

Chapter 35. Connective Tissue Diseases, Arthritides, and Other Diseases

I. Connective Tissue Diseases

A. Marfan syndrome (

Table 1)


1. Overview


a. Marfan syndrome is a connective tissue disorder affecting elasticity that results in joint laxity, scoliosis, and cardiac valve and aortic dilatation, among others.


b. Incidence is 1 in 10,000, with no ethnic or gender predilections.


2. Pathoanatomy



Autosomal dominant; 25% new mutations


[Table 1. Marfan Syndrome]


Figure 1. MRI of the lower spine in a patient with Marfan syndrome demonstrates dural ectasia of the lumbosacral junction.]


Mutation is in fibrillin-1 gene on chromosome 15q21; multiple mutations have been identified.


3. Evaluation


a. Affected individuals often are tall and thin with long limbs (dolichostenomelia) and spider-like fingers (arachnodactyly) and joint hypermobility.


b. Positive wrist sign (Walker sign)—The thumb and little finger overlap when used to encircle the opposite wrist.


c. Positive thumb sign (Steinberg sign)—When the thumb is adducted across the hand and the fingers are closed in a fist over it, the thumb protrudes out the other side of the hand.


d. Arm span-to-height ratio >1.05


e. Cardiac defects, especially aortic root dilatation and later dissection, are common; accordingly, if Marfan is suspected, an echocardiogram and a cardiology consultation should be ordered.


f. Scoliosis is seen in 60% to 70% of patients with Marfan and is hard to brace. Because dural ectasia is common (>60%), an MRI should be obtained before surgery (Figure 1).


g. Pectus excavatum and spontaneous pneumothoraces can occur in the chest (

Figure 2).


h. Superior lens dislocation (ectopia lentis) and myopia are common. (Remember inferior lens dislocation is seen in homocysteinuria.)


i. Protrusio acetabuli and severe pes planovalgus are seen in the lower extremity.


[Figure 2. Pectus deformity in a patient with Marfan syndrome.]

4. Classification


a. Ghent system requires one major criterion in each of two different organ systems and involvement in a third system.


b. MASS (mitral valve prolapse, aortic root diameter at upper limits of normal, stretch marks, skeletal manifestations of Marfan) phenotype—These patients do not have ectopia lentis or aortic dissections and have a better prognosis.


5. Treatment


a. Nonsurgical


i. Beta blockers for mitral valve prolapse, aortic dilatation


ii. Bracing for early scoliosis, pes planovalgus


b. Surgical


i. For progressive scoliosis, long scoliosis fusion is indicated to correct junctional problems (with mandatory preoperative cardiac workup and preoperative MRI to assess dural ectasia); this surgery has a high pseudarthrosis rate.


ii. For progressive protrusio acetabuli, closure of the triradiate cartilage is indicated.


iii. For progressive pes planovalgus, corrective surgery is indicated.


B. Ehlers-Danlos syndrome (EDS) (

Table 2)


1. EDS is a connective tissue disorder with skin and joint hypermobility.


[Table 2. Ehlers-Danlos Syndrome Classification]

2. Pathoanatomy


a. 40% to 50% of patients have a mutation in COL5A1 or COL5A2, the gene for type V collagen (type V collagen is important in the assembly of proper skin matrix collagen fibrils and of the basement membrane); this classic form is autosomal dominant.


b. Type VI, autosomal recessive, is a mutation in lysyl hydroxylase, an enzyme important in collagen cross-linking. Severe kyphoscoliosis is characteristic.


c. Type IV, autosomal dominant, is a mutation in COL3A1 resulting in abnormal collagen III; arterial, intestinal, and uterine rupture are seen.


3. Evaluation


a. Skin is velvety and fragile. Severe scarring with minor trauma is common.


b. Joints are hypermobile, particularly the shoulders, patellae, and ankles.


c. Up to one third of patients have aortic root dilatation; therefore, an echocardiogram and a cardiac evaluation are mandatory.


d. The vascular subtype can have spontaneous visceral or arterial ruptures.


4. Treatment


a. Avoid surgery for lax joints; soft-tissue procedures are unlikely to work.


b. Scoliosis is most common in type VI EDS (

Figure 3) and usually is progressive. Surgery is indicated for progressive curves, and longer fusions are necessary to prevent junctional problems.


c. Chronic musculoskeletal pain is present in more than 50% of these patients; treat supportively if at all possible.


[Figure 3. PA spine views of a patient with EDS type VI. A, Preoperative view demonstrates severe scoliosis. B, Postoperative view demonstrates the long fusion needed in connective tissue syndromes.]

II. Arthritides

A. Rheumatoid (seropositive) arthritis (RA) (

Table 3)


1. Overview—RA is an inflammatory autoimmune arthritis that causes joint destruction at a younger age than does osteoarthritis (OA).


2. Pathoanatomy


a. The synovium thickens and fills with B-cells, T-cells, and macrophages, which erode the cartilage.


b. The process is autoimmune and systemic.


3. Evaluation


a. Rheumatoid factor is found in only half of patients with RA and in 5% of the general population; however, it may help identify more aggressive cases.


b. Prevalence is 1% in the general population; it is higher in aboriginal North Americans. Twin concordance is only 12% to 15% for monozygotic twins.


c. Physical examination demonstrates multiple hot, swollen, stiff joints. Subcutaneous calcified nodules and iridis may be present.


d. Radiographic findings include symmetric joint space narrowing, periarticular erosions, and osteopenia.


4. Treatment


a. Nonsurgical—Most treatment is now medical, by rheumatologists, with a combination of NSAIDs and disease-modifying antirheumatic drugs (DMARDs). Most DMARDs are immunosuppressive and must be stopped before orthopaedic procedures and the cell count checked to avoid neutropenia.


b. Surgical—involves synovectomy and joint realignment early and joint arthroplasty in the later stages.


B. Juvenile idiopathic arthritis (JIA) (previously known as juvenile rheumatoid arthritis, or JRA)


1. Definition—JIA is an autoimmune inflammatory arthritis of joints in children lasting more than 6 weeks.


[Table 3. Differentiating Osteoarthritis from Rheumatoid Arthritis]

2. Pathoanatomy


a. As in adult RA, autoimmune erosion of cartilage occurs.


b. Positive rheumatoid factor and antinuclear antibody (ANA) may indicate a more aggressive course.


3. Types of JIA


a. Systemic JIA/JRA (Still disease)


i. Rash, high fever, multiple inflamed joints, and acute presentation are typical.


ii. Anemia and/or a high white blood cell (WBC) count may occur.


iii. Serositis, hepatosplenomegaly, lymphadenopathy, pericarditis may be present.


iv. Infection must be ruled out.


v. Usually presents at age 5 to 10 years; girls and boys affected equally


vi. Poorest long-term prognosis


vii. Least common type of JIA (accounts for 20%)


b. Oligoarticular JIA (previously known as pauciarticular JRA)


i. Most common type of JIA (accounts for 30% to 40%)


ii. Four or fewer joints are involved; usually large joints, commonly knees and ankles, are affected.


iii. Peak age 2 to 3 years; four times as common in girls as in boys.


iv. A limp that improves during the day is typical.


v. 20% have uveitis. Ophthalmology evaluation needed every 4 months if ANA-positive, every 6 months if ANA-negative


vi. Limb-length discrepancy with the affected side often longer is another sequela.


vii. Best prognosis for long-term remission (70%)


c. Polyarticular JIA/polyarticular JRA


i. Five or more joints are involved; often, small joints (hand/wrist) are affected.


ii. Uveitis sometimes present, but less common than in oligoarticular JIA


iii. More common in girls


iv. Prognosis is good (60% remission).


4. Treatment


a. Limb-length discrepancy may require epiphysiodesis; arthroplasty may be needed in adulthood for destroyed joints.


b. Medical management with NSAIDs or DMARDs by a rheumatologist is usual.


c. An arthrocentesis or synovial biopsy may be needed for diagnosis.


d. Steroid injections and synovectomy may help if medical management fails.


C. Seronegative spondyloarthopathies


1. Definition—Autoimmune arthropathies with a negative rheumatoid factor.


2. Types of seronegative spondyloarthropathies


a. Ankylosing spondylitis


i. Onset age 15 to 35 years; affects males more commonly than females; characterized by morning stiffness, low back pain


ii. Sacroiliitis and progressive fusion of the spine ("bamboo spine") are typical.


iii. Peripheral joint arthritis, usually unilateral, is common.


iv. Uveitis is common in up to 40% of patients; cardiac and pulmonary disease can also occur. Aphthous mouth ulcers and fatigue are common.


v. Aggressive physical therapy and NSAIDs are indicated.


vi. Spinal fractures are highly unstable and have high rates of neurologic injury.


vii. 95% of whites and 50% of blacks with ankylosing spondylitis are HLA-B27-positive, although < 5% of all HLA-B27-positive individuals have ankylosing spondylitis.


b. Psoriatic arthritis


i. The typical psoriatic skin plaques (scaly extensor surface, silvery plaques) usually precede the arthritis, but in 20% of patients, the arthritis occurs first.


ii. Common radiographic finding is "pencil-in-cup" deformity of hand; X-linked recessive.


iii. Nail pitting and dactylitis are common.


c. Reactive arthritis/Reiter syndrome


i. Reactive arthritis is triggered by an infectious disease such as Chlamydia, Yersinia, Salmonella, Campylobacter, or Shigella that causes an autoimmune complex deposition in the joints (commonly the knee), which leads to painful swelling.


ii. The mnemonic "Can't see, can't pee, can't climb a tree" is useful to remember the associated conjunctivitis and dysuria. Mouth ulcers and a rash on the hands and feet can occur.


iii. The underlying condition should be treated, and the arthritis should be managed supportively.


d. Enteropathic arthropathies—Arthritis associated with inflammatory bowel disease such as Crohn or ulcerative colitis.


i. These arthropathies occur in 20% of patients with inflammatory bowel disease.


ii. They should be managed supportively.

III. Other Conditions With Musculoskeletal Involvement

A. Rickets


1. Overview


a. Defective mineralization in growing bone is due to a variety of causes.


b. The most common form of rickets in North America is hypophosphatemic rickets.


2. Pathoanatomy


a. Calcium/phosphate homeostasis is disturbed, leading to poor calcification of the cartilage matrix of growing long bones.


b. Radiographic features (

Figure 4) include widened osteoid seams, metaphyseal cupping, prominence of the rib heads (osteochondral junction [ie, rachitic rosary]), bowing (particularly genu varum), fractures.


c. Microscopically, the zone of proliferation is disordered and elongated in the growth plate.


3. Evaluation


a. Serum Ca2+, phosphorus, alkaline phosphatase, parathyroid hormone (PTH), 25 hydroxyvitamin D, and 1,25 dihydroxyvitamin D must be checked to assess the cause.


b. A history of breast-feeding with little sun exposure is the most likely scenario for vitamin D-deficient rickets.


4. Classification/treatment (

Table 4)


5. Surgery is indicated for lower limb bowing that does not resolve after medical treatment of the rickets; hemiepiphysiodesis or osteotomy may be indicated.


B. Trisomy 21 (Down syndrome)


1. Trisomy 21 is the most common chromosomal abnormality, with an incidence of 1 in 800 to 1,000 live births. Incidence increases with advanced maternal age.


2. Pathoanatomy—Usually a duplication of maternal


[Figure 4. Radiographic features of rickets. A, PA view of the wrist in a child with rickets shows radial and ulnar metaphyseal fraying and cupping (arrows). B, AP view of the lower extremities in a child with rickets demonstrates bowing of the femurs and tibias (white arrows) as well as metaphyseal widening and irregularity (black arrows).]

[Table 4. Most Common Types of Rickets With Associated Genetics, Features, and Treatment]

   chromosome 21, ie, three copies of chromosome 21.


3. Evaluation



Phenotypic features include flattened face, upward slanting eyes with epicanthal folds, single palmar crease, mental retardation (varies), congenital heart disease (endocardial cushion defects 50%), duodenal atresia, hypothyroidism, hearing loss, ligamentous laxity, high incidence of leukemia/lymphoma, diabetes and Alzheimer's in later adult life.



Table 5. Clinical Classification of Osteogenesis Imperfecta]


Table 6. Biochemical Classification of Type I Collagen Mutations in Osteogenesis Imperfecta]



i. Atlantoaxial instability is present in 9% to 22%; it is controversial if flexion-extension views are needed before participation in sports.


ii. Scoliosis in present in up to 50%.


iii. Spondylolisthesis is present in up to 6%.


Metatarsus primus varus/pes planovalgus/hallux valgus are seen.


Patellar dislocation, pain, and instability are common.


Hip instability (often late) is common, sometimes with only mild bony abnormality.


4. Treatment


a. Supportive bracing is indicated for feet (supramalleolar or University of California at Berkeley Laboratory orthoses for pes planovalgus) and knees (patellar stabilizing braces) and for hips (hip abduction braces) in children younger than 6 years.


b. Atlanto-dens interval (ADI) of ≤5 mm is normal.


c. Treatment of asymptomatic ADI of 5 to 10 mm is controversial; many watch and obtain an MRI to look for cord compromise.


d. Fusion is indicated if cord compromise is seen on MRI or if there is ADI >5 and the patient has symptoms; however, fusion has a high (up to 50%) complication rate.


e. Soft-tissue surgeries fail due to ligamentous laxity and hypotonia; therefore, if surgery is done, bony realignment is indicated (ie, periacetabular osteotomy for hip dislocation, tibial tubercle osteotomy for lateral patellar dislocation).



Figure 5. Images of the femur of a patient with type III OI. A, Preoperative frog-lateral hip-to-ankle radiograph demonstrates femoral deformity. B, Postoperative frog-lateral fluoroscopic radiograph shows osteotomies and fixation with a telescoping rod.]

C. Osteogenesis imperfecta (OI) (Tables 5 and 6)


1. Overview


a. Weak organic bone matrix causes frequent fractures and severe bowing and deformity in the more severe types.


b. Intelligence is normal.


2. Pathoanatomy


a. Types I through IV are a mutation in the COL1A1 and COL1A2 genes that encode type I collagen, the mainstay of the organic bone matrix.


i. The result is bone that has a decreased number of trabeculae and decreased cortical thickness (wormian bone).


ii. Specific mutation is identified by DNA analysis of blood.


b. Types V through VII have no collagen I mutation but have a similar phenotype and abnormal bone on microscopy.


3. Evaluation


a. Child abuse should not be ruled out in OI patients; conversely, OI should not be ruled out in a child abuse workup.


b. Particularly in types II and III, basilar invagination and severe scoliosis may occur.


c. Olecranon apophyseal avulsion fractures are characteristic; children presenting with these should be evaluated for OI.


d. Associated dentinogenesis imperfecta, hearing loss, blue sclerae, joint hyperlaxity, and wormian skull bones (puzzle piece appearance to the skull after fontanelle closure) are seen.


4. Treatment


a. Manage fractures with light splints.


b. Bisphosphonates and growth hormone are used; bisphosphonates inhibit osteoclasts, yielding increased cortical thickness with decreased fracture rates and pain.


c. For severe bowing of the limbs or recurrent fracture, intramedullary fixation is indicated with or without osteotomy. Newer devices have telescoping rods to allow growth (Figure 5).


d. Progressive scoliosis/basilar invagination is treated with spinal fusion.


D. Gaucher disease


1. Overview—An enzymatic defect leads to overaccumulation of glucocerebrosides (lipids) in many organ systems, including the bone marrow and the spleen.


2. Pathoanatomy


a. Defect in the gene encoding beta glucocerebrosidase, which breaks down glucocerebrosides, leads to accumulation of glucocerebrosides in macrophages in many organ systems.


b. Always autosomal recessive



Figure 6. Radiographic features of Caffey disease. A, Lateral view of the tibia shows increased bone formation throughout the diaphysis (black arrows) with increased diameter and soft-tissue swelling (white arrows). B, Lateral view of the forearm shows increased diameter of the diaphysis in the radius (black arrows), extensive periosteal reaction (white arrows), and soft-tissue swelling (arrowhead).]

3. Evaluation


a. A WBC examination for enzyme activity is diagnostic.


b. Three forms are identified, based on age of onset.


i. Type 1 (adult): easy bruising (thrombocytopenia), anemia, enlarged liver/spleen, bone pain/fractures


ii. Type 2 (infantile): enlarged spleen/liver by age 3 months; brain involvement; lethal by age 2 years


iii. Type 3 (juvenile): onset in teen years; (thrombocytopenia), anemia, enlarged liver/spleen, bone pain/fractures; gradual and mild brain involvement


c. Radiographic findings include Erlenmeyer flask appearance of distal femurs (also seen in osteopetrosis), osteonecrosis of hips/femoral condyles, cortical thinning.


4. Treatment


a. Enzyme replacement therapy is now available and works well for all but neurologic symptoms.


b. Bone marrow transplant performed early can be curative.


E. Caffey disease


1. Definition—A cortical hyperostosis of infancy (average age of onset <9 weeks) that is self-resolving and is a diagnosis of exclusion.


2. Pathoanatomy


a. The erythrocyte sedimentation rate (ESR) and alkaline phosphatase are elevated, but cultures are negative.


b. Pathology shows hyperplasia of collagen fibers and fibrinoid degeneration.


3. Evaluation


a. Bones of the jaw (mandible) and forearm (ulna) are most commonly affected, with diffuse cortical thickening present, but any bone except the vertebrae and phalanges may be affected (Figure 6).


b. Febrile illness with hyperirritability, swelling of soft tissues, and cortical thickening of the bone


4. Treatment is supportive, with occasional glucocorticoid use.

Top Testing Facts

1. Dural ectasia is commonly seen in Marfan syndrome and may cause back pain and complicate scoliosis surgery; preoperative MRI is mandatory.


2. Ectopia lentis associated with Marfan syndrome is a superior dislocation; with homocysteinuria, the lens dislocation is inferior.


3. MASS phenotype patients never have ectopia lentis or aortic dissections.


4. Marfan syndrome is caused by a mutation in the fibrillin-1 gene.


5. JIA is commonly associated with uveitis, which should be screened for. JIA may be associated with limb-length discrepancy.


6. The most common form of rickets in North America is hypophosphatemic rickets, which is X-linked dominant.


7. The most common chromosomal abnormality is trisomy 21.


8. Olecranon apophyseal avulsion fractures are characteristic of OI.


9. Erlenmyer flask deformities of the femurs are seen in Gaucher disease and osteopetrosis.


10. Gaucher disease is associated with a defect in the gene encoding beta glucocerebrosidase.


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