Pediatric Mixed Connective Tissue Disease Clinical Presentation

• The most frequent presentation of mixed connective tissue disease (MCTD) is a child with polyarthritis, general malaise, and Raynaud phenomenon.
• Patients may present with the following:

  • Sclerodermatous skin (usually limited to fingers but can be more extensive).
  • Sausage-shaped fingers
  • Proximal muscle weakness^[8]
  • Rash (finger ulcers or pits, Gottren papules)
  • Vasculitic rashes (usually palpable purpuric rashes)
  • Dysphagia
  • Gastroesophageal reflux disease (GERD) symptoms
  • Fever
  • Rheumatoid nodules
  • Lymphadenopathy
  • Alopecia
  • Telangiectasia
  • Headache

Detailed physical examination is critical.^[9]

• Classification criteria other than autoantibody status rely on clinical examination and diagnostic tests.
• Consider the following to make the diagnosis:

  • Alopecia
  • Pleuritic chest pain
  • Pericardial rub
  • Arthritis
  • Raynaud phenomenon
  • Malar rash
  • Petechial rash
  • Muscle weakness
  • Swollen hands (especially dorsal surface)
  • Trigeminal neuropathy
  • Acrosclerosis or sclerodermatous skin changes
  • Epigastric tenderness

The following lists, published by several authors, are the criteria for making a diagnosis of mixed connective tissue disease:^{[1, 2, 3]}

• Sharp criteria

  • Definite diagnosis requires 4 major criteria with positive anti-U1 RNP greater than 1:4000 and a negative anti-Sm Ab. U1 RNP is the specific RNP protein associated with this syndrome.
  • Probable diagnosis requires either 3 major criteria or 2 major criteria (which must come from the first 3 major criteria listed) and 2 minor criteria plus an anti-U1 RNP greater than 1:1000.
  • Possible diagnosis requires 3 major criteria without serologic evidence of disease or, if anti-U1 RNP is greater than 1:100, 2 major criteria or 1 major and 3 minor criteria.
    • Major criteria include severe myositis, pulmonary involvement (diffusing capacity of lung for carbon monoxide 70% of normal, pulmonary hypertension, proliferating vascular lesions on lung biopsy), Raynaud phenomenon or esophageal hypomotility, swollen hands or sclerodactyly, and highest observed anti-U1 RNP (>1:10,000) with negative anti-Sm Ab.
    • Minor criteria include alopecia, leukopenia (4000 WBC/mL), anemia (< 10 g/dL for females, < 12 g/dL for males), pleuritis, pericarditis, arthritis, trigeminal neuralgia, malar rash, thrombocytopenia (< 100,000/mL), mild myositis, and history of swollen hands.
• Alarcon-Segovia and Villareal classification

  • Serologic criterion is a positive anti-RNP at a titer of 1:1600 or higher.
  • Clinical criteria (at least 3) are edema of the hands, Raynaud phenomenon (ie, 2 or 3 color changes), acrosclerosis, synovitis, and myositis (laboratory or biopsy evidence).
• Kasukawa criteria

  • Diagnosis requires the following 3 conditions: (1) positive in either 1 of 2 common symptoms, (2) positive anti-RNP antibody, and (3) positive in 1 or more findings in 2 of 3 disease categories of A, B, and C. The following are disease findings A, B, and C:
    • SLE-like conditions (polyarthritis, lymphadenopathy, facial erythema, pericarditis or pleuritis, leukopenia [< 4000/mL], or thrombocytopenia [< 100,000/mL])
    • Progressive systemic sclerosislike findings (sclerodactyly, pulmonary fibrosis, restrictive lung disease [vital capacity < 80%] or reduced diffusion capacity [< 70%], hypomotility, or dilation of the esophagus)
    • Polymyositislike findings (muscle weakness, increased serum level of myogenic enzymes [creatine kinase], myogenic pattern on electromyogram)
  • Common symptoms include Raynaud phenomenon and swollen fingers or hands.

Specific causes of mixed connective tissue disease remain undefined.^[10]

• Research suggests that many factors, including genetics, hormones, and environment, contribute to development of autoimmune syndromes.
• As mentioned in the Introduction, the hallmark of mixed connective tissue disease is the presence of autoantibodies to U1 small nuclear ribonucleoproteins, in particular a 70-kDa U1 protein. During cell death or apoptosis, the 70-kDa protein is cleaved by caspase-3 into a small 40-kDa protein. Several research groups have described this apoptotic form.
• Specific anti-RNP autoantibodies that preferentially bind to the apoptotic form of the U1 protein have been demonstrated in a group of patients with mixed connective tissue disease (29 of 53 tested). Furthermore, the concentration of the autoantibody is high early in the disease and decreases over time, suggesting that it correlates or represents an inciting event in disease onset.