Pediatric Mixed Connective Tissue Disease

Updated: Oct 24, 2018
  • Author: Marisa S Klein-Gitelman, MD, MPH; Chief Editor: Lawrence K Jung, MD  more...
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Sharp and colleagues first proposed mixed connective tissue disease (MCTD) as a separate autoimmune disorder. [1] The initial definition identified patients with a specific autoantibody profile, high titers of anti-U1 ribonucleoprotein (70-kD) autoantibody (anti-RNP Ab) but without anti-Smith autoantibody (anti-Sm Ab), in association with specific clinical criteria. Alarcon-Segovia and Villareal and Kasukawa et al subsequently suggested 2 alternate sets of criteria. [2, 3] A comparison of the sensitivity and specificity of the above 3 sets of criteria along with a fourth set of criteria developed by Kahn et al demonstrated that the Kahn and Alarcon-Segovia criteria are the most sensitive and specific for disease diagnosis. [4]

In pediatrics, Kasukawa criteria are used most frequently in published series and have more conservative requirements. Mixed connective tissue disease remains a controversial diagnosis. Some rheumatologists view mixed connective tissue disease as a separate disease; others classify the disorder as an undifferentiated connective tissue disease or overlap syndrome, which may have features of lupus, progressive systemic sclerosis, rheumatoid arthritis, and myositis but should not have its own separate name. [5, 6]

Adding support to the concept of mixed connective tissue disease as a distinct entity, in 1993, Mairesse et al described an autoantibody to the constitutive 73-kD heat shock protein found at high levels exclusively in patients with mixed connective tissue disease. [4] This autoantibody was found in reduced levels in patients with progressive systemic sclerosis and rheumatoid arthritis. The autoantibody was not found in significant quantities in patients with systemic lupus erythematosus (SLE) or myositis. This finding has not been duplicated and must be interpreted with caution. However, the authors redefine mixed connective tissue disease as "a core of minor symptoms (ie, Raynaud phenomenon, puffy fingers, mild myositis, and arthritis) associated significantly with anti-U1-68kD antibody, defining an undifferentiated connective tissue (UCTD) disease that may ultimately overlap with features of major connective tissue disease."

Although confusing, perhaps the best way to consider mixed connective tissue disease is as an undifferentiated connective tissue disease represented mostly by Raynaud phenomenon and anti-RNP antibody. See the image below.

Raynaud phenomenon showing demarcation of color di Raynaud phenomenon showing demarcation of color difference.

This disorder may evolve into one of several major connective tissue diseases or to an overlap syndrome of the major connective tissue diseases. The evolution of this disease requires the physician to carefully assess and constantly reassess the patient in anticipation of change and to provide early intervention with appropriate medical therapy.






United States

In a literature review, Michels counted 224 cases of mixed connective tissue disease. [8] Pediatric-onset mixed connective tissue disease accounts for an estimated one quarter of all cases. Most large pediatric rheumatology centers in major cities have 5-15 active pediatric cases, although some studies estimate that mixed connective tissue disease occurs in 0.6% of all pediatric rheumatology patients.


US data are derived from international data.


Literature describes pediatric mixed connective tissue disease from individual case reports to small series. Mortality is 0-50%. The review by Michels found a mortality figure of 7.6%. [8] More recent data assess pediatric mortality at 3-4 per 1000 population versus adult mortality at 12-23 per 1000 population. Serious organ involvement included 47% of patients with renal disease, 54% with restrictive lung disease, and 29% with GI disease. Although rare, morbidity from cerebral disease, cardiomyopathy, myopericarditis, and pulmonary hypertension has been reported and is associated with a significant risk of mortality.


Ethnic distribution for pediatric mixed connective tissue disease has not been reported. Literature suggests that no specific protection or propensity based on race is noted.


A female predominance, which is typical of other autoimmune diseases, is noted in mixed connective tissue disease. Three published series on pediatric mixed connective tissue disease report 89 of 105 patients to be female, or a female-to-male ratio of approximately 6:1.


Age range for pediatric onset disease is younger than 16 years by definition. No specific age of onset is excluded. The median age at onset is 12 years, based on reported pediatric series. The youngest reported age at onset is 2 years. A recent 15-year retrospective study concluded the mean age at disease onset was 10.7 years. [9]