Undifferentiated Connective Tissue Disease, Mixed Connective Tissue Disease, and Overlap Syndromes in Children

Mixed connective tissue disorder

Clinical signs of at least two of the following diseases:

1. Juvenile idiopathic arthritis

2. Systemic lupus erythematosus

3. Juvenile dermatomyositis

4. Systemic scleroderma

Positive serological findings

1. High titer of anti-U1 snRNP and the 70 kD A and C polypeptides

2. Anti-U1 RNA antibodies

Presence of HLA-DR4 or DR2


Mixed connective tissue disorder is a rare disorder in the pediatric age, and very little information is available about the prevalence and incidence of MCTD. In a nationwide study in Norway, the prevalence of MCTD was 3.8 per 100,000 adults, with an incidence of 2.1 per million per year [3]. MCTD is much more common in girls than in boys, although estimates of the difference range widely (from a ratio of 3.3:1 up to 16:1). While the US Pediatric Rheumatology Database reported a prevalence of 0.3 %, another study from Japan revealed a prevalence of 2.7 per 100,000 [46]. No prevalence-related data is available from the Indian subcontinent. Most adults present in their second or third decade, but this disease has been reported in children as young as 4 years.


The exact etiology of MCTD remains unknown. Immunological, genetic, and environmental factors play a role in the pathogenesis. Autoimmunity seems to be the hallmark with both T- and B-cell involvement. The 70 kD peptide of the U1 RNP antigen is the dominant antigen against which autoantibodies are produced [7]. However, immune complex formation is not very characteristic.

Genetic associations with HLA-DR4 and DR2 have been recognized though familial occurrence is rare. In a Norwegian cohort, HLA-B*08 and DRB1*04:01 were identified as risk alleles for MCTD, while DRB1*04:04, DRB1*13:01, and DRB1*13:02 were protective. A novel association between HLA-DRB1*03:01 and pulmonary fibrosis in MCTD was also identified. This study reinforced the fact that HLA profile of patients with MCTD was distinct compared to other CTDs, and MCTD was a different entity than other rheumatological diseases [3].

Unlike SLE, sun exposure is not a precipitating factor. Drug-induced MCTD is a rare occurrence but may be occasionally seen with anti-tumor necrosis factor (TNF) therapy. Vinyl chloride and silica are the only environmental agents that have been associated with MCTD.

Generation of U1 RNP Autoimmunity

Antibody response in patients with MCTD is characterized by hypergammaglobulinemia that can amount to 30 % of the total serum immunoglobulins [8]. High ANA titers should prompt the measurement of antibodies to U1 ribonucleoprotein (RNP) along with anti-Ro, anti-La, and anti-Sm. The major target of this ANA is 70 kD epitope on U1 RNP molecules.


Obliterative and proliferative vascular lesions with a relative paucity of inflammatory infiltrates are characteristic. Increased synthesis of type III collagen is also demonstrated that results in abnormal type I/type III collagen ratio, while this ratio is maintained in children with scleroderma. In the lungs too, fibrosis is not a prominent feature as in scleroderma, where intimal proliferation and vascular occlusion predominate.

Clinical Features

The diagnosis of MCTD is a challenge, and most often a careful follow-up would provide definitive diagnosis as the disease evolves. The early clinical features are nonspecific and may consist of general malaise, arthralgias, myalgias, and low-grade fever. Presence of a positive ANA (speckled pattern) and association with Raynaud’s phenomenon give a clue for CTD. Although, almost any organ system can be involved in MCTD, there are four clinical features that suggest the presence of MCTD rather than another CTD such as SLE or SSc:

  • Raynaud’s phenomenon, as well as swollen hands or puffy fingers

  • Absence of severe renal and central nervous system (CNS) disease

  • More severe arthritis and the insidious onset of pulmonary hypertension (not related to lung fibrosis), which differentiate MCTD from both SLE and SSc

  • Autoantibodies to 70 kD protein of U1 ribonucleoprotein (RNP)

A recent French multicenter study reported 19 patients from 10 pediatric centers and illustrated that MCTD is a chronic multisystem disease with periods of remissions and flares. All systems of the body can be involved, but pulmonary and digestive manifestations are the most severe [9].


Skin involvement is often the presenting feature and occurs in most patients. Raynaud’s phenomenon occurs early in the course of disease [10]. Puffy fingers and occasionally hand edema may also be noted. Superficial vasculitis of the digits, acrosclerosis, and calcinosis cutis have also been described. Skin manifestations such as discoid plaques and malar rash are indistinguishable from SLE. Mucous membrane involvement can include orogenital and buccal ulcerations, nasal septal perforation, and the sicca complex [11].


Fever of unknown origin may be the presenting feature of MCTD [12]. In this setting, the cause can be usually traced to a coexistent myositis, aseptic meningitis, serositis, lymphadenopathy, or intercurrent infection.


Articular involvement in MCTD is more common and severe than in classic SLE. Approximately 60 % of patients with MCTD develop an obvious arthritis [13], often with boutonniere deformities and swan-neck changes. In adults, rheumatoid factor is present in 70 % of patients with MCTD and anti-cyclic citrullinated peptide (CCP) antibodies in about 50 % patients [14, 15].


One of the three overlap features required for the diagnosis of MCTD is an inflammatory myopathy clinically and histologically identical to polymyositis (PM). Myalgia is a common symptom in patients with the MCTD syndrome. In the early phase, electromyographic (EMG) abnormality or elevation of muscle enzymes may be the only finding. It is unclear whether the symptoms represent a low-grade myositis or an associated fibromyalgia syndrome. However, a clinical myositis may occur over time. The histology of muscle involvement in MCTD is the same as that of idiopathic inflammatory myopathy. It is increasingly apparent that a diagnosis of “pure” PM is relatively rare, and most patients with an inflammatory myopathy evolve into an overlap syndrome [16].

Cardiac disease

Cardiac involvement accounts for 20 % of mortality in MCTD. While 30 % of MCTD patients have symptomatic heart disease, nearly 40 % have subclinical disease [17]. An abnormal electrocardiogram is noted in about 20 % of patients. The most common electrocardiographic abnormalities include hemiblock, bundle branch block, and atrioventricular block. Pericardial effusion and mitral valve prolapse are among the most common echocardiographic abnormalities. Pericarditis is the most common clinical manifestation of cardiac involvement, reported in up to 40 % of patients [18].

There is also increasing recognition of accelerated atherosclerosis in MCTD, and the risk factors include elevated high-sensitivity C-reactive protein (CRP) levels, dyslipidemia, anti-endothelial antibodies, antiphospholipid antibodies, and vitamin D deficiency.

Pulmonary Involvement

Lungs are commonly affected in MCTD with involvement in about 75 % of patients [19]. A wide spectrum of pulmonary problems can occur in MCTD such as pleural effusion or pain, pulmonary arterial hypertension (PAH), interstitial lung disease (ILD), thromboembolic disease, alveolar hemorrhage, diaphragmatic dysfunction, aspiration pneumonitis/pneumonia, obstructive airways disease, pulmonary infections, or vasculitis. Early symptoms include dry cough, dyspnea, and pleuritic chest pain.

Interstitial Lung Disease

ILD occurs in about 50–66% of patients with MCTD [20]. A reduction in the single breath-diffusing capacity for carbon monoxide (DLCO) is a feature noted in the early stages of ILD. High-resolution computed tomography (HRCT) is a sensitive diagnostic modality to determine the presence of ILD. The most common HRCT findings are septal thickening, ground-glass opacities, non-septal linear opacities, and peripheral/lower lobe predominance.

Rapid clearance of technetium-labeled diethylenetriaminepentaacetate (DTPA lung scan) is closely correlated with CT evidence of interstitial lung disease and with a decreased DLCO [21]. Patients with more severe fibrosis exhibit further decreases in DLCO and reduced forced vital capacity and forced expiratory volume, consistent with restrictive lung disease. Reduced 6-min walk distance test is a basic clinical test which can be utilized for monitoring of patients with ILD.

Based upon a combination of HRCT and DTPA scans, the prevalence of ILD in MCTD was reported to be 67 % [22]. Esophageal dilatation has been associated with a tendency to develop interstitial lung disease in MCTD (Figs. 31.1, 31.2, and 31.3).


Fig. 31.1
High-resolution computed tomography of the chest showing interstitial lung disease in a child with MCTD


Fig. 31.2
MRI of thigh muscles showing T2-weighted hyperintensities suggesting inflammatory myositis


Fig. 31.3
(a) Clinical picture of a child with MCTD showing heliotrope rash and edema over the face. (b) Gottron papules in the same child

Pulmonary Hypertension

A major cause of death in MCTD is PAH. This complication is caused by bland intimal proliferation and medial hypertrophy of pulmonary arterioles.

The presence of PAH may be suspected from the history, physical findings, and laboratory tests, particularly if the patient has four or more of the following: exertional dyspnea, systolic pulsation at the left sternal border, an accentuated second pulmonary sound, dilation of the pulmonary artery on radiograph, and right ventricular hypertrophy on electrocardiogram or on echocardiogram.

The early detection of PAH is increasingly important, as there are potentially effective therapeutic options. Two-dimensional echocardiography with Doppler flow studies is the most useful screening test with a definitive diagnosis requiring cardiac catheterization showing a mean resting pulmonary artery pressure greater than 25 mmHg at rest. The development of PAH has been correlated with a nail fold capillary pattern [23] similar to that seen in SSc, with anti-endothelial cell antibodies (AECA) and with anticardiolipin antibodies.

Renal Disease

Absence of severe renal disease is a hallmark of MCTD. It is possible that high titers of anti-U1 RNP antibodies, which are characteristic of MCTD, may protect against the development of diffuse proliferative glomerulonephritis, independent of whether these antibodies occur in MCTD or in classic SLE.

However, some degree of renal involvement occurs in about 25 % of patients [24]. Membranous nephropathy is the most common finding and hypertensive crises similar to scleroderma renal crisis have also been reported.

Gastrointestinal Disease

Gastrointestinal involvement is the most common clinical overlap feature with SSc, occurring in about 60–80 % of patients [25]. Disordered motility in the upper gastrointestinal tract is the most common.

There have been case reports of hemoperitoneum, hematobilia, duodenal bleeding, megacolon, pancreatitis, ascites, protein-losing enteropathy, primary biliary cirrhosis, portal hypertension, pneumatosis intestinalis, and autoimmune hepatitis [26]. Malabsorption syndrome can occur secondarily to small bowel dilation with bacterial overgrowth. Liver involvement in the form of chronic active hepatitis and Budd-Chiari syndrome has been described [26]. Pseudo-diverticulae, identical to those seen in SSc, may be seen along the anti-mesenteric border of the colon. Abdominal pain in MCTD may result from bowel hypomotility, serositis, mesenteric vasculitis, colonic perforation, and pancreatitis.

Central Nervous System Disease

The original description of MCTD emphasized the lack of CNS involvement. This observation remains largely correct, since patients with MCTD do not develop severe complications such as cerebritis, psychosis, or seizures. However, approximately 25 % of patients may have some mild form of CNS disease [27]. The most frequent CNS manifestation is a trigeminal (fifth cranial) nerve neuropathy, which may be the presenting feature of the disease, and this is also the most common CNS problem in patients with SSc. Headaches which are vascular in origin are common. Aseptic meningitis may also be noted. Sensorineural hearing loss is often not recognized, but it is reported to occur in about 50 % of MCTD patients.

Hematologic and Laboratory Abnormalities

Nonspecific hematologic and laboratory abnormalities are common in MCTD. Approximately 75 % patients have a low-grade anemia [14]. Leukopenia, mainly affecting the lymphocyte series, is a common finding that tends to correlate with disease activity. While majority have hypergammaglobulinemia [28], rheumatoid factor is positive in 50–70 % and anti-CCP antibodies are found in about 50 % of patients. Many patients have antibodies directed against heterogeneous nuclear ribonucleoprotein (hnRNP)-A2, fibrillin-1, and nucleosomes but not against ribonucleic acid (RNA) polymerases. Antiphospholipid antibodies occur less frequently than in SLE. If present, they tend to correlate with thrombocytopenia and PAH, but not with thrombosis and/or abortions. Anti-endothelial cell antibodies (AECA) occur in 50 % adults with MCTD. The use of trimethoprim-sulfamethoxazole is a significant risk factor for the development of AECA.

The one universal serological finding in MCTD is a positive ANA whose fine specificity is anti-U1 RNP, especially antibodies to the 68 kD protein. A positive anti-U1 RNP with negative anti-Sm antibodies and anti-DNA antibodies is an important discriminating finding for MCTD from SLE.


Raynaud’s phenomenon is a typical early feature of MCTD. Its absence should raise a suspicion against the diagnosis of MCTD. The characteristic vascular lesion of MCTD is bland intimal proliferation and medial hypertrophy affecting medium- and small-sized vessels. These pathologic changes differ from those usually noted in SLE, in which perivascular inflammatory infiltrates and necrosis are more characteristic. Similar to SSc, abnormal fingernail capillaroscopy is a common feature of MCTD [23]. The capillary pattern is characterized by dilatation and dropout. Angiographic studies reveal a high prevalence of medium-sized arterial occlusions.

What Differentiates MCTD from Other CTDs?

MCTD is distinct from other CTDs with the following features:
Oct 25, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Undifferentiated Connective Tissue Disease, Mixed Connective Tissue Disease, and Overlap Syndromes in Children
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