Autoimmune Disease, Multisystem, Infantile-Onset, 1

A number sign (#) is used with this entry because infantile-onset multisystem autoimmune disease-1 (ADMIO1) is caused by heterozygous mutation in the STAT3 gene (102582) on chromosome 17q21.

Description

Infantile-onset multisystem autoimmune disease-1 is characterized by early childhood onset of a spectrum of autoimmune disorders affecting multiple organs. Common manifestations include insulin-dependent diabetes mellitus and autoimmune enteropathy, or celiac disease, and autoimmune hematologic disorders. Other features include short stature and nonspecific dermatitis. More variable features include hypothyroidism, autoimmune arthritis, and delayed puberty. Some patients may show recurrent infections. The disorder results from an inborn error of cytokine signaling (summary by Flanagan et al., 2014 and Milner et al., 2015).

Genetic Heterogeneity of Infantile-Onset Multisystem Autoimmune Disease

See also ADMIO2 (617006), caused by mutation in the ZAP70 gene (176947) on chromosome 2q12.

Clinical Features

Flanagan et al. (2014) reported 5 unrelated patients with early-onset autoimmune disease. Three patients were diagnosed with type 1 insulin-dependent diabetes in the first weeks of life, and a fourth was diagnosed with diabetes at 43 weeks of age. Autoimmune enteropathy or celiac disease presented in the first 2 years of life in 3 patients. Additional autoimmune disorders diagnosed during childhood included autoimmune interstitial lung disease, juvenile-onset arthritis, and primary hypothyroidism. Other common features included short stature, eczema, delayed puberty, and dental abnormalities. Two patients had evidence of immunodeficiency with recurrent respiratory infections, and 1 patient developed large granular lymphocytic T-cell leukemia. Laboratory studies of 2 patients showed decreased numbers of regulatory T cells, and 1 patient had evidence of increased cytokine production.

Haapaniemi et al. (2015) reported further details of 2 of the patients reported by Flanagan et al. (2014) and presented a third patient with the disorder. All had recurrent infections and autoimmune features, 1 had lymphadenopathy, and 1 developed T-cell leukemia. The third patient was a 22-year-old woman with late-onset ADMIO. She had recurrent ear infections in childhood, but normal response to vaccination, including BCG. In her late teens, she presented with lymphocytic colitis, autoimmune thrombocytopenia, hypogammaglobulinemia, joint pain, eczema, and Mycobacterium avium pneumonia. Detailed laboratory studies of these patients showed increased numbers of double-negative (CD4-, CD8-) T cells, decreased dendritic, T regulatory, NK, and Th17 cells, as well as hypogammaglobulinemia associated with decreased switched memory B cells. Two patients had decreased numbers of circulating eosinophils. The findings indicated that the disorder can affect multiple immune cell lineages.

Milner et al. (2015) reported 13 patients from 10 families with childhood-onset of various autoimmune disorders associated with lymphoproliferation. The age at onset ranged from infancy to 15 years, but most presented before age 5. There was a high prevalence of autoimmune hematologic disorders, including hemolytic anemia, thrombocytopenia, and neutropenia. Two developed insulin-dependent diabetes mellitus and 5 had autoimmune enteropathy. Several had various other manifestations, such as scleroderma, arthritis, atopic dermatitis, and inflammatory lung disease. Almost all had lymphadenopathy, often with hepatosplenomegaly. Several patients had short stature and poor overall growth. Many patients also had recurrent infections, including 4 with fungal infections, and some of these patients showed hypogammaglobulinemia. Results of immunologic work-ups were variable, but showed moderate T-cell lymphopenia, hypogammaglobulinemia, and increased double-negative (CD4-, CD8-) T cells. Two families showed evidence of incomplete penetrance. All patients required significant immunosuppression to control their diseases, and 2 patients underwent hematopoietic stem cell transplant. One patient who was treated with pharmacologic IL6 blockade demonstrated a dramatic improvement in his arthritis.

Molecular Genetics

In 5 unrelated patients with ADMIO1, Flanagan et al. (2014) identified 4 different de novo heterozygous missense mutations in the STAT3 gene (102582.0008-102582.0011). The mutation in the first patient was found by exome sequencing, and the mutations in the subsequent patients were found by sequencing the coding exons of the STAT3 gene in 24 individuals with early-onset autoimmune disorder. In vitro functional expression studies showed that all the mutations resulted in a gain of function, with increased STAT3-responsive reporter activity and an increase in cytokine-related function compared to wildtype and compared to dominant-negative inactivating STAT3 mutations associated with HIES (147060).

In 13 patients from 10 families with ADMIO1, Milner et al. (2015) identified 9 different heterozygous missense mutations in the STAT3 gene (see, e.g., 102582.0008; 102582.0012-102582.0014). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, occurred throughout the gene and affected multiple protein domains. In vitro functional expression studies showed that all the mutant proteins had increased basal transcriptional activity and increased activity in response to cytokines compared to wildtype, consistent with a gain of function. The mutations also caused secondary defects in STAT5 (601511) and STAT1 (600555) phosphorylation. Patient cells showed increased expression of the downstream target SOCS3 (604176) and diminished numbers of regulatory T cells.