Autoinflammatory syndrome, familial, X-linked, Behcet-like M35.1

Only the male sex is affected.

This was caused by several hemizygous mutations in the ELF4 gene (W251S, 300775.0001 and c.1015delG, 300775.0002). A frameshift mutation resulted in loss of both ELF4 mRNA and protein.

Versch. Studies suggest that ELF4 normally inhibits Th17 cell differentiation and suppresses macrophage inflammatory responses. The results define ELF4 as a key transcriptional regulator of inflammation.

1st decade of life

X-linked familial autoinflammatory Behcet's syndrome-like syndrome 2 (AIFBL2) is characterized by the appearance of inflammatory symptoms in the first decade of life in male patients. Affected patients frequently present with ulcers of the oral mucosa and skin inflammation. Variable features include gastrointestinal ulceration, arthritis, recurrent fever, and iron deficiency anemia. Laboratory studies suggest immune system dysregulation, as evidenced by elevated inflammatory markers and variable immune cell abnormalities, such as decreased NK cells and low numbers of memory B cells.

One patient had recurrent infections and immunodeficiency in addition to autoinflammation. The disease results from a defect in ELF4, which normally acts as a negative regulator of inflammation. Symptoms may respond to blockade of IL1 (147760) or TNFA (191160) (Tyler et al. 2021 and Sun et al. 2022).

Increased ESR; lymphocytosis with increased B cells and thrombocytosis; NK cells and memory B cells rather decreased.

Histologically, there is neutrophilic mucositis in colon and buccal mucosa; increased expression of cytokines IL17A (603149) and RORC (602943) compared to patients with IBD and control subjects.

1. Sun G et al. (2022) Loss of function mutation in ELF4 causes autoinflammatory and immunodeficiency disease in humans. J Clin Immun
2. Tyler PM et al (2021) Human autoinflammatory disease reveals ELF4 as a transcriptional regulator of inflammation. Nature Immun 22: 1118-1126.