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. 2024 Jan 17;44(2):44.
doi: 10.1007/s10875-023-01610-8.

"Deficiency in ELF4, X-Linked": a Monogenic Disease Entity Resembling Behçet's Syndrome and Inflammatory Bowel Disease

Sam J Olyha  1 , Shannon K O'Connor  2   3 , Marat Kribis  4 , Molly L Bucklin  1 , Dinesh Babu Uthaya Kumar  1 , Paul M Tyler  1 , Faiad Alam  1 , Kate M Jones  1 , Hassan Sheikha  1   2 , Liza Konnikova  2   5   6   7 , Saquib A Lakhani  2   8 , Ruth R Montgomery  4 , Jason Catanzaro  9 , Hongqiang Du  10   11   12   13 , Daniel V DiGiacomo  14 , Holly Rothermel  15 , Christopher J Moran  16 , Karoline Fiedler  17   18 , Neil Warner  18 , Esther P A H Hoppenreijs  19 , Caspar I van der Made  20 , Alexander Hoischen  20 , Peter Olbrich  21   22   23 , Olaf Neth  21   22 , Alejandro Rodríguez-Martínez  24 , José Manuel Lucena Soto  25 , Annemarie M C van Rossum  26   27 , Virgil A S H Dalm  28   29   30 , Aleixo M Muise  17   18   31 , Carrie L Lucas  32   33
Affiliations

"Deficiency in ELF4, X-Linked": a Monogenic Disease Entity Resembling Behçet's Syndrome and Inflammatory Bowel Disease

Sam J Olyha et al. J Clin Immunol. .

Abstract

Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα.

Keywords: Behcet’s disease; DEX; Deficiency in ELF4 X-linked; ELF4; Inborn error of immunity; Inflammation; Inflammatory bowel disease.

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Conflict of interest statement

C.L.L. reports an advisory/consulting role for Pharming Healthcare Inc. and unrelated funding support from Ono Pharma. S.A.L. is part owner of Qiyas Higher Health, a startup company unrelated to this work. All other authors declare no competing interests.

Figures

Figure 1:
Figure 1:. Deleterious ELF4 mutations in patients with DEX.
(a) Schematic diagram of ELF4 protein indicating the location of each known variant. Numbers indicate amino acid position. ETS, ETS DNA binding domain; NLS, nuclear localization sequence indicated by blue bars. (b) Pedigrees from four families with five newly reported patients with DEX (P1–P5). Square, males; circles, females; diamond, sex unknown; WT, wild-type; X, X chromosome; Y, Y chromosome; red, ELF4 variants with protein change indicated; ?, genotype unknown (c) Amino acid sequence alignment of ELF4 ETS domains across species and ETS domains from related proteins in other species (lower panel), with residues mutated in patients with DEX highlighted in red. Red text above sequences indicates DEX variant. (d) Combined annotation-dependent deletion (CADD) scores (GRCh37-v1.6) versus minor allele frequency (MAF) for ELF4 variants in DEX patients (highlighted in red, with protein change indicated) as compared with ELF4 variants present in males with a MAF cutoff of > 10−4 from the gnomAD database (v2.1.1). (e) Activity of ELF4 variants (protein change indicated) ectopically overexpressed in 293T cells co-transfected with a transcriptional luciferase reporter. WT, wild-type. Data shown are from 3 pooled independent experiments ± s.d. Statistical analyses were performed using two-tailed, unpaired Student’s t-test. ****, P<0.0001. (f) Immunoblot for myc-tagged ELF4 and β-actin in 293T cells overexpressing ELF4 variants used in luciferase reporter assay.
Figure 2:
Figure 2:. Clinical symptoms and laboratory findings in DEX.
Representative images of skin inflammation on the arms (a & b) and foot (c) of P3, and the leg of P5 (d). Highest recorded (e) ESR and (f) CRP values reported for P1, P3, P4, P5, P6, P7, P8, and P9. Mean with SEM is shown, with shaded gray region in (e) indicating the most conservative normal range for ESR (< 28 mm/hr). Shaded gray region in (f) indicates a normal range of < 3mg/L for CRP. Exact reference ranges vary by age and laboratory. (g) Immunophenotyping of peripheral blood mononuclear cells (PBMCs) by mass cytometry (CyTOF) from DEX patients P1, P6, and P8 and sex-matched healthy pediatric controls. Cell subset frequencies are shown as a percentage of each patient’s total live PBMCs along with mean and SEM. Populations between HC (n = 6) and DEX (n =3) patients were not statistically significant. Treg, T regulatory cell; NK, natural killer cell; DC, dendritic cell; ILC, innate lymphoid cell.
Figure 3:
Figure 3:. Clinical and immunological findings of patients with Deficiency in ELF4, X-linked (DEX).
GI, gastrointestinal tract; NK, natural killer cells.
See this image and copyright information in PMC

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