Two Sides of the Same Coin, Pathogenic RTEL1 Mutations

Background Regulator of telomere elongation helicase 1 (RTEL1) is a gene that encodes a DNA helicase crucial for DNA repair and telomere maintenance. It belongs to a family of genes associated with telomere biology disorders (TBD). The phenotypic spectrum of RTEL1 mutations is highly variable, encompassing bone marrow failure, idiopathic pulmonary fibrosis, cirrhosis, and malignancy due to excessive telomere erosion. Objective We describe two patients at opposite ends of age, both with pathogenic variants in RTEL1. Clinical Case Descriptions Patient 1 was admitted to the hospital at 3 years of age due to failure to thrive and chronic diarrhea, found to have refractory CMV colitis and CMV and HHV6 viremia. She developed toxic megacolon secondary to CMV, requiring a subtotal colectomy. She underwent a reduced-intensity conditioning matched sibling donor bone marrow transplant (BMT) and ileorectal anastomosis. She was referred at age 4 for immune evaluation due to severe inflammatory bowel disease (IBD)-like gastrointestinal (GI) disease with suboptimal response to steroids and vedolizumab. She was treated with danazol with resolution of her diarrhea and, interestingly, hair regrowth. Patient 2 is a 61-year-old female with leukopenia and recurrent fevers without infection. She was previously healthy with no history of autoimmunity or recurrent infections. She had atypical CD8-positive T cell lymphoid infiltration on liver biopsy with elevated inflammatory cytokines and was referred for immune dysregulation. Investigations Patient 1 had an elevated fecal calprotectin of 889 ug/g and had a homozygous pathogenic RTEL1 variant c.2869C>T (P.Arg957Trp). Patient 2 had an expanded CD8+ T cell population (74%) with a low CD4/CD8 ratio (0.19) and reduced B cells (1%), while immunoglobulin levels remained within the normal range. Cytokine studies showed elevated IFN-y (49pg/mL), elevated CXCL9 (32, 454pg/mL), and elevated soluble IL-2 receptor (5,899 pg/mL) with no evidence of hemophagocytic lymphohistiocytosis (HLH) or granulomas on bone marrow biopsy. She had a heterozygous pathogenic RTEL1 variant: c.3791G>A (p.Arg1264His). Discussion These two cases highlight the phenotypically distinct presentations of pathogenic RTEL1 across the age spectrum. When discovered in older adults, it raises the question of somatic mutations, though germline heterozygous pathogenic variants have been described. Danazol and BMT are being considered in patient 2. Figure 1. Schematic representation of RTEL1 variants with respect to functional protein domains. Variants in P1 and P2 with respect to the RTEL1 function protein domains. HD, N-terminal helicase domain; HHD1 and HHD2, harmonin homology domains 1 and 2; PIP, PCNA-interacting protein box; RING, C-terminal C4C4 type RING domain. Reference transcript NM_001283009.2, adapted from (1). Created using Biorender.com.