Prevalence and Spectrum of Autoimmune Diseases Among Patients with Telomere Biology Disorder

Introduction

Telomeres are the protective ends of linear chromosomes that prevent DNA degradation with each replication. Premature attrition or dysfunction of telomeres due to an inherited defect in a telomere maintenance gene results in a spectrum of phenotypes collectively known as telomere biology disorders (TBD). To date, 18 genes have been implicated in TBD. Disease phenotypes are variable including bone marrow failure, immunodeficiency, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), idiopathic pulmonary fibrosis (IPF), liver cirrhosis, nail dystrophy, and premature graying of hair. Short telomeres have been observed in patients with autoimmune disorders (AID) and have been shown to increase the risk of AID. Furthermore, TBD have been associated with T cell dysfunction and exhaustion, mechanisms which may predispose to autoimmune phenotypes. Given the potential relationship between short telomeres and immune dysregulation, we hypothesize that the prevalence of AID may be increased in patients with a diagnosis of TBD. The aim of this study is to describe the prevalence and spectrum of AID in a cohort of patients with TBD.

Methods

Health record data were reviewed for 34 adult patients with confirmed TBD treated at the University of Wisconsin-Madison. A TBD diagnosis was established for patients who had a compatible clinical history plus either critically short lymphocyte telomere lengths (<1^st percentile for age as measured by FlowFISH) or one or more pathogenic/likely pathogenic variant(s) in a gene known to cause TBD. Demographics, rheumatologic history, serologies, and family history were collected. AID were included if diagnoses were made by a rheumatologist or other appropriate specialist with clinical features, physical exam findings, and/or serologies meeting diagnostic criteria per subspecialty guidelines.

Results

Eight of 34 patients (23.5%) with TBD had a concomitant diagnosis of a primary autoimmune condition. Specific AID included inflammatory bowel disease, Graves’ disease, Hashimoto’s thyroiditis, rheumatoid arthritis, scleroderma, and Sjogren’s syndrome (Table 1). Two patients had autoimmune cytopenias, including steroid-responsive immune thrombocytopenic purpura and pure red cell aplasia (PRCA). Patient 8 was diagnosed with PRCA mixed with spur cell anemia prior to transplant, and bone marrow biopsy showed pure erythroid hypoplasia without evidence of malignancy. He responded to treatment with steroids and immunosuppression. Of the eight patients with a primary autoimmune condition, two had pathogenic/like pathogenic variants, two had rare variants of uncertain significance, and four had no detectable variants in a telomere associated gene. Twenty-three patients (67.6%) had a first- or second-degree relative with an autoimmune disorder.

Conclusions

An AID, as defined by strict diagnostic criteria per subspecialty guidelines, was present in 23.5% of patients with TBD defined by conservative diagnostic criteria. The spectrum of AID was diverse, including two patients with autoimmune hematologic disorders, and the majority had a family history of various AID. Thus, TBD may be associated with an increased prevalence of AID, though confirmation in a larger cohort of genetically defined TBD patients is needed. In the absence of a causative genetic lesion, diagnosis of a TBD based on critically short telomeres in those with multisystem autoimmune disorders with features that overlap TBD phenotypes can be challenging. Screening for AID as part of routine TBD comprehensive assessments as well as offering germline genetic testing for individuals with primary autoimmune disease with a compatible TBD phenotypes and studies to determine the mechanistic relationship between telomere length and autoimmunity are warranted.