Late Onset Telomere Biology Disorder Presenting With Pancytopenia, Immune Dysregulation, Interstitial Lung Disease and Alopecia

A 60-year-old Eastern European woman presented to primary care with progressive fatigue and dyspnea. Her family history includes no known hematologic concerns; mother: died age 39 of an accident; father: alive aged 91; sister: alive, aged 63; her two daughters aged 39 and 33 are healthy. Physical examination showed a slim female of average height with moderate, diffuse alopecia. Bloodwork revealed pancytopenia, progressive since detection 2 years previously: hemoglobin 85 g/L [reference 115–150], MCV 103 fL [82–98], platelets 69 × 109/L [150–400], neutrophils 1.2 × 109/L [2–7]. Her CBC was normal greater than 2 years prior. Extensive hematologic, autoimmune, and infectious work-up revealed polyclonal hypergammaglobulinemia and a detectable low-level EBV viremia of < 1000 copies/mL (Appendix A: Figures A1 and A2). Two bone marrow biopsies done a year apart both showed hypercellularity at nearly 100% with reticulin fibrosis (Figure 1A,B). There was near complete effacement of normal marrow architecture by an atypical infiltrate composed of abundant small mature lymphocytes and scattered histiocytes. T-cell clonality was positive. The significance of the lymphohistiocytic infiltrate was unclear but not felt to be consistent with a lymphoma. A third bone marrow biopsy done 2 years after the index biopsy demonstrated a mildly hypocellular marrow (30%–40% cellularity) without dysplasia, suggesting a patchy involvement with this lymphohistiocytic infiltrate. Karyotype was normal, and a next-generation sequencing panel demonstrated no somatic variants. She underwent pan-CT, PET scan, bone scan, and upper GI endoscopy; together these showed interstitial lung disease (ILD) with mild apical subpleural scarring and fibrosis. After evaluation with hematology, respirology, and infectious diseases without a diagnosis, she was seen by the rare diseases clinic in our center. She underwent gene panel sequencing (Blueprint immune and cytopenia panel) which revealed a heterozygous variant in RTEL1 NM_032957 transcript (c.805del, pp.Thr269Glnfs*3) with a VAF of 47%. This variant is absent in gnomAD and causes a frameshift in exon 9 (of 35 total exons), resulting in a premature stop codon and is predicted to lead to loss of normal protein function. This was curated as likely pathogenic by the reporting laboratory, meeting criteria for PVS1 and PM2_supp. RTEL1 encodes a DNA helicase involved in DNA repair and telomere maintenance; RTEL1 variants are associated with telomere biology disorders (TBDs). TBDs resulting from deleterious germline RTEL1 variants can exhibit autosomal dominant (AD) or autosomal recessive (AR) modes of inheritance. Patients with AR RTEL1-associated TBDs present with a more severe phenotype, often associated with the classic mucocutaneous triad or Hoyeraal–Hreidarsson syndrome. Patients with AD RTEL1-associated TBDs can have a more subtle presentation and can manifest later in life. This patient's presentation was consistent with an autosomal dominant TBD. Telomere length testing by Flow-FISH (Repeat Diagnostics) demonstrated median telomere lengths of 2.6 kb (< 1st percentile, normal median telomere length for age (MTLN) 6.1 kb) in the lymphoid series and 3.3 kb (< 1st percentile, MTLN 7.9 kb) in the myeloid series (Figure 1C). The RTEL1 variant was identified in the lymphocyte fraction on sorted lymphocyte testing as well as on cultured fibroblasts, confirming its germline origin. She is currently on observation and a donor search is underway for potential allogeneic stem cell transplant in the future should she develop consequences from immune dysregulation, persistent infections, refractory cytopenias despite conservative management, or clonal myeloid findings. This case highlights that germline variants and hereditary marrow failure disorders may manifest clinically in older adulthood. The identification of her polyclonal hypergammaglobulinemia and lymphohistiocytic infiltrate may be a potential feature of TBDs, potentially related to immune dysregulation. With increasing accessibility, genetic analysis should be considered in the investigation of unusual clinical presentations that have escaped explanation with conventional work-up. N.H., H.A.L., R.J.S., L.Y.C.C., A.G. were involved in patient care. B.A.W. and L.Y.C.C. drafted the manuscript. H.N. provided the hematopathology figures and pathology expertise. T.M. provided the radiology figures and expertise. A.T. provided inherited bone marrow disorders expertise. All authors edited and approved the final manuscript. The patient provided written consent for publication of the case. Luke Chen's research is supported by the Hsu & Taylor Family. The authors have written informed consent from the patient to submit this clinical picture for publication. Ethics approval was not required by our institutional ethics review board for case reports. The authors declare no conflicts of interest. Peripheral blood flow cytometry showed an expanded NK-cell population and a positive T-cell clonality study. The significance of the lymphohistiocytic infiltrate was unclear but was not felt to be consistent with a lymphoma. There was a mild reduction in Diffusing capacity for carbon monoxide (DLCO 71% predicted), spinal compression fractures with osteoporosis were seen on whole body CT, and PET scan showed low-grade increased FDG-uptake in the spleen and throughout the marrow, overall negative for malignancy. The Blueprint genetic immunodeficiency and cytopenia panel identified a pathogenic heterozygous RTEL1 truncating deletion at c805, p.Thr269Glnfs*3 of exon 9. Additional findings include a pathogenic heterozygous ERCC2 c1703_1704 deletion and variants of uncertain significance (JAK2, NOD2, CFTR).