Autoimmune Neutropenia and Immune-Dysregulation in a Patient Carrying a TINF2 Variant

Abstract

In recent years, the knowledge about the immune-mediated impairment of bone marrow precursors in immune-dysregulation and autoimmune disorders has increased. In addition, immune-dysregulation, secondary to marrow failure, has been reported as being, in some cases, the most evident and early sign of the disease and making the diagnosis of both groups of disorders challenging. Dyskeratosis congenita is a disorder characterized by premature telomere erosion, typically showing marrow failure, nail dystrophy and leukoplakia, although incomplete genetic penetrance and phenotypes with immune-dysregulation features have been described. We report on a previously healthy 17-year-old girl, with a cousin successfully treated for acute lymphoblastic leukemia, who presented with leukopenia and neutropenia. The diagnostic work-up showed positive anti-neutrophil antibodies, leading to the diagnosis of autoimmune neutropenia, a slightly low NK count and high TCR-αβ+-double-negative T-cells. A next-generation sequencing (NGS) analysis showed the 734C>A variant on exon 6 of the TINF2 gene, leading to the p.Ser245Tyr. The telomere length was short on the lymphocytes and granulocytes, suggesting the diagnosis of an atypical telomeropathy showing with immune-dysregulation. This case underlines the importance of an accurate diagnostic work-up of patients with immune-dysregulation, who should undergo NGS or whole exome sequencing to identify specific disorders that deserve targeted follow-up and treatment.

Late‐onset and long‐lasting neutropenias in the young: A new entity anticipating immune‐dysregulation disorders

“…In patients n.8 and n.9, the same variant of the TINF2 gene (p. Ser245Tyr), reported as VUS by reference databases was detected 31 . Since this variant has also been described in the literature in two patients with bone marrow aplasia its role remains debatable 32,33 …”

“…31 Since this variant has also been described in the literature in two patients with bone marrow aplasia its role remains debatable. 32,33 A variant of the TERT (p. Glu441del) and RTEL1 (p. Gln421Glu) genes were found in patients n.2 and n.14. In both cases, a double heterozygosity was associated with a P and VUS TNFSRF13 variant (pts n. 2 and n.14).…”