Late onset and long lasting neutropenia & primary immune-dysregulation : Early signals & genetic connections Free

Background. Children affected with neutropenia that appears after age 5 years (Late Onset neutropenia, LO-Np) or lasts longer than 3 years (Long Lasting neutropenia, LL-Np) have been recently described as a new entity of neutropenia characterized by mild phenotype and a peculiar immunological pattern including reduced B and NK cells

In a small subgroup of LO-Np and LL-Np patients, pathogenic or likely pathogenic variants related to immune dysregulation have been identified. Immune neutropenia and other mono/bilinear cytopenias were recently suggested as potentially anticipatory events of Inborn Error of Immunity (IEI). However, extensive data on association between immune neutropenia and clinical, immunological, genetic findings of IEI in support of this hypothesis are scarce.

Aim of the study. To describe the immunological and genetic pattern of a population of patients affected with LO-Np and LL-Np in order to identify predictive aspects of IEI.

Patients and Methods. Demographic, clinical and immunological/autoimmune data were extracted from the Italian Registry of Neutropenia after informed consent. An extensive immunological panel including IgA-M-G serum levels, multiple B (CD27-CD10+CD38+ B Transitional,CD27+IgD-IgM- B Switched memory, CD27-IgD-CD21low DN2, CD27-CD10+-CD38+-IgD+CD21low) and T-cell markers (CD4+CD45RA+CD27+TH naive, CD4+CD45RA-CD27+ TH central memory,CD8+CD45RA+CD27+ TC naive, CD8+CD45RA-CD27+ TC central memory, CD3+Cd4+CD25^br+ CD45 RA- Treg) was applied. A 13-marker composite scoring system including these parameters along with clinical and lab sign of autoimmunity was applied to the study population. Finally, patients were tested with a 160-bone marrow failure and PIRD-related NGS gene panel.

Results. From January 2005 to June 2024 a total of 85 patients (46 females, 54%, median age at examination 14.5 years, range 0.4-55 years) affected with LO/LL neutropenia entered the study. Neutropenia at diagnosis was mild, moderate and severe in 29 (34%), 32 (38%), and 24 (28%) patients respectively. Indirect anti-neutrophils antibodies were detected in 35 (41%) of patients. NGS panel showed Pathogenic/Likely Pathogenic (P/LP) variants in 9 (12%) patients (7 TNFRSF13B, 2 CARD11, and 1 FASL). Almost all subjects (99%) were positive for at least one of the 13 markers of the scoring system. Signs of autoimmunity and low IgG levels were documented in 19 (22%) and in 4 (5%) patients respectively. In subjects in whom full lymphocyte panel was tested we found the following abnormal distributions: > B Transitional (23%), <B switched memory (51%), > B DN2 IgD- (21%), >B DN2 IgD+ (10%), < CD4+ naive (41%), >CD4 central memory (43%) ,< CD8+ naive (47%) , >CD8+ central memory (51%), <T reg (75%) that was the most frequent abnormality.

When we applied the 13-marker composite system we found that a score equal or greater than 5 was represented in 80% of patients carrying P/LP variants and in 37% of those without PIRD P/LP variants.

Conclusions. This retrospective study, suggest that extensive clinical and immunological evaluation may identify since the beginning forms of neutropenia that might conceal a PIRD. A composite scoring system of 13 markers including clinical, autoimmunity signs and an enlarged B and T-cell panel, particularly when T regs are reduced, may be helpful to orient towards a genetic diagnosis of PIRD. This approach can be very important for appropriate management and surveillance of these diseases.