To describe a child carrying a GFI1 -variant with autoimmune neutropenia.

Single subject case report.

This is a case report of a 1 year-and-10-months-old female presenting severe chronic neutropenia (0,03 × 109/L) with mild infections. The frequency of infections reduced as she got older. Physical examinations outside of infections were always normal and she had expected development. She did not have monocytosis or other hematologic disorders, and lymphocytes evaluation by flow cytometry analysis resulted normal. Viral diseases were negative, immunoglobulins dosage was normal for the age group, and screening for systemic autoimmune disease (sAID) was negative. Bone marrow aspirate analysis with karyotype resulted normal, without maturation arrest or dysplasia. Inborn errors of metabolism (IRM) and immunity (IRI) were ruled out. Antineutrophil (anti-HNA) autoantibody was detected on two occasions: at ages of 2-years-and-9-months-old and 5-years-and-3-months-old, presenting the same intensity and the same pan-reactivity to the FCγRIIIb glycoprotein. She has no siblings, but her father presented recurrent otitis until 6-year-old and hemogram with a persistent mild neutropenia documented since childhood. Ethnic benign neutropenia was ruled out. Both expressed Fyb on erythrocytes and were heterozygotes for single nucleotide polymorphism rs2814778 in the ACKR1. She did not present remission of the disease until the age of 5 years and 7 months. A whole exome sequencing, showed a heterozygotic non-pathogenic GFI-1 variant in exon 6 (c.929G>A:p.Arg310Gln). The variant, confirmed by Sanger sequencing, was also present in her father. He has no antineutrophil antibodies detected to date.

Most cases of pAIN are diagnosed between 3 to 8 months. Spontaneous remission in about 90% could be expected in 7 to 24 months of diagnosis or up to age of 4-5 years. In this reported case, the patient had severe neutropenia demonstrated since 1 year-and-10-month-old. Even 45 months after the beginning she remains neutropenic, carrying anti-HNA autoantibody with the same pan-reactivity features. The persistence of anti-HNA with no specificity may be associated to persistent autoimmune neutropenia (AIN) as well as a characteristic of secondary AIN, but screening for both sAID and IEI were negative. Due to the persistence of neutropenia, a whole exome sequencing was performed, presenting GFI-1 variant inherited from her father, also neutropenic. The patient does not present features of GFI-1 -variants, clinical course and the bone marrow were not compatible with SCN. In addition to regulating myelopoiesis, GFI-1 also plays a role in the maturation of B and T lymphocytes, and in process of antigen-mediated lymphocyte activation. Although mature B-cells do not express GFI-1, this loss may be correlated with the increase of some IgG fractions, and some works have correlated GFI-1 changes with autoimmune conditions and could be the cause of AIN reported.

For patients with persistent pAIN, perfoming tests to detect a genetic involvement may be useful to understand the cause of the disease. In this case, the presence of GFI-1 variant could be the trigger of AIN reported.