Case report: Neonatal autoimmune lymphoproliferative syndrome with a novel pathogenic homozygous FAS variant effectively treated with sirolimus

Abstract

Background: Autoimmune lymphoproliferative syndrome (ALPS) is a rare disease characterized by defective FAS signaling, which results in chronic, nonmalignant lymphoproliferation and autoimmunity accompanied by increased numbers of "double-negative" T-cells (DNTs) (T-cell receptor αβ+ CD4-CD8-) and an increased risk of developing malignancies later in life.

Case presentation: We herein report a case of a newborn boy with a novel germline homozygous variant identified in the FAS gene, exon 9, c.775del, which was considered pathogenic. The consequence of this sequence change was the creation of a premature translational stop signal p.(lle259*), associated with a severe clinical phenotype of ALPS-FAS. The elder brother of the proband was also affected by ALPS and has been found to have the same FAS homozygous variant associated with a severe clinical phenotype of ALPS-FAS, whereas the unaffected parents are heterozygous carriers of this variant. This new variant has not previously been described in population databases (gnomAD and ExAC) or in patients with FAS-related conditions. Treatment with sirolimus effectively improved the patient clinical manifestations with obvious reduction in the percentage of DNTs.

Conclusion: We described a new ALPS-FAS clinical phenotype-associated germline FAS homozygous pathogenic variant, exon 9, c.775del, that produces a premature translational stop signal p.(lle259*). Sirolimus significantly reduced DNTs and substantially relieved the patient's clinical symptoms.

Keywords: ALPS (autoimmune lymphoproliferative syndrome); DNT-cells; FAS; autosomal recessive; newborn; novel variant; sirolimus.

Figure 1

Peripheral blood smear, wright stain depicts moderate normocytic normochromic anemia with leukocytosis, and marked lymphocytosis composed of pleomorphic mature-looking lymphoid cells (A); many atypical forms showing marked nuclear irregularities with multilobated forms (flower-like cells) (B); and/or cytoplasmic projections/pseudopods (C).

Figure 2

(A) Baseline flow cytometry plot gated on CD3+ T-cells to assess the expression of CD4 and CD8. Lower left quadrant indicates DNTs (including αβ and γδ T-cells). (B) Baseline flow cytometry plot gated on DNTs showing predominant αβ vs. γδ T-cell receptor expression. (C) Post-treatment flow cytometry plot gated on CD3+ T-cells to assess CD4 and CD8 expression. The huge population of DNT noted pretreatment in the lower left quadrant has almost completely disappeared. DNT, double-negative CD3+ T-cells.

Figure 3

Schematic diagram of FAS protein. The structure of FAS protein is indicated. The pathogenic variant affects the death domain, consequently affecting the signal transduction pathway, which would normally involve recruitment of FADD and activation of pro-caspase 8 or 10. Diagram courtesy of Khadija Karim.