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Case Reports
. 2022 Jul 28:10:868193.
doi: 10.3389/fped.2022.868193. eCollection 2022.

Case report: Effectiveness of sirolimus in a de novo FAS mutation leading to autoimmune lymphoproliferative syndrome-FAS and elevated DNT/Treg ratio

Hao Gu  1 , Zhenping Chen  2 , Jie Ma  1 , Jingyao Ma  1 , Lingling Fu  1 , Rui Zhang  1 , Tianyou Wang  2 , Runhui Wu  1
Affiliations
Case Reports

Case report: Effectiveness of sirolimus in a de novo FAS mutation leading to autoimmune lymphoproliferative syndrome-FAS and elevated DNT/Treg ratio

Hao Gu et al. Front Pediatr. .

Abstract

Background: The autoimmune lymphoproliferative syndrome (ALPS) is a rare disease characterized by defective function of the FAS death receptor, which results in chronic, non-malignant lymphoproliferation and autoimmunity accompanied by elevated numbers of double-negative (DN) T cells (T-cell receptor α/β + CD4-CD8-) and an increased risk of developing malignancies later in life.

Case description: Here, we report a patient with a de novo FAS mutation with a severe phenotype of ALPS-FAS. The FAS gene identified as a novel spontaneous germline heterozygous missense mutation (c.857G > A, p.G286E) in exon 9, causing an amino acid exchange and difference in hydrogen bond formation. Consequently, the treatment with sirolimus was initiated. Subsequently, the patient's clinical condition improved rapidly. Moreover, DNT ratio continuously decreased during sirolimus application.

Conclusion: We described a novel germline FAS mutation (c.857G > A, p.G286E) associated with a severe clinical phenotype of ALPS-FAS. Sirolimus effectively improved the patient clinical manifestations with obvious reduction of the DNT ratio.

Keywords: ALPS (autoimmune lymphoproliferative syndrome); DNT; FAS (APO-1/CD95); Treg - regulatory T-cell; sirolimus (rapamycin).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
(A) Sanger sequencing of the FAS gene (c.857G > A, p.G286E) germlinemutation of patients (left: DNA of patient’s peripheral blood; right: DNA of patient’s nail). (B) Sanger sequencing of father’s FAS gene. (C) Sanger sequencing of mother’s FAS gene. (D) Crystal structure of the FAS/FADD death domain complex (3ezq.1.A). (E) A hydrogen bond is formed between amino acids 286G and 289E; a hydrogen bond is formed between amino acid 286G and 290A. (F) A total of two hydrogen bonds are formed between amino acids 286E and 289E; A hydrogen bond is formed between amino acid 286E and 290A. The green and red squares in panels (E,F) show the difference of hydrogen bond formation between wildtype and the mutation.
FIGURE 2
FIGURE 2
(A) A representative dot plot analysis of CD4-CD8-TCRαβ + cells gated in the CD3 + cell fraction showed elevated DNT ratio compared to a healthy control. The DNT ratio of the patient decreased after sirolimus treatment. (B) A representative dot polt analysis of CD25 + foxP3 + cells gated in the CD4 + cell fraction showed decreased Treg ratio compared to a healthy control. The Treg ratio of the patient increased after sirolimus treatment.
FIGURE 3
FIGURE 3
(A) Changes in patient’s hemoglobulin during sirolimus therapy. (B) Changes in patient’s neutrophil count during sirolimus therapy. (C) Changes in patient’s platelet count during sirolimus therapy. (D) Changes in DNTs during sirolimus therapy.
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