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Review
. 2024 Jul 24:15:1430938.
doi: 10.3389/fimmu.2024.1430938. eCollection 2024.

Retrospective identification of the first cord blood-transplanted severe aplastic anemia in a STAT1-associated chronic mucocutaneous candidiasis family: case report, review of literature and pathophysiologic background

Franz-Martin Fink  1 , Reinhard Höpfl  2 , Martina Witsch-Baumgartner  3 , Gabriele Kropshofer  4 , Sabine Martin  1 , Valentin Fink  1 , Maximilian Heeg  5 , Christina Peters  6   7 , Johannes Zschocke  3 , Oskar A Haas  8   9
Affiliations
Review

Retrospective identification of the first cord blood-transplanted severe aplastic anemia in a STAT1-associated chronic mucocutaneous candidiasis family: case report, review of literature and pathophysiologic background

Franz-Martin Fink et al. Front Immunol. .

Abstract

Severe aplastic anemia (SAA) is a life-threatening bone marrow failure syndrome whose development can be triggered by environmental, autoimmune, and/or genetic factors. The latter comprises germ line pathogenic variants in genes that bring about habitually predisposing syndromes as well as immune deficiencies that do so only occasionally. One of these disorders is the autosomal dominant form of chronic mucocutaneous candidiasis (CMC), which is defined by germ line STAT1 gain-of-function (GOF) pathogenic variants. The resultant overexpression and constitutive activation of STAT1 dysregulate the Janus kinase/signal transducer and activator of transcription 1 (STAT) signaling pathway, which normally organizes the development and proper interaction of different components of the immunologic and hematopoietic system. Although SAA is an extremely rare complication in this disorder, it gained a more widespread interest when it became clear that the underlying causative pathomechanism may, in a similar fashion, also be instrumental in at least some of the idiopathic SAA cases. Based on these premises, we present herein what is the historically most likely first cord blood-transplanted SAA case in a CMC family with a documented STAT1 GOF pathogenic variant. In addition, we recapitulate the characteristics of the six CMC SAA cases that have been reported so far and discuss the significance of STAT1 GOF pathogenic variants and other STAT1 signaling derangements in the context of these specific types of bone marrow failure syndromes. Because a constitutively activated STAT1 signaling, be it driven by STAT1 GOF germ line pathogenic variants or any other pathogenic variant-independent events, is apparently important for initiating and maintaining the SAA disease process, we propose to acknowledge that SAA is one of the definite disease manifestations in STAT1-mutated CMC cases. For the same reason, we deem it necessary to also incorporate molecular and functional analyses of STAT1 into the diagnostic work-up of SAA cases.

Keywords: STAT1; chronic mucocutaneous candidiasis (CMC); gain-of-function pathogenic variant; severe aplastic anemia (SAA); transplantation.

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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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Photographs of the CMC manifestations in the two boys: Candida paronychias and onychodystrophic thumbnails (A, B) and periocular seborrheic eczema (C) in the index patient 1, and oral candidiasis in his brother (D).
Figure 2
Figure 2
Result of the pathogenic variant screening in our CMC family. In the index patient, targeted pathogenic variant screening revealed a heterozygous c.1013G>T (p.Gly338Val) missense pathogenic variant in the STAT1 gene, which was subsequently also identified in the peripheral blood of his brother and in the fibroblasts of his father with Sanger sequencing the respective PCR-amplified Exon 11, but not in the healthy mother.
Figure 3
Figure 3
Results of the analyses of the functional consequences of the STAT1 c.1013G>T (p.Gly338Val) missense pathogenic variant. Compared to healthy controls, stimulation with interferon-α as well as interferon-γ leads to the hyperphosphorylation of STAT1 in the monocytes (left) of the index patient and his brother (not shown). Conversely, stimulation with the NF-κB activator phorbol myristate acetate and ionomycin revealed the impaired expression of interleukin-17 as well as interferon-γ in their CD45RO+CD4+ T cells. Together, these findings provide persuasive evidence for the GOF effect of this pathogenic variant.
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. We are grateful for the financial support provided by the St. Anna Children’s Cancer Research Institute (CCRI) Vienna, the Department of Dermatology and Venerology and the Institute of Human Genetics, Medical University Innsbruck, to cover the publication costs.