Chronic mucocutaneous Candidiasis caused by a novel STAT1 mutation: a report of 4 patients
Abstract
Background: Chronic mucocutaneous Candidiasis (CMCC) is characterized by recurrent or persistent fungal infections of the skin, nails, and oral and genital mucosae. There are several underlying genetic causes for CMCC, with mutations in Signal Transducer and Activator of Transcription-1 (STAT1) accounting for the majority of cases.
Aim: To broaden the genotypic spectrum of CMCC caused by STAT1 mutations.
Methods: We evaluated a young patient and her family with CMCC. Immune workup and targeted gene sequencing were performed.
Results: The proband presented at 7 years of age with persistent oral thrush. Immune evaluation revealed her cellular and humoral immunity to be within normal range. Given that her family history was significant for oral lesions in father, siblings, and paternal family members, STAT1 gene sequencing was performed. A novel heterozygous missense c.G799A, predicting a p. Ala267Thr amino acid change within the coiled-coil domain, was identified in our patient and 3 of her family members.
Conclusion: Gain-of-function mutations in STAT1 have been associated with a variety of phenotypes, ranging from isolated CMCC to severe fatal combined immunodeficiency, mycobacterial infections, autoimmune disorders, as well as malignancy and aneurysms. Here, we describe a novel STAT1 mutation, c.G799A, resulting in a very mild phenotype of isolated CMCC in 4 members of one kindred.
Statement of novelty: We describe 4 patients with a mild phenotype of CMCC caused by a novel STAT1 heterozygous mutation.
Introduction
Chronic mucocutaneous Candidiasis (CMCC) is a group of disorders characterized by susceptibility to Candidal infection of the skin, nails, and mucous membranes. The range of genetic etiologies underlying CMCC is broad, including defects in Autoimmune Regulator (AIRE), IL-17 pathway members (IL17RA, IL17RC, IL17F), Dectin-1, Caspase Recruitment Domain Family Member 9 (CARD9), Signal Transducer and Activator of Transcription (STAT1), and STAT3 (Tangye et al. 2020).
STAT1 is a key transcription factor mediating signaling of various cytokines, notably interferons (IFN), playing roles in cell homeostasis, stress response, and defense against intracellular pathogens. Its activation is dependent upon initial phosphorylation in the cytoplasm by tyrosine kinases, of the Janus-kinase (JAK) family, formation of dimerization, and translocation to the nucleus, where it binds to promoters to impact transcription (Zheng et al. 2015). In response to IFN-γ stimulation, STAT1 forms homodimers (known as gamma-activating factor, GAF) or heterodimers with STAT3 that bind to gamma-activating sequence (GAS) in gene promoters. In response to IFN-α or IFN-β stimulation, STAT1 forms a heterotrimer with STAT2 and IFN-regulatory factor 9 (IRF9), also known as IFN-stimulated gene factor 3 (ISGF3) which binds to interferon-stimulated response element (ISRE) in gene promoters (Gough et al. 2008).
The clinical spectrum associated with STAT1 GOF is broad, ranging from mild infections to life-threatening bacterial, viral and opportunistic infections, CMCC, endocrinopathies, variable autoimmune manifestations and gradually declining lymphocyte number and function (van de Veerdonk et al. 2011; Sharfe et al. 2014; Toubiana et al. 2016). Complications such as bronchiectasis (Toubiana et al. 2016; Breuer et al. 2017), intracranial aneurysms (Toubiana et al. 2016) and squamous cell carcinoma (Koo et al. 2017) have also been reported.
Herein, we report on 4 family members with a novel STAT1 mutation, resulting in a mild phenotype of isolated CMCC.
Case presentation
Proband
A 7-year-old female was referred to the Immunology clinic for persistent oral thrush involving her tongue, buccal mucosa, and hard palate, starting at 4 years of age. She was diagnosed with CMCC confirmed by positive swabs and oral biopsy. She did not experience dysphagia or odynophagia, nor involvement of the nails, skin, or vaginal mucosa. There was no history of invasive fungal infections or other systemic infections, and no features suggestive of endocrinopathy. Review of past medical history demonstrated that she had been born at term to nonconsanguineous parents of English descent following a normal pregnancy and uncomplicated delivery. She had undergone an eye surgery for correction of strabismus at early childhood. She had been otherwise well and developed normally. Family history was significant for similar oral lesions in her 2 younger male twin siblings and father, all of whom were healthy apart from CMCC. Other paternal family members (great grandfather and great aunts) also had a history of oral fungal infections (Figure 1).
Figure 1:
Investigations
A full immunological laboratory assessment, including complete blood-count and differential, lymphocyte subsets, total immunoglobulins, and T-cell stimulation to mitogen, were all within normal range, while specific antibody responses to measles, mumps, and varicella were all non-reactive (Table 1). Thyroid and parathyroid functions normal as well. Given a history of possibly autosomal dominant CMCC, targeted gene sequencing was carried out, revealing a novel heterozygous STAT1 gene mutation in all 4 clinically affected family members. The mutation, c.G799A, results in the amino acid change Ala267Thr affecting the coiled-coil domain (Figure 2). To our knowledge, this variant has not been previously reported in large population databases, nor in previous reports of STAT1 GOF.
Table 1:
Figure 2:
Outcome
The proband (currently 14 years old), her 11-year-old twin siblings, and 48-year-old father, have continued to be well over the last 7 years, with the exception of ongoing oral CMCC requiring prolonged topical anti-fungal treatment.
Discussion
STAT1 GOF was first described in 2011 by 2 groups, with initial disease manifestations reported CMCC and autoimmunity (in particular, hypothyroidism) (Liu et al. 2011; van de Veerdonk et al. 2011). Over the next few years, the disease spectrum was expanded to include a wide host of infectious susceptibilities, autoimmunity, intracranial aneurysms, and malignancy (Sampaio et al. 2013; Sharfe et al. 2014; Toubiana et al. 2016; Koo et al. 2017).
We herein report on multiple members of one kindred, found to have a heterozygous STAT1 gene mutation causing chronic oral Candidiasis. In this family, the onset of CMCC was in early childhood, and all affected members presented with a mild disease phenotype. The mutation, c.G799A, predicts an amino acid change A267T in the coiled-coil domain of STAT1, a domain involved in protein-protein interactions which plays a key role in the dimerization of STAT1 and nuclear STAT1 dephosphorylation (Levy and Darnell 2002). It is the most commonly affected domain implicated in STAT1 GOF, with the 267 residue (and in particular the A267V mutation) being the most common mutation identified in large STAT1 GOF cohorts (Toubiana et al. 2016). Clinical manifestations seen in patients with the A267V mutation have included CMCC, bacterial and viral infections, atopy, thyroid dysfunction, bronchiectasis, aneurysms, and squamous cell carcinoma. Notably, some of the more severe disease manifestations, such as malignancy, typically developed in adulthood between the third and fifth decade of life (Toubiana et al. 2016).
The current report expands the genotypic spectrum of STAT1 GOF, and supports the notion of genetic testing for an underlying immunodeficiency in patients and families with CMCC. While the patients in the current report have displayed mild disease to date, we suggest that regular and life-long follow up should be performed in all cases of STAT1 GOF, screening periodically not only for changes in immune function, but also for late-onset disease manifestations, such as malignancies. Further studies looking into establishing genotype-phenotype correlation for STAT1 GOF, are warranted and may help determine which mutations predispose patients to severe or life-threatening complications.
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Published In
LymphoSign Journal
Volume 8 • Number 2 • June 2021
Pages: 64 - 67
History
Received: 8 May 2021
Accepted: 20 May 2021
Accepted manuscript online: 2 June 2021
Copyright
© 2021.
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JennyGarkaby and OriScott. 2021. Chronic mucocutaneous Candidiasis caused by a novel STAT1 mutation: a report of 4 patients. LymphoSign Journal.
8(2): 64-67. https://doi.org/10.14785/lymphosign-2021-0019
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