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.

Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is associated with biallelic variants in SGPL1, comprising a multisystemic disease characterized by steroid resistant nephrotic syndrome, primary adrenal insufficiency, neurological problems, skin abnormalities and immunodeficiency in described cases. Signal transducer and activator of transcription 1 (STAT1) plays an important role in orchestrating an appropriate immune response through JAK-STAT pathway. Biallelic STAT1 loss of function (LOF) variants lead to STAT1 deficiency with a severe phenotype of immunodeficiency with increased frequency of infections and poor outcome if untreated.
We report novel homozygous SGPL1 and STAT1 variants in a newborn of Gambian ethnicity with clinical features of SPLIS and severe combined immunodeficiency. The patient presented early in life with nephrotic syndrome, severe respiratory infection requiring ventilation, ichthyosis, and hearing loss, with T-cell lymphopenia. The combination of these two conditions led to severe combined immunodeficiency with inability to clear respiratory tract infections of viral, fungal, and bacterial nature, as well as severe nephrotic syndrome. The child sadly died at 6 weeks of age despite targeted treatments.
We report the finding of two novel, homozygous variants in SGPL1 and STAT1 in a patient with a severe clinical phenotype and fatal outcome early in life. This case highlights the importance of completing the primary immunodeficiency genetic panel in full to avoid missing a second diagnosis in other patients presenting with similar severe clinical phenotype early in life. For SPLIS no curative treatment is available and more research is needed to investigate different treatment modalities. Hematopoietic stem cell transplantation (HSCT) shows promising results in patients with autosomal recessive STAT1 deficiency. For this patient\'s family, identification of the dual diagnosis has important implications for future family planning. In addition, future siblings with the familial STAT1 variant can be offered curative treatment with HSCT.

Talaromyces marneffei and Pneumocystis jirovecii are the common opportunistic pathogens in immunodeficient patients. There have been no reports of T. marneffei and P. jirovecii coinfection in immunodeficient children. Signal transducer and activator of transcription 1 (STAT1) is a key transcription factor in immune responses. STAT1 mutations are predominately associated with chronic mucocutaneous candidiasis and invasive mycosis. We report a 1-year-2-month-old boy diagnosed with severe laryngitis and pneumonia caused by T. marneffei and P. jirovecii coinfection, which was confirmed by smear, culture, polymerase chain reaction and metagenome next-generation sequencing of bronchoalveolar lavage fluid. He has a known STAT1 mutation at amino acid 274 in the coiled-coil domain of STAT1 according to whole exome sequencing. Based on the pathogen results, itraconazole and trimethoprim-sulfamethoxazole were administered. This patient\'s condition improved, and he was discharged after two weeks of targeted therapy. In the one-year follow-up, the boy remained symptom-free without recurrence.

UNASSIGNED: Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations are characterized by chronic mucocutaneous candidiasis and autoimmune diseases. Type 1 diabetes mellitus is one of the well-characterized autoimmune conditions.
UNASSIGNED: We reported a 5-year-old boy who presented with polydipsia and polyuria, with a medical history of chronic oral mucocutaneous candidiasis, recurrent respiratory infection, hepatosplenomegaly, and abnormal liver function. Genetic analysis identified a heterozygous GOF mutation (c.866A > G, p.Y289C) in STAT1.
UNASSIGNED: Various medicines were given to the boy during the follow-up, including insulin to keep blood glucose stable, intravenous immunoglobulin and antifungal agents for recurrent infections, and antituberculosis drugs (isoniazid, rifampicin) to combat tuberculosis infection. He did not show recurrent infection, but chronic oral mucocutaneous candidiasis still occurred twice per month. The blood glucose level was well controlled.
UNASSIGNED: This article illustrates that early diagnosis and identification of STAT1 mutation are essential for assessing the severity of the disease and determining reasonable treatment options.

STAT1 gain-of-function (GOF) is a primary immune dysregulatory disorder marked by wide infectious predisposition (most notably chronic mucocutaneous Candidiasis), autoimmunity, vascular disease and malignant predisposition. While atopic features have been described in some STAT1 GOF patients, they are not considered a predominant feature of the disease. Additionally, while eosinophilic gastrointestinal infiltration has been reported in some cases, this has always been described in the context of pre-existing oropharyngeal and/or esophageal Candidiasis.
Herein, we report 3 members of a multi-generational family diagnosed with STAT1 GOF caused by a novel mutation in the N-terminal domain, c.194A>C (p.D65A). The proband presented initially with a long-standing history of treatment-refractory eosinophilic esophagitis (EoE) without preceding gastrointestinal tract fungal infections, and her mother was diagnosed with esophagitis as well.
EoE has been previously associated with alterations to STAT6 and STAT3 signaling pathways. The current report expands the possible association between JAK/STAT-related disorders and EoE, suggesting that EoE could be a primary disease manifestation of STAT1 GOF, even in the absence of oropharyngeal and/or esophageal Candidiasis.

Chronic mucocutaneous candidiasis (CMC) is a disorder of recurrent or persistent chronic noninvasive symptomatic infections of the skin, nails and mucous membranes. This disorder is primarily caused by Candida albicans. Many factors, including primary immunodeficiencies, can make a host more susceptible to CMC. Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations are the most common genetic etiologies of CMC. We describe a case of CMC with disseminated Talaromyces marneffei infection caused by a new pathogenic Y287N mutation at amino acid 287 in the coiled-coiled domain of STAT1, which was identified using whole-exome sequencing. Position 287 might be a hot spot for missense mutations because several amino acid substitutions were found there. Flow cytometry suggested that the Y287N mutation might reduce the expression of IL-17 of Th17 cells in peripheral blood mononuclear cells stimulated by phorbol myristate acetate and ionomycin. The STAT1 Y287N GOF mutation may be the direct cause of recurrent cutaneous and mucosal candidiasis, including the T. marneffei infection in this patient.

BACKGROUND: Chronic mucocutaneous candidiasis (CMC) is the most common clinical symptom of singer transducer and signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations. Bronchiectasis is a chronic lung disease that is characterized by permanent bronchiectasis, causing cough, expectoration, and even haemoptysis. The underlying pathogeny is not yet clear. Immunoglobulin (Ig) A is derived from memory B cells and correlates with immune-related diseases. STAT1 is closely associated with signal transmission and immune regulation.
METHODS: We report a 17-year-old male patient carrying a GOF mutation in STAT1. The variant led to CMC, bronchiectasis, and elevated serum IgA levels, as well as stunting. Whole-exome sequencing (WES) revealed a c.986C>G (p.P329R) heterozygous mutation in the STAT1 gene.
CONCLUSIONS: Further Sanger sequencing analysis of STAT1 in the patient and his parents showed that the patient harboured a de novo mutation.