Case Report: A New Gain-of-Function Mutation of STAT1 Identified in a Patient With Chronic Mucocutaneous Candidiasis and Rosacea-Like Demodicosis: An Emerging Association

PurposeHeterozygous missense STAT1 mutations leading to a gain of function (GOF) are the most frequent genetic cause of chronic mucocutaneous candidiasis (CMC). We describe the case of a patient presenting a new GOF mutation of STAT1 with the clinical symptoms of CMC, recurrent pneumonia, and persistent central erythema with papulopustules with ocular involvement related to rosacea-like demodicosis.MethodsGenetic analysis via targeted next-generation sequencing (NGS; NGS panel DIPAI v.1) exploring the 98 genes most frequently involved in primary immunodeficiencies, including STAT1, was performed to identify an underlying genetic defect.ResultsNGS identified a novel variant of STAT1, c.884C>A (exon 10), p.T295Y, not previously described. This variant was found to be gain of function using an in vitro luciferase reporter assay. Rosacea-like demodicosis was confirmed by substantial Demodex proliferation observed via the microscopic examination of a cutaneous sample. A review of literature retrieved 20 other cases of STAT1 GOF mutations associated with early-onset rosacea-like demodicosis, most with ocular involvement.ConclusionWe describe a new STAT1 GOF mutation associated with a phenotype of CMC and rosacea-like demodicosis. Rosacea-like demodicosis appears as a novel and important clinical phenotype among patients with STAT1 GOF mutation.

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type-1 (APS-1), is a rare monogenic autoimmune disease caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene. AIRE deficiency impairs immune tolerance in the thymus and results in the peripheral escape of self-reactive T lymphocytes and the generation of several cytokine- and tissue antigen-targeted autoantibodies. APECED features a classic triad of characteristic clinical manifestations consisting of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenal insufficiency (Addison's disease). In addition, APECED patients develop several non-endocrine autoimmune manifestations with variable frequencies, whose recognition by pediatricians should facilitate an earlier diagnosis and allow for the prompt implementation of targeted screening, preventive, and therapeutic strategies. This review summarizes our current understanding of the genetic, immunological, clinical, diagnostic, and treatment features of APECED.

Intracranial Calcifications in Autoimmune Polyendocrine Ectodermal Dystrophy Syndrome (APECED): About A Case Report

Autoimmune polyendocrinopathy ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS I), is an uncommon, but debilitating autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE), It is characterized by a broad and diverse clinical spectrum which can lead to severe metabolic alterations and eventually life-threatening events. Hypoparathyroidism is one of the major criteria for clinical diagnosis, in addition to chronic mucocutaneous candidiasis and autoimmune adrenal insufficiency. This component is responsible for the forming of brain calcifications which tend to have a characteristic predilection for the basal ganglia. In this article, we report an additional case to the literature and provide a literature review of the expanding radiological spectrum of this syndrome

Autoimmune hepatitis as the first manifestation of autoimmune polyendocrine syndrome type 1 in a 5-year-old girl

Autoimmune hepatitis is a chronic inflammatory liver disease of unknown etiology; the prevalence of juvenile autoimmune hepatitis is unknown. Autoimmune hepatitis occurs in 10–20% of patients with type 1 autoimmune polyendocrine syndrome, a rare (orphan) disease, which is characterized by a clinical triad in 70–100% of cases: chronic mucocutaneous candidiasis, hypopara thy roidismand adrenal insufficiency, as well as more 25 possible autoimmune endocrine and non-endocrine manifestations.Thisstudy describes a case of a 5-year-old girl with autoimmune hepatitis as the first clinical manifestation of the disease. The symptoms of chronic mucocutaneous candidiasis enabled us to suggest and genetically confirm the diagnosis of autoimmune poly endocrine syndrome type 1 before the lesions of endocrine organs. The girl had nonsense mutations R257 * and p.Q94* of the AIRE gene in a compound heterozygous state. Later, there appeared another autoimmune disorder – common vitiligo.Timelydiagnosisoftype1autoimmunepolyendocrinesyndromeinachildwiththefirstnon-endocrine autoimmune manifestation, initiation of therapy and further medical management made it possible to preventseve recomplications and improve the patient’s quality of life.

Genetic Analysis of a Cohort of 275 Patients with Hyper-IgE Syndromes and/or Chronic Mucocutaneous Candidiasis

Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in DOCK8 (26 patients), STAT3 (21), STAT1 (15), CARD9 (6), AIRE (3), IL17RA (2), SPINK5 (3), ZNF341 (2), CARMIL2/RLTPR (1), IL12RB1 (1), and WAS (1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers.

Case Report: Disseminated Talaromyces marneffei Infection in a Patient With Chronic Mucocutaneous Candidiasis and a Novel STAT1 Gain-of-Function Mutation

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.

Co-Occurrence of Chronic Mucocutaneous Candidiasis with Woolly Hair

Chronic mucocutaneous candidiasis is an immunodeficiency state, inherited or acquired, characterized by recurrent and/or persistent candidiasis of skin, nails, and mucous membranes. Woolly hair is a congenital structural anomaly of scalp hair, characterized by light-colored, short, extremely kinky, and thin hair due to premature termination of anagen phase of hair cycle. Both conditions are known to present in syndromic and non-syndromic forms. We report the co-occurrence of both these conditions in a 10-year-old female child. The diagnosis was confirmed with clinical, trichoscopic, microbiologic, histopathologic, and laboratory evaluation, though mutational analysis could not be done due to resource constraints. The occurrence of both these diseases in the same individual has not been previously reported to the best of our knowledge. It could be a result of an association with ectodermal dysplasia.

A Novel IL17RA Mutation In A Male Child With Chronic Mucocutaneous Candidiasis

Purpose: Chronic mucocutaneous candidiasis (CMC) is characterized by persistent or recurrent fungal infections involving the nails, skin, oral and genital mucosa. Impaired IL17 mediated immunity is a cause for CMC. Patient and Methods: After the next-generation sequencing analysis showed the IL17RA variant, confirmation by Sanger sequencing was done. Functional validation of the variant by flow cytometry was performed. Results: We present a 6-year-old male patient who presented with recurrent oral and genital candida infections and eczema. He had staphylococcal skin lesions in addition to the fungal susceptibility and eczema. The patient was found to carry a previously unreported homozygous nonsense [(c.787C> T) (p.Arg263Ter)] mutation in the IL17RA gene. Sanger sequencing confirmed the variant and showed the segregation of the variant in the family. We used flow cytometry to detect IL17RA protein expression in patients’ PBMCs and measured the Th17 cell percentages. Severely decreased IL17RA protein expression was observed in patient’s PBMCs and decreased CD4+ IL17+ cell percentage as well as decreased IL17F expression in CD4+ cells compared with healthy control. Conclusion: In patients with chronic recurrent fungal and bacterial and/or infections of the skin, mucosa, and nails, advanced immunological studies should be performed to document the genetic susceptibility even if basic immunological tests are normal.