title: Clinical heterogeneity of dominant chronic mucocutaneous candidiasis disease: presenting as treatment-resistant candidiasis and chronic lung disease.
abstract: In gain-of-function STAT1 mutations, chronic mucocutaneous candidiasis disease (CMCD) represents the phenotypic manifestation of a complex immunodeficiency characterized by clinical and immunological heterogeneity. We aimed to study clinical manifestations, long-term complications, molecular basis, and immune profile of patients with dominant CMCD. We identified nine patients with heterozygous mutations in STAT1, including novel amino acid substitutions (L283M, L351F, L400V). High risk of azole-resistance was observed, particularly when intermittent regimens of antifungal treatment or use of suboptimal dosage occurs. We report a case of Cryptococcosis and various bacterial and viral infections. Risk of developing bronchiectasis in early childhood or gradually evolving to chronic lung disease in adolescent or adult ages emerges. Lymphopenia is variable, likely progressing by adulthood. We conclude that continuous antifungal prophylaxis associated to drug monitoring might prevent resistance to treatment; prompt diagnosis and therapy of lung disease might control long-term progression; careful monitoring of lymphopenia-related infections might improve prognosis.
authors.affiliation: Department of Clinical and Experimental Sciences, Institute of Molecular Medicine "Angelo Nocivelli", University of Brescia, Brescia, Italy. Electronic address: lauradotta@icloud.com.
authors.forename: Laura
authors.initials: L
authors.lastname: Dotta
authors.affiliation: Department of Clinical and Experimental Sciences, Institute of Molecular Medicine "Angelo Nocivelli", University of Brescia, Brescia, Italy.
authors.forename: Omar
authors.initials: O
authors.lastname: Scomodon
authors.affiliation: Unit of Paediatric Pneumonology, Spedali Civili of Brescia, Brescia, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Padoan
authors.affiliation: Unit of Paediatric Pneumonology, Spedali Civili of Brescia, Brescia, Italy.
authors.forename: Silviana
authors.initials: S
authors.lastname: Timpano
authors.affiliation: Department of Clinical and Experimental Sciences, Institute of Molecular Medicine "Angelo Nocivelli", University of Brescia, Brescia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.affiliation: Department of Clinical and Experimental Sciences, Institute of Molecular Medicine "Angelo Nocivelli", University of Brescia, Brescia, Italy.
authors.forename: Annarosa
authors.initials: A
authors.lastname: Soresina
authors.affiliation: Department of Clinical and Experimental Sciences, Institute of Molecular Medicine "Angelo Nocivelli", University of Brescia, Brescia, Italy.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Lougaris
authors.affiliation: Department of Paediatrics, University of Catanzaro, Catanzaro, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Concolino
authors.affiliation: Department of Paediatrics, University of Catanzaro, Catanzaro, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Nicoletti
authors.affiliation: Department of Translational Medical Sciences, Federico II University, Naples, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Giardino
authors.affiliation: Department of Paediatrics, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
authors.forename: Amelia
authors.initials: A
authors.lastname: Licari
authors.affiliation: Department of Paediatrics, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Marseglia
authors.affiliation: Department of Translational Medical Sciences, Federico II University, Naples, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pignata
authors.affiliation: Department of Medicine, General Pathology Unit, University of Verona, Verona, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Tamassia
authors.affiliation: Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia, Brescia, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Vairo
authors.affiliation: Department of Clinical and Experimental Sciences, Institute of Molecular Medicine "Angelo Nocivelli", University of Brescia, Brescia, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Badolato
mesh_terms: D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000627:therapeutic use; D015551:Autoimmunity; D001393:Azoles / Q000627:therapeutic use; D001424:Bacterial Infections / Q000150:complications; D002178:Candidiasis, Chronic Mucocutaneous / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D002648:Child; D002908:Chronic Disease; D003453:Cryptococcosis / Q000150:complications; D003455:Cryptococcus neoformans; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007898:Leishmaniasis, Visceral / Q000150:complications; D008171:Lung Diseases / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D008231:Lymphopenia / Q000150:complications; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D014777:Virus Diseases / Q000150:complications; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human
keywords: Autoimmunity; Bronchiectasis; Chronic lung disease; Chronic mucocutaneous candidiasis; Gain of function STAT1; Lymphopenia