Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

Abstract

Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guérin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis.

Figure 1

Kaplan-Meier curves for onset of CMC and outcome. (A) Onset of CMC. Exact age at onset of CMC was available for 253 patients. (B) Overall survival curves. Age at the time of the study was available for 269 patients. Patients with severe complications (ie, patients who displayed invasive infections, aneurysms, and/or tumors) were compared with patients without any severe complication (log-rank test, P < .001).

Figure 2

Photographs of patients with STAT1 GOF mutations. (A) Thrush. (B-C) Onycomycosis. (D-F) Cutaneous candidiasis. (G) Dermatophytes. (H) Cutaneous and genital candidiasis. (I) Cutaneous candidiasis. (J) Angular stomatitis. (K) Esophageal candidiasis. (L) Bronchiectasis. (M) Cerebral aneurysm. Complete phenotype of each patient is described in the supplemental Tables 1-3.