CP 5 - STAT1 gain-of-function mutation presenting as chronic mucocutaneous candidiasis in childhood: a case report report.

Palipane EG, Karunatilake RMCH, de Silva R, Dasanayake D , Department of Immunology, Medical Research Institute, Colombo 08

Abstract

Introduction

Pathogenic gain-of-function (GOF) variants in the STAT1 gene result in a rare inborn error of immunity (IEI) characterized by immune dysregulation and immunodeficiency, most commonly presenting with chronic mucocutaneous candidiasis (CMC).

Case report

A 16-month-old boy, born to non-consanguineous parents, presented with recurrent mucocutaneous candidiasis involving skin, nails and oral mucosa from 1.5 months of age, which was refractory to topical antifungal therapy. At 8 months, he presented with diarrhoea and growth faltering. At 16 months, he was admitted with bronchopneumonia. Investigations revealed normal leukocyte counts, iron deficiency anaemia, and elevated C-reactive protein levels. Imaging confirmed bronchopneumonia, while bronchoalveolar lavage culture yielded a mixed growth of coliforms and Pseudomonas species. HIV serology and serum galactomannan were negative. Gastric aspirate for Mycobacterium tuberculosis PCR and mycobacterial cultures was negative. Upper gastrointestinal endoscopy demonstrated extensive oesophageal candidiasis. The patient was treated with intravenous antibiotics and fluconazole, followed by oral itraconazole. Oropharyngeal cultures detected a growth of Candida albicans, sensitive to fluconazole, and the patient was converted to fluconazole therapy. Immunological evaluation with nitro-blue tetrazolium test, serum immunoglobulin levels and lymphocyte subset counts were normal. Whole-exome sequencing confirmed a heterozygous STAT1-GOF pathogenic variant. Fluconazole was discontinued due to liver injury. The patient had persistent CMC at follow-up despite topical anti-fungal therapy.

 Discussion

STAT1-GOF variants are autosomal dominant disorders characterized by substantial clinical heterogeneity. Persistent candidiasis despite susceptible antifungal therapy is attributed to STAT1-GOF associated impairment of Th17-mediated mucosal immunity. Patients may also experience recurrent sinopulmonary bacterial infections and autoimmune manifestations such as cytopenias and enteropathy. Differential diagnosis includes IEIs such as primary T cell disorders, STAT3 loss of function and DOCK8 deficiency. Autoimmune endocrinopathy may point to a diagnosis of Autoimmune-Polyendocrinopathy-Candidiasis-Ectodermal-Dystrophy (APECED). This report highlights the critical role of genetic testing in the evaluation of paediatric patients with CMC to enable diagnosis of underlying IEIs. Assessment of the Th17-mediated pathway by immunoprofiling may aid diagnosis and guide targeted therapeutics such as JAK inhibitors.  This report underscores the importance of recognizing rare IEIs in children presenting with persistent infections refractory to susceptible antimicrobials.