Angela Nicoletti

Clinical heterogeneity of dominant chronic mucocutaneous candidiasis disease: presenting as treatment-resistant candidiasis and chronic lung disease

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.

Gastrointestinal Symptoms of Patients with Fabry Disease

In order to characterize gastrointestinal (GI) symptoms of 50 patients with Fabry disease (FD) (22 M; age range: 4–70 y; 35 adults and 15 children), validated questionnaires of GI symptoms were used to diagnose the functional gastrointestinal disorders (FGIDs) of the patients with GI symptoms (33/50 (66%); 25/35 adults and 8/15 children) according to Rome III criteria. In 16/25 of these adults and 2/8 of these children, the symptoms mimicked FGID. The adult subgroup included patients with unspecified functional bowel disorder (n = 9), functional bloating (n = 7), and IBS (n = 5), and the child subgroup included patients with abdominal migraine (n = 1) and IBS (n = 1). Among the 25 adults, 14 reported feeling full after a regular-size meal, and 12 complained of abdominal bloating/distension. All of the children with GI symptoms complained of low abdominal pain associated with changes in the form of the stool/improvements with defecation. In conclusion, according to Rome III criteria, the most frequent diagnoses of FGID among the adults with FD were unspecified functional bowel disorder, followed by functional bloating and IBS. The most frequent GI symptom in the children in our population was IBS-like abdominal pain, while the adults exhibited a full feeling following a regular-size meal and abdominal bloating/distension.

Clinical and immunological data of nine patients with chronic mucocutaneous candidiasis disease

This paper describes the heterogeneous clinical phenotype of a cohort of nine patients diagnosed with heterozygous mutations in STAT1. We report data of extended immunophenotyping over time and we show lung damage in four patients. The increased phosphorylation of STAT1 in response to IFNγ and IFNα stimulation proves the gain-of-function nature of the defects. The data are supplemental to our original article concurrently published “Clinical heterogeneity of dominant chronic mucocutaneous candidiasis disease: presenting as treatment-resistant candidiasis and chronic lung disease” [1], where additional results and interpretation of our research can be found.

Genetic variants associated with gastrointestinal symptoms in Fabry disease

Gastrointestinal symptoms (GIS) are often among the earliest presenting events in Fabry disease (FD), an X-linked lysosomal disorder caused by the deficiency of α-galactosidase A. Despite recent advances in clinical and molecular characterization of FD, the pathophysiology of the GIS is still poorly understood. To shed light either on differential clinical presentation or on intervariability of GIS in FD, we genotyped 1936 genetic markers across 231 genes that encode for drug-metabolizing enzymes and drug transport proteins in 49 FD patients, using the DMET Plus platform. All nine single nucleotide polymorphisms (SNPs) mapped within four genes showed statistically significant differences in genotype frequencies between FD patients who experienced GIS and patients without GIS: ABCB11 (odd ratio (OR) = 18.07, P = 0,0019; OR = 8.21, P = 0,0083; OR=8.21, P = 0,0083; OR = 8.21, P = 0,0083),SLCO1B1 (OR = 9.23, P = 0,0065; OR = 5.08, P = 0,0289; OR = 8.21, P = 0,0083), NR1I3 (OR = 5.40, P = 0,0191) and ABCC5 (OR = 14.44, P = 0,0060). This is the first study that investigates the relationships between genetic heterogeneity in drug absorption, distribution, metabolism and excretion (ADME) related genes and GIS in FD. Our findings provide a novel genetic variant framework which warrants further investigation for precision medicine in FD.