Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome is a rare disorder that has become a model of monogenic autoimmunity. IPEX is caused by mutations in FOXP3 gene, a master regulator of regulatory T cells (Treg). Cases reported in the last 20 years demonstrate that IPEX clinical spectrum encompasses more than the classical triad of early-onset intractable diarrhea, type 1 diabetes (T1D) and eczema. Atypical cases of IPEX include patients with late-onset of symptoms, single-organ involvement, mild disease phenotypes or rare clinical features (e.g., atrophic gastritis, interstitial lung disease, nephropathy etc.). Several atypical presentations have recently been reported, suggesting that IPEX incidence might be underestimated. Immunosuppression (IS) treatment strategies can control the disease, however at the moment allogeneic hematopoietic stem cell transplantation (HSCT) is the only available definitive cure, therefore it is important to achieve a prompt diagnosis. This review aims to describe unusual clinical phenotypes, beyond classical IPEX. Overall, our analysis contributes to increase awareness and finally improve diagnosis and treatment intervention in IPEX in order to ensure a good quality of life.

Autoimmune lymphoproliferative syndrome (ALPS) is a primary immune regulatory disorder characterized by benign or malignant lymphoproliferation and autoimmunity. Classically, ALPS is due to mutations in FAS and other related genes; however, recent research revealed that other genes could be responsible for similar clinical features. Therefore, ALPS classification and diagnostic criteria have changed over time, and several ALPS-like disorders have been recently identified. Moreover, mutations in FAS often show an incomplete penetrance, and certain genotypes have been associated to a dominant or recessive inheritance pattern. FAS mutations may also be acquired or could become pathogenic when associated to variants in other genes, delineating a possible digenic type of inheritance. Intriguingly, variants in FAS and increased TCR αβ double-negative T cells (DNTs, a hallmark of ALPS) have been identified in multifactorial autoimmune diseases, while FAS itself could play a potential role in carcinogenesis. These findings suggest that alterations of FAS-mediated apoptosis could trespass the universe of inborn errors of immunity and that somatic mutations leading to ALPS could only be the tip of the iceberg of acquired immunodeficiencies.

Background and objectives. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is extremely rare in children. We report the clinico-pathological features, long-term outcomes, and prognostic factors of a large paediatric cohort of patients with ANCA-associated kidney vasculitis. Design, setting, participants, and measurements. This retrospective study included 85 consecutive patients with kidney biopsy-proven ANCA-associated vasculitis followed at tertiary referral centres in Italy and Canada. Kidney biopsies were categorised as focal, crescentic, sclerotic or mixed following Berden's classification. The prognostic significance of baseline clinical, laboratory and histological findings was analysed with respect to kidney failure or chronic kidney disease (CKD) 3-5/kidney failure. Results. Fifty-three patients had microscopic polyangiitis (62%) and 32 granulomatosis with polyangiitis (38%). Rapidly progressive glomerulonephritis was the most frequent presentation (39%); one third of the patients also had nephrotic-range proteinuria. Kidney biopsies were classified as focal in 21% of the patients, crescentic in 51%, sclerotic in 15% and mixed in 13%. Remission-induction therapies included cyclophosphamide in 78% of cases. Twenty-five patients (29%) reached kidney failure. The median time to kidney failure or last follow-up was 35 months (6-89) in the whole cohort, and 73 months (24-109) among the patients who did not reach this outcome. Cases with sclerotic histology showed significantly shorter kidney survival [HR 11.80 (95% CI 2.49-55.99)] and CKD 3-5-free survival [HR 8.88 (95% CI 2.43-32.48)] as compared with focal/mixed ones. Baseline eGFR, low serum albumin, hypertension, central nervous system complications and sclerotic histology, which reflected severe kidney involvement, were associated with both kidney failure or CKD stage 3-5/kidney failure at unadjusted analysis; no independent prognostic factors emerged at multivariate analysis. Conclusions. Children with ANCA-associated kidney vasculitis often have aggressive presentation; one-third of them progress to kidney failure and usually do so early during the follow-up. A severe renal presentation is associated with the development of CKD or kidney failure.