Starting from 2010, the 13-valent pneumococcal conjugate vaccine (PCV13) was introduced in several countries. This paper discusses some of the problems recently emerged after PCV13 use and their clinical impact. The impact of PCV13 has been relevant and has saved millions of children and adults by severe infectious diseases. However, it seems likely that in the future, effectiveness of the vaccine might be even higher than that presently evidenced. This is because long-term administration of PCV13 to the pediatric population can favor a more extensive reduction of nasopharyngeal colonization with vaccine serotypes of both vaccinated and unvaccinated subjects and further reduce invasive pneumococcal disease in all the individuals (herd immunity). While waiting for new vaccines to be able to overcome the problem of a limited number of pneumococcal strains included in PCV13, it is recommended to increase pneumococcal vaccination coverage in the entire pediatric population.

Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, and the proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated myeloid-related proteinemia inflammatory (PAMI) syndrome are two distinct clinical conditions caused by heterozygous mutations of the PSTPIP1 gene. While skin and joint involvements are shared by both conditions, PAMI is characterized by hepatosplenomegaly, pancytopenia, and growth failure. Kidney involvement is exceptional in PSTPIP1-mediated disorders. The two missense PSTPIP1 variants associated with PAMI syndrome are p.E250K and p.E257K. Long-term treatment with interleukin (IL)-1 inhibitors is effective to control inflammatory manifestations and is usually well-tolerated. We report a case of a patient carrying the PSTPIP1 p.E250K mutation who developed a late-onset kidney involvement despite a long treatment with canakinumab and anakinra. Kidney biopsy showed focal segmental glomerulosclerosis that was treated with tacrolimus (0.1 mg/kg/day in two doses). A literature revision with the aim to assess the proportion and type of kidney involvement in PAMI syndrome revealed that heterogeneous nephropathies may be part of the clinical spectrum. Our study supports the importance of a periodic diagnostic work-up, including kidney laboratory tests and kidney biopsy, in individuals affected with PAMI syndrome. Kidney and liver functions may be impaired regardless of anti-cytokines treatments and additional therapy approaches (i.e., multi-drugs, hematopoietic stem cell transplantation) should be carefully considered.

Purpose To report the incidence of 4–12% of differentiated thyroid cancer (DTC) and up to 50% of benign thyroid nodular disease and to describe nodular thyroid disease in a multicentre pediatric population with PTEN mutations. Methods: Retrospective data of pediatric patients with PTEN mutations collected from tertiary Departments of Pediatric Endocrinology of Turin, Milan and Genua, Italy, in the period 2010–2020. Results Seventeen children with PTEN mutations were recruited in the study. Thyroid involvement was present in 12/17 (70.6%) subjects, showing a multinodular struma in 6/17 (35.3%), nodules with benign ultrasound features in 5/17 (29.4%) and a follicular adenoma in 1/17 (6%). No correlation was found between thyroid disease and gender, puberty, vascular manifestations, delayed development, or brain MRI abnormalities, while multiple lipomas were associated with thyroid disease (p = 0.03), as was macrocephaly. Standard Deviation (SD) score head circumference was 4.35 ± 1.35 cm in subjects with thyroid disease, 3 ± 0.43 cm (p = 0.02) in the group without thyroid disease. Thyroid involvement was present in all subjects with mutations in exon 6 (4/4) and exon 8 (3/3) of the PTEN gene (p = 0.02). Conclusion In the presented cohort, benign thyroid disorders were prevalent, with no evidence of DTC. A correlation was found between thyroid lesions and head circumference and the occurrence of multiple lipomas. Future studies in larger cohorts should assess whether risk stratification is needed when recommending surveillance strategies in children or young adolescents with PTEN hamartoma syndrome.

Background Pathogenic variants in PEX-genes can affect peroxisome assembly and function and cause Zellweger spectrum disorders (ZSDs), characterized by variable phenotypes in terms of disease severity, age of onset and clinical presentations. So far, defects in at least 15 PEX-genes have been implicated in Mendelian diseases, but in some of the ultra-rare ZSD subtypes genotype–phenotype correlations and disease mechanisms remain elusive. Methods We report five families carrying biallelic variants in PEX13. The identified variants were initially evaluated by using a combination of computational approaches. Immunofluorescence and complementation studies on patient-derived fibroblasts were performed in two patients to investigate the cellular impact of the identified mutations. Results Three out of five families carried a recurrent p.Arg294Trp non-synonymous variant. Individuals affected with PEX13-related ZSD presented heterogeneous clinical features, including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy. Computational predictions highlighted the involvement of the Arg294 residue in PEX13 homodimerization, and the analysis of blind docking predicted that the p.Arg294Trp variant alters the formation of dimers, impairing the stability of the PEX13/PEX14 translocation module. Studies on muscle tissues and patient-derived fibroblasts revealed biochemical alterations of mitochondrial function and identified mislocalized mitochondria and a reduced number of peroxisomes with abnormal PEX13 concentration. Conclusions This study expands the phenotypic and mutational spectrum of PEX13-related ZSDs and also highlight a variety of disease mechanisms contributing to PEX13-related clinical phenotypes, including the emerging contribution of secondary mitochondrial dysfunction to the pathophysiology of ZSDs.

Cardiorenal syndrome (CRS) is defined as a disorder resulting from the abnormal interaction between the heart and kidney, in which acute or chronic dysfunction of one organ may lead to acute and/or chronic dysfunction of the other. The functional interplay between the heart and kidney is characterized by a complex bidirectional symbiotic interaction, regulated by a wide array of both genetic and environmental mechanisms. There are at least five known subtypes of CRS, based on the severity of clinical features and the degree of heart/renal failure. The fourth subtype (cardiorenal syndrome type 4 (CRS4)) is characterized by a primary chronic kidney disease (CKD), which in turn leads to a decreased cardiac function. Impairment of renal function is among the most important pathophysiological factors contributing to heart failure (HF) in the pediatric age group, and cardiovascular complications could be one of the most important causes of mortality in pediatric patients with advanced CKD. In this context, a loss of glomerular filtration rate directly correlates with both the progression of cardiovascular complications in CRS and the risk of HF. This review describes the interaction pathways between the heart and kidney and the recently identified pathophysiological mechanisms underlying pediatric CRS, with a special focus on CRS4, which encompasses both primary CKD and cardiovascular disease (CVD).