The Bardet Biedl syndrome (BBS) is a rare inherited disorder considered a model of non-motile ciliopathy. It is in fact caused by mutations of genes encoding for proteins mainly localized to the base of the cilium. Clinical features of BBS patients are widely shared with patients suffering from other ciliopathies, especially autosomal recessive syndromic disorders; moreover, mutations in cilia-related genes can cause different clinical ciliopathy entities. Besides the best-known clinical features, as retinal degeneration, learning disabilities, polydactyly, obesity and renal defects, several additional clinical signs have been reported in BBS, expanding our understanding of the complexity of its clinical spectrum. The present review aims to describe the current knowledge of BBS i) pathophysiology, ii) clinical manifestations, highlighting both the most common and the less described features, iii) current and future perspective for treatment.

Chronic kidney disease (CKD) is a critical prognostic factor in Bardet-Biedl syndrome (BBS). Early diagnosis and intervention are essential for improving patient outcomes. The present study analyzed kidney function in patients with BBS, with the aim to explore the impact of genetic variants and common risk factors for kidney disease. A monocentric cross-sectional study was conducted. Patients underwent genetic analysis via next generation sequencing; renal function was assessed and the relationship with the following: (i) age, obesity, hypertension and (ii) genetic mutations was analyzed. A total of 65 patients with BBS were enrolled in the study; renal function was variable, with 25% of patients showing an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m². Patients’ age was inversely correlated with the eGFR (P = 0.002). Reduced eGFR significantly correlated with truncating mutations in any BBS gene and hypertension; moreover, multivariate analysis using eGFR as an objective variable and multiple risk factors as explanatory variables, showed that body mass index (BMI) was independently associated with eGFR decline (β = −2.45, P < 0.0001), in addition to age. Interestingly, significant discordance in renal phenotype was revealed in 50% of subgroups of consanguineous or nonconsanguineous patients sharing the same pathogenic variants, indicating clinical variability even in this setting. The present study suggests that BBS is a condition of vulnerability to develop kidney disease, and that age, hypertension and obesity are associated with eGFR decline in adult patients with BBS. Whether effective interventions to treat modifiable factors will reduce CKD risk requires further studies.

Mutations in COL4A3-A5 cause a spectrum of glomerular disorders, including thin basement membrane nephropathy (TBMN) and Alport syndrome (AS). The wide application of next-generation sequencing (NGS) in the last few years has revealed that mutations in these genes are not limited to these clinical entities. In this study, 176 individuals with a clinical diagnosis of inherited kidney disorders underwent an NGS-based analysis to address the underlying cause; those who changed or perfected the clinical diagnosis after molecular analysis were selected. In 5 out of 83 individuals reaching a molecular diagnosis, the genetic result was unexpected: three individuals showed mutations in collagen type IV genes. These patients showed the following clinical pictures: (1) familial focal segmental glomerulosclerosis; (2) end-stage renal disease (ESRD) diagnosed incidentally in a 49-year-old man, with diffuse cortical calcifications on renal imaging; and (3) dysmorphic and asymmetric kidneys with multiple cysts and signs of tubule–interstitial defects. Genetic analysis revealed rare heterozygote/compound heterozygote COL4A4-A5 variants. Our study highlights the key role of NGS in the diagnosis of inherited renal disorders and shows the phenotype variability in patients carrying mutations in collagen type IV genes.

Background: Genetic diseases collectively affect more than 300 million individuals worldwide, posing a significant health burden, as diagnosis is often challenging and therapeutic options are limited. Recent genetic technological advancements are improving the management of many inherited disorders, including genetic kidney disorders (GKDs), the leading cause of early-onset chronic kidney disease (CKD) and the cause of 10–15% of kidney replacement therapy in adults. Summary: GKDs fall into different clinical categories, including cystic and fibro-cystic diseases in the setting of ciliopathies, rare conditions caused by the dysfunction of the primary cilium, typically characterized by multiorgan dysfunction. CKD is a significant cause of morbidity and mortality in these patients and a correct diagnosis is crucial for patient’s management. Key Message: The present review analyzes whether advances in genomic technologies have provided benefit in the ciliopathy field, in both modeling renal diseases and improving patient’s care.

Introduction: Cystinuria (CYS) is the most common monogenic kidney stone disease. Methods: Starting from an unusual case of CYS associated to primary sclerosing cholangitis, inflammatory bowel disease (IBD), and autoimmune hepatitis in a young male, we carefully review the literature and propose here a working hypothesis regarding the potential risk of cystinuric patients to develop conditions due to immune system dysregulation. To corroborate this hypothesis, we retrospectively evaluate the frequency of dysimmunity in a monocentric cohort including 36 cystinuric patients compared to healthy and disease controls. Results: CYS patients have an increased prevalence of atopic disease compared to disease controls (p = 0.03) and 16.7% of CYS subjects were diagnosed with allergic disease to a variety of antigens. Conclusion: Further studies are needed to define the relationship between proximal tubular transport defect of CYS and dysregulated immunity.

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a potentially life-threatening condition associatedwith poor clinical outcomes if not treated adequately. Eculizumab has become the standard of care, whereasravulizumab, a second-generation, high-affinity complement C5 inhibitor, demonstrates comparable efficacyin improving renal function, hematological markers, and dialysis rates. In addition, ravulizumab offers practicaladvantages, including a longer dosing interval and immediate, complete, and sustained inhibition of free C5,making it a valuable therapeutic option.Methods: Given the limited real-world experience with ravulizumab, we present a case series of six treatmentnaïveaHUS patients who received ravulizumab as first-line therapy.Results: These cases include one pregnancy-related aHUS, one postpartum case, one related to a urinary tractinfection, one associated with hypertension, one with a pneumonia-related trigger, and one kidney transplantpatient with a prior verotoxin-producing E. coli infection. Altogether, these cases illustrate the challenges in diagnosing aHUS. The choice to administer ravulizumab as first-line treatment was sometimes made in the presence of a clear clinical suspicion, even when not all minor criteria seemed to confirm the diagnosis. In most patients, renal function improved rapidly after ravulizumab administration, followed by recovery of hematological parameters, which were stable in the longer term. As improvements remained sustained over time, the possibility of discontinuing ravulizumab can be evaluated on a case-by-case basis.Conclusion: These cases highlight the importance of early diagnosis, prompt intervention, and multidisciplinarycare in managing aHUS. Ravulizumab as first-line therapy proved effective and well-tolerated, with sustainedclinical improvements observed across diverse real-world scenarios.