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BACKGROUND: Sitosterolemia (STSL) is a rare autosomal recessive disorder caused by mutations in ABCG5 or ABCG8, characterized by hemolytic anemia, xanthomas, and atherosclerosis. Nephronophthisis (NPHP), another autosomal recessive disorder, is characterized by its devastating progression toward renal failure. METHODS: We analyzed the clinical, laboratory, and genetic data of a Chinese boy with concurrent STSL and NPHP. Separately, we conducted a comprehensive review of the phenotypic and genotypic profiles of all previously reported STSL cases in China. RESULTS: The proband presented with recurrent fever, thrombocytopenia, splenomegaly, and renal dysfunction and was initially misdiagnosed with hemophagocytic lymphohistiocytosis. Genetic testing confirmed biallelic ABCG8 mutations (c.490C>T and c.323-1G>C) and a homozygous NPHP1 deletion. A comprehensive review of 131 Chinese STSL cases (130 from the literature) found that xanthomas, hypercholesterolemia, and elevated low-density lipoprotein cholesterol (LDL-C) were the most common manifestations (each with a prevalence of 82.4%), followed by splenomegaly (32.1%), thrombocytopenia (32.1%), and anemia (30.5%). Hypercholesterolemia and high LDL-C were more common in children, whereas hematologic abnormalities and organ damage were more prevalent in adults. Mutations in ABCG5 accounted for 77.1% of patients. CONCLUSIONS: Genetic testing is crucial when clinical findings conflict with the initial diagnosis. This study summarizes the largest cohort of Chinese STSL patients to date, which may aid in the early recognition and management of this condition.

Both genetics and the environment affect the phenotypes of polycystic kidney diseases (PKD), such as autosomal dominant (AD) PKD, autosomal recessive (AR) PKD and nephronophthisis (NPH). Variable phenotypes, pleiotropy, divergent severity and progression, even in family members who inherited the same disease-causing mutation(s), signal the involvement of networked genes and modifiers. Several PKD-linked genes function in development and renal tubule morphogenesis. Cystic renal tissues feature metabolic remodeling, functional reprogramming and dysregulation of several shared factors and pathways. ADPKD, ARPKD and NPH partially phenocopy each other. Understanding the developmental arc of cystic kidney disease and its complex phenotypes would improve diagnostics and help develop effective personalized treatments. However, this is challenging to study in vertebrate systems due to genetic redundancy, functional overlap, and a dearth of genetic tools. Underused in this context, Drosophila melanogaster offers high genomic and pathway conservation, a wealth of genetic tools, and rapid generation times, making it a reliable and sustainable model for mechanistic, genome-wide, and precision medicine studies. Here, we surveyed ADPKD, ARPKD, and NPH, compared renal and extrarenal phenotypes, and examined the network of shared and unique contributors, their healthy and diseased functions and conservation from the perspective of mechanistic whole-animal modeling.

BACKGROUND: Pediatric combined liver-kidney transplantation is uncommon, and evidence from Latin America is scarce. METHODS: We report a single-center case series of four pediatric recipients who underwent combined liver-kidney transplantation at a tertiary Latin-American center. We summarize primary indications, perioperative course, early complications, and graft function at follow-up. RESULTS: Underlying diseases were primary hyperoxaluria type I (n = 1), nephronophthisis type 3 (n = 2), and hepatorenal fibropolycystic disease/autosomal recessive polycystic kidney disease (n = 1). Early complications included bacterial and viral infections, bleeding, and acute tubular necrosis. Three biopsy-proven acute rejection episodes occurred (one moderate-severe hepatic and two renal, including one late T-cell-mediated episode); all responded to treatment. At last follow-up, all four patients were alive with functioning liver and kidney grafts. In three cases with long-term follow-up, the estimated glomerular filtration rate was 72, 64, and 48 mL/min/1.73 m2 with normal liver profiles; in one case with shorter institutional follow-up, the estimated glomerular filtration rate was 74 mL/min/1.73 m2 with a transient liver profile abnormality. CONCLUSIONS: This first pediatric series from Latin America suggests that combined liver-kidney transplantation is feasible and can achieve favorable long-term patient and graft survival when candidates are appropriately selected and infectious and rejection complications are managed in a protocolized manner.

OBJECTIVES: Joubert syndrome is a rare ciliopathy in which kidney disease can quietly progress to end -stage kidney disease, often in children and young adults. For these patients and their families, kidney transplant is a turning point, yet published experience remains limited. Here, we share our center's experience with kidney transplant in 5 patients with Joubert syndrome who progressed to end -stage kidney disease, highlighting medical outcomes and practical challenges. MATERIALS AND METHODS: We conducted a retrospective case series of 5 patients with Joubert syndrome and end -stage kidney disease who received kidney transplants at our center. We reviewed medical records for demographic data, neurological and extrarenal features, renal course, transplant details, immunosuppression, complications, and long -term graft and patient outcomes. RESULTS: The cohort included 3 male and 2 female patients who received transplants between 12 and 40 years of age. Two patients had genetically confirmed Joubert syndrome, and 3 patients had a clinical diagnosis. Nephronophthisis was the documented cause of end -stage kidney disease in 2 children, whereas 3 patients had end -stage kidney disease attributed to Joubert syndrome without further histology classification. All patients received calcineurin inhibitor -based triple immunosuppression. Delayed graft function occurred in all 5 recipients. Two patients developed biopsy -proven T -cell -mediated acute rejection, successfully treated with pulse steroids. At last follow -up, 3 patients were alive with functional grafts, 1 patient was alive on dialysis after graft loss due to chronic pyelonephritis, and 1 patient died from severe infection with a functional graft. CONCLUSIONS: Kidney transplant is feasible and generally effective in patients with Joubert syndrome, offering durable renal replacement in most cases. However, the universal occurrence of delayed graft function and the effect of infectious complications, which led to 1 graft loss and 1 death, emphasize the need for careful perioperative management, urological assessment, and close long -term follow -up within a multidisciplinary framework.

Nephronophthisis type 4 (NPHP4) is a rare genetic kidney disorder progressing to end-stage renal disease (ESRD). In this study, we aimed to identify the genetic cause of NPHP4 in a pedigree with three affected individuals. Whole-exome sequencing was performed on the proband, and variants were filtered, analyzed, and evaluated using in silico tools. Co-segregation analysis was conducted using Sanger sequencing. Protein modeling for the wild-type and mutant forms was performed using AlphFold3. We identified a homozygous deletion (c.2999_3005delTGTGTGT/ p.Asn1000SerfsTer4) in exon 21 of NPHP4, which co-segregated with the disease in the pedigree, demonstrating an autosomal recessive inheritance. 3D protein modeling predicted significant structural changes due to the truncation. The results of this study reveal a deletion variant NPHP4 c.2999_3005del (p.Asn1000SerfsTer4) that causes NPHP4 disease. This study, as a second report of a variant, reaffirms this very variant's pathogenicity and illuminates a critical locus prone to disruption, enhancing our understanding of genotype-phenotype correlations in NPHP4. The concurrence of independent observations of the same variants in NPHP4 emphasizing C-terminal truncation strengthens evidence that disruption of this region is clinically relevant in NPHP4-related disease. These findings together can provide improved understanding of the genetic basis of the disease, therefore better guidance for genetic counseling and family planning strategies for additional affected families.