Glomerulocystic renal disease has numerous etiologies, including HNF1B mutations. In addition to cysts, morphologic renal findings in a setting of HNF1B mutations include cystic renal dysplasia, solitary functioning kidney, horseshoe kidney, and oligomeganephronia. Embryonal hyperplasia resembling nephrogenic rests has been reported in rare cases of glomerulocystic disease, but none have been genetically characterized. We report a case of bilateral glomerulocystic kidney disease (GCKD) showing extensive embryonal hyperplasia in a setting of germline HNF1B mutation with progressive renal failure. Explant showed numerous epithelial proliferations throughout the intervening stroma. GCKD may be seen in a setting of HNF1B mutation; however, the additional finding of extensive embryonal hyperplasia in a case with a known mutation has never been reported. Reports of similar embryonal hyperplasia, associated with either cystic kidney disease or other disease processes, appear to represent a heterogeneous population of presentations and etiologies, though there is sufficient evidence to suggest that this is a finding, that is, recurrently associated with cystic kidney diseases. The underlying pathobiology of embryonal hyperplasia and the neoplastic potential in this setting is unknown. We report this case to highlight a novel combination of morphologic and genetic findings in GCKD and to raise awareness of this rare finding.

Background and Clinical Significance: Wolf-Hirschhorn syndrome (WHS, OMIM #194190) is caused by deletion of the distal short arm of chromosome 4. It is characterized by intrauterine growth restriction (IUGR), developmental delay, epilepsy, distinctive facial features, and urinary tract anomalies, particularly renal hypoplasia. However, the histological profile of renal involvement in WHS is rarely documented. Case presentation: We report a case of fetal WHS with renal hypoplasia and histological evidence of oligomeganephronia (OMN). At 21 weeks' gestation, a prenatal ultrasound revealed oligo/anhydramnios and IUGR. Genetic testing (karyotype and CGH-array) confirmed a de novo 17.92 Mb terminal deletion from 4p16.3 to 4p15.31. The pregnancy was legally terminated at 23 weeks. The autopsy showed characteristic WHS dysmorphisms, growth restriction, and markedly small kidneys. Histology revealed OMN with a thinned renal cortex with reduced glomeruli, mainly hypoplastic, some of which were hypertrophic, and dilated proximal tubules. Scattered medullary tubules were present within the tubulointerstitial compartment, alongside thickened tubular basement membranes highlighted by Collagen IV staining. Conclusions: This case suggests that OMN may be a histological hallmark of renal hypoplasia in WHS, especially in larger 4p deletions. Recognizing this pattern may help with prenatal prognosis and clinical management. Further studies are needed to confirm this association.

Oligomeganephronia is a congenital anomaly of the kidney and urinary tract. It is often categorized as one of the hypoplastic kidney conditions. The pathological diagnosis of oligomeganephronia is challenged by the absence of clear diagnostic criteria, which often leads to subjective interpretations by pathologists. This report presents the case of a 7-year-old girl who was diagnosed with oligomeganephronia through a third renal biopsy, which was confirmed by gene analysis revealing PAX2 deletion. Two previous renal biopsies, with the naked eye through a microscope, failed to identify glomerular hypertrophy and sparse glomerular distribution density. However, using digital images, the glomeruli were larger than those of age-matched controls, and the number of glomeruli within the renal cortex area revealed sparse glomerular distribution density. Image processing allows for objective evaluation of the glomerular size and glomerular distribution density, providing a quantitative assessment. For earlier diagnosis of oligomeganephronia, an appropriate objective standardized method for measuring glomerular size and glomerular distribution density should be established.

This study highlights the importance of a combined diagnostic approach in the diagnosis of rare diseases, such as adult-onset genetic FSGS. We present three adult patient cases evaluated with kidney biopsy for proteinuria, chronic kidney disease, and hypertension, which were suggestive of adult-onset genetic FSGS. Renal biopsy samples and formalin-fixed, paraffin-embedded fetal kidneys were evaluated using standard light microscopical stainings, direct immunofluorescence on cryostat sections, and electron microscopy. Clinical exome sequencing was performed for each case, and 45 FSGS-related genes were analyzed. Identifying mutations in the PAX2, ACTN4, and COL4A5 genes have prompted a re-evaluation of the previous histopathological examinations. The PAX2 mutation led to a thinner nephrogenic zone and decreased number of glomeruli, resulting in oligohydramnios during fetal development and oligomeganephronia and adaptive focal-segmental glomerulosclerosis in adulthood. The ACTN4 mutation caused distinct electron-dense aggregates in podocyte cell bodies, while the COL4A5 mutation led to segmental sclerosis of glomeruli with marked interstitial fibrosis and tubular atrophy. The identification of specific mutations and their histopathological consequences can lead to a better understanding of the disease and its progression, as well as potential treatment options.

Oligomeganephronia (OMN) is a rare congenital renal hypoplasia reported more often in children than in adults. The diagnosis of OMN relies on renal biopsy and exhibits a significant reduction in the number of glomeruli and pronounced glomerular hypertrophy. Here, we report the case of an 8-year-old boy with recurrent proteinuria and abnormal external ears. A renal biopsy revealed large and rare glomeruli. The histological findings confirmed the diagnosis of OMN. Whole-exome sequencing of the patient revealed a new pathogenic variant in PBX1 (hg19, NM_002585, c.262delA, p.Thr88Glnfs*3). The PBX1 gene encodes a transcription factor whose pathogenic variants can result in congenital renal and urinary system anomalies, with or without hearing loss, abnormal ears, and developmental retardation (CAKUTED). This is the first report to detect PBX1 pathogenic variants in children with OMN, a novel phenotype of human PBX1 pathogenic variants. We performed functional prediction analyses of deletions in the corresponding structural domains. We summarized 27 cases of PBX1 single pathogenic variants reported between 2003 and 2023 in terms of truncating and missense pathogenic variants, which can deepen our understanding of the PBX1 structural domain and expand our knowledge of the PBX1 genotype and phenotype.