Clinical spectrum, genetics and management insights of PAX2-related disorder in nine children

Abstract

Background

Renal coloboma syndrome (RCS) is a rare autosomal dominant genetic disorder associated with the paired box gene 2 (PAX2). Over the past three decades, PAX2 variants have manifested with vast phenotype and genotype heterogeneity, with limited experience gained regarding its clinical progression and management strategies.

Methods

We included nine Chinese children diagnosed with PAX2-related disorder at Beijing Children's Hospital. The medical records were retrospectively reviewed, and the demographic data, clinical manifestations, genetic testing results, imaging examination findings, laboratory tests, and renal biopsy results were recorded and analyzed.

Results

Eight distinct PAX2 pathogenic variants, including four novel variants, were identified in nine children. All patients exhibited developmental abnormalities of the urinary system, while two presented with ocular abnormalities with retinal myelinated nerve fibers identified as a novel manifestation of PAX2-related disorder. Cranial imaging examinations were performed on three patients, revealing vascular anatomical abnormalities. Five patients received empirical treatment with angiotensin-converting enzyme inhibitors (ACEIs), resulting in varied therapeutic outcomes.

Conclusion

PAX2 variants exhibit significant clinical diversity, and our findings further expand the genotype–phenotype spectrum of PAX2-related disorder. The variable efficacy of ACEIs highlights the importance of personalized evaluation and treatment strategies and extended follow-up periods in the future.

Background

The paired box (PAX) family of transcriptional genes, characterized by a conserved DNA-binding domain, exhibits remarkable evolutionary conservation and plays a pivotal role in embryonic patterning and organogenesis [1]. The vertebrate PAX family comprises nine genes, and is classified into four subgroups based on their genomic structure, sequence similarity, and conserved function. Members of the third subgroup—PAX2, PAX5, and PAX8, have a conserved paired-like DNA-binding domain (PD), octapeptide motif (OP), and a paired-type homeobox DNA-binding domain (PTHD) structure, and are expressed in a conserved expression manner across multiple tissues. In human PAX2, the protein consists of a PD (residues 16–142), an OP (residues 185–192), a PTHD (residues 250–278), and a C-terminal transactivation domain (residues 279–373). Specifically, the PAX2 gene demonstrates tissue- and/or organ-specific expression in the central nervous system, kidney, optic nerve, and ear.

PAX2 (paired box gene 2, MIM: *67,409), located on chromosome 10q24.31, has 12 transcript variants according to the Ensembl genome database and contains nine to ten exons encoding the PAX2 protein [2]. Proper expression of the PAX2 gene is essential for the development of critical renal structures, including renal vesicles, comma-shaped bodies, S-shaped bodies, and, ultimately, the glomeruli and tubules. Alterations in PAX2 levels, whether upregulated or downregulated, are believed to negatively impact kidney structure and function throughout an individual's lifetime [3].

In addition, the PAX2 gene also plays an important role in the formation of the midbrain–hindbrain boundary organizer, visual system, and inner ear development [4,5,6]. The crucial role of PAX2 in vertebrates has also been demonstrated in animal models. Research by S. Porteous et al. revealed that mice with homozygous mutations of PAX2 die within 24 h after birth, while heterozygous mutant mice would exhibit abnormalities such as optic nerve development and hypoplastic kidneys, known as renal coloboma syndrome (RCS) or papillorenal syndrome in human counterparts [7].

Since Weaver et al. first reported RCS related to the PAX2 gene in 1995, an increasing number of PAX2 variant sites and associated clinical phenotypes have been documented [8]. To date, a total of 567 PAX2 variants have been recorded in updated in the ClinVar databases. Patients with PAX2 variants may present with a wide range of urinary system abnormalities, including congenital anomalies of the kidney and urinary tract (CAKUT), nephrotic syndrome, immunoglobulin A nephropathy (IgAN), renal fibrosis, renal tumors, and chronic kidney disease (CKD) of undetermined etiology [9]. Optic nerve dysplasia is the most common ophthalmological manifestation of this disorder [10, 11]. Additionally, other systemic symptoms such as hernia, hearing loss, seizures, developmental dysplasia of the right hip, and gout have also been previously reported in relevant studies [10, 12].

Renal dysplasia related to PAX2 variants will ultimately progress to kidney failure (KF) [13]. The clinical management of these patients to delay disease progression is a critical concern for pediatricians. Currently, existing cohort studies on PAX2 variants primarily focus on describing the spectrum of genotypes and phenotypes, with limited emphasis on comprehensive family histories, which are crucial for understanding monogenic diseases. Additionally, there is a notable absence of detailed reports on the clinical management strategies and long-term follow-up of affected individuals, despite their particular importance in the context of rare diseases.

In this study, we described the clinical and genetic characteristics of nine Chinese children with eight distinct PAX2 variants, four of which were reported for the first time. Five patients received empirical treatment with angiotensin-converting enzyme inhibitors (ACEIs) and exhibited varied outcomes during follow-up. This study aims to broaden the genotype and phenotype spectrum of PAX2 variants, and provide valuable information on the clinical management strategy for patients with PAX2-related disorder.

Methods

Patients

From January 2019 to September 2024, we retrospectively included nine patients (four boys and five girls) and their families who were identified with pathogenic PAX2 variants through gene sequencing. These patients underwent family-based genetic testing because they were suspected to have inherited metabolic disorders, significant urinary system abnormalities, and kidney tubule diseases [14]. Before the genetic tests, informed consent was obtained from all families. Patient 5, who was adopted, underwent genetic testing solely on himself as biological family information was unavailable.

Data collection

General information and data related to clinical, renal, and ophthalmological characteristics were retrieved from the electronic medical record system. Additional examination and follow-up data from other hospitals were collected via telephone interviews with their parents. The assessment of height and weight were conducted using the standardized growth curves for Chinese children published by the Capital Institute of Pediatrics [15, 16]. Renal length evaluations were based on a curve chart derived from a multi-center statistical analysis of pediatric renal lengths released in 2021 [17]. The definitions of the primary clinical manifestations, encompassing renal and ocular symptoms, as well as the methodologies employed for assessing renal function, are provided in Table S1 [18, 19].

Gene sequencing and genetic analysis

Following the approved protocol by the Institutional Review Board and with the consent of the children's guardians, 3 mL of peripheral blood samples were collected from parent–child triads or probands using an ethylenediaminetetraacetic acid anticoagulant tube at Beijing Children’s Hospital. Genomic deoxyribonucleic acid (DNA) was extracted from these samples using a non-centrifugal column-based blood genomic DNA extraction system (Beijing Tiangen Biotechnology Co., Ltd.). Exon capture sequencing was conducted using the Agilent SureSelect Human All Exon V5 kit, and high-throughput sequencing was performed on the Illumina HiSeq platform. The sequencing fragments were aligned to the University of California, Santa Cruz Human Genome version 19 (UCSC hg19) reference genome using BWA software (version 0.7.9a). The reference sequence used for the PAX2 variant nomenclature was NM_000278.5.

Pathogenicity classification and variant data interpretation were performed following the American College of Medical Genetics and Genomics (ACMG), and the ClinGen Sequence Variant Interpretation expert group's recommendations [20,21,22,23]. Variants with frequencies below 1% in the Exome Aggregation Consortium (ExAC), gnomAD, Chinese Genomes Database, and 1,000 Genomes databases were considered for analysis. Furthermore, non-functional variants, including somatic and non-coding variants, were excluded. The Human Gene Mutation (HGMD), Leiden Open Variation Database (LOVD), and ClinVar databases were checked for the PAX2 variants described in the publications retrieved. The pathogenicity of missense variants was assessed using computational prediction tools such as PolyPhen2, SIFT, Mutation Taster, and Genomic Evolutionary Rate Profiling +  + (GERP + +). Variants suspected to be associated with clinical phenotypes were validated through Sanger sequencing within the family.

Protein structural analysis

Amino acid sequences of PAX2 and other homologs were collected from human (Q02962), mouse (P32114), frog (O57682), rat (D4ACZ2), zebrafish (Q90268), caenorhabditis elegans (Q21263), via UniProt. Multiple-sequence alignment was performed using SnapGene software. The tertiary structures of the wildtype and mutant PAX2 proteins were predicted using SWISS-MODEL (http://swiss-model.expasy.org/). The impact of mutagenesis in terms of electrostatic surface potentials was analyzed via PyMOL (The PyMOL Molecular Graphics System, Version 2.5.0a0 Schrödinger, LLC.)

Results

Characteristics of children with PAX2-related disorder

A total of nine unrelated children, consisting of four boys and five girls, were identified with PAX2 variants. The primary diagnoses included two (22.2%) RCS cases and seven (77.8%) renal dysplasia cases. Excluding Patient 3, who lacked prenatal checkup information, renal anomalies were detected in four (50%) out of the remaining eight patients during the fetal period. Among these, three patients presented with small kidneys, and one patient exhibited increased renal echogenicity.

The onset and presentation of the disorder vary among the children. Apart from the four children with abnormal prenatal findings who were monitored routinely after birth, one child presented with abdominal pain, two sought medical attention due to irregular urination, and two others exhibited symptoms of fever, cough, and decreased appetite. The baseline characteristics of the patients are summarized in Table 1.

Table 1 Baseline characteristics of the nine children

Kidney manifestations

Various structural and functional kidney abnormalities in this study are summarized in Table 2. Proteinuria was observed in seven patients (77.8%), with three (33.3%) exhibiting nephrotic-range proteinuria. The estimated glomerular filtration rate (eGFR) assessment indicated renal function decline for eight patients (88.9%), including one patient who had already progressed to KF at the initial consultation.

Table 2 Kidney phenotypes of patients with variants in PAX2

Abnormal elevations in early markers of renal injury were observed in eight patients (88.9%), six of whom (75.0%) demonstrated simultaneous involvement of both glomeruli and renal tubules. Renal ultrasonography revealed abnormalities in all patients, with renal cysts being the most common finding. Among the seven patients with cysts, six exhibited multiple cystic lesions. Voiding cystourethrography (VCUG) was not routinely performed; however, one patient (Patient 9) with a urinary tract infection underwent this examination, which revealed unilateral grade 4 vesicoureteral reflux on the left side. Additionally, kidney lengths were measured for all patients and compared to the reference curves for normal pediatric kidney lengths. All patients had kidney lengths below the 10th percentile for their respective age and gender. Detailed information on each patient's kidney manifestation is presented in Table 2.

Ophthalmological and other system manifestations

Seven patients underwent fundoscopic examinations, revealing abnormalities in two cases. Patient 5 exhibited bilateral strabismus and optic nerve hypoplasia, while Patient 8 displayed retinal medullated nerve fibers (RMNF), a condition not previously reported in PAX2-related ophthalmological manifestations (Fig. 1). In addition to abnormalities in the kidneys and eyes, almost all patients showed abnormalities in other systems, such as intellectual disability, ventricular septal defect, anemia, persistent falciform sinus, and electrolyte imbalance. Notably, eight of the nine patients demonstrated delayed growth and development, as evidenced by heights below the 25th percentile for their age and gender. This growth delay may be the consequence of impaired kidney function. Detailed information on the ophthalmological and other system manifestations of each patient is presented in Table 3 and Figure S1.

Fig. 1

Fundus photography of Patient 8. Fundus photographs of the proband reveal both eyes displaying a pale hue with a subtle leopard-like pattern. Feather-like changes are noted around the optic disc on the left, and an arrow highlights the presence of myelinated retinal nerve fibers

Table 3 Ophthalmological and other system manifestations

PAX2 variants and pathogenicity analysis

In this study, eight distinct variants were identified, four of which were reported for the first time. Table 4 summarizes the genetic characteristics of these variants, including nucleotide changes, deduced protein changes, protein domain, zygosity, ACMG classification, and bioinformatic predictions such as SIFT, PolyPhen2, MutationTaster, and GERP +  + . Notably, seven variants were classified as pathogenic or likely pathogenic, while one variant (PAX2 c.242G > A, p. (G81D) in Patient 6) was classified as a variant of uncertain significance (VUS) and requires further analysis. Among the eight variations identified in this study, five are located within the second and third exons, which encode the PD domain of the PAX2 protein. The PD domain is a critical functional region responsible for DNA binding and transcriptional regulation. Variations in this domain may impair its interaction with DNA, potentially leading to developmental abnormalities in organs such as the kidneys and eyes, as observed in affected patients.

Table 4 Genetic characteristic and bioinformatic analyses of PAX2 variants

Given that the PAX2 c.242G > A, p. (G81D) variant is the only one in our cohort classified as a VUS by ACMG guidelines, we conducted additional analyses. Recognizing that protein structure underpins function, our structural model reveals that the variant is located in the flexible linker region between two α-helices—a region essential for modulating protein conformation (Figure S2A). Alterations in this linker region can restrict or dysregulate the movement between adjacent functional domains, thereby impairing overall protein coordination [24]. Protein sequence homology analysis further indicates that this residue is evolutionarily conserved (Figure S2B). In addition, surface electrostatic potential shows the substitution of Glycine (Gly) for Aspartate (Asp) at the 81st residue of the PAX2 protein alters local electric potential from negative to positive (Figure S2C). Since PAX2 functions as a transcription factor whose DNA binding relies on the interaction between positively charged amino acids and the negatively charged phosphate backbone of DNA, the loss or reversal of the positive charge at position 81 is likely to disrupt this critical interaction, thereby weakening or even abolishing its affinity for the target DNA sequence. Clinically, Patient 6—who carries this variant—was diagnosed via renal biopsy with oligomeganephronic renal hypoplasia, a pathology typically associated with PAX2 variants. Moreover, the variant was inherited from his mother, who also presented with abnormal urinalysis findings (Fig. 2).

Fig. 2

Pedigree of the families in this study

Based on the integrated evidence from clinical manifestations, familial segregation, evolutionary conservation, structural–functional analysis, and electrostatic potential alterations, the PAX2 c.242G > A variant is strongly suggested to be pathogenic.

In this study, four children inherited variants from one of their parents, and all of whom exhibited renal and/or urinalysis abnormalities. Although significant clinical symptoms were not observed in the mothers of Patients 1, 4, and 6, their urine tests indicated proteinuria with or without microscopic hematuria. Patient 3's father had a history of IgA nephropathy and underwent a kidney transplant. Patient 5 was adopted, and the health status and genetic characteristics of his biological parents were unclear (Fig. 2). The detailed clinical assessments of the relatives of patients 1, 3, 4, and 6 are provided in Table S2.

Clinical management and follow-up

The patient cohort was followed longitudinally for a period ranging from 0.2 to 5.2 years (Table 5). The age at initial detection of creatinine abnormalities varied significantly, from as young as 0.1 years to as old as 9.3 years. Patient 9, an infant over 30 days old, was hospitalized due to a urinary tract infection, CKD stage was not calculated at the time of initial diagnosis. Patient 5 was diagnosed with KF upon initial hospital admission and subsequently underwent a kidney transplant at another medical facility. At the latest follow-up, this patient was classified as CKD stage 2, based on a recent estimated glomerular filtration rate (eGRF) of 66.7 mL/(min·1.73 m²). Five patients (Patients 1, 4, 6, 8, and 9) with decreased renal function and concomitant proteinuria were treated with ACEIs, and their renal function was monitored longitudinally (Fig. 3). Obviously, Patients 1, 6, and 9 exhibited stable renal function under ACEIs treatment. In contrast, Patients 4 and 8, who were already at CKD stage 3 or higher at their first visit, demonstrated a decline in eGFR during the follow-up assessments. It is worth mentioning that Patient 8 initially has stabilized eGFR values after commencing oral captopril therapy. However, after discontinuing the medication voluntarily one year later, the patient experienced a sharp decline in eGFR and progressed to CKD stage 5. During the treatment process, both the blood pressure and serum potassium levels in these patients remained within the normal ranges.

Table 5 Periodic follow-up of renal function in patients with variants in PAX2

Fig. 3

Periodic follow-up of eGFR values in patients treated with ACEIs. A Patient 1 treated with Fosinopril for 5.2 years; B Patient 4 treated with Fosinopril for 3.0 years; C Patient 6 treated with Fosinopril for 0.5 years; D Patient 8 treated with Captopril for 1.0 year followed by discontinuation for 1.5 years; E Patient 9 treated with Enalapril for 1.2 years. Arrows below the horizontal axis indicate the duration of medication administration and follow-up period

Three patients (Patients 2, 3, and 7) did not receive ACEIs intervention following their initial consultation. For Patient 2, urinary microalbumin levels, an early kidney injury marker, increased significantly from 7.08 mg/L to 94.3 mg/L in urinary microalbumin levels more than three years ago. Patient 3 felt good subjectively and did not undergo any reexamination. Patient 7 had only one follow-up visit about 2 months after the initial visit. Detailed information regarding the follow-up conditions for each patient is presented in Table 5 and Fig. 3.

Discussion

With the increasing accessibility of genetic testing, it has become evident that PAX2 variants exhibit substantial clinical heterogeneity. Several studies have documented the diverse clinical spectrum associated with these variants [10,11,12, 25]. For instance, Deng et al. [12] and Xiong et al. [25] each reported on 10 Chinese children with PAX2 variations—Deng et al. [12] identified novel phenotypes such as skeletal deformities and ovarian teratomas, while Xiong et al. [25] highlighted the distinctive histological feature of C1q renal deposition. Additionally, Rossanti et al. [11] described 38 Japanese patients harboring 19 distinct PAX2 variants, including two cases with cystic adenomatoid malformation of the lung. Yang et al. [10] further reviewed 32 registered cases, emphasizing both the extensive phenotypic spectrum and genotype–phenotype correlations, and underscoring the diagnostic value of structure-based analysis methods. Our study corroborates these findings by demonstrating that PAX2 variations are associated with ubiquitous renal structural abnormalities and diverse extrarenal manifestations, thereby highlighting the clinical importance of genetic diagnosis. Notably, these reports provide only limited descriptions of renal manifestations and genetic pedigrees and generally lack long-term clinical follow-up data. Moreover, although ACEIs are well established for reducing proteinuria and affording renal protection in CKD patients, no studies to date have specifically evaluated their efficacy in patients with CKD harboring PAX2 variants.

Our study provides detailed clinical and genetic information for nine patients with eight distinct PAX2 variants, four of which are newly identified. All patients in this study presented with renal structural and/or functional abnormalities at the onset of the disease. One patient underwent a renal biopsy, and histological examination revealed findings consistent with oligomeganephronia. Additionally, two patients presented with ocular abnormalities, including RMNF observed in one patient’s fundus—a finding that has not been previously reported in association with PAX2 variants. The detection of renal anomalies during the fetal period in half of the patients with available prenatal data suggests that PAX2 variants may lead to early developmental abnormalities. Furthermore, the empirical use of ACEIs in this cohort offers valuable insights into the clinical management of PAX2-related kidney injury in children.

Genetic diagnosis is indispensable in clinical practice, particularly for the diagnosis and management of rare and complex disorders such as PAX2-related renal abnormalities. Through high-precision gene sequencing and variant analysis, it enables the early detection of pathogenic variants, thereby establishing a robust molecular basis for accurate diagnosis and guiding clinical management. As gene testing technologies continue to advance and integrate into clinical workflows, genetic diagnosis is increasingly applied across multiple organ systems—including the nervous system, kidneys, and retina—with its role being especially critical in rare conditions like PAX2-related renal anomalies [26,27,28,29]. Among the variants identified in this cohort, four variants (c.70G > C, c.187G > A, c.752del, c.890C > G) have been previously reported. However, detailed clinical information remains scarce, and clinical manifestations associated with these variant sites exhibit significant variability. For example, Patient 3, who harbors the c.890C > G variant inherited from her father (diagnosed with IgAN in his thirties), only presented with renal cysts but showed no decline in eGFR. This variant has previously been reported to be associated with steroid-resistant nephrotic syndrome (SRNS)/focal segmental glomerulosclerosis (FSGS) [30]. Patients 1 and 9 both carried the c.187G > A variant but exhibited different phenotypes: Patient 1 presented with renal dysplasia, while Patient 9 exhibited concurrent vesicoureteral reflux in addition to renal dysplasia. This variant has previously been linked to adult-onset mesangial proliferative glomerulonephritis and renal agenesis in prior studies [31, 32]. The remaining two variants, c.70G > C and c.752del, also demonstrated considerable inter-individual variability in clinical presentation [11, 33, 34]. These findings highlight the variability in expressivity and penetrance observed in PAX2-related disorders, which follow a dominant inheritance pattern, and underscore the critical role of genetic diagnosis in clinical practice.

The PAX2 gene plays a crucial role in neural development, and mutations are linked to various neurodevelopmental disorders, including developmental delay, epilepsy, intellectual disability, and autism spectrum disorder [11, 12, 35]. In this study, only one patient underwent an intelligence assessment, which revealed mild intellectual impairment. Cranial imaging was performed for three patients exhibiting abnormal cranial vascular anatomy—a finding not previously reported in individuals with PAX2 variants. One of these patients (Patient 7) also had periventricular leukomalacia. Notably, Patient 7 was delivered full-term via natural birth without a history of asphyxia, suggesting that the white matter alterations observed may be attributed to the deletion of chromosomal segments [36, 37].

CAKUT, including PAX2 variations, is a leading cause of CKD in children, accounting for over 50% of pediatric kidney failure cases [38]. How to improve the prognosis for these patients remains a significant challenge for pediatricians. There is a consensus that ACEIs could slow the rate of progression and reduce proteinuria in CKD patients [39, 40]. On the one hand, ACEIs mitigate renal failure progression by optimizing blood pressure, reducing intraglomerular pressure, and decreasing proteinuria. On the other hand, the anti-fibrotic and anti-inflammatory effects offer supplementary benefits in preserving renal function [41].

Although no studies have specifically examined the efficacy of ACEIs in CKD patients with PAX2 variations, existing research suggests potential benefits for such patients. Wagner et al. demonstrated that specific activation of PAX2 in podocytes led to ESKD in mice shortly after birth, and ACEIs administration was able to reduce proteinuria and restore renal function [42]. Additionally, the effectiveness of ACEIs in other congenital kidney diseases, such as Alport syndrome and FSGS, has been extensively validated. In FSGS, ACEIs have been shown to increase podocyte numbers and mitigate glomerular sclerosis, while in Alport syndrome, early and sustained use of ACEIs has been proven to delay renal failure progression and decrease proteinuria [43, 44]. These findings provide a theoretical foundation for the application of ACEIs in PAX2-related diseases, and our study offers new clinical data supporting this approach.

In this study, five patients with CKD stage 2 or higher received ACEIs treatment and demonstrated variable outcomes. Notably, Patients 1 and 4 had a relatively long duration of follow-up in this study. Patient 1 maintained stable renal function during follow-up, while Patient 4 experienced a gradual decline in eGFR, which may be attributable to the lower baseline eGFR. Additionally, Patient 8 discontinued captopril treatment on his initiative, and subsequently exhibited a gradual decline in eGFR over the next 1.5 years. This observation underscores the potential protective effect of ACEIs in PAX2-associated renal injury. Although Patient 9, an infant, exhibited an increase in eGFR, this should be interpreted in the context of kidney development.

The role of RAAS inhibitors in slowing CKD progression in adults is well established, yet studies in pediatric CKD remain relatively limited. In adults, CKD is predominantly associated with glomerular diseases, whereas CAKUT is the leading cause of CKD in children [41]. Although the ESCAPE study demonstrated that intensive blood pressure control can delay CKD progression in pediatric patients, and ACEIs have shown significant potential in the treatment of certain monogenic kidney diseases (e.g., Alport syndrome), the variable clinical outcomes observed in our study raise the possibility that structural abnormalities—such as congenital renal dysplasia and cystic changes—might attenuate the therapeutic effects of ACEIs [44, 45]. Consequently, the renal protective effects of ACEIs may be less pronounced in CKD arising from these structural defects compared to other etiologies. These findings underscore the necessity for further research to optimize treatment strategies in pediatric patients with PAX2 variants.

In conclusion, given the limited sample size, scarce clinical management references, and significant individual heterogeneity in CKD with PAX2 variants, the application strategy of ACEIs should involve comprehensive evaluation followed by personalized and exploratory therapeutic strategies. We advocate for future multi-center, large-scale, and long-term studies to thoroughly assess the efficacy and safety of ACEIs in patients with PAX2-related kidney injury.

Our study has two primary limitations. First, the small sample size and relatively short follow-up period limit the ability to draw definitive conclusions. However, given the rarity and individual variability of PAX2 variations, the clinical management experience from this cohort offers valuable insights and serves as a reference for other clinicians and future studies. In this endeavor, we will leverage the unique strengths of China's pediatric medical centers to collaboratively establish a comprehensive, multi-center registry for PAX2-related diseases. By partnering with the nephrology departments of various children's hospitals, we aim to create a national cohort of patients harboring PAX2 variants and conduct periodic data reviews to enhance the robustness of future research. Second, patients treated with ACEIs lack reliable urinary protein follow-up data, as only qualitative assessments were performed among some patients, which are significantly influenced by the timing and method of sample collection. Future studies or clinical practice should incorporate quantitative assessments, such as the urinary protein-to-creatinine ratio, to improve the accuracy and reliability of follow-up evaluations for these patients. Third, for chronic conditions such as CKD, an extended follow-up period is essential to fully assess disease progression and evaluate the long-term effects of ACEIs therapy.

Conclusions

This study involves nine patients with eight distinct PAX2 variants, four of which are reported for the first time. RMNF was identified as a novel ocular manifestation of PAX2 gene variations. Significant clinical heterogeneity was observed among individuals carrying the same PAX2 variants. The effects of ACEIs on PAX2-associated CKD were variable, emphasizing the need for larger cohort studies with extended follow-up periods to provide more definitive conclusions.