Genetic disorders in neonates often present with overlapping clinical features, posing significant diagnostic challenges. Glycogen storage diseases (GSD) disrupt glycogen metabolism, leading to energy deficits. Pathogenic variants in the Wilms tumor 1 (WT1) gene represent a rare but significant cause of early-onset steroid-resistant nephrotic syndrome (SRNS), associated with a broad range of both kidney and extrakidney phenotypic manifestations. The coexistence of these genetic diseases in a single patient has not been previously reported. Herein, we present a case of a newborn with symptomatic hypoglycemia and metabolic acidosis that was transferred to the Neonatal Intensive Care Unit. During hospitalization, he developed hyponatremia and nephrotic-range proteinuria, a genetic test was performed, and he was transferred to the nephrology unit. Genetic analysis identified a compound homozygous mutation (c.247 C > T) in the G6PC gene, confirming glycogen storage disease type 1a (GSD-1a) and a pathogenic WT1 mutation (c.1400G > A) associated with Denys-Drash syndrome. This case highlights the importance of a multidisciplinary approach in the evaluation and management of neonates with a complex combination of genetically-determined conditions.

The renin-angiotensin-aldosterone system is essential for blood pressure regulation, and its absence in children with bilateral kidney loss predisposes them to hypotension unresponsive to standard therapies. However, the longer-term hemodynamic consequences and neurologic risks in this setting remain poorly understood. We report three pediatric patients with bilateral congenital or acquired kidney absence that developed prolonged hypotension unresponsive to multiple antihypotensive therapy. A systematic literature review identified seven additional cases. The clinical features, interventions, and outcomes are descriptively summarized for these 10 patients. All three patients exhibited hypotension lasting 6-28 days despite preserved cardiac function without hypovolemia. In the combined literature review of 10 patients, the median age at hypotension onset was 7 months (range, 1-48 months). The etiology of kidney loss was congenital in 2 patients and bilateral nephrectomy in 8 patients. The median interval between kidney loss and hypotension onset was 14 days (range, 0 days-3 years). Among the 10 patients, blood pressure normalized in 8, of whom 4 survived without neurologic complications. Four patients developed hypoxic-ischemic encephalopathy. Five patients died, including three with neurologic complications. Management strategies included fluid overload, vasopressors, and midodrine. Angiotensin II was associated with favorable outcomes in two cases. Children with bilateral kidney absence can recover from prolonged hypotension; however, this condition is associated with an increased risk of neurologic complications. Careful monitoring and supportive strategies, including approaches reported to be associated with recovery such as Angiotensin II or fluid overload, may help minimize risk.

Mutations of the Wilms tumor suppressor-1 gene (WT1) cause a WT1-related nephropathy characterized by a triad of glomerulopathy, defective genital development, and Wilms or gonadal tumor. WT1 mutations affecting the second to third zinc finger motifs (residue 428-511) often lead to infantile-onset glomerulopathy that progresses rapidly to end-stage renal failure by the age of 2.5 years. Most of these cases have been reported as Denys-Drash syndrome (DDS). We report a patient harboring a WT1 p.Arg467Gln variant who developed a severe neonatal-onset renal failure since birth, with an unusual cystic pattern of kidney enlargement on ultrasound. A 22-day-old neonate manifested acute anuric renal failure shortly after birth. Renal ultrasound revealed moderately enlarged, bilaterally hyperechoic kidneys (+2.0 to +3.0 SD), the appearance of which resembled that of polycystic kidney disease. The patient showed normal male external genitalia development except for undescended testes. There were no abnormalities in the hepatobiliary duct systems or lungs. The occurrence of the same cystic kidney disorder in the elder sibling born to healthy parents suggests germline mosaicism. He died from multiorgan failure on postnatal day 47. The next-generation sequencing (NGS) screening panel analysis of 4,503 known disease genes revealed a heterozygous pathogenic WT1 p.Arg467Gln variant, which has been reported elsewhere in children formerly categorized under the DDS subtype. The Arg467 residue is the most frequent site of mutations in DDS and is predicted to hinder the binding of the third zinc finger to DNA. Additionally, a heterozygous COL4A4 p.Gly864Val missense variant of uncertain significance (VUS) was detected. Genome-wide copy number analysis did not detect any structural abnormalities. Our observation highlights two aspects of the WT1 p.Arg467Gln variant in WT1-related nephropathy: (1) The p.Arg467Gln variant causes severe neonatal-onset nephropathy likely through a potent dominant-negative inhibition, and (2) it may manifest a cystic/dysplastic renal phenotype in the presence of coexisting cytogenic modifiers. Future studies are necessary to assess the relevance of the COL4A4 variant in cystic disease and to explore hidden modifier genes through deep sequencing.

Denys Drash syndrome (DDS) results from a mutation in the WT1 tumor suppressor gene manifesting early in childhood. The classic presentation is characterized by early end-stage renal disease (ESRD), differences of sexual differentiation (DSD), and high risk of Wilms tumor (WT). Management varies based on individual patient presentations. We present a rare case of an adult with DDS who presented with functional, native renal tissue and a new renal mass, who was previously treated for WT in childhood. We discuss this unique clinical presentation and review the complex management of patients with DDS primarily as it relates to WT.

Denys-Drash syndrome (DDS) is defined by early onset nephrotic syndrome rapidly progressing to end stage renal disease (ESRD) before 4 years of age, male pseudohermaphroditism, and Wilms tumor (WT). DDS is associated with mutations in the WT1 gene, most commonly in exons 8 or 9. ACTN4 mutations are associated with nephrotic syndrome and renal dysfunction, with an onset in early adulthood. We present the case of an 18-year-old male with a past medical history of Wilms tumor (status post right nephrectomy, chemotherapy, and radiation during infancy), Denys-Drash syndrome, chronic kidney disease stage 2, and autism spectrum disorder. The patient presented to our clinic with worsening proteinuria discovered secondary to pyelonephritis. Genetic evaluation revealed a WT1 mutation, c.388_389insAC (p.Pro130Hisfs*34), complicated by an ACTN4 mutation, c.2698T > A (p.Ser900Thr). Under our care, his worsening proteinuria stabilized, and his estimated glomerular filtration rate (eGFR) remained at 83 mL/min/1.73 m2 (1.38 mL/s/1.73 m2), indicating preserved renal function. We used a multidisciplinary approach to manage this patient through lifestyle modification, regular monitoring, and conservative measures. Surveillance with regular ultrasounds and labs has been key in management. We chose to forgo biopsy because of the risk to the remaining kidney, and we will continue to evaluate the need for an angiotensin-converting enzyme (ACE) inhibitor on the basis of hemodynamic stability. In this case, we present a patient with delayed nephropathy in the presence of novel WT1 and ACTN4 mutations, suggesting the potential for a new genotype‒phenotype relationship of DDS or the attenuation of disease behavior. When diagnostic testing is limited due to increased risk to the patient, we emphasize the need for personalized treatment plans and a multimodal approach with close monitoring in the long-term management of such complicated cases. This case documents novel mutations, highlights the importance of genetic testing, and justifies further investigation into the relationship between genotype and phenotype for patients with mutations contributing to renal pathology. Not applicable. The online version contains supplementary material available at 10.1186/s12882-025-04433-4.