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Background <p>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 <i>WT1</i> gene, most commonly in exons 8 or 9. <i>ACTN4</i> mutations are associated with nephrotic syndrome and renal dysfunction, with an onset in early adulthood.</p> Case presentation <p>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 <i>WT1</i> mutation, c.388_389insAC (p.Pro130Hisfs*34), complicated by an <i>ACTN4</i> mutation, c.2698T &gt; A (p.Ser900Thr). Under our care, his worsening proteinuria stabilized, and his estimated glomerular filtration rate (eGFR) remained at 83 mL/min/1.73 m<sup>2</sup> (1.38 mL/s/1.73 m<sup>2</sup>), 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.</p> Conclusion <p>In this case, we present a patient with delayed nephropathy in the presence of novel <i>WT1</i> and <i>ACTN4</i> 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.</p> Clinical trial registration <p>Not applicable.</p>

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Novel WT1 and ACTN4 co-mutations in a patient with Denys-Drash syndrome and an atypical, potentially attenuated presentation of nephropathy: a case report

  • 期刊论文

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  • 发表日期：

    2025年9月1日

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  • Eric Frazier,
  • Ryan Sabour,
  • Matthew D. Nguyen,
  • Dao Le,
  • Ramy Hanna

摘要

Background

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.

Case presentation

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.

Conclusion

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.

Clinical trial registration

Not applicable.