Introduction: RENI syndrome (renal, endocrine, neurologic, and immune syndrome), also known as sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS), is a rare autosomal recessive disorder caused by pathogenic variants in the SGPL1 gene. This gene encodes sphingosine-1- phosphate lyase, an enzyme responsible for the final step in sphingolipid degradation. Impaired enzyme activity results in the accumulation of sphingolipid intermediates, leading to multisystem involvement affecting the kidneys, adrenal glands, skin, immune system, and nervous system. Frequently reported manifestations include steroid-resistant nephrotic syndrome, primary adrenal insufficiency, ichthyosis, and neurological abnormalities. Case: We report a 15-year-old male with a history of primary adrenal insufficiency diagnosed at age three after presenting with recurrent vomiting and abdominal pain. He was started on steroid replacement therapy and remained stable without episodes of adrenal crisis. He also had ichthyosis requiring dermatological follow-up. During routine surveillance, persistent proteinuria was detected, and urinary protein excretion increased over time. Ultrasound showed renal parenchymal changes despite preserved renal function. Whole-exome sequencing identified a homozygous variant of uncertain significance in the SGPL1 gene, consistent with RENI syndrome. He was started on enalapril for his proteinuria and continues to undergo multidisciplinary follow-ups. Both parents are consanguineous, but were not screened. Mutations in SGPL1 have increasingly been recognized as a monogenic cause of syndromic steroid-resistant nephrotic syndrome, associated with endocrine and dermatological features. Renal histopathology in cases reported often shows focal segmental glomerulosclerosis, reflecting podocyte injury due to disruption of sphingolipid signaling pathways. Early recognition is crucial, as patients need multidisciplinary care. Conclusion This case highlights the importance of considering RENI syndrome in patients presenting with early-onset primary adrenal insufficiency accompanied by renal and dermatological symptoms. Increased clinical awareness and prompt genetic testing can enable earlier diagnosis, guide long-term monitoring, and support appropriate genetic counseling.
Adrenal Insufficiency ; Proteinuria ; Ichthyosis