Sphingosine-1-phosphate lyase deficiency syndrome is a rare disease, recently described, characterized by multisystem involvement including glomerulopathy, adrenal and hemato-immune. The age of onset and the course of the disease are variable; the most severe form appears very early during the neonatal period or even in-utero with rapid progression towards end-stage renal failure. We report the case of a girl, from a consanguineous marriage, followed since the age of 20 months for primary adrenal insufficiency and hypothyroidism; the etiological investigation was negative, put on hydrocortisone. At the age of 7, she presented with renal failure with stage 2 arterial hypertension. Clinical examination revealed edematous syndrome and diffuse ichthyosis. The assessments revealed nephrotic syndrome, combined immunodeficiency and non-specific multifocal segmental hyalinosis on renal biopsy. Sphingosine-1- phosphate lyase deficiency syndrome is due to an autosomal recessive mutation in the SGPL1 gene, which combines nephrotic syndrome and primary adrenal insufficiency; other disorders are often present, such as immunodeficiency, hypothyroidism and ichthyosis. Sphingosine-1-phosphate lyase deficiency syndrome is unique among sphingolipidoses presenting multiple endocrinopathies, multisystem and renal involvement. Given the multisystem and progressive nature of this rare disease, a genetic diagnosis is crucial for optimal management and appropriate screening for comorbidities in these patients.