Variant analysis and biochemical investigation in two siblings with late onset idiopathic secondary erythrocytosis: A case report.

RATIONALE: The potential etiological factors for acquired secondary erythrocytosis (SE) include sleep apnea, smoking, and renal cysts. However, there is limited evidence to consistently support an association between these factors and SE. Additionally, identifying the genetic variants underlying SE requires specific and expensive testing methods. These diagnostic challenges mean that many cases of SE are classified as idiopathic, which complicates the development of tailored diagnostic and therapeutic strategies. PATIENT CONCERNS: This study examined 2 brothers (brother I [BI] and brother II [BII]) with idiopathic SE who were undergoing monthly phlebotomy. DIAGNOSES: A diagnosis of polycythemia vera or other acquired causes, such as pulmonary disease or malignancy, was excluded. Both subjects exhibited mild to moderate sleep apnea, while their erythropoietin levels were within the normal range. INTERVENTIONS: To identify potential disease-causing variants shared by the brothers, gene panel exome-sequencing and further biochemical investigations were conducted. OUTCOMES: The following was identified in BI and BII: potential causative mutations in the EPAS1 gene, which were ruled out as causative factors through variant annotation and gene expression analysis; a heterozygous missense variant in the PIGV gene (p.Ala341Glu), which is known to damage proteins. The red blood cells of the brothers exhibited reduced fragility and lower hemolysis levels compared to healthy controls, with a slight increase in CD59 surface exposure. LESSONS: These findings suggest that red blood cells from BI and BII are more resistant to hemolysis. However, given that PIGV is involved in glycosylphosphatidylinositol biosynthesis and that CD59 exposure affects hemolysis, further investigation is required to elucidate these pathogenic mechanisms. Molecular and biochemical characterization of patients with idiopathic SE may pave the way for identifying novel mechanisms involved in the disease.