Splenic structural and functional abnormalities in individuals with NR5A1/SF-1 variants.

Purpose: Steroidogenic factor 1 (SF-1), encoded by NR5A1, is essential for spleen development and function. NR5A1 variants have been linked to abnormal spleen development. Hyposplenism exposes individuals to severe complications with potentially serious sequelae. This study aimed to determine the prevalence and principal features of hyposplenism in a cohort of French patients with NR5A1 variants. Methods: We conducted a cross-sectional multicentre ancillary study among 34 patients carrying heterozygous NR5A1 variants within the GR-EX cohort, which includes individuals from families affected by red blood cell diseases. All participants underwent splenic imaging (ultrasound, CT, or MRI) and pocked red blood cell (pRBC) quantification. pRBC thresholds of <7%, 7-20%, and >20% corresponded to normal splenic function, moderate hyposplenism, and severe hyposplenism, respectively. The primary endpoints were the prevalence of hyposplenism and its severity. Results: Functional hyposplenism was observed in 21/34 patients (61.7%), including 16/34 (47%) with severe forms. Morphological spleen abnormalities were identified in 15/34 patients (44.1%), with asplenia in 4/34 (11.7%). All patients with morphological spleen abnormalities on imaging also presented functional hyposplenism. Conversely, 6/21 patients (28%) with functional hyposplenism showed no morphological abnormalities on imaging. No association was found between NR5A1 genotypes, gonadal phenotypes, and splenic anomalies. Conclusions: Functional hyposplenism was frequent in this cohort of patients carrying NR5A1 variants, regardless of genotype and gonadal phenotype. Assessing splenic function is mandatory to help manage these patients. Preventive measures are also critical when hyposplenism is present.