ESPE Abstracts (2021) 94 FC5.5

1Department of Internal Medicine and Paediatrics, Ghent, Belgium.;2Primary Immunodeficiency Research Lab, Ghent University and Ghent University Hospital, Ghent, Belgium.;3VIB-UGent Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation, Ghent, Belgium.;4Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium.;5Department of Diagnostic Science, Ghent University, Ghent, Belgium.;6Pediatric Endocrinology Service, Palestine Red Crescent Society Hospital, Hebron, Palestine.;7Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium.;8Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.;9Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.;10Department of Medical Imaging, Ghent University Hospital, Ghent, Belgium.;11Division of Pediatric Endocrinology, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.;12Department of Clinical Genetics, Erasmus MC, Sophia Children’s Hospital, University Medical Center, Rotterdam, Netherlands.;13Department of Pediatric Infectiology, Erasmus MC, Sophia Children’s Hospital, University Medical Center, Rotterdam, Netherlands.;14Erasmus Medical Centre, Sophia Children’s Hospital, Department of Pediatric Endocrinology, Rotterdam, Netherlands.;15Leiden University Medical Centre, Department of Pediatrics, Leiden, Netherlands.;16Department of Clinical Chemistry, Erasmus MC, University Medical Center, Rotterdam, Netherlands.;17Pediatric Pneumology Service, Ghent University Hospital, Ghent, Belgium.;18Pediatric Endocrinology Service, Ghent University Hospital, Ghent, Belgium

Background: Hetero- and homozygous mutations in Steroidogenic Factor1 (SF1, NR5A1) cause 46,XY and 46,XX disorders of sex development (DSD), azoospermia, and primary ovarian insufficiency. NR5A1 is also involved in embryonic spleen development, by transactivation of T-cell Leukemia Homeobox 1 (TLX1). Hypo- or asplenism have occasionally been observed in DSD patients with NR5A1 mutations.

Aims: We aimed to determine the prevalence and functional consequences of splenic defects associated with NR5A1 mutations. We assessed spleen anatomy and function in 22 DSD patients (5 homozygous; karyotypes: 46,XY in 17; 46,XX in 5) and 5 asymptomatic carriers from 18 families, harboring 14 different NR5A1 mutations, all classified as (likely) pathogenic. Spleen function was investigated by total blood and thrombocyte counts, % pitted red blood cells (PRBC), Howell-Jolly Bodies (HJB) and relative counts of spleen-dependent non-switched memory B cells. Spleen anatomy was studied by ultrasound, the functional impact of 7/14 NR5A1 variants on TLX1 transactivation capacity was assessed by luciferase assays.

Results: One 46,XY girl homozygous for a NR5A1 mutation, experienced a pneumococcal sepsis at 9 months. Fifty-nine percent of patients and 40% of carriers had thrombocytosis. Increased % PRBC was not observed; HJB were present in 5/19 (26%) tested patients and 0/5 carriers. Non-switched memory B cells were significantly lower in heterozygous patients and family member carriers as a group in comparison with age-matched controls (P < 0.05), but significantly higher than in patients with non-NR5A1 related asplenism (P = 0.003), with no differences between heterozygous patients and carriers (ns). Anatomical spleen defects, mostly hypoplasia, were observed in 14/22 (63%) patients and 2/5 (40%) carriers. Asplenism was diagnosed in 4/5 individuals with homozygous mutations. In vitro transactivation of TLX1 by NR5A1 mutants relative to WT was significantly decreased for 4/7 tested variants, increased for 1 and did not significantly differ from WT for 2 variants.

Conclusions: Anatomical and/or functional hypo- or asplenism is suggested by at least one test in 77% of patients and 60% of family member carriers with NR5A1 mutations. Any single test is not sufficiently sensitive or specific to indicate functional hyposplenism, and clinically applying a combination of techniques is complex and expensive. Given our findings, extensive assessment of splenic anatomy and function and consequent management of hypo- or asplenism is crucial in both patients with homozygous and heterozygous NR5A1 mutations as well as their asymptomatic family member carriers. This includes low-threshold use of antibiotics and preventive vaccination against encapsulated bacteria.

Volume 94

59th Annual ESPE (ESPE 2021 Online)

22 Sep 2021 - 26 Sep 2021

European Society for Paediatric Endocrinology 

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