TY - JOUR
T1 - Spleen function is reduced in individuals with NR5A1 variants with or without a difference of sex development
T2 - a cross-sectional study
AU - Cools, Martine
AU - Grijp, Celien
AU - Neirinck, Jana
AU - Tavernier, Simon J.
AU - Schelstraete, Petra
AU - van de Velde, Julie
AU - Morbée, Lieve
AU - de Baere, Elfride
AU - Bonroy, Carolien
AU - van Bever, Yolande
AU - Bruggenwirth, Hennie
AU - Vermont, Clementien
AU - Hannema, Sabine E.
AU - de Rijke, Yolanda
AU - Abdulhadi-Atwan, Maha
AU - Zangen, David
AU - Verdin, Hannah
AU - Haerynck, Filomeen
N1 - Funding Information: No specific funding for this study was available. M.C. (1801018N) and E.D.B. (1802220N) are senior clinical investigators of the Flanders Research Foundation (FWO). M.C. is supported by a FIKO-IV institutional fund. F.H. is supported by a Flemish Government Special Research Fund (BOF-Tenure track 01N13519) and by the Jeffrey Modell Foundation. C.B. and F.H. are supported by an FWO TBM grant (T000119N). J.N. (11L2822N) is a PhD fellow of the FWO. S.J.T. holds an FWO junior postdoctoral fellowship (1236920N). D.Z. (2295/2019) is supported by the Israel Science Foundation (ISF). None of the funding bodies had a role in study design, data collection, analysis, interpretation, writing, or in the decision to submit this manuscript for publication. Publisher Copyright: © 2024 BioScientifica Ltd.. All rights reserved.
PY - 2024/1/3
Y1 - 2024/1/3
N2 - OBJECTIVE: NR5A1 is a key regulator of sex differentiation and has been implicated in spleen development through transcription activation of TLX1. Concerns exist about hypo- or asplenism in individuals who have a difference of sex development (DSD) due to an NR5A1 disease-causing variant. We aimed to assess spleen anatomy and function in a clinical cohort of such individuals and in their asymptomatic family member carriers. DESIGN: Cross-sectional assessment in 22 patients with a DSD or primary ovarian insufficiency and 5 asymptomatic carriers from 18 families, harboring 14 different NR5A1 variants. METHODS: Spleen anatomy was assessed by ultrasound, spleen function by peripheral blood cell count, white blood cell differentiation, percentage of nonswitched memory B cells, specific pneumococcal antibody response, % pitted red blood cells, and Howell-Jolly bodies. RESULTS: Patients and asymptomatic heterozygous individuals had significantly decreased nonswitched memory B cells compared to healthy controls, but higher than asplenic patients. Thrombocytosis and spleen hypoplasia were present in 50% of heterozygous individuals. Four out of 5 individuals homozygous for the previously described p.(Arg103Gln) variant had asplenia. CONCLUSIONS: Individuals harboring a heterozygous NR5A1 variant that may cause DSD have a considerable risk for functional hyposplenism, irrespective of their gonadal phenotype. Splenic function should be assessed in these individuals, and if affected or unknown, prophylaxis is recommended to prevent invasive encapsulated bacterial infections. The splenic phenotype associated with NR5A1 variants is more severe in homozygous individuals and is, at least for the p.(Arg103Gln) variant, associated with asplenism.
AB - OBJECTIVE: NR5A1 is a key regulator of sex differentiation and has been implicated in spleen development through transcription activation of TLX1. Concerns exist about hypo- or asplenism in individuals who have a difference of sex development (DSD) due to an NR5A1 disease-causing variant. We aimed to assess spleen anatomy and function in a clinical cohort of such individuals and in their asymptomatic family member carriers. DESIGN: Cross-sectional assessment in 22 patients with a DSD or primary ovarian insufficiency and 5 asymptomatic carriers from 18 families, harboring 14 different NR5A1 variants. METHODS: Spleen anatomy was assessed by ultrasound, spleen function by peripheral blood cell count, white blood cell differentiation, percentage of nonswitched memory B cells, specific pneumococcal antibody response, % pitted red blood cells, and Howell-Jolly bodies. RESULTS: Patients and asymptomatic heterozygous individuals had significantly decreased nonswitched memory B cells compared to healthy controls, but higher than asplenic patients. Thrombocytosis and spleen hypoplasia were present in 50% of heterozygous individuals. Four out of 5 individuals homozygous for the previously described p.(Arg103Gln) variant had asplenia. CONCLUSIONS: Individuals harboring a heterozygous NR5A1 variant that may cause DSD have a considerable risk for functional hyposplenism, irrespective of their gonadal phenotype. Splenic function should be assessed in these individuals, and if affected or unknown, prophylaxis is recommended to prevent invasive encapsulated bacterial infections. The splenic phenotype associated with NR5A1 variants is more severe in homozygous individuals and is, at least for the p.(Arg103Gln) variant, associated with asplenism.
KW - DSD
KW - NR5A1
KW - PPV-23
KW - SF1
KW - asplenism
KW - difference/disorder of sex development
KW - hyposplenism
KW - primary ovarian insufficiency
KW - spleen function
UR - http://www.scopus.com/inward/record.url?scp=85181762942&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/ejendo/lvad174
DO - https://doi.org/10.1093/ejendo/lvad174
M3 - Article
C2 - 38128121
SN - 0804-4643
VL - 190
SP - 34
EP - 43
JO - European journal of endocrinology
JF - European journal of endocrinology
IS - 1
ER -