Background: Mutations in Steroidogenic factor 1 (SF-1; also known as NR5A1), a transcription factor involved in sexual differentiation, steroidogenesis and reproduction, have been associated with mild to severe XY and XX DSDs and adrenal failure. Asplenia and complete XY sex reversal were recently reported in a Palestinian patient homozygous for p.R103Q NR5A1 mutation.
Clinical Cases: Five Palestinian girls (three 46, XY and two 46, XX) from 3 unrelated families presented between 13-15 years of age with absence of spontaneous pubertal development and primary amenorrhea for investigations. Three cases had 46, XY karyotype and female external genitalia. They had a significant history for infectious diseases (e.g. pneumococcal sepsis at 9 months of age, aseptic meningitis, hepatitis A, suppurative hip arthritis), asplenia, bilateral inguinal dysgenetic or absent testes, rudimentary or absent uterus and undetectable AMH levels. The 2 other cases (sisters) had 46, XX karyotype, hyposplenia, infantile uterus, absence of ovaries in imaging studies and undetected serum AMH.
Asplenia was recognized only lately in all of the cases except for case 4, where it was diagnosed at age of 6 months. Interestingly case 2 exemplified delayed adrenarche and undetectable levels of Dehydroepiandrosterone, androstenedione, and testosterone.
All five cases had the homozygous NR5A1 p.R103Q mutation, originating from one founder. (1).
Conclusions: The homozygous R103Q NR5A1 mutation causes complete XY sex reversal but also completely disables the development of an ovary. DSD in the context of significant infections should alert to asplenia and NR5A1 mutation, and consequently indicate lifesaving preventive measures such as vaccinations and antibiotic prophylaxis. The undetectable AMH levels in this cohort suggests a critical role of human SF-1 in AMH transcription. The delayed adrenarche, and the undetected serum androgens levels in case 2 proves that SF-1 is required for CYP17A1 transcription. The presence of Mullerian structures in this case is the most severe reported XY DSD phenotype of NR5A1 mutation.
Reference: (1) Zangen et al. Testicular differentiation factor SF-1 is required for human spleen development. J Clin Invest. 2014 May;124(5):2071-5.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology