MON-257 46,Xy Female With Gonadal Dysgenesis Due to Pathogenic Myrf Variant: Expanding the Phenotype of Myrf-Related Cardiac-Urogenital Syndrome

Abstract Disclosure: S.L. Echeverri: None. Background The myelin regulatory factor (MYRF) gene encodes a transcription factor essential for central nervous system myelination and development of various organ systems, including the heart, diaphragm, and genitourinary tract. Variants in MYRF are linked to MYRF-related cardiac-urogenital syndrome (CUGS), a rare autosomal dominant disorder featuring congenital diaphragmatic hernias, cardiac defects, and genitourinary malformations. Mutations of MYRF have been identified as a cause of DSD in 46,XX and 46,XY individuals. To our knowledge, 36 cases of MYRF-related CUGS have been reported. We present a case with a MYRF variant, expanding the phenotype to include gonadal dysgenesis. Case Presentation The patient presented at birth with abdominal distension, prompting an abdominal ultrasound, which revealed a uterus without ovarian development. Karyotype was 46,XY. At 6 weeks of life, laboratory evaluation demonstrated elevated gonadotropins, low testosterone, undetectable estradiol, and very low anti-Müllerian hormone (AMH), consistent with primary hypogonadism. Whole-exome sequencing identified a de novo pathogenic MYRF variant (c.1084dup:p.(A362Glyfs*7)). The patient’s past medical history included small-for-gestational-age birth with catch-up growth by 2 years of age, atrial septal defect (ASD), persistent left superior vena cava, and speech delay. Upon physical examination the patient had a triangular face, deep-set eyes, a prominent nasal tip, normal female external genitalia with a 0.5 cm phallus, and severe hyperopia. Laboratory findings supported partial gonadal dysgenesis, and imaging confirmed a visualized uterus. To our knowledge, this is the second case of gonadal dysgenesis reported in patients with MYRF-related CUGS. Conclusion This case adds to the growing understanding of MYRF-related disorders, which exhibit phenotypic variability, including congenital heart defects, urogenital anomalies, and diaphragmatic hernias. Less frequently reported are disorders of sex development (DSD) and gonadal dysgenesis. Our findings align with prior studies while emphasizing the importance of MYRF in gonadal development. Further research is needed to elucidate the underlying mechanisms and variability associated with MYRF variants. Presentation: Monday, July 14, 2025