Producción CyT
Sexual development - A novel POR variant recurrently found in Argentine patients results in a wide spectrum of undervirilised phenotypes in 46,XY patients
Congreso
Autoría:
LOPEZ DACAL, JIMENA CLAUDIA ; Nora Sanguineti ; Roxana Marino ; Pablo Ramirez ; Natalia Perez Garrido ; Elisa Vaiani ; Maria Natalia Rojas Velazquez ; Katyayani Sharma ; Gabriela Guercio ; Paula Scaglia ; María Esnaola Azcoiti ; Agustín Izquierdo ; Gabriela Sansó ; Marcela Bailez ; María Gabriela Ropelato ; Mariana Costanzo ; Alicia Belgorosky ; Ignacio Bergadá ; Rodolfo A. Rey ; Amit V Pandey ; Romina P. GrinsponFecha:
2022Editorial y Lugar de Edición:
KargerResumen *
Background: Cytochrome P450 oxidoreductase (POR) deficiency results in defective steroid production in the gonads and adrenals. Mutations in POR cause ambiguous genitalia in both 46,XX and 46,XY patients and adrenal insufficiency with/without bone malformations resembling Antley-Bixler syndrome.Methods: To report a novel p.Gly88Ser variant in POR identified in 4 Argentine families.Results: All index cases had 46,XY karyotype; patients 1-3 were assigned male and patient 4, female. Sex Dev 2022;16(suppl 1):1–91 DOI: 10.1159/00052556427Patient 1 had micropenis, perineoscrotal hypospadias, partially fused labioscrotal folds, and inguinal gonads. External Genital Score (EGS) was 4.5 and he had bulbous nose and auricular skin tags.Patient 2 had micropenis without hypospadias, fused and bifid labioscrotal folds with palpable gonads and EGS of 9. He had imperforate anus and colo-vesical fistula.Patient 3 had micropenis, perineoscrotal hypospadias, partially fused labioscrotal folds with palpable gonads, and EGS of 7. His affected sister (46,XX) presented with primary hypogonadism at pubertal age.Patient 4 presented with genital tubercle length within female range, one genital orifice and a left inguinal gonad. She had unilateral kidney agenesis and dysmorphic features (bulbous nose, flat nasal bridge, arachnodactyly, thoracic kyphosis).All patients showed elevated basal ACTH, 17-OH progesterone and progesterone, normalcortisol without response to ACTH, and low androstenedione and testosterone without response to hCG. POR deficiency was suspected. None presented radiographic signs of AntleyBixler syndrome. A novel homozygous variant NM_000941.3:c.262G>A/p.Gly88Ser in POR was found in all four patients and patient 3’s sister. The variant was also detected in the heterozygous state in the parents that could be studied. No common ancestors have been found between the families. The variant was classified as likely pathogenic (PM1, PM2, PS4, PP3) according to ACMG. Functional studies in vitro showed severe effects of the Gly88Ser variant on POR activitysupporting the defect in steroid and drug metabolismConclusion: The suspicion of a POR defect was mainly based on the characteristic biochemical pattern in undervirilised patients with 46,XY DSD. The p.Gly88Ser variant in POR presents a wide phenotypic spectrum. The existence of the same variant, not previously described, in 4 Argentine families raises the possibility of the existence of a founder effect. Información suministrada por el agente en SIGEVAPalabras Clave
46,XY DSDPOR