ESPE Abstracts

The genetic causes of 46, XY disorders of sex development (DSD) are mostly unknown, having been identified in only 20-35%. Mitogen-activated protein kinase 1, part of the MAPK signaling pathway, which controls testicular development, is one of the etiological genetic pathways. Here, we present a case of 46, XY DSD with heterozygous MAP3K1 variant. A 6-month-old baby was referred to pediatric endocrinology because of ambiguous genitalia. They were born by C-section at 28 weeks with birthweight 790g (-2.42SDS). The parents were not consanguineous and pregnancy history was unremarkable. The family were informed of female gender during antenatal ultrasound, and chose a girl’s name. On examination, there was bifid scrotum, gonads were bilaterally palpable under the labioscrotal folds, incomplete posterior fusion, perineoscrotal hypospadias, and phallus 12 mm with chordee. The severity ofambiguous genitalia was assessed as 3b (Sinnecker classification), external genital score (EGS) was 5/12 Pelvic and abdominal ultrasound showed no internal female genital structures. Electrolytes were compatible with patient age. Follicle-stimulating hormone(FSH) was 1.71mIU/mL, luteinizing hormone (LH) was 4.13mIU/mL, testosterone (T) was 0.94g/L, dehydroepiandrosterone sulfate (DHEAS) was 9.7μmol/L (2.93-16.5), and androstenedione was 11nmol/L (1-11.5). Adrenocorticotropic hormone (ACTH) was 32.8pmol/L (5-111) and 17- hydroxyprogesterone was 13.4pmol/L (0–10). Anti-Müllerian hormone (AMH) was 68.8pmol/L (4–174.4). Beta-human chorionic gonadotropin (-hCG) stimulation test was performed (500 IU). T increased to 10.6g/L and dihydrotestosterone (DHT) was 3206pg/mL with a T/DHT ratio of 13.3. Following the -hCG test, the phallus increased from 1.0 to 5,5 cm in length. The karyotype was 46, XY. A heterozygous mutation of MAP3K1(NM_005921/2) c.3418A> G (p. Met1140Val) was detected by WES. Cystoscopy was performed and a closed-end vaginal structure was seen. The case was discussed at the DSD council and corrective surgery was recommended. The patient’s family was consulted and decided to raise the patient as male. The clinical presentation of the MAP3K1 mutation ranges from a normal external female phenotype to hypospadias phenotype, as well as complete or partial gonadal dysgenesis associated with a risk of gonadoblastoma. There are very few studies of this mutation but patients tend to be raised in the female gender and diagnosed late. The presented case was diagnosed in the first year. Although the EGS was in the female half of the range, there was increased testosterone in response to -hCG stimulation and the choice to raise as male may be appropriate.