ESPE Abstracts

Introduction: The MAMLD1 gene is expressed in fetal and adult testes. It contributes to the development and formation of the male external genitalia in late stages of fetal organogenesis (week 8-12) and to testosterone biosynthesis. The pathogenic genetic variants of this gene determine a significant reduction in plasma testosterone concentrations, although they are not undetectable. Its most common phenotypic manifestation is hypospadias, also described in patients with microphallus with or without cryptorchidism.

Patient Description: 40 weeks gestation newborn with a microphallus of 1.5cm in length (nv:3.5cm ± 0.4) and terminal hypospadias with 3ml testes located in the scrotal bag. Normal anthropometry. At 6 days of life, a hormonal study was carried out with the following result: LH: 4.4IU/l (nv: 0.40-10.1IU/l), FSH: 3.8IU/l (nv: 0,6-7IU/l), Testosterone: 69 ng/dl (nv:288-300 ng/dl), IGF-I: 61 ng/ml, and IGFBP3: 1.8g/dl. Normal thyroid and adrenal hormone profile. Karyotype 46, XY. Normal hypothalamic-pituitary magnetic resonance and testicular ultrasound with homogeneous echostructure and normal size testicles. At 1 month of age a 25mg dose of testosterone IM is administered. At 2 months of age the length of the penis is 2 cm with following hormonal profile: LH: 4.8U/l, FSH: 3U/l, testosterone: 49 ng/dl, dihydrotestosterone (DHT): 0,1 ng/ml (nv:0.25-0.99 ng/ml), antimullerian hormone (AMH): 77.2 ng/ml (nv: 97.9 ± 34.4 ng/ml), inhibin B: 192 pg/ml (nv: 209-321 pg/ml). At the age of 4 months, a stimulation test with hCG 1000IU/dose is performed 3 times/week for 2 weeks without observing a significant increase in the concentrations of testosterone (111.1 ng/dl), DHT (0.05 ng/ml) or the length of the penis. The DSD massive gene sequencing panel identifies a hemizygosity pathogenic variant in the MAMLD1 gene (c.1738C>T:p.Gln580Ter)in exon3). Treatment with intramuscular testosterone 50mg every 3 weeks (2 doses) was started, showing a favorable response to treatment with an increase in penis length to 3.5 cm.

Conclusions: Our patient presents a pathogenic variant in MAMDL1 not previously described in the literature that predicts "in silico" a truncated protein that could justify his genital phenotype. The existence of low testosterone concentrations during the infant's minipuberty stage and the absence of a significant increase in plasma concentrations of testosterone and DHT in the hCG test highlights the potential role of this gene in the biosynthesis of testosterone during the fetal stage and minipuberty of the infant. This case would be the first time that a decrease in DHT has been described in a patient with an abnormal MAMLD1. IM testosterone treatment is effective in these patients.