Endocrine Abstracts

Background

Aromatase deficiency is an extremely rare autosomal recessive condition due to mutations on CYP19A1 gene. Despite the size and complexity of this gene, only about 40 cases with aromatase deficiency have been reported.

Case report

The patient was born at term from non-consanguineous parents. Maternal signs of virilization were verified during third trimester (deep voice, acne on arms and face enlargement). Ambiguous genitalia were recognized at birth. The patient was referred to the Pediatric Endocrinology Department (PED) and presented complete fusion of the labia majora, clitoromegaly, and a posterior urethra. Mother reported improvement in virilization signs few days after birth. Laboratory work-up at 2 days of life showed 17-hydroxy progesterone (17-OHP) of 18 (0.07–0.77) ng/ml, total testosterone (TT) of 0.7 (20–64) ng/dl, whereas ionogram, adrenocorticotropic hormone, dehydroepiandrosterone sulfate, aldosterone and renin were normal; at 15 days, 17OHP was 12.4 (0.13–10.6) ng/ml, TT <20.0 (20–64) ng/dl and androstenedione 2.8 (0.18–0.80) ng/ml. The karyotype was 46, XX and pelvic ultrasound revealed a normal uterus, vagina and bladder. At 11 months of age, she was submitted to vulvoplasty and the parents decided to suspend the follow-up at the PED. At 12 years and 4 months, she presented to the emergency department (ED) with severe pain in the left iliac fossa, absence of stool passage for 2 days and vomiting, presenting Tanner stage III pubic hair and Tanner stage I breasts. Laboratory findings showed 17-OHP 1.86 (0.11–0.98) ng/ml, TT 0.4 (0.07–0.28) ng/ml, LH 31 (0.02–4.7) mUI/ml, FSH 33 (1.0–10.8) mUI/ml and estradiol 16 (10–24) pg/ml. Pelvic MRI revealed a complex genital malformation, ovarian cystics and suspected hydrocolpos. Treatment with LHRH agonist was implemented. She underwent left oophorosalpingectomy and histology documented left anexal necrosis with multicystic left ovary torsion, without hydrocolpos, and treatment with LHRH agonist was suspended. At 13 years and 2 months, she was admitted to the ED with right ovary torsion and underwent urgent laparoscopic surgery. LHRH agonist was restarted. Genetic analysis of the patient revealed two probably pathogenic variants in heterozygote in the CYP19A1 gene: a previously described mutation (c.1263+5G>A p.?) and a novel mutation [c.456_462del p.(Ser153Profs*24). Puberty was induced with transdermal estrogens.

Conclusion

We identified a novel mutation in the CYP19A1 gene in a patient who presented with ambiguous genitalia and maternal virilization during pregnancy. Our case had large polycystic ovaries and two episodes of ovarian torsion. In addition, it shows the difficulties during the follow-up and the complexity of the disease. We speculate that these mutations can potentially result in partial aromatase activity with remaining estrogen biosynthesis.