A Novel Compound Heterozygous Mutation of the Aromatase Gene in an Adult Man: Reinforced Evidence on the Relationship Between Congenital Oestrogen Deficiency, Adiposity and the Metabolic Syndrome

Background: Descriptions of new cases of human aromatase deficiency are useful for a better understanding of male oestrogen pathophysiology, as some aspects remain controversial.

Objective: To present a new case of an adult man affected by aromatase deficiency, along with a description of clinical phenotype, and hormonal and genetic analysis.

Design: Case report study.

Patient: A 25-year-old man with continuing linear growth, eunuchoid body habitus and diffuse bone pain.

Measurements: Amplification and sequencing of all coding exons with their flanking intronic sequences of the CYP19A1 gene. Aromatase expression of the mutant human cDNAs was compared with wild type. Serum LH, FSH, testosterone, oestradiol, insulin, glucose, glycosylated haemoglobin (HbA1c), serum lipids and liver enzymes were measured. Histological analysis of liver and testis biopsies was performed.

Results: Two novel heterozygous compound inactivating mutations of the CYP19A1 gene were disclosed. The first mutation is at bp380 (T-->G) in exon IV and the second one at bp 1124 (G-->A) in exon IX. LH and testosterone were normal, FSH was slightly elevated, and serum oestradiol undetectable. The subject showed a metabolic syndrome characterized by abdominal obesity, hyperinsulinaemia, acanthosis nigricans and nonalcoholic fatty liver disease.

Conclusions: These novel mutations improve our knowledge on genetics of the CYP19A1 gene. This new case of aromatase deficiency sheds new light on the heterogeneity of mutations in the CYP19A1 gene causing loss of function of the aromatase enzyme. The evidence of metabolic syndrome and of obesity associated with congenital oestrogen deprivation emphasizes the role of oestrogens in fat accumulation and distribution in men, a role that has long been partially overlooked in these patients.