ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 P137

A novel compound heterozygous mutation of the aromatase gene in adult man: new insight into the role of estrogen on gonadal development

Fabio Lanfranco1, Lucia Zirilli2, Matteo Baldi1, Alessandra Luberto2, Elisa Pignatti2, Francesca Magnani2, Gianluca Aimaretti1, Cesare Carani2 & Vincenzo Rochira2


1Division of Endocrinology and Metabolic Diseases, Department of Internal Medicine, University of Turin, Turin, Italy; 2Chair of Endocrinology, Integrated Department of Medicine, Endocrinology Metabolism and Geriatrics, University of Modena and Reggio Emilia, Modena, Italy.


We present a novel heterozygous compound inactivating mutation of the CYP19A1 (P450arom) gene in a 26-year-old 46-XY Caucasian Italian male leading to aromatase deficiency. The patient phenotype resembled those observed in the other estrogen-deficient patients: tall stature with continuing linear growth, bilateral genu valgum, unfused epiphyses and delayed bone age, osteopenia. A dysmetabolic syndrome characterized by overweight (BMI 29), hyperinsulinaemia, low serum HDL and increased LDL was present. Virilization, penis and testis (15 and 20 ml for right and left testes respectively) size were normal. Right cryptorchidism was surgically corrected when he was 3-year-old. Sperm count was normal with reduced viability. Gonadal axis presented normal serum LH and testosterone, increased serum FSH and undetectable estradiol. DNA analysis: all coding exons with their flanking intron sequences of the CYP19A1 gene, along with untranslated exon I.4 and its 5 flanking region, were amplified by PCR and sequenced on a ABI Prism 3100 Genetic Analyzer. DNA sequencing of the CYP19A1 gene revealed a pattern of compound heterozygosity due to a 23 bp deletion in exon IV and a point mutation in the first nucleotide of intron IX, respectively. The heterozygous deletion would be expected to cause a frameshift with a premature stop codon at nucleotide 361 in exon IV; instead the single base mutation in the first nucleotide of intron IX would lead to an aberrant splicing of the mRNA. This new case of aromatase deficiency confirms the well-known effect of congenital estrogen deprivation on skeletal maturation and bone mineral density. Furthermore the concomitant presence of cryptorchidism described in other two men with aromatase deficiency support a possible role of estrogens in the male gonadal development.