CYP19A1 – Aromatase Deficiency

Aromatase deficiency is an autosomal recessive disorder of estrogen biosynthesis caused by biallelic loss-of-function variants in CYP19A1. Affected 46,XX individuals present with prenatal virilization of the mother and the female fetus, ambiguous genitalia at birth, and failure of pubertal development, whereas 46,XY patients often manifest with tall stature, delayed epiphyseal closure, osteopenia, and metabolic dysregulation.

Over 30 unrelated probands from more than 20 families have been reported with compound heterozygous or homozygous CYP19A1 variants, with segregation demonstrated in parents and siblings across multiple pedigrees ([PMID:8265607], [PMID:9177373], [PMID:10566648]). Maternal inheritance of missense alleles (e.g., p.Arg435Cys) and consanguineous pedigrees confirm autosomal recessive transmission.

The variant spectrum includes missense substitutions (e.g., c.1303C>T (p.Arg435Cys)), splice-site changes (e.g., c.1263+5G>A), small deletions and duplications causing frameshifts (e.g., c.1224del (p.Lys409fs)), and promoter variants. A founder splice mutation c.628G>A (p.Glu210Lys) is enriched in Argentinean patients ([PMID:25415177]).

Phenotypic features encompass ambiguous genitalia (HP:0000062), primary amenorrhea (HP:0000786), polycystic ovaries (HP:0000147), maternal virilization, variable breast development, obesity, insulin resistance, type II diabetes, and osteoporosis. The worldwide incidence is unknown but likely underdiagnosed due to phenotypic overlap with congenital adrenal hyperplasia.

Functional assays in transfected cells and site-directed mutagenesis consistently show severely reduced aromatase activity (<2% of wild type for R435C) or complete loss of activity for C437Y and splice variants ([PMID:8265607], [PMID:21521281]). Structural studies confirm disruption of the heme-binding region and substrate access channels.

Taken together, genetic and experimental data support a Strong gene-disease association for CYP19A1 and aromatase deficiency, with Strong genetic evidence from >30 probands and Moderate functional evidence from concordant in vitro assays. Early molecular diagnosis enables timely estrogen replacement to prevent bone and metabolic complications. Key take-home: CYP19A1 sequencing is clinically actionable for patients with disorders of sexual development and estrogen deficiency.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1993 • Molecular basis of aromatase deficiency in an adult female with sexual infantilism and polycystic ovaries PMID:8265607
• The Journal of Clinical Endocrinology and Metabolism • 1997 • Aromatase deficiency in a female who is compound heterozygote for two new point mutations in the P450arom gene PMID:9177373
• The Journal of Clinical Endocrinology and Metabolism • 2004 • Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene PMID:14715828
• Clinical Endocrinology • 2011 • Aromatase deficiency owing to a functional variant in the placenta promoter and a novel missense mutation in the CYP19A1 gene PMID:21521281
• Journal of Pediatric Endocrinology & Metabolism • 2012 • Growth and hormonal profile from birth to adolescence of a girl with aromatase deficiency PMID:23329769
• The Journal of Clinical Endocrinology and Metabolism • 2015 • Five new cases of 46,XX aromatase deficiency: clinical follow-up from birth to puberty, a novel mutation, and a founder effect PMID:25415177

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