CYP19A1 – Aromatase Excess Syndrome

Aromatase excess syndrome (AEXS) is a rare autosomal dominant disorder characterized by increased extraglandular aromatization of androgens and resultant estrogen excess. Affected males present with pre- or peri-pubertal gynecomastia, hypogonadotropic hypogonadism, advanced bone age and short adult stature, while females may exhibit premature thelarche, macromastia, uterine enlargement and menstrual irregularities. The syndrome was first described in two adult siblings born to unrelated parents demonstrating clinical and biochemical evidence of estrogen excess without coding mutations in CYP19A1, and marked overexpression of aromatase mRNA in patient fibroblasts ([PMID:12843139]).

Genetic analyses across multiple families implicate structural rearrangements at chromosome 15q21 disrupting CYP19A1 regulatory architecture. In a kindred of 16 affected individuals (both sexes) linkage to CYP19A1 was supported by LOD scores up to 1.5, and 5′-RACE revealed fusion of a TRPM7-derived exon upstream of CYP19A1, suggesting a rearrangement-mediated cryptic promoter driving aberrant aromatase transcription ([PMID:15811932]).

Human Molecular Genetics characterized five distinct heterozygous rearrangements—four inversions and one deletion—in three unrelated families and two sporadic cases (nine patients) that juxtapose constitutively active promoters of TMOD3, MAPK6, TLN2, CGNL1 or DMXL2 upstream of CYP19A1. These cryptic promoters splice into the native coding region, yielding overexpressed aromatase transcripts and phenocopying human AEXS ([PMID:17584767]).

A 2024 Frontiers in Endocrinology report described a monoallelic 0.3-Mb deletion in 15q21 that includes parts of CYP19A1, GLDN and DMXL2 in four family members with AEXS. This study reaffirmed the dose-dependent effect of CYP19A1 rearrangements on adult height, gynecomastia prevention with early letrozole therapy, and variable phenotypic expressivity despite identical microdeletions ([PMID:39634186]).

Expression studies demonstrate >10-fold increased aromatase mRNA in patient tissues, concordant with experiments in steroid 5α-reductase type 1–deficient mice that also exhibit hyperestrogenism through increased androgen substrate availability. Together these data establish a promoter-switch mechanism as the pathogenic basis of AEXS ([PMID:12843139]).

Local tissue-specific analyses in gynecomastia surgical specimens identified cryptic recruitment of adipose I.4, placental I.2 and ubiquitous I.7 promoters in CYP19A1 expressing cells, further validating promoter heterogeneity and overexpression in prepubertal males with gynecomastia ([PMID:35667691]).

Conflicting evidence is minimal; no coding-region point mutations have been associated with AEXS, and linkage to SRD5A1 has been excluded. All functional and segregation data converge on structural alterations of CYP19A1 regulatory elements.

Definitive genetic and mechanistic data support CYP19A1 rearrangements as the cause of AEXS. These findings enable accurate molecular diagnosis, inform early aromatase-inhibitor therapy, and provide a robust framework for future therapeutic and mechanistic studies.

Key Take-home: Structural rearrangements creating cryptic promoters at CYP19A1 cause autosomal dominant aromatase excess syndrome, with strong diagnostic and therapeutic implications.

References

• The Journal of Clinical Endocrinology and Metabolism | 2003 | Familial hyperestrogenism in both sexes: clinical, hormonal, and molecular studies of two siblings. PMID:12843139
• The Journal of Clinical Endocrinology and Metabolism | 2005 | A potential rearrangement between CYP19 and TRPM7 genes on chromosome 15q21.2 as a cause of aromatase excess syndrome. PMID:15811932
• Human Molecular Genetics | 2007 | Regional rearrangements in chromosome 15q21 cause formation of cryptic promoters for the CYP19 (aromatase) gene. PMID:17584767
• Frontiers in Endocrinology | 2024 | Long term effects of aromatase inhibitor treatment in patients with aromatase excess syndrome. PMID:39634186
• Journal of Pediatric Endocrinology & Metabolism | 2022 | Local aromatase excess with recruitment of unusual promoters of CYP19A1 gene in prepubertal patients with gynecomastia. PMID:35667691

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