Aromatase Excess Syndrome: Identification of Cryptic Duplications and Deletions Leading to Gain of Function ofCYP19A1and Assessment of Phenotypic Determinants

Abstract

This study provides novel mechanisms leading to gain of function of CYP19A1. Furthermore, it appears that clinical severity of AEXS is primarily determined by the tissue expression pattern of relevant genes and by the structural property of promoter-associated exons of chimeric mRNA.

Aromatase excess syndrome in a family with upstream deletion of CYP19A1

“…3 Thus, phenotype of the present family can be ascribed to CYP19A1 overexpression due to cryptic use of a widely expressed promoter. To date, two other deletions have been identified in four families with AEXS.…”

“…These intervals are likely to provide a hotspot for recombination-and replication-mediated errors, because the present deletion is consistent with a replication-mediated error that occurs independently of repetitive sequences and is associated with microhomology at the fusion junctions, 4 while the previously reported deletions are ascribed to recombination-mediated mechanisms. 3 Two points are noteworthy for the clinical features of this family. First, the phenotypes in the present family are comparable to those in other families with deletions.…”

Effects and significance of estradiol in men

“…Az androgének (androszténdion, tesztoszteron, dihidrotesztoszteron) szérumszintje szintén alacsony, az ösztra diol/tesztoszteron arány magas. Aromatázinhibitor adására a gynecomastia enyhülését, a hormonértékek normalizálódását tapasztalták [11]. E ritka genetikai betegségen kívül a szérumösztradiol koncentrációja számos patológiai állapotban megnöve-kedhet.…”

An Aroma of Complexity: How the Unique Genetics of Aromatase (CYP19A1) Explain Diverse Phenotypes From Hens and Hyenas to Human Gynecomastia, and Testicular and Other Tumors

“…Yet, the exact boundaries of these abnormalities and the resulting transcripts had to wait until the full sequence of the region became available. Fukami et al (59,60) recently published in the JCEM a series of these recombination-and replication-mediated rearrangements, including in patients that were reported previously (55) and had been analyzed only by fluorescent in situ hybridization. Interestingly, even deletions of the region upstream of, but not involving, the CYP19A1 gene lead to P450arom overexpression by activating (after fusion of regulatory sequences) a widely used promoter of the gene (59,61).…”

“…Fukami et al (59,60) recently published in the JCEM a series of these recombination-and replication-mediated rearrangements, including in patients that were reported previously (55) and had been analyzed only by fluorescent in situ hybridization. Interestingly, even deletions of the region upstream of, but not involving, the CYP19A1 gene lead to P450arom overexpression by activating (after fusion of regulatory sequences) a widely used promoter of the gene (59,61). Such genomic rearrangements are now increasingly found as the cause of a number of human diseases from autism to cancer (62,63), and their potential generating mechanisms are elegantly reviewed by Fukami et al (60).…”