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J Am Soc Nephrol 10:2215-2218, 1999
© 1999 American Society of Nephrology

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Frasier Syndrome

A Cause of Focal Segmental Glomerulosclerosis in a46,XX Female

LAURIE DEMMER*, WILLIAM PRIMACK*,{dagger}, VALERIE LOIK{ddagger}, ROSALIND BROWN*, NICOLE THERVILLE§ and KEN MCELREAVEY§

* Department of Pediatrics, University of Massachusetts Memorial Health Care, Worcester, Massachusetts
{dagger} Fallon Clinic, Worcester, Massachusetts
{ddagger} Department of Obstetrics & Gynecology, Baystate Medical Center, Springfield, Massachusetts
§ Department of Human Immunogenetics, Institut Pasteur, Paris, France.

Correspondence to Dr. Laurie Demmer, Director of Genetics, Department of Pediatrics, University of Massachusetts Memorial Health Care, 55 Lake Avenue North, Worcester, MA 01655. Phone: 508-856-3949; Fax: 508-856-4287; E-mail: laurie.demmer{at}ummhc.org

Abstract

Abstract. The description of Frasier syndrome until now has been restricted to XY females with gonadal dysgenesis, progressive glomerulopathy, and a significant risk of gonadoblastoma. Mutations in the donor splice site in intron 9 of the Wilms' tumor (WT1) gene have been shown to cause Frasier syndrome and are distinct from WT1 exon mutations associated with Denys-Drash syndrome. The WT1 gene, which is essential for normal kidney and gonadal development, encodes a zinc finger transcription factor. The intron 9 alternative splice donor site mutation seen in Frasier syndrome leads to loss of three amino acids (+KTS isoform), thus disrupting the normal ratio of the +KTS/-KTS isoforms critical for proper gonadal and renal development. This study examines two sisters with identical intron 9 mutations. The proband carries a classic diagnosis of Frasier syndrome with 46, XY gonadal dysgenesis, whereas her sister has progressive glomerulopathy but a 46, XX karyotype and normal female development. This indicates that the proper WT1 isoform ratio is critical for renal and testicular development, but apparently does not affect either ovarian development or function. It is proposed that the clinical definition of Frasier syndrome should be broadened to include 46,XX females with normal genital development and focal segmental glomerulosclerosis associated with a WT1 intron 9 donor splice site mutation. Nephrologists need to consider the possibility of this heritable syndrome in evaluation of females with focal segmental glomerulosclerosis and to consider their risk for gonadal malignancy, as well as the risk for kidney disease, gonadal dysgenesis, and malignancy in their offspring.




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