BRIEF COMMUNICATIONS Frasier Syndrome: A Cause of Focal Segmental Glomerulosclerosis in a 46,XX Female

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 (1KTS isoform), thus disrupting the normal ratio of the 1KTS/2KTS 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. Frasier syndrome is a rare disease in phenotypic females who develop nephrotic-range proteinuria in childhood, have idiopathic focal segmental glomerulosclerosis (FSGS), and progress to end-stage renal disease by the second or third decade of life (1). These patients are often diagnosed when evaluated for primary amenorrhea since, until the current report, the classic description of Frasier syndrome patients has been limited to XY females. They have a normal sex-determining gene on the Y chromosome (SRY) but have gonadal dysgenesis and streak gonads with a significant risk of gonadoblastoma. Recently, mutations of the Wilms’ tumor (WT1) gene have been shown to cause Frasier syndrome (2). The WT1 gene is located on chromosome 11p13 and encodes a zinc finger transcription system essential for normal renal and genital development and for tumor suppression. The mutation of WT1 in Frasier syndrome is distinct from the WT1 exon mutations associated with Denys-Drash and the chromosome 11 deletion known to cause WAGR syndrome (3). In Frasier syndrome, the mutations reported thus far are within the intron 9 donor splice site of WT1. These are predicted to lead to an imbalance of the ratio of isoforms resulting from an alternative splice site located between the third and fourth zinc fingers of WT1 (2,4). Here we report two sisters with Frasier syndrome. The proband has classical Frasier syndrome with FSGS and 46,XY gonadal dysgenesis. However, her sister also has FSGS but has a 46,XX karyotype and normal female gonadal development. This is the first fully characterized demonstration of Frasier syndrome in a genetic female. It demonstrates that the FSGS of Frasier syndrome is caused by the WT1 mutation regardless of the patient’s genetic sex; however, in contrast to the picture seen in XY individuals, patients with a XX karyotype have apparently normal ovarian development. Also, some cases of FSGS in otherwise normal females may possibly be due to Frasier syndrome, especially when more than one girl in a family is affected. Materials and Methods Patients The proband had asymptomatic 41 proteinuria noted during a routine physical examination at age 7. She had no edema. Her 24-h urinary protein excretion was 3.5 g and serum albumin was 3.5 g/dl. Serum creatinine was 0.5 mg/dl and cholesterol 301 mg/dl. She failed to respond to prednisone, and a renal biopsy demonstrated FSGS in two of 44 glomeruli (Figure 1A). Received April 28, 1999. Accepted July 31, 1999. 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: [email protected]