Frasier syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

For the anatomical abnormality observed in 1965, see Fraser syndrome.

Overview

Frasier syndrome is a urogenital anomaly associated with the WT1 (Wilms tumor 1 gene) gene.

Historical Perspective

It was first characterized in 1964.

Presentation

Frasier syndrome presents at birth with male pseudohermaphroditism (the external genitalia have a female appearance despite an XY genotype), streak gonads and progressive glomerulonephropathy (focal segmental glomerulosclerosis). Patients are also at increased risk of genito-urinary tumors (usually gonadoblastoma).

The glomerulonephropathy presents later than in Denys-Drash syndrome, and the tumour risk phenotype is different - whilst DDS is associated with Wilms' tumour, Frasier syndrome is associated with gonadoblastoma. Differentiating between the two syndromes can be challenging.

Inheritance pattern

Frasier syndrome is inherited in an autosomal dominant fashion, indicating the need for only one mutated allele in a cell to lead to expression of the disease. Mutations predominantly occur de novo, allowing for expression in an individual that has no family history of it. The mutations occur during gamete formation or early in embryogenesis.

WT1 gene and mutations

The WT1 gene exists on chromosome 11 (at 11p13), and codes for a four zinc finger transcription factor. Its role as a transcription factor is related to proper kidney and gonadal development. The link between kidney and gonadal development and WT1 was highlighted in past studies looking at the related Denys-Drash syndrome. Results of various investigations identified the loss of function of WT1 to be a prerequisite of Wilms' tumour development, and also a key trait of individuals with genital abnormalities.

Mutations responsible for Frasier syndrome predominantly occur in intron 9 of the WT1 gene, specifically nucleotide substitutions that influence an intron splice site. Mutations in this region proved for the absence of three amino acids—KTS—between the third and fourth WT1 zinc fingers. Referring to the autosomal dominant expressive nature of this disease, it is only necessary for an individual to have one compliment of the mutated intronic sequence to appear affected. Differing from the similar Denys-Drash syndrome, where a mutated form of the WT1 protein exists, Frasier syndrome expression works solely on the existence of a changed ratio of KTS isoforms: normal WT1 proteins including the KTS site (+KTS), and mutated, shortened proteins lacking the KTS site (–KTS). Through alternative splicing, a specific ratio of the two isoforms normally exists, though the mutation in the intron 9 splice site severely lowers levels of the +KTS isoform; this leads to Frasier syndrome.