Frasier syndrome

Overview

Frasier Syndrome is a rare genetic disorder affecting sexual development and kidney function. It is categorized as a disorder of sex development (DSD) and is typically seen in individuals with a 46,XY karyotype. The syndrome is characterized by gonadal dysgenesis (underdeveloped gonads), progressive kidney disease (leading to focal segmental glomerulosclerosis), and an increased risk of gonadoblastoma (a type of tumor). Frasier Syndrome is distinct from, but related to, other syndromes involving the WT1 gene, such as Denys–Drash Syndrome.

Causes

Frasier Syndrome is caused by specific mutations in the WT1 gene (Wilms Tumor 1 gene), which plays a crucial role in the development of kidneys and gonads. The condition is inherited in an X-linked dominant or de novo manner, depending on the mutation. In Frasier Syndrome, the mutation specifically affects the alternative splicing of exon 9 of the WT1 gene, disrupting the balance of WT1 isoforms (KTS+ and KTS−), which is critical for normal development of kidney and gonadal tissues.

Symptoms

Symptoms of Frasier Syndrome typically appear in early childhood or adolescence and involve both renal and gonadal manifestations. Common features include:

Renal Symptoms

• Proteinuria (excess protein in the urine)

• Progressive kidney disease

• Focal segmental glomerulosclerosis (FSGS)

• End-stage renal disease (ESRD), often before adulthood

Gonadal and Reproductive Symptoms

• 46,XY karyotype with female external genitalia (complete gonadal dysgenesis)

• Streak gonads (non-functional fibrous tissue instead of testes)

• Primary amenorrhea (no menstruation by puberty)

• Delayed or absent puberty

• High risk of gonadoblastoma or dysgerminoma

Diagnosis

Diagnosis of Frasier Syndrome involves clinical, genetic, and laboratory evaluations. Steps include:

• Karyotype analysis: Reveals 46,XY chromosomes in individuals with female genitalia.

• Genetic testing: Detects mutations in the WT1 gene, particularly affecting exon 9 splicing.

• Urinalysis: Identifies proteinuria, often the first sign of kidney disease.

• Renal biopsy: Confirms focal segmental glomerulosclerosis (FSGS).

• Hormonal assays: Indicate gonadal dysgenesis with low levels of sex hormones.

• Imaging studies: Ultrasound or MRI to assess gonadal structure and detect tumors.

Treatment

Treatment for Frasier Syndrome is multidisciplinary, aiming to manage renal disease, prevent malignancy, and address hormonal needs. Common approaches include:

Renal Management

• ACE inhibitors or ARBs to reduce proteinuria

• Monitoring and management of blood pressure

• Dialysis and kidney transplantation for end-stage renal disease

Gonadal Management

• Prophylactic gonadectomy (surgical removal of gonads) to prevent gonadoblastoma

Hormonal and Supportive Therapies

• Hormone replacement therapy (HRT) to induce puberty and maintain secondary sexual characteristics

• Psychological counseling and gender identity support as needed

Genetic Counseling

• Essential for affected individuals and families to understand inheritance, recurrence risks, and reproductive options

Prognosis

The prognosis for Frasier Syndrome varies depending on the timing of diagnosis and the severity of kidney involvement. Most individuals progress to end-stage renal disease in adolescence or early adulthood. Early detection and kidney transplantation can significantly improve outcomes. With proper management of hormonal and reproductive health, individuals can lead relatively normal lives. However, lifelong medical follow-up is necessary to monitor renal function and screen for potential complications such as gonadal tumors.