Frasier syndrome

Frasier syndrome is a condition that affects the kidneys and genitalia.

Frasier syndrome is characterized by kidney disease that begins in early childhood. Affected individuals have a condition called focal segmental glomerulosclerosis, in which scar tissue forms in some glomeruli, which are the tiny blood vessels in the kidneys that filter waste from blood. In people with Frasier syndrome, this condition often leads to kidney failure by adolescence.

Although males with Frasier syndrome have the typical male chromosome pattern (46,XY), they have gonadal dysgenesis, in which external genitalia do not look clearly male or clearly female (ambiguous genitalia) or the genitalia appear completely female. The internal reproductive organs (gonads) are typically undeveloped and referred to as streak gonads. These abnormal gonads are nonfunctional and often become cancerous, so they are usually removed surgically early in life.

Epidemiology

Frasier syndrome is thought to be a rare condition; approximately 50 cases have been described in the scientific literature.

Cause

Mutations in the WT1 gene cause Frasier syndrome. The WT1 gene provides instructions for making a protein that regulates the activity of other genes by attaching (binding) to specific regions of DNA. On the basis of this action, the WT1 protein is called a transcription factor. The WT1 protein plays a role in the development of the kidneys and gonads (ovaries in females and testes in males) before birth.

The WT1 gene mutations that cause Frasier syndrome lead to the production of a protein with an impaired ability to control gene activity and regulate the development of the kidneys and reproductive organs, resulting in the signs and symptoms of Frasier syndrome.

Frasier syndrome has features similar to another condition called Denys-Drash syndrome, which is also caused by mutations in the WT1 gene. Because these two conditions share a genetic cause and have overlapping features, some researchers have suggested that they are part of a spectrum and not two distinct conditions.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Signs and symptoms

Nephropathy is the hallmark of the disease. It develops during childhood presenting as persistent proteinuria and subsequently steroid-resistant nephrotic syndrome (SRNS) and progresses to end-stage renal disease (ESRD) in the second or third decade of life.

On renal biopsy, focal segmental glomeruloscrelosis (FSGS) is the most common histopathological finding. Individuals have a 46, XY karyotype and present with female external genitalia, complete gonadal dysgenesis and have a higher risk of gonadoblastoma.

These individuals are later evaluated for delayed puberty or primary amenorrhea. Since (modest) breast development occurs also without estrogen stimulus, failure to recognize a delayed puberty is not rare.

In addition, the clinical picture may be confused by attributing pubertal delay to previous immunosuppressive therapy, renal insufficiency itself or renal transplantation. Complete gonadal dysgenesis results in infertility, female external genitalia and presence of Mullerian structures. Wilms tumor is not common in individuals with Frasier syndrome.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 100% of people have these symptoms

• Ambiguous genitalia, male(Ambiguous genitalia in males)
• Glomerulopathy
• Male pseudohermaphroditism

80%-99% of people have these symptoms

• Decreased serum estradiol
• Focal segmental glomerulosclerosis
• Gonadal dysgenesis with female appearance, male
• Hypergonadotropic hypogonadism
• Increased circulating gonadotropin level(Elevated gonadotropins)
• Primary amenorrhea
• Proteinuria(High urine protein levels)

30%-79% of people have these symptoms

• Gonadoblastoma
• Hypertension
• Nephrotic syndrome
• Renal insufficiency(Renal failure)
• Streak ovary

1%-4% of people have these symptoms

• Nephroblastoma

Diagnosis

The diagnosis is suspected on childhood onset of progressive glomerulopathy with findings of FSGS on histological analysis. Phenotypic females with delayed puberty or primary amenorrhea, should be carefully evaluated for signs of nephropathy.

When the clinical findings suggest the diagnosis of WT1 associated disorders, single gene testing of the hotspot 8-9 exons with adjacent introns can be performed. Karyotype testing is recommended for all individuals with WT1 intron 9 pathogenic variants.

Differential diagnosis The main differential diagnosis is idiopathic steroid-resistant nephrotic syndrome, and other WT1 associated diseases including Denys-Drash syndrome, genetic steroid resistant nephrotic syndrome and disorders of testicular development.

Treatment

Management is multidisciplinary and should involve a nephrologist for management of chronic renal failure (initially with nephroprotective medical therapy and afterwards with renal replacement therapies or transplantation when ESRD occurs), an endocrinologists for treatment of associated disorder of testicular development, and oncologists and surgeons to evaluate the need for an early gonadectomy in order to prevent tumorigenesis. Preemptive bilateral gonadectomy at the time of renal transplant or placement of a peritoneal dialysis catheter might be an option.

Prognosis

There is limited information on life expectancy. After kidney transplantation, nephrotic syndrome does not recur. 46,XY individuals with complete gonadal dysgenesis are infertile.

NIH genetic and rare disease info

• NIH info on Frasier syndrome

Frasier syndrome is a rare disease.

Frasier syndrome Resources
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