What Is Fraiser Syndrome?
Fraiser syndrome is a rare genetic disorder characterized by anomalies of the kidney and genitalia. Frasier syndrome patients develop nephrotic syndrome with focal segmental glomerulosclerosis (FSGS), resistant to steroid treatment in childhood. In adolescence, male patients can be born with female external genitalia (pseudo-hermaphroditism) and develop gonadoblastoma.
What Causes Fraiser Syndrome?
Frasier syndrome is caused by mutations in the Wilms' tumor (WT1) gene's splice donor site at intron 9; these mutations result in an imbalanced ratio of WT1 protein isoforms and affect urogenital tract development, podocyte function, and tumor suppression. In other words, the WT1 mutation that causes Fraiser syndrome causes the production of a protein with an impaired ability to control gene activity and regulate the development of the kidneys and reproductive organs, hence causing the symptoms and signs of Fraiser syndrome.
What Is Wt1 Gene?
The WT1 gene exists on chromosome 11 and codes for a four-zinc finger transcription factor. The WT1 gene codes for a protein that controls the activity of other genes by attaching (binding) to specific regions of DNA (deoxyribonucleic acid). After birth, WT1 protein activity is restricted to the glomerulus, which filters blood through the kidneys. The WT1 protein is involved in cell growth, differentiation (the process by which cells mature to perform specific functions), and cell self-destruction (apoptosis). For carrying out these functions, the WT1 protein attaches (binds) to specific regions of DNA to regulate the activity of other genes. The WT1 protein is known as a transcription factor because of this action.
What Are the Signs And Symptoms of Fraiser Syndrome?
Frasier syndrome can affect both men and women, but the symptoms can differ.
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The affected females usually have normal genitalia and gonads and only exhibit symptoms of impaired renal function, which may not appear until early childhood or adolescence. Females are generally diagnosed with isolated nephrotic syndrome because they do not have all of the signs of the condition (e.g., gonadal dysgenesis).
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Frasier syndrome in some infants may thus go unnoticed until the affected child exhibits signs of renal impairment and further testing is performed to determine the cause. As a result, gonadal dysgenesis causes intersex in infants with the XY genotype.
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Males with Frasier syndrome have the typical male chromosome pattern (46, XY); however, they have gonadal dysgenesis, in which the external genitalia may not look male or female (ambiguous genitalia), or the genitalia may appear entirely female.
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In addition, the internal reproductive organs (gonads) are usually undeveloped and known as streak gonads. Because these abnormal gonads are nonfunctional and frequently become cancerous, they are usually surgically removed early in life. The condition's renal features include progressive glomerulonephropathy (focal segmental glomerulosclerosis). Patients are also more likely to develop genito-urinary tumors (usually gonadoblastoma).
How Is Fraiser Syndrome Inherited?
This disorder is inherited in an autosomal dominant pattern, which means that one copy of the altered gene in each cell is enough to cause the disease. The gene is autosomal if found on any chromosome other than the X or Y chromosomes (sex chromosomes). Genes, like chromosomes, are typically found in pairs. Dominant means that for a person to have the disease, only one copy of the responsible gene (causal gene) must have a disease-causing change (pathogenic variant). A mutation is an older term occasionally used to refer to a pathogenic variant.
Sometimes, the pathogenic variant is inherited from a parent with the genetic disease. In other cases, the disease arises from a new pathogenic variant (de novo) in the causal gene with no family history of the disease. Each child of a person with an autosomal dominant disease has a 50 percent (1 in 2) chance of inheriting the variant and the disease. Children who inherit a dominant variant will typically develop the disease, but they may be more or less severely affected than their parents. A person may carry a pathogenic variant for an autosomal dominant disease while displaying no signs or symptoms.
How Is Fraiser Syndrome Diagnosed?
Genetic screening of children with amenorrhea and steroid-resistant nephrotic syndrome can detect Fraiser syndrome early; however, the slow progression of renal failure makes detecting the condition difficult.
How Is Fraiser Syndrome Treated?
The treatment is multidisciplinary and primarily involves a nephrologist to manage chronic renal failure (first with nephroprotective medical therapy and then with renal replacement therapies or transplantation when ESRD occurs). An endocrinologist in treating associated disorders of testicular development, and oncologists and surgeons should evaluate the need for an early gonadectomy to prevent tumorigenesis. In addition, preemptive bilateral gonadectomy during renal transplantation or placement of a peritoneal dialysis catheter could be options.
What Are Other Diseases That Could Be Similar to Fraiser Syndrome?
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Denys-Drash Syndrome: Denys-Drash syndrome is also caused by WT1 gene mutations. Denys-Drash syndrome and Fraiser syndrome have previously been distinguished by differences in nephropathy, with Denys-Drash syndrome patients having diffuse mesangial sclerosis (DMS) as opposed to FS patients having focal and segmental glomerulosclerosis (FSGS). However, because these two conditions share a genetic cause and have overlapping characteristics, some researchers believe they are part of a spectrum rather than two distinct conditions.
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Genetic Steroid-Resistant Nephrotic Syndrome: The absence of remission after one month of initial daily prednisone therapy at a dose of 60 mg/m2 per day is defined as a steroid-resistant nephrotic syndrome (SRNS). A recessive form of steroid-resistant nephrotic syndrome can be caused by mutations in the NPHS2 gene, which encodes podocin.
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Wilms Tumour: Wilms tumour is caused by a germline mutation in the WT1 gene, leading to uncontrolled growth and division of cells in the kidney and allowing tumor development.
Conclusion:
Fraiser syndrome is a rare condition caused by mutations of the WT1 gene resulting in kidney and genital anomalies. It is an autosomal dominant genetic disorder. It may affect both males and females, but the symptoms differ. It is more pronounced and easily diagnosed in males than in females. Genetic counseling and proper treatment can help manage the disease. Genetic screening of children with amenorrhea and steroid-resistant nephrotic syndrome can detect Fraiser syndrome early. Multidisciplinary treatment modalities that are symptom-based can help manage the condition.
