Frasier syndrome is a

urogenital The genitourinary system, or urogenital system, are the organs of the reproductive system and the urinary system. These are grouped together because of their proximity to each other, their common embryological origin and the use of common pathwa ...

anomaly associated with the ''

WT1 Wilms tumor protein (WT33) is a protein that in humans is encoded by the ''WT1'' gene on chromosome 11p. Function This gene encodes a transcription factor that contains four zinc finger motifs at the C-terminus and a proline / glutamine-ric ...

'' (Wilms tumor 1 gene) gene. It was first characterized in 1964.

Presentation

Both males and females can have Frasier syndrome but their presentations can be different. Affected females usually have normal genitalia and gonads and have only the features of impaired renal function, which may not present until early childhood or even adolescence. Because females do not have all the features of the condition (e.g. gonadal dysgenesis), females are usually given the diagnosis of isolated nephrotic syndrom
Medline ref
Frasier syndrome in some infants may therefore go unrecognized until the affected child presents with signs of renal impairment and further testing is undertaken to evaluate the cause. In infants with XY genotype it causes an intersex condition as a result of gonadal dysgenesis. Although males with Frasier syndrome have the typical male chromosome pattern (46,XY), they have gonadal dysgenesis, in which external genitalia may 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 gonad
Source
These abnormal gonads are nonfunctional and often become cancerous, so they are usually removed surgically early in life. Renal features of the condition include progressive glomerulonephropathy (focal segmental

glomerulosclerosis Glomerulosclerosis is the hardening of the glomeruli in the kidney. It is a general term to describe scarring of the kidneys' tiny blood vessels, the glomeruli, the functional units in the kidney that filter urea from the blood. Proteinuria (larg ...

). Patients are also at increased risk of genito-urinary tumors (usually

gonadoblastoma A gonadoblastoma is a complex neoplasm composed of a mixture of gonadal elements, such as large primordial germ cells, immature Sertoli cells or granulosa cells of the sex cord, and gonadal stromal cells. Gonadoblastomas are by definition benign, ...

). The glomerulonephropathy presents later than in Denys-Drash syndrome, and the tumour risk

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological pr ...

is different; whilst Denys-Drash syndrome is associated with

Wilms' tumour Wilms' tumor or Wilms tumor, also known as nephroblastoma, is a cancer of the kidneys that typically occurs in children, rarely in adults.; and occurs most commonly as a renal tumor in child patients. It is named after Max Wilms, the German surge ...

, Frasier syndrome is associated with

. Differentiating between the two syndromes can be challenging.

Genetics

The ''

'' gene exists on

chromosome 11 Chromosome 11 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome. Chromosome 11 spans about 135 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...

(at 11p13), and codes for a four

zinc finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struct ...

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

. 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— K T S—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 complement 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 A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...

: 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.

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.

Diagnosis

Genetic screening of children experiencing

amenorrhea Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses ...

and steroid resistant nephrotic syndrome can diagnose Fraiser syndrome early, although the slow progression of renal failure makes diagnosis difficult.

Treatment

Reconstructive surgery is an option for this condition

References

External links

{{Medical resources , DiseasesDB = 32455 , ICD10 = , ICD9 = , ICDO = , OMIM = 136680 , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeshID = D052159 Genitourinary system diseases Male genital disorders Syndromes