Frasier Syndrome (FS)

External Ids:

Disease Ontology 12 DOID:0050438 OMIM 56 136680 MeSH 43 D052159 NCIt 49 C122805 MESH via Orphanet 44 D052159 ICD10 via Orphanet 33 N04.1

UMLS via Orphanet 72 C0950122 Orphanet 58 ORPHA347 MedGen 41 C0950122 SNOMED-CT via HPO 68 111332007 124975008 166449002 197679002 205681004 236403004 236423003 24184005 25081006 25821008 263681008 29738008 302849000 370999003 38341003 38804009 42399005 433146000 52254009 70550008 716594002 74751003 83579008 8913004 95219002 more UMLS 71 C0950122

NIH Rare Diseases : ⁵² The following summary is from Orphanet , a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 347 Definition A rare genetic, syndromic glomerular disorder characterized by the association of progressive glomerular nephropathy and 46,XY complete gonadal dysgenesis with a high risk of developing gonadoblastoma. Epidemiology To date, less than 150 cases have been described. Clinical description 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. Etiology Frasier syndrome has been associated to specific pathogenic variants affecting nucleotides 4-5 of the intron 9 (previously referred to as IVS9+4; IVS9+5) in the WT1 gene (11p13). WT1 encodes for a protein that serves as regulatory transcription factor important both for renal and gonadal development. Diagnostic methods 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. Genetic counseling Most affected individuals have a de novo pathogenic variant and hence negative family history ; however, autosomal dominant inheritance has been reported. Where karyotyping is indicated, pre-testing genetic counselling on the possibility of detecting sex reversal should be offered. Management and 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. Visit the Orphanet disease page for more resources.

MalaCards based summary : Frasier Syndrome, also known as fs, is related to pseudohermaphroditism and gonadoblastoma. An important gene associated with Frasier Syndrome is WT1 (WT1 Transcription Factor), and among its related pathways/superpathways are Primary Focal Segmental Glomerulosclerosis FSGS and Nephrin interactions. Affiliated tissues include Kidney, breast and testes, and related phenotypes are glomerulopathy and male pseudohermaphroditism

Disease Ontology : ¹² A syndrome that is characterized by gonadal dysgenesis, streak gonads, progressive focal segmental glomerulonephropathy and the development of urogenital cancers that is the result of mutation in the WT1 gene.

Genetics Home Reference : ²⁵ 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. Affected females usually have normal genitalia and gonads and have only the kidney features of the condition. Because they do not have all the features of the condition, females are usually given the diagnosis of isolated nephrotic syndrome.

OMIM : ⁵⁶ Frasier syndrome is a rare disorder defined by pseudohermaphroditism and progressive glomerulopathy (Frasier et al., 1964; Haning et al., 1985; Kinberg et al., 1987). Patients present with normal female external genitalia, streak gonads, and XY karyotype, and frequently develop gonadoblastoma (Blanchet et al., 1977). Glomerular symptoms consist of childhood proteinuria and nephrotic syndrome, characterized by nonspecific focal and segmental glomerular sclerosis, progressing to end-stage renal failure in adolescence or early adulthood. Wilms tumor is not a usual feature (Barbaux et al., 1997). (136680)

UniProtKB/Swiss-Prot : ⁷³ Frasier syndrome: Characterized by a slowly progressing nephropathy leading to renal failure in adolescence or early adulthood, male pseudohermaphroditism, and no Wilms tumor. As for histological findings of the kidneys, focal glomerular sclerosis is often observed. There is phenotypic overlap with Denys-Drash syndrome. Inheritance is autosomal dominant.

Wikipedia : ⁷⁴ Frasier syndrome is a urogenital anomaly associated with the WT1 (Wilms tumor 1 gene)... more...

Clinical features from OMIM:

136680

Search NIH Clinical Center for Frasier Syndrome

Search GEO for disease gene expression data for Frasier Syndrome.