Frasier Syndrome Research Articles

Immunosuppressant-resistant nephrotic syndrome and primary amenorrhea: A case report of adult Frasier syndrome and literature review.

We present a case of a 19-year-old who developed nephrotic syndrome with preserved renal function. Renal biopsy confirmed focal segmental glomerular sclerosis (FSGS). No remission was achieved despite 2 years of treatment with glucocorticoids, mycophenolate mofetil, tacrolimus, and cyclophosphamide. After transfer to our center, we performed re-examination of renal pathology by electron microscope (EM), chromosomal karyotype, and gene analysis. EM revealed uneven thickness of the glomerular basement membrane without obvious stratification or fracture. Gene analysis revealed a splice mutation (1447+1G>A) in IVS9 and chromosomal karyotype was (46, XY), confirming the diagnosis of Frasier syndrome, which was consistent with primary amenorrhea overlooked by local nephrologists. Cyclosporin A was prescribed to reduce the proteinuria, but serum creatinine increased to 152 μmol/L.

A review of the genetic background in complicated WT1-related disorders.

The Wilms tumor 1 (WT1) gene was first identified in 1990 as a strong candidate for conferring a predisposition to Wilms tumor. The WT1 protein has four zinc finger structures (DNA binding domain) at the C-terminus, which bind to transcriptional regulatory sequences on DNA, and acts as a transcription factor. WT1 is expressed during kidney development and regulates differentiation, and is also expressed in glomerular epithelial cells after birth to maintain the structure of podocytes. WT1-related disorders are a group of conditions associated with an aberrant or absent copy of the WT1 gene. This group of conditions encompasses a wide phenotypic spectrum that includes Denys-Drash syndrome (DDS), Frasier syndrome (FS), Wilms-aniridia-genitourinary-mental retardation syndrome, and isolated manifestations of nephropathy or Wilms tumor. The genotype-phenotype correlation is becoming clearer: patients with missense variants in DNA binding sites including C2H2 sites manifest DDS and develop early-onset and rapidly developing end-stage kidney disease. A deeper understanding of the genotype-phenotype correlation has also been obtained in DDS, but no such correlation has been observed in FS. The incidence of Wilms tumor is higher in patients with DDS and exon-truncating variants than in those with non-truncating variants. Here, we briefly describe the genetic background of this highly complicated WT1-related disorders.

Evaluation of pathogenicity of WT1 intron variants by in vitro splicing analysis.

Wilms tumor 1 (WT1; NM_024426) causes Denys-Drash syndrome, Frasier syndrome, or isolated focal segmental glomerulosclerosis. Several WT1 intron variants are pathogenic; however, the pathogenicity of some variants remains undefined. Whether a candidate variant detected in a patient is pathogenic is very important for determining the therapeutic options for the patient. In this study, we evaluated the pathogenicity of WT1 gene intron variants with undetermined pathogenicity by comparing their splicing patterns with those of the wild-type using an in vitro splicing assay using minigenes. The three variants registered as likely disease-causing genes: Mut1 (c.1017-9T > C(IVS5)), Mut2 (c.1355-28C > T(IVS8)), Mut3 (c.1447 + 1G > C(IVS9)), were included as subjects along the 34 splicing variants registered in the Human Gene Mutation Database (HGMD)®. The results showed no significant differences in splicing patterns between Mut1 or Mut2 and the wild-type; however, significant differences were observed in Mut3. We concluded that Mut1 and Mut2 do not possess pathogenicity although they were registered as likely pathogenic, whereas Mut3 exhibits pathogenicity. Our results suggest that the pathogenicity of intronic variants detected in patients should be carefully evaluated.

WT1-related disorders: more than Denys-Drash syndrome.

Historically, specific mutations in WT1 gene have been associated with distinct syndromes based on phenotypic characteristics, including Denys-Drash syndrome (DDS), Frasier syndrome (FS), Meacham syndrome, and WAGR syndrome. DDS is classically defined by the triad of steroid-resistant nephrotic syndrome (SRNS) onset in the first year of life, disorders of sex development (DSD), and a predisposition to Wilms tumor (WT). Currently, a paradigm shift acknowledges a diverse spectrum of presentations beyond traditional syndromic definitions. Consequently, the concept of WT1-related disorders becomes more precise. A genotype-phenotype correlation has been established, emphasizing that the location and type of WT1 mutations significantly influence the clinical presentation, the condition severity, and the chronology of patient manifestations. Individuals presenting with persistent proteinuria, with or without nephrotic syndrome, and varying degrees of kidney dysfunction accompanied by genital malformations should prompt suspicion of WT1 mutations. Recent genetic advances enable a more accurate estimation of malignancy risk in these patients, facilitating a conservative nephron-sparing surgery (NSS) approach in select cases, with a focus on preserving residual kidney function and delaying nephrectomies. Other key management strategies include kidney transplantation and addressing DSD and gonadoblastoma. In summary, recent genetic insights underscore the imperative to implement individualized, integrated, and multidisciplinary management strategies for WT1-related disorders. This approach is pivotal in optimizing patient outcomes and addressing the complexities associated with these diverse clinical manifestations.

The -KTS splice variant of WT1 is essential for ovarian determination in mice.

Sex determination in mammals depends on the differentiation of the supporting lineage of the gonads into Sertoli or pregranulosa cells that govern testis and ovary development, respectively. Although the Y-linked testis-determining gene Sry has been identified, the ovarian-determining factor remains unknown. In this study, we identified -KTS, a major, alternatively spliced isoform of the Wilms tumor suppressor WT1, as a key determinant of female sex determination. Loss of -KTS variants blocked gonadal differentiation in mice, whereas increased expression, as found in Frasier syndrome, induced precocious differentiation of ovaries independently of their genetic sex. In XY embryos, this antagonized Sry expression, resulting in male-to-female sex reversal. Our results identify -KTS as an ovarian-determining factor and demonstrate that its time of activation is critical in gonadal sex differentiation.

Wilms' tumor gene 1: lessons from the interface between kidney development and cancer.

In 1990, mutations of the Wilms' tumor-1 gene (WT1), encoding a transcription factor in the embryonic kidney, were found in 10-15% of Wilms' tumors; germline WT1 mutations were associated with hereditary syndromes involving glomerular and reproductive tract dysplasia. For more than three decades, these discoveries prompted investigators to explore the embryonic role of WT1 and the mechanisms by which loss of WT1 leads to malignant transformation. Here, we discuss how alternative splicing of WT1 generates isoforms that act in a context-specific manner to activate or repress target gene transcription. WT1 also regulates posttranscriptional regulation, alters the epigenetic landscape, and activates miRNA expression. WT1 functions at multiple stages of kidney development, including the transition from resting stem cells to committed nephron progenitor, which it primes to respond to WNT9b signals from the ureteric bud. WT1 then drives nephrogenesis by activating WNT4 expression and directing the development of glomerular podocytes. We review the WT1 mutations that account for Denys-Drash syndrome, Frasier syndrome, and WAGR syndrome. Although the WT1 story began with Wilms' tumors, an understanding of the pathways that link aberrant kidney development to malignant transformation still has some important gaps. Loss of WT1 in nephrogenic rests may leave these premalignant clones with inadequate DNA repair enzymes and may disturb the epigenetic landscape. Yet none of these observations provide a complete picture of Wilms' tumor pathogenesis. It appears that the WT1 odyssey is unfinished and still holds a great deal of untilled ground to be explored.

High-Throughput Splicing Assays Identify Known and Novel WT1 Exon 9 Variants in Nephrotic Syndrome

Frasier syndrome (FS) is a rare Mendelian form of nephrotic syndrome (NS) caused by variants which disrupt the proper splicing of WT1. This key transcription factor gene is alternatively spliced at exon 9 to produce 2 isoforms ("KTS+" and "KTS-"), which are normally expressed in the kidney at a ∼2:1 (KTS+:KTS-) ratio. FS results from variants that reduce this ratio by disrupting the splice donor of the KTS+ isoform. FS is extremely rare, and it is unclear whether any variants beyond the 8 already known could cause FS. To prospectively identify other splicing-disruptive variants, we leveraged a massively parallel splicing assay. We tested every possible single nucleotide variant (n= 519) in and around WT1 exon 9 for effects upon exon inclusion and KTS+/- ratio. Splice disruptive variants (SDVs) made up 11% of the tested point variants overall and were tightly concentrated near the canonical acceptor and the KTS+/- alternate donors. Our map successfully identified all 8 known FS or focal segmental glomerulosclerosis (FSGS) variants and 16 additional novel variants which were comparably disruptive to these known pathogenic variants. We also identified 19 variants that, conversely, increased the KTS+/KTS- ratio, of which 2 are observed in unrelated individuals with 46,XX ovotesticular disorder of sex development (46,XX OTDSD). This splicing effect map can serve as functional evidence to guide the clinical interpretation of newly observed variants in and around WT1 exon9.

Genotype-phenotype correlation of WT1 mutation-related nephropathy in Chinese children.

This study aimed to analyze the clinical characteristics of nephropathy associated with WT1 gene mutations in Chinese children and explore the relationship between genotype and clinical phenotype. Cases diagnosed at the Guangzhou Women and Children's Medical Center, were combined with those retrieved from PubMed and China National Knowledge Infrastructure (CNKI) databases from January 2015 to June 2022 and integrated into a study cohort; grouped according to gene mutation sites, clinical phenotype, and renal pathological types. The clinical characteristics between groups were compared, and the relationship between genotype and age of onset, clinical phenotype, and pathological type were retrospectively analyzed. The center enrolled 15 confirmed children: seven cases of non-simple nephropathy, including Denys-Drash syndrome (DDS) and Frasier syndrome (FS); eight cases of isolated steroid-resistant nephrotic syndrome (ISRNS); and 13 cases (86.7%) that progressed to end-stage renal disease (ESRD). The initial hemoglobin and bicarbonate levels of patients with clinical non-simple nephropathy were significantly lower than those with simple nephropathy, whereas the serum creatinine levels were higher than those of patients with simple nephropathy. A total of 75 cases of nephropathy associated with WT1 mutations in the study cohort met the inclusion and exclusion criteria. The most common clinical manifestations of WT1 mutations in this cohort were DDS (29/75, 38.7%) and ISRNS (37/75, 49.3%). A renal biopsy was performed in 43 patients, and the common types of renal pathology were focal segmental glomerulosclerosis (23/43, 53.5%) and DMS (13/43, 30.2%). Within the cohort, there were 12 cases (16.0%) in the exon 8 mutation group, 32 (42.6%) in the exon 9 group, 19 (25.3%) in the intron 9 group, and 12 (16.0%) in other gene site mutation groups. Common sites of WT1 mutations in Chinese children were exons 9 and intron 9. Exon 8 mutations were uniquely correlated with the age of onset within three months [5/7; 71.4%; Adjusted standardized residual (AR) = 4.2]. The renal survival time in the exon 8 mutation group was the shortest (P = 0.003). The molecular and biological characteristics of WT1 mutation-related nephropathy determine the clinical type, pathological features, and renal survival time of the disease; and there was a strong correlation between the genotype and clinical phenotype.

Frasier Syndrome: A 15-Year-Old Phenotypically Female Adolescent Presenting with Delayed Puberty and Nephropathy

Frasier syndrome (FS) is a rare inherited disorder characterized by gonadal dysgenesis and progressive nephropathy, resulting from mutations in the intron 9 splice donor site of the Wilms tumor 1 (WT1) gene. It is associated with male gonadal dysgenesis (female external genitalia with a 46 XY karyotype), and a high risk of gonadoblastoma during adolescence. Patients with FS present early in childhood with proteinuria that progressively worsens with a high likelihood of end-stage renal disease (ESRD). Herein, we report a 15-year-old female (karyotype 46, XY) patient characterized by delayed puberty and steroid-resistant nephrotic syndrome, in whom whole genome sequencing showed a mutation in intron 9 of the WT1 gene, c.1447 + 4 C>T. This is the first case of FS with delayed puberty as the first complaint with no previous renal symptoms. We consider delayed puberty as an important manifestation of FS and summarize the diagnostic process of delayed puberty in the female phenotype. For clinicians, delayed puberty is a common disorder in pediatrics but requires vigilance for some rare causes. Etiological screening and chromosome karyotype analysis are important for the early diagnosis of FS in patients with delayed puberty.

Congenital diaphragmatic eventration with pulmonary dysplasia in Frasier syndrome due to a WT1 mutation of c.1432+5(IVS9)G>A

WT1 disorder is caused by a heterozygous variant in the gene WT1 (Wilms' tumor suppressor gene 1), and is clinically diagnosed as Denys-Drash, Meacham, or Frasier syndrome, on a phenotypic continuum that presents as abnormalities of the urogenital system and gonads. Rarely, manifestations appear in the lung, especially in Frasier syndrome. Here we describe the first noted case of congenital diaphragmatic eventration with pulmonary dysplasia in a child with Frasier syndrome. A c.1432+5G > A mutation in intron 9 of WT1 was found. We also summarize pulmonary diseases associated with WT1 mutations in WT1 disorder.

A case of Potter sequence with WT1 mutation.

Wilms tumor 1 (WT1) is the causative gene of Denys-Drash syndrome and Frasier syndrome, and in most cases, kidney failure develops after birth. We report an unusual case of Potter sequence due to fetal nephropathy and kidney failure with a WT1 mutation. The neonate was born at 37weeks of gestation, and had no distinctive facial appearance or anomalies of the extremities. The external genitalia were ambiguous. Presence of a penile-like structure or hypertrophic clitoris was noted, and the urethra opened at the base of the penis or clitoris. On ultrasonographic examination, the kidney sizes were small. No kidney cysts were noted, but the kidney parenchymal luminosity was increased. Although the neonate received mechanical ventilation because of severe retractive breathing after birth, he died of poor oxygenation due to air leak syndrome at 60h after birth. The congenital anomalies of the kidney and urinary tract (CAKUT) gene panel revealed a heterozygous missense mutation in WT1 [NM_024426.6:exon9:c.1400G > A, p.(Arg467Gln)]. In WT1, missense mutations are associated with earlier onset of nephropathy than nonsense or splicing mutations. However, severe cases of fetal onset and early neonatal death with WT1 mutations are rare, and only one severe case with the same missense mutation in WT1 has been reported. Therefore, WT1 mutation may be suspected in Potter sequence patients with external genital abnormalities, and the WT1 missense mutation in our case [NM_024426.6:exon9:c.1400G > A, p.(Arg467Gln)] may indicate a severe case with fetal onset of nephropathy and kidney failure.

WT1 complete gonadal dysgenesis with membranoproliferative glomerulonephritis: case series and literature review

BackgroundIntronic WT1 mutations are usually causative of Frasier syndrome with focal segmental glomerulosclerosis as the characteristic nephropathy. Membranoproliferative glomerulonephritis is not commonly associated with disorders of sex development but has been recently identified as a WT1-associated nephropathy, but usually in cases of exonic mutations in either isolated Wilms tumor or Denys-Drash syndrome.MethodsThe clinical and genetic data from 3 individuals are reported.ResultsThis report describes the kidney manifestations in 3 individuals from 2 unrelated families with Frasier syndrome intronic WT1 mutations, noting that 2 of the 3 individuals have histologically confirmed membranoproliferative glomerulonephritis.ConclusionsThese case reports support expansion of the clinical spectrum of the kidney phenotypes associated with Frasier syndrome providing evidence of an association between WT1 mutation and an immune complex-related membranoproliferative glomerulonephritis.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Underrecognized Frasier syndrome revisited: Paradoxical immunocomplex deposition

Underrecognized Frasier syndrome revisited: Paradoxical immunocomplex deposition

Exonic WT1 pathogenic variants in 46,XY DSD associated with gonadoblastoma.

Objective The literature regarding gonadoblastoma risk in exonic Wilms’ tumor suppressor gene (WT1) pathogenic variants is sparse. The aim of this study is to describe the phenotypic and genotypic characteristics of Asian–Indian patients with WT1 pathogenic variants and systematically review the literature on association of exonic WT1 pathogenic variants and gonadoblastoma.Design Combined retrospective–prospective analysis.Methods In this study, 46,XY DSD patients with WT1 pathogenic variants detected by clinical exome sequencing from a cohort of 150 index patients and their affected relatives were included. The PubMed database was searched for the literature on gonadoblastoma with exonic WT1 pathogenic variants.Results The prevalence of WT1 pathogenic variants among 46,XY DSD index patients was 2.7% (4/150). All the four patients had atypical genitalia and cryptorchidism. None of them had Wilms’ tumor till the last follow-up, whereas one patient had late-onset nephropathy. 11p13 deletion was present in one patient with aniridia. The family with p.Arg458Gln pathogenic variant had varied phenotypic spectrum of Frasier syndrome; two siblings had gonadoblastoma, one of them had growing teratoma syndrome (first to report with WT1). On literature review, of >100 exonic point pathogenic variants, only eight variants (p.Arg462Trp, p.Tyr177*, p.Arg434His, p.Met410Arg, p.Gln142*, p.Glu437Lys, p.Arg458*, and p.Arg458Gln) in WT1 were associated with gonadoblastoma in a total of 15 cases (including our two cases).ConclusionsWT1 alterations account for 3% of 46,XY DSD patients in our cohort. 46,XY DSD patients harboring exonic WT1 pathogenic variants carry a small but definitive risk of gonadoblastoma; hence, these patients require a gonadoblastoma surveillance with a more stringent surveillance in those harboring a gonadoblastoma-associated variant.

WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease

Wilms’ tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of WT1 have been classically associated with Denys–Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between WT1 disorders has been frequently observed. New WT1 variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic WT1 variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of WT1 between exons 9 and 10. Two pathogenic missense WT1 variants were identified in two 46,XY individuals with Wilms’ tumors; both patients were <1 year of age at the time of diagnosis. A novel WT1 variant, c.1453_1456 (p.Arg485Glyfs*14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with WT1 variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.

Disorders of Sex Development.

Disorders of Sex Development.

Pulmonary Hypertension from Cardiorenal Sequelae in an 18-Year-Old 46, XY Phenotypically Female Patient with Denys-Drash Syndrome: Case Report and Review of Literature

Denys-Drash Syndrome (DDS) is a rare cause of end-stage renal disease (ESRD) stemming from genetic mutations in the Wilms’ tumor 1 (WT1) gene. Albeit uncommon, it and other congenital nephropathies (e.g., Frasier syndrome) may warrant a clinical workup of cardiovascular disease in symptomatic patients with cardiopulmonary deficits, as the latter is associated with renal dysfunction given the multifarious physiologic roles and nodes of action concerning the kidneys. These include not only serving as a site of neural and hormonal stimuli that affect systemic equilibrium, but the regulation of blood pressure and osmolality as well. The cardiorenal demise classically seen in later stages of chronic kidney disease (CKD) in relatively older adults may arise earlier in these patients. We report the case of an 18-year-old 46, XY phenotypic female with DDS who complained of increasingly nettlesome dyspnea. Initially, she presented with a low index of suspicion for diminished cardiopulmonary fitness. However, further clinical workup which included catheterization and cardiac imaging was significant for findings of pulmonary hypertension.

Frasier Syndrome: A Rare Disorder in a Patient With Nephrotic Syndrome

Frasier syndrome is a rare genetic disorder characterized by the association of progressive renal glomerulopathy, 46,XY complete gonadal dysgenesis with a high risk of developing gonadoblastoma. Mutations in the Wilms' tumor suppressor gene (WT1) located in 11p23 responsible for this syndrome. Patients with this syndrome commonly present with normal female genitalia, streak gonads, and 46, XY karyotyping. Nephropathy in Frasier syndrome conferred as a nephrotic syndrome (NS) with proteinuria that begins early in childhood and progressively increases with age, mainly due to nonspecific focal and segmental glomerular sclerosis (FSGS). We herein discuss a 4 year-old-girl who presented as a steroid-resistant nephrotic syndrome and later on diagnosed as a Frasier syndrome.

Syndromic Wilms tumor: a review of predisposing conditions, surveillance and treatment.

Predisposing syndromes associated with an increased risk of Wilms tumor (WT) are responsible for 9–17% of all cases of the malignancy. Due to an earlier age at WT diagnosis and an increased incidence of bilateral and metachronous disease, management of syndromic WT warrants a distinct approach from that of non-syndromic WT. This review of English-language manuscripts about WT focuses on the most common syndromes, surveillance protocols and current treatment strategies. Highlighted syndromes include those associated with WT1, such as WAGR (Wilms-Aniridia-Genitourinary-mental Retardation), Denys-Drash syndrome (DDS), and Frasier syndrome, 11p15 defects, such as Beckwith-Wiedemann syndrome (BWS), among others. General surveillance guidelines include screening renal or abdominal ultrasound every 3–4 months until the age of 5 or 7, depending on the syndrome. Further, some of the predisposing conditions also increase the risk of other malignancies, such as gonadoblastoma and hepatoblastoma. With promising results for nephron-sparing surgery in bilateral non-syndromic WT, there are increasing reports and recommendations to pursue nephron-sparing for these patients who are at greater risk of bilateral, metachronous lesions. In addition to the loss of renal parenchyma from malignancy, many patients are at risk of developing renal insufficiency as part of their syndrome. Although there may be some increase in the complication rate, recurrence free survival seems equivalent. Some conditions require specialized approaches to adjuvant therapy, as their syndrome may make them especially susceptible to side effects.

Immune-complex glomerulonephritis with a membranoproliferative pattern in Frasier syndrome: a case report and review of the literature

BackgroundMutations in the Wilms tumor 1 gene cause a spectrum of podocytopathy ranging from diffuse mesangial sclerosis to focal segmental glomerulosclerosis. In a considerable fraction of patients with Wilms tumor 1 mutations, the distinctive histology of immune-complex-type glomerulonephritis has been reported. However, the clinical relevance and etiologic mechanisms remain unknown.Case presentationA 5-year-old child presented with steroid-resistant nephrotic range proteinuria. Initial renal biopsy revealed predominant diffuse mesangial proliferation with a double-contour and coexisting milder changes of focal segmental glomerulosclerosis. Immunofluorescence and electron microscopy revealed a full-house-pattern deposition of immune complexes in the subendothelial and paramesangial areas. Serial biopsies at 6 and 8 years of age revealed that more remarkable changes of focal segmental glomerulosclerosis had developed on top of the initial proliferative glomerulonephritis. Identification of a de novo Wilms tumor 1 splice donor-site mutation in intron 9 (NM_024426.6:c.1447 + 4C > T) and 46,XY-gonadal dysgenesis led to the diagnosis of Frasier syndrome.ConclusionsOur findings, together with those of others, point to the importance of heterogeneity in clinicopathological phenotypes caused by Wilms tumor 1 mutations and suggest that immune-complex-mediated membranoproliferative glomerulopathy should be considered as a histological variant.