Frasier syndrome: A rare syndrome with WT-1 gene mutation

Frasier syndrome is a rare disorder of sex development. It is caused by mutation in Wilms’ tumor suppressor gene (WT-1) located in 11p23. This gene encodes a transcription factor involved in the development of kidney and gonads. The syndrome is characterized by female external genitalia in 46, XY patients, streak gonads with a higher risk of gonadal tumors, mainly gonadoblastoma. Nephropathy consists of nephrotic syndrome (NS) mainly due to focal segmental glomerular sclerosis (FSGS). NS presents early in childhood and responds poorly to steroid and immunosuppressive agents. Progression to End Stage Renal Disease (ESRD) usually occurs by second or third decade of life. We present a 6 years old female child with insignificant past medical history diagnosed as steroid resistant nephrotic syndrome. Renal biopsy showed FSGS. CT Abdomen showed streak gonads with rudimentary uterus. Further genotype showed WT-1 mutation with Karyotype of 46XY. Elective bilateral gonadectomy was done and histopathology showed bilateral dysgerminoma. After a year, her disease progressed to ESRD and she succumbed to the illness.

Download Full-text

Frasier syndrome: four new cases with unusual presentations

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302012000800011 ◽

2012 ◽

Vol 56 (8) ◽

pp. 525-532 ◽

Cited By ~ 10

Author(s):

Mara Sanches Guaragna ◽

Anna Cristina Gervásio de Britto Lutaif ◽

Viviane Barros Bittencourt ◽

Cristiane Santos Cruz Piveta ◽

Fernanda Caroline Soardi ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Wilms Tumor ◽

Horseshoe Kidney ◽

External Genitalia ◽

Great Majority ◽

Delayed Puberty ◽

Glomerular Sclerosis ◽

Primary Amenorrhea ◽

Normal Female ◽

Frasier Syndrome

Frasier syndrome (FS) is characterized by gonadal dysgenesis and nephropathy. It is caused by specific mutations in the Wilms' tumor suppressor gene (WT1) located in 11p23. Patients with the 46,XY karyotype present normal female genitalia with streak gonads, and have higher risk of gonadal tumor, mainly, gonadoblastoma. Therefore, elective bilateral gonadectomy is indicated. Nephropathy in FS consists in 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). Patients are generally unresponsive to steroid and immunosuppressive therapies, and will develop end-stage renal failure (ESRF) during the second or third decade of life. We report here four cases of FS diagnosis after identification of WT1 mutations. Case 1 was part of a large cohort of patients diagnosed with steroid-resistant nephrotic syndrome, in whom the screening for mutations within WT1 8-9 hotspot fragment identified the IVS9+5G>A mutation. Beside FS, this patient showed unusual characteristics, such as urinary malformation (horseshoe kidney), and bilateral dysgerminoma. Cases 2 and 3, also bearing the IVS9+5G>A mutation, and case 4, with IVS9+1G>A mutation, were studied due to FSGS and/or delayed puberty; additionally, patients 2 and 4 developed bilateral gonadal tumors. Since the great majority of FS patients have normal female external genitalia, sex reversal is not suspected before they present delayed puberty and/or primary amenorrhea. Therefore, molecular screening of WT1 gene is very important to confirm the FS diagnosis. Arq Bras Endocrinol Metab. 2012;56(8):525-32

Download Full-text

Frasier Syndrome: A Rare Cause of Refractory Steroid-Resistant Nephrotic Syndrome

Children ◽

10.3390/children8080617 ◽

2021 ◽

Vol 8 (8) ◽

pp. 617

Author(s):

Yung-Chieh Huang ◽

Ming-Chin Tsai ◽

Chi-Ren Tsai ◽

Lin-Shien Fu

Keyword(s):

Nephrotic Syndrome ◽

Wilms Tumor ◽

Donor Site ◽

External Genitalia ◽

Protein Isoforms ◽

Splice Donor Site ◽

Frasier Syndrome ◽

Mixed Germ Cell Tumor ◽

Male Patients

Frasier syndrome is a rare disease that affects the kidneys and genitalia. Patients who have Frasier syndrome develop nephrotic syndrome (NS) featuring focal segmental glomerulosclerosis (FSGS) that is resistant to steroid treatment in early childhood. Male patients can have female external genitalia (pseudo-hermaphroditism) at birth and develop gonado-blastoma in their adolescence. Frasier syndrome is caused by mutations in the splice donor site at intron 9 of the Wilms’ tumor WT1 gene; these mutations result in an imbalanced ratio of WT1 protein isoforms and affect the development of the urogenital tract, podocyte function, and tumor suppression. Here, we report on a patient with long-term refractory NS who developed a malignant mixed germ cell tumor arising in a gonado-blastoma of the ovary 8 years after the onset of proteinuria.

Download Full-text

Analysis of the Wilms' Tumor Suppressor Gene (WT1) in Patients 46,XY Disorders of Sex Development

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-2804 ◽

2011 ◽

Vol 96 (7) ◽

pp. E1131-E1136 ◽

Cited By ~ 32

Author(s):

B. Köhler ◽

H. Biebermann ◽

V. Friedsam ◽

J. Gellermann ◽

R. F. Maier ◽

...

Keyword(s):

Kidney Disease ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Gonadal Dysgenesis ◽

Kidney Development ◽

Wilms Tumor ◽

Disorders Of Sex Development ◽

Suppressor Gene ◽

Sex Development ◽

Cryptorchid Testis

Abstract Context: The Wilms' tumor suppressor gene (WT1) is one of the major regulators of early gonadal and kidney development. WT1 mutations have been identified in 46,XY disorders of sex development (DSD) with associated kidney disease and in few isolated forms of 46,XY DSD. Objective: The objective of the study was the evaluation of WT1 mutations in different phenotypes of isolated 46,XY DSD and clinical consequences. Design: The design of the study was: 1) sequencing of the WT1 gene in 210 patients with 46,XY DSD from the German DSD network, consisting of 150 males with severe hypospadias (70 without cryptorchidism, 80 with at least one cryptorchid testis), 10 males with vanishing testes syndrome, and 50 raised females with partial to complete 46,XY gonadal dysgenesis; and 2) genotype-phenotype correlation of our and all published patients with 46,XY DSD and WT1 mutations. Results: We have detected WT1 mutations in six of 80 patients with severe hypospadias (7.5%) and at least one cryptorchid testis and in one of 10 patients with vanishing testes syndrome (10%). All patients except one developed Wilms' tumor and/or nephropathy in childhood or adolescence. Conclusion: WT1 analysis should be performed in newborns with complex hypospadias with at least one cryptorchid testis and in isolated 46,XY partial to complete gonadal dysgenesis. Kidney disease might not develop until later life in these cases. WT1 analysis is mandatory in all 46,XY DSD with associated kidney disease. WT1 analysis is not indicated in newborns with isolated hypospadias without cryptorchidism. Patients with WT1 mutations should be followed up closely because the risk of developing a Wilms' tumor, nephropathy, and/or gonadal tumor is very high.

Download Full-text

Long-Term Evaluation of Children with Nephrotic Syndrome and Focal Segmental Glomerular Sclerosis

Nephron ◽

10.1159/000183086 ◽

1983 ◽

Vol 35 (4) ◽

pp. 225-231 ◽

Cited By ~ 45

Author(s):

Amir Tejani ◽

Anthony D. Nicastri ◽

Dilip Sen ◽

C.K. Chen ◽

Kishore Phadke ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Glomerular Sclerosis ◽

Focal Segmental Glomerular Sclerosis ◽

Term Evaluation ◽

Segmental Glomerular Sclerosis

Download Full-text

Effective cholesterol lowering after myocardial infarction in patients with nephrotic syndrome may require a multi-pharmacological approach: a case report

European Heart Journal - Case Reports ◽

10.1093/ehjcr/ytab151 ◽

2021 ◽

Vol 5 (5) ◽

Author(s):

Simon Sjuls ◽

Ulf Jensen ◽

Karin Littmann ◽

Annette Bruchfeld ◽

Jonas Brinck

Keyword(s):

Myocardial Infarction ◽

Nephrotic Syndrome ◽

Sglt2 Inhibitor ◽

Lipid Lowering ◽

Glomerular Sclerosis ◽

Lipid Lowering Therapy ◽

Inhibitory Antibody ◽

Pcsk9 Inhibitors ◽

Focal Segmental Glomerular Sclerosis ◽

Lowering Therapy

Abstract Background Nephrotic syndrome causes severe hypercholesterolaemia due to increased production and altered clearance of lipoproteins from the liver. It is challenging for patients with nephrotic syndrome and coronary heart disease to meet LDL-cholesterol (LDL-C) goals for secondary prevention with conventional lipid-lowering therapy. Case summary We present a man with nephrotic syndrome caused by focal segmental glomerular sclerosis (FSGS) and hypercholesterolaemia. He presented at the emergency room (ER) with an ST-elevation myocardial infarction at the age of 26. On follow-up, the patient had persistent hypercholesterolaemia [LDL-C 3.9 mmol/L and lipoprotein(a) 308 nmol/L] despite a combination of lipid-lowering therapy with atorvastatin 80 mg/day and ezetimibe 10 mg/day. Addition of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitory antibody evolocumab 140 mg bi-monthly did not improve cholesterol levels. However, after addition of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin 10 mg/day on top of other anti-proteinuric treatments, the patient’s proteinuria was reduced and a dramatic drop in LDL-C level by 3.2–0.6 mmol/L (−81%) was observed when evolocumab was re-introduced. Discussion We show that target LDL-C levels were obtained in this patient with therapy-resistant FSGS and hypercholesterolaemia following multi-pharmacological treatment with SGLT2 and PCSK9 inhibitors on top of conventional lipid-lowering therapy. The SGLT2-inhibitor reduced proteinuria and, speculatively, also reduced urinary loss of PCSK9-antibody. Therefore, in patients with nephrotic syndrome and cardiovascular disease novel therapeutic options to manage proteinuria could be considered to improve the efficacy of the lipid-lowering therapy, especially when the protein-based PCSK9 inhibitors are used.

Download Full-text

Terapia della sindrome nefrosica idiopatica: ruolo delle tecniche aferetiche

Giornale di Clinica Nefrologica e Dialisi ◽

10.33393/gcnd.2013.1090 ◽

2013 ◽

Vol 25 (4_suppl) ◽

pp. S41-S45

Author(s):

Luigi Moriconi

Keyword(s):

Nephrotic Syndrome ◽

Idiopathic Nephrotic Syndrome ◽

Sono State ◽

Minimal Change ◽

Glomerular Sclerosis ◽

Minimal Change Nephropathy ◽

Focal Segmental Glomerular Sclerosis ◽

Segmental Glomerular Sclerosis ◽

State Identificate

La Sindrome Nefrosica Idiopatica (Idiopathic Nephrotic Syndrome, INS) ricorre essenzialmente in presenza di due glomerulopatie: la MCN (Minimal Change Nephropathy) e la FSGS (Focal Segmental Glomerular Sclerosis). La prima ha un decorso più benigno ed è più frequente nei bambini, mentre la seconda ha un decorso più severo, può portare a Insufficienza Renale Cronica Terminale e può re-cidivare nel trapianto. Soprattutto per la FSGS sono state identificate possibili eziologie virali o genetiche, oltre a forme secondarie in corso di altre malattie, per cui non è semplice classificare queste glomerulopatie. Le forme ricorrenti nel rene trapiantato costituiscono un gruppo più omogeneo. I fattori che sembrano essere comuni alla MCN e alla FSGS, anche se maggiormente espressi e studiati nella seconda, sono la lesione glomerulare caratterizzante a carico dei podociti, e il frequente riscontro di sostanze circolanti, definite fattori di permeabilità (PFs), capaci di indurre proteinuria. Corticosteroidi e Immunosoppressori sono la terapia standard della INS. Tuttavia, la presenza di casi farmaco-resistenti e l'identificazione di alcuni PFs circolanti hanno consentito di utilizzare nuove terapie dirette a bloccare la sintesi o l'azione di queste molecole e hanno fornito un ulteriore razionale alla loro rimozione mediante plasmaferesi convenzionale (PEX) o aferesi selettiva.

Download Full-text

Therapeutic Response and Long-Term Renal Outcomes in Childhood Idiopathic Steroid-Resistant Nephrotic Syndrome: A Single-Center Study

Nephron ◽

10.1159/000520362 ◽

2021 ◽

pp. 1-8

Author(s):

Jiwon Jung ◽

Joo Hoon Lee ◽

Young Seo Park

Keyword(s):

Renal Function ◽

Nephrotic Syndrome ◽

Therapeutic Response ◽

Glomerular Sclerosis ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Renal Outcomes ◽

Focal Segmental Glomerular Sclerosis

Purpose: We aimed to evaluate therapeutic response and long-term renal outcomes of childhood idiopathic steroid-resistant nephrotic syndrome (iSRNS). Methods: We retrospectively reviewed treatment regimens, especially calcineurin inhibitor (CNI), pathologic diagnoses, and long-term renal outcomes of iSRNS patients for 30 years. Results: Of 516 patients with idiopathic NS, 52 (10.1%) had iSRNS. Renal biopsies from 48 patients showed minimal change disease (MCD) in 23 (47.9%), focal segmental glomerulosclerosis in 24 (50.0%), and mesangioproliferative glomerulonephritis in 1 (2.1%). The median follow-up period was 66.5 (range, 4–275) months, and 90.4% of them were treated with a CNI. CNI induced remission in 70.2% within 50.4 ± 43.5 days. Of the patients with MCD and focal segmental glomerular sclerosis (FSGS), 86.4% (19/22) and 45.0% (9/20) (p = 0.005) responded to CNI, respectively. Mean time until remission after using CNI was longer with FSGS (90.4 ± 54.0 days) than with MCD (29.6 ± 26.3 days) (p = 0.010). CNI-responsive patients with FSGS or MCD showed preserved renal function, and CNI nonresponsive MCD patients also showed preserved renal function during follow-up. However, end-stage renal disease (ESRD) progressed in 8 out of 11 patients with FSGS nonresponsive to the CNI for an average of 44.9 ± 18.4 months after diagnosis. Conclusion: Different response rates and times for remission were achieved with the CNI according to the pathology of iSRNS. All MCD patients regardless of CNI response and all CNI-responsive patients with FSGS showed excellent renal outcomes, while almost all FSGS patients nonresponsive to CNI eventually progressed to ESRD.

Download Full-text