Frasier syndrome: A case report / El síndrome de Frasier, caso clínico

Introduction: Frasier syndrome is a genetic disorder produced by a mutation in intron 9 of the WT1 gene, responsible for renal and genital dysfunctions. Clinical findings: It is characterized by discrepancy between the individual karyotype and the individual phenotype and corticosteroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis. Patients usually have a female phenotype with a 46 XY karyotype, which increases the risk of gonadoblastoma in 50% of cases. Kidney disease requires kidney transplantation in adulthood. Cardiovascular and bone-derived comorbidities such as hyperlipidaemia and osteopenia/osteoporosis, respectively, are also common. Main diagnoses: Mutations of the WT1 gene can lead to different clinical entities, most notably Denysh-Drash syndrome, Frasier syndrome, or isolated focal segmental glomerulosclerosis. We present a clinical case of a woman who debuted in childhood with difficult-to-control nephrotic syndrome, the lack of pubertal development, primary amenorrhoea and the absence of ovaries on imaging tests in adolescence, alerted to an underlying genetic problem that, after cytogenetic studies, allowed a diagnosis of Frasier syndrome. Therapeutic interventions: It is recommended to remove the gonads due to increased risk of developing gonadoblastoma. Treatment of associated dyslipidaemia and osteopenia is also necessary. Conclusion: Frasier syndrome is an unusual cause of infertility due to gonadal dysgenesis and is associated with kidney problems.(AU)

Introducción: El síndrome de Frasier es un trastorno genético producido por una mutación en el intrón 9 del gen WT1, responsable de disfunciones a nivel renal y genital. Principales síntomas: Se caracteriza por disgenesia gonadal con discrepancia entre cariotipo-fenotipo y síndrome nefrótico resistente a corticoides debido a glomeruloesclerosis focal y segmentaria. Las pacientes presentan habitualmente fenotipo femenino con cariotipo 46 XY, lo que aumenta el riesgo de gonadoblastoma en un 50% de los casos. La enfermedad renal obliga a trasplante renal en la edad adulta. Son habituales también las comorbilidades derivadas a nivel cardiovascular y óseo como hiperlipidemia y osteopenia/osteoporosis, respectivamente. Diagnósticos principales: Las mutaciones del gen WT1 pueden conducir en distintas entidades clínicas entre las que destaca el síndrome de Denys-Drash, el síndrome de Frasier o la glomeruloesclerosis focal y segmentaria aislada. Se presenta un caso clínico de una mujer que debutó en la infancia con síndrome nefrótico de difícil control y que, durante la adolescencia, ante la falta de desarrollo puberal, la amenorrea primaria y la ausencia de ovarios en las pruebas de imagen alertaron de un problema genético subyacente que, tras estudios citogenéticos, permitió el diagnóstico de síndrome de Frasier. Intervenciones terapéuticas: Se recomienda la exéresis de las gónadas debido al riesgo incrementado de gonadoblastoma. El tratamiento de la dislipemia y la osteopenia asociadas también es necesario. Conclusión: El síndrome de Frasier es una causa inusual de infertilidad debido a una disgenesia gonadal y se asocia con problemas a nivel renal.(AU)

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.

Bilateral Gonadoblastoma in a 6-Year-old Girl With Frasier Syndrome: Need for Early Preventive Gonadectomy.

Frasier syndrome (FS) is a rare condition, caused by splice-site mutations of intron 9 in the Wilms' tumor suppressor gene 1 (WT1 gene). The WT1 protein is essential for urogenital development and patients with 46XY karyotype present with female (FS type 1) or male phenotype, gonadal dysgenesis, progressive glomerulopathy, and high risk of gonadoblastoma. We describe a female patient with an IVS9+4C>T donor splice-site mutation, who underwent a preventive gonadectomy at the age of 6 years due to imaging findings of dysplastic gonads. The biopsy revealed bilateral gonadoblastoma, emphasizing the need for early gonadectomy in 46XY FS patients.

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

BACKGROUND: Intronic 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. METHODS: The clinical and genetic data from 3 individuals are reported. RESULTS: This 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. CONCLUSIONS: These 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. A higher resolution version of the Graphical abstract is available as Supplementary information.

A Unique Presentation of XY Gonadal Dysgenesis in Frasier Syndrome due to WT1 Mutation and a Literature Review.

Frasier syndrome (FS), a rare disease caused by inherited or de novo mutation in Wilm's Tumor suppressor gene 1 (WT1), is characterized by slow progressive nephropathy, XY gonadal dysgenesis (XY-DSD), and increased risk for gonadal tumors. Early childhood (1-6 years) nephropathy progresses with age to refractory nephrotic syndrome, and end-stage renal failure in late adolescence, when delayed puberty and/or primary amenorrhea are clinically evident. We report a unique case of FS presenting initially with primary amenorrhea at 16 years, without previous or concomitant renal damage. Only subsequently she developed an extremely late-onset nephropathy. Genetic analysis revealed the IVS9 + 5 G>A mutation in intron 9 of the WT1 gene. This clinical presentation and review of WT1 literature highlights the importance of considering FS in the differential diagnosis of patients with 46,XY disorders of Sexual development, even without nephropathy. Furthermore, the identification WT1 gene mutation prior to evident renal dysfunction indicates an immediate and close surveillance of renal function enabling an optimal and timely medical response.

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

BACKGROUND: Mutations 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 PRESENTATION: A 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. CONCLUSIONS: Our 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.

Síndrome de Frasier en una adolescente: asociación con disgenesia gonadal y enfermedad renal crónica / Frasier Syndrome in an adolescent: association to gonadal dysgenesis and renal chronic disease

Se describe el caso clínico de una adolescente de 16 años de edad, con aparente buen estado de salud, quien había sido atendida desde hacía 3 años aproximadamente en la consulta de Pediatría por presentar falta de desarrollo puberal, amenorrea primaria, así como aumento de volumen en miembros inferiores. Se le realizaron los exámenes complementarios pertinentes y dado el conjunto de elementos clínicos que presentaba, incluida una proteinuria significativa asociada a dismorfismos corporales e hipogenitalismo, se consultó el caso con un equipo multidisciplinario, integrado por nefrólogos, endocrinólogos, genetistas y psicólogos. Se le diagnosticó el síndrome de Frasier, como una asociación síndrome nefrótico-disgenesia gonadal.

The case report of a 16 years adolescent with apparent good health state who had been attended approximately for 3 years in the Pediatrics service to present lack of puberal changes, primary amenorrhoea, as well as increase of volume in lower members is described. The pertinent and complementary examinations were carried out and taking into account the group of clinical elements she presented, including a significant proteinuria associated with corporal dysmorfisms and hypogenitalism, the case was exposed to a multidisciplinary team, formed by nephrologists, Endocrinology specialists, geneticists and psychologists. Frasier syndrome was diagnosed, associated to nephrotic syndrome and gonadal dysgenesis.

Síndrome de Frasier, primer caso reportado en Perú: first reported case in Peru / Frasier´s syndrome: first reported case in Peru

El síndrome de Frasier es una enfermedad rara producida por la mutación del gen WT1, caracterizado por pseudohermafroditismo masculino, disgenesia gonadal 46XY y enfermedad glomerular. Reportamos el caso de una mujer de 18 años, diagnosticada a los 12 años de síndrome nefrótico con desarrollo precoz de enfermedad renal crónica terminal y requerimiento de diálisis. A los 17 años se le detectó una tumoración abdominal. La laparotomía exploratoria reveló tumoración anexada a la trompa derecha que se extendía hasta la pared posterior del útero. Se le realizó histerectomía abdominal total con salpingo-ooforectomía bilateral. El diagnóstico anátomo-patológico fue disgerminoma. La paciente tenía amenorrea primaria y ausencia de caracteres sexuales secundarios. El estudio de corpúsculo de Barr de células de mucosa bucal fue negativo para cromatina sexual y el cariotipo fue 46, XY (Disgenesia Gonadal). El estudio genético reportó mutación heterocigótica en el intrón 9 del gen WT1. El cuadro es compatible con síndrome de Frasier, primer caso reportado en Perú. (AU)

Frasier´s syndrome is a rare disease caused by a mutation in the WT1 gene and is characterized by male pseudo hermaphroditism, gonadal dysgenesis 46XY and glomerular disease. We report the case of an 18-year-old female patient diagnosed at the age of 12 years of age of nephrotic syndrome who rapidly progressed to chronic failure needing dialysis. At the age of 17-years of age she presented an abdominal tumor, a laparotomy revealed a tumor attached to the right fallopian tube. An hysterectomy with bilateral fallopian tube extirpation, pathological findings revealed a dysgerminoma. The patient had a history of primary amenorrhea and absence of secondary sexual features. The study of Barr´s corpuscle of the oral mucosa was negative for sexual chromatin and the karyotype was 46 XY (gonadal dysgenesis). The genetic study revealed heterozygous mutation in the 9 gene WT1. The clinical presentation is compatible with Frasier´s syndrome, fist time reported in Peru. (AU)

Once-Daily Low-Dose Cyclosporine A Treatment with Angiotensin Blockade for Long-Term Remission of Nephropathy in Frasier Syndrome.

Cyclosporine A is known to be effective in some genetic podocyte injury. However, the efficacy of cyclosporine A depends on the degree of histopathological findings, and the relationship between long-term use and renal prognosis remains unknown. Frasier syndrome is a rare genetic disorder caused by intronic mutations in WT1, and is characterized by progressive glomerulopathy, a 46,XY disorder of sex development, and an increased risk of gonadoblastoma. We report here a 16-year-old phenotypically female patient with Frasier syndrome. A renal biopsy at the age of seven years showed segmentally effaced podocyte foot processes with no evidence of glomerulosclerosis. Steroid-resistant proteinuria progressed to the nephrotic range at the age of 10 years, which responded to once-daily administration of cyclosporine A with low two-hour post-dose cyclosporine A (C2) levels; she then achieved stable partial remission in combination with renin-angiotensin system (RAS) blockade. At the age of 12 years, examinations for delayed puberty confirmed the diagnosis of Frasier syndrome. The second renal biopsy showed widespread foot process effacement and a minor lesion of segmental glomerulosclerosis without findings suggestive of cyclosporine A nephropathy. She maintained partial remission and normal renal function with the continuation of once-daily low-dose cyclosporine A. The C2 levels required for the remission were between 212 and 520 ng/ml. Cyclosporine A dosages sufficient for maintaining the C2 levels were 1.1-1.2 mg/kg per day. In conclusion, the long-lasting treatment of once-daily low-dose cyclosporine A with RAS inhibition was effective for induction and maintenance of partial remission in Frasier syndrome.

Laparoscopically Removed Streak Gonad Revealed Gonadoblastoma in Frasier Syndrome.

BACKGROUND: Frasier syndrome (FS) is characterized by gonadal dysgenesis and progressive nephropathy caused by mutation in the Wilm's tumor gene (WT1). We report a case of FS in which diagnosis was based on amenorrhea with nephropathy, and laparoscopically-removed streak gonad which revealed gonadoblastoma. CASE REPORT: At the age of 3 years, the patient developed nephrotic syndrome. This later became steroid-resistant and, by the age of 16 years, had progressed to end-stage renal failure with peritoneal dialysis. At the age of 17 years, the patient presented primary amenorrhea and was referred to our department. Physical examination was consistent with Tanner 1 development and external genitalia were female phenotype. Speculum examination showed uterine cervix and uterine body and bilateral ovaries were not palpable on pelvic examination. Multi-sliced computed tomography of abdomen and pelvis revealed streaked structure along the bilateral external iliac artery at pelvic wall and hypoplastic uterus. Serum testing revealed primary hypogonadism pattern, elevated follicle-stimulating hormone and luteinizing hormone with low concentrations of estradiol and testosterone. The patient underwent genetic counseling with her parents. Chromosomal status was 46XY karyotype and DNA sequencing confirmed FS due to a heterozygous WT1 mutation (IVS9+5G>A). Elective laparoscopic bilateral salpingo-oophorectomy was performed to avoid increased risk for gonadoblastoma. Pathological examination revealed gonadoblastoma in the right gonad. CONCLUSION: Although a rare disease, the diagnosis of FS should be considered in the case of primary amenorrhea with nephropathy. Prophylatic gonadectomy is recommended due to the high risk of gonadoblastoma in the dysgenetic gonad.

Repression of CMIP transcription by WT1 is relevant to podocyte health.

The WT1 (Wilm's tumor suppressor) gene is expressed throughout life in podocytes and is essential for the functional integrity of the glomerular filtration barrier. We have previously shown that CMIP (C-Maf inducing protein) is overproduced in podocyte diseases and alters intracellular signaling. Here we isolated the proximal region of the human CMIP promoter and showed by chromatin immunoprecipitation assays and electrophoretic-mobility shift that Wilm's tumor protein (WT1) bound to 2 WT1 response elements, located at positions -290/-274 and -57/-41 relative to transcription start site. Unlike the human CMIP gene, only one Wt1 response element was identified in the mouse Cmip proximal promoter located at position -217/-206. Luciferase reporter assays indicated that WT1 dose-dependently inhibited the transcriptional induction of the CMIP promoter. Transfection of decoy oligonucleotides mimicking the WT1 response elements prevented the inhibition of WT1 on CMIP promoter activity. Furthermore, WT1 silencing promoted Cmip expression. In line with these findings, the abundance of Cmip was early and significantly increased at the transcript and protein level in podocytes displaying a primary defect in Wt1, including Denys-Drash syndrome and Frasier syndrome. Thus, WT1 is a major repressor of the CMIP gene in physiological situations, while conditional deletion of CMIP in the developing kidney did not affect the development of mature glomeruli.

Clinical Aspects of WT1 and the Kidney.

For more than 30 years, WT1 mutations have been associated with complex developmental syndromes involving the kidney. Acting as a transcription factor, WT1 is expressed throughout the nephron and controls the reciprocal interactions and phenotypic changes required for normal renal development. In the adult, WT1 expression remains extremely high in the renal podocyte, and at a lower level in the parietal epithelial cells. Wt1-null mice are unable to form kidneys [1]. Unsurprisingly, WT1 mutations lead to significant abnormalities of the renal and genitourinary tract, causing a number of human diseases including syndromes such as Denys-Drash syndrome, Frasier syndrome, and WAGR syndrome. Recent methodological advances have improved the identification of WT1 mutations, highlighting its importance even in nonsyndromic renal disease, particularly in steroid-resistant nephrotic syndrome. This vast spectrum of WT1-related disease typifies the varied and complex activity of WT1 in development, disease, and tissue maintenance.

Total Laparoscopic Colocolpopoiesis in a Kidney Transplant Recipient With Frasier Syndrome.

BACKGROUND: The absence of a normal functioning vagina can have a profound impact on women's quality of life and psychological well being. Frasier syndrome is a rare autosomal recessive disorder which presents with male pseudohermaphroditism with gonadal dysgenesis, renal failure in early adulthood and increased risk of developing gonadoblastoma. Kidney transplant recipients are reported to have a high complication rate after colorectal surgery, most probably resulting from immunosuppressive therapy. CASE: A 25-year-old female kidney transplant recipient with Frasier syndrome consulted our department to discuss the possibilities of surgically constructing a functional vagina. She successfully underwent a total laparoscopic colocolpopoiesis without any complications. A sigmoid segment of 16 cm long was isolated laparoscopically and transferred caudally in a dissected pouch between bladder and rectum on its vascular pedicle. There was no short-term morbidity and no complications up to 3 years postoperatively. She experienced no neovaginal symptoms and was able to engage in neovaginal penetration by means of vibrator or neovaginal dilatator. CONCLUSIONS: The positive results in this patient lead us to recommend laparoscopic colocolpopoiesis in kidney transplant patients who are seeking vaginoplasty. We advocate considering a total laparoscopic approach whenever rectosigmoid colocolpopoiesis is indicated, even after a kidney transplantation.

Aetiological bases of 46,XY disorders of sex development in the Hong Kong Chinese population.

OBJECTIVE: Disorders of sex development are due to congenital defects in chromosomal, gonadal, or anatomical sex development. The objective of this study was to determine the aetiology of this group of disorders in the Hong Kong Chinese population. SETTING: Five public hospitals in Hong Kong. PATIENTS: Patients with 46,XY disorders of sex development under the care of paediatric endocrinologists between July 2009 and June 2011. MAIN OUTCOME MEASURES: Measurement of serum gonadotropins, adrenal and testicular hormones, and urinary steroid profiling. Mutational analysis of genes involved in sexual differentiation by direct DNA sequencing and multiplex ligation-dependent probe amplification. RESULTS: Overall, 64 patients were recruited for the study. Their age at presentation ranged from birth to 17 years. The majority presented with ambiguous external genitalia including micropenis and severe hypospadias. A few presented with delayed puberty and primary amenorrhea. Baseline and post-human chorionic gonadotropin-stimulated testosterone and dihydrotestosterone levels were not discriminatory in patients with or without AR gene mutations. Of the patients, 22 had a confirmed genetic disease, with 11 having 5α-reductase 2 deficiency, seven with androgen insensitivity syndrome, one each with cholesterol side-chain cleavage enzyme deficiency, Frasier syndrome, NR5A1-related sex reversal, and persistent Müllerian duct syndrome. CONCLUSIONS: Our findings suggest that 5α-reductase 2 deficiency and androgen insensitivity syndrome are possibly the two most common causes of 46,XY disorders of sex development in the Hong Kong Chinese population. Since hormonal findings can be unreliable, mutational analysis of the SRD5A2 and AR genes should be considered the first-line tests for these patients.

Gonadal tumor in Frasier syndrome: a review and classification.

Frasier syndrome is a rare inherited disease characterized by steroid-resistant nephrotic syndrome, gonadal tumor, and male pseudohermaphroditism (female external genitalia with sex chromosomes XY), which is based on a splice site mutation of Wilms tumor-suppressor gene 1 (WT1). Several unusual Frasier syndrome cases have been reported in which male pseudohermaphroditism was absent. We reviewed 88 Frasier syndrome cases in the literature and classified them into three types (type 1-3) according to external genitalia and sex chromosomes, and described their clinical phenotypes. Type 1 Frasier syndrome is characterized by female external genitalia with 46,XY (n = 72); type 2 by male external genitalia with 46,XY (n = 8); and type 3 by female external genitalia with 46,XX (n = 8). Clinical course differs markedly among the types. Although type 1 is noticed at the mean age of 16 due to mainly primary amenorrhea, type 2 and 3 do not present delayed secondary sex characteristics, making diagnosis difficult. The prevalence of gonadal tumor is high in type 1 (67%) and also found in 3 of the 8 type 2 cases, but not in any type 3 cases, which emphasize that preventive gonadectomy is unnecessary in type 3. On the basis of our findings, we propose a new diagnostic algorithm for Frasier syndrome.

Malformation syndromes associated with disorders of sex development.

When embryological development of the internal and/or external genitalia is disrupted, the patient presents with a disorder of sex development (DSD) in the neonatal period or sometime later in life. Some of these patients have other, nongenital malformations, which makes their overall management more complex than if they just had a DSD. This Review summarises these malformation syndromes and discusses the recent research into their aetiology. The genetic causes of these malformation syndromes, when they are known, will also be described. Many specific genetic mutations are now known in malformation syndromes with a defect in hormonal function. By contrast, the genetic causes remain unknown in many nonhormonal morphological anomalies that affect the genitalia.

Post-transplant lymphoproliferative disorder--case reports of three children with kidney transplant.

INTRODUCTION: Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases, characterized by abnormal lymphoid proliferation following transplantation. It is a disease of the immunosuppressed state, and its occurrence is mostly associated with the use of T-cell depleting agents, and also intensification of immunosuppressive regimens. In the majority of cases, PTLD is a consequence of Epstein-Barr virus (EBV) infection and is a B-cell hyperplasia with CD-20 positive lymphocytes. The 2008 World Health Organization classification for lymphoid malignancies divides PTLD into four major categories: early lesions, polymorphic PTLD, monomorphic PTLD and Hodgkin PTLD. The treatment and prognosis depend on histology. The cornerstone of PTLD therapy includes reduction/withdrawal of immunosuppression, monoclonal anti CD-20 antibody (rituximab) and chemotherapy. OUTLINE OF CASES: We reported here our experiences with three patients, two girls aged 7.5 and 15 and a 16-year old boy. They had different organ involvement: brain, combined spleen-liver and intestines, respectively. Even though EBV was a trigger of lymphoid proliferation as it was confirmed by histopathology or in cerebrospinal fluid, qualitative EBV-PCR was positive only in one patient at disease presentation. Reduction of immunosuppression therapy was applied in treatment of all three patients, while two of them received rituximab and ganciclovir. They had an excellent outcome besides many difficulties in diagnosis and management of disease. CONCLUSION: Qualitative EBV-PCR is not useful marker in pediatric transplant recipients. Our suggestion is that patients with the risk factors like T-cell depleting agents, immunosuppressant protocol or increasing immunosuppressive therapy and EBV miss-match with donor must be more accurately monitored with quantitative EBV PCR.

Proteinuria in Frasier syndrome.

INTRODUCTION: Frasier syndrome (FS) is a genetic form of glomerulopathy, which results from mutations in the Wilms'tumour suppressor gene (WT1). Proteinuria in FS has been traditionally considered unresponsive to any medication and FS inevitably progresses to end stage renal failure. CASE OUTLINE: We present a patient with FS who had atypical clinical manifestation and unusual beneficial antiproteinuric response to renin-angiotensin system (RAS) inhibitors given in combination with indomethacin. After 13 years of follow-up, the patient is now 17-year old with normal renal functions and no proteinuria. CONCLUSION: RAS inhibitors combined with indomethacin showed beneficial effect in our patient. Thus, this combination might be the initial treatment of patients with FS. If this treatment strategy was not satisfied for at least 3 months, then CsA would be considered to be administered taking account of the nephrotoxicity and the increased risk of malignancy. Further prospective study is required to clarify this issue.