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.

Detailed clinical manifestations at onset and prognosis of neonatal-onset Denys-Drash syndrome and congenital nephrotic syndrome of the Finnish type.

BACKGROUND: Neonatal-onset Denys-Drash syndrome (NODDS) is a distinctive clinical entity and has a poor renal and life outcome. Early diagnosis of NODDS is important for managing disorders of sexual development and determining assigned gender. Although patients with NODDS and congenital nephrotic syndrome of the Finnish type (CNF) present with nephrotic syndrome in neonatal life or infancy, the clinical course of NODDS and factors distinguishing these diseases at onset is unknown. METHODS: We performed a retrospective cohort study of patients with NODDS and CNF between 1997 and 2017. Patients with nephrotic syndrome and WT1 or NPHS1 mutations with neonatal onset (within 30 days) were eligible. RESULTS: We studied eight patients with NODDS and 15 with CNF. The median serum creatinine level at onset in the NODDS group was significantly higher (1.85 mg/dL) than that in the CNF group (0.15 mg/dL; P = 0.002). The median placental/fetal weight ratio in the NODDS and CNF group was 41.8% and 21.0%, respectively (P = 0.001). Kaplan-Meier analysis showed that the median number of days for progression to ESRD from onset in the NODDS and CNF groups was 6 and 910 days, respectively (P < 0.001). All patients in the NODDS group were alive at follow-up. Only one patient in the CNF group died of cardiac complications during follow-up. CONCLUSION: CNS, renal dysfunction at onset, and a relatively large placenta are prominent signs of NODDS. Prognosis for patients with NODDS is satisfactory if appropriate and active management is performed.

Hemolytic uremic syndrome as the presenting manifestation of WT1 mutation and Denys-Drash syndrome: a case report.

BACKGROUND: Hemolytic uremic syndrome (HUS) can occur as a primary process due to mutations in complement genes or secondary to another underlying disease. HUS sometimes occurs in the setting of glomerular diseases, and it has been described in association with Denys-Drash syndrome (DDS), which is characterized by the triad of abnormal genitourinary development; a pathognomonic glomerulopathy, diffuse mesangial sclerosis; and the development of Wilms tumor. CASE PRESENTATION: We report the case of a 46, XX female infant who presented with HUS and biopsy-proven thrombotic microangiopathy. Next generation sequencing of genes with known mutations causative of atypical HUS found that she was homozygous for the Complement Factor H H3 haplotype and heterozygous for a variant of unknown significance in the DGKE gene. Whole exome sequencing identified a de novo heterozygous WT1 c.1384C > T; p.R394W mutation, which is classically associated with Denys-Drash syndrome (DDS). At the time of bilateral nephrectomy five months after her initial biopsy, she had diffuse mesangial sclerosis, typical of Denys-Drash syndrome, without evidence of thrombotic microangiopathy. CONCLUSION: This unique case highlights HUS as a rare but important manifestation of WT1 mutation and provides new insight into the genetics underlying this association.

A novel WT1 gene mutation in a patient with Wilms' tumor and 46, XY gonadal dysgenesis.

Denys-Drash syndrome (DDS) is a rare genetic disorder featuring the triad of Wilms' tumor, early-onset renal failure, and 46, XY disorder of sex development. DDS is usually caused by heterozygous missense mutations in the zinc-finger region of the WT1 gene. The most frequent constitutional WT1 mutations in DDS patients are missense mutations in exons 8 and 9. We present a new case of variable DDS in a child who was found to have a novel heterozygous missense mutation in exon 7 (c.905G>T) and a splicing mutation in exon 6 (IVS6-1G>T).

Unusual Presentation of Denys-Drash Syndrome in a Girl with Undisclosed Consumption of Biotin

We describe a 46,XX girl with Denys-Drash syndrome, showing both kidney disease and genital abnormalities, in whom a misdiagnosis of hyperandrogenism was made. A 15 year-old girl was affected by neonatal nephrotic syndrome, progressing to end stage kidney failure. Hair loss and voice deepening were noted during puberty. Pelvic ultrasound and magnetic resonance imaging showed utero-tubaric agenesis, vaginal atresia and urogenital sinus, with inguinal gonads. Gonadotrophin and estradiol levels were normal, but testosterone was increased up to 285 ng/dL at Tanner stage 3. She underwent prophylactic gonadectomy. Histopathology reported fibrotic ovarian cortex containing numerous follicles in different maturation stages and rudimental remnants of Fallopian tubes. No features of gonadoblastoma were detected. Unexpectedly, testosterone levels were elevated four months after gonadectomy (157 ng/dL). Recent medical history revealed chronic daily comsumption of high dose biotin, as a therapeutic support for hair loss. Laboratory immunoassay instruments used streptavidin-biotin interaction to detect hormones and, in competitive immunoassays, high concentrations of biotin can result in false high results. Total testosterone, measured using liquid chromatography tandem mass spectrometry, was within reference intervals. Similar testosterone levels were detected on repeat immunoassay two weeks after biotin uptake interruption. Discordance between clinical presentation and biochemical results in patients taking biotin, should raise the suspicion of erroneous results. Improved communication among patients, health care providers, and laboratory professionals is required concerning the likelihood of biotin interference with immunoassays.

Papers presented at the fall 2020 Pediatric Urologic Oncology Work Group of the Societies of Pediatric Urology meetingNeonatal Serum Electrolyte and Proteinuria Screening on 46,XY Ambiguous Genitalia Patients May Allow Early Diagnosis of Denys-Drash Syndrome: A Case Report.

A term infant with prenatally noted ambiguous genitalia and nonpalpable gonads presented with life-threatening hyponatremia, hypertension, acidosis, and anuric renal failure requiring peritoneal dialysis at age 3 months.Sequencing confirmed 46, XY Denys-Drash syndrome (DDS) due to heterozygous Wilms tumor-1 exon 8 mutation encoding p.His445Arg. Renal US identified bilateral multifocal renal masses at age 8 months. Bilateral retroperitoneal nephrectomies found bilateral nephroblastomatosis without Wilms' tumor avoiding chemotherapy, followed by bilateral laparoscopic orchiopexies. We suggest monthly screening of 46, XY DSD cases for DDS by evaluating for proteinuria and electrolyte disarray starting at diagnosis of DSD to prevent acute life-threatening renal failure presentation.

[WT1 mutation as a cause of progressive nephropathy in Frasier syndrome--case report]. / Mutacja genu WT1 jako przyczyna postepujacej nefropatii w zespole Frasiera--opis przypadku.

Frasier syndrome is an uncommon genetic disorder featuring progressive glomerulopathy, male pseudohermaphroditism and gonadal dysgenesis. It is caused by mutations in intron 9 of the WT1 gene. Because of its rarity there is limited literature available on the diagnosis and treatment of this syndrome. The aim of the study was to present the clinicopathological findings and molecular analysis of phenotypically female adolescent presenting with severe proteinuria and primary amenorrhea. The significance of early recognition of Frasier syndrome and its differentiation from Denys-Drash syndrome was discussed. WT1 mutation analysis should be routinely done in females with steroid-resistant nephritic syndrome.

46-XY Denys-Drash Syndrome. Is There a Role for Nephron-sparing Modalities in Management of Renal Masses? A Report of 2 Cases.

Denys-Drash syndrome (DDS) is a combination of genital and urinary anomalies that are mostly associated with renal and gonadal malignancies. We report 2 patients who presented with genital ambiguity and were diagnosed as 46-XY DDS. Both patients had renal masses during follow-up and underwent partial nephrectomy aiming to have transplant at older age.

[Denys-Drash syndrome. Experience gathered in Erlangen illustrated by two case reports]. / Denys-Drash-Syndrom. Erlanger Erfahrungen am Beispiel zweier Fallberichte.

Denys-Drash syndrome is a rare symptom complex associated with obligatory childhood nephrotic syndrome, male pseudohermaphroditism, and Wilms' tumor. The etiology of Denys-Drash syndrome is attributed to a mutation of the WT1 gene. We report on two cases of Deny-Drash syndrome confirmed by genetic testing. Rapidly evolving terminal renal insufficiency was detected in both patients necessitating bilateral nephrectomies with prophylactic intent. In one of the patients, a Wilms' tumor had already been verified in one kidney so that chemotherapy had to be initiated.The risk of Wilms' tumor is very high in patients with a WT1 mutation, which leads to the need for removal of both kidneys during or before transplantation. It would be important to perform a diagnostic work-up for WT1 gene mutation in children who develop renal failure in the 1st year of life.

Denys-Drash syndrome.

Constitutional missense mutations in the WT1 gene are usually associated with Denys-Drash syndrome. This rare syndrome is characterized by a rapid progressive nephropathy, male pseudohermaphroditism, and an increased risk for Wilms tumor. We report on a patient with incomplete Denys-Drash syndrome, which was evident by the clinical data and proved by molecular genetics methods. The patient has the mutation p.R394W in the WT1 gene and clinical symptoms of Denys-Drash syndrome.

Renal and adrenal tumors in children.

Survival rates for children with kidney tumors approach 90% for even the most advanced stages of disease, but the surgical management of large lesions remains challenging. With the development of additional chemotherapeutic regimens and the use of radiation therapy, survival rates have improved dramatically. The National Wilms' Tumor Study has conducted four long-term studies addressing how adjunctive therapy may be tailored optimally to maximize survival and minimize the exposure to chemotherapy and radiation therapy.

WT1 gene mutation responsible for male sex reversal and renal failure: the Frasier syndrome.

We report the case of a young woman with primary amenorrhea. In her childhood, she suffered from renal failure requesting kidney transplantation at the age of 11. The investigations for primary amenorrhea revealed a hypergonadotropic hypogonadism associated with 46 XY karyotype. The association of primary amenorrhea with renal failure suggested Frasier syndrome (FS) or Denys-Drash syndrome (DDS). Genetic analysis revealed a Wilms' tumour (WT1) gene mutation characteristic of the Frasier syndrome. Dysgenetic ovaries were removed laparoscopically due to the risk of gonadal cancer.

Gonadoblastoma and dysgerminoma associated with XY gonadal dysgenesis in an adolescent with chronic renal failure: a case of Frasier syndrome.

STUDY OBJECTIVES: To report a rare reason for primary amenorrhea, a Frasier syndrome, XY gonadal dysgenesis associated with renal failure with eventual development of gonadoblastoma. To study immunohistochemical analysis of gonadoblastoma and dysgerminoma. To analyze the possibility of androgen receptor mutation in this rare syndrome. METHODS: We report a case of a 16-yr-old female with this syndrome. She underwent a laparoscopic bilateral gonadectomy and salpingectomy. A histopathological examination revealed gonadoblastoma with focal malignant dysgerminoma in the left dysgenetic gonad and an immunohistochemical of these fairly rare, malignant tumors. An androgen receptor was coded. Analysis was done. RESULTS: Immunohistochemical analysis showed that inhibin was strongly positive in gonadoblastoma but negative in dysgerminoma. No mutations of the androgen receptor gene were found. CONCLUSIONS: Inhibin positivity in gonadal stroma and in gonadoblastoma may indicate hormonal activity causing advanced puberty in patients with XY gonadal dysgenesis.

[Denys-Drash syndrome: a case report]. / Zespól Denysa-Drasha--opis przypadku.

Nephrotic syndrome (NS) rarely develops before the age of 1 year. The case is presented of nephrotic syndrome occurring in the form of Denys-Drash syndrome. In a newborn of female sex in birth certificate, dysmorphia was found of the external urogenital organs. The karyotype was 46XY. Massive proteinuria, low total serum protein level, dysproteinaemia, hypercholesterolaemia justified the diagnosis of NS. In renal biopsy performed diffuse mesangial fibrosis was found. The progression of renal insufficiency was very rapid and within few weeks terminal renal failure developed. The parents refused consent to renal replacement treatment. The baby died at the age of 102 days. The autopsy examination confirmed renal changes in the form of diffuse fibrosis; gonads of testicular structure were found in the abdominal cavity.

An unusual presentation of Denys-Drash syndrome due to bigenic disease.

We report a case of Denys-Drash syndrome (DDS) in a 3-month-old girl presenting with bilateral renal cortical cysts mimicking polycystic kidney disease. Genetic analysis revealed a de novo heterozygous missense mutation c.1186G>A (p.Asp396Asn) in the WT1 gene, confirming the diagnosis of DDS. Because multiple renal cysts have never been reported in DDS, we explored several genes responsible for these renal manifestations, such as HNF-1ß, PAX2, PKD1, and PKD2. Remarkably, we identified a heterozygous missense variant c.12439A>G (p.Lys4147Glu) in the PKD1 gene. The same variant was found in the patient's mother, who had no renal cysts, and in the grandfather, who had several renal cysts. Mutation prediction programs classified the c.12439A>G variant as being "likely pathogenic." We hypothesize that the severe cystic phenotype in the index patient could be due to the WT1 mutation, enhancing pathogenicity of the "hypomorph" PKD1 allele. A possible role for Wilms tumor suppressor 1 (WT1) in renal cyst development should be considered. From a conceptual point of view, this case shows that an unusual presentation of a known genetic syndrome might point to bigenic inheritance, with unexpected interference of mutated genes causing an uncommon clinical phenotype.

Expanding the clinical spectrum of Frasier syndrome.

Frasier syndrome is an uncommon genetic disorder featuring progressive glomerulopathy, male pseudohermaphroditism, and gonadal dysgenesis with increased risk of gonadoblastoma and malignant germ cell tumors. It is caused by mutations in the donor splice site in intron 9 of the WT1 gene. However, because of its rarity there is limited literature available on the precise spectrum and recommended treatment modalities of this syndrome. We present the clinicopathological findings in 4 patients: 3 phenotypically female adolescents presenting with proteinuria and primary amenorrhea and a 6-month-old baby girl presenting with nephrotic syndrome in whom this very unusual case of early onset was confirmed by molecular studies. The significance of early recognition of Frasier syndrome and its differentiation from Denys-Drash syndrome is reviewed and discussed. Our observation of a case presenting with early clinical manifestations, in contrast with the classical presentation in adolescence, justifies the expansion of the clinical spectrum of Frasier syndrome and contributes to the understanding and appropriate clinical management of these patients.