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Familial Wilms Tumor and Related Syndromes
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
WAGR syndrome is one of the main syndromic conditions associated with germline WT1 mutations (the others being DDS and FS). Having an incidence of 7–8 cases per 1000 individuals with WT, WAGR syndrome displays WT, complete or partial aniridia (an eye problem), ambiguous external genitalia and cryptorchidism in males, and mental retardation (intellectual disability). Molecularly, the condition is attributed to heterozygous contiguous gene deletion of chromosome 11p13 that includes both WT1 (whose deletion causes genitourinary features and WT predisposition) and PAX6 (which lies within 0.6 Mb of WT1 and whose deletion is responsible for aniridia) (first hit) followed by the mutation in the second WT1 allele (second hit). With a 45%–60% lifetime risk of WT, WAGR syndrome has an early age at diagnosis (90% patients developing WT by age 4 and 98% by age 7), and a frequent bilateral disease [1,3].
Pediatrie genitourinary oncology
Published in J Kellogg Parsons, E James Wright, The Brady Urology Manual, 2019
Jennifer Miles-Thomas, Matthew E Nielsen, Caleb P Nelson
WAGR syndrome: Wilms’ tumor, Aniridia, GU anomalies, Mental RetardationUsually presents before age 3Associated with an 11p13 deletionEar deformities, inguinal/umbilical hernias, renal hypoplasia, ectopia/fusions/duplications, hypospadias, cryptorchidism, pseudohermaphroditism.
Paediatric oncology
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Stephen Lowis, Rachel Cox, John Moppett, Antony Ng
At least three genes are associated with WT and because the incidence of familial WT is less than 1%, the genetics of WT do not always follow the simple two-hit model of tumour suppressor genes.243 Patients with the WAGR syndrome have a constitutional deletion of the WT suppressor gene, WT1, which is located at 11p13.243 Although constitutional mutations of WT1 are described for children with the rare Denys–Drash syndrome, specific mutations of WT1 have been found in less than 10% sporadic WT.244WT2 has been found to map to 11p15.5, which is also the location of the Beckwith–Weidemann gene abnormality, and familial WT genes are also located at 17q12 and 7p13.241
Genetic causes of nystagmus, foveal hypoplasia and subnormal visual acuity- other than albinism
Published in Ophthalmic Genetics, 2021
Miriam Ehrenberg, Laura Bagdonite-Bejarano, Anne B. Fulton, Naama Orenstein, Claudia Yahalom
Defects in the PAX6 gene affect embryonal eye development and result in a range of clinical phenotypes, the most common being aniridia, a panocular disorder characterized by iris hypoplasia combined with foveal hypoplasia. Aniridia is associated with other, typically later-onset ocular abnormalities, including cataract, glaucoma, and keratopathy (16). Infrequently, deletions present both in the PAX6 and its neighbor gene WT1. The resultant phenotype, known as WAGR syndrome, is characterized by a life-threatening kidney tumor, in addition to the abovementioned ophthalmic findings. Hence, early identification of this gene mutation is important. Milder forms of PAX6- related eye disease have been described (17). These are noted by only mild anterior segment dysgenesis such as corectopia (accompanied by foveal hypoplasia and nystagmus), isolated transillumination defects or even by only isolated foveal hypoplasia and nystagmus (17,18). In our study, 33% of the individuals in the PAX6 group had corectopia as the sole anterior segment sign. The others had additional anterior segment dysgenesis such as cataract or iridolental strands. These helped lead to the suspicion of PAX6 as the causative gene. Though mild, the anterior segment changes prompted the treating clinicians to sequence the PAX6 genes before broadening the work-up with an ERG exam. This may explain the significantly lower proportion of patients in the PAX6- group that had undergone an ERG exam: 20% compared to 71% of those in both SLC38A8 and diverse gene mutation groups.
A rare case of an isolated PAX6 mutation, aniridia, and Wilms tumor
Published in Ophthalmic Genetics, 2021
Katherine T. Lind, Nicholas G. Cost, Kelsey Zegar, Susan A. Kuldanek, Robert W. Enzenauer, Kami W. Schneider
His personal medical history was notable for the following: pregnancy was complicated by placenta previa requiring a Cesarean section at 39 weeks gestational age and, at birth, he require oxygen supplementation (which is commonly seen at increased altitude, particularly after Cesarean sections). He weaned to room air shortly thereafter and, outside of the notable aniridia, was well appearing. Given the association between WT and aniridia in the setting of WAGR syndrome, he initially had a chromosomal microarray that did not identify any duplications or deletions. At that time, PAX6 sequencing was performed and identified a single heterozygous point mutation in PAX6 (c.991 C > T); a nonsense variation that results in premature termination of the PAX6 protein in the proline-serine-threonine-rich domain. Given his isolated PAX6 nonsense mutation, WT surveillance was discontinued. No further WT-related genetic testing nor surveillance was recommended nor performed.
WAGR, Sex Reversal, Bilateral Gonadoblastomas, and Intralobar Nephrogenic Rests: Uncertainties of Pre-Biopsy Chemotherapy in a High Risk Syndrome for Nephroblastoma.
Published in Fetal and Pediatric Pathology, 2023
Randall Craver, Matthew Stark, Stephanie Moss, Sarah Long, Pinki Prasad, Christopher C. Roth
Mutations in WT1, resulting in Fraser or Denys-Drash syndromes, may also be associated with 46, XY sex reversal, along with development of nephroblastomas and gonadoblastomas [1, 2]. WT1 deletions result in the WAGR syndrome, with aniridia, genitourinary abnormalities, developmental neurocognitive delays and a propensity for developing nephroblastomas [3]. For suspected nephroblastoma, newer cooperative group protocols will treat with chemotherapy without histologic confirmation [4]. We present a sex-reversed 46, XY, del11p phenotypic girl with bilateral gonadoblastomas who underwent chemotherapy for suspected bilateral nephroblastomas (not biopsied) that upon resection, contained only residual treated intralobular nephrogenic rests.