ABSTRACT
Introduction: Nephroblastoma (Wilms tumor (WT)) is an embryonal tumor accounting for >90% of pediatric renal cancers. About 10% of WTs harbor pathogenic germline mutations. The REST gene, classified as a putative tumor suppressor, is affected in 2% of WTs. High-throughput molecular methods facilitate advanced diagnostics of cancer. In addition to this, germline mutations in REST are also associated with familial gingival fibromatosis (GFM). Reciprocally, none of the articles on RESTmut WT mentions GFM as a comorbid condition. This report provides unique evidence on the WT-GFM comorbidity in RESTmut carriers. Case presentation: Patient 1 (a 5-year-old boy with unilateral WT) is a proband, who has two healthy siblings. Patient 2 (a 4-year-old girl with bilateral WT) is a proband from in vitro fertilization (IVF) triplets, with a sister and brother without WT. We analyzed probands' DNA extracted from peripheral blood leucocytes with a custom-targeted next-generation sequencing (NGS)-198 gene panel. The detected variants were checked in family members by Sanger sequencing. Patient 1 had a pathogenic germline mutation in REST: c.1035_1036insTA, p.(E346*), as did his mother and both brothers. There were two other WT cases in this family (proband's maternal uncles). Patient 2 had a pathogenic germline variant in REST: c.2668_2671del, p.(E891Pfs*6), as well as her sister. The mutation was probably inherited from their deceased father, as he had gingival fibromatosis. Family members with REST mutations from both families had gingival fibromatosis. A somatic REST c.663C>A p.C221* mutation was identified in one patient with WT. At the moment both patients with WT are under dynamic observation without signs of the disease. Conclusion: Here, we describe two clinical cases of WT in nonrelated young children with germline-inactivating REST variants identified by next-generation sequencing. Both patients present with familial gingival fibromatosis, regarded as clinically useful comorbidity indicative of the tumor predisposition syndrome. The two cases illustrate Wilms tumor-gingival fibromatosis comorbidity in carriers of germline-inactivated REST alleles previously identified as a predisposition factor for both conditions.
ABSTRACT
BACKGROUND: Diamond Blackfan anemia (DBA) is a genetically and clinically heterogeneous ribosomopathy and inherited bone marrow failure syndrome characterized by anemia, reticulocytopenia, and decreased erythroid precursors in the bone marrow with an increased risk of malignancy and, in approximately 50%, physical abnormalities. METHODS: We retrospectively analyzed clinical data from 77 patients with DBA born in the Russian Federation from 1993 to 2014. In 74 families there was one clinically affected individual; in only three instances a multiplex family was identified. Genomic DNA from 57 DBA patients and their first-degree relatives was sequenced for mutations in RPS19, RPS10, RPS24, RPS26, RPS7, RPS17, RPL5, RPL11, RPL35a, and GATA1. RESULTS: Severe anemia presented before 8 months of age in all 77 patients; before 2 months in 61 (78.2%); before 4 months in 71 (92.2%). Corticosteroid therapy was initiated after 1 year of age in the majority of patients. Most responded initially to steroids, while 5 responses were transient. Mutations in RP genes were detected in 35 of 57 patients studied: 15 in RPS19, 6 in RPL5, 3 in RPS7, 3 each in RPS10, RPS26, and RPL11 and 1 each in RPS24 and RPL35a; 24 of these mutations have not been previously reported. One patient had a balanced chromosomal translocation involving RPS19. No mutations in GATA1 were found. CONCLUSION: In our cohort from an ethnically diverse population the distribution of mutations among RP genes was approximately the same as was reported by others, although within genotypes most of the mutations had not been previously reported.