Hirsch Betsy, Shimamura Akiko, Moreau Lisa, Baldinger Shari, Hag-alshiekh Maha, Bostrom Bruce, Sencer Susan, D'Andrea Alan D
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, USA.
Blood. 2004 Apr 1;103(7):2554-9. doi: 10.1182/blood-2003-06-1970. Epub 2003 Dec 11.
The clinical, cytogenetic, and molecular findings of 2 Fanconi anemia (FA) subtype D1 kindreds, initially identified through a young child with a solid tumor (medullobastoma, Wilms tumor), are described. Each kindred subsequently had a second affected child; one developed Wilms tumor followed by a medulloblastoma, and the other developed T-lineage acute lymphoblastic leukemia. Cytogenetic studies revealed an unusually high spontaneous chromosome aberration rate, contrasting with other FA subtypes. Molecular analysis revealed biallelic BRCA2/FANCD1 mutations. The patients did not exhibit bone marrow failure. Our studies suggest that the D1 subtype represents a severe end of the cytogenetic spectrum within FA, consistent with a critical downstream role of BRCA2 in the FA pathway. Furthermore, this FA subgroup may be preferentially associated with an increased predisposition to solid tumors in early childhood. Recognition of this constellation of findings has significant implications for medical management and genetic counseling of FA families.
描述了2个范可尼贫血（FA）D1亚型家系的临床、细胞遗传学和分子学发现，这些家系最初是通过一名患有实体瘤（髓母细胞瘤、肾母细胞瘤）的幼儿被识别出来的。每个家系随后都有第二名患病儿童；其中一名先患肾母细胞瘤，后患髓母细胞瘤，另一名则患T系急性淋巴细胞白血病。细胞遗传学研究显示，与其他FA亚型相比，自发染色体畸变率异常高。分子分析揭示了双等位基因BRCA2/FANCD1突变。这些患者未表现出骨髓衰竭。我们的研究表明，D1亚型代表了FA细胞遗传学谱中的一个严重极端情况，这与BRCA2在FA通路中的关键下游作用一致。此外，这个FA亚组可能优先与儿童早期实体瘤易感性增加相关。认识到这一系列发现对FA家族的医疗管理和遗传咨询具有重要意义。
