Wilms' tumor is the most common renal malignancy of childhood. Survival rates for favorable histology of Wilms' tumor currently approach 90%. Recent advances in the molecular genetics of Wilms' tumor have led to insights into the genetic factors involved in the development of Wilms' tumor, normal renal development, and the mechanisms of tumorigenesis.
Key Points
PS can be overlooked in the differential diagnosis of children with severe congenital anemia. mtDNA deletion testing should be included in the genetic evaluation of patients with congenital anemia of unclear etiology.
We studied an infant with severe nonimmune hemolytic anemia and hydrops fetalis at birth. His neonatal course was marked by ongoing hemolysis of undetermined etiology requiring repeated erythrocyte transfusions. He has remained transfusion-dependent for more than 2 yr. A previous sibling born with hemolytic anemia and hydrops fetalis died on the second day of life. Peripheral blood smears from the parents revealed rare elliptocytes. Examination of their erythrocyte membranes revealed abnormal mechanical stability as well as structural and functional abnormalities in spectrin. Genetic studies revealed that the proband and his deceased sister were homozygous for a mutation of  I ⌺ 1 spectrin, L2025R, in a region of spectrin that is critical for normal function. The importance of leucine in this position of the proposed triple helical model of spectrin repeats is highlighted by its evolutionary conservation in all  spectrins from Drosophila to humans. Molecular modeling demonstrated the disruption of hydrophobic interactions in the interior of the triple helix critical for spectrin function caused by the replacement of the hydrophobic, uncharged leucine by a hydrophilic, positively charged arginine. This mutation must also be expressed in the  I ⌺ 2 spectrin found in muscle, yet pathologic and immunohistochemical examination of skeletal muscle from the deceased sibling was unremarkable. ( J. Clin. Invest. 1997. 99:267-277.)
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