ABSTRACT
This report describes clinical characteristics in families with a Type 2A phenotype and functional properties of a novel von Hippel Lindau variant (X214L). Pedigrees were analyzed. Analysis of von Hippel Lindau (VHL) coding exons and flanking intronic sequences in DNA from a proband with pheochromocytoma and islet cell tumor was performed. Western blot assays for VHL protein (pVHL), HIFα, and Jun B were conducted using VHL null renal clear carcinoma cell lines that were engineered to produce wild-type or X214L mutant pVHL. Pedigree analysis indicated that the variant tracked with disease and the same or similar VHL point mutations were identified in several Type 2A families. The predicted 14 amino acid extended pVHL variant, when reintroduced into VHL null cells, was stable and retained the ability to downregulate HIFα in a hydroxylationdependent manner. In contrast, the variant was defective with respect to downregulation of JunB. pVHL X214L, like other pVHL variants associated with a low risk of clear cell renal carcinoma, largely preserves the ability to downregulate HIF. In contrast, this variant, like other pVHL variants linked to Type 2A disease, fails to suppress JunB. This underscores that JunB may play a role in the pathogenesis of Type 2A VHL disease.
Subject(s)
Carcinoma, Renal Cell/genetics , Kidney Neoplasms/genetics , Point Mutation , Von Hippel-Lindau Tumor Suppressor Protein/genetics , von Hippel-Lindau Disease/genetics , Adult , Cell Line, Tumor , Female , Genetic Association Studies , Genotype , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Male , Middle Aged , Pedigree , Phenotype , Proto-Oncogene Proteins c-jun/metabolism , Von Hippel-Lindau Tumor Suppressor Protein/metabolism , Young Adult , von Hippel-Lindau Disease/diagnosis , von Hippel-Lindau Disease/metabolismABSTRACT
An 11-year-old black male presenting with severe subacute sensory ataxia, unusual skin hyperpigmentation, megaloblastic anemia, low serum B12 levels, and an abnormal part I Schilling test was diagnosed with pernicious anemia in the context of a polyglandular syndrome. Intrinsic factor and thyroid microsomal antibodies were positive, and thyroid-stimulating hormone levels were undetectable. There was a strong familial aggregation because the mother, a maternal aunt, the maternal grandfather, and the maternal great-grandmother had been diagnosed with pernicious anemia, albeit of unspecified etiology. Spinal magnetic resonance imaging (MRI) demonstrated extensive demyelination of the posterior columns along the entire length of the cord, as well as areas of contrast enhancement. Treatment with cobalamin produced complete remission of the neurologic deficits and normalization of the MRI findings in the short space of 2 months. Although rare, childhood pernicious anemia is a treatable disease that should be included in the differential diagnosis of the sensory ataxias in children. In this article, we review the causes of pernicious anemia in children and discuss the MRI findings.
