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Phenotypic heterogeneity in CF sibs compound heterozygous for the G85E and 621 + 1G→T mutations

To the Editor: The recent publication of a letter reporting phenotypic intrafamilial heterogeneity in an Italian cystic fibrosis (CF) family (Borgo et al. 1993) prompted us to report another family with an uncommon genotype in which two affected sisters showed phenotype heterogeneity. We also show that, based on a single case report, it is difficult to assess whether a CF mutation is mild or severe. Although several studies have analyzed the relationship between phenotype and genotype, using several combinations, few studies have been conducted on intrafamilial phenotypic variation since the cystic fibrosis transmembrane regulator (CFTR) gene has been identified. During a survey of the CFTR mutations in a cohort of 91 families from Saguenay-Lac-Saint-Jean, the G85E mutation was found in only one family (two sisters) in association with the 621 + 1G+T mutation (Zielenski et al. 1991, Rozen et al. 1992). The phenotypic characteristics of both sisters are presented in Table 1. Both sisters had pancreatic insufficiency (determined by fecal-fat balance studies). However, only sister no. 2 presented with meconium ileus and experienced several episodes of intestinal subocclusion and meconium ileus equivalent. Liver cirrhosis was diagnosed when she was 15 years old and is believed to be a consequence of cystic fibrosis. Her clinical course deteriorated due to her liver condition, including portal hypertension, splenomegaly, esophageal varices and hemorrhages of the upper intestinal tract, of which she eventually died at 18 years of age. Both sisters experienced several episodes of bronchopneumonia and colonization by Pseudomonas aeruginosa. However, the respiratory function test (FVC, FEY FEF) results remained Received 15 November 1993, revised version received 7 April, accepted for publication 4 May I 1994