Identification of 12 novel mutations in the CFTR gene

Over 200 mutations, besides the deletion     

COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy

Type IV collagen α1 and α2 chains form heterotrimers that constitute an essential component of basement membranes. Mutations in COL4A1, encoding the α1 chain, cause a multisystem disease with prominent cerebrovascular manifestations, including porencephaly, bleeding-prone cerebral small vessel disease, and intracranial aneurysms. Mutations in COL4A2 have only been reported in a few porencephaly families so far. Herein, we report on a young adult patient with recurrent intracerebral hemorrhage, leukoencephalopathy, intracranial aneurysms, nephropathy, and myopathy associated with a novel COL4A2 mutation. We extensively investigated a 29-year-old male patient with recurrent deep intracerebral hemorrhages causing mild motor and sensory hemisyndromes. Brain MRI showed deep intracerebral hemorrhages of different age, diffuse leukoencephalopathy, multiple cerebral microbleeds and small aneurysms of the carotid siphon bilaterally. Laboratory work-up revealed significant microscopic hematuria and elevation of creatine-kinase. Genetic testing found a de novo glycine mutation within the COL4A2 triple helical domain. The presented case completes the spectrum of cerebral and systemic manifestations of COL4A2 mutations that appears to be very similar to that in COL4A1 mutations. Therefore, we emphasize the importance of screening both COL4A1 and COL4A2 in patients showing recurrent intracerebral hemorrhage of unknown etiology, particularly if associated with leukoencephalopathy.     

Diagnosis and outcome of complete hydatidiform mole coexisting with a live twin fetus

OBJECTIVE: The aim of this study was to highlight the outcome of complete hydatidiform mole (CHM) coexisting with a live co-twin. METHODS: We investigated four cases of such pregnancy by ultrasound, pathological, cytogenetic, and molecular techniques. Information on clinical follow-up and outcome was also available. RESULTS: All four pregnancies were spontaneous: two ended with the delivery of a live-born baby, while the other two were terminated because of signs of serious maternal pathology or intrauterine fetal death. The criteria for carrying on with the pregnancy are reviewed. The immediate outcome depends on the maternal criteria of serious pathology and on the likelihood of intrauterine fetal death. The risk of persistent trophoblastic disease (PTD) is the same as in the case of a singleton complete mole and also seems to be correlated with the zygosity mechanism identified by molecular analysis. CONCLUSION: Hydatiform mole with a live co-twin fetus is a rare obstetric occurrence. In the case of a normal fetal karyotype, it is justifiable to await developments in the absence of maternal complications. However, treatment criteria still need improvement and diligent maternal follow-up is always warranted in the postpartum period.     

Genotype analysis of adult cystic fibrosis patients

To assess the relationship between the genotype and phenotypeof adult CF patients we have selected from a group of 512 CFpatients attending centres In France, all these of greater than35 years. We have analysed the entire coding sequence of theirCFTR genes. The complete genotype was determined in 7 of the8 patients and clinical data regarding pancreatic, respiratoryand reproductive function were carefully evaluated. All thesepatients are compound heterozygote, seven carrying the     

Cystic fibrosis mutations and genotype-pulmonary phenotype analysis.

BACKGROUND: Although there are more than 1000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, most of them are uncommon and only limited information exists regarding genotype-pulmonary phenotype relationships. METHODS: We determined and classified the CFTR mutations using denaturing high-performance liquid chromatography and developed new, quantitative methods to categorize pulmonary phenotypes. RESULTS: Two novel alleles were discovered, namely G1047R and 1525-2A-->G, which were accompanied by F508del and G551D mutations, respectively. Assessment of numerous options revealed that CF pulmonary phenotype categorization in children cannot be accomplished with clinical or pulmonary function data but is facilitated by longitudinal quantitative chest radiology. It was most useful to categorize pulmonary disease status by evaluating the typical pattern of abnormalities in patients homozygous for the F508del mutation, and then compare patients with minor mutations to this typical CF pulmonary phenotype. By this method, both patients with novel mutations have pulmonary phenotypes typical of F508del homozygotes. However, patients with class IV mutations (e.g., R347P) or with pancreatic sufficiency showed serial chest radiographs that were atypically mild. CONCLUSIONS: Longitudinal quantitative chest radiography provides a new strategy for CF pulmonary phenotype categorization that should be useful for genotype-phenotype delineation in individual patients and in both epidemiologic studies and clinical trials involving groups of children with CF.