ATYPICAL CYSTIC FIBROSIS ASSOCIATED WITH COMPLEX ALLELE: DIAGNOSTIC AND MANAGEMENT DILEMMAS

Abstract

trans with a 5 thymidines (5T) sequence within the intron 8 Splice Variant (IVS8) region. 5T is responsible of an exacerbated skipping of exon 9, decreasing the functional product levels. It has been demonstrated that 5T phenotypic expression is influenced by another adjacent polymorphic region, constituted by 9 to 13 TG repeats. In particular, 5T/TG13 combination was found only in affected subjects. Case Report: We report a case regarding two sisters, aged 23 and 18 years, carriers of the F508del mutation associated with the 5T/TG13 combination. DHPLC investigation did not detect a second mutation. Both sisters present mild pulmonary symptoms started in puberty, bronchiectasis, pancreatic sufficiency and border-line chloride values at the sweat test. However, they differ because the elder patient has more evident bronchiectasis, and she also presents pansinusitis, a positive sputum culture and a slightly reduced FEV1. Conclusions: The natural history of non classic CF is poorly understood. It may be asymptomatic for years but a significant lung involvement may occur, as seen in the elder sister. This finding suggests that a prevention therapy could be necessary also in mild, non classic CF and an early diagnosis may prevent the organ deterioration, as in the younger sister. Early diagnosis may be supported by TG repeats testing in individuals carrying the 5T variant; in fact, our report confirms that the presence of 5T allele, in trans with a severe CFTR mutation, is associated with non classic CF and that TG13 variant acts as a real mild mutation, enhancing the 5T penetrance and determining the onset of a mild symptomatology in all patients.