Two novel and correlated CF-causing insertions in the (TG)mTn tract of the CFTR gene

Two novel and related pathogenic variants of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene were structurally and functionally characterized. These alterations have not been previously described in literature. Two patients with diagnosis of Cystic Fibrosis (CF) based on the presence of one mutated allele, p.Phe508del, pathological sweat test and clinical symptoms were studied. To complete the genotypes of both patients, an extensive genetic and functional analysis of the CFTR gene was performed. Extensive genetic characterization confirmed the presence of p.Phe508del pathogenic variant and revealed, in both patients, the presence of an insertion of part of intron 10 in intron 9 of the CFTR gene, within the (TG)m repeat, with a variable poly-T stretch. The molecular lesions resulted to be very similar in both patients, with only a difference in the number of T in the poly-T stretch. The functional characterization at RNA level revealed a complete anomalous splicing, without exon 10, from the allele with the insertion of both patients. Consequently, the alleles with the insertions are expected not to contribute to the formation of a functional CFTR protein. Molecular and functional features of these alterations are compatible with the definition of novel CF-causing variants of the CFTR gene. This also allowed the completion of the genetic characterization of both patients

Linear and whorled nevoid hypermelanosis in a 6 year old boy

A case of linear and whorled nevoid hypermelanosis with multisystem malformations in a 6 year old boy was reported. The Authors discussed the differential diagnosis and the chromosome, pathological and ultramicroscopy alterations of the patient

291 Colon cancer screening program in adult CF patients: an Italian cross-sectional pilot study

Objectives: Adult CF patients have a significantly increased risk of colon adenomatous polyps, yet there is currently no consensus about the optimal screening protocol. The aim of this study is to evaluate the prevalence of colon precancerous abnormalities in CF patient by a systematic colonoscopic screening and surveillance program. Methods: In a cross-sectional design, each individual out of 184 CF patients aged 40+ followed by the Regional CF Centre of Ancona (Marche), Verona (Veneto) and Atri (Abruzzo) is being asked to undergo within the next six months a screening colonoscopy after execution of Fecal Occult Blood Test (FOBT). Assessed outcomes: probability of having at least one polyp, 3+ polyps, one adenoma with severe dysplasia, a colon cancer diagnosis; positive and negative predictive value of FOBT for colonic mucosa lesions. Additional risk factors, such as familiarity for colorectal or breast cancer, IBD and cumulative dose of NSAIDs in the last five years, are being recorded. Results: Until nowadays, 20 patients out of 184 have been evaluated, with 4 positive for polyps (histology in progress). The results of the screening program will be available in the next months. Conclusion: Preliminary data show an increase of potentially evolutionary colonic lesions in CF adults. The precise burden, the optimal screening strategies, the influence of conventional or disease-associated risk factors must be clarified for an effective program. Our study is one of the first pilot experiences to address this aspect

Ataluren improves myelopoiesis and neutrophil chemotaxis by restoring ribosome biogenesis and reducing p53 levels in Shwachman–Diamond syndrome cells

Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency and skeletal abnormalities. SDS bone marrow haematopoietic progenitors show increased apoptosis and impairment in granulocytic differentiation. Loss of Shwachman-Bodian-Diamond syndrome (SBDS) expression results in reduced eukaryotic 80S ribosome maturation. Biallelic mutations in the SBDS gene are found in ~90% of SDS patients, ~55% of whom carry the c.183-184TA>CT nonsense mutation. Several translational readthrough-inducing drugs aimed at suppressing nonsense mutations have been developed. One of these, ataluren, has received approval in Europe for the treatment of Duchenne muscular dystrophy. We previously showed that ataluren can restore full-length SBDS protein synthesis in SDS-derived bone marrow cells. Here, we extend our preclinical study to assess the functional restoration of SBDS capabilities in vitro and ex vivo. Ataluren improved 80S ribosome assembly and total protein synthesis in SDS-derived cells, restored myelopoiesis in myeloid progenitors, improved neutrophil chemotaxis in vitro and reduced neutrophil dysplastic markers ex vivo. Ataluren also restored full-length SBDS synthesis in primary osteoblasts, suggesting that its beneficial role may go beyond the myeloid compartment. Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation

Clinical outcomes of a large cohort of individuals with the F508del/5T;TG12 CFTR genotype

Background: In recent years, patients with cystic fibrosis (CF) conductance regulator (CFTR) variant poly(T) sequences have been increasingly reported with a wide spectrum of clinical severity. We describe the long-term clinical outcomes and progression to a CF diagnosis over time in a large Italian cohort of patients carrying the CFTR F508del/5T;TG12 genotype. Methods: A retrospective analysis of subjects from 10 CF centres in Italy with the F508del/5T;TG12 genotype was performed. Demographic, clinical, microbiological, and biochemical data, as well as information about the follow-ups and complications of the enroled patients, were collected. Results: A total of 129 subjects (54 females; median age: 15.0 years, range: 0–58 years; 59 older than 18 years) were included. In terms of initial diagnoses, 30 were CF (23.3%), 41 were CFTR-related disorder (CFTR-RD) (31.7%), and 58 were CF transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID) (45.0%). After a median follow-up of 6.7 years (range 0.2–25 years), 15 patients progressed to CF, bringing the total number of CF diagnoses to 45/129 (34.9%). Most of these patients had mild lung diseases with pancreatic sufficiency and a low prevalence of CF-related complications. Conclusions: At the end of the study, 34.9% of subjects with the CFTR F508del/5T;TG12 genotype were diagnosed with CF. We suggest including patients with the F508del/5T;TG12 genotype in long-term follow-ups