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The distribution of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) genotypes is not well characterised in patients with CF diagnosed after childhood, the majority of whom are compound heterozygotes for ΔF508.1 We describe such a patient with a rare genotype more commonly associated with inherited infertility in males.
A 54 year old man who had never smoked was referred with bilateral bronchiectasis and chronic sinusitis. He had no known allergy, no history of pancreatitis, and no family history of CF or consanguinity. Obstructive infertility with azoospermia had been established by spermography. The patient reported recurrent lower respiratory tract infections since childhood and pneumonia at the age of 45. He had undergone sinus surgery for nasal polyposis.
CF was suspected. A first sweat test was positive with a chloride concentration of 65 mmol/l (normal <40 mmol/l). The patient had chronic cough productive of purulent sputum, mild dyspnoea, chronic nasal obstruction with nasal polyps and anosmia. His weight was 70 kg and his height 1.75 m. He had no digestive symptoms. Lung and heart auscultation was normal. A chest CT scan showed diffuse bronchiectasis predominating in the right upper and left lower lobes (fig 1). Lung function was near normal with forced expiratory volume in 1 second (FEV1) of 3.1 l (89% predicted), FEV1/forced vital capacity 0.73, total lung capacity 7 litres (100% predicted), and forced expiratory flow25–75% 61% of predicted. Arterial oxygen tension was normal. Both sputum and bronchoalveolar lavage cultures were positive for mucinous Pseudomonas aeruginosa but no mycobacteria or fungi were found. Serological examination for Aspergillus fumigatus was negative. Exocrine pancreatic sufficiency was confirmed by normal elastase levels in the stools. A second sweat test was normal (25 mmol/l).
A screening test for the 22 most frequent mutations of the CFTR gene encountered in France was negative. However, mutations of the CFTR gene were confirmed by the presence of homozygozity for the 5T allele in the polythymidine tract of intron 8 (IVS8-5T) with 11 TG repeats. The M470V polymorphism was absent. Sequencing of the full CFTR coding sequence including all 27 exons and the flanking splice sites showed no other mutation.
This patient had clinical features typical of CF involving several organs (bilateral bronchiectasis, chronic sinus disease, male infertility) together with two pathogenic CFTR gene mutations, so a diagnosis of non-classic CF can be made.2 The sweat test was positive on only one of two occasions, suggesting partial dysfunction of the CFTR protein.1
The IVS8-5T allele is associated with poorly effective usage of the intron 8 splice acceptor site compared with the two other existing alleles (7T and 9T) and results in frequent skipping of exon 9. Patients homozygous for the IVS8-5T allele have lower than normal levels of full length CFTR messenger RNA3 and protein. Heterozygous IVS8-5T polymorphism is considered equivalent to a “mild” CFTR mutation. When intrans with a known CFTR mutation, the IVS8-5T allele may be responsible for congenital bilateral absence of the vas deferens or recurrent pancreatitis.4 It may modulate the variable expression of “mild” CFTR mutations such as when present in cis of the R117H mutation, thus causing a CF phenotype.
Compound heterozygotes with IVS8-5T and ΔF508 may present with classic or late onset CF.1 Whether IVS8-5T homozygosity may be sufficient by itself to cause disease has not hitherto been established. Non-classic CF was reported in a 48 year old woman homozygous for IVS8-5T, but the M470V polymorphism and TG12 repeat sequence known to modulate the disease penetrance of IVS8-5T were also present.5
This observation shows that individuals homozygous for the IVS8-5T allele as the sole variation of the whole CFTR coding sequence may present as non-classic CF with sinopulmonary disease and male infertility. However, given the high prevalence of the IVS8-5T allele (5–10% in the general population), the expected frequency of individuals homozygous for IVS8-5T may be higher than the prevalence of CF, suggesting that other factors may contribute to the disease. The IVS8-5T allele should be included in the systematic screening for CFTR mutations in patients with suspected or confirmed CF.
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