1 Adult Cystic Fibrosis Care Centre, Centre Hospitalier Lyon-Sud, Pierre-Bénite Cédex, 2 Laboratoire de Biochimie Endocrinienne et Moléculaire, Hôpital Debrousse, Lyon Cédex, 3 Institut Rhonalpin pour l'étude de la reproduction, Bron, 4 Fédération d'Endocrinologie, Hôpital de L'Antiquaille and 5 Service de génétique, Hôtel-Dieu, Lyon, France
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Abstract |
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Key words: congenital bilateral absence of vas deferens/cystic fibrosis/outcome of paternity
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Introduction |
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The aims of our retrospective study were to investigate CF-related phenotype and clinical outcome in a cohort of 50 males with CBAVD, as well as to determine the issue of pregnancies for couples after genetic counselling.
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Materials and methods |
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Analysis of CF gene mutations was made by extracting leukocyte genomic DNA from blood samples collected in ethylenediaminetetra-acetic acid. Leukocytes samples were analysed for a series of 22 CF mutations including the five most frequently encountered in our region (The CF Genotype Consortium, 1994): F508, G542X, N1303K, 1717-GA, 885E; and 17 others: R117H, R334W, R347H, R347P, 556delA, S549N, S549I, S549R, G551D, R553X, R560T, G1244E, S1255X, W1282X, R1283K, 3898ins C, D1270N. The identification of the poly-T variant of intron 8 was also tested in stored specimens.
Biological data recorded included liver function tests, serum pancreatic enzymes (amylasaemia, lipasaemia, trypsinaemia), total cholesterol, fat-soluble vitamins, glucose serum concentration, and glycosylated haemoglobin. All patients had chest roentgenograms, pulmonary function tests, computerized tomographic scan of paranasal sinuses and abdominal ultrasonography.
Genetic counselling was proposed to all couples, including genotype analysis of CFTR mutations for the spouse and geneticist consultation for the couple.
Survey of CF-related clinical symptoms and paternity outcome
Information on medical assisted reproduction techniques was obtained in January 2000, from the andrologist in charge of each patient. Accurate oral information on CF clinical symptoms and genetic counselling was provided to each patient at the first evaluation. A mail investigation carried out throughout 1999 for the 41 patients seen between December 1992 and April 1998 allowed registration of any sign suggesting CF-related non-genital manifestations such as bronchial or sinus infections, gastrointestinal symptoms or any other relevant medical event.
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Results |
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sCFTR mutation was detected in 56 alleles of the 50 patients: F508 in 30 alleles, R117H in six, D1270N in two, G542X in one, 1717+G-A in one, 2789+5G-A in one, R347H in one and the 5T allele in 14. Fifteen patients (30%) were compound heterozygote, 26 patients (52%) had only one CF mutation and nine (18%) had no CF mutation detected (Table I
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Twenty-six patients (52%) had computed tomographic scan sinuses anomalies corresponding to polyposis or maxillar sinusitis.
Four cases, not detected previously, were diagnosed as `classical' CF in view of clinical signs suggesting CF as proposed by Stern (Stern et al., 1982): two patients (numbers 5 and 17 in Table I
) with CF genotype
F508/5T and
F508/- respectively had repeated bronchial infections, colonization of sputum with haemophilus influenzae and staphylococcus aureus, reduced forced expiratory volume in one second (FEV1) (60% of predicted value) and positive sweat test (90 mmol/l); the two other patients with one CFTR mutation (D1270N) in number 36 and 5T/5T CFTR genotype for number 15 had positive sweat test (103 and 77 mmol/l respectively) and significantly elevated pancreatic enzymes (two-fold normal values) without steatorrhoea, but with diabetes mellitus in one case.
One patient had asthma since infancy and a negative sweat test, another patient had chronic cough but severe tobacco addiction; two patients had asymptomatic gallstones; and all patients had normal liver function tests.
Paternity outcome
Results are summarized in Table II. Among the 50 CBAVD men, 28 underwent at least one ICSI procedure and three others are in progress (62%). ICSI led to successful pregnancies with live births in eight cases, including two twin pregnancies (10 newborns). Following ICSI failures in 20 cases, six couples underwent IVF with sperm donors (IVFSD) resulting in two successful pregnancies and live births and four failures. Two couples adopted a child after unsuccessful ICSI; for one of them ICSI was attempted in 1991, before any clinical evaluation or genetic counselling. The existence of a
F508 mutation in one woman led the couple to choose adoption rather than another ICSI attempt.
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Four couples chose adoption without any attempt at assisted reproduction: one case was motivated by F508 heterozygote mutation in the woman; another case by the age and hormonal status of the woman, and two remaining cases for personal reasons.
Ten men did not undergo any procedure for paternity and for one of them this decision was motivated by CF mutation in his spouse.
In total, 21 men (42%) became fathers, following ICSI procedures in eight cases, AID in five cases, IVFSD in two, and through adoption for six of them (Table II).
Mail survey for CF criteria
Information was obtained for 24 patients of the 41 patients included in the survey (58.5%) with a median follow-up period of 2.8 years (range 0.55 years). Bronchial infections only concerned patients with initial respiratory symptoms. Three patients reported symptomatic sinusitis. No patient reported signs suggesting digestive or pancreatic involvement, nor onset of diabetes mellitus.
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Discussion |
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In our cohort of CBAVD, the rate of paternity after a median follow-up period of 2.8 years is 42%, which is lower than in other reports concerning ICSI outcomes (Phillipson et al., 2000). Several explanations could account for this result: (i) the recruitment of our patients did not depend on their motivation for assisted reproduction since ten patients (22%) did not undergo any procedure for paternity; (ii) the identification of a
F508 mutation in four women led to giving up ICSI; (iii) the follow-up period is probably not sufficient since some ICSI procedures are in progress. Twenty one patients achieved paternity: through ICSI for eight patients, sperm donor (AID or IVFSD) for seven patients and adoption for the remaining six.
In conclusion, in our cohort of men presenting with CBAVD, 42% became fathers using various procedures. When no initial symptoms were registered, a short median follow-up period of 2.8 years did not reveal any new clinical signs. Diagnosis of CBAVD requires genetic counselling before proceeding to assisted reproduction. Even in cases without any demand for assisted reproduction, CF gene screening should be associated with sweat testing and an initial thorough clinical evaluation because of possible mild forms of CF disease.
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Notes |
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References |
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Submitted on March 22, 2001; accepted on June 22, 2001.