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Cystic fibrosis and Young's syndrome
CORRESPONDENCE
Cystic fibrosis and Young’s syndrome Sir—I was interested to read Diana Wellesley and Martin Schwarz’s research letter (July 4, p38)1 about cystic fibrosis and Young’s syndrome. There is no need to confuse the two conditions because clinical examination of the man should provide the correct diagnosis. In Young’s syndrome, the obstructive azoospermia is due to a blockage between the caput and body of the epididymis; in cystic fibrosis there is usually vasal aplasia, the head of the epididymis is palpable but the body, tail, and vas deferens are absent. In Young’s syndrome the semen volume is normal, whereas in vasal aplasia the semen volume is small (0·5–1 mL). Since the semen is mainly prostatic secretions, it is acid (pH 7–7·5) and does not contain fructose which is secreted by the seminal vesicles. John P Pryor Institute of Urology, The Lister Hospital, London SW1 8RH, UK 1
Wellesley D, Schwarz M. Cystic fibrosis, Young’s syndrome and normal sweat chloride. Lancet 1998; 352: 38.
Sir—Diana Wellesley and Martin Schwarz1 suggest that in some cases Young’s syndrome might be a mild form of cystic fibrosis, and that more extensive gene mutation analysis might clarify the true nature of the diagnosis in men with azoospermia and chronic respiratory disorders. The sweat electrolyte figures were not cited, yet even in adults, borderline or upper range of normal sweat chloride would raise the suspicion of disease mediated by the cystic fibrosis transmembrane conductance regulator protein (CFTR). Measurement of transepithelial nasal potential difference (NPD) has further clarified the relation between Young’s syndrome and cystic fibrosis. Men with Young’s syndrome have no abnormality of electrolyte transport on NPD measurements, whereas men with cystic fibrosis have reduced chloride transport.2 Furthermore, men with isolated congenital absence of the vas deferens, 80% of whom have at least one CFTR mutation,3 have epithelial chloride transport mid-way between cystic fibrosis patients and healthy people.4 The investigators are right to consider cystic fibrosis as a cause of azoospermia and chronic respiratory disease, and although gene mutation analysis may reveal CFTR
THE LANCET • Vol 352 • September 26, 1998
mutations as the cause in some patients, Young’s syndrome seems to be a separate entity and can be distinguished by NPD measurement. John Massie Specialist Respiratory Clinic, Royal Children’s Hospital, Melbourne, Victoria 3052, Australia 1
2
3
4
Wellesley D, Schwarz M. Cystic fibrosis, Young’s Syndrome and normal sweat chloride. Lancet 1998; 352: 38. Alton EWFW, Currie D, Logan-Sinclair R, Warner JO, Hodson ME, Geddes DM. Nasal potential difference: a clinical diagnostic test for cystic fibrosis. Eur Resp J 1990;3:922–26. Costes B, Girdon E, Ghanem N, et al. Frequent occurrence of the CFTR intron 8 (TG)n 5T allele in men with congenital absence of the vas deferens. Eur J Hum Genet 1995; 3: 285–93. Osborne LR, Lynch M, Middleton P, et al. Nasal epithelial ion transport and genetic analysis of infertile men with congenital bilateral of the vas deferens. Hum Mol Genet 1993; 2: 1605–09.
Authors’ reply Sir—John Pryor and John Massie each point out that Young’s syndrome can be distinguished from cystic fibrosis by either nasal potential difference measurement or by investigation of the vasa deferentia. Although these investigations might allow a more precise definition of Young’s syndrome, the difficulty to which we wished to draw attention is not a confusion of the two conditions, but awareness of the involvement of the CFTR gene in the aetiology of several overlapping conditions, collectively known as CFTR-gene diseases. The inclusion of Young’s syndrome in this group depends on more detailed analysis of the CFTR gene in these patients. Earlier (inconclusive) investigations of the CFTR gene in Young’s syndrome concentrated on a few known cystic fibrosis mutations, but in an investigation of congenital bilateral absence of vas deferens (CBAVD),1 more extensive analysis revealed several previously unreported CFTR mutations, some of which might prove exclusive to CBAVD and not typical of cystic fibrosis. Similarly, the occurrence of the 5T allele of the intron 8 polythymide repeat (referred to as a partly penetrant mutation) in CBAVD,2 disseminated bronchiectasis,3 chronic pancreatitis,4 and allergic bronchopulmonary aspergillosis,5 shows the involvement of atypical mutations in CFTR gene disease. Therefore, a more comprehensive screen of the CFTR gene might be warranted in Young’s syndrome. Although genetic investigation
frequently allows a more well defined categorisation of diseases there is an increasingly broad “grey area” between disease-causing mutation and benign polymorphism, and it is in this area that many of the mutations associated with CBAVD are found. The finding of two CFTR mutations does not necessitate a relabelling of the diagnosis cystic fibrosis if the only symptom present is CBAVD. Identification of CFTR mutations increases the understanding of the aetiology of the disease and also allows cystic fibrosis carrier testing to be offered to the relatives of patients. With respect to clinical aspects, Pryor offers helpful urological advice for differentiation between Young’s syndrome and cystic fibrosis in men. However, in babies and small children the distinction between the spermatic cord and vas is more difficult, and many paediatricians would not be confident in this technique. In this age group lung disease and failure to thrive are still the main prompts to search for CFTR mutations. It is true, however, that a CFTR mutation should be sought in every boy with an absent vas, so perhaps this is a skill that should be acquired, or at least increasingly used, by respiratory paediatricians and physicians. Massie discusses the value of NPD in distinguishing between Young’s syndrome and cystic fibrosis. This test is currently only available in a few centres in the country and for children of at least 7 years of age. Thus, its value remains in research and will perhaps be helpful in our understanding of the rare CFTR mutations when they are discovered, but is not yet of use in diagnosis and management of young children. Your correspondents both introduce interesting and relevant issues for research. The main aim of our letter, however, was to promote the earlier search for CFTR mutations in children who fulfill some, but not all, the expected criteria for cystic fibrosis, with the hope of providing optimum management. *Diana Wellesley, Martin Schwarz *Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, UK; and Molecular Genetics Laboratory, Royal Children’s Hospital, Manchester 1
2
3
Dork T, Dworniczak B, Aulehla-Scholz C, et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet 1997; 100: 365–77. Costes B, Girodon E, Ghanem N, et al. Frequent occurrence of the CFTR intron 8(TG)n 5T allele in men with congenital bilateral absence of the vas deferens. Eur J Hum Genet 1995; 3(5): 275–93. Pignatti PF, Bombieri C, Benetazzo M, et al. CFTR gene variant IVS8-5T in disseminated bronchiectasis.
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Cystic fibrosis and Young’s syndrome Sir—I was interested to read Diana Wellesley and Martin Schwarz’s research letter (July 4, p38)1 about cystic fibrosis and Young’s syndrome. There is no need to confuse the two conditions because clinical examination of the man should provide the correct diagnosis. In Young’s syndrome, the obstructive azoospermia is due to a blockage between the caput and body of the epididymis; in cystic fibrosis there is usually vasal aplasia, the head of the epididymis is palpable but the body, tail, and vas deferens are absent. In Young’s syndrome the semen volume is normal, whereas in vasal aplasia the semen volume is small (0·5–1 mL). Since the semen is mainly prostatic secretions, it is acid (pH 7–7·5) and does not contain fructose which is secreted by the seminal vesicles. John P Pryor Institute of Urology, The Lister Hospital, London SW1 8RH, UK 1
Wellesley D, Schwarz M. Cystic fibrosis, Young’s syndrome and normal sweat chloride. Lancet 1998; 352: 38.
Sir—Diana Wellesley and Martin Schwarz1 suggest that in some cases Young’s syndrome might be a mild form of cystic fibrosis, and that more extensive gene mutation analysis might clarify the true nature of the diagnosis in men with azoospermia and chronic respiratory disorders. The sweat electrolyte figures were not cited, yet even in adults, borderline or upper range of normal sweat chloride would raise the suspicion of disease mediated by the cystic fibrosis transmembrane conductance regulator protein (CFTR). Measurement of transepithelial nasal potential difference (NPD) has further clarified the relation between Young’s syndrome and cystic fibrosis. Men with Young’s syndrome have no abnormality of electrolyte transport on NPD measurements, whereas men with cystic fibrosis have reduced chloride transport.2 Furthermore, men with isolated congenital absence of the vas deferens, 80% of whom have at least one CFTR mutation,3 have epithelial chloride transport mid-way between cystic fibrosis patients and healthy people.4 The investigators are right to consider cystic fibrosis as a cause of azoospermia and chronic respiratory disease, and although gene mutation analysis may reveal CFTR
THE LANCET • Vol 352 • September 26, 1998
mutations as the cause in some patients, Young’s syndrome seems to be a separate entity and can be distinguished by NPD measurement. John Massie Specialist Respiratory Clinic, Royal Children’s Hospital, Melbourne, Victoria 3052, Australia 1
2
3
4
Wellesley D, Schwarz M. Cystic fibrosis, Young’s Syndrome and normal sweat chloride. Lancet 1998; 352: 38. Alton EWFW, Currie D, Logan-Sinclair R, Warner JO, Hodson ME, Geddes DM. Nasal potential difference: a clinical diagnostic test for cystic fibrosis. Eur Resp J 1990;3:922–26. Costes B, Girdon E, Ghanem N, et al. Frequent occurrence of the CFTR intron 8 (TG)n 5T allele in men with congenital absence of the vas deferens. Eur J Hum Genet 1995; 3: 285–93. Osborne LR, Lynch M, Middleton P, et al. Nasal epithelial ion transport and genetic analysis of infertile men with congenital bilateral of the vas deferens. Hum Mol Genet 1993; 2: 1605–09.
Authors’ reply Sir—John Pryor and John Massie each point out that Young’s syndrome can be distinguished from cystic fibrosis by either nasal potential difference measurement or by investigation of the vasa deferentia. Although these investigations might allow a more precise definition of Young’s syndrome, the difficulty to which we wished to draw attention is not a confusion of the two conditions, but awareness of the involvement of the CFTR gene in the aetiology of several overlapping conditions, collectively known as CFTR-gene diseases. The inclusion of Young’s syndrome in this group depends on more detailed analysis of the CFTR gene in these patients. Earlier (inconclusive) investigations of the CFTR gene in Young’s syndrome concentrated on a few known cystic fibrosis mutations, but in an investigation of congenital bilateral absence of vas deferens (CBAVD),1 more extensive analysis revealed several previously unreported CFTR mutations, some of which might prove exclusive to CBAVD and not typical of cystic fibrosis. Similarly, the occurrence of the 5T allele of the intron 8 polythymide repeat (referred to as a partly penetrant mutation) in CBAVD,2 disseminated bronchiectasis,3 chronic pancreatitis,4 and allergic bronchopulmonary aspergillosis,5 shows the involvement of atypical mutations in CFTR gene disease. Therefore, a more comprehensive screen of the CFTR gene might be warranted in Young’s syndrome. Although genetic investigation
frequently allows a more well defined categorisation of diseases there is an increasingly broad “grey area” between disease-causing mutation and benign polymorphism, and it is in this area that many of the mutations associated with CBAVD are found. The finding of two CFTR mutations does not necessitate a relabelling of the diagnosis cystic fibrosis if the only symptom present is CBAVD. Identification of CFTR mutations increases the understanding of the aetiology of the disease and also allows cystic fibrosis carrier testing to be offered to the relatives of patients. With respect to clinical aspects, Pryor offers helpful urological advice for differentiation between Young’s syndrome and cystic fibrosis in men. However, in babies and small children the distinction between the spermatic cord and vas is more difficult, and many paediatricians would not be confident in this technique. In this age group lung disease and failure to thrive are still the main prompts to search for CFTR mutations. It is true, however, that a CFTR mutation should be sought in every boy with an absent vas, so perhaps this is a skill that should be acquired, or at least increasingly used, by respiratory paediatricians and physicians. Massie discusses the value of NPD in distinguishing between Young’s syndrome and cystic fibrosis. This test is currently only available in a few centres in the country and for children of at least 7 years of age. Thus, its value remains in research and will perhaps be helpful in our understanding of the rare CFTR mutations when they are discovered, but is not yet of use in diagnosis and management of young children. Your correspondents both introduce interesting and relevant issues for research. The main aim of our letter, however, was to promote the earlier search for CFTR mutations in children who fulfill some, but not all, the expected criteria for cystic fibrosis, with the hope of providing optimum management. *Diana Wellesley, Martin Schwarz *Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, UK; and Molecular Genetics Laboratory, Royal Children’s Hospital, Manchester 1
2
3
Dork T, Dworniczak B, Aulehla-Scholz C, et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet 1997; 100: 365–77. Costes B, Girodon E, Ghanem N, et al. Frequent occurrence of the CFTR intron 8(TG)n 5T allele in men with congenital bilateral absence of the vas deferens. Eur J Hum Genet 1995; 3(5): 275–93. Pignatti PF, Bombieri C, Benetazzo M, et al. CFTR gene variant IVS8-5T in disseminated bronchiectasis.
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