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Obstructive azoospermia associated with chronic sinopulmonary infection and situs inversus totalis
CASE REPORT
OBSTRUCTIVE AZOOSPERMIA ASSOCIATED WITH CHRONIC SINOPULMONARY INFECTION AND SITUS INVERSUS TOTALIS KENTARO ICHIOKA, NAOKI KOHEI, KAZUTOSHI OKUBO, HIROYUKI NISHIYAMA, AND AKITO TERAI
ABSTRACT We describe 2 cases of obstructive azoospermia associated with situs inversus and sinopulmonary infection due to ciliary defects. Electron microscopy of testicular sperm flagella demonstrated normal morphology with nine peripheral doublets surrounding a central pair and complete sets of inner and outer dynein arms. Electron microscopy of the nasal mucosa revealed partial defects of the dynein arms of cilia, although the “9⫹2” morphology was preserved. Our cases were considered unique variants of Young’s syndrome but also had characteristic features of Kartagener syndrome, and thus support the hypothesis that Young’s syndrome has a genetic etiology similar to that of Kartagener syndrome. UROLOGY 68: 204.e5–204.e7, 2006. © 2006 Elsevier Inc.
I
n 1970, Young1 reported a significant correlation between chronic sinobronchial disease and obstructive azoospermia. The etiology of Young’s syndrome has been partially determined,2– 8 but whether this syndrome has a genetic or an environmental basis is still unknown. Kartagener syndrome consists of chronic sinopulmonary infection due to immotile cilia, immotile spermatozoa, and situs inversus. Although Young’s syndrome is somewhat similar to Kartagener syndrome, they have been considered different conditions. We experienced 2 cases of obstructive azoospermia associated with situs inversus and chronic sinopulmonary infection. In the present report, we describe these 2 cases and present a hypothesis concerning the etiology of Young’s syndrome. CASE REPORT CASE 1 A 30-year-old man presented to our hospital with infertility. A diagnosis of situs inversus totalis From the Department of Urology, Kurashiki Central Hospital, Kurashiki, Okayama, Japan; and Department of Urology, Kyoto University Graduate School of Medicine, Shogoin, Sakyo, Kyoto, Japan Address for correspondence: Kentaro Ichioka, Department of Urology, Kyoto Katsura Hospital, 17 Yamadahiraocho, Nishikyo, Kyoto 615-8256, Japan. E-mail: [email protected] Submitted: November 2, 2005, accepted (with revisions): January 30, 2006 © 2006 ELSEVIER INC. ALL RIGHTS RESERVED
had been previously made, and he had had repeated upper sinopulmonary infections since early childhood. He was otherwise an apparently healthy man. Scrotal examination revealed normal testes and vas deferens bilaterally. Serum concentrations of luteinizing hormone (2.5 mIU/mL, normal 2.0 to 12.0), follicle-stimulating hormone (3.8 mIU/mL, normal 1.0 to 12.0), testosterone (269 ng/dL, normal 250 to 1100), and prolactin (12.1 mIU/mL, normal 2.4 to 13.0) were within the normal range. Multiple semen analyses confirmed azoospermia. Cytogenetic investigation after informed consent confirmed a normal karyotype. No microdeletion was found on the Y chromosome. Chest and sinus x-ray examinations indicated chronic sinusitis, pulmonary inflammation, bronchiectasis, and situs inversus. Testicular biopsies were performed, and motile spermatozoa with a normal shape were confirmed by light microscopy. Histologic evaluation revealed mature seminiferous tubules with normal spermatogenesis. Electron microscopy demonstrated preservation of the classic “9⫹2” morphology of the sperm flagella, with nine peripheral doublets surrounding a central pair. Inner and outer dynein arms were visible. Nasal mucosa biopsies were taken for electron microscopy. The “9⫹2” morphology of the cilia was preserved, but partial defects of the outer dynein arms were identified. However, pregnancy was not confirmed after two 0090-4295/06/$32.00 doi:10.1016/j.urology.2006.01.072 204.e5
cycles of intracytoplasmic sperm injection using testicular sperm. CASE 2 A 32-year-old man presented to our hospital with infertility. He had a history of recurrent chest infections and sinusitis. Multiple semen analyses confirmed azoospermia. The testes and vas deferens were intact bilaterally. No abnormality was found on endocrinologic evaluation. Cytogenetic investigation confirmed a normal karyotype. No microdeletion was confirmed on the Y chromosome. Chest and sinus x-ray examination indicated severe sinusitis, pulmonary inflammation, and situs inversus totalis. Testicular biopsies confirmed normal spermatogenesis. Motile spermatozoa with a normal shape were obtained from the head of epididymis, but no sperm was identified from the middle or tail of the epididymis. Obstruction at the level of the epididymis was thus confirmed. Electron microscopy of nasal mucosa revealed partial defects of the inner and outer dynein arms. The “9⫹2” morphology of the cilia was preserved. After receiving informed consent, intracytoplasmic sperm injection using epididymal sperm was performed. Successful pregnancy was achieved, and a healthy baby boy was born. The baby had no respiratory disease or situs inversus totalis. COMMENT The coexistence of male infertility and chronic sinopulmonary infection has been described in cystic fibrosis, immotile-cilia syndrome, Kartagener syndrome, and Young’s syndrome. Patients with male immotile-cilia syndrome exhibit immotile spermatozoa. In these patients, a congenital defect in the cilia and sperm tails causes chronic sinopulmonary infection and male sterility. Some patients with immotile-cilia syndrome also have situs inversus, and this is called Kartagener syndrome. Kartagener syndrome has been considered a variant of immotile-cilia syndrome. The existence of Kartagener syndrome implies a relationship between cilial function and left-right axis patterning. Experimental findings have revealed a genetic relationship between immotile cilia and situs inversus. Polycystin-2, a product of polycystic kidney disease gene 2, plays a central role in the left-right axis patterning and cilial movement.9 Polaris, another protein involved in left-right determination, plays a role in ciliogenesis and sperm axoneme development.10 These findings suggest that Kartagener syndrome has a genetic basis. Young’s syndrome consists of azoospermia with bilateral epididymal obstruction and chronic sino204.e6
pulmonary infections. Young’s syndrome is somewhat similar to immotile-cilia syndrome, but these conditions differ in that Young’s syndrome features azoospermia and motile testicular sperm, and the ejaculated sperm of patients with immotile-cilia syndrome are immotile. It is still unclear whether Young’s syndrome has a genetic or an environmental basis. Hendry et al.4 hypothesized that Young’s syndrome was caused by exposure to mercury in childhood. Their hypothesis was based on the decline in the incidence of Young’s syndrome in those born after 1955, corresponding with the decline in the rate of death due to mercury intoxication. This is an important speculation, but has not yet been proved. Because of the clinical similarities with cystic fibrosis, the cystic fibrosis transmembrane conductance regulator gene has been examined in men with Young’s syndrome. Although the largest study addressing this issue yielded no findings,5 some reports have demonstrated cystic fibrosis transmembrane conductance regulator mutations in patients with Young’s syndrome.6 Previous studies have suggested that a functional defect in Young’s syndrome may exist that might interfere with normal cilia function in the respiratory and epididymal epithelia. The relative disorientation of the distal ciliary axoneme in patients with Young’s syndrome compared with normal subjects may result from a structural defect but is more likely to be a consequence of abnormal mucus.7 This has been supported by a previous report in which it was found that in men with Young’s syndrome, azoospermia was due to obstruction of the epididymis by inspissated secretions.8 This would be closer to what it is observed in cystic fibrosis rather than in Kartagener syndrome. Our 2 patients exhibited obstructive azoospermia, chronic sinopulmonary infection, and situs inversus totalis. Although they are rare, we found another five reports previously published of the coexistence of azoospermia, chronic sinopulmonary infection, and situs inversus totalis.11–15 Although two of the five reports were not indicative of whether the azoospermia was obstructive or nonobstructive, the others concluded that their cases were obstructive. Seven cases, including our two, were different in the electron microscopy findings, but these differences could have been minor phenotypic variations in the microstructures of cilia and sperm flagella. At least 7 cases have had the same clinical characteristics, strongly suggesting that obstructive azoospermia, chronic sinopulmonary infection, and situs inversus totalis share the same etiology. In our cases, obstructive azoospermia and chronic sinopulmonary infection were compatible with Young’s syndrome, and they therefore were conUROLOGY 68 (1), 2006
sidered variants of Young’s syndrome. In contrast, chronic sinopulmonary infection due to ultrastructural defects of cilia and situs inversus totalis are characteristic features of Kartagener syndrome. Our findings thus suggest the possibility that Kartagener syndrome and Young’s syndrome have similar genetic etiologies. REFERENCES 1. Young D: Surgical treatment of male infertility. J Reprod Fertil 23: 541–542, 1970. 2. Teichtahl H, Temple-Smith PD, Johnson JL, et al: Obstructive azoospermia and chronic sinobronchial disease (Young’s syndrome) in identical twins. Fertil Steril 47: 879–881, 1987. 3. Wilton LJ, Southwick GJ, Teichtahl H, et al: Young’s syndrome (obstructive azoospermia and chronic sinobronchial infection): a quantitative study of axonemal ultrastructure and function. Fertil Steril 55: 144 –151, 1991. 4. Hendry WF, A’Hern RP, and Cole PJ: Was Young’s syndrome caused by exposure to mercury in childhood? BMJ 307: 1579 –1582, 1993. 5. Le Lannou D, Jezequel P, Blayau M, et al: Obstructive azoospermia with agenesis of vas deferens or with bronchiectasia (Young’s syndrome): a genetic approach. Hum Reprod 10: 338 –341, 1995. 6. Hirsh A, Williams C, and Williamson B: Young’s syndrome and cystic fibrosis mutation ⌬F508. Lancet 342: 118, 1993.
UROLOGY 68 (1), 2006
7. Handelsman DJ, Conway AJ, Boylan LM, et al: Young’s syndrome: obstructive azoospermia and chronic sinopulmonary infections. N Engl J Med 310: 3–9, 1984. 8. De Iongh R, Ing A, and Rutland J: Mucociliary function, ciliary ultrastructure, and ciliary orientation in Young’s syndrome. Thorax 47: 184 –187, 1992. 9. McGrath J, Somlo S, Makova S, et al: Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell 114: 61–73, 2003. 10. Taulman PD, Haycraft CJ, Balkovetz DF, et al: Polaris, a protein involved in left-right axis patterning, localizes to basal bodies and cilia. Mol Biol Cell 12: 589 –599, 2001. 11. Imafuku T, Ogihara T, Kudo H, et al: Kartagener’s syndrome associated with infundibular pulmonic stenosis, chronic renal failure and azoospermia: a report of a case. Jap J Med 25: 195–198, 1986. 12. Matwijiw I, Thliveris JA, and Faiman C: Aplasia of nasal cilia with situs inversus, azoospermia and normal sperm flagella: a unique variant of the immotile cilia syndrome. J Urol 137: 522–524, 1987. 13. Bashi S, Khan MA, Guirjis A, et al: Immotile-cilia syndrome with azoospermia: a case report and review of the literature. Br J Dis Chest 82: 194 –196, 1988. 14. Gill TS, Sharma S, Mishra RR, et al: Syndrome of primary ciliary dyskinesia: Kartagener’s syndrome with empyema thoracis and azoospermia. Indian J Chest Dis Allied Sci 38: 201–204, 1996. 15. Shiraishi K, Ono N, Eguchi S, et al: Young’s syndrome associated with situs inversus totalis. Arch Androl 50: 169 – 172, 2004.
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OBSTRUCTIVE AZOOSPERMIA ASSOCIATED WITH CHRONIC SINOPULMONARY INFECTION AND SITUS INVERSUS TOTALIS KENTARO ICHIOKA, NAOKI KOHEI, KAZUTOSHI OKUBO, HIROYUKI NISHIYAMA, AND AKITO TERAI
ABSTRACT We describe 2 cases of obstructive azoospermia associated with situs inversus and sinopulmonary infection due to ciliary defects. Electron microscopy of testicular sperm flagella demonstrated normal morphology with nine peripheral doublets surrounding a central pair and complete sets of inner and outer dynein arms. Electron microscopy of the nasal mucosa revealed partial defects of the dynein arms of cilia, although the “9⫹2” morphology was preserved. Our cases were considered unique variants of Young’s syndrome but also had characteristic features of Kartagener syndrome, and thus support the hypothesis that Young’s syndrome has a genetic etiology similar to that of Kartagener syndrome. UROLOGY 68: 204.e5–204.e7, 2006. © 2006 Elsevier Inc.
I
n 1970, Young1 reported a significant correlation between chronic sinobronchial disease and obstructive azoospermia. The etiology of Young’s syndrome has been partially determined,2– 8 but whether this syndrome has a genetic or an environmental basis is still unknown. Kartagener syndrome consists of chronic sinopulmonary infection due to immotile cilia, immotile spermatozoa, and situs inversus. Although Young’s syndrome is somewhat similar to Kartagener syndrome, they have been considered different conditions. We experienced 2 cases of obstructive azoospermia associated with situs inversus and chronic sinopulmonary infection. In the present report, we describe these 2 cases and present a hypothesis concerning the etiology of Young’s syndrome. CASE REPORT CASE 1 A 30-year-old man presented to our hospital with infertility. A diagnosis of situs inversus totalis From the Department of Urology, Kurashiki Central Hospital, Kurashiki, Okayama, Japan; and Department of Urology, Kyoto University Graduate School of Medicine, Shogoin, Sakyo, Kyoto, Japan Address for correspondence: Kentaro Ichioka, Department of Urology, Kyoto Katsura Hospital, 17 Yamadahiraocho, Nishikyo, Kyoto 615-8256, Japan. E-mail: [email protected] Submitted: November 2, 2005, accepted (with revisions): January 30, 2006 © 2006 ELSEVIER INC. ALL RIGHTS RESERVED
had been previously made, and he had had repeated upper sinopulmonary infections since early childhood. He was otherwise an apparently healthy man. Scrotal examination revealed normal testes and vas deferens bilaterally. Serum concentrations of luteinizing hormone (2.5 mIU/mL, normal 2.0 to 12.0), follicle-stimulating hormone (3.8 mIU/mL, normal 1.0 to 12.0), testosterone (269 ng/dL, normal 250 to 1100), and prolactin (12.1 mIU/mL, normal 2.4 to 13.0) were within the normal range. Multiple semen analyses confirmed azoospermia. Cytogenetic investigation after informed consent confirmed a normal karyotype. No microdeletion was found on the Y chromosome. Chest and sinus x-ray examinations indicated chronic sinusitis, pulmonary inflammation, bronchiectasis, and situs inversus. Testicular biopsies were performed, and motile spermatozoa with a normal shape were confirmed by light microscopy. Histologic evaluation revealed mature seminiferous tubules with normal spermatogenesis. Electron microscopy demonstrated preservation of the classic “9⫹2” morphology of the sperm flagella, with nine peripheral doublets surrounding a central pair. Inner and outer dynein arms were visible. Nasal mucosa biopsies were taken for electron microscopy. The “9⫹2” morphology of the cilia was preserved, but partial defects of the outer dynein arms were identified. However, pregnancy was not confirmed after two 0090-4295/06/$32.00 doi:10.1016/j.urology.2006.01.072 204.e5
cycles of intracytoplasmic sperm injection using testicular sperm. CASE 2 A 32-year-old man presented to our hospital with infertility. He had a history of recurrent chest infections and sinusitis. Multiple semen analyses confirmed azoospermia. The testes and vas deferens were intact bilaterally. No abnormality was found on endocrinologic evaluation. Cytogenetic investigation confirmed a normal karyotype. No microdeletion was confirmed on the Y chromosome. Chest and sinus x-ray examination indicated severe sinusitis, pulmonary inflammation, and situs inversus totalis. Testicular biopsies confirmed normal spermatogenesis. Motile spermatozoa with a normal shape were obtained from the head of epididymis, but no sperm was identified from the middle or tail of the epididymis. Obstruction at the level of the epididymis was thus confirmed. Electron microscopy of nasal mucosa revealed partial defects of the inner and outer dynein arms. The “9⫹2” morphology of the cilia was preserved. After receiving informed consent, intracytoplasmic sperm injection using epididymal sperm was performed. Successful pregnancy was achieved, and a healthy baby boy was born. The baby had no respiratory disease or situs inversus totalis. COMMENT The coexistence of male infertility and chronic sinopulmonary infection has been described in cystic fibrosis, immotile-cilia syndrome, Kartagener syndrome, and Young’s syndrome. Patients with male immotile-cilia syndrome exhibit immotile spermatozoa. In these patients, a congenital defect in the cilia and sperm tails causes chronic sinopulmonary infection and male sterility. Some patients with immotile-cilia syndrome also have situs inversus, and this is called Kartagener syndrome. Kartagener syndrome has been considered a variant of immotile-cilia syndrome. The existence of Kartagener syndrome implies a relationship between cilial function and left-right axis patterning. Experimental findings have revealed a genetic relationship between immotile cilia and situs inversus. Polycystin-2, a product of polycystic kidney disease gene 2, plays a central role in the left-right axis patterning and cilial movement.9 Polaris, another protein involved in left-right determination, plays a role in ciliogenesis and sperm axoneme development.10 These findings suggest that Kartagener syndrome has a genetic basis. Young’s syndrome consists of azoospermia with bilateral epididymal obstruction and chronic sino204.e6
pulmonary infections. Young’s syndrome is somewhat similar to immotile-cilia syndrome, but these conditions differ in that Young’s syndrome features azoospermia and motile testicular sperm, and the ejaculated sperm of patients with immotile-cilia syndrome are immotile. It is still unclear whether Young’s syndrome has a genetic or an environmental basis. Hendry et al.4 hypothesized that Young’s syndrome was caused by exposure to mercury in childhood. Their hypothesis was based on the decline in the incidence of Young’s syndrome in those born after 1955, corresponding with the decline in the rate of death due to mercury intoxication. This is an important speculation, but has not yet been proved. Because of the clinical similarities with cystic fibrosis, the cystic fibrosis transmembrane conductance regulator gene has been examined in men with Young’s syndrome. Although the largest study addressing this issue yielded no findings,5 some reports have demonstrated cystic fibrosis transmembrane conductance regulator mutations in patients with Young’s syndrome.6 Previous studies have suggested that a functional defect in Young’s syndrome may exist that might interfere with normal cilia function in the respiratory and epididymal epithelia. The relative disorientation of the distal ciliary axoneme in patients with Young’s syndrome compared with normal subjects may result from a structural defect but is more likely to be a consequence of abnormal mucus.7 This has been supported by a previous report in which it was found that in men with Young’s syndrome, azoospermia was due to obstruction of the epididymis by inspissated secretions.8 This would be closer to what it is observed in cystic fibrosis rather than in Kartagener syndrome. Our 2 patients exhibited obstructive azoospermia, chronic sinopulmonary infection, and situs inversus totalis. Although they are rare, we found another five reports previously published of the coexistence of azoospermia, chronic sinopulmonary infection, and situs inversus totalis.11–15 Although two of the five reports were not indicative of whether the azoospermia was obstructive or nonobstructive, the others concluded that their cases were obstructive. Seven cases, including our two, were different in the electron microscopy findings, but these differences could have been minor phenotypic variations in the microstructures of cilia and sperm flagella. At least 7 cases have had the same clinical characteristics, strongly suggesting that obstructive azoospermia, chronic sinopulmonary infection, and situs inversus totalis share the same etiology. In our cases, obstructive azoospermia and chronic sinopulmonary infection were compatible with Young’s syndrome, and they therefore were conUROLOGY 68 (1), 2006
sidered variants of Young’s syndrome. In contrast, chronic sinopulmonary infection due to ultrastructural defects of cilia and situs inversus totalis are characteristic features of Kartagener syndrome. Our findings thus suggest the possibility that Kartagener syndrome and Young’s syndrome have similar genetic etiologies. REFERENCES 1. Young D: Surgical treatment of male infertility. J Reprod Fertil 23: 541–542, 1970. 2. Teichtahl H, Temple-Smith PD, Johnson JL, et al: Obstructive azoospermia and chronic sinobronchial disease (Young’s syndrome) in identical twins. Fertil Steril 47: 879–881, 1987. 3. Wilton LJ, Southwick GJ, Teichtahl H, et al: Young’s syndrome (obstructive azoospermia and chronic sinobronchial infection): a quantitative study of axonemal ultrastructure and function. Fertil Steril 55: 144 –151, 1991. 4. Hendry WF, A’Hern RP, and Cole PJ: Was Young’s syndrome caused by exposure to mercury in childhood? BMJ 307: 1579 –1582, 1993. 5. Le Lannou D, Jezequel P, Blayau M, et al: Obstructive azoospermia with agenesis of vas deferens or with bronchiectasia (Young’s syndrome): a genetic approach. Hum Reprod 10: 338 –341, 1995. 6. Hirsh A, Williams C, and Williamson B: Young’s syndrome and cystic fibrosis mutation ⌬F508. Lancet 342: 118, 1993.
UROLOGY 68 (1), 2006
7. Handelsman DJ, Conway AJ, Boylan LM, et al: Young’s syndrome: obstructive azoospermia and chronic sinopulmonary infections. N Engl J Med 310: 3–9, 1984. 8. De Iongh R, Ing A, and Rutland J: Mucociliary function, ciliary ultrastructure, and ciliary orientation in Young’s syndrome. Thorax 47: 184 –187, 1992. 9. McGrath J, Somlo S, Makova S, et al: Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell 114: 61–73, 2003. 10. Taulman PD, Haycraft CJ, Balkovetz DF, et al: Polaris, a protein involved in left-right axis patterning, localizes to basal bodies and cilia. Mol Biol Cell 12: 589 –599, 2001. 11. Imafuku T, Ogihara T, Kudo H, et al: Kartagener’s syndrome associated with infundibular pulmonic stenosis, chronic renal failure and azoospermia: a report of a case. Jap J Med 25: 195–198, 1986. 12. Matwijiw I, Thliveris JA, and Faiman C: Aplasia of nasal cilia with situs inversus, azoospermia and normal sperm flagella: a unique variant of the immotile cilia syndrome. J Urol 137: 522–524, 1987. 13. Bashi S, Khan MA, Guirjis A, et al: Immotile-cilia syndrome with azoospermia: a case report and review of the literature. Br J Dis Chest 82: 194 –196, 1988. 14. Gill TS, Sharma S, Mishra RR, et al: Syndrome of primary ciliary dyskinesia: Kartagener’s syndrome with empyema thoracis and azoospermia. Indian J Chest Dis Allied Sci 38: 201–204, 1996. 15. Shiraishi K, Ono N, Eguchi S, et al: Young’s syndrome associated with situs inversus totalis. Arch Androl 50: 169 – 172, 2004.
204.e7