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CASE REPORT

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OBSTRUCTIVE AZOOSPERMIA ASSOCIATED WITHCHRONIC SINOPULMONARY INFECTION AND SITUS

INVERSUS TOTALIS

KENTARO ICHIOKA, NAOKI KOHEI, KAZUTOSHI OKUBO, HIROYUKI NISHIYAMA,AND AKITO TERAI

ABSTRACTe describe 2 cases of obstructive azoospermia associated with situs inversus and sinopulmonary infection due

o ciliary defects. Electron microscopy of testicular sperm flagella demonstrated normal morphology with nineeripheral doublets surrounding a central pair and complete sets of inner and outer dynein arms. Electronicroscopy of the nasal mucosa revealed partial defects of the dynein arms of cilia, although the “9�2”orphology was preserved. Our cases were considered unique variants of Young’s syndrome but also had

haracteristic features of Kartagener syndrome, and thus support the hypothesis that Young’s syndrome has aenetic etiology similar to that of Kartagener syndrome. UROLOGY 68: 204.e5–204.e7, 2006. © 2006 Elseviernc.

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n 1970, Young1 reported a significant correlationbetween chronic sinobronchial disease and ob-

tructive azoospermia. The etiology of Young’s syn-rome has been partially determined,2–8 but whetherhis syndrome has a genetic or an environmental ba-is is still unknown. Kartagener syndrome consistsf chronic sinopulmonary infection due to immo-ile cilia, immotile spermatozoa, and situs inver-us. Although Young’s syndrome is somewhat sim-lar to Kartagener syndrome, they have beenonsidered different conditions.We experienced 2 cases of obstructive azoosper-ia associated with situs inversus and chronic si-opulmonary infection. In the present report, weescribe these 2 cases and present a hypothesisoncerning the etiology of Young’s syndrome.

CASE REPORT

ASE 1A 30-year-old man presented to our hospitalith infertility. A diagnosis of situs inversus totalis

rom the Department of Urology, Kurashiki Central Hospital,urashiki, Okayama, Japan; and Department of Urology, Kyotoniversity Graduate School of Medicine, Shogoin, Sakyo, Kyoto,

apanAddress for correspondence: Kentaro Ichioka, Department of

rology, Kyoto Katsura Hospital, 17 Yamadahiraocho, Nish-kyo, Kyoto 615-8256, Japan. E-mail: ichioka@mq.0038.net

Submitted: November 2, 2005, accepted (with revisions): Jan-

ary 30, 2006

2006 ELSEVIER INC.LL RIGHTS RESERVED

ad been previously made, and he had had repeatedpper sinopulmonary infections since early child-ood. He was otherwise an apparently healthy man.Scrotal examination revealed normal testes and

as deferens bilaterally. Serum concentrations ofuteinizing hormone (2.5 mIU/mL, normal 2.0 to2.0), follicle-stimulating hormone (3.8 mIU/mL,ormal 1.0 to 12.0), testosterone (269 ng/dL, normal50 to 1100), and prolactin (12.1 mIU/mL, normal.4 to 13.0) were within the normal range. Multipleemen analyses confirmed azoospermia. Cytoge-etic investigation after informed consent con-rmed a normal karyotype. No microdeletion was

ound on the Y chromosome. Chest and sinus x-rayxaminations indicated chronic sinusitis, pulmonarynflammation, bronchiectasis, and situs inversus.

Testicular biopsies were performed, and motilepermatozoa with a normal shape were confirmed byight microscopy. Histologic evaluation revealed ma-ure seminiferous tubules with normal spermato-enesis. Electron microscopy demonstrated pres-rvation of the classic “9�2” morphology of theperm flagella, with nine peripheral doublets sur-ounding a central pair. Inner and outer dyneinrms were visible.Nasal mucosa biopsies were taken for electronicroscopy. The “9�2” morphology of the ciliaas preserved, but partial defects of the outer dy-ein arms were identified.

However, pregnancy was not confirmed after two

0090-4295/06/$32.00doi:10.1016/j.urology.2006.01.072 204.e5

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ycles of intracytoplasmic sperm injection usingesticular sperm.

ASE 2A 32-year-old man presented to our hospitalith infertility. He had a history of recurrent chest

nfections and sinusitis. Multiple semen analysesonfirmed azoospermia. The testes and vas defer-ns were intact bilaterally. No abnormality wasound on endocrinologic evaluation. Cytogeneticnvestigation confirmed a normal karyotype. No

icrodeletion was confirmed on the Y chromo-ome. Chest and sinus x-ray examination indicatedevere sinusitis, pulmonary inflammation, and si-us inversus totalis.Testicular biopsies confirmed normal spermato-

enesis. Motile spermatozoa with a normal shapeere obtained from the head of epididymis, but no

perm was identified from the middle or tail of thepididymis. Obstruction at the level of the epidid-mis was thus confirmed.Electron microscopy of nasal mucosa revealed

artial defects of the inner and outer dynein arms.he “9�2” morphology of the cilia was preserved.After receiving informed consent, intracytoplas-ic sperm injection using epididymal sperm was

erformed. Successful pregnancy was achieved,nd a healthy baby boy was born. The baby had noespiratory disease or situs inversus totalis.

COMMENT

The coexistence of male infertility and chronicinopulmonary infection has been described inystic fibrosis, immotile-cilia syndrome, Kartage-er syndrome, and Young’s syndrome. Patientsith male immotile-cilia syndrome exhibit immo-

ile spermatozoa. In these patients, a congenitalefect in the cilia and sperm tails causes chronicinopulmonary infection and male sterility. Someatients with immotile-cilia syndrome also haveitus inversus, and this is called Kartagener syn-rome. Kartagener syndrome has been consideredvariant of immotile-cilia syndrome.The existence of Kartagener syndrome implies a

elationship between cilial function and left-rightxis patterning. Experimental findings have re-ealed a genetic relationship between immotileilia and situs inversus. Polycystin-2, a product ofolycystic kidney disease gene 2, plays a centralole in the left-right axis patterning and cilialovement.9 Polaris, another protein involved in

eft-right determination, plays a role in ciliogenesisnd sperm axoneme development.10 These find-ngs suggest that Kartagener syndrome has a ge-etic basis.Young’s syndrome consists of azoospermia with

ilateral epididymal obstruction and chronic sino- Y

04.e6

ulmonary infections. Young’s syndrome is some-hat similar to immotile-cilia syndrome, but theseonditions differ in that Young’s syndrome featureszoospermia and motile testicular sperm, and thejaculated sperm of patients with immotile-ciliayndrome are immotile.It is still unclear whether Young’s syndrome hasgenetic or an environmental basis. Hendry et al.4ypothesized that Young’s syndrome was causedy exposure to mercury in childhood. Their hy-othesis was based on the decline in the incidencef Young’s syndrome in those born after 1955, cor-esponding with the decline in the rate of deathue to mercury intoxication. This is an importantpeculation, but has not yet been proved. Be-ause of the clinical similarities with cystic fibro-is, the cystic fibrosis transmembrane conduc-ance regulator gene has been examined in menith Young’s syndrome. Although the largest study

ddressing this issue yielded no findings,5 some re-orts have demonstrated cystic fibrosis transmem-rane conductance regulator mutations in patientsith Young’s syndrome.6Previous studies have suggested that a functional

efect in Young’s syndrome may exist that mightnterfere with normal cilia function in the respira-ory and epididymal epithelia. The relative disori-ntation of the distal ciliary axoneme in patientsith Young’s syndrome compared with normal

ubjects may result from a structural defect but isore likely to be a consequence of abnormal mu-

us.7 This has been supported by a previous reportn which it was found that in men with Young’syndrome, azoospermia was due to obstruction ofhe epididymis by inspissated secretions.8 Thisould be closer to what it is observed in cysticbrosis rather than in Kartagener syndrome.Our 2 patients exhibited obstructive azoosper-ia, chronic sinopulmonary infection, and situs

nversus totalis. Although they are rare, we foundnother five reports previously published of theoexistence of azoospermia, chronic sinopulmo-ary infection, and situs inversus totalis.11–15 Al-hough two of the five reports were not indicative ofhether the azoospermia was obstructive or nonob-

tructive, the others concluded that their casesere obstructive. Seven cases, including our two,ere different in the electron microscopy findings,ut these differences could have been minor phe-otypic variations in the microstructures of ciliand sperm flagella. At least 7 cases have had theame clinical characteristics, strongly suggestinghat obstructive azoospermia, chronic sinopulmo-ary infection, and situs inversus totalis share theame etiology.In our cases, obstructive azoospermia and chronic

inopulmonary infection were compatible with

oung’s syndrome, and they therefore were con-

UROLOGY 68 (1), 2006

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idered variants of Young’s syndrome. In contrast,hronic sinopulmonary infection due to ultra-tructural defects of cilia and situs inversus totalis areharacteristic features of Kartagener syndrome. Ourndings thus suggest the possibility that Kartage-er syndrome and Young’s syndrome have similarenetic etiologies.

REFERENCES1. Young D: Surgical treatment of male infertility. J Re-

rod Fertil 23: 541–542, 1970.2. Teichtahl H, Temple-Smith PD, Johnson JL, et al: Obstruc-

ive azoospermia and chronic sinobronchial disease (Young’s syn-rome) in identical twins. Fertil Steril 47: 879–881, 1987.

3. Wilton LJ, Southwick GJ, Teichtahl H, et al: Young’syndrome (obstructive azoospermia and chronic sinobron-hial infection): a quantitative study of axonemal ultrastruc-ure and function. Fertil Steril 55: 144–151, 1991.

4. Hendry WF, A’Hern RP, and Cole PJ: Was Young’s syn-rome caused by exposure to mercury in childhood? BMJ 307:579–1582, 1993.

5. Le Lannou D, Jezequel P, Blayau M, et al: Obstructivezoospermia with agenesis of vas deferens or with bronchiec-asia (Young’s syndrome): a genetic approach. Hum Reprod0: 338–341, 1995.

6. Hirsh A, Williams C, and Williamson B: Young’s syn-

rome and cystic fibrosis mutation �F508. Lancet 342: 118, 1993. 1

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7. Handelsman DJ, Conway AJ, Boylan LM, et al: Young’syndrome: obstructive azoospermia and chronic sinopulmo-ary infections. N Engl J Med 310: 3–9, 1984.

8. De Iongh R, Ing A, and Rutland J: Mucociliary function,iliary ultrastructure, and ciliary orientation in Young’s syn-rome. Thorax 47: 184–187, 1992.

9. McGrath J, Somlo S, Makova S, et al: Two populationsf node monocilia initiate left-right asymmetry in the mouse.ell 114: 61–73, 2003.10. Taulman PD, Haycraft CJ, Balkovetz DF, et al: Polaris, a

rotein involved in left-right axis patterning, localizes to basalodies and cilia. Mol Biol Cell 12: 589–599, 2001.11. Imafuku T, Ogihara T, Kudo H, et al: Kartagener’s

yndrome associated with infundibular pulmonic stenosis,hronic renal failure and azoospermia: a report of a case. JapMed 25: 195–198, 1986.12. Matwijiw I, Thliveris JA, and Faiman C: Aplasia of nasal

ilia with situs inversus, azoospermia and normal sperm fla-ella: a unique variant of the immotile cilia syndrome. J Urol37: 522–524, 1987.13. Bashi S, Khan MA, Guirjis A, et al: Immotile-cilia syn-

rome with azoospermia: a case report and review of the lit-rature. Br J Dis Chest 82: 194–196, 1988.

14. Gill TS, Sharma S, Mishra RR, et al: Syndrome of pri-ary ciliary dyskinesia: Kartagener’s syndrome with empy-

ma thoracis and azoospermia. Indian J Chest Dis Allied Sci8: 201–204, 1996.15. Shiraishi K, Ono N, Eguchi S, et al: Young’s syndrome

ssociated with situs inversus totalis. Arch Androl 50: 169–

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