The findings in a 40-year-old man with Kartagener's triad (sinusitis, bronchiectasis, and situs inversus) and corrected transpostion of the great vessels are presented. Electron microscopy revealed normal ultrastructure of the axoneme in both respiratory cilia and sperm tails. Light microscopic evaluation of the spermatozoa showed 50 percent motility, suggesting normal fertility. This assumption is confirmed, as the patient has two children. We suggest that an abnormal, uncoordinated motility pattern of the ultrastructurally normal respiratory cilia results in improper mucociliary clearance. This coordination is not needed in swimming spermatozoa, which could explain the apparent paradox between bronchopulmonary symptoms and normal fertility in our patient.
The classic traid of bronchiectasis, recurrent rhinosinusitis, and situs inversus is known as Kartagener's syndrome, first described in 1933.[1] Associated findings are nasal polyposis, conductive deafness, absence of frontal sinus development and aeration of mastoid cells, and, less commonly, several congenital cardiac and other defects.[2] In addition, male patients are almost invariably infertile.[3] Whereas female fertility is usually impaired, it is never completely absent.[4] The discovery of the absence or deficiency of the dynein arms of the microtubular doublets in the axonemal structure of both cilia and spermatozoa by several investigators has led to the definition of a new concept, "the immotile cilia syndrome."
As further investigations have revealed other ultrastructural defects, not per se leading to immotility, but rather to abnormal motility patterns, the new concept no longer covers the entire range of defects; and a new term, "primary ciliary dyskinesia," was coined.
CASE REPORT
A 40-year-old man presented with a history of recent respiratory infection and progressive development of dyspnea, edema of the lower limbs, orthopnea, and palpitations. Throughout childhood, there had been a history of chronic cough, production of mucopurulent sputum, sinusitis, rhinorrhea, and conductive deafness. Situs inversus totalis had been diagnosed at birth, and as a child the patient had suffered from maxillary sinusitis and mastoiditis and successfully underwent surgery at the age of 12 years. Later, he underwent correction of the nasal septum and also a tympanoplasty at the age of 30 years.
Physical examination showed a slender man who was moderately dyspneic, with a blood pressure of 120/80 mm Hg and an irregular pulse rate of 140 beats per minute. There was clubbing of the fingers. Auscultation revealed a loud second heart sound, a protosystolic murmur at the apex, and displacement of the cardiac impulse toward the right side. The liver was palpable three fingerbreadths below the left costal margin. There was dullness on percussion and diminished breath sounds in the left lung base. The lower limbs showed pitting edema.
The white blood cell count was 12,200 x [10.sup.9]/L; the urea level was 47 mg/dl (normal, <46 mg/dl); the creatinine level was 1.5 mg/dl (normal, <1.2 mg/dl); [gamma]-GTP level was 48 units/L (normal, <28 units/L); and SGPT level was 34 units/L (normal, <22 units/L).
Levels of immunoproteins and [[alpha].sub.1]-antitrypsin were normal. The pleural effusion was caused by transudation.
A chest x-ray film obtained on admission showed dextrocardia, cardiomegaly, and bilateral basal pleural effusion. The electrocardiogram showed dextrocardia and atrial fibrillation with rapid ventricular response. A bronchial infection with Streptococcus pneumoniae and Branhamella catarrhalis was diagnosed. Treatment was immediately started with ampicillin, furosemide, and digoxin, with rapid clinical improvement. Echographic investigation of the abdomen confirmed the presence of total situs inversus. A CT scan of the thorax showed bronchiectatic deformation of the lung parenchyma. X-ray films and a CT scan of the sinuses showed the absence of frontal sinuses, underdevelopment of mastoid cells, and signs of pansinusitis.
Pulmonary function tests revealed a moderately broncho-obstructive pattern: [FEV.sub.1] of 2.04 L/s (49 percent of predicted), with improvement after bronchodilating therapy to an [FEV.sub.1] of 2.83 L/s (68 percent of predicted); and normal arterial blood gas levels.
During bronchoscopy, very firm purulent material was aspirated, and biopsies for light and electron microscopy were sampled. Light microscopic examination of the bronchial mucosa was compatible with signs of acute and chronic bronchitis. Electron microscopy revealed respiratory cilia with a normal axonemal structure (Fig 1). The light microscopic evaluation of the spermatozoa confirmed more than 50 percent motility. Electron microscopy of the spermatozoa showed a normal axonemal structure.
Echocardiography and a gated blood pool scan were performed, which showed dilatation and hypertrophy of the right ventricle, with a slight tricuspid regurgitation and global left ventricular ejection fraction of 46 percent. Left and right cardiac catheterization confirmed associated heart disease: congenitally corrected transposition of the great vessels and a minor atrial septal defect.
Paternity of the patient's two children was established by means of DNA investigation.
DISCUSSION
Afzelius[5] was the first to recognize that the relationship of Kartagener's triad with male infertility was due to immotility in both spermatozoa and respiratory cilia. Pedersen and Mygind[6] suggested that this immotility was caused by an abnormal structure of the axonema, consisting of the absence of dynein arms. The protein, dynein, exhibits adenosine triphosphatase activity, necessary for ciliary motility, since it induces sliding of adjacent microtubule doublets.[7] At that time a larger group of patients characterized by immotile cilia and sperm tails--without situs inversus--was gathered under the term, "immotile cilia syndrome."[8,9]
Later, other deficiencies in the ultrastructural organization were described (Fig 2): absence of the inner dynein arms (C) or the radial spokes (E); and transposition of microtubules to the center of the axonema (F).[10-14] These observations did not necessarily result in immobilization, but rather in the absence of effective movement. To include findings such as asynchronous motility patterns, reduced ciliary beating, rotational vibrational movement, and even hypermotile cilia, the term, "primary ciliary dyskinesia," was coined.[15-19]
Investigation of our patient provided the clinical diagnosis of Kartagener's syndrome associated with congenitally corrected transposition of the great vessels. To try to find an explanation for the unexpected motility of the sperm tails and the paternity in our patient, electron microscopic examination of cilia and spermatozoa was performed. No ultrastructural defects or abnormalities were detected in the axonemal structure of the respiratory tract cilia and spermatozoa.
Other investigators have observed extraordinary cases. Jonsson et al[.sup.20] reported the findings in a patient with Kartagener's syndrome and a discordance between cilia lacking dynein arms and actively motile spermatozoa without abnormalities of the flagellar ultrastructures. Escudier et al[21] described a 28-year-old man with Kartagener's syndrome and normal cilia and sperm tails, but unexplained infertility. Herzon and Murphy[22] described a 32-month-old boy with Kartagener's syndrome with normal ultrastructure of the respiratory cilia. Function studies were not performed.
Greenstone et al[23] presented the only case with normal ultrastructure and function of both respiratory cilia and spermatozoa. As Greenstone pointed out, a possible explanation for this paradox is the "supercoincidence" of a dextrocardia and -- in our patient -- corrected transposition of the great vessels, together with bronchiectasis and pansinusitis. The respiratory problems would, in this case, have arisen in childhood, probably after infections, without ultrastructural defect and thus, in the strictest sense, not representing a true case of Kartagener's or immotile-cilia syndrome. Another opinion could be that of a far-reaching heterogeneity (C), probably genetically mediated, influencing the expression of ineffective motility in these patients without recognition of ultrastructural defects of the ciliary axonema itself.
As noted by several other investigators, it is possible that asynchronous beating, reduced or excessive motility, rotating or vibrating movement, or random ciliary orientation could result in discoordination of respiratory cilia and contribute to impaired mucociliary clearance; however, this coordination is not needed in swimming spermatozoa, which could explain the apparent paradox between bronchopulmonary disease and normal fertility in our patient.[4,15,18,19]
REFERENCES
[1] Kartagener M. Zur Pathogenese der Bronchiektasien: 1. Mitteilung: Bronchiektasien bei Situs viscerum inversus. Beitr Klin Tuberk 1933; 83:498-501
[2] Rott H-D. Kartagener's syndrome and the syndrome of immotile cilia. Hum Genet 1979; 46:249-61
[3] Camner P, Mossberg B, Afzelius BA. Evidence for congenitally nonfunctioning cilia in the tracheobronchial tract in two subjects. Am Rev Respir Dis 1975; 112:807-09
[4] Afzelius BA, Eliasson R. Male and female infertility problems in the immotile-cilia syndrome. Eur J Respir Dis 1983; 64(suppl 127):144-47
[5] Afzelius BA. A human syndrome caused by immotile cilia. Science 1976; 193:317-19
[6] Pederson H, Mygind N. Absence of axonemal arms in nasal mucosa cilia in Kartagener's syndrome. Nature 1976; 262:494-95
[7] Fawcett DW. What makes cilia and sperm tails beat? N Engl J Med 1977; 297:46-8
[8] Eliason R, Mossberg B, Camner P, Afzelius BA. The immotile-cilia syndrome: A congential ciliary abnormality as an etiologic factor in chronic airway infections and male sterility. N Engl J Med 1977; 297:1-6
[9] Rossman CM, Forrest JB, Ruffin RE, Newhouse MT. Immotile cilia syndrome in persons with and without Kartagener's syndrome. Am Rev Respir Dis 1980; 121:1011-15
[10] Sturgess JM, Chao J, Wong J, Aspin N, Turner JAP. Cilia with defective radial spokes: a cause of human respiratory disease. N Engl J Med 1979; 300:53-6
[11] Sturgess JM, Chao J, Turner JAP. Transposition of ciliary microtubules: another cause of impaired ciliary motility. N Engl J Med 1980; 303:318-22
[12] Chao J, Turner JAP, Sturgess JM. Genetic heterogeneity of dynein-deficiency in cilia from patients with respiratory disease. Am Rev Respir Dis 1982; 126:302-05
[13] Van der Baan S, Veerman AJP, Weltevreden E, Feenstra L. Primaire ciliaire dyskenisie: trilhaaractiviteit en ultrastructuur bij 11 patienten met het syndroom van Kartagener. Ned Tijdschr Geneeskd 1982; 126:2376-79
[14] Levison L, Mindorff CM, Chao J, Turner JAP, Stringer DA. Pathophysiology of the ciliary motility syndromes. Eur J Respir Dis 1983; 64(suppl 127):102-16
[15] Rossman C, Forrest J, Newhouse M. Motile cilia in "immotile cilia" syndrome. Lancet 1980; 1:1360
[16] Pederson M, Mygind N. Ciliary motility in the "immotile cilia syndrome." Br J Dis Chest 1980; 74:239-44
[17] Rossman CM, Forrest JB, Lee RMKW, Newhouse MT. The dyskinetic cilia syndrome: ciliary motility in immotile cilia syndrome. Chest 1978; 4:580-82
[18] Rutland J, De Iongh RU. Random ciliary orientation: a cause of respiratory tract disease. N Engl J Med 1990; 13:1681-84
[19] Pederson M, Stafanger G. Bronchopulmonary symptoms in primary ciliary dyskinesia: a clinical study of 27 patients. Eur J Respir Dis 1983; 64(suppl 127):118-28
[20] Jonsson MS, McCormick JR, Gillies CG, Gondos B. Kartagener's syndrome with motile spermatozoa. N Engl J Med 1982; 307:1131-33
[21] Escudier E, Escalier D, Homasson JP, Pinchon MC, Bernaudin JF. Unexpectedly normal cilia and spermatozoa in an infertile man with Kartagener's syndrome. Eur J Respir Dis 1987; 70:180-86
[22] Herzon FS, Murphy S. Normal ciliary ultrastructure in children with Kartagener's syndrome. Ann Otol Rhinol Laryngol 1980; 89:81-3
[23] Greenstone M, Rutman A, Pavia D, Lawrence D, Cole PJ. Normal axonemal structure and function in Kartagener's syndrome: an explicable paradox. Thorax 1985; 40:956-57
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