The immotile-cilia syndrome. A congenital ciliary abnormality as an etiologic factor in chronic airway infections and male sterility.

We investigated six men and a woman suspected of suffering from congenital immotility of cilia. All had chronic airway infections, and the men had immotile spermatozoa. The woman and three men had Kartagener's syndrome. The investigations included measurements of the mucociliary transport in the lower airways and ultrastructural studies of the sperm tails or respiratory cilia (or both). Mucociliary transport was significantly delayed. Sperm tails lacked dynein arms in five patients. Respiratory cilia from the women and two men lacked dynein arms and were irregularly oriented. The results support the hypothesis that a congenital defect in the cilia and sperm tails will cause chronic respiratory-tract infections and male sterility--the immotile-cilia syndrome. In about half these patients there will also be a situs inversus--i.e., Kartagener's syndrome.     

Cilia with defective radial spokes: a cause of human respiratory disease.

We studied the fine structure of respiratory-tract cilia in three siblings with chronic respiratory disease, comparing them with those from a patient with Kartagener's syndrome who had dynein-deficient cilia and with control patients who had chronic bronchitis or chronic sinusitis. Electron microscopy of the siblings revealed a new abnormality in the ciliary axoneme--namely, lack of the radial spokes. Their cilia showed an eccentric central pair of tubules but otherwise had a normal central sheath, outer-doublet microtubules, nexin links and dynein arms. The cilia were immotile. Mucociliary clearance was completely lacking in the three siblings and in the patient with Kartagener's syndrome, but was normal in their parents and unaffected siblings. Sperm from the male sibling showed identical structural abnormalities and were immotile. We consider the radial spoke defect to be the congenital anomaly responsible for dysfunction of the mucociliary clearance mechanism in these three patients and of the immotile sperm in one of the them. This defect is apparently another cause of the "immotilecilia syndrome."     

Atypical bronchial cilia in children with recurrent respiratory tract infections. A comparative ultrastructural study

Ultrastructurally atypical bronchial cilia are studied and semiquantitatively analysed in 24 children suffering from recurrent respiratory tract infections with or without bronchiectasis. In patients with Kartagener's syndrome normal-looking and shortened dynein arms are present at some axonemal microtubular doublets. This finding suggests that the polymerization or assemblage of dynein molecules on microtubules only is defective but not totally lacking. Bilateral, local and partial absence of dynein arms is demonstrated in some of the patients with acquired unilateral bronchiectases. These patients also reveal anomalies of the "9 + 2" microtubular axonemal pattern. It is suggested that these abnormalities of the tubulin-dynein system are local and acquired defects that may impair bronchial mucociliary clearance. None of the patients with pneumonia and asthma or with cystic fibrosis studied show any anomalies of the dynein arms. However aberrant axonemal microtubular patterns and other ciliopathies such as naked axonemes and megacilia are present at times in these patients. We postulate that these atypical cilia are secondary acquired abnormalities. Only some patients with bacterial or viral pneumonia demonstrate a partial lack of dynein arms in bronchial cilia. Other ciliopathies such as megacilia, naked and intracytoplasmic axonemes and apical blebs are more frequent and more common in these patients. We suppose they manifest a secondary and rather aspecific pathogenic influence upon the bronchial ciliary substructure.     

Ultrastructural Abnormalities in Respiratory Cilia and Sperm Tails in a Patient with Kartagener's Syndrome

Ultrastructural abnormalities of spermatozoa and respiratory cilia have been reported in a male patient with Kartagener's syndrome and infertility.

In this patient both respiratory cilia and sperm tails showed defects in radial spokes and dynein arms. Such defects are heretofore undescribed in the same subject with immotile cilia syndrome.

Absence of both inner and outer dynein arms and absence of the inner dynein arms only were detected in spermatozoa and in respiratory tract cilia, respectively. Moreover, total absence of axoneme was seen in several sperm tails from this patient.

The possibility that the features described are of genetic origin is discussed.     

Isomerism of the right atrial appendages: clinical,anatomical, and microscopic study of a long-surviving case with asplenia and ciliary abnormalities

This study describes a case of isomerism of the right atrial appendages (bilateral morphologically right atrial appendages associated with complex congenital cardiac lesions) with ciliary abnormalities. Detailed investigation included gross anatomic dissection, review of the clinical history, and light, confocal, and electron microscopy. Clinically, this 40-year-old, long-surviving male patient had relatively good health until 4 years before death, which was due to cardiac failure. Surgical intervention consisted only of a Blalock-Taussig shunt (anastomosis of the right subclavian artery to the right pulmonary artery) at 6 years of age. Despite the presence of complex cardiac malformations and asplenia, his longevity may be attributed to the connection of the pulmonary veins to the atrium without pulmonary venous obstruction, pulmonary valvar stenosis rather than atresia, no significant atrioventricular valve regurgitation, and no serious infections during his life. Microscopic examination of bronchial epithelium revealed a narrow, disorganized epithelium with abundant goblet cells and short, angulated cilia with a random orientation and possibly an abnormal central microtubule doublet. These abnormalities were not present in controls, and have been noted in primary ciliary dyskinesia (PCD) or Kartagener's syndrome. Because this syndrome has classically been thought to cause random lateralization resulting in a mirror-imaged arrangement of the organs, the occurrence of truly isomeric patterns is not widely recognized. Whereas polysplenia and left bronchial isomerism have been reported to occur in immotile cilia syndrome, this is the first report to present detailed postmortem anatomic evidence of isomerism of the right atrial appendages, right bronchial isomerism, and asplenia in association with microscopy suggesting ciliary abnormalities.     

Problems in the differential diagnosis of Kartagener's syndrome and ATP-ase deficiency

Two cases of Kartagener's syndrome with a partial loss of the dynein arms and the central spokes within the cilia are presented. In light microscopic examination the predominant cell types were mast cells within the stroma and the epithelium and plasma cells and lymphocytes in the stroma. The reaction for the magnesium-activated ATP-ase located in the apical cytoplasm of ciliated cells was negative in one case and slightly positive in the same case on year later; in our second case, the ATP-ase reaction was variable, slightly to moderately positive, in the same biopsy. Besides the dynein arm defect this is a second defect of another ATP-ase, located in the apical region of the ciliated and mucus producing epithelial cells. Based on histological examination of nasal mucosal biopsies a differential diagnosis has been established for Kartagener's syndrome, the more common cystic fibrosis and the relative frequent allergic rhinitis.     

Ultrastructure of airways in children with asthma

This study describes the histopathology and ultrastructure of bronchial mucosa in lung biopsies from two children with bronchial asthma in remission, and compares them with lung samples from two children who died in status asthmaticus. Light microscopy of all samples showed changes typical of bronchial asthma, e.g. mucus plugging, goblet cell hyperplasia, 'thickening of bronchial basement membrane', peribronchial smooth muscle hypertrophy and eosinophilic infiltration. Electron microscopy revealed that the mucus plugs consisted of moderately electron-dense floccular material containing degenerate epithelial cells, macrophages and cell fragments. The luminal surfaces of ciliated cells showed cytoplasmic blebs and abnormal cilia. Mast cells in various stages of degranulation were scattered between bronchial epithelial cells. The subepithelial hyaline layer, commonly referred to as "thickened basement membrane", consisted of collagen fibrils in plexiform arrangement. The basement membrane proper appeared intact. These electron microscopic changes, particularly the presence of mast cells and subepithelial collagen deposits, were also found in autopsy samples. This combined light and electron microscopic study shows that marked, possibly irreversible changes may be present in the lungs of patients with severe bronchial asthma, even when they are asymptomatic. These pulmonary changes could be the direct consequence of mast cell activation and the release of various mediators. No evidence of immune complex deposition was found.     

Immunohistochemical analysis of rat and human respiratory cilia with anti-dynein antibody: comparison between normal cilia and pathological cilia in primary ciliary dyskinesia

Wistar Imamichi rat and human respiratory cilia were examined with anti-dynein antibody (AD2), which is specific for sea urchin sperm flagellar dynein. AD2-labelled fresh-frozen normal rat and human cilia stained clearly by immunofluorescence and the peroxidase-antiperoxidase (PAP) technique. On immunoelectron microscopy, AD2 labelled the outer dynein arms of normal human cilia. Paraffin-embedded normal human cilia also stained by immunofluorescence, although not always clearly. Neither the cilia of WIC-Hyd male rats, an animal model of Kartagener's syndrome, nor human cilia from patients with primary ciliary dyskinesia (PCD) reacted positively by the immunofluorescence or PAP technique. Western blots of normal rat cilia yielded a single band of about 450 kDa. In conclusion, AD2 recognizes the outer arm dynein heavy chains of healthy cilia and may be useful in diagnosing and classifying PCD light microscopically especially when only paraffin-embedded specimens are available. This approach may be of potential use for better defining and classifying PCD.     

Primary ciliary dyskinesia--Kartagener's syndrome and fertile male

Primary ciliary dyskinesia (PCD) is a rare genetic disease, in which a number of human organs are involved: upper and lower respiratory tract, spermatozoa in males and fallopian tube in females. In minority of cases PCD presents as Kartagener's syndrome (KS): sinusitis, bronchiectasis and inversion of internal organs. We report a case of Kartagener's syndrome in 43-year-old fertile male. After clinical and radiological examination and biopsy of the bronchial mucosa diagnosis of KS was established. The problem of fertility in KS males is discussed.     

Nine Japanese patients with immotile-dyskinetic cilia syndrome: an ultrastructural study using tannic acid-containing fixation

Respiratory cilia and sperm flagella of nine Japanese patients with immotile-dyskinetic cilia syndrome were studied ultrastructurally by using a tannic acid-containing fixative. Respiratory cilia from two female patients with Kartagener's syndrome and one male patient with situs inversus and sinobronchitis were completely immotile and lacked both dynein arms. However, approximately 30% of the spermatozoa from the male patient were weakly motile. In four patients with immotile cilia syndrome without Kartagener's triad, immotile respiratory cilia generally lacked the inner dynein arms. Two clinically unusual cases, an 11-year-old boy and a 29-year-old woman with prolonged saccharin test, recurrent bronchitis, and bronchiectasia, possessed motile respiratory cilia. Ultrastructurally, both dynein arms were normal, but numerous defective central pairs (more than 50% and 70%, respectively) were seen, and the defect in the second case was similar to the transposition of microtubules reported by Sturgess et al (N Engl J Med 303:318-322, 1980). However, defects in the first case were unique and may be congenital. We propose a new type of dyskinetic cilia syndrome with defective central pairs. Additionally, nasal cilia from a 35-year-old man with immotile cilia syndrome contained excess large singlets within ciliary axonemes consisting of 17 protofilaments.     

Genetic aspects of immotile cilia syndrome

The genetics of the immotile cilia syndrome has been analyzed in a series of 46 affected individuals from 38 families. Both sexes were equally affected: there were 20 males and 26 females in this series. All patients had upper and lower respiratory disease with chronic sinusitis, otitis, and chronic cough from early childhood. Bronchiectasis was common in older children and adults. Situs inversus occurred randomly, affecting 11 males and 15 females. Biopsies of nasal and bronchial mucosa from these subjects have been investigated by electron microscopy and identified as having specific ultrastructural defects of respiratory tract cilia including deficiencies in outer dynein arms (19), inner dynein arms (3), both inner and outer dynein arms (15), radial spoke defect (5); and microtubular transposition anomaly (4). Segregation analysis of proband sibships was consistent with autosomal recessive inheritance. However, the different ultrastructural defects that underly the immotile cilia syndrome involve presumably different genetic determinants, and the different types have not been analyzed separately. Examination of paternal age and birth order gave no evidence of new autosomal dominant mutation in the series.     

Pathomorphologic characteristics and classification of bronchitis in miners working on watered faces in coal mines

The material obtained from the lungs of 83 miners who worked in coal faces for 2-27 years, has been studied. On the basis of pathomorphological data acute and chronic bronchitis were subdivided into three forms each. Acute bronchitis: catarrhal-desquamative, productive-infiltrative, destructive-necrotic; chronic ones: productive-destructive, hypertrophic, atrophic. Each form of acute and chronic bronchitis has its own morphological varieties. The signs of professional bronchitis are not characteristic of acute bronchitis; coal just decreases the resistance of the bronchial mucous membrane. Chronic bronchitis is characterized by a number of distinctive morphological features: hyalinosis of the basal membrane, restructuring of the vascular network of the bronchial tree, and rarely squamous-cell metaplasia of the bronchial epithelium.     

The ultrastructure of the ciliary epithelium in patients with the Zivert-Kartagener syndrome, bronchiectasis and cystic hypoplasia of the lungs

Ultrastructure of the cilia of the bronchial epithelium was studied in 26 patients with Zivert-Kartagener syndrome, 12 patients with bronchiectasis and 10 patients with cystic lung hypoplasia. All changes of the cytolemma and cytoskeleton are found to be of a combined type. The degree of the bronchial inflammation was of the decisive influence on the state of the ciliary cells. Common features of the ultrastructural alterations are noted in the groups of patients compared. Ultrastructural defects characteristic for the patients with the Zivert-Kartagener triad were not found. It is concluded that all the ultrastructural defects of the ciliary epithelium were of the acquired character.     

Branching defects and mucosal diverticulosis of the bronchi in children as factors predisposing to the development of chronic inflammatory processes in the lungs

Clinical and bronchographic data were juxtaposed with the results of selective histological examination of the resected parts of lungs from 3 to 14-year-old children suffering for several years from persistent cough and recurrent pneumonias. The defects of small and mean bronchi branching are found in 66% of cases (out of 50) and in 64% there was diverticulosis of the mucous membrane of large and small bronchi that is followed by pseudopoliposis and the development of deep "pouches". All this is followed by bronchus-associated lymphoid tissue hyperplasia, development of peribronchial pneumonia foci, chronic bronchitis, obturation syndrome.     

Cilia in the Human Kidney

Utilizing transmission electron microscopy we have found multiple cilia with a 9 + 2 microtubular pattern (the same type found in the bronchial tree) in the renal tubules of four adults with the nephrotic syndrome. Each patient had a different pathologic diagnosis: amyloidosis, lipoid nephrosis, membranoprolif-erative glomerulonephritis, and focal segmental glomerulosclerosis. Previously, multiple renal tubular cilia with 9 + 2 architecture had been reported in patients with Burnett's syndrome, systemic lupus erythematosus, and congenital nephrotic syndrome. Additionally, we found multiple cilia in the metanephric tubules of 4 of 4 human fetuses. Pathologists should be aware that cilia with various microtubular patterns occur in human adult kidneys.     

Case for the Panel

Twenty-two cases displaying potentially precancerous epithelial changes of the bronchial mucosa—including basal and goblet cell hyperplasia, epidermoid metaplasia, and dysplasia—showed a wide variety of cilial abnormalities on the ultrastructural level. The changes comprised abnormal configurations of the ciliary plasma membrane, variations in the amount of ciliary matrix, disorganization of basal bodies, and diverse alterations of the axonemal microtubular pattern. More than one such alteration was observed in one and the same case, and there was no correlation with the actual type of epithelial lesion nor the degree of dysplasia. These changes, interpreted as abnormal ciliary regeneration in severely damaged ciliated cells, are potentially reversible and seem to represent a nonspecific response of the affected cells to an ample spectrum of noxes. Their diagnostic significance is poor, especially with regard to the modification of the axonemal microtubular pattern, unless the entire clinical picture suggests an immotile cilia syndrome.     

Ciliated adenocarcinomas of the lung: a tumor of non-terminal respiratory unit origin

Whereas most carcinomas occur through a sequential step, atypical adenomatous hyperplasia and bronchioloalveolar carcinoma pathway is known for pulmonary adenocarcinoma. This type is known as terminal respiratory unit adenocarcinoma. Based on our observation of transitions from normal ciliated columnar cells to adenocarcinoma via dysplastic mucous columnar cells, we reviewed our archive of pulmonary adenocarcinoma. Terminal respiratory unit type adenocarcinoma was defined as adenocarcinoma with type II pneumocyte, Clara cell, or bronchiolar cell morphology according to previous reports. Among 157 cases, 121 cases have been identified as terminal respiratory unit type adenocarcinoma and 36 cases as non-terminal respiratory unit type adenocarcinoma. Among non-terminal respiratory unit type adenocarcinoma, 24 cases revealed mucous columnar cell changes that were continuous with bronchial ciliated columnar cells. The mucous columnar cells became dysplastic showing loss of cilia, disorientation, and enlarged nuclei. Adenocarcinoma arose from these dysplastic mucous columnar cells and, characteristically, this type of adenocarcinoma showed acute inflammation, and honeycombing changes in the background. TTF1 immunostaining was consistently negative. In a case study with 14 males and 10 females, including 12 smokers or ex-smokers, EGFR and KRAS mutations were detected in 3 and 6 patients, respectively. We think that this kind of adenocarcinoma arising through mucous columnar cell change belongs to non-terminal respiratory unit type adenocarcinoma, and mucous columnar cell change is a precursor lesion of pulmonary adenocarcinoma.     

Ultrastructural changes in bronchial epithelial cilia in chronic pulmonary inflammation in children

Bronchial mucosal biopsy specimens from 40 children aged 6 to 14 years were examined, including 35 children with chronic pneumonia and 5 in whom the inflammatory process was consequent to bronchopulmonary developmental abnormalities. The ultrastructural changes revealed in the cilia are described in detail.     

Successful in-vitro fertilization pregnancy with spermatozoa from a patient with Kartagener's syndrome: case report

This paper reports on the successful treatment by in-vitro fertilization (IVF) of a couple in whom the male partner had Kartagener's syndrome. His spermatozoa were severely asthenozoospermic with deficient dynein arms and disordered microtubular configuration. On computer-assisted sperm analysis (CASA) motile spermatozoa displayed straight non-progressive motility with minimal amplitude of lateral head displacement and none were hyperactivated. This is the first case report in which spermatozoa with axonemal disruption in a man with immotile cilia syndrome (ICS) have been shown to be able to penetrate the zona pellucida and fertilize oocytes. IVF may be a suitable treatment for certain variants of ICS.