Ultrastructural abnormalities of respiratory cilia: a 25-year experience.
* Context.--Ciliary dyskinesia is a rare, but significant, cause of
chronic respiratory infections, and transmission electron microscopy is
a critical adjunct to making the diagnosis.
Objective.--To investigate a single institution's experience with patients demonstrating abnormal ciliary ultrastructure.
Design.--Retrospective clinicopathologic review of 278 bronchial or nasal turbinate brushings or biopsies from 1983 through 2007.
Results.--There were 12 women and 9 men (mean age, 19.6 years; range, 1-54 years) with abnormal ciliary ultrastructure. Clinical history was unavailable in 3 patients, 15 (83%) of 18 patients presented with chronic or recurrent upper respiratory infections, and 3 (17%) presented with infertility. Seven (39%) of 18 patients had findings of Kartagener syndrome with situs inversus, dextrocardia, and bronchiectasis. Truncation or absence of inner or outer dynein arms occurred in 15 (71%) of 21 cases, and 5 (24%) revealed transposition defects with displacement of the central microtubules and peripheral doublets in 9 + 0 and 8 + 1 patterns. Radial spoke defects with microtubular disarray occurred in 4 (19%) of 21 cases. Compound cilia with multiple axonemes within a single outer sheath and supernumerary microtubules each occurred in 2 (10%) of the cases. Random ciliary orientation was also found in 2 (10%) of the cases, and dense granular basal body inclusions occurred in 1 case (5%). Multiple abnormalities occurred in 6 (29%) of the 21 cases.
Conclusions.--Most patients presented with chronic respiratory tract infections or infertility. Dynein arm defects, transposition defects, and radial spoke defects were the most commonly encountered abnormal findings. Less-frequent abnormal findings included compound cilia, supernumerary microtubules, and dense granular basal body inclusions.
Respiratory tract infections
(Development and progression)
Cilia and ciliary motion (Properties)
Transmission electron microscopes (Usage)
Clinical pathology (Research)
Plesec, Thomas P.
McMahon, James T.
Prayson, Richard A.
|Publication:||Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2008 College of American Pathologists ISSN: 1543-2165|
|Issue:||Date: Nov, 2008 Source Volume: 132 Source Issue: 11|
|Topic:||Event Code: 310 Science & research|
|Geographic:||Geographic Scope: United States Geographic Code: 1USA United States|
Ciliated cells are found lining various body cavities, such as the
respiratory tract, the ventricles in the central nervous system, the
ductuli efferentes, the fallopian tubes, and the retina. Defects in
ciliary anatomy can, therefore, lead to an array of diseases, such as
chronic respiratory infections, hydrocephalus, infertility, and
blindness. Normal ciliary ultrastructure was initially described by
Afzelius in 1959 and consists of 9 peripheral microtubule doublets
surrounding a central pair of microtubule singlets (Figure 1). (1) Each
doublet has inner and outer dynein arms, which are able to
"walk" along the adjacent microtubular doublet, bending the
cilium. Radial spokes between the doublets and a central sheath provide
structural support. (2) Similar microtubular structures are also present
in spermatozoal flagella, and the absence of one or both dynein arms in
patients with immotile spermatozoa was first reported in 1975. (1) These
patients were also diagnosed with Kartagener syndrome, characterized by
the classic triad of sinusitis, bronchiectasis, and situs inversus.
Since then, numerous other ciliary structural defects have been
described and implicated as causes of ciliarelated disease. These
include absence of radial spokes with microtubular disarray, absence of
the central pair of microtubules (with or without transposition of one
of the outer pairs of microtubules to the center position, socalled 9 +
0 or 8 + 1 defects), absence of the central sheath, supernumerary
doublets, absence of the axoneme, elongated cilia, and random ciliary
orientation, among others. (1,2)
Several series (3-6) since 2000 have reported on patients with ciliary dyskinesia, often focusing on clinical presentations and outcomes. This study sought to add to the literature by reviewing one institution's experience with ciliary biopsy and brushing specimens, specifically focusing on the clinicopathologic features of cases with ultrastructurally abnormal cilia.
MATERIALS AND METHODS
After receiving institutional review board approval, results of transmission electron microscopy (TEM) performed on respiratory cilia of patients from 1983 through 2007 were retrospectively reviewed. The study group consisted of those cases with ultrastructurally abnormal cilia. Specimens consisted of bronchial or nasal turbinate brushings. Motility was assessed by evaluation of saline wet-mount preparations for assessment of wave patterns. In specimens demonstrating absent ciliary motility, cell viability was assessed by trypan blue dye exclusion. Tissue submitted for ultrastructural evaluation was fixed in 3.75% glutaraldehyde, 6% sucrose, and buffered with 0.1M cacodylate at pH 7.2 to 7.4. Postfixation used 1% osmium tetroxide and 0.1M cacodylate at pH 7.2 to 7.4. Tannic acid was not used. Forty- to sixty-nanometer sections were cut and stained in uranyl acetate and lead citrate. Surgical pathology reports were reviewed to classify the ultrastructural ciliary defects. At the time of diagnosis, at least 50 cross sections were examined, similar to other reports in the literature. (7-10) The retrospective nature of this series precluded precise quantification of the ciliary defects, given the possibility of selection bias in the preserved photomicrographs. However, upon review of the TEM photomicrographs, a semiquantitative analysis was performed. Those defects that occurred in a minority of ciliary cross sections (approximately <20%) were ruled out as an etiology of primary ciliary dyskinesia (PCD) because these defect frequencies are often seen in healthy patients or in secondary processes.8,11-15
[FIGURE 1 OMITTED]
Ciliary brushing results from 278 patients were reviewed. Of those, 128 (46%) were excluded because they lacked TEM studies after the motility study findings were normal or, rarely, because the specimens were inadequate. The remaining 150 (54%) of 278 specimens underwent electron microscopic examination, with or without motility studies, and 14% (21/150) were found to have abnormal ciliary structure.
The clinicopathologic features of the 21 patients with abnormal TEM findings are summarized in Table 1. The group consisted of 12 women and 9 men (mean age, 19.6 years; range 1-54 years). In 3 (14%) of the 21 patients, clinical information was unavailable. Of the remaining 18 patients, 15 (83%) presented with chronic or recurrent upper respiratory infections. Three (17%) of the 18 patients presented with infertility, 1 of whom had infertility as the sole complaint. Seven (39%) of the 18 patients had findings consistent with Kartagener syndrome, with situs inversus, dextrocardia, and bronchiectasis. Fourteen (78%) of the 18 patients with available clinical history were found to have PCD, whereas only 1 (6%) of the 18 patients was documented to have acquired or secondary ciliary dyskinesia (SCD).
Fresh tissue studies demonstrated absent or weak ciliary motility in viable epithelial cells in 14 (67%) of 21 cases. Two additional cases had viable epithelial cells that demonstrated abnormal motility: one with rapid ciliary activity and metachronous wave patterns with focal immotility and premature ending of the wave motion, and the other with demonstrated activity but no identifiable metachronicity. Three cases (14%) showed normal ciliary motility with metachronic wave patterns. Ciliary motility studies were not performed in 2 patients.
Table 2 lists the various cilia ultrastructural abnormalities and correlates those abnormalities with the presence or absence of documented PCD. Most cases of PCD involved dynein arm defects (10/14; 71%). Other defects associated with documented PCD included transposition defects (2/14; 14%), abnormal ciliary orientation (1/14; 7%), and radial spoke defects (1/14;7%). When abnormalities were encountered only rarely or infrequently (<20%), they were excluded as an etiology for the PCD. Cases with only rare or infrequent ultrastructural abnormalities included transposition defects (n = 2), supernumerary microtubules (n = 2), radial spoke defects (n = 1), compound cilia (n = 1), and basal body inclusions (n = 1).
Truncation or absence of inner or outer dynein arms was the most frequently encountered ultrastructural abnormality, occurring in 71% (15/21; Figure 2, A) of the cases. The abnormality was the sole defect in all but 1 case, which showed radial spoke defects and compound cilia. Follow-up evaluation in that case, 4 months later, revealed normal ciliary motility and completely normal cilia ultrastructure, findings consistent with acquired defects.
Cilia in 5 (24%) of the 21 cases revealed displacement of the central microtubules and peripheral doublets in 9 + 0 and 8 + 1 patterns (Figure 2, B). The resultant axoneme was seen in an 8 + 1 pattern, if a doublet was displaced to the center--the so-called transposition defect--and in a 9 + 0 arrangement, if no displacement occurred. Three cases with transposition defects also revealed other abnormalities, including supernumerary microtubules and radial spoke defects in one case, radial spoke defects and compound cilia in another, and random ciliary orientation in the third.
Radial spoke defects were evidenced by microtubule disarray or displacement (not absence) of the central singlet pair, and these defects involved 4 (19%) of the 21 cases (Figure 2, C). Three contained additional abnormalities of cilia. Two cases showed transposition defects, and 2 cases revealed compound cilia. A single case with radial spoke defects demonstrated supernumerary microtubules, whereas another showed absent dynein arms.
Random ciliary orientation was seen in 2 (10%) of the 21 cases (Figure 2, D): one had transposition defects, and the other had dense granular basal body inclusions along with supernumerary microtubules. Compound cilia (Figure 3, A), which consisted of multiple axonemes within a single outer sheath, occurred in 2 (10%) of the cases. The TEM showed each had multiple other abnormalities of the cilia, including radial spoke defects in both, as well as transposition defects and absent dynein arms in 1 each. Supernumerary microtubules (Figure 3, B) occurred in 2 (10%) of the cases, each with defects, including transposition defects and radial spoke defects in 1 and dense granular basal body inclusions in another (Figure 3, C). Multiple abnormalities were observed in 6 (29%) of the 21 cases.
Abnormal cilia are a common occurrence in human bronchial epithelium; 4% to 10% of cilia in healthy patients can reveal ultrastructural abnormalities. (8,13,14) In chronic respiratory disease, the percentage of abnormal cilia can increase to 20%. (8,11-15) McDowell et al (11) reported that 97% (30/31) of the patients with various neoplastic and nonneoplastic diseases had abnormal ciliary ultrastructure. However, the abnormalities were rare in all specimens, with most of the cilia examined revealing normal ultra structure. Al-Rawi et al (15) found that 87% (20/23) of the patients with severe chronic sinusitis had ultrastructural defects, including compound cilia, microtubule defects, and dynein arm defects. Although not precisely quantified, the abnormalities were typically found in a minority of the cilia. Therefore, authorities have concluded that patients with acquired ciliary abnormalities have only a minority of cilia with ultrastructural defects, whereas patients with PCD have defects in most, or all, cilia. (13,15,18,19)
[FIGURE 2 OMITTED]
[FIGURE 3 OMITTED]
Secondary ciliary dyskinesia refers to ciliary abnormalities caused by environmental factors, such as viral or bacterial infections or other sources of chronic mucosal inflammation. Distinguishing PCD from SCD by light microscopy or electron microscopy can be quite difficult but is important because SCD is potentially reversible.2 Perhaps the most definitive laboratory method for distinguishing PCD from SCD was described by Jorissen et al.20 Ciliated cells were biopsied and stimulated to undergo ciliogenesis in culture. After ciliogenesis, the cultured cilia from all patients with SCD had coordinated ciliary activity, whereas none of the cilia from patients with PCD did. The major drawbacks are that the test takes up to 6 weeks and is performed by only a few centers.
In truth, few ultrastructural defects are specific for either PCD or SCD. Possible exceptions include the absence of dynein arms and the high percentage of eccentric or absent central pairs, defects generally thought to be specific for PCD. (2,20) However, not all patients with PCD have disease characterized by the absence of dynein arms or by absent central pairs, and numerous other defects have been described. Even normal ultrastructural findings have been reported, (20) and 25% of patients with PCD may have nonclassic findings.20,21 Although groups have attempted to standardize criteria for the diagnosis of PCD by TEM, (7,14,22) none have been universally accepted. The causes of this lack of standardization are multifaceted. Primary ciliary dyskinesia is quite rare, with an estimated incidence of 1:15000; it has many clinical manifestations and mimics; and it lacks a universally agreed upon, sensitive, and specific diagnostic test. (17) Transmission electron microscopy has been heralded as the gold standard, but again, standard diagnostic criteria for the diagnosis are lacking. The multitude of ultrastructural defects reportedly associated with PCD (12 according to Afzelius)2 and the rarity of the disease make standardization of TEM interpretation difficult, if not impossible. Even false-positive and false-negative rates have never been reported for TEM. (16) In the absence of ciliary culture, documenting the persistence of the ultrastructural defects over time may provide added specificity to the diagnosis of PCD. (12,14)
Dynein arm defects are considered the most frequent ultrastructural abnormality of cilia, comprising from 50% to greater than 80% of all abnormalities. (6,14,22-25) Of the patients studied in this series, 71% (15/21) demonstrated absent or truncated dynein arms, 10 of whom had documented PCD. The inner and outer dynein arms serve as the motor apparatus for the bending of cilia.26 Peripheral microtubule doublets contain both the inner and outer dynein arms, and dynein arm defects are characterized by complete absence or shortening of one or both of the arms. The defects are considered by most to be congenital in nature and inherited in an autosomal recessive manner. (25) Two genes have been documented to cause dynein arm defects, accounting for up to 38% of PCD cases. (25) The DNAI1 gene, located on bands 9p13 to 9p21, encodes a component protein of the outer dynein arm. These patients often present with PCD, randomization of right/left body symmetry, and infertility. (23,25) The second gene, DNAH5, is located on chromosome arm 5p, and mutations have been associated with outer dynein arm absence or shortening and right/left asymmetry. (23,25,27) A mutation to DNAH11 on band 7p21 was initially described in one patient with PCD, and situs inversus and has been validated in a kindred of 6, interestingly, with normal ciliary ultrastructural findings. (21,28)
Twenty-four percent of the patients demonstrated transposition defects, 2 of whom had documented PCD. These defects are thought to comprise roughly 10% of ciliary abnormalities. (23) The normal ciliary axoneme arrangement consists of a pair of central microtubule singlets surrounded by 9 microtubule doublets, the 9 + 2 arrangement. The transposition defect results from absence of the central singlet pair, causing a 9 + 0 arrangement to the axoneme. Often, 1 of the 9 peripheral doublets is translocated to the center of the axoneme, causing an 8 + 1 arrangement. (29) To date, there are no genes known to cause the transposition defect.
Nineteen percent of patients with ultrastructural ciliary abnormalities exhibited radial spoke defects, 1 of whom had documented PCD. According to reports, radial spoke defects are thought to account for about 6% of defects. (23) Radial spokes are proteins that provide structural support and tethering to the central pair through connections between each microtubule pair and the central sheath. Absence of the radial spokes causes displacement without loss of the central pair and is readily recognized by TEM. (30) Again, no specific genetic causes have been found so far.
A variety of other abnormalities were seen less frequently in this series. Compound cilia were seen in 2 cases and are thought to be secondary defects. (26) They are evidenced by multiple axonemes within one outer sheath. Supernumerary microtubules also occurred in 2 patients and have been reported as a cause of PCD. (31) Supernumerary microtubules consist of extra microtubules, beyond the normal 9 + 2 arrangement. Abnormal or random ciliary orientation with normal individual ciliary ultrastructural findings were also identified in 2 patients, 1 of whom had documented PCD. To effectively clear mucus via coordinated movement, cilia need to be oriented in a similar plane. Random ciliary orientation as a cause of PCD was first reported in 1990 (32) and has since been challenged by Jorissen and Willems (24) who found that ciliary disorientation as the sole ultrastructural abnormality was eliminated after ciliogenesis in culture.
Our series provides further evidence that absent dynein arms are the most common ciliary abnormality in patients with PCD. Other less-frequent defects associated with PCD include transposition, radial spokes, and abnormal cilia orientation. The other abnormalities encountered in this series were rare and were never the sole defect in patients with documented PCD. Although standardized pathologic criteria for the diagnosis of PCD are lacking, this series provides further evidence that frequent dynein arm, transposition, radial spoke, and orientation defects are associated with the disease.
Accepted for publication April 23, 2008.
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Thomas P. Plesec, MD; Angela Ruiz, MD; James T. McMahon, PhD; Richard A. Prayson, MD
From the Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Richard A. Prayson, MD, Department of Anatomic Pathology (L25), Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland OH 44195 (e-mail: firstname.lastname@example.org).
Table 1. Clinicopathologic Summary of 21 Patients With Abnormal Cilia Ultrastructure * Case Age, No. y/Sex Clinical Presentation PCD 1 7/F Recurrent sinusitis, otitis media, Yes situs inversus, dextrocardia 2 8/M Recurrent sinusitis, otitis media, Yes pneumonia, situs inversus, mesocardia, multiple congenital cardiac malformations 3 25/F Recurrent upper respiratory tract Yes infections, infertility 4 8/M Chronic otitis media, recurrent Yes cough, situs inversus, dextrocardia 5 4/M Recurrent sinusitis, pneumonia No f/u 6 10/F Chronic sinusitis, recurrent Yes pneumonia, otitis media, bronchiecta- sis, situs inversus, dextrocardia 7 54/M Data unavailable No f/u 8 13/F Chronic productive cough, bronchi- Yes ectasis, situs inversus, dextrocardia 9 53/F Chronic sinusitis, bronchiectasis No f/u 10 6/M Data unavailable No f/u 11 5/F Chronic sinusitis, asthma, Yes bronchiectasis 12 33/M Infertility No f/u 13 7/M Data unavailable No f/u 14 49/F Chronic sinusitis, bronchiectasis Yes and infertility 15 40/F Chronic sinusitis and diffuse Yes bronchiectasis 16 7/F Chronic sinusitis and productive Yes cough, bronchiectasis 17 2/F Chronic otitis media, sinusitis, Yes and cough 18 1/M Recurrent otitis media, asthma Yes 19 7/F Chronic otitis media, asthma, situs Yes inversus, dextrocardia, seizures 20 46/F Laryngeal dysfunction No 21 26/M Situs inversus Yes Case Age, No. y/Sex Ciliary Motility Ultrastructure 1 7/F None Absent/truncated dynein arms 2 8/M Mostly none; Absent/truncated dynein arms rare jerky movement 3 25/F Metachronic wave Transposition defect; abnormal pattern with orientation focally absent, sluggish 4 8/M Rare twitchy Radial spoke defect; rare movement; absent supernumerary microtubules; motility rare transposition defect 5 4/M Normal Rare supernumerary microtubules; rare dense granular basal body inclusions 6 10/F None Absent/truncated dynein arms 7 54/M None Transposition defect 8 13/F None Absent/truncated dynein arms 9 53/F None Radial spoke defect 10 6/M Normal Absent/truncated dynein arms 11 5/F Focal metachronic Transposition defect; rare radial wave pattern spoke defect; rare compound cilia 12 33/M None Absent/truncated dynein arms 13 7/M None Absent/truncated dynein arms 14 49/F Immotile and Absent/truncated dynein arms sluggish 15 40/F None Absent/truncated dynein arms 16 7/F Present; no Abnormal orientation; rare metachronicity transposition defect 17 2/F Absent/sluggish Absent/truncated dynein arms 18 1/M Quivering/sluggish Absent/truncated dynein arms 19 7/F None Absent/truncated dynein arms 20 46/F Not performed Absent/truncated dynein arms, radial spoke defect, compound cilia 21 26/M Not performed Absent/truncated dynein arms * PCD indicates primary ciliary dyskinesia; f/u, follow-up. Table 2. Frequency of Specific Cilia Ultrastructure Abnormalities and Associations With Primary Ciliary Dyskinesia (PCD) * Rare/ PCD Infrequent Cilia Defect No. (%) (n = 14) Defects Dynein arm 15 (71) Yes (10) 0/15 Transposition 5 (24) Yes (2) 2/5 Radial spoke 4 (19) Yes (1) 1/4 Abnormal orientation 2 (10) Yes (1) 0/2 Compound cilia 2 (10) No 1/2 Supernumerary microtubules 2 (10) No 2/2 Basal body inclusions 1 (5) No 1/1 Multiple defects 6 (29) NA NA * Cases with rare/infrequent defects occurred in <20% of cilia cross sections. NA indicates not applicable.
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