SIEWERT SYNDROME, INCLUDED
IMMOTILE CILIA SYNDROME
DEXTROCARDIA, BRONCHIECTASIS, AND SINUSITIS, INCLUDED
CILIARY DYSKINESIA, PRIMARY, 1, WITH OR WITHOUT SITUS INVERSUS
POLYNESIAN BRONCHIECTASIS KARTAGENER SYNDROME, INCLUDED
PCD
ICS
CILD1
Primary ciliary dyskinesia is a genetically heterogeneous autosomal recessive disorder resulting from loss of function of different parts of the primary ciliary apparatus, most often dynein arms. Kartagener (pronounced KART-agayner) syndrome is characterized by the combination of primary ... Primary ciliary dyskinesia is a genetically heterogeneous autosomal recessive disorder resulting from loss of function of different parts of the primary ciliary apparatus, most often dynein arms. Kartagener (pronounced KART-agayner) syndrome is characterized by the combination of primary ciliary dyskinesia and situs inversus (270100), and occurs in approximately half of patients with ciliary dyskinesia. Since normal nodal ciliary movement in the embryo is required for normal visceral asymmetry, absence of normal ciliary movement results in a lack of definitive patterning; thus, random chance alone appears to determine whether the viscera take up the normal or reversed left-right position during embryogenesis. This explains why approximately 50% of patients, even within the same family, have situs inversus (Afzelius, 1976; El Zein et al., 2003). - Genetic Heterogeneity of Primary Ciliary Dyskinesia Other forms of primary ciliary dyskinesia include CILD2 (606763), caused by mutation in the DNAAF3 gene (614566) on chromosome 19q13; CILD3 (608644), caused by mutation in the DNAH5 gene (603335) on 5p; CILD4 (608646) on 15q13; CILD5 (608647), caused by mutation in the HYDIN gene (610812) on 16q22; CILD6 (610852), caused by mutation in the TXNDC3 gene (607421) on 7p14-p13; CILD7 (611884), caused by mutation in the DNAH11 gene (603339) on 7p21; CILD8 (612274) on 15q24-q25; CILD9 (612444), caused by mutation in the DNAI2 gene (605483) on 17q25; CILD10 (612518), caused by mutation in the KTU gene (612517) on 14q21.3; CILD11 (612649), caused by mutation in the RSPH4A gene (612647) on 6q22; CILD12 (612650), caused by mutation in the RSPH9 gene (612648) on 6p21; CILD13 (613193), caused by mutation in the DNAAF1 gene (613190) on 16q24.1; CILD14 (613807), caused by mutation in the CCDC39 gene (613798) gene on 3q26.33; CILD15 (613808), caused by mutation in the CCDC40 gene (613799) on 17q25.3; CILD16 (614017), caused by mutation in the DNAL1 gene (610062) on 14q24.3; CILD17 (614679), caused by mutation in the CCDC103 gene (614677) on 17q21; CILD18 (614874), caused by mutation in the HEATR2 gene (614864) on 7p22; CILD19 (614935), caused by mutation in the LRRC6 gene (614930) on 8q24; CILD20 (615067), caused by mutation in the CCDC114 gene (615038) on 19q13; CILD21 (615294), caused by mutation in the DRC1 gene (615288) on 2p23; CILD22 (615444), caused by mutation in the ZMYND10 gene (606070) on 3p21; CILD23 (615451), caused by mutation in the ARMC4 gene (615408) on 10p; CILD24 (615481), caused by mutation in the RSPH1 gene (609314) on chromosome 21q22; CILD25 (615482), caused by mutation in the DYX1C1 gene (608706) on chromosome 15q21; CILD26 (615500), causd by mutation in the C21ORF56 gene (615494) on chromosome 21q22; CILD27 (615504), caused by mutation in the CCDC65 gene (611088) on chromosome 12q13; and CILD28 (615505), caused by mutation in the SPAG1 gene (603395) on chromosome 8q22. Ciliary abnormalities have also been reported in association with both X-linked and autosomal forms of retinitis pigmentosa. Mutations in the RPGR gene (312610), which underlie X-linked retinitis pigmentosa (RP3; 300029), are in some instances (e.g., 312610.0016) associated with recurrent respiratory infections indistinguishable from immotile cilia syndrome; see 300455. Afzelius (1979) gave an extensive review of cilia and their disorders. There are also several possibly distinct CILDs described based on the electron microscopic appearance of abnormal cilia, including CILD with transposition of the microtubules (215520), CILD with excessively long cilia (242680), and CILD with defective radial spokes (242670).
Kartagener, an internist in Zurich, and Horlacher described a familial form of bronchiectasis with dextrocardia and nasal polyps (Kartagener and Horlacher, 1936). Kartagener and Stucki (1962) found 334 cases in the literature and added 2 more cases of ... Kartagener, an internist in Zurich, and Horlacher described a familial form of bronchiectasis with dextrocardia and nasal polyps (Kartagener and Horlacher, 1936). Kartagener and Stucki (1962) found 334 cases in the literature and added 2 more cases of bronchiectasis with situs inversus. Arge (1960) described transposition of the viscera and sterility in men. Afzelius et al. (1975) and Afzelius (1976) reported a total of 3 patients with chronic sinusitis, bronchitis, and frequent pneumonias, colds, and ear infections since childhood. Two patients had bronchiectasis. All 3 patients also had situs inversus totalis. The 3 patients, and a brother of 1 of them, also had immotile spermatozoa, with the sperm tail appearing straight and stiff. Studies of tracheobronchial clearance showed no mucociliary transport, and studies of a bronchial mucosal biopsy of 1 patient showed no ciliary motion. Electron microscopy of the respiratory cilia and sperm showed scarce or absent dynein arms. Dynein arms normally form temporary cross bridges between ciliary filaments, and likely aid in generating movement in cilia and sperm tails. Afzelius (1976) concluded that the primary defect was in the production or function of dynein arms, which resulted in immotility with secondary recurrent infections. He further postulated that normal visceral asymmetry is determined by movement of cilia in certain embryonic epithelial tissues. Absence of normal ciliary movement from lack of dynein arms results in lack of definitive patterning; thus, chance alone would determine whether the viscera take up the normal or reversed position during embryogenesis. This hypothesis can explain why approximately half of familial cases of immotile cilia syndrome have situs inversus. Afzelius (1976) noted that semi-sterility of affected females had been observed. Eliasson et al. (1977) investigated 6 men and a woman with congenital immotility of cilia. All had chronic airway infections and the men had immotile spermatozoa. The woman and 3 men had situs inversus, consistent with a diagnosis of Kartagener syndrome. Mucociliary transport was significantly delayed in all patients, and the sperm tails lacked dynein arms in 5 men. Respiratory cilia from the women and 2 men lacked dynein arms and were irregularly oriented. The results supported the hypothesis that a congenital defect in the cilia and sperm tails resulted in chronic respiratory tract infections and male sterility. Approximately half of these patients have Kartagener syndrome. Eliasson et al. (1977) concluded that the gene involved may control normal situs. This control may be lacking in homozygotes such that situs is random. Waite et al. (1978) reported that Polynesian New Zealand Maori and Samoan Islanders with bronchiectasis had decreased or absent pulmonary mucociliary clearance and immotile sperm. Electron microscopy showed a defect in dynein arms in both sperm tails and pulmonary cilia. None had dextrocardia. Waite et al. (1981) found that ciliated bronchial or nasal epithelium from 20 Polynesian bronchiectatic patients showed partial or complete loss of dynein arms when examined by electron microscopy. Many patients had other ciliary abnormalities, with over 25% of cilia affected. Bronchiectasis tended to progress even after segmental resection. A population-based survey indicated a rate of bronchiectasis of 600 per 100,000. This same survey showed dextrocardia in 9 of 56,000 persons, none of whom showed radiologic evidence of bronchiectasis. Guerrant et al. (1978) noted that patients with the immotile cilia syndrome may present with bronchiectasis, sinusitis, and infertility; dextrocardia may not be present. Neustein et al. (1980) reported a patient with absence of only the inner dynein arm in respiratory cilia, rather than total absence of the dynein arms. The patient had repair of duodenal atresia at birth. Jonsson et al. (1982) described a 21-year-old man with recurrent sinusitis, bronchitis and otitis media, and situs inversus viscerum including left-sided appendix with appendicitis at age 12. He had a normal 4-year-old son. Electron microscopy of nasal and bronchial mucosa in the proband showed abnormal orientation of the basal processes of the cilia and absent dynein arms, but completely normal sperm. Schidlow et al. (1982) reported a family in which 1 sib had Kartagener syndrome and another had the polysplenia syndrome (208530). Only a small percentage (less than 20%) of the respiratory cilia of these 2 children were abnormal. Two female third cousins had Kartagener syndrome. Schidlow and Katz (1983) noted that structurally normal respiratory cilia may be found in otherwise typical Kartagener syndrome. Eavey et al. (1986) found significantly fewer ciliary outer dynein arms in all 4 patients with full-blown Kartagener syndrome and in 2 of 5 patients with sinusitis and bronchiectasis but no dextrocardia. No changes were found in carriers or in any other persons studied. The count of outer dynein arms was consistent in a given individual. Samuel (1987) reported a 26-year-old man with typical Kartagener syndrome except for the presence of normal spermatozoa. He had chronic sinopulmonary symptoms, situs inversus, and absent frontal sinuses, while his spermatozoa had normal motility, ultrastructure, and fertilizing capacity. Repeated brush biopsies of the bronchial epithelium showed only keratinized squamous epithelium and no ciliated cells. The patient had a twin brother, probably monozygotic, who died in early infancy following a respiratory infection. Noone et al. (1999) reported monozygotic twin women with primary ciliary dyskinesia associated with bronchiectasis, chronic sinusitis, and middle ear disease. Ciliary ultrastructural analysis showed deficiency of the inner dynein arms. One of the twins had situs solitus, and the other had situs inversus totalis. The findings were considered consistent with the hypothesis that situs inversus occurring in patients with primary ciliary dyskinesia is a random but 'complete' event in the fetal development of patients with this disorder.
In a patient with primary ciliary dyskinesia, Pennarun et al. (1999) identified 2 loss-of-function mutations in the DNAI1 gene (604366.0001-604366.0002). The patient was a 9-year-old boy, born to unrelated parents, who presented in early childhood with chronic respiratory ... In a patient with primary ciliary dyskinesia, Pennarun et al. (1999) identified 2 loss-of-function mutations in the DNAI1 gene (604366.0001-604366.0002). The patient was a 9-year-old boy, born to unrelated parents, who presented in early childhood with chronic respiratory symptoms characterized by chronic sinusitis, serous otitis, and recurrent episodes of bronchitis associated with severe segmental atelectasis that necessitated partial lobectomy. There was no family history of a similar disorder and no evidence of situs inversus. No ciliary beating was observed in samples of trachea mucosa, and transmission electron microscopy showed the absence of outer dynein arms in all cilia. Pennarun et al. (1999) excluded linkage between the DNAI1 gene and similar phenotypes in 5 other unrelated, consanguineous families, providing a clear demonstration of locus heterogeneity. Guichard et al. (2001) described a patient with Kartagener syndrome who was compound heterozygous for mutations in the DNAI1 gene (604366.0001; 604366.0003). The proband's brother had recurrent upper and lower respiratory tract infections and sterility without situs inversus. Repeated spermograms demonstrated immotile spermatozoa flagellae. Both brothers also had ureteral lithiasis. The cilia of the brother showed absent or truncated outer dynein arms. A second patient with Kartagener syndrome had situs inversus totalis, chronic sinusitis, bronchitis, recurrent otitis, and aplasia of the frontal sinus. She was found to be compound heterozygous for 2 mutations in the DNAI1 gene (604366.0001; 604366.0004).