Ciliary Dyskinesia, Primary, 7

A number sign (#) is used with this entry because primary ciliary dyskinesia-7 (CILD7) is caused by homozygous or compound heterozygous mutation in the DNAH11 gene (603339) on chromosome 7p15.

For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia and the Kartagener syndrome, see CILD1 (244400).

Description

Primary ciliary dyskinesia is an autosomal recessive disorder resulting from loss of normal ciliary function. Kartagener (pronounced KART-agayner) syndrome is characterized by the combination of primary ciliary dyskinesia and situs inversus, 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).

Clinical Features

Schwabe et al. (2008) reported a German family in which 6 sibs had primary ciliary dyskinesia, 1 of whom also had situs inversus totalis, consistent with Kartagener syndrome. Clinical features included chronic respiratory infections, chronic sinusitis, recurrent bronchitis, and pneumonia beginning in infancy or early childhood. Three patients had recurrent otitis media. Pulmonary examination showed normal lung function with restrictive or obstructive changes during exacerbation. Three individuals had bronchiectasis, and 5 had chronic mucosal inflammatory changes with purulent hypersecretions and the presence of bacteria. One affected male fathered a child without use of medical assistance, suggesting normal fertility. Analysis of respiratory cilia from 5 patients showed severely altered beating patterns, with nonflexible and hyperkinetic beating of axonemes only detectable in slow-motion analysis of video microscopy. Electron microscopy showed normal axonemal ultrastructure.

Lucas et al. (2012) reported 2 unrelated patients with CILD7. Both had neonatal respiratory symptoms, chronic cough, rhinitis, and otitis. Electron microscopy showed normal ciliary ultrastructure in both patients. However, functional studies showed that 1 patient had rapid, erratic, dyskinetic ciliary beating, whereas the other had static cilia with slow activity.

Cytogenetics

Pan et al. (1998) reported an infant boy with primary ciliary dyskinesia, complete situs inversus, and cystic fibrosis (CF; 219700). He developed respiratory distress at 10 days of age and later showed growth retardation. Genetic analysis showed paternal isodisomy for 21 loci on chromosome 7 as well as homozygosity for a common mutation in the CFTR gene (602421.0001) on chromosome 7q31, which was absent in the mother. Bronchial cilia showed no normal ciliary motion but were structurally normal on electron microscopy. Other known genetic causes for the situs abnormalities were excluded. Pan et al. (1998) suggested that the most likely explanation for the uniparental disomy was monosomy duplication associated with a nullisomic maternal gamete, or a paternal meiosis II nondisjunction resulting in a trisomic conceptus, with subsequent reduction to disomy through loss of the maternal chromosome 7, so-called trisomic rescue. The authors suggested that the child inherited 2 recessive disorders linked to chromosome 7 from his father: CF and immotile cilia associated with complete situs inversus, although it could not be excluded that the 2 disorders were unrelated. Pan et al. (1998) noted that Koiffmann et al. (1993) reported complete situs inversus in a boy with a complex karyotype involving chromosome 7q22 (ins(7;8)(q22;q12q24)), suggesting that this locus was important in the pathogenesis of the disorder.

Molecular Genetics

In a patient with primary ciliary dyskinesia and situs inversus totalis originally reported by Pan et al. (1998), Bartoloni et al. (2002) identified a homozygous mutation in the DNAH11 gene (603339.0001).

In affected members of a German family with primary ciliary dyskinesia, Schwabe et al. (2008) identified compound heterozygosity for 2 mutations in the DNAH11 gene (603339.0002; 603339.0003). One of the patients had Kartagener syndrome.

In a patient with CILD7, Lucas et al. (2012) identified compound heterozygous mutations in the DNAH11 gene (603339.0004 and 603339.0005). An unrelated patient had a heterozygous truncating mutation in the CILD7 gene (603339.0006), but a second pathogenic mutation was not identified.