Primary ciliary dyskinesia (immotile-cilia syndrome)

INTRODUCTION

Primary ciliary dyskinesia (PCD, also called the immotile-cilia syndrome) is characterized by congenital impairment of mucociliary clearance (MCC) [1,2]. Clinical manifestations include chronic cough, chronic rhinitis, and chronic sinusitis. Otitis and otosalpingitis are common in childhood, as are nasal polyposis and agenesis of the frontal sinuses. The underlying cause is a defect of cilia in the airways, making them unable to beat (ciliary immotility), unable to beat normally (ciliary dyskinesia), or to be missing altogether (ciliary aplasia). It is an inherited disease that has been described from most parts of the world and with equal prevalence in men and women of approximately one in 10,000 to 30,000 individuals [3-5].

Because the embryonic, nodal cilia are also defective, body asymmetry is randomized so that 50 percent of the patients have situs inversus totalis [6,7]. When situs inversus, chronic sinusitis, and bronchiectasis occur together, an individual is said to have Kartagener's syndrome, a subgroup of primary ciliary dyskinesia that has a prevalence of around one in 20,000 to 40,000 individuals [5]. Bronchiectasis may develop in young persons but is never present at birth; thus, no individual is born with a fully developed Kartagener's triad.

The genetics, clinical manifestations, diagnosis, and management of PCD are reviewed here. The evaluation and treatment of bronchiectasis are discussed separately. (See "Clinical manifestations and diagnosis of bronchiectasis" and "Treatment of bronchiectasis".)

GENETICS

Primary ciliary dyskinesia (PCD) is inherited as an autosomal recessive disease [8]. It is a highly heterogeneous syndrome that can be caused by a defect in any of the many polypeptide species within the axoneme (central core) of cilia or of sperm flagella, in other proteins that are present in the ciliary membrane and matrix, or in proteins needed for the proper assembly of cilia [9]. Different components may be missing or defective in different patients, and different clinical manifestations may develop depending upon the nature of the lesion. Families may have different mutated genes, but identical clinical symptoms.

Extensive locus heterogeneity of PCD is suspected, but in some cases it has been possible to identify a specific chromosomal locus and gene product [10,11]. As an example, on the basis of linkage analysis from 25 separate families, a locus on chromosome 5p was identified that encodes the axonemal dynein heavy chain 5 protein called DNAH5 (OMIM 603335) [11,12]. From these family studies, four homozygous and six heterozygous mutations of DNAH5 were identified, all in association with clinical PCD and ultrastructurally abnormal outer dynein arms. Complete absence of DNAH5 along the ciliary axoneme results in immobility, while absence of DNAH5 in the distal portion of the axoneme causes impaired mobility [13].