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Mucociliary Clearance Disorder Descriptions
  • Primary Ciliary Dyskinesia (PCD)
  • Cystic Fibrosis (CF)
  • Pseudohypoaldosteronism (PHA)

Primary Ciliary Dyskinesia (PCD)

Primary ciliary dyskinesia (PCD), or immotile cilia syndrome, is viewed as an unusual cause of persistent wheezing and cough in children. Occurring in approximately 1 in 12,000 to 20,000 births, PCD is a genetic disorder that results from ultrastructural abnormalities of the cilia. Ciliary dysfunction causes impaired mucociliary clearance, which results in the retention of inhaled particles, including bacteria, in the lung, paranasal sinuses, and middle ear. The abnormal mucociliary clearance of airway secretions causes a chronic bronchitis, and wheezing is a common clinical manifestation due to the mucus obstruction of the airways. The course of lung disease is not well defined, and its progression varies, including microbial colonization of the lower respiratory tract and development of bronchiectasis.

Primary ciliary dyskinesia has several non-pulmonary manifestations. Repeated or persistent severe upper respiratory tract infections, typically chronic pansinusitis or suppurative otitis media, occur in virtually every patient with "classic" forms of the disease. Although Kartagener initially described several patients who presented with situs inversus totalis, chronic sinusitis and bronchiectasis, situs inversus is present in only half of the cases of this syndrome. The occurrence of situs inversus totalis is random and not genetically predetermined, even within affected families. Male sterility due to the impaired movement of spermatozoa also occurs, and infertility may be the presenting feature of the disease. Cardiac anomalies and hydrocephalus have also been described in affected patients.

In this consortium, we plan to improve diagnostic testing of PCD, understand the pathogenesis, clinical presentations, and better define clinical outcomes of the disease.

Cystic Fibrosis

Cystic fibrosis (CF) is the most common, inherited disease of Caucasians, found in roughly 1 in 3,000 live births based on epidemiologic data, and multisystem disease of exocrine gland function that typically involves the lungs, paranasal sinuses, skin, pancreas, male reproductive tract (vas deferens), intestines, and biliary tract.

An autosomal recessive defect, the life expectancy of a child born with CF in the United States has gradually improved and is now extending well into adulthood. Nevertheless, much of the morbidity in the "classic" disease still results from the progressive lung disease, characterized by airway infection and inflammation that ultimately leads to bronchiectasis, respiratory failure, and death. Defective function of the cystic fibrosis transmembrane conductance regulator (CFTR) and associated channels in airway epithelial cells and submucosal glands results in dehydration of endobronchial secretions. These desiccated secretions obstruct the airways and prevent elimination of bacteria from the lung, thus allowing infection to become established. Current management of pulmonary disease in CF has been directed at the downstream consequences of CFTR dysfunction, focusing on treatment of airway infection and inflammation.

Historically, CF has been divided into distinct, clinical phenotypes, but with the advent of genetic testing for CF, milder or variant forms of the disease have been recognized. Indeed, it has become increasingly clear that the disease exists as a continuum and clinical manifestations correlate with levels of CFTR activity. The course of pulmonary disease in these milder variants has not been well defined in terms of microbial colonization of the lower respiratory tract and development of bronchiectasis.

A common problem for physicians is the presentation of children with CF-like pulmonary disease, but normal or equivocally elevated sweat electrolyte concentrations but negative for mutant CFTR alleles. These patients are a difficult, diagnostic conundrum for clinicians. We plan to characterize and better define atypical or variant forms of CF in this consortium, and determine mechanisms by which mutant CFTR expression contributes to pathogenesis and pulmonary outcomes in variant forms of the disease.

Pseudohypoaldosteronism (PHA)

Pseudohypoaldosteronism (PHA) is a rare condition characterized by loss-of-function mutations in the epithelial sodium channel (ENaC), and defective sodium transport in multiple organs, including sweat duct and salivary glands. These patients also have excessive volume of the airway surface liquid, and affected children have recurrent episodes of chest congestion and chronic cough. Curiously, older patients with PHA do not typically have chronic or progressive lung disease or bacterial endobronchitis.

In the collaborative, we plan to identify and characterize individuals with pseudohypoaldosteronism, postulating that affected patients have abnormal (or equivocal) sweat chloride levels and pulmonary manifestations.