Mucociliary clearance, in which mucus secretions are cleared from the breathing airways, is the primary defense mechanism for the lungs. Inhaled particles, including microbes that can cause infections, are normally entrapped in mucus on the airway surfaces and then cleared out by the coordinated action of tiny hair-like structures called cilia. Individuals with primary ciliary dyskinesia, variant cystic fibrosis, and pseudohypoaldosteronism have defective mucociliary clearance. The purpose of this study is to collect clinical and genetic information about these three airway diseases to improve current diagnostic procedures.

Two types of genetic diseases are associated with abnormal mucociliary clearance. The first type results in defective ciliary function and includes primary ciliary dyskinesia (PCD), also known as Kartagener Syndrome. The second type results in defective ion transportation and includes variant cystic fibrosis (CF) and pseudohypoaldosteronism (PHA). The clinical manifestations of these three diseases overlap, and current evaluation procedures are inadequate for an accurate and timely diagnosis. A delayed diagnosis, coupled with poorly defined disease categories, results in sub-optimal treatment regimens. The purpose of this study is to better define the clinical and genetic features of PCD, variant CF, and PHA to develop improved diagnostic procedures. The study will also compare prevalence and age-related information among the three diseases and classic CF. Outcomes of this study may lead to improved clinical care and novel therapeutic approaches for rare genetic disorders of the airways.

Prior to study entry, previous clinical data on all participants will be reviewed to ensure that individuals do not have common variants of asthma. In some cases, further clinical evaluation (sweat chloride testing, immunodeficiency testing, and a high-resolution computed tomography scan) may be recommended. Eligible participants will attend an initial six-hour study visit similar to a standard diagnostic evaluation. The participant's medical history will be reviewed and a physical examination will include height, weight, and vital sign measurements. Respiratory cultures, nasal samples, and blood will be collected. Non-invasive techniques will be used to measure oxyhemoglobin saturation levels and airflow; a chest x-ray will be required if none has been done in the last six months.

If a firm diagnosis of PCD or variant CF has not been established after completion of the first study visit, the participant may return for additional visits. Salivary and semen samples may be collected from some individuals. A sweat chloride test and nasal potential difference test may also be performed.

• Kartagener Syndrome
• Cystic Fibrosis
• Pseudohypoaldosteronism
• Primary Ciliary Dyskinesia

• Kennedy MP, Ostrowski LE. Primary ciliary dyskinesia and upper airway diseases. Curr Allergy Asthma Rep. 2006 Nov;6(6):513-7. Review.
• Ferkol T, Leigh M. Primary ciliary dyskinesia and newborn respiratory distress. Semin Perinatol. 2006 Dec;30(6):335-40. Review.
• Zariwala MA, Knowles MR, Omran H. Genetic defects in ciliary structure and function. Annu Rev Physiol. 2007;69:423-50. Review.
• Zariwala MA, Leigh MW, Ceppa F, Kennedy MP, Noone PG, Carson JL, Hazucha MJ, Lori A, Horvath J, Olbrich H, Loges NT, Bridoux AM, Pennarun G, Duriez B, Escudier E, Mitchison HM, Chodhari R, Chung EM, Morgan LC, de Iongh RU, Rutland J, Pradal U, Omran H, Amselem S, Knowles MR. Mutations of DNAI1 in primary ciliary dyskinesia: evidence of founder effect in a common mutation. Am J Respir Crit Care Med. 2006 Oct 15;174(8):858-66. Epub 2006 Jul 20.
• Kennedy MP, Noone PG, Carson J, Molina PL, Ghio A, Zariwala MA, Minnix SL, Knowles MR. Calcium stone lithoptysis in primary ciliary dyskinesia. Respir Med. 2007 Jan;101(1):76-83. Epub 2006 Jun 6.
• Hornef N, Olbrich H, Horvath J, Zariwala MA, Fliegauf M, Loges NT, Wildhaber J, Noone PG, Kennedy M, Antonarakis SE, Blouin JL, Bartoloni L, Nusslein T, Ahrens P, Griese M, Kuhl H, Sudbrak R, Knowles MR, Reinhardt R, Omran H. DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects. Am J Respir Crit Care Med. 2006 Jul 15;174(2):120-6. Epub 2006 Apr 20.
• Horvath J, Fliegauf M, Olbrich H, Kispert A, King SM, Mitchison H, Zariwala MA, Knowles MR, Sudbrak R, Fekete G, Neesen J, Reinhardt R, Omran H. Identification and analysis of axonemal dynein light chain 1 in primary ciliary dyskinesia patients. Am J Respir Cell Mol Biol. 2005 Jul;33(1):41-7. Epub 2005 Apr 21.

Inclusion Criteria:

• Received a standard diagnostic evaluation prior to study entry that resulted in one of the following three profiles:

  1. High likelihood of PCD diagnosis, based on ciliary ultrastructural changes seen on electron microscopy or clinical features (chronic sinopulmonary disease, chronic otitis media, history of neonatal respiratory distress or situs inversus) OR one clinical feature of PCD and a sibling with PCD
  2. Chronic sino-pulmonary disease with clinical features that overlap with variant CF and PCD, but with diagnostic tests that rule out classical CF (sweat chloride testing and CF gene mutation screening)
  3. Known or suspected PHA (or variant PHA), possibly including elevated (or borderline) sweat chloride values

Exclusion Criteria:

• Has not received a standard clinical evaluation to rule out other disorders associated with chronic sino-pulmonary disease