Rare Genetic Disorders of the Breathing Airways

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.

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