Genetic Disorders of Mucociliary Clearance in Nontuberculous Mycobacterial Lung Disease
Condition: Cystic Fibrosis; Pseudohypoaldosteronism; Nontuberculous Mycobacterial Infection; Chronic Granulomatous Disease; Primary Ciliary Dyskinesia
MeSH terms: Infections; Mycobacterium Infections; Cystic Fibrosis; Ciliary Motility Disorders; Dyskinesias; Pseudohypoaldosteronism; Granulomatous Disease, Chronic; Genetic Diseases, Inborn; Fibrosis
Study type: Observational

Summary: 
      Healthy volunteers and patients with diseases that involve problems clearing mucus from the
      lungs will be examined and tested to better understand the reasons for recurring lung
      infections in these patients and to try to develop better ways to diagnose and treat them.
      The study will also try to identify the genes responsible for these diseases.

      Healthy volunteers 18 years of age and older and patients 2 years of age or older with
      suspected primary ciliary dyskinesia (PCD), variant cystic fibrosis (CF) or
      pseudohypoaldosteronism (PHA) may be eligible for this study. Patients enrolled in the
      Natural History Study of Nontuberculous Mycobacteria at NIH or other NIH natural history
      protocols may also be enrolled. Participants undergo the following tests and procedures
      during a 1-day visit at the NIH Clinical Center, as follows:

      All patients and normal volunteers have the following procedures:

        -  Physical examination and review of medical and genetic history and family genetic
           history.

        -  Lung function test and measurement of oxygen saturation level.

        -  Nitric oxide measurement to measure the amount of nitric oxide production in the nose: A
           small tube is placed in the nose while the subject breathes through the mouth into a
           cardboard tube.

      All patients have the following additional procedures:

        -  Blood tests for liver and kidney function, blood count, immunoglobulins and pregnancy
           test (where appropriate).

        -  Blood test or buccal scrape (brushing the inside of the cheek) to obtain DNA to look for
           gene mutations that cause PCD, CF or PHA.

        -  Scrape biopsy of cell lining the inside of the nose: A small toothpick-sized plastic
           stick with a tiny cup on the end is used to get nasal lining cells to look at the cilia
           (hair-like structures that move mucus).

        -  Semen analysis (in some men) to test sperm tail function or structure.

      Patients suspected of having a variant of CF or PHA, including nontuberculous mycobacterial
      lung disease, have the following additional procedures:

        -  Sweat chloride test: A medicine is placed on the arm to produce sweat; then, a very low
           level of electric current is applied for 5 to 12 minutes. Sweat is collected in a
           plastic tube and tested for salt content.

        -  Blood draw for CF genetic testing, if necessary, and to measure levels of the enzyme
           trypsin.

        -  Saliva collection to measure sodium and chloride content.

        -  Nasal potential difference to measure the electrical activity of the cells lining the
           inside of the nose: A soft plastic tube filled with a salt solution is passed into the
           nasal passage and a sterile needle is placed under the skin of the arm. This test
           provides information about how the lining of the nose is able to get used to changes in
           temperature and humidity. (Normal volunteers also have this test.)
    

Detailed description: 
      Background: Nontuberculous mycobacteria (NTM) are ubiquitous environmental organisms that
      have been increasingly associated with human disease, commonly involving the lung. Post
      menopausal Caucasian women seem particularly predisposed to the development of peripheral
      nodules and dilated airways (bronchiectasis) associated with these organisms. These women
      have distinguishing body characteristics of being taller and thinner than age and gender
      matched controls yet have no identifiable systemic immune defects. There is, however,
      considerable overlap with genetic disorders of mucociliary clearance such as cystic fibrosis
      (CF) and primary ciliary dyskinesia (PCD). The Genetic Diseases of Mucociliary Clearance
      Consortium (GDMCC) is one of 10 consortia in the Rare Diseases Clinical Research Network
      formed under the Office of Rare Diseases in collaboration with NCRR, NICHD, NINDS, NIAMS,
      NIDDK, NHLBI in response to the Rare Diseases Act of 2002. The GDMCC is comprised of 5
      geographically-dispersed clinical research sites that are designed to study rare diseases
      which involve defects in clearance of mucus secretions from the airways (defective
      "mucociliary clearance"). These sites will collaborate in diagnostic, genetic, and other
      studies in patients with impairments of mucociliary clearance, including primary ciliary
      dyskinesia (PCD), variant cystic fibrosis (CF), and pseudohypoaldosteronism (PHA). These
      studies are also applicable to diseases where altered airways clearance may play a primary or
      contributory role such as nontuberculous mycobacterial lung disease, chronic granulomatous
      disease, and the hyper-IgE syndromes. Disorders such as PCD, CF, and PHA reflect genetic
      defects in airway host-defense, and typically result in chronic infection of the airways.
      Patients with these disorders of the conducting airways and sinuses have delayed (or
      incorrect) diagnoses, because diagnostic tests are not readily available. These patients may
      also have sub-optimal management of their clinical disease, because the cause of these
      disorders is not well-defined, and treatment regimens are usually not driven by
      evidence-based medicine.

      Aims: The major aim of this study is to employ a systematic approach to the diagnostic and
      functional evaluation of these patients with chronic airways disease in individual patients,
      better define host susceptibility to infections from environmental organisms such as the
      nontuberculous mycobacteria, and potentially lead to the development of better diagnostic
      techniques, including genetic testing. In addition, we will compare/contrast clinical
      features (phenotype) across these disorders. A rigorous cross-sectional comparison of the
      clinical features will provide better understanding of the clinical disease of these
      disorders; in turn this will lead not only to a better standard of clinical care, but will
      also assist in the identification of novel therapeutic approaches.

      Methods: This is a cross-sectional diagnostic / mechanistic protocol to investigate airway
      host-defenses. The patient populations for these studies include individuals with recurring
      airway infections such as those with nontuberculous mycobacteria lung disease who may have
      defective airway host defenses as a predisposing factor, individuals carrying a tentative
      diagnosis of the three known genetic disorders of mucociliary clearance (PCD, variant CF, or
      PHA), and individuals suspected to have one of these disorders but with inadequate or
      inconclusive diagnostic tests. Individuals in this latter category must have a preliminary
      clinical evaluation to evaluate for other more common disorders that may have similar
      manifestations including classical CF, immunodeficiency, asthma, and severe gastroesophageal
      reflux. The evaluation will include a detailed assessment of clinical features; specialized
      laboratory measurements such as nasal potential difference to evaluate the function of
      chloride and sodium channels associated with CF and PHA, nasal biopsy specimens and nasal
      nitric oxide measurements to assess cilia structure and function which are abnormal in PCD;
      and genetic studies to identify disease - causing mutations in genes associated with CF, PCD,
      and PHA.
    

Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        There are approximately 100 patients who have been referred to the Clinical Center at NIH,
        or who have contacted us directly for evaluation of nontuberculous mycobacterial lung
        disease. Most of these are post-menopausal Caucasian women. Some had known diagnoses of CF
        or PCD at the time of referral and others have been subsequently diagnosed with these
        disorders after evaluation here. This population likely reflects a concentrated source
        population of potential cases of PCD and variant CF to feed into the Consortium.
        Additionally, the Clinical Center will serve as a referral site for cases of suspected PCD,
        variant CF, and PHA who don't necessarily have nontuberculous mycobacterial infections.
        These referrals will likely be concentrated in the National Capital Area and constitute a
        minority of the patients evaluated on the protocol.
      
Keywords: Nontuberculous Mycobacterial Infection; Primary Ciliary Dyskinesia; Cystic Fibrosis; Pseudohypoaldosteronism; Chronic Granulomatous Disease; Natural History; Mycobacterial Infection; PCD; CF; PHA; Healthy Volunteer; HV