Defining the Genetic Basis for the Development of Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and the Carney Complex
Condition: Cushing's Syndrome; Pituitary Adenoma; Carney Complex; Primary Pigmented Nodular Adrenocortical Disease; Peutz-Jeghers Syndrome
MeSH terms: Adenoma; Pituitary Neoplasms; Peutz-Jeghers Syndrome; Carney Complex; Pituitary Diseases; Cushing Syndrome; Syndrome
Study type: Observational

Summary: 
      Lentiginosis refers to groups of diseases marked by the presence of pigmented spots on the
      skin. These conditions are most commonly associated with multiple tumors and changes in
      hormone producing glands. The cause of these diseases is unknown, but researchers suggest
      there may be a level of inheritance involved in their development. Meaning to say that some
      of these diseases may "run in the family" and be passed down form generation to generation.

      Primary pigmented nodular adrenocortical disease (PPNAD) is a pituitary-independent, primary
      adrenal form of hypercortisolism characterized by;

        1. Resistance to suppression by the drug dexamethasone

        2. The body is unable to secrete cortisol in a normal rhythm

        3. Distinct microscopic changes of both adrenal glands

      PPNAD can be associated with tumors (myxomas) of the skin, heart, breast, tumors (swannomas)
      of the nerve sheaths, pigmented spots (nevi and lentigines) of the skin, growth hormone (GH)
      producing tumors of the pituitary gland, and tumors of the testicles, ovaries, and thyroid
      gland. In the presence of these associations the condition is referred to as the Carney
      Complex. Presently there are no tests for screening of PPNAD and the Carney Complex. In
      addition, it is unknown how these conditions are genetically transferred from generation to
      generation.

      This study proposes to use standard methods of clinical testing for endocrine and
      nonendocrine diseases and genetic testing in order to;

        1. Define the genetic basis for PPNAD and/or the Carney Complex.

        2. Determine the molecular changes associated with the development of the tumors.

        3. Identify carriers of the disease.

        4. Determine the prognosis for carriers and affected individuals.

        5. Provide sufficient data for genetic counseling of families with PPNAD and/or Carney
           Complex.<TAB>...
    

Detailed description: 
      Primary pigmented nodular adrenocortical disease (PPNAD) is a pituitary-independent, primary
      adrenal form of hypercortisolism characterized by (a) resistance to suppression by
      dexamethasone and abolition of the normal diurnal rhythm of cortisol secretion, and (b)
      distinctive, bilateral, histopathologic changes of the adrenal glands, such as the formation
      of variably sized, pigmented nodular adenomas, loss of normal zonation and atrophy of the
      extranodular cortex. PPNAD can be associated with a variety of other manifestations, such as
      myxomas of the skin, heart, breast and other sites, psammomatous melanotic swannomas
      involving the peripheral nervous system (PNS), lentigines and blue nevi of the skin and
      mucosae, growth hormone (GH)-producing adenomas of the pituitary, testicular Sertoli cell
      tumors, and possibly other neoplasms (adrenocortical and thyroid follicular carcinoma, and
      ovarian cysts). These associations constitute a distinct clinical syndrome, Carney complex, a
      genetic syndrome. At present, there are no standardized screening tests for the members of
      families with affected individuals and the molecular mechanism(s) of this hereditary single
      and/or multiple neoplasia syndrome have not been completely elucidated (e.g. patients who
      meet clinical criteria for Carney complex but test negative for PRKAR1A mutation . This study
      seeks to define the genetic basis of PPNAD and/or Carney complex in sporadic and familial
      cases and the molecular pathogenesis of their tumors, to identify the carriers of the
      familial forms of the disease, and to determine the prognosis for carriers and affected
      individuals. The methods include standard clinical testing for endocrine and nonendocrine
      pathologic conditions of the subjects of the study, linkage analysis with DNA markers from
      areas of the genome likely to harbor the responsible gene(s), and finally genetic screening
      of these genes. Molecular studies of the tumors of the patients will provide additional clues
      for the pathophysiologic mechanisms leading to PPNAD/Carney complex. The study will
      ultimately provide sufficient data for genetic counseling of families with PPNAD and/or
      Carney complex, and, ultimately, the means for genetic screening and prenatal testing.
    

Intervention name(s): oCRH
Intervention type(s): Drug
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Research subjects who present with PPNAD, Carney Complex, Peutz-Jeghers Syndrome and
        related conditions. Research subjects who need screening based on clinical and biochemical
        data for PPNAD, Carney Complex, Peutz-Jeghers Syndrome and related conditions.
      
Keywords: Cushing's Syndrome; Genetics; Pituitary Adenoma; PPNAD; Carney Complex; Natural History