Defining the Genetic Basis for the Development of Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and the Carney Complex

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.

- INCLUSION CRITERIA:

1. All patients with PPNAD and/or Carney Complex by history and their siblings,
children and parents. Additional relatives and their families that are suspected
to have the same disorder on clinical grounds will be recruited:

1. PPNAD patients will be included if their diagnosis is fully documented.
First-degree relatives of patients with the disease will be accepted also
for evaluation, or if already conclusively evaluated elsewhere, for DNA
linkage analysis only.

2. Patients with suspected Carney complex will be accepted for evaluation
and/or DNA analysis for linkage, if they have at least two of the following:

1. cardiac myxoma

2. cutaneous myxoma

3. breast myxoma

4. oral myxoma

5. myxoma of the external ear

6. spotty mucocutaneous pigmentation (lentigines)

7. testicular tumor

8. pituitary growth hormone secreting adenoma

9. nerve tumor, such as psammomatous melanotic schwannoma

10. first-, second-, or third-degree relatives with Carney complex

(c) Patients with one of the familial lentiginosis syndromes: Peutz-Jeghers and
LEOPARD syndrome, other forms of familial lentiginosis.

EXCLUSION CRITERIA:

1. For DNA analysis and linkage study:

1. Unwillingness to participate.

2. For clinical evaluation and DNA analysis/linkage study:

1. Patients with major illnesses, such as severe renal failure, restrictive or
obstructive lung disease, cardiac disease, anemia and/or terminal cancer that
will not be able to undergo appropriate testing or the stress of hospitalization.
Also, patients with Carney complex and a known heart tumor (heart myxoma) will
not be able to enter the clinical part of the study until after surgical
treatment of their tumor. These patients, however, will be asked to participate
in the DNA analysis study.