Definition of the Genotype and Clinical Phenotype of Primary Pigmented Nodular Adrenocortical Disease (PPNAD), Carney Complex, Peutz-Jeghers Syndrome and Related Conditions

Trial Information

Definition of the Genotype and Clinical Phenotype of Primary Pigmented Nodular Adrenocortical Disease (PPNAD), Carney Complex, Peutz-Jeghers Syndrome and Related Conditions

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.