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

3 Years
Open (Enrolling)
Cushing's Syndrome, Hereditary Neoplastic Syndrome, Lentigo, Neoplasm, Testicular Neoplasm

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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.

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

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

2. Informed consent, and for children and/ or mentally impaired, parental or
legal custodian's consent and subject assent.


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.

Type of Study:


Study Design:


Principal Investigator

Constantine A Stratakis, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)


United States: Federal Government

Study ID:




Start Date:

January 1995

Completion Date:

Related Keywords:

  • Cushing's Syndrome
  • Hereditary Neoplastic Syndrome
  • Lentigo
  • Neoplasm
  • Testicular Neoplasm
  • Cushing Syndrome
  • Gene Mapping
  • Linkage
  • Oncogene
  • Linkage Analysis
  • Gene Identification
  • Tumors
  • Familial Neoplasia
  • Adrenal Gland
  • Lentigines
  • Carney Complex
  • Neoplasms
  • Cushing Syndrome
  • Lentigo
  • Neoplastic Syndromes, Hereditary
  • Peutz-Jeghers Syndrome
  • Testicular Neoplasms
  • Carney Complex



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