Bilateral primary pigmented nodular adrenocortical disease. Rare cause of the Cushing syndrome. Am J Surg Pathol
Four patients (two males and two females, ages 12-21 years) had clinical features of the Cushing syndrome. Results of biochemical tests (in three patients tested) suggested the presence of an autonomously functioning adrenocortical neoplasm. However, radiologic examination of the adrenals did not show an adrenal tumor. The four patients underwent curative bilateral total adrenalectomy and did not manifest the Nelson syndrome postoperatively (follow-up, 2-22 years). The adrenal pathologic findings in these patients were similar. Gross findings included: 1) decreased, normal, or slightly increased total gland weight; 2) studding of the external and cut surfaces by small (less than 4 mm) black, brown, dark-green , red, or (rarely) yellow nodules; and 3) cortical atrophy and disorganization of the normal zonation between the nodules. Microscopically, the nodules were composed predominantly of enlarged, globular, cortical cells with granular eosinophilic cytoplasm that often contained lipofuscin. Twenty-four similar cases have been reported. Findings in these plus our four cases identify a special type of adrenocortical pathology associated with Cushing syndrome, for which we suggest the name "primary pigmented nodular adrenocortical disease."
Available from: Chyi-Chia Richard Lee
- "PPNAD usually presents in the 2nd or 3rd decade of life, without demonstrating the strong female predilection seen in adult patients with Cushing’s syndrome . The disease is named after the small, cortisol producing, pigmented micronodules seen in the adrenal cortex . The hypercortisolism may manifest as the classic constellation of Cushing’s characteristics or with isolated features, like mild growth retardation (short stature), severe precocious osteoporosis and severe muscle and skin wasting . "
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ABSTRACT: The complex of myxomas, spotty skin pigmentation and endocrine overactivity, or Carney complex (CNC), is a familial multiple endocrine neoplasia and lentiginosis syndrome. CNC is inherited in an autosomal dominant manner and is genetically heterogeneous. Its features overlap those of McCune-Albright syndrome and other multiple endocrine neoplasia (MEN) syndromes. Spotty skin pigmentation is the major clinical manifestation of the syndrome, followed by multicentric heart myxomas, which occur at a young age and are the lethal component of the disease. Myxomas may also occur on the skin (eyelid, external ear canal and nipple) and the breast. Breast myxomas, when present, are multiple and bilateral among female CNC patients, an entity which is also described as “breast-myxomatosis” and is a characteristic feature of the syndrome. Affected CNC patients often have tumours of two or more endocrine glands, including primary pigmented nodular adrenocortical disease (PPNAD), an adrenocorticotropin hormone (ACTH)-independent cause of Cushing’s syndrome, growth hormone (GH)-secreting and prolactin (PRL)-secreting pituitary adenomas, thyroid adenomas or carcinomas, testicular neoplasms (large-cell calcifying Sertoli cell tumours [LCCSCT]) and ovarian lesions (cysts and cancinomas). Additional infrequent but characteristic manifestations of CNC are psammomatous melanotic schwannomas (PMS), breast ductal adenomas (DAs) with tubular features, and osteochondromyxomas or “Carney bone tumour”.
• Almost 60 % of the known CNC kindreds have a germline inactivating mutations in the PRKAR1A gene.
• Spotty skin pigmentation is the major clinical manifestation of CNC, followed by heart myxomas.
• Indicative imaging signs of PPNAD are contour abnormality and hypodense spots within the gland.
• Two breast tumours may present in CNC: myxoid fibroadenomas (breast myxomatosis) and ductal adenomas.
• Additional findings of CNC are psammomatous melanotic schwannomas (PMSs) and osteochondromyxomas.
Available from: PubMed Central
- "PPNAD is a rare disease observed mostly in patients with CNC. The disease was named after the macroscopic appearance of the adrenals that is characterized by the small pigmented micronodules observed in the cortex (Figure 1) . The disease is usually bilateral with primary involvement of both adrenals. "
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ABSTRACT: The Carney complex (CNC) is a dominantly inherited syndrome characterized by spotty skin pigmentation, endocrine overactivity and myxomas. Skin pigmentation anomalies include lentigines and blue naevi. The most common endocrine gland manifestations are acromegaly, thyroid and testicular tumors, and adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). PPNAD, a rare cause of Cushing's syndrome, is due to primary bilateral adrenal defect that can be also observed in some patients without other CNC manifestations or familial history of the disease. Myxomas can be observed in the heart, skin and breast. Cardiac myxomas can develop in any cardiac chamber and may be multiple. One of the putative CNC genes located on 17q22-24, (PRKAR1A), has been identified to encode the regulatory subunit (R1A) of protein kinase A. Heterozygous inactivating mutations of PRKAR1A were reported initially in 45 to 65% of CNC index cases, and may be present in about 80% of the CNC families presenting mainly with Cushing's syndrome. PRKAR1A is a key component of the cAMP signaling pathway that has been implicated in endocrine tumorigenesis and could, at least partly, function as a tumor suppressor gene. Genetic analysis should be proposed to all CNC index cases. Patients with CNC or with a genetic predisposition to CNC should have regular screening for manifestations of the disease. Clinical work-up for all the manifestations of CNC should be performed at least once a year in all patients and should start in infancy. Cardiac myxomas require surgical removal. Treatment of the other manifestations of CNC should be discussed and may include follow-up, surgery, or medical treatment depending on the location of the tumor, its size, the existence of clinical signs of tumor mass or hormonal excess, and the suspicion of malignancy. Bilateral adrenalectomy is the most common treatment for Cushing's syndrome due to PPNAD.
Available from: endocrinology-journals.org
- "PPNAD leads to a pituitary-independent, primary adrenal form of hypercortisolism (Fig. 1). It is essentially a form of MiAD, perhaps the most frequent one, which is characterized by small, pigmented nodules that are surrounded by mostly atrophic cortex in an otherwise normal-sized gland (Shenoy et al. 1984). Most cases of PPNAD, inherited or sporadic, are associated with CNC (Stratakis et al. 2001). "
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ABSTRACT: The type 1 alpha regulatory subunit (R1alpha) of cAMP-dependent protein kinase A (PKA) (PRKAR1A) is an important regulator of the serine-threonine kinase activity catalyzed by the PKA holoenzyme. Carney complex (CNC) describes the association 'of spotty skin pigmentation, myxomas, and endocrine overactivity'; CNC is in essence the latest form of multiple endocrine neoplasia to be described and affects the pituitary, thyroid, adrenal and gonadal glands. Primary pigmented nodular adrenocortical disease (PPNAD), a micronodular form of bilateral adrenal hyperplasia that causes a unique, inherited form of Cushing syndrome, is also the most common endocrine manifestation of CNC. CNC and PPNAD are genetically heterogeneous but one of the responsible genes is PRKAR1A, at least for those families that map to 17q22-24 (the chromosomal region that harbors PRKAR1A). CNC and/or PPNAD are the first human diseases to be caused by mutations in one of the subunits of the PKA holoenzyme. Despite the extensive literature on R1alpha and PKA, little is known about their potential involvement in cell cycle regulation, growth and/or proliferation. The presence of inactivating germline mutations and the loss of its wild-type allele in CNC lesions indicated that PRKAR1A could function as a tumor-suppressor gene in these tissues. However, there are conflicting data in the literature about PRKAR1A's role in human neoplasms, cancer cell lines and animal models. In this report, we review briefly the genetics of CNC and focus on the involvement of PRKAR1A in human tumorigenesis in an effort to reconcile the often diametrically opposite reports on R1alpha.
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