Clinical and molecular genetics of primary pigmented nodular adrenocortical disease

Abstract

Carney complex (CNC) is a multiple endocrine neoplasia (MEN) syndrome associated with other, non-endocrine manifestations such as lentigines, cardiac myxomas and schwannomas. Primary pigmented nodular adrenocortical disease (PPNAD), leading to corticotrophin-independent Cushing's syndrome is the most frequent endocrine lesion in CNC. The complex has been mapped to 2p16 and 17q22-24, although additional heterogeneity may exist. The gene coding for the protein kinase A (PKA) type I-a regulatory subunit (RIa), PRKAR1A, had been mapped to 17q. Cloning of the PRKAR1A genomic structure and its sequencing showed mutations in CNC-, CNC with PPNAD-and sporadic PPNAD-patients. In CNC tumors, PKA activity showed increased stimulation by cAMP, whereas PKA activity ratio was decreased, and in CNC tumors, there is LOH of the normal allele, suggesting that normal PRKAR1A may be a tumor suppressor in these tissues. CNC is the first human disease caused by mutations of one of the subunits of the PKA enzyme, a critical component of the cAMP signaling system and a potential participant in many other signaling pathways. RESUMOClínica e Genética Molecular da Doença Nodular Adrenocortical Pigmentada Primária. Complexo de Carney (CNC) é uma síndrome de neoplasia endócrina múltipla (MEN) associada com outras manifestações não endócrinas, como lentígenes, cardiomixomas e adenomas de células de Schwann. A doença nodular pigmentada primária da adrenal (PPNAD), que apresenta-se como síndrome de Cushing independente de corticotropina é a lesão mais freqüente observada em CNC. O CNC tem sido relacionados aos sítios cromossômicos 2p16 e 17q22-24, entretanto, heterogenicidade pode ocorrer. O gene codificador da proteína reguladora tipo 1A da proteína quinase A(RIa), PRKAR1A, tem sido localizado no cromossomo 17q. A clonagem da estrutura genômica e seqüenciamento do gene PRKAR1A revelou mutações em pacientes com CNC e em formas esporádicas de PPNAD. Em tumores de pacientes com CNC, a proteína quinase A apresenta uma resposta de atividade maior após o estímulo com AMPc. Também, nestes tecidos, é observada a perda de heterozigose do alelo normal. Isto sugere que o gene normal do PRKAR1A pode funcionar como um gene de supressão tumoral nos tecidos estudados. CNC é a primeira doença conhecida a ocorrer devido a mutações de uma das sub-unidades da proteína quinase A, um componente crucial na via de sinalização do AMPc e um potencial participante de outras vias de sinalização celular.

Primary pigmented nodular adrenocortical disease associated with Carney complex: case report and literature review

“…In studies on autopsies of patients with CNC, PPNAD was observed in almost all cases. 4,10,11 Although our patient presented a classical picture of Cushing's syndrome, her two-year history of amenorrhea, which was thought to have been caused previously by PCOS, and her short stature could be indicative of a disease that emerged atypically a long time earlier.…”

“…9 PPNAD is a rare form of ACTH-independent Cushing's syndrome that may occur alone, but is found to be associated with CNC in 90% of the cases. 10 It is the most common endocrinal hyperactivity in these patients, and has been described in 25% of them. This incidence, however, is probably an underestimate, because of untypical and subclinical cases, and the cycles of the disease.…”

“…This is considered to be one of the major criteria for CNC. 10,12 Stratakis et al studied 16 cases of PPNAD and compared them with control patients with adrenal adenoma and macronodular adrenal hyperplasia. 12 They found that an increase of 50% or more in 24-hour UFC made it possible to identify a great number of PPNAD cases (approximately 70%), but only a few adenoma cases and no macronodular hyperplasia cases presented the same type of response.…”

A Case of Primary Pigmented Nodular Adrenocortical Disease as a Cause of Cushing Syndrome and a Coincident Pituitary Adenoma

“…Cutaneous myxomas are also seen on the eyelids and in the external ear canals. 1,7 Presence of 2 or more of these manifestations, including PPNAD, are required to make the diagnosis. 8 PPNAD is the most frequent and characteristic endocrine tumor observed in CNC.…”

Absence of PRKAR1A loss of heterozygosity in laser-captured microdissected pigmented nodular adrenocortical tissue from a patient with Carney complex caused by the novel nonsense mutation p.Y21X

“…Primary pigmented nodular adrenocortical disease (PPNAD), a rare cause of ACTHindependent Cushing syndrome, is the main endocrine manifestation of Carney complex (1,2). Mutations of the gene encoding protein kinase A regulatory subunit 1α (PRKAR1A) represent the molecular aetiology of approximately 41% of the kindreds affected by Carney complex (3)(4)(5)(6). Additionally, genetic linkage analysis has identifi ed other genetic loci on chromosome 2p in families with Carney complex (7,8).…”