The first description of CNC included 40 patients [
1], among them 10 were familial cases, leading to the hypothesis of a genetic origin, at least in a subset of patients. CNC seems to be a genetically heterogeneous disease and linkage analysis has shown that at least two loci are involved: 2p16 and 17q22-24 [
11,
12]. The
CNC1 gene, located on 17q22-24, has been identified as the regulatory subunit (R1A) of the protein kinase A (
PRKAR1A) [
13,
14]. PRKAR1A is a key component of the cAMP signaling pathway that has been implicated in endocrine tumorigenesis. Heterozygous inactivating mutations of
PRKAR1A have been detected in about 45 to 65 % of CNC families [
3,
4]. In CNC patients with Cushing's syndrome the frequency of
PRKAR1A mutations is about 80 %, suggesting that families with PPNAD are more likely to carry a 17q22-24 defect [
5]. Interestingly, patients with isolated PPNAD and no familial history of CNC may also carry a germline
de novo mutation in
PRKAR1A [
6]. In the tumors of CNC patients loss of heterozygosity (LOH) at 17q22-24 may be observed, suggesting that
PRKAR1A is a tumor suppressor gene. Somatic mutation of
PRKAR1A in a patient with PPNAD already carrying a germline mutation may lead to inactivation of the wild type allele [
6]. However, inactivation of the remaining wild type allele by genetic alteration does not appear to be a constant step in PPNAD and CNC tumor development [
5]. In a mice transgenic model with heterozygous inactivation of
PRKAR1A, tumors may develop without allelic loss [
4]. This suggests that the classic model of tumor suppressor gene with a germline inactivating first allelic alteration, followed by a second genetic hit leading to inactivation of the remaining wild type allele, might to some extent be applicable to PRKAR1A. It is also possible that in PPNAD, a general polyclonal expansion might be stimulated by haploinsufficiency due to the first germline defect; a second genetic hit would then lead to inactivation of the wild type allele and further stimulate tumorigenesis and the development of adrenocortical nodules.
A putative
CNC2 gene located at the 2p16 locus remains to be determined [
3,
11]. Somatic alterations of the 2p16 region have been reported in CNC tumors, even in patients with mutation of the
CNC1 gene (
i.e. PRKAR1A located on 17q22-24) [
15]. These alterations are usually gene amplifications, suggesting that the gene located at 2p16 is a potential oncogene. Considering the genetics in isolated PPNAD, it should be mentioned that the clinical manifestations in a subgroup of very young PPNAD patients may differ from those in older patients with CNC. In these patients the classical pathological finding of pigmented nodules may be absent although micronodules are present [
10,
16]. In this subgroup of very young PPNAD patients, Cushing's syndrome may occur between birth and the age of 5-yrs. The main reason for differentiating this group of PPNAD or PPNAD-like patients is the lower rate of germline inactivating mutation.