Pigmented Nodular Adrenocortical Disease, Primary, 4

A number sign (#) is used with this entry because primary pigmented nodular adrenocortical disease-4 (PPNAD4) is caused by a duplication on chromosome 19p13 that includes the PRKACA gene (601639). A recurrent somatic mutation in the PRKACA gene has been found in up to 70% of cortisol-secreting adrenocortical adenomas.

For a general phenotypic description and a discussion of genetic heterogeneity of primary pigmented nodular adrenocortical disease, see PPNAD1 (610489).

Description

Cushing syndrome is a clinical designation for the systemic signs and symptoms arising from excess cortisol production. Affected individuals typically show hypertension, impaired glucose tolerance, central obesity, osteoporosis, and sometimes depression. Corticotropin-independent Cushing syndrome results from autonomous cortisol production by the adrenal glands, often associated with adrenocortical tumors. Adrenocortical tumors are most common in adult females (summary by Cao et al., 2014; Sato et al., 2014).

Clinical Features

Beuschlein et al. (2014) reported 5 patients, including a mother and son, with bilateral ACTH-independent adrenal hyperplasia resulting in clinical Cushing syndrome symptoms. The other 3 patients were boys between 3 and 9 years of age. Four patients were diagnosed with primary pigmented nodular adrenocortical disease (PPNAD) and 1 with ACTH-independent macronodular adrenal hyperplasia (AIMAH). The diagnosis of ACTH-independent Cushing syndrome was based on biochemical hallmarks of hypercortisolism, suppressed plasma corticotropin levels, and nonsuppressible serum cortisol levels after dexamethasone administration. Catabolic features included muscle weakness, skin fragility, and osteoporosis.

Goh et al. (2014) reported 13 unrelated patients with Cushing syndrome due to a cortisol-producing adrenocortical adenoma. Clinical symptoms were variable, but included Cushingoid appearance with recent weight gain, 'moon facies,' hirsutism, thinning of hair, acne, dordocervical fat pad, proximal muscle weakness, ecchymoses, osteopenia, diabetes mellitus, hypertension, and emotional lability or depression.

Sato et al. (2014) found that patients with adrenocortical adenomas associated with the somatic L206R mutation in the PRKACA gene had clinical symptoms of Cushing syndrome and tended to have significantly smaller adenoma sizes as well as higher cortisol production compared to individuals with non-PRKACA-mutated adrenal adenomas.

Cytogenetics

In 5 of 35 patients with overt ACTH-independent Cushing syndrome due to bilateral adrenal adenomas, Beuschlein et al. (2014) identified germline heterozygous duplications of chromosome 19p13. The duplications ranged in size from 294 kb to 2.7 Mb, but all included the entire PRKACA gene. Patient cells showed increased protein levels of the PKA catalytic subunit as well as increased basal protein kinase A activity, consistent with a gain of function. No PRKACA whole-gene duplications were found in the Database of Genomic Variants or in an in-house database of 2,000 persons with intellectual disability, congenital malformation, or both.

Molecular Genetics

In 8 of 10 cortisol-secreting adrenal adenomas from patients with overt Cushing syndrome, Beuschlein et al. (2014) identified a somatic heterozygous mutation in the PRKACA gene. Seven of the tumors carried the same L206R mutation (601639.0001) that was demonstrated in vitro to result in constitutive activation of protein kinase A that could not be suppressed by the regulatory subunit. The mutations were found by whole-exome sequencing. Subsequent analysis of the PRKACA gene in 129 additional adenomas found the somatic L206R variant in tumor tissue from 14 patients with overt Cushing syndrome. Overall, 22 (37%) of 59 patients with overt Cushing syndrome due to a unilateral adrenal adenoma carried a somatic heterozygous PRKACA mutation. PRKACA genomic alterations were not found in patients with subclinical Cushing syndrome.

Simultaneously and independently, Cao et al. (2014), Sato et al. (2014), and Goh et al. (2014) found the recurrent L206R somatic mutation in adrenocortical tumors derived from patients with clinical Cushing syndrome. The mutations, which were found by whole-exome sequencing, were confirmed in additional cohorts of tumor samples. Cao et al. (2014) identified the mutation in up to 69.2% of samples, Sato et al. (2014) in 52.3%, and Goh et al. (2014) in 35%. Each group demonstrated in vitro that the mutation resulted in cAMP-independent activation of protein kinase A with increased substrate phosphorylation. Sato et al. (2014) and Goh et al. (2014) found that the L206R variant disrupted the interface of the catalytic and regulatory subunits, resulting in constitutive activation of protein kinase A and a gain-of-function effect.