A large family with Carney complex caused by the S147G PRKAR1A mutation shows a unique spectrum of disease including adrenocortical cancer

Abstract

Context: Most tumors in Carney complex (CNC) are benign, including primary pigmented nodular adrenocortical disease (PPNAD), the main endocrine tumor in CNC. Adrenocortical cancer (AC) has never been observed in the syndrome. Herein, we describe a large Azorean family with CNC caused by a point mutation in the PRKAR1A gene coding for type 1-α (RIα) regulatory subunit of the cAMP-dependent protein kinase A, in which the index patient presented with AC.

Objective: We studied the genotype-phenotype correlation in CNC.

Design and setting: We reported on case series and in vitro testing of the PRKAR1A mutation in a tertiary care referral center.

Patients: Twenty-two members of a family were investigated for Cushing syndrome and other CNC components; their DNA was sequenced for PRKAR1A mutations.

Results: Cushing syndrome due to PPNAD occurred in four patients, including the proposita who presented with AC and three who had Cushing syndrome and/or PPNAD. Lentigines were found in six additional patients who did not have PPNAD. A base substitution (c.439A>G/p.S147G) in PRKAR1A was identified in the proposita, in the three others with PPNAD, in the proposita's twin daughters who had lentigines but no evidence of hypercortisolism, and in five other family members, including one without lentigines or evidence of hypercortisolism. Unlike in other RIα defects, loss of heterozygosity was not observed in AC. The S147G mutation was compared to other expressed PRKAR1A mutations; it led to decreased cAMP and catalytic subunit binding by RIα and increased protein kinase A activity in vitro.

Conclusions: In a large family with CNC, one amino acid substitution caused a spectrum of adrenal disease that ranged from lack of manifestations to cancer. PPNAD and AC were the only manifestations of CNC in these patients, in addition to lentigines. These data have implications for counseling patients with CNC and are significant in documenting the first case of AC in the context of PPNAD.

Fig. 1.

A, Pedigree of the CAR609 family. B, The proposita. C, AC from the proposita: the tumor had a maximum diameter of 12 cm. D, Family members with PPNAD had a “paradoxical” increase in their cortisol secretion in response to dexamethasone, whereas their relatives with normal PRKAR1A sequence suppressed their cortisol secretion in response to dexamethasone. E and F, Individual III-15 before (E) and after (F) bilateral adrenalectomy. G, Subject IV-12 is a carrier of the S147G mutation and has lentigines but remains healthy and eucortisolemic to date.

Fig. 2.

A, The right adrenal removed from individual III-15 with the appearance of classic PPNAD. B, The adrenal gland excised from the proposita had characteristic features of PPNAD, including micronodules of eosinophilic cells with pigment. C, Cytoplasmic pigmentation (arrow) (magnified 40×). D–F, AC showing penetration of the capsule (D) and vascular invasion (E and F).

Fig. 3.

Immunostaining did not show nuclear accumulation of β-catenin in the PPNAD (A) or in the AC cells (B) from the proposita's lesions (magnified 40×).

Fig. 4.

A, PKA activity of the S147G mutation is comparable to that of other pathogenic RIα defects and greater than that of the WT molecule. B, cAMP binding affinity is lower for the S147G mutation than that of the WT RIα but generally higher than that in other expressed variants.