Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations

Abstract

Objective: We have recently reported five patients with bilateral adrenocortical hyperplasia (BAH) and Cushing's syndrome (CS) caused by constitutive activation of the catalytic subunit of protein kinase A (PRKACA). By doing new in-depth analysis of their cytogenetic abnormality, we attempted a better genotype-phenotype correlation of their PRKACA amplification.

Design: This study is a case series.

Methods: Molecular cytogenetic, genomic, clinical, and histopathological analyses were performed in five patients with CS.

Results: Reinvestigation of the defects of previously described patients by state-of-the-art molecular cytogenetics showed complex genomic rearrangements in the chromosome 19p13.2p13.12 locus, resulting in copy number gains encompassing the entire PRKACA gene; three patients (one sporadic case and two related cases) were observed with gains consistent with duplications, while two sporadic patients were observed with gains consistent with triplications. Although all five patients presented with ACTH-independent CS, the three sporadic patients had micronodular BAH and underwent bilateral adrenalectomy in early childhood, whereas the two related patients, a mother and a son, presented with macronodular BAH as adults. In at least one patient, PRKACA triplication was associated with a more severe phenotype.

Conclusions: Constitutional chromosomal PRKACA gene amplification is a recently identified genetic defect associated with CS, a trait that may be inherited in an autosomal dominant manner or occur de novo. Genomic rearrangements can be complex and can result in different copy number states of dosage-sensitive genes, e.g., duplication and triplication. PRKACA amplification can lead to variable phenotypes clinically and pathologically, both micro- and macro-nodular BAH, the latter of which we speculate may depend on the extent of amplification.

Trial registration: ClinicalTrials.gov NCT00001452.

Conflict of interest statement

Disclosure summary: The authors have no conflicts of interest to declare.

Declaration of Interest

The authors have no conflict of interest to report

© 2015 European Society of Endocrinology.

Figures

Figure 1

Facial appearance of patients 1–3 before and after adrenalectomy and their corresponding HD-aCGH results. The photographs of the patients are shown in the left column, and their HG-aCGH studies are show accordingly in the right column. aCGH plots covering the critical region (Chr19:12346258-16058758) are shown. Red dots, probes with log2 ratio greater than 0.25; black dots, probes with log2 ratio between −0.25 and 0.25; green dots, probes with log2 ratio smaller than −0.25. The vertical red bar represents the position of PRKACA, and the log2 ratios of the amplified segments encompassing PRKACA are listed between each aCGH plot.

Figure 2

Histopathology from adrenal glands in Patient 1. A and B: Histologic sections show an adrenal gland with cortical nodular hyperplasia. Multiple nodules are present which contain compact and few lipid-rich cells (A, H&E 40X original magnification; B, H&E 100X original magnification). C and D: Hyperplastic nodules are highlighted by immunohistochemistry stains for Synaptophysin (C, 100X original magnification) and Inhibin (D, 40X original magnification).