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Eur J Endocrinol. 2015 Jun;172(6):803-11. doi: 10.1530/EJE-14-1154.

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

Author information

1
Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Building 10-CRC, Room 9D42, 10 Center Drive, MSC, 1103, Bethesda, Maryland 20892, USA
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
3
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
4
Department of Clinical Genetics, Guy's Hospital, London, UK
5
Department of Endocrinology, Great Ormond Street Hospital for Children, London, UK
6
Department of Pediatrics, Our Lady of the Lake Children's Hospital, Baton Rouge, Louisiana, USA
7
Department of Pathology, National Cancer Institute, Bethesda, Maryland, USA
8
Emeritus Member, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
9
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
10
Texas Children's Hospital, Houston, Texas, USA

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.

PMID:
25924874
PMCID:
PMC4428149
DOI:
10.1530/EJE-14-1154
[Indexed for MEDLINE]
Free PMC Article

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