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



This study is a case series.



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



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.



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.
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
Maya B
MB
Lodish
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
Bo
B
Yuan
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
Isaac
I
Levy
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Glenn D
GD
Braunstein
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
Charalampos
C
Lyssikatos
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
Paraskevi
P
Salpea
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
Eva
E
Szarek
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
Alexander S
AS
Karageorgiadis
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
Elena
E
Belyavskaya
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
Margarita
M
Raygada
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
Fabio Rueda
FR
Faucz
Department of Clinical Genetics, Guy's Hospital, London, UK
Louise
L
Izzat
Department of Endocrinology, Great Ormond Street Hospital for Children, London, UK
Caroline
C
Brain
Department of Pediatrics, Our Lady of the Lake Children's Hospital, Baton Rouge, Louisiana, USA
James
J
Gardner
Department of Pathology, National Cancer Institute, Bethesda, Maryland, USA
Martha
M
Quezado
Emeritus Member, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
J Aidan
JA
Carney
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA|Texas Children's Hospital, Houston, Texas, USA
James R
JR
Lupski
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
Constantine A
CA
Stratakis
D000311:Adrenal Glands / Q000473:pathology* / Q000503:physiopathology / Q000601:surgery; D000315:Adrenalectomy; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003480:Cushing Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D005784:Gene Amplification / Q000235:genetics*; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008297:Male; D010641:Phenotype; D055815:Young Adult
D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517757:PRKACA protein, human