Novel Mutation in PRKAR1A in Carney Complex
A 19-year-old woman was admitted due to slowly progressing right hemiparesis. At the time of admission, apart from a slightly drowsy mental status, her presentation was unremarkable with stable vital signs and no past medical history. On physical examination, she had multiple tiny brown pigmented macules on her face and abdomen, and a bean-shaped brownish papule on the axilla and left upper arm. She also had groups of brownish papules on both nipples (). Her mother and elder sister had a history of cardiac myxoma.\nMagnetic resonance imaging (MRI) of the brain demonstrated diffuse hemorrhagic infarction in the middle cerebral artery territory. Echocardiography showed a 3×2.5×2 cm echogenic mass in her left atrium (). The cardiac mass was resected through an open thoracotomy, and the masses on both nipples were also excised during the operation. The histologic diagnosis of all three masses was myxoma. Her multiple myxomas, skin pigmentation, and familial history of cardiac myxoma were compatible with CNC. Upon evaluation for endocrinologic derangement, the laboratory data including adrenocorticotropic hormone, cortisol, estradiol, and testosterone were within the normal range. Follow-up was planned for the patient with regular echocardiography and ultrasonography (US) on her breasts and thyroid glands.\nDuring 5 years of follow-up, US demonstrated several isoechoic or hypoechoic nodules in both of her breasts. US-guided core needle biopsy of these lesions revealed fibroadenomas. The number of nodules on her breasts gradually increased, and numerous nodules of various sizes were found on her breasts and axilla. Her thyroid glands had several tiny cystic nodules on both lobes, but the overall number or size of the nodules remained unchanged.\nMost recently, the patient was admitted due to a perianal mass that she had for 1 year. It did not cause any pain, tenderness, or dyschezia. MRI demonstrated a 6.7×5.8×4.0 cm round mass occupying the subcutaneous soft tissue, abutting the inferior border of the internal sphincter. The mass showed a low signal intensity on T1-weighted imaging (WI) and a bright high signal intensity on T2WI, and on fat suppression T2WI. With gadolinium enhancement, the mass revealed multiple enhancing internal septa (). With the presumptive diagnosis of a malignant mucinous neoplasm, surgical resection was performed. Grossly, multiple thin fibrous septa were identified within the gray to white gelatinous surface. Histologic examination of the tumor showed a multilobular growth of myxoid stroma and loosely deposited spindle cells. The thin fibrous septa traversed the tumor parenchyma. Occasional prominent arborizing blood vessels were also identified (). These findings were consistent with superficial angiomyxoma.\nDNA was extracted using a QIAamp DNA mini kit (Qiagen, Hilden, Germany) from the perianal specimen. Polymerase chain reaction was performed using a thermal cycler (GeneAmp PCR System 9600, Perkin-Elmer, Wellesley, MA, USA) for which the primers of 10 exons of PRKAR1A, exon 16 of myosin, heavy chain 8, skeletal muscle, perinatal (MYH8), and 7 exons of PDE11A were prepared (). The cycle sequencing procedure was followed by the use of the BigDye Terminator v3.1 cycle sequencing kit (Applied Biosystems, Foster City, CA, USA) according to the manufacturer's recommendations, and the reaction mixture was analyzed on an ABI Prism 3100 DNA sequencer (Applied Biosystems). The genetic analysis found a novel deletion mutation (c.537delA) in the PRKAR1A gene in exon 6. This resulted in a frameshift mutation and introduced a premature stop codon downstream in exon 7 (). Genetic studies of the PDE11A gene showed mutations in exons 1 and 20, but these mutations were also found in the normal control DNA; we used stored normal DNA that was extracted from a normal volunteer. No mutations were found in the MYH8 gene.