Fatal Carney Complex in Siblings Due to De Novo Large Gene Deletion

Abstract

Context: Carney complex (CNC) is a rare multiple neoplasia syndrome involving cardiac, endocrine, neural, and cutaneous tumors and a variety of pigmented skin lesions. CNC can be inherited as an autosomal dominant trait, but in about one-third of patients, the disease is caused by de novo mutation in the PRKAR1A gene localized on chromosome 17q22-24. Most of the mutations include single base substitutions and small deletions/insertions not exceeding 15 base pairs. Recently, large germline PRKAR1A deletions have been described and may cause a more severe phenotype.

Case description: Herein, we report the cases of two siblings with CNC with a de novo large deletion of 107 kb at 17q24.2 associated with acromegaly in both and primary pigmented nodular adrenocortical disease, cardiac myxoma, and lethal metastatic melanotic schwannian tumor at the age of 27 years in one of them, supporting the hypothesis that large deletions of PRKAR1A lead to severe disease.

Conclusions: To our knowledge, this is the first description of familial CNC in siblings in which neither parent carried the deletion in blood-derived DNA, suggesting that one of them had germ cell mosaicism for this deletion. Testing for large gene deletions should be obtained in all patients who meet the diagnostic criteria for CNC but do not have a PRKAR1A mutation by Sanger sequencing.

Figure 1.

(A) Acromegalic features in the proband. Note chest scar from previous cardiac myxoma operation (triangle), typical facial features (wide nose, prognathism, prominent eyebrow and thickened lips), cutaneous myxomas on left thumb and right wrist (open arrows), large left hand, and spastic right hand due to the hemiplegia (closed arrow). He also had enlarged feet and tongue. (B) Computed tomography of the pelvis of the proband revealed a 14.0-cm × 8.5-cm tumor (star). (C) Gadolinium-enhanced coronal magnetic resonance imaging scan of the head of the proband showed four abnormalities: a pituitary adenoma (open arrow), a large left hemispheric cavity in the left cerebral hemisphere after childhood embolic stroke (star), multiple middle cerebral artery aneurysms (triangle) resulting from myxoma emboli stroke and the probable cause of the patient’s epileptic fits, and right optic nerve atrophy (closed arrow). Image is slightly fuzzy due to patient movement artifact. (D) Scrotal ultrasound of the proband revealed bilateral calcified testicular tumors. (E) Metastatic melanotic schwannian tumor. Low-power magnification image showed sheets of pigmented tumor cells with degenerative fibrosis surrounded by a thick fibrous capsule (hematoxylin and eosin, ×40). (F) High-power magnification revealed pigmented polygonal and spindle cells with a few nonpigmented elongated tumor cells (black arrows) (hematoxylin and eosin, ×200). (G) Mild acromegalic features in the sister. (H) Myxoma on the hard palate in the sister. (I) Gadolinium-enhanced magnetic resonance imaging scan revealed an intrasellar pituitary microadenoma in the sister. (J) Representative image of the computed tomography scan showing normal adrenal glands in the sister, despite the abnormal biochemistry results.

Figure 2.

Representative depiction of chromosome 17 with the area marked of the maximum size of the deletion (dotted arrow, from base-pairs 66,481,332 to 66,588,508; numbers are according to the GRCh37/hg19 human genome assembly) and the minimum size of deletion (dashed arrow, from 66,527,381 to 66,568,637). PRKAR1A gene (located at 66,507,921 to 66,529,570) is represented with coding exons (longer lines) and untranslated exons (shorter lines/area).