Carney complex is an autosomal dominant multiple neoplasia syndrome characterized by cardiac, endocrine, cutaneous, and neural myxomatous tumors, as well as a variety of pigmented lesions of the skin and mucosae. Carney complex may simultaneously involve multiple endocrine ... Carney complex is an autosomal dominant multiple neoplasia syndrome characterized by cardiac, endocrine, cutaneous, and neural myxomatous tumors, as well as a variety of pigmented lesions of the skin and mucosae. Carney complex may simultaneously involve multiple endocrine glands, similar to classic MEN syndromes (MEN1; 131100 and MEN2; 171400). Carney complex shows some similarities to McCune-Albright syndrome (MAS; 174800), a sporadic condition that is also characterized by multiple endocrine and nonendocrine tumors, and shares skin abnormalities and some nonendocrine tumors with the lentiginoses and certain of the hamartomatoses, particularly Peutz-Jeghers syndrome (PJS; 175200). Carney complex is often associated with the unusual large-cell calcifying Sertoli cell tumor and psammomatous melanotic schwannomas (Kirschner et al., 2000; Stratakis et al., 2001).
Rees et al. (1973) reported a young man with red hair and fair skin who had multiple lentigines and a left atrial myxoma. Autosomal dominant inheritance was suggested. Follow-up of this patient by Atherton et al. (1980) referred ... Rees et al. (1973) reported a young man with red hair and fair skin who had multiple lentigines and a left atrial myxoma. Autosomal dominant inheritance was suggested. Follow-up of this patient by Atherton et al. (1980) referred to a palatal tumor with characteristics of myxoid neurofibroma. Atherton et al. (1980) reported a 10-year-old boy with cutaneous pigmented lesions, subcutaneous myxoid neurofibromata, and atrial myxoma. At birth, 3 pigmented lesions were noted on the neck, trunk, and thigh; a large number of pigmented lesions developed in the first few weeks of life. He developed several myxoid neurofibromata on the ear, chin, and anterior chest, as well as 2 cardiac atrial myxomas. The boy had blue eyes and hair of a distinctive rust-red color. Both parents had multiple freckles, although less so than the patient. Atherton et al. (1980) suggested the designation 'NAME syndrome' as an acronym for nevi, atrial myxoma, myxoid neurofibromata, and ephelides (freckles). Koopman and Happle (1991) suggested that the acronym NAME could stand for nevi, atrial myxoma, mucinosis of the skin, and endocrine overactivity. Proppe and Scully (1980) reported familial occurrence of large-cell calcifying Sertoli cell tumor of the testes and cardiac myxoma. In a follow-up of a family reported by Proppe and Scully (1980), Carney et al. (1986) noted that 2 affected brothers also had nodular adrenocortical hyperplasia. Their mother had skin pigmentation and left atrial myxoma. Schweizer-Cagianut et al. (1980) reported a brother and sister with Cushing syndrome associated with primary adrenocortical micronodular dysplasia. The brother also had fibromas of the skin, suggesting the diagnosis of neurofibromatosis type 1 (NF1; 162200), but cafe-au-lait spots were absent. The sister had a documented intracranial bleed, fibromas of the eyelid, and microcalcification of the breasts. Functional tests suggested an intrinsic defect in the adrenals and no hypothalamic-pituitary dysfunction. In a follow-up report of the same family, Schweizer-Cagianut et al. (1982) noted that an older brother had died at age 5 years of atrial myxoma; he had a hemangioma of the right groin. On autopsy at age 36 years, the affected sister was found to have a cardiac myxoma. The fibroma of her eyelid was reinterpreted as a myxoma; both breasts contained multiple small benign fibroadenomas with an unusual myxomatous and vascularized stroma, and she was noted to have had finely freckled pigmentation around the mouth and lips. Schweizer-Cagianut et al. (1982) concluded that the family had a syndrome comprising adrenocortical nodular dysplasia, Cushing syndrome, and myxomatous tumors. Barlow et al. (1983) described 2 sisters with the combination of Cushing syndrome, cardiac myxomas, other myxoid tumors, and spotty facial and labial pigmentation. Carney et al. (1985) presented evidence for the existence of a distinct familial syndrome consisting of spotty cutaneous pigmentation, myxomas of the heart and elsewhere, and Cushing syndrome resulting from nodular adrenocortical dysplasia. In their family, a brother of the patient had pigmented spots of the face and lips, had multiple nodular and pedunculated myxomas of the skin, and at age 21 was found to have acromegaly caused by pituitary adenoma. Successful hypophysectomy was performed. A single pigmented macule was found in the mouth in only 2 of 40 patients, in contrast to the Peutz-Jeghers syndrome in which buccal spotting is a standard feature. Pigmented skin lesions were identified on the face, eyelids, ears, and vermilion borders of the lips, conjunctiva or sclera, vulva, back of hands and fingers, anal verge, and glans penis. Testicular tumors were identified in 9 of 17 male patients; they were bilateral in 7 patients and multicentric in each affected testis. The testicular tumors were large-cell calcifying Sertoli cell tumor, Leydig cell tumor, or adrenocortical rest tumor. Sexual precocity occurred with the first 2 types. Two patients had an unusual tumor referred to as a 'calcifying pigmented neuroectodermal tumor.' Wilsher et al. (1986) described an affected mother and her son and daughter. The mother had left and right atrial myxomata, and the daughter had a left ventricular myxoma, subcutaneous myxoid neurofibromata, and mammary fibroadenosis. Although the son had no evidence of cardiac myxoma, photos demonstrated that all 3 had melanin spots around the lips and over the bridge of the nose. Vidaillet et al. (1987) found 5 cases of what they termed 'syndrome myxoma' out of a total of 75 patients with cardiac myxoma seen at the Mayo Clinic between January 1954 and December 1985. They compared 49 cases of syndrome myxoma with cases of sporadic myxoma; the former showed a younger age, a higher frequency of familial occurrence, ventricular location of tumor (13% vs 0%), multiple tumors (50% vs 1%), and recurrent tumor (18% vs 0%). Young et al. (1989) provided a 50-year follow-up report of a woman seen at the Mayo Clinic at the age of 17 for Cushing syndrome associated with adrenal dysfunction. The adrenals were mottled brown in appearance and contained nodules composed of large adrenocortical cells with moderately intense brown cytoplasmic pigment. A photograph taken at that time showed spotty pigmentation involving the face and vermilion borders of the lips as well as the chest and shoulders. A fraternal twin of this woman had the same features of Cushing syndrome and spotty facial and labial pigmentation. He was found to have abnormal adrenal glands with 2- to 3-mm reddish brown bulging nodules and coarsely granular brown pigment. Both daughters of the proband had spotty facial pigmentation; 1 also had primary pigmented nodular adrenal cortical disease and a nasopharyngeal schwannoma. Several other members of the family had spotty facial pigmentation. Handley et al. (1992) described the Carney syndrome in a mother and her son and daughter. All 3 had varying degrees of centrofacial/mucosal lentigines and cutaneous myxoid tumors. The mother had myxoid mammary fibroadenomatosis and a left atrial myxoma; her daughter developed a prolactin-secreting pituitary adenoma; the son had bilateral large-cell calcified Sertoli cell testicular tumors and an axillary psammomatous melanotic schwannoma. In a review of 53 patients with Carney complex from 12 families, Stratakis et al. (1997) identified 2 patients with thyroid carcinoma (1 papillary and 1 follicular; 3.8%) and 1 with a follicular adenoma. Detailed laboratory studies of the thyroid gland of 5 affected adults and 6 affected children showed normal results, but thyroid ultrasonography showed hypoechoic, cystic, solid, or mixed lesions in 3 of the 5 adults (60%) and 4 of the 6 children (67%). Thyroid gland abnormalities were documented in 5 sibs and 1 parent-child pair. Stratakis et al. (1997) concluded that thyroid gland pathology is common in patients with Carney complex, and includes a spectrum of abnormalities ranging from follicular hyperplasia and/or cystic changes to carcinoma. Nwokoro et al. (1997) reported an extensively affected family. The proband was a 34-year-old woman with multiple nevi, diffuse facial lentigines, and labial pigmentation present from an early age. Right ventricular myxomas were resected at the age of 30. She also had invasive follicular carcinoma of the thyroid gland, Barrett metaplasia of the esophagus, neoplastic colonic polyps, bipolar affective disorder, and atypical mesenchymal neoplasm of the uterine cervix distinct from the myxoid uterine leiomyoma usually seen in this syndrome. Diagnosis of Carney syndrome was established in her 9-year-old son, and there was a probable diagnosis in her 12-year-old daughter. Various endocrine manifestations occurred in at least 9 relatives in 3 generations. Pituitary microadenoma and calcifying testicular tumor were present in 1 relative each. Legius et al. (1998) reported a 41-year-old man with the Carney complex. Clinical features included a pigmented schwannoma on a lumbar nerve root with microscopically demonstrated psammoma bodies (melanocytic schwannoma), atrial myxoma resulting in a cerebellar ischemic stroke, and melanin spots on the vermilion border of the lips, eyelids, and back of the hands. He also had a left nonfunctional adrenal adenoma, macroorchidism, and reduced fertility. Goldstein et al. (1999) reported a 40-year-old man who was a member of a family segregating for Carney complex, but was initially not thought to be affected. However, a review of pathologic studies and haplotype analysis based on genotyping studies with 17q2 microsatellites showed that he was affected. He presented with recurrent neurofibroma, a tumor that had not been considered a component of Carney complex. Subsequent review revealed findings consistent with cutaneous myxoma. Echocardiography displayed interatrial septal thickening. In addition, he was noted to have abnormal facial and eyelid hyperpigmented spots with involvement of the buccal mucosa.
In patients with Carney complex, Kirschner et al. (2000) identified mutations in the PRKAR1A gene (188830.00001-188830.0003).
Kirschner et al. (2000) identified 15 distinct PRKAR1A mutations in affected members of 22 (41%) of 54 kindreds with Carney ... In patients with Carney complex, Kirschner et al. (2000) identified mutations in the PRKAR1A gene (188830.00001-188830.0003). Kirschner et al. (2000) identified 15 distinct PRKAR1A mutations in affected members of 22 (41%) of 54 kindreds with Carney complex. Six families showed linkage to CNC2. In affected members of 3 unrelated families, Casey et al. (2000) identified PRKAR1A frameshift mutations resulting in haploinsufficiency of R1-alpha (188830.0005-188830.0007). - Loss of Heterozygosity Studies Stratakis et al. (1998) noted that the lesions in patients with CNC are similar to those seen in Peutz-Jeghers syndrome and other lentiginosis syndromes. In tumors and cell lines from 2 CNC families excluded from the CNC2 locus, Stratakis et al. (1998) found no evidence for loss of heterozygosity (LOH) involving the Peutz-Jeghers syndrome locus on 19p13 (STK11; 602216) or Cowden disease (158350)/Bannayan-Zonana syndrome (153480) locus on 10q23 (PTEN; 601728). Studies of 16 additional CNC patients also did not show LOH at these loci in tumors that were histologically identical to those seen in Peutz-Jeghers syndrome. The authors concluded that despite substantial clinical overlap among CNC, Peutz-Jeghers syndrome, Cowden disease, and Bannayan-Zonana syndrome, LOH for the STK11 and PTEN loci is an infrequent event in CNC-related tumors. Pack et al. (2000) investigated the pituitary glands of 8 patients with CNC1 and acromegaly. Tumor DNA from 4 tumors was used for comparative genomic hybridization. All 8 tumors stained for both growth hormone (GH; 139250) and prolactin (PRL; 176760), and some for other hormones, as well as the guanine nucleotide-binding protein alpha-subunit (GNAS; 139320), which is mutated in McCune-Albright syndrome. Evidence for somatomammotroph hyperplasia was present in proximity to adenoma tissue in 5 of 8 patients; in the remaining 3, only adenoma tissue was available for study. Comparative genomic hybridization showed multiple changes involving losses of chromosomal regions 6q, 7q, 11p, and 11q, and gains of 1pter-p32, 2q35-qter, 9q33-qter, 12q24-qter, 16, 17, 19p, 20p, 20q, 22p and 22q in the most aggressive tumor, an invasive macroadenoma; no chromosomal changes were seen in 3 microadenomas diagnosed prospectively. The authors concluded that, in at least some patients with CNC1, the pituitary gland is characterized by somatotroph hyperplasia, which precedes GH-producing tumor formation, in a pathway similar to that suggested for McCune-Albright syndrome-related pituitary tumors.