Carney Complex, Type 1

A number sign (#) is used with this entry because Carney complex type 1 (CNC1) is caused by heterozygous mutation in the protein kinase A regulatory subunit-1-alpha gene (PRKAR1A; 188830) on chromosome 17q24.

Description

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).

Genetic Heterogeneity of Carney Complex

Carney complex type 2 (CNC2; 605244) has been mapped to chromosome 2p16, indicating genetic heterogeneity.

See also isolated primary pigmented nodular adrenocortical disease (PPNAD1; 610489) and isolated cardiac myxoma (255960), both of which are manifestations of the Carney complex that can be seen in isolation.

A family with features of the Carney complex and distal arthrogryposis (608837) associated with a mutation in the MYH8 gene (160741) has also been reported.

Clinical Features

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.

Inheritance

Carney et al. (1986) suggested autosomal dominant inheritance. At least one manifestation of the syndrome occurred in 3 successive generations of an affected family. Both males and females were affected, and 5 of 11 children of affected persons had the disorder, although no male-to-male transmission had been reported until the report of Koopman and Happle (1991).

Diagnosis

Kennedy et al. (1987) emphasized the diagnostic usefulness of ophthalmologic abnormalities in Carney complex. Of 63 patients studied, eyelid myxomas were present in 16%, facial and eyelid lentigines in 70%, and pigmented lesions on the caruncle or conjunctival semilunar fold in 27%. Spotty pigmentation of the skin involved the vermilion border of the lips but only infrequently affected the buccal mucosa.

Bandelin et al. (2008) reported a 32-year-old woman who presented with clinical hypercortisolism, including a 30-lb weight gain, central obesity, oligomenorrhea, hirsutism, and hypertension with hypokalemia. The patient reported easy bruisability, and her surgical history included bilateral breast fibrous adenomas within a myxoid stroma. An adrenal computed tomography (CT) revealed bilateral nodularity; a positron emission tomography (PET)-CT demonstrated F(18)-fluorodeoxyglucose uptake in both adrenals. Bandelin et al. (2008) stated that, to their knowledge, this was the first report of PET-CT imaging of the adrenal glands in primary pigmented nodular adrenocortical disease. They concluded that PET-CT imaging may be useful in the evaluation of patients with ACTH-independent hypercortisolism, and that, apparently, not all F18-fluorodeoxyglucose-avid adrenal glands contain malignancies.

Mapping

Stratakis et al. (1996) first identified a locus for Carney complex on chromosome 2q, which is now designated CNC2. In a family with Carney complex, Basson et al. (1997) excluded linkage to the CNC2 locus identified by Stratakis et al. (1996), indicating genetic heterogeneity of this disorder.

By studies of 4 kindreds with Carney complex, Casey et al. (1998) found linkage to a 17-cM locus on chromosome 17q2 (maximal pairwise lod scores of 5.9, 1.5, 1.8, and 2.9 in each family, respectively).

Molecular Genetics

In patients with Carney complex, Kirschner et al. (2000) identified mutations in the PRKAR1A gene (188830.0001-188830.0003).

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 syndrome (158350) 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, and Cowden disease, 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.

Pathogenesis

To evaluate the role of PKA isozymes on proliferation and cell cycle, Nesterova et al. (2008) studied the association of inactivating mutations of PRKAR1A with tumor formation. A cell line with RI-alpha (encoded by PRKAR1A) haploinsufficiency due to an inactivating PRKAR1A mutation was transfected with constructs encoding PKA subunits. Introduction of PKA subunits led to changes in proliferation and cell cycle: a decrease in aneuploidy and G2/M for the PRKAR1A-transfected cells, and an increase in S phase and aneuploidy for cells transfected with PRKAR2B (176912), a known PRKAR1A mutant (RI-alpha), and the PKA catalytic subunit (PRKACA; 601639). There were alterations in cAMP levels, PK subunit expression, cyclins, and E2F factors; E2F1 (189971) was shown to possibly mediate PKA effects on cell cycle by small interfering RNA studies. cAMP levels and constitutive and stimulated cAMP signaling were altered in transfected cells.

Nomenclature

Carney et al. (1985) suggested that the acronym NAME syndrome, as well as the acronym LAMB syndrome (lentigines, atrial myxoma, mucocutaneous myxoma, and blue nevi) reported by Rhodes et al. (1984), could represent this pleiotropic syndrome of cutaneous, cardiac, and endocrine involvement.

Stratakis et al. (1998) suggested that this disorder should be called Carney complex (CNC), as proposed by Bain (1986). In part, this is to differentiate it from the triad of gastric leiomyosarcoma, pulmonary chondroma, and extraadrenal paraganglioma described by Carney (1983) and sometimes also called Carney syndrome; see 604287. Basson (1999) indicated that he and other students of Carney complex have used the symbol CAR for the locus. This symbol has, however, been preempted for other usage.

Salomon et al. (1990) noted that Schweizer-Cagianut et al. (1982) provided the first comprehensive description of Carney complex and suggested that it be called the 'Swiss syndrome' to reflect the country in which it was described.

History

Carney (1995) described a fascinating search, which was eventually successful, for Harvey Cushing's case of Minnie G., who was reported in his 1912 monograph on the pituitary and its disorders. Carney (1995) postulated that this patient might have had 'his' syndrome. The patient, then 23 years old, had been referred to Cushing at The Johns Hopkins Hospital in 1910. Minnie, whose actual given name was Maita, died in 1958 at the age of 71 years. Having assembled the family pedigree, Carney (1995) could find no evidence of other affected members in the extended family.