Version May 2024
INTRODUCTION — Carney complex (CNC; MIM #160980) is a rare multiple endocrine neoplasia syndrome characterized by distinctive pigmented lesions of the skin and mucosal surfaces, cardiac and noncardiac myxomatous tumors, and multiple endocrine tumors [1,2]. CNC is most frequently associated with mutations in the protein kinase A type I-alpha regulatory subunit gene (PRKAR1A) and is inherited in an autosomal dominant fashion. Approximately 25 percent of cases occur sporadically, as a result of a de novo mutation.
CNC has been previously called NAME (nevi, atrial myxoma, ephelides) and LAMB (lentigines, atrial myxoma, blue nevi) syndrome. It should not be confused with the Carney triad, which consists of paragangliomas, gastric stromal tumors, and pulmonary chondromas [3]. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology" and "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors".)
This topic review will focus on the cutaneous manifestations, diagnosis, and differential diagnosis of CNC. Endocrine and nonendocrine tumors associated with CNC are discussed separately.
●(See "Cardiac tumors", section on 'Myxomas'.)
●(See "Testicular sex cord stromal tumors", section on 'Sertoli cell tumors'.)
EPIDEMIOLOGY — CNC is a rare condition, but over 750 patients have been described in many different ethnic groups [1]. Given the significant variability in the clinical manifestations, even within a given family, careful clinical evaluation of first-degree family members is warranted in presumed "sporadic" cases [4]. Familial transmission has been reported more frequently via the affected mother, suggesting a non-Mendelian inheritance or impaired male fertility of affected individuals [4]. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)".)
PATHOGENESIS — CNC is inherited in an autosomal dominant pattern with high penetrance but heterogeneous expression. Approximately one-quarter of cases may be due to de novo mutations. Two genetic loci have been linked to CNC. Inactivating mutations in the protein kinase A type I-alpha regulatory subunit (PRKAR1A) gene on chromosome 17q22-24 are found in the majority of CNC patients [5]. A second locus on chromosome 2p16 is also associated with CNC (Carney complex type 2 [CNC2], MIM 605244). PRKAR1A mutations have been more frequently associated with pigmented skin lesions, myxomas, and early-onset thyroid and gonadal tumors [6].
CLINICAL FEATURES
Skin
Pigmented lesions — Lentiginous skin pigmentation is the most readily identifiable sign of CNC and is found in 70 to 80 percent of patients [1]. Lentigines are stable, well-demarcated, and small (typically <5 mm) tan, brown, or black pigmented macules. In contrast with ephelides (freckles), which tend to be lighter in color and most prominent on the photo-exposed areas of the skin, lentigines may occur anywhere on the body and also on mucosal surfaces. Occasionally, dark to black lentigines have a so-called "ink spot" appearance, with the central pigmentation "bleeding" into the surrounding skin (picture 1) [7]. (See "Benign pigmented skin lesions other than melanocytic nevi (moles)".)
Lentigines associated with CNC typically manifest in the first two decades of life, becoming more prominent at puberty, and may fade in adulthood [8]. They have a predominant centrofacial distribution with perioral and periocular (picture 2) accentuation but may also involve the chest, palms, fingers, and toes. Lentiginous pigmentation of the genital mucosa is common in women (picture 3A-B).
The presence of lentiginous macules on the vermilion borders of the lips, lid margin, and, in particular, on the lacrimal caruncle (picture 4) is uncommon in the general population and is therefore an important clue to the clinical diagnosis of CNC. Conjunctival pigmentation (picture 5) has been reported in approximately 25 percent of CNC patients [9].
Blue nevi are intensely pigmented dark blue or gray papules (picture 6A-B) [1]. Multiple blue nevi are identified in approximately 40 percent of CNC patients. Blue nevi of a rare subtype characterized by epithelioid histology are frequently found in patients with CNC [7]. Although not specific to CNC, a finding of epithelioid blue nevi should alert the clinician to the possibility of a CNC diagnosis.
Café-au-lait macules, nevus spilus, and, rarely, Spitz nevus can also be seen in patients with CNC [7]. (See "Acquired melanocytic nevi (moles)", section on 'Blue nevi' and "Spitz nevus and atypical Spitz tumors".)
Myxomas — Cutaneous myxomas are benign dermal tumors presenting as sharply demarcated subcutaneous nodules, a few millimeters to 1.5 cm in diameter, that vary in color from skin-colored to translucent to blue and may be slightly raised above the skin or exophytic (picture 7A-E). Cutaneous myxomas are seen in less than one-half of CNC patients, but when histologically confirmed, strongly suggest the diagnosis of CNC. Lesions may be solitary or multiple and occur more often on the head, neck, and trunk. Common locations are the eyelids, external ear canal, and areolae.
Endocrine tumors — Endocrine abnormalities due to tumors of the adrenal and pituitary glands or testicular tumors are the most frequent systemic manifestations of CNC [1]:
●Primary pigmented nodular adrenocortical disease – Primary pigmented nodular adrenocortical disease (PPNAD), resulting in adrenocorticotropic hormone-independent overproduction of cortisol and Cushing's syndrome, occurs in 25 to 45 percent of all patients with CNC. It commonly presents with weight gain, hypertension, diabetes mellitus, striae, and easy bruising. In some patients, Cushing's syndrome may be subclinical or may be the only manifestation of CNC. (See "Cushing syndrome due to primary pigmented nodular adrenocortical disease".)
●Asymptomatic growth hormone hypersecretion – Asymptomatic growth hormone (GH) hypersecretion occurs in approximately two-thirds of CNC patients, in most cases without imaging evidence of pituitary adenoma. Acromegaly due to GH-secreting pituitary adenomas occur in approximately 10 to 15 percent of CNC patients, usually in the third or fourth decade of life [1]. Gigantism resulting from increased GH secretion before puberty is rare. Tumors may be single or multiple and occasionally associated with mammosomatotroph hyperplasia [10]. (See "Pituitary gigantism" and "Causes and clinical manifestations of acromegaly".)
●Large cell calcifying Sertoli cell tumor – Large cell calcifying Sertoli cell tumors (LCCSCTs) of the testicles develop in approximately 75 percent of male patients and may lead to gynecomastia in prepubertal boys due to increased aromatase conversion of androgens to estrogens, as well as premature epiphyseal fusion and induction of central precocious puberty [1,11]. The majority of LCCSCTs are benign. Malignancy is found in approximately 17 percent of LCCSCTs, especially in large tumors (>4 cm) or in patients older than 20 years [12,13]. Indices of malignancy include size larger than 4 cm, significant nuclear atypia, >3 per 10 high-power fields, tumor necrosis, and angiolymphatic invasion. (See "Gynecomastia in children and adolescents", section on 'Tumors' and "Definition, etiology, and evaluation of precocious puberty", section on 'Males' and "Testicular sex cord stromal tumors", section on 'Sertoli cell tumors'.)
Thyroid nodules occur in up to 75 percent of patients with CNC and typically develop early in life, with adenomatous disease reported in 25 percent of patients. However, patients with CNC are generally euthyroid. Thyroid cancer (papillary and follicular carcinoma) develops in less than 10 percent of patients [14]. (See "Thyroid nodules and cancer in children".)
Ovarian cysts, serous cystadenoma, teratomas, and endometrioid carcinoma have also been reported in women with CNC [15]. (See "Adnexal mass: Differential diagnosis", section on 'Serous or mucinous cystadenoma' and "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Histopathology", section on 'Endometrioid carcinoma'.)
Nonendocrine tumors — Highly characteristic, nonendocrine tumors associated with CNC include cardiac myxomas (most frequent), psammomatous melanotic schwannomas, breast myxomas and ductal adenomas, and osteochondromyxomas [16-19]:
●Cardiac myxomas – Approximately 3 to 10 percent of all cardiac myxomas are associated with CNC [20,21]. In contrast with sporadic cardiac myxomas, tumors associated with CNC tend to occur at a younger age and may develop simultaneously in multiple chambers of the heart [21]. A review of 319 CNC patients reported cardiac myxoma in 35 percent of females and 45 percent of males by age 30. Forty-four percent of patients had recurrences [22]. Cardiac myxomas are friable and may present as a painful arterial embolism in a previously well patient. Symptoms of cardiac outflow obstruction range from fatigue and dyspnea to heart failure and sudden death. Cardiac myxomas may not be identified by routine auscultation, and transthoracic and/or transesophageal echocardiography is preferred [23]. (See "Cardiac tumors", section on 'Myxomas' and "Cardiac tumors".)
●Psammomatous melanotic schwannomas – Psammomatous melanotic schwannomas may be located anywhere in the central or peripheral nervous system, but in most cases, they occur in the gastrointestinal tract and in the spinal nerve roots. Approximately 20 percent of these tumors associated with CNC are malignant. (See "Peripheral nerve tumors", section on 'Schwannoma'.)
●Benign breast tumors – Benign breast tumor, including myxomas, myxoid fibroadenomas, and ductal adenomas with tubular features, have been reported in approximately 14 percent of female patients with CNC [1,24]. They develop after puberty and may be mistaken for fibrocystic breast disease. (See "Overview of benign breast diseases".)
PATHOLOGY — Skin biopsy is usually not performed for lentiginous pigmentation unless there is a suspicion for malignancy. Histologically, lentigines are characterized by elongation of epidermal ridges with increased pigmentation of the basal layer.
Cutaneous myxomas demonstrate a nonencapsulated proliferation of spindled or stellate dermal fibroblasts in a loose, mucinous stroma in the dermis. Bizarre multinucleated cells and regular mitotic figures can be seen.
Blue nevi characteristically demonstrate highly pigmented melanocytes in the superficial and reticular dermis. Large, epithelioid cells with minimal pigmentation and abundant cytoplasm arranged in nests in the dermis are features suggestive of epithelioid blue nevus [7,25].
DIAGNOSIS
Clinical suspicion — The diagnosis of CNC is suspected in patients presenting with characteristic cutaneous findings, in particular:
●Lentiginosis with periorificial distribution
●Lentigines located on the lid margin or lacrimal caruncle
●Multiple blue nevi or blue nevi with epithelioid histology
●Cutaneous myxoma(s) histologically confirmed
The diagnosis should also be suspected in patients with a history of cardiac myxoma, especially if multiple and with onset at a young age, and in patients with concurrent cutaneous lesions and endocrine disease (eg, Cushing's syndrome, gigantism/acromegaly).
Diagnostic criteria — Diagnostic criteria for CNC are shown in the table (table 1) [4]. The diagnosis is established in the following situations [26]:
●Two or more major criteria are present.
●A pathogenic variant is identified in the protein kinase A type I-alpha regulatory subunit (PRKAR1A).
●One major criterion is present, and a first-degree relative has CNC or an inactivating mutation of PRKAR1A.
In patients presenting with cardiac myxomas, immunohistochemical staining of the tumor tissue for loss of PRKAR1A protein expression was proposed as a rapid and sensitive screening method for CNC [20]. However, loss of PRKAR1A staining showed low specificity (68 percent) in a large cohort of sporadic atrial myxomas and also would not identify patients with CNC associated with the 2p16 locus.
DIFFERENTIAL DIAGNOSIS — CNC should be differentiated from several genetic syndromes associated with lentiginosis. They are summarized in the tables (table 2 and table 3) and include [27]:
●Peutz-Jeghers syndrome – Spotty facial pigmentation, particularly of the lips and oral mucosa, is a hallmark feature of Peutz-Jeghers syndrome (PJS; MIM #175200), an autosomal dominant syndrome characterized by multiple hamartomatous polyps in the gastrointestinal tract, mucocutaneous pigmentation, and an increased risk of gastrointestinal and nongastrointestinal cancer [28]. Both CNC and PJS are associated with thyroid disease and increased risk of large cell calcifying Sertoli cell tumors in males. However, PJS is also strongly associated with early onset gastrointestinal polyposis, as well as markedly elevated risk of gastrointestinal, genitourinary, and other malignancies. Clinically, the lentiginous pigmentation in PJS most commonly occurs on the lips and perioral skin, oral mucosa, rectal mucosa, and palms and soles (picture 8) but, in contrast with CNC, usually spares the periocular skin. Moreover, PJS is not associated with cutaneous myxomas or blue nevi. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management".)
●LEOPARD syndrome – LEOPARD syndrome (lentigines, EKG [electrocardiogram] abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness), also called progressive cardiomyopathic lentiginosis (MIM #151100), is a rare autosomal dominant disorder caused by mutations in the protein tyrosine phosphatase gene (PTPN11). Multiple, disseminated lentigines are the most prominent feature of LEOPARD syndrome. They appear during infancy and early childhood, increase in number over time, and, in contrast with CNC, tend to involve a large portion of the skin, including the face, neck, and upper trunk (picture 9). Cardiac and other systemic abnormalities of LEOPARD are distinct from those seen in CNC. (See "Congenital and inherited hyperpigmentation disorders", section on 'LEOPARD syndrome'.)
●PTEN hamartoma tumor syndromes – The phosphatase and tensin homolog (PTEN) hamartoma tumor syndromes (PHTS) are a group of rare inherited disorders associated with macrocephaly and an increased risk of developing multiple hamartomas in various organ systems, such as the breast, skin, thyroid, central nervous system, and gastrointestinal tract [29,30]. PHTS include Cowden disease and Bannayan-Riley-Ruvalcaba syndrome. The development of lentigines on the glans penis beginning in childhood is considered a marker of Bannayan-Riley-Ruvalcaba syndrome. Distinctive mucocutaneous lesions, including multiple facial trichilemmomas (picture 10), oral papillomas (picture 11), and acral keratoses, and extracutaneous features (eg, macrocephaly; gastrointestinal hamartomatous polyps; breast, thyroid, and endometrial cancers) distinguish PHTS from CNC. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome".)
●McCune-Albright syndrome – Perioral and mucosal pigmentation may be also seen in McCune-Albright syndrome, a mosaic disorder caused by postzygotic activating mutations of the GNAS1 gene, encoding the alpha subunit of the stimulatory G protein [31]. The syndrome is characterized by the triad of polyostotic fibrous dysplasia, striking café-au-lait macules (picture 12), and endocrine hyperactivity, classically causing precocious puberty. (See "Definition, etiology, and evaluation of precocious puberty", section on 'McCune-Albright syndrome'.)
●Benign familial lentiginosis – Patterned lentiginosis is a benign generalized lentiginosis inherited in an autosomal dominant manner in the absence of systemic abnormalities [32]. Lentigines are present on the face, lips, extremities, buttocks, and palms and soles but spare the mucosal surfaces. The condition is common in light‐skinned Black people, especially in those with reddish‐brown hair.
TREATMENT AND FOLLOW-UP — The management of patients with a diagnosis of CNC involves ongoing surveillance to assess the extent of disease and treatment of systemic manifestations and complications:
●Cardiac myxomas – Surgical resection is the treatment of choice for cardiac myxomas. They may recur in affected patients; follow-up monitoring is required. (See "Cardiac tumors", section on 'Treatment and prognosis'.)
●Cushing's syndrome – Bilateral adrenalectomy is the recommended treatment for Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). (See "Cushing syndrome due to primary pigmented nodular adrenocortical disease", section on 'Treatment'.)
●Thyroid nodules – Fine needle aspiration is indicated for patients with thyroid nodules. Patients with lesions suspicious for malignancy should be referred for surgery. (See "Diagnostic approach to and treatment of thyroid nodules".)
●Pituitary adenomas – Pituitary adenomas are treated with transsphenoidal surgery. (See "Transsphenoidal surgery for pituitary adenomas and other sellar masses".)
●Calcifying Sertoli cell tumors – In children, most large cell calcifying Sertoli cell tumors (LCCSCTs), especially when bilateral, are benign and require imaging surveillance alone [12]. If measures of tumor markers or imaging features indicate a suspicion for malignancy, then testicle-sparing surgery may be considered for small tumors to allow for histopathologic examination. There are a few reports of prepubertal boys with LCCSCT treated with aromatase inhibitors [33-35].
Malignant LCCSCTs usually occur in older patients (mean age 39 years) and in those who have unilateral and unifocal disease [12]. Orchiectomy is the treatment of choice for malignant LCCSCTs. (See "Testicular sex cord stromal tumors", section on 'Management after orchiectomy'.)
●Psammomatous melanotic schwannomas – Psammomatous melanotic schwannomas are treated with complete surgical resection with tumor-free margins. Chemotherapy and radiation therapy may be required for malignant tumors. (See "Peripheral nerve tumors", section on 'Schwannoma'.)
Specific surveillance guidelines for patients with CNC are lacking. Suggested laboratory and imaging evaluations following the diagnosis of CNC may include [36]:
●Annual echocardiogram for cardiac myxomas in children and adults. This study may be performed every six months in children and adolescents with a history of excised myxoma. (See "Cardiac tumors".)
●Annual thyroid ultrasound for thyroid nodules in children and adults.
●Annual testicular ultrasound in boys before puberty, with follow-up by a urologist familiar with CNC if nodules are noted.
●Annual measurement of 24-hour urinary free cortisol (UFC) excretion beginning in adolescence. If PPNAD is suspected despite normal UFC, diurnal cortisol levels and/or dexamethasone-stimulation test, and adrenal computed tomography are indicated. (See "Cushing syndrome due to primary pigmented nodular adrenocortical disease", section on 'Diagnosis'.)
●Annual measurement of insulin-like growth factor-1 and prolactin beginning in adolescence to screen for pituitary overactivity. These tests may be performed earlier based upon clinical findings (abnormal growth rate/pubertal staging). (See "Pituitary gigantism" and "Diagnosis of acromegaly".)
●Transabdominal ultrasound is recommended in women at the time of diagnosis but does not need to be repeated if normal [37].
GENETIC COUNSELING — Genetic testing for mutations in the protein kinase A type I-alpha regulatory subunit (PRKAR1A) is indicated for other potentially affected family members of patients with CNC. However, clinical surveillance is advisable for at-risk family members even when a PRKAR1A pathogenic variant is not identified. When neither parent of an individual with CNC has the pathogenic gene variant or any clinical features of CNC, the affected patient has likely a de novo mutation. (See "Genetic testing".)
Counseling regarding the potential risks for the offspring should be offered to adults and to children prior to childbearing age with or at risk for CNC. The availability of prenatal and preimplantation genetic testing should also be discussed. (See "Genetic counseling: Family history interpretation and risk assessment".)
PROGNOSIS — The greatest risk of mortality in CNC is associated with cardiac disease (57 percent), specifically cardiac myxomas and complications of cardiac surgery [4]. Other major causes of mortality include metastatic or intracranial psammomatous melanotic schwannoma (14 percent), carcinoma or metastatic tumor (14 percent), and noncardiac postoperative complications (12 percent) [4].
SUMMARY AND RECOMMENDATIONS
●Definition and pathogenesis – Carney complex (CNC) is a rare multiple neoplasia syndrome associated with distinctive cutaneous lesions. It is caused by inactivating mutations in the protein kinase A type I-alpha regulatory subunit (PRKAR1A) gene and is inherited in an autosomal dominant manner. (See 'Introduction' above and 'Pathogenesis' above.)
●Clinical manifestations:
•Cutaneous – Lentiginous skin pigmentation is the most readily identifiable sign of CNC and is found in 70 to 80 percent of patients. Lentigines often have a periorificial distribution and may be found on the lid margin and lacrimal caruncle. Other distinctive skin lesions include dark "ink spot" lentigines, multiple blue nevi, especially histologically epithelioid blue nevi, and cutaneous myxomas. Cutaneous myxomas are less frequently seen in patients with CNC. They are benign dermal tumors presenting as sharply demarcated subcutaneous nodules, a few millimeters to 1.5 cm in diameter (picture 7A-E). (See 'Skin' above.)
•Extracutaneous – Systemic manifestations of CNC result from endocrine and nonendocrine tumors. Endocrine tumors include primary pigmented nodular adrenocortical disease (PPNAD), testicular large cell calcifying Sertoli tumors, growth hormone-secreting pituitary adenomas, thyroid adenomas and carcinomas, and ovarian cysts. Rare but highly characteristic nonendocrine tumors associated with CNC include cardiac myxomas, psammomatous melanotic schwannomas, breast ductal adenomas, and osteochondromyxomas. (See 'Endocrine tumors' above and 'Nonendocrine tumors' above.)
●Diagnosis – Diagnostic criteria for CNC are shown in the table (table 1). The diagnosis is established in patients with two or more major clinical criteria and in patients in whom a pathogenetic variant is identified in PRKAR1A. (See 'Diagnosis' above.)
●Management – Management of patients with a diagnosis of CNC involves ongoing surveillance to assess the extent of disease and treatment of systemic manifestations and complications. Surgical resection is the mainstay of treatment of endocrine and nonendocrine tumors associated with CNC. (See 'Treatment and follow-up' above.)
ACKNOWLEGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the National Institutes of Health or the United States Government or its components.
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