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Unit on Genetics and Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development (C.A.S., L.S.K.), National Institutes of Health, Bethesda, Maryland 20892; and Department of Laboratory Medicine and Pathology (J.A.C.), Emeritus Staff, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905
Address all correspondence and requests for reprints to: Constantine A. Stratakis, M.D., DSc, Chief, Unit on Genetics and Endocrinology, DEB, NICHD, NIH, Building 10, Room 10N262, 10 Center Drive MSC1862, Bethesda, Maryland 20892-1862. E-mail: stratakc{at}cc1.nichd.nih.gov
Abstract
Carney complex is a multiple neoplasia syndrome featuring
cardiac, endocrine, cutaneous, and neural tumors, as well as a variety
of pigmented lesions of the skin and mucosae. Carney complex is
inherited as an autosomal dominant trait and may simultaneously involve
multiple endocrine glands, as in the classic multiple endocrine
neoplasia syndromes 1 and 2. Carney complex also has some similarities
to McCuneAlbright syndrome, a sporadic condition that is also
characterized by multiple endocrine and nonendocrine tumors. Carney
complex shares skin abnormalities and some nonendocrine tumors with the
lentiginoses and certain of the hamartomatoses, particularly
Peutz-Jeghers syndrome, with which it shares mucosal lentiginosis and
an unusual gonadal tumor, large-cell calcifying Sertoli cell tumor.
Careful clinical analysis has enabled positional cloning efforts to
identify two chromosomal loci harboring potential candidate genes for
Carney complex. Most recently, at the 17q22–24 locus, the tumor
suppressor gene PRKAR1A, coding for the type 1
regulatory subunit of PKA, was found to be mutated in approximately
half of the known Carney complex kindreds. PRKAR1A acts
a classic tumor suppressor gene as demonstrated by loss of
heterozygosity at the 17q22–24 locus in tumors associated with the
complex. The second locus, at chromosome 2p16, to which most (but not
all) of the remaining kindreds map, is also involved in the molecular
pathogenesis of Carney complex tumors, as demonstrated by multiple
genetic changes at this locus, including loss of heterozygosity and
copy number gain. Despite the known genetic heterogeneity in the
disease, clinical analysis has not detected any corresponding
phenotypic differences between patients with PRKAR1A
mutations and those without. This article summarizes the clinical
manifestations of Carney complex from a worldwide collection of
affected patients and also presents revised diagnostic criteria for
Carney complex. In light of the recent identification of mutations
in the PRKAR1A gene, an estimate of penetrance and
recommendations for genetic screening are provided.
THE COMPLEX OF "spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas" or Carney complex (CNC) (1) (MIM 160980) (2) is an autosomal dominant, multiple neoplasia syndrome (3) that was initially described in 1985 under the rubric "the complex of myxomas, spotty pigmentation, and endocrine overactivity" (4). Isolated patients with some components of the complex, in particular cardiac myxomas and pigmentary anomalies, had previously been described under the acronyms NAME (nevi, atrial myxomas, and ephelides) and LAMB (lentigines, atrial myxomas, and blue nevi) (5, 6). Today, it is accepted that most, if not all, of these patients had CNC (7).
CNC may be viewed as a form of multiple endocrine neoplasia (8, 9) because affected patients often have tumors of two or more endocrine glands, including primary pigmented nodular adrenocortical disease (PPNAD), GH- and PRL-producing pituitary adenoma, testicular neoplasms [primarily large-cell calcifying Sertoli cell tumor (LCCSCT)], thyroid adenoma or carcinoma, and ovarian cysts (10, 11, 12, 13, 14, 15, 16). Additional unusual manifestations include psammomatous melanotic schwannoma (PMS), breast ductal adenoma, and, a rare bone tumor, osteochondromyxoma (17, 18, 19, 20, 21).
Epidemiology and inheritance of CNC
Three hundred thirty-eight patients with CNC are known: 144 (43%) males and 194 (57%) females, including Caucasians, African-Americans, and Asians from all continents [North and South America, Europe, Asia (Japan, China, India), Australia, and New Zealand]. Most of the patients (70%) belonged to 67 affected families, whereas 88 had no known affected relative. The genetic origin of the complex could not be definitively determined in 12 cases.
Previous estimates had indicated that approximately half of the cases of CNC were familial (1, 7, 22). The increased number of familial cases that we have observed reflects the application of a rigorous screening protocol for all firstdegree relatives of affected patients (9). Careful history-taking often identified ancestors of an affected patient with cutaneous pigmented spots or obvious signs of endocrine disease. The detailed family data also demonstrated significant variability in clinical manifestations between patients, including members of the same family. This clinical variability was responsible for the apparent "skip" of a generation in extended CNC pedigrees and renders designation of a case as "sporadic" doubtful, unless careful clinical, imaging, and biochemical screening of all first-degree relatives has been obtained.
Transmission of CNC occurred through a female affected parent in 43 cases and from a male in only 9 cases. This excess of female transmission in an autosomal dominant syndrome (3) has been noted previously (23). CNC may have non-Mendelian features in some aspects of its inheritance (23), not unlike MEN 2 (24) and perhaps other familial cancer syndromes. However, LCCSCT, a frequent component of CNC in male patients (15), causes replacement and obstruction of seminiferous tubules and may also impair fertility by inappropriate hormone production or aromatization. In addition, several patients with CNC had undergone bilateral orchiectomy for LCCSCT (15, 25).
Although there were many families with CNC, the number of affected members in the majority of these was small. The maximum number of affected generations in a family was 5 (26). The small size of most CNC families precludes the use of genetic linkage studies in counseling kindreds that do not have PRKAR1A mutations (see below).
Age at detection of the first component
CNC is a developmental disorder. Diagnosis of the disease was made at birth in at least five patients. The median age at detection among 235 cases was 20 yr.
Although abnormal skin pigmentation may be present at birth, the characteristic skin changes, lentigines, usually do not assume their characteristic distribution, density, and intensity until the peripubertal period. Unlike other pigmented lesions affecting the aging skin, lentigines associated with CNC tend to fade after the fourth decade of life, but may be appreciable as late as the eighth decade.
Other pigmented lesions, including blue and other nevi, café-au-lait spots, and depigmented lesions may also be present at birth and referred to as "birthmarks"; more commonly, however, these lesions develop in the early childhood years. The café-au-lait spots in CNC are usually smaller and less pigmented than those in McCune-Albright syndrome. They also tend to fade with time. Their shape is reminiscent of those associated with the neurofibromatosis (NF) syndromes; however, unlike those of NF, café-au-lait spots in CNC do not usually enlarge with time.
During infancy, cardiac and cutaneous myxomas, and PPNAD are the most common tumors encountered. LCCSCT and thyroid nodules (appearing as microcalcifications and multiple, small, hypoechoic lesions on testicular and thyroid ultrasonography, respectively) often appear within the first 10 yr of life. The earliest detection of LCCSCT (by ultrasonography) was made in a 2-yr-old boy.
There seems to be a bimodal age distribution of PPNAD among CNC patients, a minority present during the first 2–3 yr, whereas the majority manifest in the second and third decade of life. Acromegaly usually is observed during the third and fourth decade of life. Gigantism is rare, as in the case of other familial forms of acromegaly (27). In contrast, cardiac myxomas are fairly equally distributed among the ages.
Clinical manifestations of CNC: a global perspective
The major clinical manifestations of CNC (at the time of
presentation) are listed in Table 1
. As
has already been mentioned, spotty skin pigmentation is the most common
clinical manifestation of CNC (1, 8, 22), although it is
not invariably present. Other pigmentary abnormalities in the patients
in addition to those already mentioned included usual and
epithelioid-type blue nevi, combined nevi, and depigmented lesions.
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Among the endocrine tumors, PPNAD was the most frequent manifestation of the disease, occurring in about one quarter of the patients. This number, however, significantly underestimates the true incidence of PPNAD among patients with CNC: biochemical screening by a dexamethasone-stimulation test has been shown to detect additional patients with PPNAD-associated subclinical, atypical, or periodic Cushing’s syndrome, as suggested by Stratakis et al. (10). Furthermore, histologic evidence of PPNAD has been found in almost every patient with the complex who underwent an autopsy.
Another very common tumor was LCCSCT, which was often multicentric and
bilateral. Again, the number presented in Table 1
is a major
underestimate of the true incidence of this tumor among patients
with CNC: ultrasonography identified testicular microcalcifications in
most examined affected adult patients with CNC (15). Thus,
LCCSCT is very prevalent and ultrasonography is an effective and
inexpensive screening technique for its detection. LCCSCT is almost
always benign (28); metastasis of the tumor has occurred
in a 62-yr-old patient (28A ). Testicular ultrasonography
has also detected other tumors in CNC patients, including Leydig cell
(two patients) and (pigmented nodular) adrenocortical rest tumors
(three patients). In all the latter patients, LCCSCT was also present;
one patient had all three testicular tumors. LCCSCT in CNC, as in
Peutz-Jeghers syndrome, may be hormone producing; it has caused
gynecomastia in prepubertal and peripubertal boys (five patients in our
series) due to increased P-450 aromatase expression (25).
The gynecomastia, unlike that due to familial aromatase excess, in
which medical treatment with inhibitors of aromatization seems to be
effective (29), usually requires orchiectomy to avoid
premature epiphyseal fusion and induction of central precocious
puberty.
Clinically evident acromegaly is a relatively infrequent manifestation of CNC. However, asymptomatic elevation of GH and IGF-I levels, as well as subtle hyperprolactinemia, may be present in up to 75% of the patients (11, 12, 13). Biochemical acromegaly is often unmasked by abnormal results of oral glucose tolerance test (oGTT) or paradoxical responses to TRH administration. Somatomammotroph hyperplasia, a putative precursor of GH-producing adenoma, may explain the insidious and protracted period of establishment of clinical acromegaly in CNC patients (13).
Up to 75% of patients with CNC may have multiple thyroid nodules, detected as small, hypoechoic lesions on ultrasonography (14). In our series of patients, most of these nodules were follicular adenomas, which were confirmed histologically in six patients (hyperfunctioning in two). Five thyroid carcinomas occurred among CNC patients, three papillary and two follicular, including one that developed in a patient with a long history of multiple adenomas (14, 30, 31). Thyroid ultrasonography is recommended as a satisfactory, cost-effective method for determining thyroid involvement in pediatric and young adult patients with CNC (9, 14); its value, however, is questionable in older patients.
PMS, a very rare tumor, occurred in 33 patients (17, 18). In six patients, the tumor was malignant. PMS may occur anywhere in the peripheral nervous system, but it is most frequently found in the gastrointestinal tract (esophagus and stomach) and paraspinal sympathetic chain. CNC is the only genetic condition other than the NF syndromes and isolated familial schwannomatosis that includes schwannomas. The particular schwannoma in CNC is distinctive because of its heavy pigmentation (melanin), frequent calcification, and multicentricity (18). If there are symptoms suggestive of this tumor, imaging of the spine, chest, abdomen (in particular the retroperitoneum), and the pelvis may be necessary for its detection.
Breast ductal adenoma, an unusual mammary tumor akin to intraductal
papilloma, was detected in six women with CNC, and it was bilateral in
three (19, 20). Other conditions probably associated with
CNC are presented in Table 2; among them,
only osteochondromyxoma of the bone (21) is, at present,
considered a candidate component of the disorder. Parotid mixed tumor,
marfanoid habitus, bronchogenic cyst, and hepatocellular adenoma, each
occurred in one patient and are thought unlikely to be related to CNC.
Finally, congenital heart disease, tetralogy of Fallot, in particular,
has been observed in a number of families with CNC, although none of
these patients had been screened for other manifestations of CNC; DNA
from these patients is not available for molecular testing, but the
association appears likely.
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Life span was decreased in patients with CNC. Fifty-one patients
in the series (15%) are deceased, 29 due to heart-related causes (57%
of the deaths). Table 3 presents a
comprehensive list of causes of death in our series.
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An initial linkage study of families with CNC demonstrated a
genetic locus on 2p16 with an aggregate logarithm of odds score of 5.97
(
= 0.03), although no single family had a logarithm of odds
score greater than 1.8 for the locus (22). Additional
genetic studies uncovered families, in whom CNC did not segregate with
2p16 markers (32, 33). A genome-wide screen among the
latter demonstrated linkage to a locus on 17q22–24
(26).
Most recently, two independent groups identified mutations of the
PRKAR1A gene on 17q in CNC families that mapped to 17q22–24
and in several sporadic cases (34, 35). This gene encodes
the type 1 regulatory subunit of PKA, which is known to be an
important effector molecule in many endocrine signaling pathways
(36). On screening a large cohort of 53 CNC kindreds
collected over the past 20 yr at the NIH (Bethesda, MD) and the Mayo
Clinic (Rochester, MN), mutations of PRKAR1A were identified
in 15 of 34 families (44%), as well as 7 of 20 sporadic cases (35%),
for an overall mutation rate of 40.7% (37) (Fig. 1).
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Each of the PRKAR1A mutations reported to date (Fig. 1) is predicted to lead to the production of a truncated protein product, so it is possible that the mutations could act by either haploinsufficiency (loss of function) or by a dominant negative effect (gain of function). To address this question, protein lysates from CNC cells examined by Western blotting have shown that foreshortened forms of the PRKAR1A protein are not produced (34, 37). Furthermore, analysis of mRNA in these cells has demonstrated selective degradation of the mutant messages, a phenomenon known as nonsense-mediated mRNA decay (37). Thus, both at the protein and mRNA levels, mutant PRKAR1A alleles have been demonstrated to be functionally null, indicating that constitutional (germ line) loss of one allele of PRKAR1A is the key factor in the pathogenesis of the disease. In CNC tumors, this loss of the PRKAR1A protein leads to enhanced intracellular signaling by PKA, as evidenced by an almost 2-fold greater response to cAMP in CNC tumors when compared with non-CNC tumors (34).
Because all of the chromosome 17 CNC alleles are functionally equivalent to null alleles, one would predict a lack of a genotype-phenotype correlation in patients with mutations of PRKAR1A. Indeed, this hypothesis is borne out by clinical study of the NIH-Mayo Clinic cohort of patients. Additionally, no significant differences have been identified between CNC patients that carry null mutations of PRKAR1A and those that do not (Stratakis, C. A., and L. S. Kirschner, unpublished observations). Thus, genetic, but not clinical, heterogeneity has been demonstrated in CNC (37, 38).
Penetrance of CNC
Because of the known genetic heterogeneity in CNC, and for the purposes of genetic counseling, it has been essential to use uniform criteria for the diagnosis of the disease. Preliminary diagnostic criteria were established for the initial clinical and genetic studies of Stratakis et al. (9, 22); these criteria were refined during an international meeting at the NIH in 1998 (39). The subsequent 3 yr have witnessed major additions to clinical and molecular knowledge of CNC.
The recent identification of the PRKAR1A gene defects in approximately 40% of CNC kindreds (37) has provided for the first time a means of estimating true penetrance of the disease in PRKAR1A mutation carriers, based on the diagnostic criteria previously suggested (9, 22). Among 48 subjects with inactivating mutations of the PRKAR1A gene, only one did not fully meet these criteria (2%). Thus, penetrance for CNC due to PRKAR1A defects seems to be close to 100%. However, because more than half of the examined kindreds did not harbor PRKAR1A mutations, it cannot be assumed that this estimate of penetrance applies to kindreds with CNC caused by other genetic defects.
Summary: diagnostic criteria for CNC and recommendations for screening and follow-up
The diagnostic criteria for CNC are provided in Table 4. These have been modified from those
previously suggested (9, 22) by inclusion of imaging and
biochemical screening and molecular testing procedures.
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. Their presence may be considered
suggestive of the disease and should stimulate careful patient and
family history-taking and, possibly, further clinical, imaging, and
laboratory studies.
|
More elaborate clinical and imaging studies may be necessary for the detection of PPNAD and GH-producing pituitary adenoma in patients without overt clinical manifestations of adrenal or pituitary disease, respectively. For the former, a dexamethasone-stimulation test is recommended, performed, and interpreted with the diagnostic criteria suggested by Stratakis et al. (10). Diurnal cortisol levels ("short" diurnal variation test: insertion of an indwelling venous catheter to a hospitalized patient, followed by sampling for cortisol levels at 2330 h and 2400 h for the nighttime sample, and at 0730 h and 0800 h for the morning sample), in addition to adrenal computed tomography, may also be obtained. For the detection of early acromegaly, oGTT and TRH testing may be obtained in addition to IGF-I levels and pituitary MRI. IGF-I, oGTT, or TRH testing may be abnormal in patients with CNC several years before a pituitary tumor is visible on MRI (if one is ever detected) (13).
Pediatric patients with CNC should have echocardiography during the first 6 months of life and annually thereafter; biannual echocardiographic evaluation may be necessary for pediatric patients with history of an excised myxoma. Most endocrine tumors in CNC do not become clinically significant until the second decade in life (although they might be detectable at a much earlier age) and imaging or biochemical screening in young, prepubertal children are not considered necessary, except for diagnostic purposes. However, pediatric patients with LCCSCT (or a microcalcification upon testicular ultrasonography) need close monitoring of growth rate and pubertal status; some may require bone age determination and further laboratory evaluation, especially if gynecomastia is present.
Conclusions
Clinical and biochemical screening for CNC remains the gold standard for the diagnosis of CNC. Testing for PRKAR1A mutations is not recommended at present for patients with CNC, but may be advised for detection of affected patients in families with known mutations of that gene to avoid unnecessary medical surveillance of noncarriers. Once the other gene(s) responsible for the disease is identified, DNA testing may become the most effective screening tool for patients suspected of having CNC. However, it is unlikely, that DNA testing will have 100% accuracy; this limitation suggests that molecular diagnosis will aid, but never replace, thorough clinical investigation.
Acknowledgments
Footnotes
J.A.C. is an Emeritus member of the Department of Laboratory Medicine and Pathology.
Abbreviations: CNC, Carney complex; LOH, loss of heterozygosity; LCCSCT, large-cell calcifying Sertoli cell tumor; MRI, magnetic resonance imaging; oGTT, oral glucose tolerance test; PMS, psammomatous melanotic schwannoma; PPNAD, primary pigmented nodular adrenocortical disease.
Received September 15, 2000.
Accepted May 18, 2001.
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I. Bourdeau, A. Lacroix, W. Schurch, P. Caron, T. Antakly, and C. A. Stratakis Primary Pigmented Nodular Adrenocortical Disease: Paradoxical Responses of Cortisol Secretion to Dexamethasone Occur in Vitro and Are Associated with Increased Expression of the Glucocorticoid Receptor J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3931 - 3937. [Abstract] [Full Text] [PDF]
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,
Nonsense mutations; 
, frameshifts 
, splice site mutations. Each
of the mutations in exon 4B represents the same 2-bp deletion. One of
the exon 2 nonsense mutations and the exon 3 splice site mutation are
seen in two kindreds each, whereas all other mutations are unique.
(Data are from Refs.