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Clinical phenotypes and molecular genetic mechanisms of Carney complex
Review
Clinical phenotypes and molecular genetic mechanisms of Carney complex David Wilkes*, Deborah A McDermott*, Craig T Basson
Carney complex is a familial multiple neoplasia disorder with characteristic features such as cardiac and cutaneous myxomas and spotty pigmentation of the skin. Clinical genetic analyses have shown that Carney complex is transmitted in an autosomal dominant way and can present with a wide array of other tumours, such as psammomatous melanotic schwannoma, testicular Sertoli-cell tumours, and pituitary adenomas. Molecular genetic studies show that mutations in the PRKAR1A gene, encoding the R1 regulatory subunit of cyclic-AMPdependent protein kinase A, are the cause of Carney complex in most patients. Investigation of genetically engineered animal models confirms the role of PRKAR1A as a tumour suppressor and has begun to elaborate mechanisms underlying tumorigenesis in this disorder. Further genetic studies in human beings have highlighted novel variant phenotypes, such as congenital contractures, which are potentially associated with Carney complex, and have identified alternative genetic pathways to cardiac tumorigenesis, including mutation of the MYH8 gene that encodes perinatal myosin.
Introduction Carney complex (online mendelian inheritance in man 160980, 608837) is a multiple neoplasia and lentiginosis syndrome that shows variable expression with nearly complete penetrance.1,2 Cardiac and cutaneous myxomas, lentigines, endocrinopathy, and both endocrine and non-endocrine tumours are characteristic findings in individuals with the complex (figure 1). The incidence of the syndrome is not well established, but it has been described in a variety of racial and ethnic groups.1 The diagnosis is given to anyone with at least one characteristic clinical finding associated with the disorder and a family history of Carney complex or at least two characteristic clinical findings in the absence of a family history.1,4 Co-occurrence of cardiac myxomas, in the right atrium or both atria, with spotty skin pigmentation was first reported more than 50 years ago.5,6 In 1980, Atherton and colleagues7 proposed the descriptive term NAME (naevi, atrial myxoma, myxoid neurofibromata, ephelides) syndrome, for the constellation of clinical findings they recorded in a young man with lentigines, cardiac myxoma, and subcutaneous myxoid neurofibromata. Although a hereditary syndrome was suspected, the investigators noted skin pigmentation in both parents of the proband and thus were unable to distinguish between recessive and dominant modes of mendelian inheritance. However, the patient’s clinical features were much the same as those reported previously by Rees and colleagues,8 who had suggested an autosomal dominant inheritance pattern. Koopman and Happle9 agreed with the idea of autosomal dominant inheritance of NAME syndrome and recorded the syndrome in related individuals from two generations of a single family, along with male to male transmission. Koopman and Happle reinterpreted the acronym NAME to encompass the syndrome’s features more accurately: naevi; atrial myxoma; mucinosis of the skin; and endocrine overactivity. Endocrinopathy in the http://oncology.thelancet.com Vol 6 July 2005
syndrome was highlighted by Schweizer-Cagianut and colleagues’ report10 of a family with familial Cushing’s syndrome due to primary pigmented nodular adrenocortical dysplasia in the setting of skin and eyelid fibromas, atrial myxoma, phaeochromocytoma, and breast microcalcifications. In 1983, Rhodes and colleagues11 reported a 13-yearold girl with clinical features consistent with several of the previous reports. They suggested using the acronym LAMB (lentigines, atrial myxoma, mucocutaneous, and blue naevi) syndrome instead of NAME syndrome, since it was regarded as a better descriptor of the findings in these individuals and avoided potential diagnostic confusion with LEOPARD syndrome, which is typified by lentigines and hypertrophic cardiomyopathy and is now known to be caused by mutations in the PTPN11 gene.12 However, the term LAMB did not incorporate the A
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Lancet Oncol 2005; 6: 501–08 *These investigators contributed equally to this work. Molecular Cardiology Laboratory, Greenberg Division of Cardiology, Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA (D Wilkes PhD, D A McDermott MS, Prof C T Basson MD) Correspondence to: Prof Craig T Basson, Director, Cardiovascular Research, Greenberg Division of Cardiology, Department of Medicine, Weill Medical College of Cornell University, 525 E 68th Street, New York, NY 10021, USA [email protected]
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Figure 1: Typical clinical features of Carney complex Examples of cutaneous (A) and cardiac (B–D) manifestations of Carney complex in three individuals from the same family.3 (A) typical spotty pigmentation and lentiginosis. Note hyperpigmentation of lips and large naevus on right temple (arrow). Later in life, this patient developed recurrent intracardiac myxomas. (B) Echocardiographic view of left atrium (LA) bordered by mitral valve (mv) below left ventricle (LV) and interatrial septum. Note large mass (atrial myxoma; arrow) arising from the interatrial septum(S). This patient shows lentiginosis much the same as that in her cousin (A) and has needed resection of a cutaneous myxoma as well. (C) This patient, who has typical hyperpigmentation and lentiginosis, needed resection of this left atrial intracardiac mass after developing symptoms of an embolic stroke. (D) Histopathological analysis (haematoxylin-eosin stain) of mass shown in (C) shows typical stellate myxoma cells (arrows) surrounded by abundant extracellular matrix and a capillary (c) coursing through area. [Bar=30 m]. Reproduced with permission from ref 3.
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thyroid nodules and congenital naevomelanocytic naevi recorded in this young woman because these investigators were uncertain as to whether these findings were part of the syndrome or sporadic occurrences in the setting of the syndrome. In 1985, Carney and co-workers2 systematically reviewed the published work and searched the Mayo Clinic Tissue Registry; they identified 40 individuals who had at least two of the following features, Cushing’s syndrome, confirmed cardiac myxoma, cutaneous myxoma, myxoid mammary fibroadenoma, or spotty pigmentation of the skin. Their review included individuals with primary pigmented nodular adrenocortical disease, cardiac myxoma, or Sertoli-cell tumour of the testes for whom they were able to obtain follow-up clinical information and tumour histopathology as well. The co-occurrence of these rather rare findings suggested a single disorder that united these features. Vidaillet and colleagues13 reviewed the Mayo Clinic databases and identified 75 patients with cardiac myxomas seen there between 1954 and 1985. They noted that five such patients had unusual presentations consistent with a multisystem syndromic form of myxoma, syndroma myxoma, which was much the same as the previously reported NAME syndrome. These investigators avoided the use of the NAME and LAMB nomenclature because they viewed these acronyms as rather restricted in their description of the full range of the syndrome. Carney complex should not be confused with Carney syndrome, or triad, (online mendelian inheritance in man 604287) which is a distinct neoplasia syndrome, the characteristics of which are gastric leiomyosarcoma, pulmonary chondroma, and extra-adrenal paraganglioma.
Cardiac myxomas The most common primary cardiac tumour in adults is cardiac myxoma; these tumours account for nearly half of cardiac tumours and are present in up to 0·17% of the population at autopsy.14,15 Although these tumours are benign, they can lead to obstruction or embolisation and therefore pose substantial risks of morbidity and mortality. Individuals with cardiac myxomas classically present with a triad of findings, including signs and symptoms of intracardiac obstruction (ie, heart failure), embolism (eg, stroke, pulmonary embolism, and myocardial infarction), and constitutional symptoms suggesting rheumatological disease. Such symptoms probably relate to production of interleukin 6, a proinflammatory cytokine, by the tumour. Cardiac myxomas occur most commonly in women of middle age and localise to the left atrial aspect of the interatrial septum at the fossa ovalis. Most cardiac myxomas are cured by surgical resection and do not recur.16 An estimated 5–10%, or possibly more, of cardiac myxomas can be attributed to Carney complex, and they 502
are one of the most common manifestations of this syndrome. Carney-complex-related cardiac myxomas are familial and have unusual presentations and prognoses.13,17 By contrast with sporadic cases, individuals with Carney complex can present with one or more cardiac myxomas simultaneously in any intracardiac location irrespective of sex and age, although they are less common in childhood. Importantly, even with adequate surgical margins, individuals who undergo resection of Carney-complexrelated cardiac myxomas are at risk of future development of new cardiac tumours at previously affected sites or distant locations.13,17 There are no histological features to distinguish between hereditary Carney-complex-related myxomas and those that arise sporadically. In general, the tumours consist of polygonal to stellate cells that can be found singly or clustered against a bland proteoglycan myxoid background. Cardiac myxomas are generally thought to arise from a population of multipotent mesenchymal reserve cells that are capable of differentiation along several mesenchymal and epithelial lineages. Various unusual tumour-cell types have been found in cardiac myxomas, including epithelial cells organised into acinar structures, chondrocytes, osteoblasts, and haemopoietic precursors. These findings suggest that these tumours arise from a more primitive subendocardial mesenchymal multipotent precursor cell that has been referred to as a reserve cell but has yet to be specifically identified and cultured.13,16,18–20
Dermatological findings Pigmentation abnormalities, though quite variable, and other cutaneous involvement are the most common features recorded in individuals with Carney complex.1–3,21, Most affected individuals show some form of unusual spotty pigmentation of the skin, orogenital mucosa, or corneas that ranges from subtle single lesions to large areas of dense, commonly centrofacial, lentiginosis that is reminiscent of PeutzJeghers syndrome. Epithelioid blue naevi are also seen in some individuals with Carney complex. Careful assessment for spotty pigmentation and dermatological lesions involving the ocular region is important. In one series of patients, 70% had facial and eyelid lentigines, 27% had pigmented lesions on the caruncle or conjunctival semilunar fold, and 16% had eyelid myxomas.22 Carney complex should be considered in any individual with one or more cutaneous myxomas. These lesions can be localised to the upper dermis, dermis and subcutis, or to the subcutaneous layer. They are generally symptomless, and can be flesh coloured or even appear pink, blue, or iridescent. Epithelial components are present in about 25% of tumours, are typically marked by basaloid proliferation, and could be misdiagnosed as basal-cell carcinoma.23 http://oncology.thelancet.com Vol 6 July 2005
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Endocrine manifestations In the general population, primary pigmented nodular adrenocortical dysplasia is a rare cause of Cushing’s syndrome. However, it is the most common endocrine finding in Carney complex. Bertherat and colleagues24 suggested that some sporadic adrenocortical tumours share genetic changes that are much the same as those seen in Carney-complex-associated endocrine tumours. The diagnosis of primary pigmented nodular adrenocortical dysplasia as the underlying cause of Cushing’s syndrome might be challenging in some patients because of intermittent hypercortisolism and absence of adrenal masses on imaging studies. Unlike other primary causes of Cushing’s syndrome, primary pigmented nodular adrenocortical dysplasia can be associated with a paradoxical rise in glucocorticoid secretion after dexamethasone suppression. Definitive diagnosis can only be made by histology. At gross examination of the glands after adrenalectomy, small nodules that can be black, brown, red, dark green, or yellow in appearance can be seen. The nodules are separated by atrophied adrenal cortex.25,26 Pituitary adenomas, specifically somatotropinomas that secrete growth hormone, occur in about 10% of individuals with Carney complex and should be considered when acromegaly or gigantism is noted.27 In many patients, a raised growth-hormone concentration might not lead to acromegaly or other symptoms. Some individuals with Carney complex present with prolactin secretion abnormalities.4 Sporadic pituitary adenomas do not share a common genetic aetiology with those in individuals with Carney complex. However, familial presentations of pituitary adenomas or co-occurrence of these tumours with other features of Carney complex could prompt a diagnosis of the complex.28 Various clinical findings involving the thyroid gland have been reported in individuals with Carney complex, and they should be kept in mind in the continuing care of such individuals. The findings include cystic changes, follicular hyperplasia, and non-medullary carcinomas.29
Other neoplastic lesions The diagnosis of Carney complex is made in some affected men with the discovery of multicentric, bilateral, large-cell-calcifying, Sertoli-cell tumours. This rare form of testicular tumour has low malignant potential and accounts for less than 1% of all such tumours but is estimated to occur in about 50% of men with Carney complex. The tumours are commonly nonpalpable and can be distinguished from some other testicular tumours on the basis of their calcified appearance on ultrasonography and MRI.30,31 Careful consideration should be given to traditional treatment options, particularly bilateral orchiectomy. Leydig-cell tumours and adrenocortical rest tumours have also been reported in Carney complex and should be considered in male patients with sexual precocity. http://oncology.thelancet.com Vol 6 July 2005
Impaired fertility, hypomotile sperm, and oligospermia have been seen in men with Carney complex1 (Burton K, personal communication). However, such impaired fertility is independent of the presence of any testicular neoplasms. Appropriate fertility investigations and referrals should be considered for affected men who report difficulty in achieving pregnancy with their partners. Another cardinal neoplasm in patients with Carney complex is psammomatous melanotic schwannoma. Evidence of such a tumour strongly suggests Carney complex. These rare benign neoplasms arise in the peripheral nervous system. They are encapsulated and composed of elongated spindle-shaped Schwann cells with melanogenic potential. The occurrence of schwannomas in Carney complex, along with the dermatological findings, highlight the potential phenotypic overlap of the disorder with neurofibromatosis.32,33 About a fifth of women with Carney complex34,35 show abnormal but generally benign breast pathology. Lobular mesenchymal lesions are the typical finding and can be multicentric and bilateral. The lobular stroma takes on a myxoid appearance histologically, due to the accumulation of ground substance. Ductal adenomas of the breast have also been proposed to be a recurrent finding in women with Carney complex. Although women with Carney complex might have a higher than average likelihood of developing ovarian cysts,36 whether there is a truly increased risk of ovarian tumours in these women is unclear. Uterine myxoid tumours in the setting of right-atrial myxoma have been reported too.37
Molecular genetics Pedigree analyses of several large families3,21 affected by Carney complex clearly show that the disorder is transmitted in a mendelian autosomal dominant way. Thus, genetic linkage analyses of these families have been used to identify genes that cause Carney complex. Although initial linkage analyses21 suggested a potential locus on chromosome 2p, the importance of this locus has remained controversial. However, further genetic analyses3 showed the presence of a highly important locus containing a gene for Carney complex at chromosome 17q24 (at least one family thought at first21 to have linkage to chromosome 2p was subsequently shown to have linkage to chromosome 17q24).3 Positional cloning studies of the chromosome 17q24 locus led to the identification of disease-causing mutations (figure 2) in the PRKAR1A gene encoding the R1 regulatory subunit of cyclic AMP-dependent protein kinase.38,40 The R1 protein is composed of four functional domains, a dimerisation domain, a hinge domain, and two cyclic AMP binding domains, and is one of four known types f protein kinase A regulatory subunits (RI, RI, RII, and RII). Two such regulatory subunits bind to each other and bind to two protein kinase A catalytic subunits to form an inactive protein kinase A holotetramer. When 503
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cyclic AMP binds to the regulatory subunits, they are released from the catalytic subunits and leave behind enzymatically active free catalytic subunits.42 In an analysis of 51 unrelated patients with Carney complex, 65% had PRKAR1A mutations.1 PRKAR1A mutations have been found in patients from a wide variety of racial and ethnic backgrounds, including White, Black, Hispanic, and Asian.1,38–41,43 All PRKAR1A mutations (except one) identified thus far in patients with Carney complex are nonsense, frameshift, and splice-site mutations. In general, these mutations are all thought to produce PRKAR1A haploinsufficiency, as described below, and include two mutation hotspots, del(TG)576–577 and C769T.1 One missense mutation has been described, C307T, which predicts substitution of cysteine for arginine 74 at this highly conserved residue.1 Consistent with a common mechanism of disease causation underlying these diverse mutations (ie, haploinsufficiency) no genotype–phenotype correlations have been recorded in patients with Carney complex.1 Furthermore, mutations are evenly distributed among the PRKAR1A exons. Despite this genomic distribution, when PRKAR1A mutations are regarded on the basis of functional domains of the encoded protein rather than by exons1 (figure 2), there is a striking predilection for the first cyclic-AMP binding domain. IVS51GA Del(TGAT)618-621 IVS6 del-9-2 IVS6 del-7-2 AA653CAC
IVS1-2AG G12A A88G C169T Del(CTATT)188-192 C211T
Ins(T)781 IVS71GT Ins(AA)799 Ins(A)810 Del(GAGGAATTCCTTA)815-827 Del(AT)850-851 GG873CT IVS93GA Hinge
Dimerisation domain
cAMP-binding domain A
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Del(TG)139-140 C307T [R74C]
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cAMP-binding domain B 8
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IVS85GC Del(TC)845-846 C769T
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11 Del(A)1038 C997T
Ins(A)710 Ins(T)891 Del(T)706 Ins(GG)675 Del(GGTCTA)-1G-642[-Exon-7] IVS6-17T Ins(C)632 Del(GATT)615-618; Ins(TATGATCAATC)615 IVS53AC IVS51GinsT C583T Del(TG)576-577 IVS4-1AG IVS41GA
Figure 2: Schematic of PRKAR1A complementary DNA, domain structures and mutational spectrum Schematic of the protein-encoding segments of the PRKAR1A cDNA, which consist of ten exons as numbered. Red bars=exon boundaries. Regions of the complementary DNA that encode the various functional and structural domains of the R1a protein: dimerisation (orange), hinge (light blue), cyclic-AMP binding domain A (dark blue), and cyclic-AMP binding domain B (violet). PRKAR1A mutations that cause Carney complex are noted. Mutations shown below the complementary DNA schematic are described in our previous studies.1,20,38,39 Mutations shown above the schematic were previously reported by others.40,41 Mutations that evade nonsense-mediated decay are shown in bold underlined. Note the clustering of mutations in cyclic-AMP binding domain A. Adapted with permission from ref 1.
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Given the complexity and expanding nature of the Carney-complex phenotype, this mutation clustering coupled with at least one disease-causing missense (ie, non-haploinsufficient) mutation raises the question of whether future refined analyses could eventually permit phenotypic predictions based on genotype. Virtually all PRKAR1A mutations1,39 lead to abnormal mRNA, which is recognised and degraded in the cell by a pathway referred to as nonsense-mediated decay. This pathway consists of a cascade of RNA-degrading enzymes and is triggered when cells recognise mutant RNAs that would encode truncated proteins, impeding normal cell function. The net result is that patients with Carney complex have half of the normal concentrations of R1 protein. In a few patients (-exon 7, del(A)1038, and C997T), mutant PRKAR1A RNAs evade nonsensemediated decay, but the consequently encoded protein is probably misfolded and degraded by other cellular machinery. Although the idea that an in-frame deletion of the exon 7 PRKAR1A mutant allele leads to the ability to encode stable protein is controversial,1,41 the only clear example of mutant R1 actually being expressed is the R74C missense mutant isoform, the functional consequences of which remain unknown. How might PRKAR1A haploinsufficiency lead to tumorigenesis? The biochemical mechanisms leading to tumorigenesis in Carney complex remain unresolved. The reduction in R1 protein in most patients with Carney complex has led to the supposition that the PRKAR1A mutation could lead to altered activity of protein kinase A, with consequent increased cell proliferation and tumorigenesis.39 However, depending on the cell type being studied, increased or reduced activity of protein kinase A has been variably associated with a rise in cell proliferation.44 Antisense compounds to knockdown R1 have antiproliferative activity rather than neoplastic activity in breast, prostate, and colon cancer.45–48 Although some Carney-complex tumour cells that have no PRKAR1A alleles could show increased cyclicAMP-stimulated activity of protein kinase A,49 such altered activity is not evident in non-tumour cells from patients with Carney complex1 or in tissues from genetically engineered mice carrying a heterozygous Prkar1a genotype that is equivalent to the genotype in human beings with Carney complex. Moreover, assays show much the same biochemical activity of protein kinase A tetramers using the disease-causing mutant R74C R1 isoform as those using wildtype R1.1 Thus, it seems probable that other pathogenetic mechanisms at least contribute to tumorigenesis. These mechanisms could include altered subcellular localisation of mutant R1 protein or compensatory changes in concentrations of other regulatory subunits of protein kinase A within crucial subcellular compartments. Another controversial topic in the pathogenesis of Carney complex is the contribution of PRKAR1A loss of heterozygosity to tumorigenesis. Some studies have http://oncology.thelancet.com Vol 6 July 2005
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shown PRKAR1A loss of heterozygosity in selected tumours of Carney complex.40,50 Griffin and colleagues51 used overexpression of a Prkar1a antisense construct in transgenic mice that subsequently develop tumours to argue that a reduction of more than 50% in PRKAR1A is needed for tumorigenesis. However, there have been several reports of Carney-complex tumours in human beings that do not show PRKAR1A loss of heterozygosity.38–40 Moreover, unlike the mice described by Griffin and colleagues51 which variably post-transcriptionally regulate Prkar1a expression, Prkar1a /– knockout mice1 that have a constitutionally haploinsufficient genotype as in Carney complex in human beings, do develop mesenchymal tumours and have other Carney complex-related phenotypes such as male infertility. However, tumour cells from Prkar1a heterozygous mice consistently show preservation of the wildtype Prkar1a allele.1 Thus, although PRKAR1A loss of heterozygosity could be one factor contributing to tumorigenesis, it is certainly not essential and other genetic abnormalities remain to be identified that contribute to neoplastic transformation in Carney complex.
Widening the phenotype and genotype of Carney complex Analysis of Prkar1a knockout mice has also prompted the reassessment of cohorts of patients with Carney complex and has highlighted several novel phenotypes that can be associated with Carney complex. As noted above, Prkar1a heterozygous male mice show reduced fertility, with abnormal sperm counts and morphology52 (Burton K, personal communication). Re-examination of patients with Carney complex shows much the same phenotype.1 Men with Carney complex show much the same abnormal semen analyses as the mouse model. Further comparisons of Prkar1a knockout mice and patients with Carney complex have highlighted other under-recognised features of Carney complex. For instance the increased frequency of congenital heart malformations in individuals with Carney complex1,53 is consistent with the impaired heart-tube formation that is the cause of embryonic lethality in mice with complete loss of Prkar1a.52 Furthermore, electrocardiographic analyses1 of Prkar1a heterozygous mice showed striking reductions in heart-rate variability that further studies showed were in human beings with Carney complex as well. Such changes in heart-rate variability suggest that autonomic tone could underlie some reports of sudden death in patients with Carney complex.21 Additional genetic analyses of human beings in families affected by Carney complex have also highlighted new pathogenetic mechanisms. As described above, in addition to the chromosome 17q24 PRKAR1A locus, at least one other locus for Carney complex, on chromosome 2p, has been postulated.1,21,43,54 However, no gene has yet been identified at this locus, and no single family reported thus far has shown significant http://oncology.thelancet.com Vol 6 July 2005
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Figure 3: Carney complex and trismus pseudocamptodactyly in a family Individuals from a family show clinical findings typical of Carney complex, including spotty pigmentation of the skin and cardiac and cutaneous myxomas. (A) Facial and periorbital spotty pigmentation including on vermillion borders of lips (arrows). (B) Cutaneous lesion (arrow) on the left ear (presumptive myxoma or trichofolliculoma). (C) Trismus, signs of trismus pseudocamptodactyly. (D) Positional arthrogryposis.55
(logarithm of odds score 3·0) evidence of linkage to chromosome 2p. Nonetheless, PRKAR1A mutations account for only about two of every three patients with Carney complex, and several families have been reported that do not show evidence of linkage to either PRKAR1A or to chromosome 2p. Thus, other genetic causes of Carney complex remain to be identified. We described a family (figure 3) with typical signs and symptoms of Carney complex (spotty pigmentation of the skin, cardiac myxomas, and hyperendocrine states) in which affected individuals also had the hereditary distal arthrogryposis trismus pseudocamptodactyly syndrome.55 This syndrome is characterised by positional hand and foot contractures as well as an inability to open the mouth fully.56 These findings are thought to be a consequence of congenitally shortened muscle–tendon units. We did linkage and mutational analyses in this family and showed that this variant form of Carney complex was not due to mutations of PRKAR1A or abnormalities at chromosome 2p. However, a random genome search showed linkage to chromosome 17p12–p13·1 with a probability of about 25 000 to 1.55 Dijkhuizen and colleagues57 have shown that chromosome 17p is among the most commonly rearranged loci in cardiac myxomas. Sequence analysis of candidate genes at this locus showed a missense mutation (Arg674Gln) in the MYH8 gene encoding the perinatal isoform of the myosin heavy chain. The same mutation was also found in two families with a disorder that was previously thought to be isolated trismus pseudocamptodactyly syndrome,55 and MYH8 polymorphisms were identified in individuals with familial cardiac myxomas but without trismus pseudocamptodactyly syndrome. The mechanism by 505
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which mutant forms of perinatal myosin cause cardiac myxomas remains unknown, but perinatal myosin could act as a developmental switch to govern the normal loss of multipotent embryonic cardiac cells as the myocardium matures into a non-proliferative, highly differentiated tissue. Mutation of perinatal myosin could cause the failure of such a switch. Consistent with a Knudson two-hit model of tumorigenesis,58 the consequent survival of embryonic cells in the adult heart could provide a substrate for second tumorigenic genetic events, potentially affecting the PRKAR1A gene, that result in cardiac neoplasia.
Clinical application of molecular genetics Clinical diagnosis of Carney complex can be challenging in the absence of a known family history. All the neoplasms associated with Carney complex have agerelated and incomplete penetrance, whereas pigmentation findings (ranging from subtle single atypical lentigines to striking spotty pigmentation) are completely penetrant and thus are highly useful in the diagnosis of this disorder. For instance, although cardiac myxomas can be a common occurrence in some families, they do not arise in others. When there is a family or personal history of a cardinal Carneycomplex neoplasm—eg, cardiac myxoma or Sertoli-cell tumour—diagnosis in other family members can often rely on the presence of a spotty skin pigmentation of variable intensity since this remains the most penetrant feature of Carney complex. Thus, exclusion of other inherited neoplasia syndromes that can also be characterised by dermatological findings is crucial. Such syndromes include Peutz-Jegher syndrome, multiple endocrine neoplasia, neurofibromatosis, and McCune-Albright, Cowden’s, Bannayan-Riley-Ruvalcaba, and Birt-Hogg-Dubé syndromes.59,60 As further phenotypes of patients with Carney complex are elucidated, diagnosis will become even more difficult and need further specialised expertise. For instance, after initial reports of the rare Carney complex variant with trismus pseudocamptodactyly syndrome,55 one retrospective review61 of a database of phenotypes of Carney complex did not reveal trismus pseudocamptodactyly syndrome; However, the patients represented in that database had not been assessed by a physician trained in the specialised orthopaedic manoeuvres needed to diagnose the positional contractures of trismus pseudocamptodactyly syndrome. Historically, patients with Carney complex have rarely been specifically examined for the more subtle phenotypes (eg, trismus pseudocamptodactyly syndrome, oligospermia, and decreased heart-rate variability) that have been elucidated. Thus, the potential of these phenotypes to augment the sensitivity and specificity of our ability to diagnose Carney complex remains to be shown in prospective analyses. 506
Nonetheless, the ability to identify a germline PRKAR1A mutation in about two of three individuals1 with Carney complex (even if MYH8 mutations are rare)55 means that molecular genetic testing will be a powerful tool for guiding appropriate clinical management of affected individuals and their at-risk family members. We have shown that denaturing high-performance liquid chromatography provides a highly sensitive and inexpensive strategy for PRKAR1A mutational analysis and is useful in identifying exons that warrant direct sequencing.1,39 Therefore, application of genetic testing to individuals known to have a 50% risk of being affected— ie, first-degree family members of patients with Carney complex with established PRKAR1A mutations—will have substantial medical benefits. Such testing will allow those who are shown not to carry a PRKAR1A mutation to avoid routine medical screening that is both costly and can provoke anxiety. In those family members who are genetically affected, establishment of a PRKAR1A mutation confirms the need for annual medical followup, including echocardiography to detect new or recurrent cardiac tumours before they embolise to the brain or lung. PRKAR1A mutational analyses could similarly have a role in assessment of individuals without a family history of Carney complex but in whom Carney complex and syndromes with overlapping phenotypes (eg, dermatological) are being considered as diagnoses. However, owing to the technical restrictions of present mutation detection techniques, in such situations, failure to detect mutations in an isolated patient might not absolutely exclude the presence of a mutation. Moreover, given the clear genetic heterogeneity of Carney complex, a substantial number of affected individuals would not be expected to have PRKAR1A mutations. Since MYH8 mutations are rare, analysis of this gene cannot be recommended in the absence of personal or family history of arthrogryposis, but consideration should be given to obtaining clinical assessment by a specialist with appropriate experience.
Conclusion The past few years have shown substantial advances in our understanding of the clinical associations and genetic underpinnings of familial cardiac myxomas. These primary cardiac tumours are now known to be common components of a complex multiple neoplasia disorder. Moreover, these tumours are commonly associated with spotty pigmentation of the skin and a wide variety of other non-neoplastic disorders including male infertility and congenital heart and limb abnormalities. Genetic studies have highlighted mutations in a subunit of protein kinase A and in the perinatal isoform of myosin, which could be primary causes of the disorders that predispose to cardiac tumorigenesis. These findings not only might lead to deciphering of cellular mechanisms controlling the http://oncology.thelancet.com Vol 6 July 2005
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Search strategy and selection criteria Data for this review were identified by searches of MEDLINE, PubMed, and references from relevant articles with the search terms “Carney complex”, “myxoma”, “PRKAR1A”, and “MYH8.” Only papers published in English between 1950 and 2005 were included.
cardiac cell cycle but also suggest events that could control cell survival in the adult and embryonic heart. Further genetic analyses with families not carrying mutations in these genes are identifying additional causes of this complex tumour syndrome, and ongoing molecular studies of samples from patients with Carney complex and genetically engineered animals will shed new light on the precise biochemical events that lead to these neoplasms. In the future, we can expect such studies to promote new therapeutic modalities for patients with cardiac myxomas and other associated neoplasms in Carney complex. Conflict of interest We declare no conflicts of interest. Acknowledgments We thank family members and their physicians for their contributions. This work was funded by National Institutes of Health grant number HL61785. References 1 Veugelers M, Wilkes D, Burton K, et al. Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice. Proc Natl Acad Sci U S A 2004; 101: 14222–27. 2 Carney JA, Gordon H, Carpenter PC, et al. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine 1985; 64: 270–83. 3 Casey M, Mah C, Merliss AD, et al. Identification of a novel genetic locus for familial cardiac myxomas and Carney complex. Circulation 1998; 98: 2560–66. 4 Stratakis CA, Kirschner LS, Carney JA. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab 2001; 86: 4041–46. 5 Kendall D, Symonds B. Epileptiform attacks due to myxoma of the right auricle. Br Heart J 1952; 14: 139–43. 6 Frankenfeld RH, Waters CH, Steiner RC. Bilateral myxomas of the heart. Ann Intern Med 1960; 53: 827–38. 7 Atherton DJ, Pitcher DW, Wells RS, MacDonald DM. A syndrome of various cutaneous pigmented lesions, myxoid neurofibromata and atrial myxoma: the NAME syndrome. Br J Dermatol 1980; 103: 421–29. 8 Rees JR, Ross FGM, Keen G. Lentiginosis and left atrial myxoma. Br Heart J 1973; 35: 874–76. 9 Koopman RJ, Happle R. Autosomal dominant transmission of the NAME syndrome (nevi, atrial myxoma, mucinosis of the skin and endocrine overactivity). Hum Genet 1991; 86: 300–04. 10 Schweizer-Cagianut M, Salomon F, Hedinger CE. Primary adrenocortical nodular dysplasia with Cushing’s syndrome and cardiac myxomas: a peculiar familial disease. Virchows Arch A Pathol Anat Histol 1982; 397: 183–92. 11 Rhodes AR, Silverman RA, Harrist TJ, Perez-Atayde AR. Mucocutaneous lentigines, cardiomucocutaneous myxomas, and multiple blue nevi: the ‘LAMB’ syndrome. J Am Acad Dermatol 1984; 10: 72–82. 12 Digilio MC, Conti E, Sarkozy A, et al. Grouping of multiplelentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 2002; 71: 389–94.
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Vidaillet HJ Jr, Seward JB, Fyke FE 3rd, et al. “Syndrome myxoma”: a subset of patients with cardiac myxoma associated with pigmented skin lesions and peripheral and endocrine neoplasms. Br Heart J 1987; 57: 247–55. Burke A, Virmani R. Tumors of the heart and great vessels. Atlas of tumor pathology, third series, fascicle 16. Washington DC: Armed Forces Institute of Pathology, 1996. 1–46. Burke AP, Tazelaar, Gomez-Roman JJ, et al. Benign tumors of pluripotent mesenchyme. In: WD Travis, Brambilla E, MullerHermelink HK, Harris CC, eds. World Health Organization classification of tumors: pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press, 2004: 260–65. Reynen K. Cardiac myxomas. N Engl J Med 1995; 333: 1610–17. McCarthy PM, Piehler JM, Schaff HV, et al. The significance of multiple, recurrent, and “complex” cardiac myxomas. J Thorac Cardiovasc Surg 1986; 91: 389–96. Ferrans VJ, Roberts WC. Structural features of cardiac myxomas: histology, histochemistry and electron microscopy. Hum Pathol 1973; 4: 111–46. Lie J T. The identity and histogenesis of cardiac myxomas: a controversy put to rest. Arch Pathol Lab Med 1989; 113: 724–26. Basson CT, Aretz HT. Case records of the Massachusetts General Hospital: weekly clinicopathological exercises, case 11-2002— a 27 year-old woman with two intracardiac masses and a history of endocrinopathy. N Engl J Med 2002; 346: 1152–58. Stratakis CA, Carney JA, Lin JP, et al. Carney complex, a familial multiple neoplasia and lentiginosis syndrome: analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Invest 1996; 97: 699–705. Kennedy RH, Waller RR, Carney JA. Ocular pigmented spots and eyelid myxomas. Am J Ophthalmol 1987; 104: 533–38. Carney JA, Headington JT, Su WP. Cutaneous myxomas: a major component of the complex of myxomas, spotty pigmentation, and endocrine overactivity. Arch Dermatol 1986; 122: 790–98. Bertherat J, Groussin L, Sandrini F, et al. Molecular and functional analysis of PRKAR1A and its locus (17q22-24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity. Cancer Res 2003; 63: 5308–19. Schweizer-Cagianut M, Froesch ER, Hedinger C. Familial Cushing’s syndrome with primary adrenocortical microadenomatosis (primary adrenocortical nodular dysplasia). Acta Endocrinol (Copenh) 1980; 94: 529–35. Young WF Jr, Carney JA, Musa BU, et al. Familial Cushing’s syndrome due to primary pigmented nodular adrenocortical disease: reinvestigation 50 years later. N Engl J Med 1989; 321: 1659–64. Kurtkaya-Yapicier O, Scheithauer BW, Carney JA, et al. Pituitary adenoma in Carney complex: an immunohistochemical, ultrastructural, and immunoelectron microscopic study. Ultrastruct Pathol 2002; 26: 345–53. Kaltsas GA, Kola B, Borboli N, et al. Sequence analysis of the PRKAR1A gene in sporadic somatotroph and other pituitary tumours. Clin Endocrinol (Oxf) 2002; 57: 443–48. Stratakis CA, Courcoutsakis NA, Abati A, et al. Thyroid gland abnormalities in patients with the syndrome of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas (Carney complex) J Clin Endocrinol Metab 1997; 82: 2037–43. Radin R, Kempf RA. Carney complex: report of three cases. Radiology 1995; 196: 383–86. Premkumar A, Stratakis CA, Shawker TH, et al. Testicular ultrasound in Carney complex: report of three cases. J Clin Ultrasound 1997; 25: 211–14. Utiger CA, Headington JT. Psammomatous melanotic schwannoma: a new cutaneous marker for Carney’s complex. Arch Dermatol 1993; 129: 202–04. Claessens N, Heymans O, Arrese JE, et al. Cutaneous psammomatous melanotic schwannoma: non-recurrence with surgical excision. Am J Clin Dermatol 2003; 4: 799–802. Carney JA, Toorkey BC. Myxoid fibroadenoma and allied conditions (myxomatosis) of the breast: a heritable disorder with special associations including cardiac and cutaneous myxomas. Am J Surg Pathol 1991; 15: 713–21.
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Carney JA, Toorkey BC. Ductal adenoma of the breast with tubular features: a probable component of the complex of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas. Am J Surg Pathol 1991; 15: 722–31. Stratakis CA, Papageorgiou T, Premkumar A, et al. Ovarian lesions in Carney complex: clinical genetics and possible predisposition to malignancy. J Clin Endocrinol Metab 2000; 85: 4359–66. Barlow JF, Abu-Gazeleh S, Tam GE, et al. Myxoid tumor of the uterus and right atrial myxomas. S D J Med 1983; 36: 9–13. Casey M, Vaughan CJ, He J, et al. Mutations in the protein kinase A R1alpha regulatory subunit cause familial cardiac myxomas and Carney complex. J Clin Invest 2000; 106: R31–38. Veugelers M, Vaughan CJ, Basson CT. Familial cardiac myxomas and Carney complex. In: Vogelstein B, Kinzler K, eds. the genetic basis of human cancer, 2nd ed New York: McGraw Hill, 2002: 635–42. Kirschner LS, Carney JA, Pack SD, et al. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet 2000; 26: 89–92. Groussin L, Kirschner LS, Vincent-Dejean C, et al. Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD. Am J Hum Genet 2002; 71: 1433–42. Taylor SS, Buechler JA, Yonemoto W. cAMP-dependent protein kinase: framework for a diverse family of regulatory enzymes. Annu Rev Biochem 1990; 59: 971–1005. Kirschner LS, Sandrini F, Monbo J, et al. Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex. Hum Mol Genet 2000; 9: 3037–46. Cho-Chung YS. Role of cyclic AMP receptor proteins in growth, differentiation, and suppression of malignancy: new approaches to therapy. Cancer Res 1990; 50: 7093–100. Nesterova M, Noguchi K, Park YG, et al. Compensatory stabilization of RIIbeta protein, cell cycle deregulation, and growth arrest in colon and prostate carcinoma cells by antisense-directed down-regulation of protein kinase A RIalpha protein. Clin Cancer Res 2000; 6: 3434–41. Nesterova MV, Cho-Chung YS. Antisense protein kinase A RIalpha inhibits 7,12-dimethylbenz(a)anthracene-induction of mammary cancer: blockade at the initial phase of carcinogenesis. Clin Cancer Res 2004; 10: 4568–77. Tortora G, Ciardiello F. Antisense targeting protein kinase A type I as a drug for integrated strategies of cancer therapy. Ann N Y Acad Sci 2003; 1002: 236–43
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Mani S, Goel S, Nesterova M, et al. Clinical studies in patients with solid tumors using a second-generation antisense oligonucleotide (GEM 231) targeted against protein kinase A type I. Ann N Y Acad Sci 2003; 1002: 252–62. Robinson-White A, Hundley TR, Shiferaw M, et al. Protein kinase-A activity in PRKAR1A-mutant cells, and regulation of mitogenactivated protein kinases ERK1/2. Hum Mol Genet 2003; 12: 1475–84. Bossis I, Voutetakis A, Matyakhina L, et al. A pleiomorphic GH pituitary adenoma from a Carney complex patient displays universal allelic loss at the protein kinase A regulatory subunit 1A (PRKARIA) locus. J Med Genet 2004; 41: 596–600. Griffin KJ, Kirschner LS, Matyakhina L, et al. A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase A develops endocrine and other tumours: comparison with Carney complex and other PRKAR1A induced lesions. J Med Genet 2004; 41: 923–31. Amieux PS, McKnight GS. The essential role of RI alpha in the maintenance of regulated PKA activity. Ann N Y Acad Sci 2002; 968: 75–95. Powers JC, Falkoff M, Heinle RA, et al. Familial cardiac myxoma: emphasis on unusual clinical manifestations. J Thorac Cardiovasc Surg 1979; 77: 782–88. Stratakis CA, Kirschner LS, Taymans SE, et al. Genetic heterogeneity in Carney complex (OMIM 160980): contributions of loci at chromosomes 2 and 17 in its genetics. Am J Hum Genet 1999; 65: A2537. Veugelers M, Bressan M, McDermott DA, et al. Mutation of perinatal myosin heavy chain associated with a Carney complex variant. N Engl J Med 2004; 351: 460–69. Hall JG, Reed SD, Greene G. The distal arthrogryposes: delineation of new entities—review and nosologic discussion. Am J Med Genet 1982; 11: 185–239. Dijkhuizen T, de Jong B, Meuzelaar JJ, et al. No cytogenetic evidence for involvement of gene(s) at 2p16 in sporadic cardiac myxomas: cytogenetic changes in ten sporadic cardiac myxomas. Cancer Genet Cytogenet 2001; 126: 162–65. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 1971; 68: 820–23. Goldstein MM, Casey M, Carney JA, Basson CT. Molecular genetic diagnosis of the familial myxoma syndrome (Carney complex). Am J Med Genet 1999; 86: 62–65. Stratakis CA, Kirschner LS, Taymans SE, et al. Carney complex, Peutz-Jeghers syndrome, Cowden disease, and Bannayan-Zonana syndrome share cutaneous and endocrine manifestations, but not genetic loci. J Clin Endocrinol Metab 1998; 83: 2972–76. Stratakis CA, Bertherat J, Carney JA. Mutation of perinatal myosin heavy chain. N Engl J Med 2004; 351: 2556–58.
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Clinical phenotypes and molecular genetic mechanisms of Carney complex David Wilkes*, Deborah A McDermott*, Craig T Basson
Carney complex is a familial multiple neoplasia disorder with characteristic features such as cardiac and cutaneous myxomas and spotty pigmentation of the skin. Clinical genetic analyses have shown that Carney complex is transmitted in an autosomal dominant way and can present with a wide array of other tumours, such as psammomatous melanotic schwannoma, testicular Sertoli-cell tumours, and pituitary adenomas. Molecular genetic studies show that mutations in the PRKAR1A gene, encoding the R1 regulatory subunit of cyclic-AMPdependent protein kinase A, are the cause of Carney complex in most patients. Investigation of genetically engineered animal models confirms the role of PRKAR1A as a tumour suppressor and has begun to elaborate mechanisms underlying tumorigenesis in this disorder. Further genetic studies in human beings have highlighted novel variant phenotypes, such as congenital contractures, which are potentially associated with Carney complex, and have identified alternative genetic pathways to cardiac tumorigenesis, including mutation of the MYH8 gene that encodes perinatal myosin.
Introduction Carney complex (online mendelian inheritance in man 160980, 608837) is a multiple neoplasia and lentiginosis syndrome that shows variable expression with nearly complete penetrance.1,2 Cardiac and cutaneous myxomas, lentigines, endocrinopathy, and both endocrine and non-endocrine tumours are characteristic findings in individuals with the complex (figure 1). The incidence of the syndrome is not well established, but it has been described in a variety of racial and ethnic groups.1 The diagnosis is given to anyone with at least one characteristic clinical finding associated with the disorder and a family history of Carney complex or at least two characteristic clinical findings in the absence of a family history.1,4 Co-occurrence of cardiac myxomas, in the right atrium or both atria, with spotty skin pigmentation was first reported more than 50 years ago.5,6 In 1980, Atherton and colleagues7 proposed the descriptive term NAME (naevi, atrial myxoma, myxoid neurofibromata, ephelides) syndrome, for the constellation of clinical findings they recorded in a young man with lentigines, cardiac myxoma, and subcutaneous myxoid neurofibromata. Although a hereditary syndrome was suspected, the investigators noted skin pigmentation in both parents of the proband and thus were unable to distinguish between recessive and dominant modes of mendelian inheritance. However, the patient’s clinical features were much the same as those reported previously by Rees and colleagues,8 who had suggested an autosomal dominant inheritance pattern. Koopman and Happle9 agreed with the idea of autosomal dominant inheritance of NAME syndrome and recorded the syndrome in related individuals from two generations of a single family, along with male to male transmission. Koopman and Happle reinterpreted the acronym NAME to encompass the syndrome’s features more accurately: naevi; atrial myxoma; mucinosis of the skin; and endocrine overactivity. Endocrinopathy in the http://oncology.thelancet.com Vol 6 July 2005
syndrome was highlighted by Schweizer-Cagianut and colleagues’ report10 of a family with familial Cushing’s syndrome due to primary pigmented nodular adrenocortical dysplasia in the setting of skin and eyelid fibromas, atrial myxoma, phaeochromocytoma, and breast microcalcifications. In 1983, Rhodes and colleagues11 reported a 13-yearold girl with clinical features consistent with several of the previous reports. They suggested using the acronym LAMB (lentigines, atrial myxoma, mucocutaneous, and blue naevi) syndrome instead of NAME syndrome, since it was regarded as a better descriptor of the findings in these individuals and avoided potential diagnostic confusion with LEOPARD syndrome, which is typified by lentigines and hypertrophic cardiomyopathy and is now known to be caused by mutations in the PTPN11 gene.12 However, the term LAMB did not incorporate the A
B
Lancet Oncol 2005; 6: 501–08 *These investigators contributed equally to this work. Molecular Cardiology Laboratory, Greenberg Division of Cardiology, Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA (D Wilkes PhD, D A McDermott MS, Prof C T Basson MD) Correspondence to: Prof Craig T Basson, Director, Cardiovascular Research, Greenberg Division of Cardiology, Department of Medicine, Weill Medical College of Cornell University, 525 E 68th Street, New York, NY 10021, USA [email protected]
C LV mv S
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Figure 1: Typical clinical features of Carney complex Examples of cutaneous (A) and cardiac (B–D) manifestations of Carney complex in three individuals from the same family.3 (A) typical spotty pigmentation and lentiginosis. Note hyperpigmentation of lips and large naevus on right temple (arrow). Later in life, this patient developed recurrent intracardiac myxomas. (B) Echocardiographic view of left atrium (LA) bordered by mitral valve (mv) below left ventricle (LV) and interatrial septum. Note large mass (atrial myxoma; arrow) arising from the interatrial septum(S). This patient shows lentiginosis much the same as that in her cousin (A) and has needed resection of a cutaneous myxoma as well. (C) This patient, who has typical hyperpigmentation and lentiginosis, needed resection of this left atrial intracardiac mass after developing symptoms of an embolic stroke. (D) Histopathological analysis (haematoxylin-eosin stain) of mass shown in (C) shows typical stellate myxoma cells (arrows) surrounded by abundant extracellular matrix and a capillary (c) coursing through area. [Bar=30 m]. Reproduced with permission from ref 3.
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thyroid nodules and congenital naevomelanocytic naevi recorded in this young woman because these investigators were uncertain as to whether these findings were part of the syndrome or sporadic occurrences in the setting of the syndrome. In 1985, Carney and co-workers2 systematically reviewed the published work and searched the Mayo Clinic Tissue Registry; they identified 40 individuals who had at least two of the following features, Cushing’s syndrome, confirmed cardiac myxoma, cutaneous myxoma, myxoid mammary fibroadenoma, or spotty pigmentation of the skin. Their review included individuals with primary pigmented nodular adrenocortical disease, cardiac myxoma, or Sertoli-cell tumour of the testes for whom they were able to obtain follow-up clinical information and tumour histopathology as well. The co-occurrence of these rather rare findings suggested a single disorder that united these features. Vidaillet and colleagues13 reviewed the Mayo Clinic databases and identified 75 patients with cardiac myxomas seen there between 1954 and 1985. They noted that five such patients had unusual presentations consistent with a multisystem syndromic form of myxoma, syndroma myxoma, which was much the same as the previously reported NAME syndrome. These investigators avoided the use of the NAME and LAMB nomenclature because they viewed these acronyms as rather restricted in their description of the full range of the syndrome. Carney complex should not be confused with Carney syndrome, or triad, (online mendelian inheritance in man 604287) which is a distinct neoplasia syndrome, the characteristics of which are gastric leiomyosarcoma, pulmonary chondroma, and extra-adrenal paraganglioma.
Cardiac myxomas The most common primary cardiac tumour in adults is cardiac myxoma; these tumours account for nearly half of cardiac tumours and are present in up to 0·17% of the population at autopsy.14,15 Although these tumours are benign, they can lead to obstruction or embolisation and therefore pose substantial risks of morbidity and mortality. Individuals with cardiac myxomas classically present with a triad of findings, including signs and symptoms of intracardiac obstruction (ie, heart failure), embolism (eg, stroke, pulmonary embolism, and myocardial infarction), and constitutional symptoms suggesting rheumatological disease. Such symptoms probably relate to production of interleukin 6, a proinflammatory cytokine, by the tumour. Cardiac myxomas occur most commonly in women of middle age and localise to the left atrial aspect of the interatrial septum at the fossa ovalis. Most cardiac myxomas are cured by surgical resection and do not recur.16 An estimated 5–10%, or possibly more, of cardiac myxomas can be attributed to Carney complex, and they 502
are one of the most common manifestations of this syndrome. Carney-complex-related cardiac myxomas are familial and have unusual presentations and prognoses.13,17 By contrast with sporadic cases, individuals with Carney complex can present with one or more cardiac myxomas simultaneously in any intracardiac location irrespective of sex and age, although they are less common in childhood. Importantly, even with adequate surgical margins, individuals who undergo resection of Carney-complexrelated cardiac myxomas are at risk of future development of new cardiac tumours at previously affected sites or distant locations.13,17 There are no histological features to distinguish between hereditary Carney-complex-related myxomas and those that arise sporadically. In general, the tumours consist of polygonal to stellate cells that can be found singly or clustered against a bland proteoglycan myxoid background. Cardiac myxomas are generally thought to arise from a population of multipotent mesenchymal reserve cells that are capable of differentiation along several mesenchymal and epithelial lineages. Various unusual tumour-cell types have been found in cardiac myxomas, including epithelial cells organised into acinar structures, chondrocytes, osteoblasts, and haemopoietic precursors. These findings suggest that these tumours arise from a more primitive subendocardial mesenchymal multipotent precursor cell that has been referred to as a reserve cell but has yet to be specifically identified and cultured.13,16,18–20
Dermatological findings Pigmentation abnormalities, though quite variable, and other cutaneous involvement are the most common features recorded in individuals with Carney complex.1–3,21, Most affected individuals show some form of unusual spotty pigmentation of the skin, orogenital mucosa, or corneas that ranges from subtle single lesions to large areas of dense, commonly centrofacial, lentiginosis that is reminiscent of PeutzJeghers syndrome. Epithelioid blue naevi are also seen in some individuals with Carney complex. Careful assessment for spotty pigmentation and dermatological lesions involving the ocular region is important. In one series of patients, 70% had facial and eyelid lentigines, 27% had pigmented lesions on the caruncle or conjunctival semilunar fold, and 16% had eyelid myxomas.22 Carney complex should be considered in any individual with one or more cutaneous myxomas. These lesions can be localised to the upper dermis, dermis and subcutis, or to the subcutaneous layer. They are generally symptomless, and can be flesh coloured or even appear pink, blue, or iridescent. Epithelial components are present in about 25% of tumours, are typically marked by basaloid proliferation, and could be misdiagnosed as basal-cell carcinoma.23 http://oncology.thelancet.com Vol 6 July 2005
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Endocrine manifestations In the general population, primary pigmented nodular adrenocortical dysplasia is a rare cause of Cushing’s syndrome. However, it is the most common endocrine finding in Carney complex. Bertherat and colleagues24 suggested that some sporadic adrenocortical tumours share genetic changes that are much the same as those seen in Carney-complex-associated endocrine tumours. The diagnosis of primary pigmented nodular adrenocortical dysplasia as the underlying cause of Cushing’s syndrome might be challenging in some patients because of intermittent hypercortisolism and absence of adrenal masses on imaging studies. Unlike other primary causes of Cushing’s syndrome, primary pigmented nodular adrenocortical dysplasia can be associated with a paradoxical rise in glucocorticoid secretion after dexamethasone suppression. Definitive diagnosis can only be made by histology. At gross examination of the glands after adrenalectomy, small nodules that can be black, brown, red, dark green, or yellow in appearance can be seen. The nodules are separated by atrophied adrenal cortex.25,26 Pituitary adenomas, specifically somatotropinomas that secrete growth hormone, occur in about 10% of individuals with Carney complex and should be considered when acromegaly or gigantism is noted.27 In many patients, a raised growth-hormone concentration might not lead to acromegaly or other symptoms. Some individuals with Carney complex present with prolactin secretion abnormalities.4 Sporadic pituitary adenomas do not share a common genetic aetiology with those in individuals with Carney complex. However, familial presentations of pituitary adenomas or co-occurrence of these tumours with other features of Carney complex could prompt a diagnosis of the complex.28 Various clinical findings involving the thyroid gland have been reported in individuals with Carney complex, and they should be kept in mind in the continuing care of such individuals. The findings include cystic changes, follicular hyperplasia, and non-medullary carcinomas.29
Other neoplastic lesions The diagnosis of Carney complex is made in some affected men with the discovery of multicentric, bilateral, large-cell-calcifying, Sertoli-cell tumours. This rare form of testicular tumour has low malignant potential and accounts for less than 1% of all such tumours but is estimated to occur in about 50% of men with Carney complex. The tumours are commonly nonpalpable and can be distinguished from some other testicular tumours on the basis of their calcified appearance on ultrasonography and MRI.30,31 Careful consideration should be given to traditional treatment options, particularly bilateral orchiectomy. Leydig-cell tumours and adrenocortical rest tumours have also been reported in Carney complex and should be considered in male patients with sexual precocity. http://oncology.thelancet.com Vol 6 July 2005
Impaired fertility, hypomotile sperm, and oligospermia have been seen in men with Carney complex1 (Burton K, personal communication). However, such impaired fertility is independent of the presence of any testicular neoplasms. Appropriate fertility investigations and referrals should be considered for affected men who report difficulty in achieving pregnancy with their partners. Another cardinal neoplasm in patients with Carney complex is psammomatous melanotic schwannoma. Evidence of such a tumour strongly suggests Carney complex. These rare benign neoplasms arise in the peripheral nervous system. They are encapsulated and composed of elongated spindle-shaped Schwann cells with melanogenic potential. The occurrence of schwannomas in Carney complex, along with the dermatological findings, highlight the potential phenotypic overlap of the disorder with neurofibromatosis.32,33 About a fifth of women with Carney complex34,35 show abnormal but generally benign breast pathology. Lobular mesenchymal lesions are the typical finding and can be multicentric and bilateral. The lobular stroma takes on a myxoid appearance histologically, due to the accumulation of ground substance. Ductal adenomas of the breast have also been proposed to be a recurrent finding in women with Carney complex. Although women with Carney complex might have a higher than average likelihood of developing ovarian cysts,36 whether there is a truly increased risk of ovarian tumours in these women is unclear. Uterine myxoid tumours in the setting of right-atrial myxoma have been reported too.37
Molecular genetics Pedigree analyses of several large families3,21 affected by Carney complex clearly show that the disorder is transmitted in a mendelian autosomal dominant way. Thus, genetic linkage analyses of these families have been used to identify genes that cause Carney complex. Although initial linkage analyses21 suggested a potential locus on chromosome 2p, the importance of this locus has remained controversial. However, further genetic analyses3 showed the presence of a highly important locus containing a gene for Carney complex at chromosome 17q24 (at least one family thought at first21 to have linkage to chromosome 2p was subsequently shown to have linkage to chromosome 17q24).3 Positional cloning studies of the chromosome 17q24 locus led to the identification of disease-causing mutations (figure 2) in the PRKAR1A gene encoding the R1 regulatory subunit of cyclic AMP-dependent protein kinase.38,40 The R1 protein is composed of four functional domains, a dimerisation domain, a hinge domain, and two cyclic AMP binding domains, and is one of four known types f protein kinase A regulatory subunits (RI, RI, RII, and RII). Two such regulatory subunits bind to each other and bind to two protein kinase A catalytic subunits to form an inactive protein kinase A holotetramer. When 503
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cyclic AMP binds to the regulatory subunits, they are released from the catalytic subunits and leave behind enzymatically active free catalytic subunits.42 In an analysis of 51 unrelated patients with Carney complex, 65% had PRKAR1A mutations.1 PRKAR1A mutations have been found in patients from a wide variety of racial and ethnic backgrounds, including White, Black, Hispanic, and Asian.1,38–41,43 All PRKAR1A mutations (except one) identified thus far in patients with Carney complex are nonsense, frameshift, and splice-site mutations. In general, these mutations are all thought to produce PRKAR1A haploinsufficiency, as described below, and include two mutation hotspots, del(TG)576–577 and C769T.1 One missense mutation has been described, C307T, which predicts substitution of cysteine for arginine 74 at this highly conserved residue.1 Consistent with a common mechanism of disease causation underlying these diverse mutations (ie, haploinsufficiency) no genotype–phenotype correlations have been recorded in patients with Carney complex.1 Furthermore, mutations are evenly distributed among the PRKAR1A exons. Despite this genomic distribution, when PRKAR1A mutations are regarded on the basis of functional domains of the encoded protein rather than by exons1 (figure 2), there is a striking predilection for the first cyclic-AMP binding domain. IVS51GA Del(TGAT)618-621 IVS6 del-9-2 IVS6 del-7-2 AA653CAC
IVS1-2AG G12A A88G C169T Del(CTATT)188-192 C211T
Ins(T)781 IVS71GT Ins(AA)799 Ins(A)810 Del(GAGGAATTCCTTA)815-827 Del(AT)850-851 GG873CT IVS93GA Hinge
Dimerisation domain
cAMP-binding domain A
2
4
3
C376T
Del(TG)139-140 C307T [R74C]
IVS31GC
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cAMP-binding domain B 8
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IVS85GC Del(TC)845-846 C769T
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11 Del(A)1038 C997T
Ins(A)710 Ins(T)891 Del(T)706 Ins(GG)675 Del(GGTCTA)-1G-642[-Exon-7] IVS6-17T Ins(C)632 Del(GATT)615-618; Ins(TATGATCAATC)615 IVS53AC IVS51GinsT C583T Del(TG)576-577 IVS4-1AG IVS41GA
Figure 2: Schematic of PRKAR1A complementary DNA, domain structures and mutational spectrum Schematic of the protein-encoding segments of the PRKAR1A cDNA, which consist of ten exons as numbered. Red bars=exon boundaries. Regions of the complementary DNA that encode the various functional and structural domains of the R1a protein: dimerisation (orange), hinge (light blue), cyclic-AMP binding domain A (dark blue), and cyclic-AMP binding domain B (violet). PRKAR1A mutations that cause Carney complex are noted. Mutations shown below the complementary DNA schematic are described in our previous studies.1,20,38,39 Mutations shown above the schematic were previously reported by others.40,41 Mutations that evade nonsense-mediated decay are shown in bold underlined. Note the clustering of mutations in cyclic-AMP binding domain A. Adapted with permission from ref 1.
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Given the complexity and expanding nature of the Carney-complex phenotype, this mutation clustering coupled with at least one disease-causing missense (ie, non-haploinsufficient) mutation raises the question of whether future refined analyses could eventually permit phenotypic predictions based on genotype. Virtually all PRKAR1A mutations1,39 lead to abnormal mRNA, which is recognised and degraded in the cell by a pathway referred to as nonsense-mediated decay. This pathway consists of a cascade of RNA-degrading enzymes and is triggered when cells recognise mutant RNAs that would encode truncated proteins, impeding normal cell function. The net result is that patients with Carney complex have half of the normal concentrations of R1 protein. In a few patients (-exon 7, del(A)1038, and C997T), mutant PRKAR1A RNAs evade nonsensemediated decay, but the consequently encoded protein is probably misfolded and degraded by other cellular machinery. Although the idea that an in-frame deletion of the exon 7 PRKAR1A mutant allele leads to the ability to encode stable protein is controversial,1,41 the only clear example of mutant R1 actually being expressed is the R74C missense mutant isoform, the functional consequences of which remain unknown. How might PRKAR1A haploinsufficiency lead to tumorigenesis? The biochemical mechanisms leading to tumorigenesis in Carney complex remain unresolved. The reduction in R1 protein in most patients with Carney complex has led to the supposition that the PRKAR1A mutation could lead to altered activity of protein kinase A, with consequent increased cell proliferation and tumorigenesis.39 However, depending on the cell type being studied, increased or reduced activity of protein kinase A has been variably associated with a rise in cell proliferation.44 Antisense compounds to knockdown R1 have antiproliferative activity rather than neoplastic activity in breast, prostate, and colon cancer.45–48 Although some Carney-complex tumour cells that have no PRKAR1A alleles could show increased cyclicAMP-stimulated activity of protein kinase A,49 such altered activity is not evident in non-tumour cells from patients with Carney complex1 or in tissues from genetically engineered mice carrying a heterozygous Prkar1a genotype that is equivalent to the genotype in human beings with Carney complex. Moreover, assays show much the same biochemical activity of protein kinase A tetramers using the disease-causing mutant R74C R1 isoform as those using wildtype R1.1 Thus, it seems probable that other pathogenetic mechanisms at least contribute to tumorigenesis. These mechanisms could include altered subcellular localisation of mutant R1 protein or compensatory changes in concentrations of other regulatory subunits of protein kinase A within crucial subcellular compartments. Another controversial topic in the pathogenesis of Carney complex is the contribution of PRKAR1A loss of heterozygosity to tumorigenesis. Some studies have http://oncology.thelancet.com Vol 6 July 2005
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shown PRKAR1A loss of heterozygosity in selected tumours of Carney complex.40,50 Griffin and colleagues51 used overexpression of a Prkar1a antisense construct in transgenic mice that subsequently develop tumours to argue that a reduction of more than 50% in PRKAR1A is needed for tumorigenesis. However, there have been several reports of Carney-complex tumours in human beings that do not show PRKAR1A loss of heterozygosity.38–40 Moreover, unlike the mice described by Griffin and colleagues51 which variably post-transcriptionally regulate Prkar1a expression, Prkar1a /– knockout mice1 that have a constitutionally haploinsufficient genotype as in Carney complex in human beings, do develop mesenchymal tumours and have other Carney complex-related phenotypes such as male infertility. However, tumour cells from Prkar1a heterozygous mice consistently show preservation of the wildtype Prkar1a allele.1 Thus, although PRKAR1A loss of heterozygosity could be one factor contributing to tumorigenesis, it is certainly not essential and other genetic abnormalities remain to be identified that contribute to neoplastic transformation in Carney complex.
Widening the phenotype and genotype of Carney complex Analysis of Prkar1a knockout mice has also prompted the reassessment of cohorts of patients with Carney complex and has highlighted several novel phenotypes that can be associated with Carney complex. As noted above, Prkar1a heterozygous male mice show reduced fertility, with abnormal sperm counts and morphology52 (Burton K, personal communication). Re-examination of patients with Carney complex shows much the same phenotype.1 Men with Carney complex show much the same abnormal semen analyses as the mouse model. Further comparisons of Prkar1a knockout mice and patients with Carney complex have highlighted other under-recognised features of Carney complex. For instance the increased frequency of congenital heart malformations in individuals with Carney complex1,53 is consistent with the impaired heart-tube formation that is the cause of embryonic lethality in mice with complete loss of Prkar1a.52 Furthermore, electrocardiographic analyses1 of Prkar1a heterozygous mice showed striking reductions in heart-rate variability that further studies showed were in human beings with Carney complex as well. Such changes in heart-rate variability suggest that autonomic tone could underlie some reports of sudden death in patients with Carney complex.21 Additional genetic analyses of human beings in families affected by Carney complex have also highlighted new pathogenetic mechanisms. As described above, in addition to the chromosome 17q24 PRKAR1A locus, at least one other locus for Carney complex, on chromosome 2p, has been postulated.1,21,43,54 However, no gene has yet been identified at this locus, and no single family reported thus far has shown significant http://oncology.thelancet.com Vol 6 July 2005
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Figure 3: Carney complex and trismus pseudocamptodactyly in a family Individuals from a family show clinical findings typical of Carney complex, including spotty pigmentation of the skin and cardiac and cutaneous myxomas. (A) Facial and periorbital spotty pigmentation including on vermillion borders of lips (arrows). (B) Cutaneous lesion (arrow) on the left ear (presumptive myxoma or trichofolliculoma). (C) Trismus, signs of trismus pseudocamptodactyly. (D) Positional arthrogryposis.55
(logarithm of odds score 3·0) evidence of linkage to chromosome 2p. Nonetheless, PRKAR1A mutations account for only about two of every three patients with Carney complex, and several families have been reported that do not show evidence of linkage to either PRKAR1A or to chromosome 2p. Thus, other genetic causes of Carney complex remain to be identified. We described a family (figure 3) with typical signs and symptoms of Carney complex (spotty pigmentation of the skin, cardiac myxomas, and hyperendocrine states) in which affected individuals also had the hereditary distal arthrogryposis trismus pseudocamptodactyly syndrome.55 This syndrome is characterised by positional hand and foot contractures as well as an inability to open the mouth fully.56 These findings are thought to be a consequence of congenitally shortened muscle–tendon units. We did linkage and mutational analyses in this family and showed that this variant form of Carney complex was not due to mutations of PRKAR1A or abnormalities at chromosome 2p. However, a random genome search showed linkage to chromosome 17p12–p13·1 with a probability of about 25 000 to 1.55 Dijkhuizen and colleagues57 have shown that chromosome 17p is among the most commonly rearranged loci in cardiac myxomas. Sequence analysis of candidate genes at this locus showed a missense mutation (Arg674Gln) in the MYH8 gene encoding the perinatal isoform of the myosin heavy chain. The same mutation was also found in two families with a disorder that was previously thought to be isolated trismus pseudocamptodactyly syndrome,55 and MYH8 polymorphisms were identified in individuals with familial cardiac myxomas but without trismus pseudocamptodactyly syndrome. The mechanism by 505
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which mutant forms of perinatal myosin cause cardiac myxomas remains unknown, but perinatal myosin could act as a developmental switch to govern the normal loss of multipotent embryonic cardiac cells as the myocardium matures into a non-proliferative, highly differentiated tissue. Mutation of perinatal myosin could cause the failure of such a switch. Consistent with a Knudson two-hit model of tumorigenesis,58 the consequent survival of embryonic cells in the adult heart could provide a substrate for second tumorigenic genetic events, potentially affecting the PRKAR1A gene, that result in cardiac neoplasia.
Clinical application of molecular genetics Clinical diagnosis of Carney complex can be challenging in the absence of a known family history. All the neoplasms associated with Carney complex have agerelated and incomplete penetrance, whereas pigmentation findings (ranging from subtle single atypical lentigines to striking spotty pigmentation) are completely penetrant and thus are highly useful in the diagnosis of this disorder. For instance, although cardiac myxomas can be a common occurrence in some families, they do not arise in others. When there is a family or personal history of a cardinal Carneycomplex neoplasm—eg, cardiac myxoma or Sertoli-cell tumour—diagnosis in other family members can often rely on the presence of a spotty skin pigmentation of variable intensity since this remains the most penetrant feature of Carney complex. Thus, exclusion of other inherited neoplasia syndromes that can also be characterised by dermatological findings is crucial. Such syndromes include Peutz-Jegher syndrome, multiple endocrine neoplasia, neurofibromatosis, and McCune-Albright, Cowden’s, Bannayan-Riley-Ruvalcaba, and Birt-Hogg-Dubé syndromes.59,60 As further phenotypes of patients with Carney complex are elucidated, diagnosis will become even more difficult and need further specialised expertise. For instance, after initial reports of the rare Carney complex variant with trismus pseudocamptodactyly syndrome,55 one retrospective review61 of a database of phenotypes of Carney complex did not reveal trismus pseudocamptodactyly syndrome; However, the patients represented in that database had not been assessed by a physician trained in the specialised orthopaedic manoeuvres needed to diagnose the positional contractures of trismus pseudocamptodactyly syndrome. Historically, patients with Carney complex have rarely been specifically examined for the more subtle phenotypes (eg, trismus pseudocamptodactyly syndrome, oligospermia, and decreased heart-rate variability) that have been elucidated. Thus, the potential of these phenotypes to augment the sensitivity and specificity of our ability to diagnose Carney complex remains to be shown in prospective analyses. 506
Nonetheless, the ability to identify a germline PRKAR1A mutation in about two of three individuals1 with Carney complex (even if MYH8 mutations are rare)55 means that molecular genetic testing will be a powerful tool for guiding appropriate clinical management of affected individuals and their at-risk family members. We have shown that denaturing high-performance liquid chromatography provides a highly sensitive and inexpensive strategy for PRKAR1A mutational analysis and is useful in identifying exons that warrant direct sequencing.1,39 Therefore, application of genetic testing to individuals known to have a 50% risk of being affected— ie, first-degree family members of patients with Carney complex with established PRKAR1A mutations—will have substantial medical benefits. Such testing will allow those who are shown not to carry a PRKAR1A mutation to avoid routine medical screening that is both costly and can provoke anxiety. In those family members who are genetically affected, establishment of a PRKAR1A mutation confirms the need for annual medical followup, including echocardiography to detect new or recurrent cardiac tumours before they embolise to the brain or lung. PRKAR1A mutational analyses could similarly have a role in assessment of individuals without a family history of Carney complex but in whom Carney complex and syndromes with overlapping phenotypes (eg, dermatological) are being considered as diagnoses. However, owing to the technical restrictions of present mutation detection techniques, in such situations, failure to detect mutations in an isolated patient might not absolutely exclude the presence of a mutation. Moreover, given the clear genetic heterogeneity of Carney complex, a substantial number of affected individuals would not be expected to have PRKAR1A mutations. Since MYH8 mutations are rare, analysis of this gene cannot be recommended in the absence of personal or family history of arthrogryposis, but consideration should be given to obtaining clinical assessment by a specialist with appropriate experience.
Conclusion The past few years have shown substantial advances in our understanding of the clinical associations and genetic underpinnings of familial cardiac myxomas. These primary cardiac tumours are now known to be common components of a complex multiple neoplasia disorder. Moreover, these tumours are commonly associated with spotty pigmentation of the skin and a wide variety of other non-neoplastic disorders including male infertility and congenital heart and limb abnormalities. Genetic studies have highlighted mutations in a subunit of protein kinase A and in the perinatal isoform of myosin, which could be primary causes of the disorders that predispose to cardiac tumorigenesis. These findings not only might lead to deciphering of cellular mechanisms controlling the http://oncology.thelancet.com Vol 6 July 2005
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Search strategy and selection criteria Data for this review were identified by searches of MEDLINE, PubMed, and references from relevant articles with the search terms “Carney complex”, “myxoma”, “PRKAR1A”, and “MYH8.” Only papers published in English between 1950 and 2005 were included.
cardiac cell cycle but also suggest events that could control cell survival in the adult and embryonic heart. Further genetic analyses with families not carrying mutations in these genes are identifying additional causes of this complex tumour syndrome, and ongoing molecular studies of samples from patients with Carney complex and genetically engineered animals will shed new light on the precise biochemical events that lead to these neoplasms. In the future, we can expect such studies to promote new therapeutic modalities for patients with cardiac myxomas and other associated neoplasms in Carney complex. Conflict of interest We declare no conflicts of interest. Acknowledgments We thank family members and their physicians for their contributions. This work was funded by National Institutes of Health grant number HL61785. References 1 Veugelers M, Wilkes D, Burton K, et al. Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice. Proc Natl Acad Sci U S A 2004; 101: 14222–27. 2 Carney JA, Gordon H, Carpenter PC, et al. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine 1985; 64: 270–83. 3 Casey M, Mah C, Merliss AD, et al. Identification of a novel genetic locus for familial cardiac myxomas and Carney complex. Circulation 1998; 98: 2560–66. 4 Stratakis CA, Kirschner LS, Carney JA. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab 2001; 86: 4041–46. 5 Kendall D, Symonds B. Epileptiform attacks due to myxoma of the right auricle. Br Heart J 1952; 14: 139–43. 6 Frankenfeld RH, Waters CH, Steiner RC. Bilateral myxomas of the heart. Ann Intern Med 1960; 53: 827–38. 7 Atherton DJ, Pitcher DW, Wells RS, MacDonald DM. A syndrome of various cutaneous pigmented lesions, myxoid neurofibromata and atrial myxoma: the NAME syndrome. Br J Dermatol 1980; 103: 421–29. 8 Rees JR, Ross FGM, Keen G. Lentiginosis and left atrial myxoma. Br Heart J 1973; 35: 874–76. 9 Koopman RJ, Happle R. Autosomal dominant transmission of the NAME syndrome (nevi, atrial myxoma, mucinosis of the skin and endocrine overactivity). Hum Genet 1991; 86: 300–04. 10 Schweizer-Cagianut M, Salomon F, Hedinger CE. Primary adrenocortical nodular dysplasia with Cushing’s syndrome and cardiac myxomas: a peculiar familial disease. Virchows Arch A Pathol Anat Histol 1982; 397: 183–92. 11 Rhodes AR, Silverman RA, Harrist TJ, Perez-Atayde AR. Mucocutaneous lentigines, cardiomucocutaneous myxomas, and multiple blue nevi: the ‘LAMB’ syndrome. J Am Acad Dermatol 1984; 10: 72–82. 12 Digilio MC, Conti E, Sarkozy A, et al. Grouping of multiplelentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 2002; 71: 389–94.
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