Chapter 21 – Carney's Complex

Updated 1 July 2010

INTRODUCTION - HISTORICAL OVERVIEW

Carney complex (CNC - Online Mendelian Inheritance in Man 160980, 608837) is a dominantly inherited syndrome of multiple neoplasia combined with cardiocutaneous manifestations. The neoplastic lesions are both endocrine (testicular Sertoli cells and occasionally adrenal, pituitary, or thyroid) and non-endocrine (myxomas, schwannomas). The skin lesions are divided in two major types: pigmented lentigines as well as blue nevi on the face, neck and trunk (Figure 1). 

This syndrome was first described by J. Aidan Carney in 1985, as "the complex of myxomas, spotty pigmentation and endocrine overactivity" after a thorough study of 40 patients, among whom 10 were familial. Additional evidence for unifying this coexistence of otherwise rare conditions in a unique syndrome was the young age at presentation and the unusual type of involvement of most affected sites, that tended to be multicentric (heart and skin) and bilateral in paired organs (adrenal, breast, and testis) (1).
One year later Carney reported observations consistent with a Mendelian dominant inheritance of the syndrome (2) that was designated as Carney complex (CNC) by Bain (3). This new entity allowed the inclusion of patients presenting cardiocutaneous lesions previously characterized as LAMB (lentigines, atrial myxoma, mucocutaneous myxoma, blue nevi) (4) or NAME (nevi, atrial myxoma, myxoid neurofibroma, ephelide)(5).
In 1996 Stratakis et al. (6) using linkage analysis reported a locus potentially linked to CNC on chromosome 2p16, close to the gene encoding proopiomelanocortin and the DNA-mismatch repair genes hMSH2 and hMSH6. However, in 1997,  the syndrome  was shown to be  genetically heterogeneous (7), and in 1998, a second possible locus located on chromosome 17q2 was also detected (8).  In 2000, two different groups demonstrated that germline mutations in the gene coding the protein kinase A R1alpha regulatory subunit (PKAR1A) located on the locus 17q22-24 were responsible for several phenotypes of CNC (9, 10).
Nowadays diagnosis of the syndrome is feasible in clinically asymptomatic patients by molecular genetic techniques commercially available.
Carney's complex should not be confused with Carney's triad, a completely different entity consisting of the triad of gastric leiomyosarcoma, pulmonary chondroma, and extra-adrenal paraganglioma.

EPIDEMIOLOGY - HERITANCE

Carney's complex is a rare disease. About 500 patients had been registered by the NIH-Mayo Clinic (USA) and the Cochin centre  until 2008 and 160 index cases of CNC are presently known (11, 12). Approximately 70% of individuals diagnosed with CNC have a familial history, while the rest 30% present a de novo germline mutation. Incidence is similar in both sexes (43% males Vs 57% females) and there is no apparent predilection concerning ethnicity. (13)
CNC is inherited as a dominant trait, although transmission through a female affected parent is almost 5 fold more frequent than the male. A possible explanation for this discrepancy might be the fact that Large Cell Calcified Sertoli Cell Tumors (LCCSCT), a frequent component of CNC in male patients, causes obstruction of the seminiferous tubules that may contribute to infertility (14). Recent data from animal models correlate haplo-insufficiency at the PRKR1A gene locus with infertility, without the presence of LCCSCT (15).
The penetrance of CNC is 70%-80% by the age of 40 years, as clinical manifestations accumulate during lifespan. The maximum number of affected generations in a kindred is 5 (8).

DIAGNOSIS

The diagnosis of CNC is initially set by clinical criteria and can be affirmed by molecular testing that has a mutation detection rate of approximately 60% (12):
The following clinical criteria were proposed in 1998 and revised in 2001 and have a sensitivity of nearly 98%.  They comprise 12 clinical manifestations that set the major criteria for diagnosis, as well as 2 supplemental criteria regarding molecular testing and family history. At least two major criteria need to be present to confirm the diagnosis of CNC. In the presence of one supplemental criterion, a single clinical manifestation is sufficient to set the diagnosis (16).
MAJOR CRITERIA
Skin pigmentation disorders

1. Spotty skin pigmentation with a typical distribution (vermilion border of the lips, conjunctiva and inner or outer canthi, vaginal and penile mucosa)
2. Blue nevus, epithelioid blue nevus (multiple)*

Myxomas

3. Cutaneous and mucosal myxoma*
4. Cardiac myxoma*
5. Breast myxomatosis* or fat-suppressed magnetic resonance imaging findings suggestive of this diagnosis3
6. Osteochondromyxoma*

Endocrine tumors / Overactivity

7. PPNAD* or evidence of adrenocortical hyperactivity demonstrated by a paradoxical positive response of urinary glucocorticosteroids to dexamethasone administration during Liddle's test4
8. Acromegaly due to GH-producing adenoma or evidence of excess GH production
9. Large-Cell Calcifying Sertoli Cell Tumor (LCCSCT)* or characteristic calcification on testicular ultrasonography
10. Thyroid adenoma or carcinoma* or multiple, hypoechoic nodules on thyroid ultrasonography, in a young patient
11. Psammomatous Melanotic Schwannoma*
12. Breast ductal adenoma (multiple)*

SUPPLEMENTAL CRITERIA:

1. Affected first-degree relative
2. Inactivating mutation of the PRKAR1A gene

*Histologically confirmed

MOLECULAR GENETICS - PATHOPHYSIOLOGY

Carney's complex is a genetically heterogeneous syndrome and linkage analysis has shown that at least two loci are involved: 2p16 and 17q22-24.
The CNC1 gene, located on 17q22-24, encodes the regulatory subunit (R1A) of the protein kinase A (PRKAR1A) and comprises 11 exons among which 10 (2-11) are coding. Heterozygous inactivating mutations of PRKAR1A have been detected in about 45 to 65 % of affected individuals. Interestingly, in patients presenting Cushing's syndrome this frequency rises to  about 80 %. Moreover, germline de novo mutations of PRKAR1A have been reported inpatients with isolated PPNAD and no familial history of CNC (17).
Protein Kinase A (PKA), is a second messenger-dependent enzyme involved in G protein coupled intracellular pathways that regulate cell metabolism, proliferation and apoptosis. Its quaternary structure consists of 4 peptide chains that form two homodimers of regulatory (R), R-I and R-II, and catalytic (C) subunits (18). . Two genes are responsible for each R subunit (R-Ia and R-Ib, and R-IIa and R-IIb and three genes for the C subunit (C-a, -b, -g) (19). When c-AMP binds to the regulatory subunits, their conformation is altered, causing the dissociation of each active C subunit from the R subunit dimer. The free catalytic subunits phosphorylate serine and threonine residues of proteins critical to the activation of downstream processes.
Up to date a total of 117 different PRKAR1A mutations have been identified (online database: http://prkar1a.nichd.nih.gov), which are evenly distributed among the PRKAR1A gene exons (12). The vast majority of mutations (83%) leads to a premature stop codon and thus, mutant mRNAs are eliminated by selective degradation, a phenomenon known as nonsense-mediated mRNA decay (NMD), resulting in a lack of detectable mutant protein. The rest of the mutations (17%) result in the expression of an altered protein that may be associated with advanced disease (20). Large PRKAR1A deletions have also been demonstrated in patients that were not diagnosed by sequencing (21). Structure of the PRKR1A gene and location of detected mutations are shown in Figure 2.

Germ line loss of one allele of PRKAR1A (haplo-insufficiency) is the key factor in the pathogenesis of CNC, since it leads to a deficiency of the R1 alpha subunit, which in turn results in enhanced intracellular signalling by PKA, as evidenced by an almost 2-fold greater response to c-AMP in CNC tumors (22). This PKA overactivity may trigger pathways that favour cell proliferation as the dysregulation of D-type cyclins (23) or  activation of the mTOR pathway (24)
Consistent with the Knudson two-hit model of hereditary tumorigenesis (25) loss of heterozygosity (LOH) at 17q22-24 may be observed in the tumors of CNC patients, suggesting that PRKAR1A is a tumor suppressor gene. However, as tumors which do not present inactivation of the remaining wild type allele have been described, simple deficiency of the PRKAR1A gene can be sufficient for tumorigenesis.
Prkar1a +/− knockout mice have a constitutionally haplo-insufficient genotype as in Carney complex, and tend to exhibit many of the manifestations of CNC (26). Moreover, male mice show reduced fertility, with abnormal sperm counts and morphology (15), whereas mice with complete loss of Prkar1a are not viable as this genotype leads to early embryonic demise.  These observations have been supported by tissue specific ablation of Prkar1a that leads to pituitary and Schwann cells tumorigenesis as well as impaired heart-tube formation and myxomagenesis (27).
Because most of the identified PRKAR1A mutations lead to functionally equivalent to null alleles due to NMD, the result is a lack of detectable mutant protein. Therefore, no genotype-phenotype correlations are expected to be seen. However, specific hot-spot mutations show some genotype-phenotype correlation. Especially those few that lead to the expression of a mutant protein are related with more severe forms of CNC syndrome, suggesting that NMD may play a protective role against the deleterious effects of mutant products (17).
The CNC2 gene located at the 2p16 locus is responsible for approximately 20% of families affected with CNC. Somatic alterations of the 2p16 region have been reported in CNC tumors which are usually gene amplifications, suggesting that the gene located at 2p16 is a potential oncogene (28). This led to the speculation that it may code a PKA catalytic subunit. However, the α, β, and γ genes of the C catalytic PKA subunits are located on chromosomes 19p, 1p, and 9q, respectively. In addition, tumor-specific LOH has not been a consistent feature of CNC2.
No statistically significant phenotypic differences have been observed between individuals with CNC1 and CNC2. Thus, genetic, but not clinical, heterogeneity has been demonstrated in CNC.

CLINICAL MANIFESTATIONS

Carney's complex is a constellation of clinical manifestations that shows significant variability between patients, even among members of the same family. Some of these features are quite specific, like primary pigmented nodular disease (PPNAD), while others are not, such as thyroid nodes or blue nevi (13). The maximum number of conditions reported to be present together in a single patient is five. Skin disorders are the most common, followed by cardiac myxomas and PPNAD. These data are summarised in Table 1.

 

Most often clinical signs appear in the teen years and early adulthood, with a median age of diagnosis at 20 years of age; however, evidence of the disease, especially cutaneous lesions, can be found even at newborns. During infancy, the most common tumors encountered are cardiac and cutaneous myxomas, as well as PPNAD, while LCCSCT and thyroid nodules appear somewhat later. Acromegaly is clinically evident during the third and fourth decade of life, while cardiac myxomas are equally distributed during the life span.
The average life expectancy of CNC patients is limited to 50 years, principally due to individuals who succumb from early cardiovascular sudden death. Indeed, complications due to cardiac myxoma (myxoma emboli, cardiomyopathy, cardiac arrhythmia, surgical intervention) comprise the major factor of mortality for CNC patients. Other less important factors are metastatic or intracranial PMS, thyroid carcinomas, and metastatic pancreatic and testicular tumors (13, 16, 29).
:

Pigmentary Disorders

These lesions may appear either as multiple lentigines or as blue nevi. They may be present at birth, however, they usually get apparent around puberty when they increase in number and appear anywhere on the body. Typically they fade after the fourth decade, although they can be detected on individuals at the age of 70 (30).
Lentigines may present as multiple small (0,2 to 2 mm) brown to black maculae typically located around as well as on the vermilion border of the lips, on the eyelids, ears and the genital area (Figure 1). Practically they can appear on any part of the body with areas of confluence and foci of deeper pigmentation. They may look similar to solar lentigines, but differ as they develop predominantly in areas that have not been exposed to sunlight (e.g. genitalia) (30).
Blue nevi on the other hand, are larger lesions (up to 8 mm), blue to black, and dome-shaped. They are less common and may be multiple with a variable distribution. Histologically, they may present features of epithelioid, junctional or even compound nevi. Occasionally caf� au lait spots and depigmented lesions have been observed (1, 31).

Myxomas

Cutaneous Myxomas

The skin myxomas present as non-pigmented subcutaneous nodules with a smooth surface and may look white, flesh-coloured, opalescent, or pink (see Figure 3). They are generally symptomless and appear up to the fourth decade. Myxomas can emerge on the face and trunk, while typical sights in CNC are the eyelids, external ear canal, and nipples. Interestingly, hands and feet are preserved (30).

Clinical diagnosis is quite difficult and histological confirmation is usually essential. Lesions can be localised to the upper dermis, dermis and subcutis and consist of polygonal to stellate cells scattered singly or in clusters against an abundant basophlilic myxoid matrix (1, 32). Although cutaneous myxomas have minimal impact in the clinical course of CNC, their identification  is crucial  since they are the most specific and sensitive among skin abnormalities regarding CNC, thus they may herald a potentially fatal cardiac neoplasm (32)

Cardiac myxomas

Although these tumours are benign they are responsible for the majority of deaths (>50%) related to CNC mainly due to cardiovascular complications. Their sporadic counterparts are rare tumors that emerge most commonly in middle aged women and localise to the left atrial aspect of the interatrial septum at the fossa ovalis. Most of them are cured by surgical resection and do not recur. On the contrary, cardiac myxomas in CNC demonstrate unusual features as they present at younger age and can develop in any cardiac chamber. In addition, they may be multiple and recurrent, therefore, their resection cannot guarantee permanent cure (33).
Heart myxomas typically present with a triad of symptoms:

• symptoms related to myxoma embolization (e.g. stroke, peripheral artery occlusions),
• heart failure due to reduced cardiac output (complete occlusion of a valvular orifice can lead to sudden death)
• constitutional symptoms probably related to production of cytokines [e.g. interleukin (IL-6)], by the tumour (29).

The tumors have a gelatinous or hemorrhagic appearance and arise from a population of multipotent subendocardial mesenchymal precursor cells (34).

Other sites for myxomas

• Breast myxomas are observed in about a fifth of women with Carney complex and are generally considered as benign breast tumors. They usually occur in females after puberty and can be multicentric as well as bilateral (see Figure 4). Their size ranges from 2 mm to 2 cm in diameter and may be pink or white with a mucoid appearance (35).

Their histological appearance is that of myxoid fibroadenomas: lobulated mesenchymal lesions characterized by accumulations of large amounts of ground substance in the lobules as well as in the interlobular stroma. The tumors may or may not be encapsulated (1).

• Osteochondrosarcomas are myxomatous tumors of the bone that principally affect nasal sinuses and long bones. They exhibit benign behaviour, however they cause bone erosion and can extent to soft tissues. Complete resection of the tumor seems to be curative. Experiments in rodents demonstrated the osteoblastic origin of the tumor. (36, 37)
• Less common sites of myxoma formation include the oropharynx (tongue, hard palate and pharynx) and the female genital tract (uterus, cervix and vagina).

Endocrine tumors / Overactivity

 

Primary pigmented Nodular Adrenal Disease (PPNAD)

PPNAD is the most frequently observed endocrine tumor in individuals with CNC. It affects the adrenal glands bilaterally and can cause clinically overt Cushing's syndrome in approximately 25 to 30 % of patients with CNC. However, histological evidence of PPNAD is evident in almost every individual as it has been demonstrated by autopsy studies. A bimodal age distribution is observed: a first peak occurs during infancy, while a second one that includes the majority of cases takes place between the second and third decade of life (16).
Histologically, adrenal cortex is dominated by small pigmented micronodules with an average size less than 10mm (see Figure 5). Although unencapsulated, the nodules are sharply demarcated from the remainder of the cortex and most of them appear to originate deep in the cortex almost at the level of the medulla. The brown pigment, lipofuscin, is contained in many of the tumor cells and is responsible for the characteristic colour of the lesions. Interestingly, tumor cells are positively stained neuroendocrine markers (e.g Synaptophysin), while normal cortical cells don�t (38). Internodular cortical atrophy is typical, thus the overall weight of the adrenal gland is more or less normal (1).

The type of hypercortisolism observed in this disorder is that of ACTH-independent hyperfunction. However, demonstrating cortisol overproduction can be difficult because it can develop progressively over years. Moreover, cyclic forms of hypercortisolism have been reported (39, 40). Clinical manifestations are no specific and similar to the ones observed in Cushingoid patients of other aetiology (central obesity, hypertension, myopathy), with a predisposition to osteoporosis. Radiological and scintigraphic findings are not specific, since the adrenals may appear bilaterally or unilaterally enlarged and in most cases normal. A 6-day Liddle's test (low dose dexamethasone for 2 days followed by high dose dexamethasone for 2 days) has been used for the distinction of PPNAD from Cushing's syndrome caused by other primary adrenal disorders. A paradoxical increase of UFC and 17-hydroxysteroids the second day after high dose dexamethasone administration is indicative of PPNAD (41). 

Growth hormone (GH)-secreting pituitary adenomas (acromegaly)

Clinically evident acromegaly due to a pituitary GH-secreting tumor occurs in approximately 10% of patients with CNC.. Moreover, gigantism, resulting from excessive GH secretion prior to puberty, is quite rare. However, most patients with CNC (~75%) present with a mild asymptomatic increase in GH, occasionially associated by mild hyperprolactinemia (42).
Somatomammotroph hyperplasia, a putative precursor of GH-producing adenoma has been detected in the pituitary glands of CNC patients and tumorigenesis is confirmed in studies using pituitary specific Prkr1a knockout mice (43, 44). Annual screening for serum IGF-1 is recommended for post-pubertal and adult CNC patients. If subclinical disease is suspected, further testing with oral glucose tolerance test should be performed.
 

Thyroid nodules

Seventy five percent of CNC patients present thyroid nodules, most of them being benign, non-toxic adenomas of follicular type. Some patients (~5%) present with papillary or follicular carcinoma usually after a long history of multiple thyroid adenomas.
In contrast of what is observed in adrenal and pituitary tumors, CNC patients with thyroid nodules do not appear to have a predilection for hyperthyroidism (45).

Testicular tumors

These tumors are of three types: Large Cell Calcifying Sertoli Cell Tumors (LCCSCT), Leydig cell and adrenocortical rest tumors. Up to date the two latter types have been observed only in patients in whom LCCSCT had already been diagnosed.
LCCSCT are observed at one-third of affected CNC males at the time of presentation, however most males will develop such tumors in their adult life. These are entities rarely observed in sporadic forms, but in CNC patients they are often multicentric and bilateral. They are almost always benign; malignancy has been reported only once, and occasionally may be hormone producing and demonstrate increased P-450 aromatase expression (14).
LCCSCT are commonly non-palpable, discovered by ultrasonography as bilateral microcalcifications (14). Otherwise they are described as rock-hard and non-tender masses. Macroscopically they are well-demarcated, yellow and calcified tumors. Clinically, these hormone producing tumors may cause sexual precocity in young males with low gonadotropin levels, as well as gynecomastia that may result from aromatase overactivity.
Leydig cell tumors and adrenocortical rests are both steroid producing tumors and macroscopically are quite similar, characterized by a brownish hue and relatively soft texture. Leydig cell tumors are entities with malignant potential and radical resection is recommended, while adrenal rests are benign lesions which do not require resection, but can lead to recurrent Cushing's syndrome after adrenalectomy.  Distinguishing them pathologically can be difficult and a distinct feature is that Leydig cell tumors contain crystalloids of Reinke. However, these crystalloids are not a constant finding (1). Helpful in this case can be testicular vein sampling which can demonstrate cortisol gradient between peripheral and testicular venous blood (46).

PSAMOMMATOUS MELANOTIC SCHWANNOMAS

Psamommatous Melanotic Schwannomas (PMS) are observed in less than 10% of individuals with CNC, which is the only hereditary syndrome other than NF and isolated familial schwannomatosis .Schwannomas in CNC are  heavy pigmentated due to melanin, frequent calcification, and multicentricity. They are dark pigmented, encapsulated tumors which are composed of elongated spindle-shaped Schwann cells with melanogenic potential. They also contain laminated calcifications called psammomas and may present haemorrhage and necrosis (47).
They can develop anywhere in the central and peripheral nervous system, however the most frequent locations are the nerves of the gastrointestinal tract and paraspinal sympathetic chain (28% of cases). Other sights involved are the chest wall and trigeminal ganglion. PMS can cause mass phenomena; whenever located in the gastrointestinal tract or within soft tissues they may evoke pain and discomfort. If they develop in the spine they may present as radiculopathy.
Schwannomas are the most difficult tumors to treat, especially when they emerge around nerve roots along the spine, a location that makes excision not feasible. In addition, in rare cases (10%), they can be malignant and then often metastasize to the lungs, liver or the brain. Unfortunately, there is practically no specific effective medical or surgical treatment for metastatic PMS (48).

 

OTHER MANIFESTATIONS

Breast ductal adenomas, benign tumors of the mammary gland ducts may also develop in the context of CNC and can be multiple and bilateral as well. Coexistence with breast myxomas can be observed (49).
Apart from the 12 major clinical manifestations there are many other features observed in CNC patients, however they are not present in a constant manner to set the diagnosis. These features are listed in Table 2

Table 2. Findings suggestive or possibly associated with CNC, but not diagnostic for the disease 1. Intense freckling (without darkly pigmented spots or typical distribution) 2. Blue nevus, usual type (if multiple) 3. Cafe-au-lait spots or other "birthmarks" 4. Elevated IGF-I levels, abnormal oGTT, or paradoxical GH responses to TRH testing in the absence of clinical acromegaly 5. Cardiomyopathy 6. Pilonidal sinus 7. History of Cushing's syndrome, acromegaly, or sudden death in extended family 8. Multiple skin tags and other skin lesions; lipomas 9. Colonic polyps (usually in association with acromegaly) 10. Hyperprolactinemia (usually mild and almost always in association with clinical or subclinical acromegaly) 11. Single, benign thyroid nodule in a young patient; multiple thyroid nodules in an older patient (detected by ultrasonography) 12. Family history of carcinoma, in particular of the thyroid, colon, pancreas and the ovary; other multiple benign or malignant tumors

 

MANAGEMENT

Clinical work-up for all the manifestations of CNC should be performed at least once a year in all patients and should start in infancy.

 

SURVEILLANCE

Prepubertal children should be screened as follows:

• Cardiac ultrasound should start during the first 6 months and be performed at least once a year thereafter. In patients with a history of cardiac myxoma, screening should be more frequent, optimally every 6 months.
• Screening for the other manifestations (only by clinical examination) should be performed in patients under 5 years-old. Especially for males, testicular ultrasonography is recommended at the initial evaluation and if microcalcifications are present it should be repeated on a yearly basis. Moreover, pubertal staging and growth rate should be monitored if LCCSCT is discovered.

Regarding postpubertal children and adults, annual screening should test for:

PPNAD by measurement of the basal levels of cortisol and plasma ACTH, urinary free cortisol, overnight suppression with 1 mg Dexamethasone, followed by a formal Low Dose Dexamethasone Test if abnormal. If this evaluation suggests cortisol hypersecretion, a 6-day Liddle's test and an adrenal CT scan is  performed.

• Acromegaly by measurement of serum GH, PRL and Insulin-Like-Growth-Factor I (IGF I). In case of abnormal findings documentation of GH hypersecretion with oral glucose suppression test (OGTT) and imaging of the pituitary region with MRI is suggested.
• Thyroid nodules by ultrasonography as needed. Fine-needle investigation might be helpful in diagnosis.
• LCCSCT in males by testicular ultrasound, especially when small sized calcifications are found
• PMS with spine MRI when the clinical signs suggest this tumor.
• Breast myxomas as well as ductal adenomas in females should be screened and followed up in the context of screening for breast cancer including self examination, clinical evaluation, mammography and ultrasound. In case of findings, MRI of the breast maybe more sensitive in mapping the lesions (see Figure 4 (16, 49).
• Ovarian lesions by transabdominal ultrasonography during the first evaluation. The test should be repeated due to the low risk of ovarian malignancy (28).
•  

TREATMENT

As CNC is generated by a constitutional genetic defect, no etiologic therapy is available yet. Therapeutic approach should target each clinical manifestation and treat accordingly.

• A cardiac myxoma requires surgical removal. However, due to high recurrence rate re-operation might be needed (33).
• Cutaneous and mammary myxomas should be surgically removed.
• Regarding PPNAD, bilateral adrenalectomy although amputative seems the more reasonable approach if Cushing's syndrome is evident. Some institutions have reported treatment with O,p'-dichlorodiphenyldichloroethane (Mitotane) (50) with long term effects, however the significant adverse events of such approach should be balanced.
• LCCSCT has been traditionally treated with orchiectomy especially in prepubertal boys in order to cope with the secondary effects of excess hormone production. However, the fact that these tumors often occur bilaterally and are grossly benign has raised an issue to consider treatment options that might preserve fertility. In limited cases, testicular-sparing surgery was performed followed by strict monitoring of growth and pubertal staging and administration of antiestrogen drugs in case of recurrence (51). Treatment of choice for Leydig cell tumor, neoplasias with malignant potential is inguinal orchiectomy,
• Pituitary adenomas according to their size and extension should be removed by  transsphenoidal or transcranial approach as indicated in sporadic tumors. Alternatively long-term medical treatment can be offered.  
• Thyroid nodules should be evaluated and treated surgically according to current guidelines.
• PMS: surgery to remove primary and/or metastatic lesions.

GENETIC COUNSELLING

Genetic analysis should be recommended to all CNC index cases taking into consideration that at present mutation detection rate of PRKR1A testing is approximately 60%. Therefore a negative test does not exclude the presence of CNC in an individual who meets clinical criteria.
If a mutation is detected, screening is recommended for first degree relatives (parents, siblings, offspring) as well. In case of a positive test, mutation carriers should undergo the same follow-up and management as that suggested for CNC patients. The first cardiac ultrasound should be performed at the same time as the molecular testing.
Genetic counselling should include the following general information:

• If a parent of the index case is affected, the risk to his siblings is 50%. On the contrary, in case of a de novo mutation this risk falls to approximately 1%.
• Each child of an individual with CNC has a 50% chance of being affected.
• Fertility may be impaired in males with CNC.
• Most tumors of CNC are in general benign with the exception of thyroid nodules and schwannomas.

Prenatal testing is available by chorionic villous sampling (CVS) at approximately ten to 12 weeks of gestation or amnioparacentesis at 15-18 weeks of gestation.
Preimplantation genetic diagnosis (PGD) is now available with the new advances in fertilization technology and allows the selection of disease free embryos for implantation.  
 

FUTURE PERSPECTIVES

Although remarkable progress has been made during the 25 years since CNC was first described there are several issues that need to be answered.  There are still CNC families that do not carry a PRKAR1Agene mutation and cannot be assigned to CNC2 either. The CNC2 gene located at the 2p16 locus is still to be determined.
Investigators speculate that the still elusive genes for the remaining cases of CNC might interact with PKA and/or PRKAR1A. Indeed, inactivating mutations in the 2q-located phosphodiesterase 11A (PDE11A) gene, have been demonstrated recently to evoke adrenal lesions similar to that of PPNAD in patients with genetic forms of adrenocortical Cushing's syndrome (52). Furthermore, a missense mutation in the 17p12-13 located MYH8 gene that encodes perinatal myosin heavy chain has been reported in a family presenting a Carney complex variant associated with distal arthrogryposis (11).
In addition, efforts have been made to relate specific phenotypes to corresponding genotypes. A study analyzing 353 patients and 80 different genotypes demonstrated that individuals carrying a PRKAR1A mutation tended to present manifestations earlier and were more likely to have pigmentary disorders, myxomas, and thyroid as well as gonadal tumors. Mutations located in exons were more often associated with acromegaly, myxomas, lentigines, and schwannomas. Grossly, nonsense PRKAR1A mutations were associated with less severe disease (17)
Novel therapeutic strategies are evolving in the search of a more specific therapy for CNC. A c-AMP analogue: 8-Cl-adenosine (8-Cl-ADO) that has been used in vitro, inhibited proliferation induced by G protein-coupled receptors (53). Advances in genomics and pharmaceutical technologies are promising for timely diagnosis and "etiologic" cure of this syndrome.