Carney complex and lentiginosis.

Within a few months a 31-year-old female patient was diagnosed with a psammomatous melanotic schwannoma, an atrial myxoma and microfollicular adenomas in both thyroid lobes. Therefore, sufficient diagnostic criteria of a Carney complex were fulfilled. The Carney complex is an inherited autosomal dominant disorder with highly variable phenotypes, which was initially described by Carney in 1985 as a complex of myxomas, spotty skin pigmentation and endocrine overactivity. Pathologists should consider this differential diagnosis in reports when confronted with a psammomatous melanotic schwannoma.

Carney complex (CNC) is a rare autosomal dominant tumor-predisposition syndrome with variable expression. Its main features are pigmentary skin lesions, soft-tissue myxomas, and endocrine overactivity or tumors. There is occasional overlap with other syndromes, and oligosymptomatic cases may escape diagnosis. This report describes the long journey of a patient until the diagnosis of CNC was finally made after a thorough diagnostic workup. The female patient was referred for treatment of a subcutaneous tumor of the lower abdomen. Medical reports detailed previous excisions of fibroma, neurofibroma and myxoma, and a malignant tumor of the cerebellopontine angle. The resected subcutaneous tumor was a myxoma. The identification of a previously unknown frameshift mutation in the gene for protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) in the patient confirmed the diagnosis of CNC. Patients with CNC may have highly variable clinical findings. Some rare lesions in CNC are more commonly recorded in other syndromes, making early diagnosis difficult in some cases. Genetic testing greatly facilitates diagnosis.

Another predictor of biologically unusual myxomas

Cardiac myxomas are rare tumors. They usually appear as a sporadic isolated condition in the left atrium of middle-aged women with no other coincidental pathology. Carney and others have described in young people a special complex group of cardiac myxomas associated to a distinctive complex pathology, giving identity to the "Syndrome Myxoma" or "Carney's Syndrome". Four additional cases of this syndrome, treated from 1977 to 1999 at the Hospital Clínico de la Universidad de Chile are presented here with a comprehensive review of the literature, accumulating 100 cases. The main features of our cases include the presence of malignant non cardiac tumors, a familial trend, follow-up of 23 years and an iterative recurrence in the elder case. To date all patients are tumor free. Reviewing the literature, patients with Carney's Syndrome were younger, with a mean age of 26 years and female predominance (62%). Cardiac myxomas affected the four chambers of the heart: 64% the left atrium; 44% the right atrium; 14% the left ventricle and 12% the right ventricle. They were multiple tumors in 41% and involved more than one chamber in 31%, being synchronous or metachronous. There was a marked familial trend (52%), a high incidence of recurrence (20%), with more than one occurring in half the cases. Extra-cardiac involvement consisted of: 68% pigmented skin lesions, 40% cutaneous myxomas, 37% adrenal cortical disease, 27% myxoid mammary fibroadenoma and 34% male patients with testes tumors. A low percentage had pituitary adenoma, melanotic schwannomas and thyroid disease. The diagnosis is made when two or more of these criteria are present. In agreement with these findings the four chambers of the heart should be examined at surgery for atypical myxoma locations, right atriotomy and combined superior-transseptal approach improve exposure of the cavities, careful screening of the first degree family members should be conducted, and closed short and long term follow up controls are important. Complex myxoma appears as a multi-systemic disorder, occasionally having an ominous prognosis and malignant potentiality, and is still undergoing investigation for better understanding and identification.

In 1981, study of the adrenal pathology in four cases of Cushing syndrome led to characterization of a unique disorder termed primary pigmented nodular adrenal disease (PPNAD). Review of the literature showed that the condition occurred in two families. In one, it had affected two siblings; a third sibling who did not have Cushing syndrome died of cardiac myxoma. To test the hypothesis that there was a connection between PPNAD and cardiac myxoma, the Mayo Clinic files and the world literature were searched for patients with both conditions. The search uncovered one Mayo Clinic patient with the two conditions. The patient’s record revealed that she was “covered in pigmented moles” and had a myxomatous tumor of the breast. A review of the literature on cardiac myxoma revealed that there were two types of the tumor, nonfamilial and familial, and that rare cases of the latter were variously associated with cutaneous pigmented spots, mammary and cutaneous myxomas, large-cell calcifying Sertoli cell tumor, and growth hormone-producing pituitary adenoma. In 1985, all these conditions were assembled into a unifying syndrome and reported as “the complex of myxomas, spotty pigmentation, and endocrine overactivity” (Carney complex).

Carney complex (CNC) is a multiple neoplasia syndrome characterised by endocrine tumours, spotty skin pigmentation, cardiac and other myxomas, psamommatous and pigmented schwannomas, large cell calcifying Sertoli cell tumours, and mammary ductal adenomas and other more rare lesions. CNC is inherited in an autosomal-dominant manner and has been mapped to at least two chromosomal loci. Patients who map to the CNC1 locus located on chromosome 17 carry inactivating mutations of the PRKAR1A gene that encodes the cAMP-dependent protein kinase regulatory subunit type 1-alpha (Kirschner et al., 2000). One gene responsible for type 2 (CNC2) is located on chromosome 2p16. Infertility in CNC can be caused by a number of factors; there is evidence that prkar1a deficiency in mice leads directly to infertility (Burton et al., 2006), but patients with CNC also have Sertoli cell tumours and a number of other reasons to affect fertility. We report on an infertile male with CNC and present evidence that male infertility should be considered as part of the phenotype of CNC.

Carney complex (CNC) is a rare autosomal dominant syndrome. Spotty skin pigmentation is the major clinical manifestation of CNC, followed by cardiac myxomas, benign tumors that usually present with features from the classical triad of obstructive cardiac, embolic and non-specific constitutional symptoms (NCS). NCS are caused by the overproduction of interleukin-6 (IL-6), a pro-inflammatory cytokine which mediates the induction of intercellular adhesion molecule 1 (ICAM-1) and promotes endothelial dysfunction and atherosclerosis. Thus, myxomas may be directly linked to an increased risk of atherosclerotic events. We report here a case of a 74-year-old woman with left atrial myxoma, skin pigmentary abnormalities, thyroid disorder and extensive atherosclerosis, with non-embolic occlusion of infrarenal abdominal aorta.

The epithelioid blue nevus has recently been associated with the Carney complex, which is characterized by myxomas, spotty skin pigmentation, endocrine overactivity, and schwannomas. Using the general criteria proposed by Carney and Ferreiro, similar lesions were identified in 33 patients with no evidence of the Carney complex. Those lesions presented on the face, trunk and extremities of 15 males and 18 females. The mean age was 35 years, much older than those in the Carney complex (mean 16.3 years). Clinical diagnoses included malignant blue nevus, atypical nevus, melanoma, congenital nevus, and dermatofibroma. The lesions were symmetric, predominantly dermal melanocytic proliferations arranged as short fascicles, small nests, and single cells. Large polygonal and epithelioid melanocytes with moderate pleomorphism, and occasional nuclear pseudoinclusions were admixed with heavily pigmented dendritic and spindled melanocytes and melanophages. Rare mitotic figures were seen in some cases. The neoplasms showed a morphologic spectrum that encompassed a group of combined blue nevi with epithelioid melanocytes and other Spitz's nevus characteristics. These epithelioid combined nevi (ECN) fell into three phenotypes with morphologies that most closely paralleled those pictured by Carney and Ferreiro in the Carney complex: the classic or Carney complex pattern (ECN-CC), those that showed overlap with deep penetrating nevus (ECN-DPN), and those that have many dermal Spitz's nevus features, [BLue + SpITZ's nevus; (ECN-BLITZ)I. In six cases, there was such an admixture of features that it was difficult to ascribe them to one of the groups. Nine lesions had associated banal congenital nevus. Follow-up that averaged over 2.5 years (31 months) (range 6-162 months) showed no evidence of malignancy or recurrent disease after excision. Epithelioid combined nevus is a type of combined nevus with blue nevus and Spitz's nevus features, which may or may not be associated with the Carney complex. It shows morphologic overlap with the epithelioid blue nevus described by Carney (ECN-CC), deep penetrating nevus (ECN-DPN), and blue nevus with intradermal Spitz's (desmoplastic) nevus (ECN-BLITZ). Epithelioid combined nevus is thought to be a fitting nosologic designation for all of these lesions.

Patient: Male, 54-year-oldFinal Diagnosis: Carney complex (CNC)Symptoms: Cough • dyspnea • heart failure • lightheadedness • palpitationMedication: —Clinical Procedure: Mitral valve repair • open heart surgery • transesophageal echocardiogram • transthoracic echocardiogramSpecialty: Cardiac Surgery • Cardiology • Endocrinology and Metabolic • GeneticsObjective:Rare diseaseBackground:Intracardiac tumors are a rare entity, with myxomas being the most common among them (approximately 50% of intracardiac tumors). Up to 80% of myxomas originate within the left atrium and while most are incidental or isolated findings in asymptomatic patients, others may result in clinical manifestations of heart failure or emboli. Moreover, in some cases, myxomas can be part of a genetically inherited syndrome known as Carney complex (CNC), and present with varied phenotypes, including skin, endocrine, and neuroendocrine tumors.Case Report:We present a case of a 54-year-old male patient who presented with a several-month history of non-specific cough, dyspnea on exertion, and palpitations along with several skin tags, nevi, and nodules. He was found to have a retrocardiac density on chest X-ray, which was revealed to be a large left atrial myxoma on echocardiography. The myxoma was surgically excised and genetic testing for a mutation of the PRKAR1A gene (the most common mutation underlying CNC) was negative. However, 2 major clinical criteria for diagnosis of CNC were fulfilled based on cardiac myxoma and spotty skin pigmentation. In this report, we focus on the clinical manifestations of CNC, including guidance on tumor surveillance and genetic variants of CNC.Conclusions:While CNC is most commonly associated with an inactivating mutation of the PRKAR1A gene, it can be diagnosed clinically in the absence of an identifiable genetic mutation. In patients presenting with atypical cardiac tumors, the early recognition of cutaneous manifestations can raise the index of suspicion for CNC, which can facilitate early diagnosis, treatment, and initiation of surveillance for neoplasia development.

Baran Budak, MD Yuksek Ihtisas Hospital Department of Cardiovascular Surgery Ankara/Turkey Sirs: Primary tumors of the heart are rare, most of them are benign and nearly half of them are myxomas [1]. Because of the lack of specific symptoms before the tumor has reached a certain size, their recognition and treatment generally take place in older patients [2]. Although nearly 90% of all myxomas are sporadic, familial myxomas have autosomal domiant transmission and are often present within the construct of a larger syndrome. The “syndrome myxoma” or “Carney’s syndrome” is characterized by both cardiac and noncardiac myxomas, spotty pigmentation, and endocrine overactivity (pituitary, adrenocortical, endocrine testicular tumors) [3, 4]. Case report

The initial description of Carney complex (CNC) in 1985 included myxomas, spotty skin pigmentation, and endocrine overactivity (of the adrenal, the pituitary, and the testis). In 1997, thyroid neoplasms were found in 3 patients with CNC and involvement of the gland in the syndrome was apparent. Herein, we describe the clinical, pathologic, and follow-up findings in 26 patients with CNC and a disorder of the thyroid gland. The patients were predominantly middle-aged women with an asymptomatic thyroid mass. Four patients had hyperthyroidism, which was caused by follicular hyperplasia in 2 patients and by toxic adenoma in 2 others. Pathologic findings included benign lesions (follicular hyperplasia, nodular hyperplasia, and follicular adenoma) in 16 patients and carcinomas (follicular or papillary) in 10 patients. The follicular carcinomas had unusual features, multifocality, bilaterality, and lymph node metastasis. The tumor was fatal in 3 of 4 patients with a tumor ≥3 cm in diameter. One patient had an unusual multifocal microscopic follicular hyperplasia. Detection and treatment of the thyroid neoplasms in patients with CNC requires long-term follow-up of patients with the syndrome.

Myxoma is the most common primary intracardiac neoplasm, ranging between 0.001% to 0.03% in the general population [1]. Cardiac myxomas are most frequently located in the left atrium in 80% of cases, with the remainder mostly originating from the right atrium [2]. Patients may present with various cardiovascular manifestations depending on the anatomical location (e.g., cardiac arrhythmia, embolization,..). It may also present with nonspecific constitutional sign and symptoms such as fever and weight loss [3,4]. The association between cardiac myxomas and other simultaneous tumors has previously been described in the case of carney complex. Carney complex is a rare autosomal dominant syndrome caused by abnormalities in the PRKAR1A gene [5]. Patients may present with skin pigmentations and a variety of endocrine and non-endocrine tumors [5]. However, multiple reports of cardiac myxomas in patients with synchronous primary tumors have been reported, speculating that cardiac myxomas may simultaneously be present with other primary cancers, not classified as the carney complex. A variety of malignancies have been documented that coincide with cardiac myxomas over the years. Meir et al., encountered a left atrial myxoma in the echocardiography of a 51-year-old woman presenting with fever after receiving first chemotherapy session for invasive lobular adenocarcinoma [6]. The association between breast adenocarcinoma and cardiac myxoma was also reported by Kataoka et al. and Özer et al. [7,8]. Nuño et al. and Hajsadeghi et al., described synchronous colorectal carcinomas with a cardiac myxoma [9,10].

Carney Syndrome (CS) is an autosomal dominant multiple neoplasia syndrome that includes cardiac, endocrine, cutaneous, and neural tumors. Cardiac myxomas can be seen in the course of CS. A 46-year-old female patient was admitted to our clinic with palpitation, cough, and exertional dyspnea. Physical examination revealed pigmented lesions, especially scattered in the neck, chest, and extremities. Echocardiography revealed a left atrial mass, 6 × 4 cm in size, originating from the interatrial septum that was protruding into the left ventricle through the mitral valve during diastole. The tumor was excised from the interatrial septum with its pedicle. The patient was discharged at the fifth postoperative day without any complication. Cardiac myxomas are a cornerstone of this disease since cardiac manifestations and related complications account for the majority of mortality seen in the course of CS.

Carney complex (CC) is a familial multiple neoplasia and lentiginosis syndrome, transmitted in an autosomal dominant manner. It is the only familial form of cardiac and skin myxomas known, and is associated with endocrine neoplasms causing Cushing syndrome and acromegaly. We recently mapped the gene(s) responsible for CC on the short arm of chromosome 2 by linkage analysis of 11 North American kindreds (Stratakis et al. J.Clin. Invest. 97 (2): 1-7, 1996). Two additional kindreds (7 affected individuals) were recently recruited. Blood and tumor samples from patients and their family members were obtained. Patient-derived lymphoblastoid and tumor cell lines were established. Linkage analysis with microsatellite markers from the short arm of chromosome 2 (band 2p16) showed co-segregation with the disease locus with no new recombination events in one of the new families. Multipoint linkage analysis defined a region of approximately 4 cM, bordered by markers CA2 and D2S378, that is likely to contain the gene(s) associated with CC. Candidate genes in the proximity included the microsatellite stability-maintaining hMSH2 and hMSH6 genes, which, however, were excluded. The gene that codes for calcineurin (CALNB1) was also recently mapped to 2p16. After determining the intron-exon junctions of this gene, SSCP analysis and direct sequencing of its 5 exons did not reveal any abnormalities in 5 patients with CC from different families. Chromosome and microsatellite analysis of 9 tumors and tumor-derived cell lines indicated significant genomic, but not microsatellite instability, which was mostly present in telomeric regions. Since these and other tumors demonstrated genomic instability, and the hMSH2, hMSH6 and CALNB1 genes were excluded, we hypothesize that other, as yet unknown genes in this region are responsible for CC, whose function may be related to the preservation of chromosomal integrity and growth of dividing human cells. In order to identify the CC and other genes, we are constructing a detailed physical map of chromosome 2p16 employing YAC, BAC, PAC and P1 libraries. New CC families are collected for further refinement of the locus.

SummaryCarney complex (CNC) is a rare autosomal dominant syndrome characterized by pigmented lesions of the skin and mucosae along with cardiac, endocrine, cutaneous, and neural myxomatous tumors. Mutations in the PRKAR1A gene have been identified in ∼70% of the CNC cases reported worldwide. A 30-year-old male was referred to the endocrinology clinic with suspected acromegaly. He had a history of recurrent atrial myxoma for the past 8 years for which he underwent repeated surgeries. Presently, he complained of having headache, excessive snoring, sweating, and also noticed increase in his shoe size. Evaluation for acromegaly revealed elevated levels of GH in random as well as in suppressed condition. Magnetic resonance imaging scan revealed enlarged sella with microadenoma in the left anterior pituitary. Screening of PRKAR1A gene was carried out for the patient, his parents and siblings who were available and willing to undergo the test. The patient was diagnosed to have the rare CNC syndrome characterized by recurrent atrial myxoma and acromegaly due to a novel 22 bp insertion mutation in PRKAR1A which was predicted to be deleterious by in silico analysis. Screening the available family members revealed the absence of this mutation in them except the elder brother who also tested positive for this mutation. The present study reports on a novel PRKAR1A insertion mutation in a patient with acromegaly and left atrial myxoma in CNC.Learning pointsIdentification of a novel deleterious PRKAR1A insertion mutation causing CNC.It is important that patients with cardiac myxoma be investigated for presence of endocrine overactivity suggestive of CNC.PRKAR1A mutation analysis should be undertaken in such cases to confirm the diagnosis in the patients as well as first degree relatives.This case highlights an important aspect of diagnosis, clinical course, and management of this rare condition.