Case Report: An Atypical Case of Carney Complex

Pseudomyxoma Originating from the Interatrial Septum in a Heart Transplant Patient

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.

Initially described as the 'complex of myxomas, spotty skin pigmentation and endocrine overactivity,' Carney complex (CNC) is known as an autosomal dominant multiple neoplasia syndrome involving skin and cardiac myxomas, pigmented skin lesions and endocrine tumors. Pigmented cutaneous manifestations in CNC are important diagnostically because they can be used for the early detection of the disease and, thus, the prevention of life-threatening complications of CNC related to heart myxomas and endocrine abnormalities. Specific for the disease skin lesions are present in more than half of the CNC patients. A major challenge is to distinguish pigmented skin lesions associated with CNC from other skin pathology, and thus accurately estimate the risk of cancer in affected patients; curiously, patients with CNC do not appear to have predisposition to skin cancers whereas this is not the case with other genetic syndromes associated with melanotic and other cutaneous lesions. In this paper, we review the current knowledge on cutaneous pathology associated with CNC and the most recent data on the molecular basis of the disease.

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.

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.

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].

Cardiac myxomas are rare tumors that may be encountered sporadically or in the context of the Carney complex. The molecular basis for the development of cardiac myxomas and Carney complex tumors is unclear. Pathological myocardial function and myocardial hypertrophy have been associated with alterations in the heterotrimeric GTP-binding proteins. The postulated proto-oncogenic character of the gene encoding the alpha sub-unit of the stimulatory GTP-binding protein Gs alpha (gsp) in pituitary and thyroid tumors, the finding of identical somatic gsp mutations in the myocardium of patients with McCune-Albright syndrome, and the associated endocrine anomalies of the Carney complex prompted us to investigate the occurrence of activating missense mutations in the Gs alpha gene in 10 sporadically occurring atrial myxomas and in 8 tumors from 7 patients with Carney complex. No gsp mutations could be demonstrated by using the polymerase chain reaction and denaturing gradient gel electrophoresis complemented by direct DNA sequencing. Thus, activating Gs alpha mutations neither are associated with the development of atrial myxomas, nor can be demonstrated in other tumors from patients with Carney complex. The significance of these mutations in the myocardium of asymptomatic patients with McCune-Albright syndrome remains to be determined.

A case of Carney complex misdiagnosed as neurofibromatosis type 1 – Diagnostic difficulty in a rare disease

Simple SummaryCardiac tumors are relatively rare. Cardiac Myxomas (CM) are considered one of the most common benign cardiac tumors. They are usually distinct from soft tissue myxoma, most often occurring as a solitary, sporadic, pedunculated mass in the left atrium, and approximately 10% are associated with Carney syndrome with a high recurrence rate. They may cause sudden death, usually due to mitral valve obstruction or congestive heart failure. Malignant changes are known to occur but are extremely rare. They may mimic malignant neoplasia because of frequent embolism and can cause neurological deficits before theirsurgical removal. The current study analyzed the outcomes after operative myxoma excision in patients with or without cerebral embolic events prior to excision.Background: Cardiac myxomas (CM) are the most common primary cardiac tumors in adults. They are usually benign; however, malignant changes are known to occur but are extremely rare. Embolization is a common complication of cardiac myxomas and can cause neurological deficits before their surgical removal. The current study analyzed the outcomes after operative myxoma excision in patients, with and without cerebral embolic events prior to excision. Methods: All 66 consecutive patients who underwent a surgical excision of CM between 2005 and 2019 at our department were analyzed retrospectively. Patients with (n = 14) and without (n = 52) preoperative strokes caused by cerebral tumor embolization were compared. Results: The mean age was 58.4 ± 12.7 years in the stroke group (SG) and 62.8 ± 11.7 years in the non-stroke group (N-SG) (p = 0.226). Gender (35.7% vs. 61.5% female; p = 0.084) did not differ significantly, and comorbidities were comparable in both groups. The left hemisphere in the territory of the middle cerebral artery was affected by preoperative cerebral infarction most commonly (28.6%). The time from diagnosis to cardiac surgery procedure was 7 (3–24) days in the SG and 23 (5–55) days in the N-SG (p = 0.120). Cardiac myxomas were localized in the left atrium in both groups more frequently (SG: 92.9% vs. N-SG: 78.8%; p = 0.436). In the SG, 57.1% of CM had a non-solid surface, were localized in the left heart, and had a pedunculated attachment away from the fossa ovalis. In the N-SG, 92.3% of CM did not meet all these criteria (p < 0.001). The maximal diameters of CM were comparable (SG: 3.4 ± 1.5 cm vs. N-SG: 3.8 ± 2.1 cm; p = 0.538). The operation times (192.5 (139.3–244.5) min vs. 215.5 (184.5–273.3) min; p = 0.046) and the cross-clamp times (54.5 (33.3–86.5) min vs. 78.5 (55–106.8) min; p = 0.035) were significantly shorter in the SG. Only in the N-SG were reconstructions of the endocardium with bovine pericardium required after resection (51.9% vs 0%; p < 0.001). In the N-SG, CM were explored via the right atrium more often (57.7% vs. 14.3%; p = 0.007). Patients in the N-SG required significantly shorter ICU care after surgery (p = 0.020). Other postoperative courses did not differ significantly. After tumor removal, 1.9% of the N-SG suffered their first stroke and 14.3% of the SG had a cerebral re-infarction (p = 0.111). The 30-day mortality rates were 1.9% in the N-SG and 7.1% in the SG (p = 0.382). In one case in the N-SG, a tumor recurrence was diagnosed. The Kaplan–Meiercurves showed a significantly better long-term prognosis for patients in the N-SG (p = 0.043). Conclusions: After the surgical removal of CM, the outcome is compromised if preoperative cerebral embolization occurs. Surgical treatment is therefore indicated as soon as possible, especially when CM have a non-solid surface, are localized in the left heart, and have a pedunculated attachment away from the fossa ovalis.

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.

Cardiac myxoma is a benign neoplasm composed of stellate to plump, cytologically bland mesenchymal cells set in a myxoid stroma. Although benign, as they can lead to severe complications, they are often removed surgically. A 39-year-old female presented with a chief complaint of generalized fatigue. Patient had a history of a large 7cm x 2.5cm left atrial myxoma resected at the age of 32 years after she presented with symptoms of dyspnea on exertion. The dyspnea was due to prolapse of the mass through the mitral valve during diastole, leading to functional severe mitral stenosis. The mass was resected with clear margins confirmed on biopsy. On physical examination, heart rate was regular with no murmurs. No signs of congestive heart failure were noted. A 2D echo revealed a mobile structure in the left atrium along with mild mitral regurgitation. Cardiac MRI showed a 21mm x 9mm well defined, pedunculated, mobile mass in the left atrium arising from inter-atrial septum. The mass was hyperintense on T2 weighted images with patchy delayed hyper-enhancement consistent with recurrence of a myxoma. The patient underwent a repeat median sternotomy with the removal of left atrial mass and repair of atrial septum with hemashield patch. The mass was sent for pathological evaluation confirming the diagnosis of recurrent myxoma. On genetic testing, patient tested negative for mutations in PRKAR1A gene (mutated in up to 60%-80% cases with Carney complex), MEN1, RET and sarcoma (TP53) genes. Cardiac myxomas are rare primary benign tumors of the heart with a small recurrence rate. Follow-up studies have rarely reported recurrences after complete resection. However, in our case not only did the patient have the sporadic form of myxoma with recurrence, but it also occurred within three years of the previous resection despite complete removal with clear margins.

A 14-year-old girl presented with sudden painless left eye vision loss. Fundus photography showed left central retinal artery occlusion (CRAO) (figure, A). Brain MRI revealed subclinical embolic infarcts (figure, B). Chest CT confirmed multicentric cardiac myxomas (figure, C). Gene testing revealed point mutation in the PRKAR1A gene (figure, D). Carney complex (CNC) is a rare autosomal dominant, multiple neoplasia syndrome with cardio-cutaneous manifestations. Multiple cardiac myxomas are unusual and strongly related to CNC. Cerebral emboli occur in 34% of patients with cardiac myxomas.1 The PRKAR1A gene is located on 17q22-24 and mutated in about 40% of patients with CNC.2

Cardiac myxoma is the most common cardiac neoplasm. In the majority of cases, it is isolated (non-syndromic) and located in the left atrium. In up to 10% cases, it is seen in syndromic association with the Carney complex where it is encountered in younger patients, with atypical and multiple locations, such as the right atrium or ventricles, and carries a high risk of recurrence. Imaging is pivotal in the diagnosis, management guidance and surveillance. Surgical excision is the established definitive treatment. Further research should address management strategies in incidentally discovered small myxomas in asymptomatic patients and the role of genetic testing and screening in syndromic myxomas.

Background/Aims: Carney complex (CNC) is a rare syndrome associated with multiple tumors and several other unique manifestations. We describe the clinical, genetic, and laboratory findings in a cohort of patients with CNC and failure to thrive (FTT). Methods: A retrospective case series of pediatric patients with CNC presenting with FTT. Results: We describe a patient with infantile Cushing syndrome (CS) who presented with severe FTT and liver disease; the patient was subsequently diagnosed with CNC. This led to the realization that at least 10 other patients with CNC and FTT have been investigated in the last 22 years at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Four of those had primary pigmented nodular adrenocortical disease (PPNAD), 2 had cardiac myxomas, and 3 had liver disease. Conclusion: Pediatric patients with CNC may present with FTT whose primary cause is variable and includes CS due to PPNAD, hepatic involvement, and other manifestations of CNC. FTT due to liver disease and/or other causes is a unique new presentation of this rare syndrome with which clinicians need to be familiar.