Pulmonary embolism from right ventricular myxoma in a child with undiagnosed Carney complex.

Pediatric pulmonary embolism occurs in 8.6-57 per 100,000 hospitalised children. We report a novel case of bilateral pulmonary emboli in a child presenting with dyspnoea who was found to have large right ventricular myxoma and subsequent diagnosis of Carney complex. After resection of the right ventricular myxoma and bilateral pulmonary embolectomy, she had a full recovery and an excellent outcome.

The spectrum of growth hormone excess in Carney complex and genotype-phenotype correlations.

CONTEXT: Carney complex (CNC) is a familial neoplasia syndrome associated with growth hormone (GH) excess (GHE). OBJECTIVE: To describe the frequency of GHE in a large cohort of patients with CNC, and to identify genotype-phenotype correlations. METHODS: Patients with CNC with at least one biochemical evaluation of GH secretion at our center from 1995-2021 (n=140) were included in the study. Diagnosis of GHE was based on levels of insulin-like growth factor-1 (IGF-1), GH suppression during oral glucose tolerance test (OGTT), GH stimulation after thyrotropin (TRH) administration and overnight GH secretion. RESULTS: Fifty patients (35.7%) had GHE and 28 subjects (20%) had symptomatic acromegaly, with median age at diagnosis of 25.3 and 26.1 years respectively. Most of the patients (99.3%) had a PRKAR1A gene defect. There was a higher risk of GHE in patients harboring a variant that led to no expression of the affected allele [Hazard risk (HR): 3.06, 95% Confidence Intervals (CI): 1.2-7.8] and for patients harboring the hotspot variant c.491_492delTG (HR: 2.10, 95%CI: 1.1-4.1). Almost half of patients with CNC had an abnormal finding on pituitary imaging. CNC patients with an abnormal pituitary imaging had higher risk of GHE (HR: 2.94, 95%CI: 1.5-5.8), especially when single or multiple adenoma-like lesions were identified. Management of patients with symptomatic acromegaly involved surgical and medical approaches. CONCLUSION: Dysregulation of GH secretion is a common finding in CNC. The clinical spectrum of this disorder and its association with genetic and imaging characteristics of the patient make prompt diagnosis and management more successful.

Carney complex predisposes to breast cancer: prospective study of 50 women.

OBJECTIVE: Carney complex (CNC) is a rare genetic syndrome, mostly due to germline loss-of-function pathogenic variants in PRKAR1A. Carney complex includes pigmented skin lesions, cardiac myxomas, primary pigmented nodular adrenocortical dysplasia, and various breast benign tumors. DESIGN: The present study was designed to describe the characteristics of breast lesions in CNC patients and their association with other manifestations of CNC and PRKAR1A genotype. METHODS: A 3-year follow-up multicenter French prospective study of CNC patients included 50 women who were analyzed for CNC manifestations and particularly breast lesions, with breast imaging, genotyping, and hormonal settings. RESULTS: Among the 38 women with breast imaging, 14 (39%) had breast lesions, half of them bilateral. Ten women (26%) presented with benign lesions and six with breast carcinomas (16%): one had ductal carcinoma in situ at 54, and five had invasive cancer before 50 years old, whom one with contralateral breast cancer during follow-up. The occurrence of breast cancer was more frequent in women with PRKAR1A pathogenic variant odds ratio = 6.34 (1.63-17.91) than in general population of same age. The mean age at breast cancer diagnosis was 44.7 years old: 17 years younger than in the general population. Breast cancer patients had good prognosis factors. All breast carcinomas occurred in individuals with familial CNC and PRKAR1A pathogenic variants. Loss of heterozygosity at the PRKAR1A locus in the 2 invasive breast carcinomas analyzed suggested a driver role of this tumor suppressor gene. CONCLUSIONS: As CNC could predispose to breast carcinoma, an adequate screening strategy and follow-up should be discussed in affected women. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov NCT00668291.

Pigmented epithelioid melanocytoma arising from a teratoma of a Carney complex patient.

A 25-year-old female Carney complex patient with a PRKAR1A mutation who had undergone surgery to remove teratomas visited our dermatology department. She was suspected of having a malignant melanoma in a teratoma. On clinical examination, a black nodule was found within the cyst. On histopathological examination, the black lesion was composed of heavily pigmented round cells with vesicular nuclei and single prominent nucleoli. Additionally, there were large cells with irregularly shaped nuclei. Upon immunohistochemical examination, the large, irregularly shaped cells were positively stained with Melan A, HMB45, S-100 protein, SOX10, CD10 (focally), and BRAFV600E , but negatively stained with PRAME. Based on the histopathological features, we diagnosed the patient with pigmented epithelioid melanocytoma (PEM) in a teratoma of a Carney complex patient. This is the first case of PEM developing from a teratoma. Since PEM lesions may spread to regional lymph nodes, careful follow-up is necessary.

Osteochodromyxoma presenting as case of congenital nasolacrimal duct obstruction.

Purpose: We report the case of a 10-month-old with nasolacrimal duct obstruction (NLDO) associated with osteochondromyxoma (OMX), a very rare bone tumor. Observations: A 10-month-old boy presented with a 6-month history of right eye epiphora not responding to digital massage and topical steroid-antibiotics eye drops. The ophthalmic exam showed right medial canthal swelling. During the ophthalmic exam an abnormal snoring sound was noted. The mother also reported that patient experienced frequent upper respiratory tract infections. Inspection of nostrils showed a right nasal lesion that upon comprehensive evaluation by ENT and pathology teams turned out to be an OMX with loss of PRKAR1A expression. Further genetic testing confirmed the Carney complex (CNC) diagnosis and the patient was referred to multidisciplinary care. To the best of our knowledge, this is one of the first cases of OMX-induced NLDO, where a typical looking congenital NLDO ended up with a diagnosis of a rare genetic disease. Conclusion and Importance: We have described a case of OMX of the nasal cavity masquerading as congenital NLDO. This case emphasizes that NLDO is not always congenital if presenting within the first few months of life. It is important to obtain a thorough history and exam to evaluate potential differential diagnoses to guide subsequent decision-making steps.

Carney Complex and Its Association With Thyroid Cancer, Molecular Pathway, and Treatment.

Thyroid cancer, being the prevailing form of endocrine malignancy, exhibits a notable surge in its incidence rates. Follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC) represent the predominant well-differentiated subtypes and are recognized as the most prevalent forms of thyroid carcinomas. Over the course of several years, numerous molecular, genetic, and epigenetic modifications have been discerned in diverse forms of thyroid neoplasms. Common occurrences comprise point mutations in the BRAF and RAS genes, along with chromosomal rearrangements involving the RET/PTC and PAX8/PPARγ genes. Thyroid carcinoma, encompassing both FTC and PTC, has been documented in individuals diagnosed with Carney complex (CNC), a hereditary syndrome passed down in an autosomal dominant manner causing increased susceptibility to diverse neoplasms. CNC manifests as a result of inactivating mutations occurring within the tumor-suppressor gene known as PRKAR1A, which is responsible for encoding the regulatory subunit of protein kinase A (PKA) type 1α. Studies have shown that this mutation leads to activation of PKA, which, in turn, can induce FTC. In this comprehensive review, we aim to elucidate the intricate molecular mechanisms underlying thyroid tumorigenesis, specifically focusing on the deleterious consequences resulting from the deactivation of the PRKAR1A gene.

Bilateral large cell calcifying Sertoli cell tumours: A testicular preservation approach in a young male.

Testicular Large cell calcifying Sertoli cell tumours (LCCSTs) are extremely rare. The primary challenge in benign LCCSTs, which are typically multifocal and bilateral tumours affecting young males, is to confirm the diagnosis to avoid radical intervention and preserve fertility potential. Patient clinical presentation, laboratory results, diagnostic radiological tests along with confirmatory histopathological studies, are the cornerstones in such cases, nevertheless genetic testing is warranted, as LCCSTs can be part of genetic syndrome such Carney complex. We present a case of bilateral benign LCCSTs in young male managed with testicular preservation approach with characteristic clinical, radiological and histopathological features.

Genetic Testing in Hereditary Pituitary Tumors.

Genetic testing is becoming part of mainstream endocrinology. An increasing number of rare and not-so-rare endocrine diseases have an identifiable genetic cause, either at the germline or at the somatic level. Here we summerise germline genetic alterations in patients with pituitary neuroendocrine tumors (pituitary adenomas). These may be disorders with isolated pituitary tumors, such as X-linked acrogigantism, or AIP-related pituitary tumors, or as part of syndromic diseases, such as multiple endocrine neoplasia type 1 or Carney complex. In some cases, this could be relevant for treatment choices and follow-up, as well as for family members, as cascade screening leads to early identification of affected relatives and improved clinical outcomes.

Malignant Melanotic Nerve Sheath Tumors: A Review of Clinicopathologic and Molecular Characteristics.

Malignant melanotic nerve sheath tumor (MMNST) which was formerly known as melanocytic schwannoma, is an uncommon aggressive type of nerve sheath tumor. It originates from nerve roots with clonal Schwann cell proliferation and melanin pigment production. MMNST which was once thought to be a benign tumor is now considered a malignant disease based on the latest 2020 World Health Organization classification of soft tissue tumors. Interestingly, despite the histologic features appearing benign with a low proliferation index, the clinical course of this tumor is malignant, which was demonstrated in case series with high rate of recurrences and metastasis. This tumor can occur sporadically or in patients with an underlying familial predisposition syndrome called, Carney's complex. Affected patients will often harbor a germline mutation in the PRKAR1A gene. MMNST can be histologically difficult to distinguish from malignant melanoma, other melanocytic tumors, and Schwannoma. Having a better understanding of its clinic pathologic characteristics and associated conditions is essential in properly diagnosing and managing affected individuals. This includes the possible need for genetic testing to detect germline mutations, genetic counseling, and surveillance according to published recommendations. In this article, we summarize the clinic pathologic and molecular features of MMNST and discuss what is known about its molecular biology and its associations with predisposing conditions. The review was conducted through an extensive PubMed search using keywords then relevant publications were selected.

A rare case of cutaneous myxoma with trichofolliculoma-like features.

Carney complex is a rare genetic disorder associated with a number of cutaneous lesions, especially cutaneous myxomas. We present a rare case of cutaneous myxoma (superficial angiomyxoma) with trichofolliculoma-like features in a patient with Carney complex, and explore how the associated histopathology provides critical context for elucidating the etiology of this benign neoplasm.

Brain and/or Spinal Cord Tumors Accompanied with Other Diseases or Syndromes.

Several medical conditions that interest both the brain and the spinal cord have been described throughout the history of medicine. Formerly grouped under the term Phacomatosis because lesions of the eye were frequently encountered or genodermatosis when typical skin lesions were present, these terms have been progressively discarded. Although originally reported centuries ago, they still represent a challenge for their complexity of cure. Nowadays, with the introduction of advanced genetics and the consequent opportunity of whole-genome sequencing, new single cancer susceptibility genes have been identified or better characterized; although there is evidence that the predisposition to a few specific tumor syndromes should be accounted to a group of mutations in different genes while certain syndromes appeared to be manifestations of different mutations in the same gene adding supplementary problems in their characterization and establishing the diagnosis. Noteworthy, many syndromes have been genetically determined and well-characterized, accordingly in the near future, we expect that new targeted therapies will be available for the definitive cure of these syndromes and other gliomas (Pour-Rashidi et al. in World Neurosurgery, 2021). The most common CNS syndromes that will be discussed in this chapter include neurofibromatosis (NF) types 1 and 2, von Hippel-Lindau (VHL) disease, and tuberous sclerosis complex (TSC), as well as syndromes having mostly extra-neural manifestations such as Cowden, Li-Fraumeni, Turcot, and Gorlin syndromes.

Case Report: Atrial myxoma combined with hyperthyroidism in an adolescent with literature review.

The most common primary cardiac tumors in adults are atrial myxomas, with adolescent-onset being uncommon. In this case report, a 15-year-old female was hospitalized with cerebrovascular embolism and later diagnosed with a left atrial myxoma. She had previously shown signs of distal vascular micro thrombosis, including recurring bilateral lower extremity rash, which are crucial for the early diagnosis and differential diagnosis of atrial mucinous neoplasm. We reviewed the various clinical symptoms and diagnostic approaches to identify left atrial mucinous neoplasm. This patient also had a combination of endocrine-related diseases. We reviewed the diagnostic approach for the Carney Complex (CNC) and discussed the role of thyroid disease in diagnosing CNC.

Case of Bilateral Atrial Myxomas in Carney Syndrome.

Carney complex is rare neoplastic disorder. Intracardiac myxoma presenting the most common non-cutaneous lesions in this complex. We are reporting a 31-year-old Saudi female known case of Carney complex presented with asymptomatic biatrial myxoma that was identified on routine transthoracic echocardiogram, and was successfully excised. However, these patients need a careful surveillance in order to detect any new masses and prevent their complications.

Atrial myxoma and associated Cushing syndrome: Carney complex / Mixoma auricular y síndrome de Cushing asociado: complejo de Carney

Abstract A 33-year-old woman with a history of high blood pressure since she was 8 years old, hypothyroidism, polycystic ovary syndrome, metabolic syndrome, multiple nevi, and a maternal family history of death at age 50 due to malignant high blood pressure and heart failure. Cushing's syndrome secondary to a secretory pituitary microadenoma was diagnosed, being the cause of secondary arterial hypertension, and ruling out other causes such as renal stenosis and coarctation of the aorta. A transthoracic and transesophageal echocardiogram was performed, which detected a left atrial myxoma. Given the presence of an atrial myxoma, Cushing's syndro me and polycystic ovary syndrome, a diagnosis of Carney Complex was made due to the presence of positive Stratakis criteria. The cardiac tumor was resected, and pathology confirmed that it was an atrial myxoma. She evolved clinically stable in outpatient controls in a 6-month follow-up. Resection of the pituitary microadenoma is planned as a curative treatment for Cushing's syndrome and arterial hypertension.

Resumen Mujer de 33 años, con antecedentes de hipertensión arterial desde los 8 años, hipotiroidismo, síndrome de ovario poliquístico, síndrome metabólico, nevos múltiples y antecedente familiar materno de muerte a los 50 años por hipertensión arterial maligna e insuficiencia cardiaca. Se diagnosticó síndrome de Cushing secundario a un mi croadenoma hipofisario secretor, siendo la causa de la hipertensión arterial secundaria, y descartándose otras causas como estenosis renal y coartación de aorta. Se realizó u n ecocardiograma transtorácico y transesofágico que detectaron un mixoma auricular izquierdo. Ante la presencia de un mixoma auricular, síndrome de Cushing y síndrome de ovario poliquístico se llegó al diagnóstico de Complejo de Carney por la presencia de criterios de Stratakis positivos. Se realizó la resección del tumor cardiaco, y la anatomía patológica confirmó que se trataba de un mixoma auricular. Evolucionó clínicamente estable en controles ambulatorios en un seguimiento de 6 meses, y se planifica la resección del microadenoma hipofisario como tratamiento curativo del síndrome de Cushing y la hipertensión arterial.

Large cell calcifying Sertoli cell tumour: molecular and immunohistochemical assessment of a series comprising non-metastasising and metastasising neoplasms.

Large cell calcifying Sertoli cell tumour (LCCSCT) is a type of testicular sex cord-stromal tumour that may occur sporadically or in the context of Carney complex and other genetic syndromes. A subset is clinically malignant, and the molecular mechanisms that drive such aggressive behaviour remain unknown. METHODS AND RESULTS: We analysed 21 samples from 20 patients with LCCSCT (12 non-metastasising and eight metastasising) using PRKAR1A immunohistochemistry (IHC) and next-generation sequencing. All tumours except two (cases 17 and 20, both metastasising) demonstrated loss of PRKAR1A expression. Among 11 cases with interpretable sequencing results, all harboured pathogenic single nucleotide variants of PRKAR1A. Evidence of loss of heterozygosity (LOH) of PRKAR1A was present in all tumours with interpretable zygosity data, but the mechanisms of LOH were different for non-metastasising and metastasising tumours. Non-metastasising tumours demonstrated only copy-neutral LOH, while metastasising tumours demonstrated a spectrum of mechanisms of LOH, including copy-loss LOH, two concurrent mutations or copy-neutral LOH. Relevant molecular findings in non-metastasising LCCSCT were limited to PRKAR1A variants. In contrast, all metastasising LCCSCTs with interpretable data harboured additional pathogenic variants, including (but not restricted to) BRCA2 mutations with evidence of LOH and bi-allelic CDKN2A/B deletions. Three patients harboured PRKAR1A variants of inferred germline origin, including one with Carney complex and two without known syndromic features. CONCLUSIONS: This study further confirms that PRKAR1A IHC is a useful diagnostic tool for both non-metastasising and metastasising tumours and suggests that molecular analyses can be helpful to identify non-metastasising tumours with malignant potential in selected patients. Importantly, these results highlight that germline assessment could be beneficial for all patients presenting with LCCSCT.

Laparoscopic right adrenalectomy in a patient with Carney syndrome: A case report.

INTRODUCTION AND IMPORTANCE: Carney complex (CNC) is an extremely infrequent multiple endocrine neoplasia syndrome characterized by distinctive pigmented skin and mucosal lesions, cardiac and noncardiac myxomatous tumors, and multiple endocrine tumors. We herein report a case of CNC and surgical and history of laparoscopic left adrenalectomy complicated with a primary pigmented nodular adrenocortical disease (PPNAD). PRESENTATION OF CASE: We present the case of a 38-year-old woman with a previous diagnosis of CNC and history of laparoscopic left adrenalectomy who consulted for severe depression refractory to medical treatment. In the laboratory tests performed, altered ACTH, prolactin, Somatomedin C-IGF-1 and estradiol. An abdomen and pelvis C/T scan was requested, where an 8 mm lesion was found at the level of the right adrenal gland. Laparoscopic right adrenalectomy was performed. Histopathology of the surgical resection specimen revealed PPNAD. DISCUSSION: CNC is an infrequent syndrome with autosomal dominant inheritance and genetically heterogeneous. PPNAD is a consistent feature in CNC patients, however, reports of Cushing's syndrome in the literature indicate that only 25-45 % of CNC patients have PPNAD. CONCLUSION: PPNAD can be present in patients with Carney complex, with surgical adrenalectomy history. With an adequate selection of patients, laparoscopic adrenalectomy with subsequent hormone replacement therapy should be performed.

Atrial myxoma and associated Cushing syndrome: Carney complex.

A 33-year-old woman with a history of high blood pressure since she was 8 years old, hypothyroidism, polycystic ovary syndrome, metabolic syndrome, multiple nevi, and a maternal family history of death at age 50 due to malignant high blood pressure and heart failure. Cushing's syndrome secondary to a secretory pituitary microadenoma was diagnosed, being the cause of secondary arterial hypertension, and ruling out other causes such as renal stenosis and coarctation of the aorta. A transthoracic and transesophageal echocardiogram was performed, which detected a left atrial myxoma. Given the presence of an atrial myxoma, Cushing's syndrome and polycystic ovary syndrome, a diagnosis of Carney Complex was made due to the presence of positive Stratakis criteria. The cardiac tumor was resected, and pathology confirmed that it was an atrial myxoma. She evolved clinically stable in outpatient controls in a 6-month follow-up. Resection of the pituitary microadenoma is planned as a curative treatment for Cushing's syndrome and arterial hypertension.

Mujer de 33 años, con antecedentes de hipertensión arterial desde los 8 años, hipotiroidismo, síndrome de ovario poliquístico, síndrome metabólico, nevos múltiples y antecedente familiar materno de muerte a los 50 años por hipertensión arterial maligna e insuficiencia cardiaca. Se diagnosticó síndrome de Cushing secundario a un microadenoma hipofisario secretor, siendo la causa de la hipertensión arterial secundaria, y descartándose otras causas como estenosis renal y coartación de aorta. Se realizó u n ecocardiograma transtorácico y transesofágico que detectaron un mixoma auricular izquierdo. Ante la presencia de un mixoma auricular, síndrome de Cushing y síndrome de ovario poliquístico se llegó al diagnóstico de Complejo de Carney por la presencia de criterios de Stratakis positivos. Se realizó la resección del tumor cardiaco, y la anatomía patológica confirmó que se trataba de un mixoma auricular. Evolucionó clínicamente estable en controles ambulatorios en un seguimiento de 6 meses, y se planifica la resección del microadenoma hipofisario como tratamiento curativo del síndrome de Cushing y la hipertensión arterial.

A case report and literature review of Carney complex with atrial adenomyxoma.

BACKGROUND: Carney complex (CNC) is a rare multiple endocrine neoplasia syndrome characterized by mucocutaneous lentigines/ blue nevi, cardiac myxoma and endocrine overactivity. Here, we report a CNC case with PRKAR1A gene mutation characterized by left atrial adenomyxoma to explore the diagnosis and treatment of CNC. CASE PRESENTATION: A 42-year-old woman with a history of cardiac tumour surgery presented with typical features of Cushing syndrome, including central obesity, buffalo hump, mild facial plethora, purple striae on the lower abdomen, and spotty skin pigmentation. Left atrial adenomyxoma and thyroid papillary carcinoma were identified by postoperative histologic assays. Genetic screening revealed a pathogenic germline heterozygous mutation of c.682C > T (p.R228X) in exon 7 of the PRKAR1A gene. The clinical features and normal ACTH levels suggest this patient suffered the ACTH-independent primary pigmented nodular adrenocortical disease (PPNAD) with cyclic hypercortisolism or ACTH-dependent Cushing syndrome. CONCLUSION: CNC is uncommon, however, if a patient develops clinical features involving multiple endocrine and non-endocrine tumors, especially Cushing syndrome and cardiac myxoma, CNC should be considered. Genetic analysis is recommended in patients with suspected CNC.

Carney complex- why thorough medical history taking is so important - report of three cases and review of the literature.

PURPOSE: To present a new case series and to review the literature on Carney complex (CNC) with an emphasis on highlighting key clinical features of the disease and pointing out possibilities of shortening the diagnostic process. METHOD: Searches of PubMed, identifying relevant reports up to April 2022. RESULTS: CNC is a rare, autosomally dominant inherited neoplasia -endocrinopathy syndrome with high clinical variability, even among members of the same family. Data on length of diagnostic process are scarce with numerous case series reporting a diagnostic delay of decades. Suggestions to shorten the diagnostic process includes awareness of the multi-faceted clinical presentations of CNC, thorough history taking of index patients and family members and awareness of diagnostic pitfalls. Importantly, unusual symptom combinations should alert the clinician to suspect a rare endocrinopathy syndrome such as CNC. Already present and coming on the horizon are databases and novel phenotyping technologies that will aid endocrinologists in their quest for timely diagnosis. CONCLUSION: In this review, we examine the current state of knowledge in CNC and suggest avenues for shortening the diagnostic journey for the afflicted patients.