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Abstract Primary pigmented nodular adrenocortical disease (PPNAD) and bilateral macronodular adrenocortical disease (BMAD) are 2 forms of adrenocortical nodular diseases causing Cushing's syndrome but are 2 very distinct conditions. PPNAD, affecting mostly young patients with an almost constant severe Cushing's syndrome, is characterized by pigmented micronodules, usually less than 1 cm, not always visible on imaging. On the contrary, BMAD is predominantly diagnosed in the fifth and sixth decades, with highly variable degrees of cortisol excess, from mild autonomous cortisol secretion to overt Cushing's syndrome. BMAD presents as large bilateral adrenal macronodules, easily observed on imaging. Both diseases are often genetically determined: frequently PPNAD is observed in a multiple neoplasia syndrome, Carney complex, and a germline genetic defect is identified in around 80% of index cases, always affecting key actors of the cAMP/protein kinase A (PKA) pathway: mostly PRKAR1A, encoding the PKA 1-alpha regulatory subunit. On the other hand, BMAD appears mostly isolated, and 2 predisposing genes are known at present: ARMC5, accounting for around 20% of index cases, and the recently identified KDM1A, causing the rare presentation with food-dependent Cushing's syndrome, mediated by the ectopic expression of the glucose-dependent insulinotropic polypeptide receptor (GIPR) in adrenal nodules. GIPR was the first demonstrated receptor to illegitimately regulate cortisol secretion in nodular adrenocortical diseases, and a myriad of other receptors and paracrine signals were discovered afterward. The last 30 years were pivotal in the understanding of the genetics and pathophysiology of bilateral adrenocortical nodular diseases, leading to a personalized approach of these fascinating conditions.

Carney complex (CNC) is a familial neoplasia syndrome associated with GH excess (GHE). To describe the frequency of GHE in a large cohort of patients with CNC and to identify genotype-phenotype correlations. Patients with CNC with at least 1 biochemical evaluation of GH secretion at our center from 1995 to 2021 (n = 140) were included in the study. Diagnosis of GHE was based on levels of IGF-1, GH suppression during oral glucose tolerance test, GH stimulation after thyrotropin administration and overnight GH secretion. 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 interval (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 abnormal pituitary imaging had a 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. Dysregulation of GH secretion is a common finding in CNC. Knowing the clinical spectrum of this disorder and its association with genetic and imaging characteristics of the patient make more likely its prompt diagnosis and better management.

Carney complex (CNC), is an autosomal dominant multiple neoplasia and lentiginosis syndrome. We aimed to identify risk factors associated with the occurrence and recurrence of cardiac myxomas, the predominant cause of death in CNC patients. Patients with CNC were monitored prospectively between 1995 and 2020 for the development of cardiac myxomas. Of the 319 patients studied, 136 (42.6%) developed myxomas. The mean age at diagnosis was 28.7±16.6 years in females and 25.0±16.4 years in males. By age 30, 35% of females and 45% of males had at least one myxoma. The CNC-related lesions, lentigines, cutaneous, mucosal, or breast myxomas, thyroid nodules, pituitary adenoma, and schwannoma were significantly more frequent (all p < 0.05) among patients with myxomas. Forty-four percent of patients had recurrences; nearly all within the first 8 and 16 years for males and females, respectively. Recurrences were more common in females. This is the largest study to date and provides the first-time risk estimates by age and gender for cardiac myxomas in CNC patients. Cardiac myxomas are common by age 30 and often recur, especially in women, but the risk drops in 10 to 20 years. These findings may guide patient counseling, screening intervals, and surgical approaches. Clinical Trial Registration: Defining the Genetic Basis for the Development of Primary Pigmented Nodular Adrenocortical Disease and the Carney complex, Registration number: NCT00001452 URL: https://clinicaltrials.gov/ct2/show/NCT00001452.

Purpose Carney complex (CNC) is a rare, autosomal dominant syndrome, most commonly caused by PRKAR1A gene mutations and characterized by pigmented skin and mucosal changes with multiple endocrine and non-endocrine tumours. This case report highlights the diagnostic challenges associated with CNC in a patient with multiple neoplasms and a complex medical history, including cortisol-producing adrenal adenoma, breast cancer, melanoma, and atrial myxoma. Methods We report the case of a 41-year-old woman with a medical history of left adrenalectomy for cortisol producing adenoma (2005) with no sign of adrenal insufficiency at follow-up, right mastectomy for BRCA1/2 negative carcinoma (2013) and left parotid BRAF-V600E wild-type melanoma (2019), treated with nivolumab adjuvant therapy. In August 2019, following the fifth nivolumab administration, the patient developed central hypocortisolism due to iatrogenic hypophysitis, confirmed by brain MRI and properly treated with oral hydrocortisone. Nivolumab was discontinued due to the patient’s decision. In October 2020 and April 2021, the patient had ischaemic strokes, requiring systemic thrombolysis. Echocardiographic examination then revealed a left atrial mass, with histological finding of myxoma. Results Given the rarity of this neoplasm and the suspicion of a syndromic disorder, a genetic evaluation was conducted, which confirmed a PRKAR1A gene mutation and the diagnosis of Carney complex. Conclusion This case illustrates the diagnostic challenges in CNC, especially in patients with multiple tumourous manifestations and a wide spectrum of life-threatening clinical presentations. It underscores the importance of a multidisciplinary approach to diagnose and manage rare diseases, improving patient outcomes through timely genetic testing and coordinated care.

PurposeGrowth hormone (GH)-producing pituitary adenomas (PAs) in childhood or young adulthood are rare, and the details surrounding these tumors remain enigmatic. We present the clinical, pathological and genetic features of this disease.MethodsWe identified 25 patients aged 20 years or younger with GH-producing PAs who underwent surgery between 2003 and 2016 at Toranomon Hospital in Tokyo. We retrospectively reviewed the clinical data, treatment outcomes and pathological features of these patients to shed light on childhood acromegaly.ResultsThe cohort comprised 14 male and 11 female patients whose average age at the time of surgery was 17.3 years. Germline AIP mutations were present in 5 of 13 patients examined, and Carney complex was identified in 2 of 25 patients. The mean maximum tumor diameter was 26.7 mm, and total resection assessed during surgery was achieved in 17 patients. Based on their respective pathological findings, patients were divided into the following 4 groups: sparsely granulated adenomas (5), densely granulated (DG) adenomas (6), plurihormonal adenomas (9), and silent subtype 3 (SS3) adenomas (5). During the mean follow-up period of 50.3 months, complete endocrinological remission was achieved in 14 of 25 patients (56%) by surgery alone and in 19 patients (76%) after postoperative adjuvant therapy.ConclusionsGH-producing PAs in young patients are intriguing and difficult to treat due to their distinct tumor characteristics, including a lower incidence of the DG subtype and a higher incidence of SS3 adenomas and genetic abnormalities. Therefore, multi-modal therapies are essential to achieve optimal clinical outcomes.

Mutations in the tumor suppressor genes SDHB , SDHC , and SDHD (or collectively SDHx ) cause the inherited paraganglioma syndromes, characterized by pheochromocytomas and paragangliomas. However, other tumors have been associated with SDHx mutations, such as gastrointestinal stromal tumors (GISTs) specifically in the context of Carney–Stratakis syndrome. Previously, we have shown that SDHB immunohistochemistry is a reliable technique for the identification of pheochromocytomas and paragangliomas caused by SDHx mutations. We hypothesized that GISTs in patients with SDHx mutations would be negative immunohistochemically for SDHB as well. Four GISTs from patients with Carney–Stratakis syndrome and six from patients with Carney triad were investigated by SDHB immunohistochemistry. Five GISTs with KIT or PDGFRA gene mutations were used as controls. In addition, SDHB immunohistochemistry was performed on 42 apparently sporadic GISTs. In cases in which the SDHB immunohistochemistry was negative, mutational analysis of SDHB , SDHC , and SDHD was performed. All GISTs from patients with Carney–Stratakis syndrome and Carney triad were negative for SDHB immunohistochemically. In one patient with Carney–Stratakis syndrome, a germline SDHB mutation was found (p.Ser92Thr). The five GISTs with a KIT or PDGFRA gene mutation were all immunohistochemically positive for SDHB. Of the 42 sporadic tumors, one GIST was SDHB-negative. Mutational analysis of this tumor did not reveal an SDHx mutation. All SDHB-negative GISTs were located in the stomach, had an epithelioid morphology, and had no KIT or PDGFRA mutations. We show that Carney–Stratakis syndrome- and Carney-triad-associated GISTs are negative by immunohistochemistry for SDHB in contrast to KIT- or PDGFR A-mutated GISTs and a majority of sporadic GISTs. We suggest that GISTs of epithelioid cell morphology are tested for SDHB immunohistochemically. In case of negative SDHB staining in GISTs, Carney–Stratakis syndrome or Carney triad should be considered and appropriate clinical surveillance should be instituted.

Carney complex (CNC) is an ultrarare disorder causing cutaneous and cardiac myxomas, primary pigmented nodular adrenocortical disease, hypophyseal adenoma, and gonadal tumours. Genetic alterations are often missed under routine genetic testing. Pathogenic variants in PRKAR1A are identified in most cases, while large exonic or chromosomal deletions have only been reported in a few cases. Our aim was to identify the causal genetic alteration in our kindred with a clinical diagnosis of CNC and prove its pathogenic role by functional investigation. Targeted testing of PRKAR1A gene, whole exome and whole genome sequencing (WGS) were performed in the proband, one clinically affected and one unaffected relative. WGS identified a novel, large, 10,662 bp (10.6 kbp; LRG_514t1:c.-10403_-7 + 265del; hg19, chr17:g.66498293_66508954del) deletion in the promoter of PRKAR1A in heterozygous form in the affected family members. The exact breakpoints and the increased enzyme activity in deletion carriers compared to wild type carrier were proved. Segregation analysis and functional evaluation of PKA activity confirmed the pathogenic role of this alteration. A novel deletion upstream of the PRKAR1A gene was proved to be the cause of CNC. Our study underlines the need for WGS in molecular genetic testing of patients with monogenic disorders where conventional genetic analysis fails.

Carney complex (CNC), an inherited disorder, is rarely diagnosed in children. We present two siblings diagnosed with CNC. The younger sister presented with primary amenorrhoea, while the brother sought evaluation for weight gain. Both siblings were cushingoid. The sister displayed characteristic features of CNC, including facial lentigines, adrenocorticotropic hormone (ACTH)-independent Cushing’s syndrome (CS), a paradoxical cortisol rise in response to dexamethasone and primary pigmented nodular adrenocortical disease (PPNAD). The second case was more challenging as he had CS but normal ACTH. Imaging was unremarkable, showing normal pituitary and adrenal glands. A previously unknown variant of the PRKAR1A gene mutation was found in both siblings. Given the sibling’s history and genetic findings, bilateral adrenalectomy was performed, confirming PPNAD. The past 5 years of follow-up have been unremarkable. Although CNC often presents as CS, evaluating beyond is crucial, as CNC includes endocrine and non-endocrine tumours. Diagnosis is challenging, necessitating a thorough family history, examination and genetic testing.

Background Carney syndrome is an uncommon autosomal disorder closely linked to mutations in the PRKAR1A gene. Skin lesions are the most pronounced feature of Carney syndrome, affecting over 80% of individuals with this condition. This syndrome is characterized by a triad of myxomas, skin pigmentation, and endocrine hyperfunction, featuring multiple endocrine neoplasms with skin and cardiac involvement. Dilated cardiomyopathy, a primary cardiomyopathy, is defined as the dilation and impaired systolic function of the left or both ventricles. Its clinical presentation varies from being asymptomatic to heart failure or sudden cardiac death, making it a leading global cause of heart failure. Currently, Dilated cardiomyopathy has an estimated prevalence of 1/2500–1/250 individuals, predominantly affecting those aged 30–40 years, with a male-to-female ratio of 3:1. This case report describes a heart failure patient with cardiac myxoma caused by Carney syndrome combined with dilated cardiomyopathy. The patient was successfully treated for heart failure by heart transplantation. Case presentation Herein, we report a case of heart failure due to Carney syndrome that resulted in cardiac myxoma combined with dilated cardiomyopathy. A 35-year-old male was admitted to the hospital three years ago because of sudden chest tightness and shortness of breath. Echocardiography indicated myxoma, and a combination of genetic screening and physical examination confirmed Carney syndrome with cardiac myxoma. Following symptomatic management, he was discharged. Surgical interventions were not considered at the time. However, the patient’s chest tightness and shortness of breath symptoms worsened, and he returned to the hospital. A New York Heart Association grade IV heart function was confirmed, and echocardiography indicated the presence of dilated cardiomyopathy accompanied by cardiac myxoma. Ultimately, the patient’s heart failure was successfully treated with heart transplantation. Conclusions Cardiac myxoma caused by Carney syndrome combined with heart failure caused by dilated cardiomyopathy can be resolved by heart transplantation.

The authors report that a gain of function in the catalytic subunit beta of the cyclic AMP–dependent protein kinase (protein kinase A), resulting from the presence of four copies of PRKACB (instead of the normal two), may lead to a Carney complex phenotype. To the Editor: Beuschlein et al. report a gain of function in PRKACA, the catalytic subunit alpha (Cα) of the cyclic AMP (cAMP)–dependent protein kinase (protein kinase A [PKA]) in cortisol-producing adenomas and micronodular adrenocortical hyperplasia. 1 Micronodular adrenocortical hyperplasia is also associated with Carney complex and inactivating mutations of the PKA regulatory subunit RIα (encoded by PRKAR1A ). 2 , 3 We report the case of a young woman with Carney complex who presented at 19 years of age with acromegaly, pigmented spots, and myxomas (Figure 1A); she did not have Cushing's syndrome (see the Supplementary Appendix, available with the full text of . . .