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Aims: Primary pigmented nodular adrenocortical disease (PPNAD), as a rare kind of Cushing's syndrome, is frequently misdiagnosed. To get a better understanding of the disease, we analyzed the clinical characteristics and pathogenic variants of PPNAD. Methods: Databases were searched, and the pathogenic variants and clinical manifestations of patients were summarized from the relevant articles. Results: A total of 210 patients in 86 articles were enrolled with a median age of 22 and a female-to-male ratio of 2:1. Sixty-six (31.43%) patients were combined with Carney complex (CNC) and 94.29% were combined with osteoporosis/osteopenia. Among 151 patients who underwent genetic testing, 87.42% (132/151) had pathogenic variants. Six gene mutations (PRKAR1A, PDE11A, PRKACA, CTNNB1, PDE8B, and ARMC5) were detected in the patients. The most common mutation was PKAR1A, accounting for 79.47% (120/151). There was a significant correlation between PRKAR1A pathogenic variant and spotty skin pigmentation in CNC concurrent with PPNAD (p < 0.05). Among pregnant patients with PPNAD, those without surgical treatment and with bilateral adrenalectomy suffered from a high-risk perinatal period. However, patients with unilateral adrenalectomy presented a safe perinatal period. Conclusions: For young patients with Cushing's syndrome, especially female patients with spotty skin pigmentation and osteoporosis/osteopenia, PPNAD should be considered. Unilateral adrenal resection may be considered as an option for women with fertility needs. In view of the difficulty of PPNAD diagnosis, genetic testing before surgery might be a reasonable option. Patients with PPNAD with spotty skin pigmentation should consider the PRKAR1A pathogenic variant and pay attention to CNC. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023416988.
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Doenças do Córtex Suprarrenal , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico , Mutação , Humanos , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Doenças do Córtex Suprarrenal/genética , Doenças do Córtex Suprarrenal/patologia , Feminino , Adulto , Masculino , Síndrome de Cushing/genética , Síndrome de Cushing/cirurgia , Síndrome de Cushing/diagnóstico , Complexo de Carney/genética , Complexo de Carney/diagnóstico , Adulto Jovem , Osteoporose/genéticaRESUMO
Objective: Carney complex is a rare autosomal dominant syndrome that has been shown to be associated with inactivation due to PRKAR1A mutations. We revealed a novel PRKAR1A gene mutation in Chinese patient with Carney complex and review the literature to enhance understanding of Carney complex. Case presentation: A 23-year-old Chinese male patient with a family history cardiac myxoma was admitted to our Department of Endocrinology because of central obesity and hyperpigmentation. Physical examination revealed a maximum blood pressure of 150/93mmHg, a waist circumference of 102cm, a weight of 70kg, a height of 170cm, and a BMI of 24.22kg/m2. Additionally, there was spotty skin pigmentation on the lip mucosa, purple striae on the abdomen, thin skin on both legs, and visible veins. Blood examination revealed hypercortisolemia, decreased adrenocorticotropic hormone (ACTH) levels and failure to suppress cortisol with low and high-dose dexamethasone suppression tests. Magnetic resonance imaging (MRI) scan revealed multiple small adrenal nodules and Retroperitoneal neurogenic tumor. Genetic testing showed a novel heterozygous mutation in exon 5 of PRKAR1A (c.500_502 + 8delAAGGTAAGGGC). The patient underwent resection of the right adrenal gland and retroperitoneal neoplasms in 2020. Postoperative pathology following the right adrenal gland resection showed nodular hyperplasia of the adrenal cortex. The pathology from the retroperitoneal tumor resection revealed spindle cell tumors rich in pigment and cells. The patient was diagnosed as Carney complex according to Stratakis CA in 2001 guidelines. After long-term follow-up, the patient's condition was stable, with weight loss, waist circumference reduction, significantly lower cortisol levels, and normal blood lipids. Conclusion: This case reported a Carney complex in a Chinese patient, characterized clinically by non-ACTH-dependent Cushing's syndrome, familial recurrent cardiac myxomas, psammomatous melanotic schwannoma (PMS) and skin and mucosal pigmentation. A novel subtype of PRKAR1A mutation was discovered, which may affect the characteristics of the PRKAR1A protein and contribute to the development of Carney complex.
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Complexo de Carney , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico , Mutação , Humanos , Complexo de Carney/genética , Complexo de Carney/patologia , Masculino , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Adulto JovemRESUMO
Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and Bilateral Macronodular Adrenocortical Disease (BMAD) are two forms of Adrenocortical Nodular Diseases causing Cushing's syndrome, but are two 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 (CNC), and a germline genetic defect is identified in around 80% of index cases, always affecting key actors of the cAMP/PKA pathway: mostly PRKAR1A, encoding the PKA 1-alpha regulatory subunit. On the other hand, BMAD appears mostly isolated, and two 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.
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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.
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Cardiomiopatia Dilatada , Complexo de Carney , Insuficiência Cardíaca , Neoplasias Cardíacas , Transplante de Coração , Mixoma , Humanos , Cardiomiopatia Dilatada/cirurgia , Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/diagnóstico por imagem , Masculino , Complexo de Carney/genética , Complexo de Carney/diagnóstico , Complexo de Carney/cirurgia , Complexo de Carney/complicações , Adulto , Mixoma/complicações , Mixoma/cirurgia , Mixoma/diagnóstico por imagem , Mixoma/diagnóstico , Mixoma/genética , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/cirurgia , Neoplasias Cardíacas/cirurgia , Neoplasias Cardíacas/complicações , Neoplasias Cardíacas/diagnóstico por imagem , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/genética , Resultado do Tratamento , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genéticaRESUMO
PURPOSE: Cardiac myxomas (CMs) are the second most common benign primary cardiac tumors, mainly originating within the left atrium. Approximately 5% of CM cases are associated with Carney Complex (CNC), an autosomal dominant multiple neoplasia syndrome often caused by germline mutations in the protein kinase A regulatory subunit 1A (PRKAR1A). Data concerning PRKAR1A alterations in sporadic myxomas are variable and sparse, with PRKAR1A mutations reported to range from 0% to 87%. Therefore, we investigated the frequency of PRKAR1A mutations in sporadic CM using next-generation sequencing (NGS). Additionally, we explored mutations in the catalytic domain of the Protein Kinase A complex (PRKACA) and examined the presence of GNAS mutations as another potential driver. METHODS AND RESULTS: This study retrospectively collected histological and clinical data from 27 patients with CM. First, we ruled out the possibility of underlying CNC through clinical evaluations and standardized interviews for each patient. Second, we performed PRKAR1A immunohistochemistry (IHC) analysis and graded the reactivity of myxoma cells semi-quantitatively. NGS was then applied to analyze the coding regions of PRKAR1A, PRKACA, and GNAS in all 27 cases. Of the 27 sporadic CM cases, 13 (48%) harbored mutations in PRKAR1A. Among these 13 mutant cases, six displayed more than one mutation in PRKAR1A. Most of the identified mutations resulted in premature stop codons or affected splicing. In PRKAR1A mutant CM cases, the loss of PRKAR1A protein expression was significantly more common. In two cases with missense mutations, protein expression remained preserved. Furthermore, a single mutation was detected in the catalytic domain of the protein kinase A complex, while no GNAS mutations were found. CONCLUSION: We identified a relatively high frequency of PRKAR1A mutations in sporadic CM. These PRKAR1A mutations may also represent an important oncogenic mechanism in sporadic myxomas, as already known in CM cases associated with CNC.
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Cromograninas , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico , Subunidades alfa Gs de Proteínas de Ligação ao GTP , Neoplasias Cardíacas , Mixoma , Humanos , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Cromograninas/genética , Neoplasias Cardíacas/genética , Neoplasias Cardíacas/patologia , Neoplasias Cardíacas/enzimologia , Pessoa de Meia-Idade , Feminino , Masculino , Mixoma/genética , Mixoma/patologia , Mixoma/enzimologia , Adulto , Idoso , Estudos Retrospectivos , Análise Mutacional de DNA , Predisposição Genética para Doença , Mutação , Adulto Jovem , Fenótipo , Sequenciamento de Nucleotídeos em Larga Escala , Adolescente , Complexo de Carney/genética , Complexo de Carney/enzimologia , Complexo de Carney/patologia , Biomarcadores Tumorais/genética , Subunidades Catalíticas da Proteína Quinase Dependente de AMP CíclicoRESUMO
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.
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Neoplasias da Mama , Complexo de Carney , Mixoma , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Complexo de Carney/genética , Estudos Prospectivos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Mixoma/genética , Genótipo , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , MutaçãoRESUMO
Large cell calcifying Sertoli cell tumors (LCCSCTs) are rare testicular tumors, representing <1 % of all testicular neoplasms. Almost 40 % of patients with LCCSCTs will present in the context of the inherited tumor predisposition syndrome, the Carney complex. While most LCCSCTs are benign, 10-20 % have malignant behavior. The aim of our study was to analyze LCCSCTs for novel molecular alterations in addition to PRKAR1A mutations and to identify potential drivers for malignant progression. Eight LCCSCTs diagnosed at two institutions were included. Two patients had the Carney complex confirmed on subsequent genetic testing, and two tumors had several adverse pathological findings. One patient presented with metastatic disease at the time of initial diagnosis. Targeted next-generation sequencing detected PRKAR1A alterations in all cases, with heterozygous PRKAR1A mutations in 5 tumors, germline Carney-complex-associated PRKAR1A mutation in 2 patients, and PRKAR1A fusion in 1 tumor. Additionally, sequencing the metastatic case identified CDKN1B and TERT promoter gene mutations. All tumors showed a low tumoral mutational burden and unremarkable copy number alterations except for frequent LOH of 17q24 encompassing the PRKAR1A locus. RNA expression analysis showed increased expression of several markers including novel PRUNE2, and usual markers like inhibin and calretinin. Our study showed that while LCCSCTs have been reported in the setting of cancer predisposition syndromes, the majority of these tumors occur sporadically. PRKAR1A alterations were present in all cases and appear to be the major driver in LCCSCTs. It remains to be determined whether malignant progression may be caused by additional driver mutations.
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Complexo de Carney , Tumor de Células de Sertoli , Neoplasias Testiculares , Masculino , Humanos , Tumor de Células de Sertoli/genética , Tumor de Células de Sertoli/patologia , Complexo de Carney/genética , Complexo de Carney/patologia , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia , Mutação , Síndrome , Fatores de Transcrição/genéticaRESUMO
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.
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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.
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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.
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Complexo de Carney , Tumor de Células de Sertoli , Tumores do Estroma Gonadal e dos Cordões Sexuais , Neoplasias Testiculares , Masculino , Humanos , Tumor de Células de Sertoli/genética , Tumor de Células de Sertoli/química , Neoplasias Testiculares/metabolismo , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , MutaçãoRESUMO
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.
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Fibrilação Atrial , Complexo de Carney , Síndrome de Cushing , Mixoma , Humanos , Complexo de Carney/complicações , Complexo de Carney/diagnóstico , Complexo de Carney/genética , Síndrome de Cushing/etiologia , Síndrome de Cushing/genética , Mixoma/complicações , Mixoma/genética , Mixoma/cirurgia , Hormônio Adrenocorticotrópico , MutaçãoRESUMO
Superficial angiomyxoma is characterized as a benign, slow-growing vascular cutaneous myxoma. A 6-year-old Arab girl with no medical history presented with a vulvar tumor located on the left labia majora. The lesion was present since birth, but it had significantly increased over the last 6 months. She did not have any associated symptoms. Physical examination revealed an exophytic tumor of the left labia majora, which measured 5 cm in its major axis. Doppler ultrasound study showed a mass with abundant arterial and venous vascularization, and magnetic resonance imaging showed a highly vascular contrast-enhanced mass with well-delimited margins, which depended on the labia majora. A macroscopically complete resection was performed, achieving a tension-free primary closure. Histologically, the lesion was characterized as a well-demarcated superficial tumor with thin-walled vessels and myxoid stroma, S100 (-), CD34 (+), vimentin (+), and actin (+). The final histopathological diagnosis was superficial angiomyxoma. The literature review of this entity in the pediatric population shows a predominance of this lesion in the vulvar location. Local recurrence has been described. Loss of PRKAR1A expression may be involved in the pathogenesis of superficial angiomyxoma.
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Mixoma , Neoplasias Cutâneas , Neoplasias Vulvares , Feminino , Humanos , Criança , Neoplasias Vulvares/diagnóstico , Neoplasias Vulvares/cirurgia , Neoplasias Vulvares/patologia , Vulva/cirurgia , Vulva/patologia , Mixoma/diagnóstico por imagem , Mixoma/cirurgia , Neoplasias Cutâneas/patologia , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Inactivating mutations of the protein kinase A regulatory subunit 1 alpha (PRKAR1A) gene have been reported in familial cardiac myxoma. However, the role of PRKAR1A mutation in sporadic cardiac myxoma remains unknown. METHODS: Targeted next-generation sequencing (NGS) was performed to identify mutations with the PRKAR1A gene in seven cases of sporadic cardiac myxomas. Sanger sequencing of DNA from cardiac myxoma specimens and matched peripheral blood samples was performed to verify the identified mutations. RESULTS: Targeted NGS of myxoma DNA revealed 232 single nucleotide variants in 141 genes and 38 insertion-deletion mutations in 13 genes. Six PRKAR1A mutations were identified in four of the seven cardiac myxoma cases, and thus, the PRKAR1A inactivating mutation rate was 57.2% (4/7, 95% CI=0.44-0.58, P<0.05). The PRKAR1A variants identified by Sanger sequencing analysis were consistent with those from the NGS analysis for the four myxoma specimens. All of the pathogenic PRKAR1A mutations led to premature termination of PRKAR1A, except for one synonymous mutation. Moreover, none of the nonsense and missense mutations found in the myxoma specimens were found in the matched peripheral blood samples. CONCLUSION: Pathogenic mutations of the PRKAR1A gene were identified in tumor specimens from four cases of sporadic cardiac myxoma, and the absence of these mutations in peripheral blood samples demonstrated that they were somatic mutations.
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Neoplasias Cardíacas , Mixoma , Humanos , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Mixoma/genética , Mixoma/metabolismo , Neoplasias Cardíacas/genética , Mutação , DNA , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genéticaRESUMO
BACKGROUND/AIM: 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. CASE REPORT: 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. CONCLUSION: 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.
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Complexo de Carney , Mixoma , Humanos , Feminino , Complexo de Carney/diagnóstico , Complexo de Carney/genética , Síndrome , Fatores de Transcrição , Mixoma/diagnóstico , Mixoma/genética , Mixoma/cirurgia , Mutação , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genéticaRESUMO
Background and Objectives: It is currently controversial whether subclinical hyperthyroidism is associated with PRKAR1A gene variants. We describe a man with subclinical hyperthyroidism and a PRKAR1A gene variant who was diagnosed with Carney complex (CNC), and we performed a systematic review of published studies to assess the association between PRKAR1A gene variants and the risk of subclinical hyperthyroidism. Design and Methods: The PubMed, EMBASE, OVID, Science Direct, and gray literature electronic databases were searched for articles published from January 2002 to May 2021 using predefined keywords and inclusion and exclusion criteria. Data on thyroid function from selected studies were extracted and analyzed. Results: We identified a CNC patient with a subclinical hyperthyroidism phenotype combined with multiple components and genetic sequenced data. In a subsequent systematic review, twenty selected studies (14 case studies and 6 series studies) enrolling 23 individuals were included in the final analysis. The patient's thyroid function data were qualitative in 11 cases and quantitative in 12 cases. The prevalence of subclinical hyperthyroidism in the CNC patients with a PRKAR1A gene variant, including our patient, was markedly higher than that in the normal population (12.5% vs. 2%). Conclusions: The findings of this systematic review provide helpful evidence that PRKAR1A gene variants and subclinical hyperthyroidism are related and suggest that subclinical hyperthyroidism may be a neglected phenotype of PRKAR1A gene variants and a novel component of CNC patients. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42021197655.
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Complexo de Carney , Hipertireoidismo , Complexo de Carney/genética , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Humanos , Hipertireoidismo/genética , FenótipoRESUMO
The Carney complex (CNC) is an autosomal dominant disorder characterized by endocrine and nonendocrine tumors. Loss-of-function variants of protein kinase A regulatory subunit 1 alpha (PRKAR1A) are common causes of CNC. Here, we present the case of a patient with CNC with a novel PRKAR1A missense variant. A 21-year-old woman was diagnosed with CNC secondary to acromegaly and adrenal Cushing syndrome. Genetic analysis revealed a novel missense heterozygous variant of PRKAR1A (c.176A>T). Her relatives, suspected of having CNC, also carried the same variant. RNA analysis revealed that this variant led to nonsense-mediated mRNA decay. In vitro functional analysis of the variant confirmed its role in increasing protein kinase A activity and cyclic adenosine monophosphate levels. This study broadens our understanding of the genetic spectrum of CNC. We suggest that PRKAR1A genetic testing and counseling be recommended for patients with CNC and their families.
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Complexo de Carney , Humanos , Feminino , Adulto Jovem , Adulto , Complexo de Carney/genética , Complexo de Carney/complicações , Complexo de Carney/metabolismo , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Fenótipo , MutaçãoRESUMO
Background: Mutations in PRKAR1A gene can lead to Carney complex (CNC), and most CNC patients develop cardiac and cutaneous myxomas. In particular, cardiac myxomas are a common cause of mortality in CNC patients. Cutaneous myxomas of the external ear are extremely rare, and do not have any specific clinical features Methods: In this retrospective study, we analyzed the clinical and genetic data of the proband and his family and fifty whole blood control samples selected from the molecular genetic database of our hospital. Whole exome DNA sequencing analysis was used to detect the mutation in the peripheral blood samples. Results: The results of the clinical analysis showed the presence of spotty skin pigmentation and external auditory canal myxoma in the proband as well as in his sister and mother. Whole-exome DNA sequencing showed a novel heterozygous mutation in the PRKAR1A gene i.e., c.824_825delAG (p.Gln275Leufs*2), in the proband and his sister and mother. Conclusion: In conclusion, the family members had the same autosomal dominant PRKAR1A mutation. DNA sequencing revealed a novel c.824_825delAG in exon 9 of PRKAR1A. This pathogenic mutation has not been reported previously, and may be related to the occurrence of external auditory canal myxomas and spotty pigmentation. This study broadens the genotypic spectrum of PRKAR1A mutations in CNC.
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In the heart, protein kinase A (PKA) is critical for activating calcium handling and sarcomeric proteins in response to beta-adrenergic stimulation leading to increased myocardial contractility and performance. The catalytic activity of PKA is tightly regulated by regulatory subunits that inhibit the catalytic subunit until released by cAMP binding. Phosphorylation of type II regulatory subunits promotes PKA activation; however, the role of phosphorylation in type I regulatory subunits remain uncertain. Here, we utilize human induced pluripotent stem cell cardiomyocytes (iPSC-CMs) to identify STK25 as a kinase of the type Iα regulatory subunit PRKAR1A. Phosphorylation of PRKAR1A leads to inhibition of PKA kinase activity and increased binding to the catalytic subunit in the presence of cAMP. Stk25 knockout in mice diminishes Prkar1a phosphorylation, increases Pka activity, and augments contractile response to beta-adrenergic stimulation. Together, these data support STK25 as a negative regulator of PKA signaling through phosphorylation of PRKAR1A.
Assuntos
Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico , Células-Tronco Pluripotentes Induzidas , Adrenérgicos/metabolismo , Animais , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Miócitos Cardíacos/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases , Transdução de SinaisRESUMO
Objective: This study aimed to report on 15 Japanese patients with acrodysostosis and pseudohypoparathyroidism (PHP) and analyze them using the newly proposed classification of the EuroPHP network to determine whether this classification system is suitable for Japanese patients. Design: We divided the patients into three groups based on hormone resistance, the number of fingers with short metacarpals, the existence of cone-shaped epiphyses and gene defects. Methods: We carried out clinical, radiological and genetic evaluations of two patients in group A (iPPSD5), six patients in group B (iPPDS4) and seven patients in group C (iPPSD2). Results: Group A consisted of two siblings without hormone resistance who had the most severe bone and physical developmental delays. PDE4D gene defects were detected in both cases. Group B consisted of six patients who showed hormone resistance without hypocalcemia. Short metacarpal bones with corn-shaped epiphyses were observed in all patients. In two cases, PRKAR1A gene defects were detected; however, their clinical and radiological features were not identical. The facial dysmorphism and developmental delay were less severe and PRKAR1A gene defects were detected in case B-3. Severe facial dysmorphism and deformity of metacarpal bones were observed, but no gene defect was detected in case B-1. Group C consisted of seven patients with PHP1a, four of whom had maternally inherited heterozygous inactivating mutations in one of the GNAS genes. The clinical and radiological features of the patients in group C were not identical either. Conclusions: The newly proposed classification is suitable for Japanese patients; however, heterogeneities still existed within groups B and C.
RESUMO
Carney complex is a rare, autosomal dominant disease accompanied by multiple endocrine neoplastic syndromes. Mutations in the PRKAR1A gene have recently been reported as a cause of Carney complex, but genotype-phenotype correlations vary widely. A 15-year-old Japanese man (Case 1) with short stature visited our hospital with suspected Cushing's syndrome. Biochemical investigations suggested corticotropin-independent Cushing's syndrome. Computed tomography revealed multiple bilateral adrenal tumors, and a two-staged partial adrenalectomy was performed. Pathological findings revealed primary pigmented nodular adrenocortical disease (PPNAD). The patient also exhibited distinctive spotty skin pigmentation. Based on these features, the patient was diagnosed as Carney complex. Cascade screening of family members was performed, and the mother (Case 2) and elder brother (Case 3) were diagnosed as Carney complex. Case 2 showed cardiac myxoma, acromegaly, spotty skin pigmentation, and mammary myxoid fibroadenoma. Case 3 exhibited gigantism, spotty skin pigmentation, and thyroid nodules. Target gene testing in Case 1 and 2 revealed the same novel mutation in PRKAR1A gene (c.503G>T, p.Gly168Val). This mutation was predicted as a pathogenic variant by multiple in silico analyses. Here, we present a family of Carney complex cases with a novel PRKAR1A pathogenic variant exhibiting varied clinical phenotypes within each case. In these cases, some specific phenotypes of Carney complex, such as pigmentary disorders, myxomas, and PPNAD are important as clues for diagnosis and prognostic factors. Clinicians should consider further examination in patients with Carney complex-specific phenotypes.