PRKAR1A Research Articles

8744 Genomic Variant Landscape In Aggressive & Treatment Resistant Prolactin-Secreting Tumors

Abstract Disclosure: D. Marrero-Rodríguez: None. K. Taniguchi-Ponciano: None. F. Martinez-Mendoza: None. E. Peña-Martinez: None. S. Vela-Patiño: None. S. Hinojosa-Alvarez: None. J. Hernandez-Perez: None. R. Chavez-Santoscoy: None. E. Sosa-Eroza: None. P.E. Espinosa Cardenas: None. M. Mercado: None. Pituitary tumors (PT) represent the second most frequent intracranial tumor and this neoplasm arises from adenohypophyseal cells. Prolactin-secreting tumor (PRL-tumors) are the most commonly neoplasm of the pituitary gland and arises from lactotrophs, and account for 50% of all pituitary tumors. Pituitary tumors are highly heterogeneous lesions and many of them are invasive in up to 45%, with up to 15% being clinically aggressive. Aggressive PRL-tumors are defined as invasive tumors with unusually rapid growth rate despite maximal tolerated dopamine agonist dose and requiring additional therapy and presenting multirecurrent potential. Predicting pituitary tumor behavior remains a challenge, therefore we performed whole exome sequencing to identify genomic variant landscape from aggressive and treatment-resistant prolactin-secreting pituitary tumors. Interestingly one tumor showed one hotspot mutation in splicing factor gene SF3B1 (c.C1873T:p.R625C), a second tumor showed an stop codon in SF3B1 (c.C496T:p.R166*). We then evaluated known hereditary-related pituitary tumor genes, identifying three patients with two different GNAS allelic variants the first one showed c.A3059G:p.N1020S and two tumors with c.C1307A:p.A436D variants. PRKAR1A gene did not showed any allelic variants in our cohort, while all tumors presented c.A1636G:p.T546A variant in MEN1 gene, in AIP gene allelic variant c.C682A:p.Q228K was present in all tumors. PAX6 gene is related to pituitary gland development and function, we found a deletion (c.980delA:p.K327Rfs*29) causing frameshift present in all tumors. The target coding-gene for cabergoline, first line of treatment, DRD2 di not showed any allelic variant. Also XRCC1 and ABCB1 genes, which are related to drug and therapy response showed c.A1196G:p.Q399R and c.T2887G:p.S963A allelic variants in 100% and 88% of tumors, respectively. Together this genomic landscape could represent higher risk to harbor aggressive non-responsive PRL secreting tumor. Presentation: 6/1/2024

8034 Putting the Pieces Together: Carney Complex, A Hyper-Rare Congenital Neoplastic Syndrome

Abstract Disclosure: G. Fontanazza: None. A.R. Conforti: None. K. Bird: None. M. Caplan: None. Intro: Carney complex (CNC) is an autosomal dominant disorder characterized by multisystem neoplasia that primarily affects the thyroid, pituitary, and adrenal glands. Its prevalence is not well established, as only 750 cases have been reported worldwide. This condition arises when an inactivating PRKAR1A gene mutation results in dysregulated cell proliferation and tumorigenesis. Complications include the potential for malignant transformation and systemic manifestations, necessitating comprehensive management and ongoing surveillance of disease progression. Case: The patient is a 58-year-old woman who initially presented as a teenager with complaints of hirsutism, truncal obesity, and violaceous abdominal striae. Initial workup revealed a low-dose dexamethasone suppression test that resulted in a non-suppressed cortisol levels. She also had undetectable adrenocorticotropic hormone (ACTH) levels. Imaging revealed no pituitary masses and demonstrated slight bilateral adrenal enlargement without adenomas. Despite these results, she was empirically treated for presumed pituitary-dependent Cushing's disease and received external beam radiation. Despite treatment, she continued to have episodes of hypercortisolism that were apparent clinically and biochemically. Over time, she developed a cardiac myxoma with six cerebrovascular accidents and multiple benign tumors. As an adult, she underwent extensive endocrine evaluation, which revealed urine cortisol excretion that paradoxically rose in response to dexamethasone. ACTH levels were always undetectable, even when she was significantly hypercortisolemic. Genetic testing revealed a homozygous mutation in the melanocortin-2 receptor (MC2R). Accordingly, she elected to have a bilateral adrenalectomy and was started on hydrocortisone and fludrocortisone. Discussion: The patient exhibited ACTH-independent micronodular adrenal hyperplasia and its most frequent variant, primary pigmented nodular adrenocortical disease. Bilateral pigmented nodular hyperplasia is a finding which can occur in association with CNC and cause episodic hypercortisolism. These patients have been shown to respond to dexamethasone with a paradoxical increase in glucocorticoid excretion. While management requires ongoing surveillance, this patient had not been diagnosed until later in life and did not have regular screening. When speculating on the late detection, her story reflects the parable of the blind men and the elephant: endocrinology managed Cushing's disease, cardiology managed atrial myxoma, and oncology managed osteochondromyxomas. Limited perspective with specialized management and an inability to see the whole picture led to prolonged diagnosis with unfortunate sequelae. This report encourages physicians to develop perspective awareness and to consider the entire picture when treating patients. Presentation: 6/2/2024

From cortisol-producing adrenal adenoma to atrial myxoma, through nivolumab-induced hypophysitis: a complicated case report of Carney Complex.

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. 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. 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. 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.

Identification of Key Genes and Imbalanced SNAREs Assembly in the Comorbidity of Polycystic Ovary Syndrome and Depression.

Women with polycystic ovary syndrome (PCOS) have increased odds of concurrent depression, indicating that the relationship between PCOS and depression is more likely to be comorbid. However, the underlying mechanism remains unclear. Here, we aimed to use bioinformatic analysis to screen for the genetic elements shared between PCOS and depression. Differentially expressed genes (DEGs) were screened out through GEO2R using the PCOS and depression datasets in NCBI. Protein-protein interaction (PPI) network analysis and enrichment analysis were performed to identify the potential hub genes. After verification using other PCOS and depression datasets, the associations between key gene polymorphism and comorbidity were further studied using data from the UK biobank (UKB) database. In this study, three key genes, namely, SNAP23, VTI1A, and PRKAR1A, and their related SNARE interactions in the vesicular transport pathway were identified in the comorbidity of PCOS and depression. The rs112568544 at SNAP23, rs11077579 and rs4458066 at PRKAR1A, and rs10885349 at VTI1A might be the genetic basis of this comorbidity. Our study suggests that the SNAP23, PRKAR1A, and VTI1A genes can directly or indirectly participate in the imbalanced assembly of SNAREs in the pathogenesis of the comorbidity of PCOS and depression. These findings may provide new strategies in diagnosis and therapy for this comorbidity.

The Spectrum of GH Excess in Carney Complex and Genotype-phenotype Correlations

Abstract Context Carney complex (CNC) is a familial neoplasia syndrome associated with 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 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. 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 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. Conclusion 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.

Abstract 15843: Biatrial and Recurrent Cardiac Myxoma in a Rare Case of Carney Complex

Primary cardiac tumors (CTs) are exceptionally rare, and are predominantly benign masses. Myxomas make up more than 60% of these lesions and most frequently develop in the left atrium (LA), followed by the right atrium (RA). Carney complex (CNC) is a rare, typically autosomal dominant, multiple endocrine neoplasia characterized by cutaneous findings, myxomas, endocrine and/or nonendocrine neoplasms. We report a rare case of CNC involving biatrial and recurrent myxomas. A 36-year-old female presented to Cardiology Clinic at our center for management of CNC. Three years prior, she was evaluated at a local hospital for acute stroke where TTE showed a myxoma (2 x 2 x 2.5cm) attached to the left atrial septum, prompting resection. On followup TTE 2 years later, she had a mass in the LA, prolapsing through the mitral valve into the left ventricle. She underwent resection of the myxoma (2.9 x 3.9 cm) and left atrial appendage, which was complicated by recurrent stroke. She was found to have a PRKAR1A gene mutation (c.97 deletion) suggestive of CNC and was referred to our center. At Cardiology Clinic, she denied chest pain, dyspnea, presyncope, and syncope. Her father and children did not have the gene mutation. Exam revealed lentigines on her lower lip and pigmentation of an inner canthus. She was diagnosed with primary pigmented nodular adrenal disease by Endocrinology. On TEE, she was found to have a recurrent LA mass (1 x 1 x 0.8 cm) attached to the interatrial septum, but no right-to-left atrial shunt. This prompted surgery consultation. Numerous intracardiac myxomas were removed during surgery; one in the LA attached to the septum, 3-4 smaller ones, and one 2 cm myxoma located in the RA. The interatrial septum was also resected given recurrent myxoma in this region. She underwent cryoablation to prevent recurrence and did well post-surgery. CTs, which includes primary CTs and secondary metastatic disease, are uncommon where the former has an incidence of 0.001-0.3%. We presented a case of recurrent and biatrial cardiac myxomas in the setting of CNC, which is seldomly reported in the literature. Taken together, given the rarity of primary CTs, genetic predispositions or syndromes should be considered especially in the setting of recurrence and/or multiple masses.

THU504 Is Carney Complex A Predisposing Syndrome For Breast Cancer? Prospective Study Of 50 Women

Abstract Disclosure: P. Vaduva: None. F. Violon: None. A. Jouinot: None. L. Bouys: None. S. Espiard: None. F. Bonnet-Serrano: None. N. Marie Odile: None. C. Cardot-bauters: None. G. Raverot: None. S. Hieronimus: None. H. Lefebvre: None. M.L. Nunes: None. A. Tabarin: None. L. Groussin Rouiller: None. G. Assié: None. M. Sibony: None. M. Vantyghem: None. P. Eric: None. J. Bertherat: None. Objective: Carney Complex (CNC) is a rare hereditary genetic syndrome, mostly due to inactivating pathogenic variants of the tumor suppressor gene PRKAR1A. It has a wide spectrum of manifestations with frequent pigmented skin lesions, cardiac myxomas, primary pigmented nodular adrenocortical dysplasia (PPNAD) causing Cushing syndrome, acromegaly and thyroid cancers. Breast benign tumors (fibroadenomas, ductal adenomas and myxoid lesions) have been associated with CNC, but so far, association with malignancy has not been investigated. Methods: The present study was designed to describe the characteristics of breast tumors diagnosed in CNC patients and their association with other manifestations of CNC and PRKAR1A genotype. Since breast cancer is the most frequent cancer in women and the leading cause of death from cancer worldwide, malignant breast lesions were carefully analyzed. This cohort comes from a 3 years’ follow-up multicenter French prospective study of CNC patients (Espiard, JCEM 2020). The 50 included women were investigated for CNC manifestations and particularly breast tumors, with breast imaging (echography+/-mammography), genetic and hormonal investigations, in order to characterize them and assess the frequency and average age of breast cancer. Results: Among the 38 women with breast imaging, 14 (28%) had breast tumors, half of them being bilateral. Ten women (20%) presented with benign tumors. Six women presented (12%) with breast carcinomas: five had invasive cancer under 50 years of age (10%) with one contralateral recurrence (4 ductal adenocarcinomas and one solid intracystic papillary carcinoma) and one had ductal carcinoma in situ. The occurrence of breast cancer was more frequent in the CNC women with PRKAR1A pathogenic variants than in the general population (OR=6.2[1.6-17.3]; p=0.006). The mean age at breast cancer diagnosis was 44.7 years old, 17 years younger than in the general population. Cumulative risk of breast cancer for women under 40 years of age was much higher in CNC women, compared to women worldwide (OR=592.1[79.7-3817.4]; p=9.58). Breast cancer had good prognosis factors: 5 out of 6 tumors were T1N0M0, so stage I. One woman had metastatic breast cancer, still alive after 15 years follow up. All breast cancers were negative for HER2, with 100% positivity for estrogen receptor and 50% for progesterone receptor. They all occurred in individuals with familial CNC and PRKAR1A pathogenic variants. Loss of heterozygosity at the PRKAR1A locus observed in 2 investigated breast carcinomas tumor tissue suggests that PRKAR1A bi-allelic inactivation could promote breast cancer development. Conclusions: Breast carcinoma occurs frequently and at an early age in women with CNC, suggesting that CNC predisposes to breast carcinoma. This suggests that adequate screening strategy (starting around 40 years old) and follow up should be discussed in CNC women. Presentation: Thursday, June 15, 2023

Whole genome sequencing resolves 10 years diagnostic odyssey in familiar myxoma

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.

Increased frequency of breast cancer in young Carney Complex patients suggests a role for inactivation of the tumor suppressor gene PRKAR1A

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Auricle Myxoma, Evidence from the Clinic to Cardiovascular Emergency Surgery, Triad: Cardiac, Systemic, Embolic

Cardiac tumors are infrequent, primary tumors, such as atrial myxoma, are estimated at 000017 to 0.13% of all cardiac neoplasms, postmortem records, n relation to its frequency, it is more than the other primary ones, in 67% the left atrial myxoma, 23% in the right atrium and less frequent the biaurals left. age group from 30 to 60 years, more in the female sex, in the childhood is more related to alterations in skin lentiginosis, nevi as Carney.autosomica dominant síndrome. In genetic studies, alterations in the PRKAR1A gene on chromosome 17 are found. We present the case of a patient with a request for pre-surgical evaluation, urological prolapse of the bladder, with systemic manifestations, weight loss, chronic anemic syndrome treated with vitamins and trace elements, by a private physician, without remission. It is worth mentioning that the physical and cardiovascular examination revealed semiotic onygomatic seizures of Duroziez in the mitral area, with auscultatory changes in the left lateral decubitus position, for which reason I propose the diagnosis of mitral valvular heart disease vs atrial myxoma, with 2 elements of clinical judgment of the classic triad of myxoma, in the performance of the transcutaneous echocardiogram, a cardiac mass was observed, at the level of the left atrium, spherical, of 5.5 cmt diameter, hyperechogenic. Great mobility in cycles cardiac, prolapse of the mitral valve in diastole with stenosis, the emergency consultation was made to cardiovascular surgery in a hospital of greater complexity, a procedure with complete excision of the tumor of approx 12 cmt by 5.5 cmt diameter, with satisfactory evolution of the patient

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

BackgroundCarney 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 presentationA 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.ConclusionCNC 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.

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.

Acrodysostosis and pseudohypoparathyroidism (PHP): adaptation of Japanese patients with a newly proposed classification and expanding the phenotypic spectrum of variants.

ObjectiveThis 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.DesignWe 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.MethodsWe 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).ResultsGroup 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.ConclusionsThe newly proposed classification is suitable for Japanese patients; however, heterogeneities still existed within groups B and C.

Genetic and clinical phenotypic analysis of carney complex with external auditory canal myxoma.

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.

Steroidogenic Factor-1 Lineage Origin of Skin Lesions in Carney Complex Syndrome

Carney complex is a rare familial multineoplastic syndrome predisposing to endocrine and nonendocrine tumors due to inactivating mutations of PRKAR1A, leading to perturbations of the cAMP‒protein kinase A signaling pathway. Skin lesions are the most common manifestation of Carney complex, including lentigines, blue nevi, and cutaneous myxomas in unusual locations such as oral and genital mucosa. Unlike endocrine disorders, the pathogenesis of skin lesions remains unexplained. In this study, we show that embryonic invalidation of the Prkar1a gene in steroidogenic factor-1‒expressing cells leads to the development of familial skin pigmentation alterations, reminiscent of those in patients with Carney complex. Immunohistological and molecular analyses, coupled with genetic monitoring of recombinant cell lineages in mouse skin, suggest that familial lentiginosis and myxomas occur in skin areas specifically enriched in dermal melanocytes. In lentigines- and blue nevi‒prone areas from mutant mice and patients, Prkar1a/PRKAR1A invalidation occurs in a subset of dermal fibroblasts capable of inducing, under the influence of protein kinase A signaling, the production of promelanogenic EDN3 and hepatocyte GF signals. Our model strongly suggests that the origin of the typical Carney complex cutaneous lesions is the result of noncell-autonomous promelanogenic activity of a dermal fibroblast population sharing a community of origin with steroidogenic factor-1 lineage.

Next-Generation Sequencing Reveals a New Class of Melanocytic Neoplasms With Hybrid Genomic Features of PEM Including Protein Kinase R 1 Alpha Gene Inactivation and Spitz Tumor-Defining Protein Kinase Fusions.

Pigmented epithelioid melanocytoma (PEM) is a subtype of melanocytic tumor with frequent involvement of the sentinel lymph node but rare distant metastasis. Rendering a diagnosis and prognosis based on histology can be challenging. Recent genomic studies identified 2 molecular variants of PEM. One variant is characterized by the activation of the mitogen-activated protein kinase pathway and inactivation of the PRKAR1a gene. The other is associated with genomic fusions involving the protein kinase C ( PRKC ) gene family. We investigated the molecular and clinicopathologic features of previously unreported PEM cases to improve tumor classification and report new classes of PEM. Next-generation sequencing and histomorphologic assessment was performed on 13 PEM cases. We identified 2 novel PEM classes. Three cases harbored PRKAR1a inactivation and genomic fusions ( ALK , NTRK , and MAP3K8 ). These tumors had overlapping histologic features with pigmented Spitz neoplasms. Three cases had genomic fusions involving PRKCB . These cases had overlapping features with PRKCA fusions but, in 2 cases, had a notable spindle cell component. The overall sample size and amount of clinical follow-up is limited, leaving some uncertainty regarding the expected clinical course of these novel cases. PRKAR1a-inactivated/Spitz fusion-associated PEMs and PRKCB fusion-associated PEMs represent 2 new molecular classes of PEM.

Abstract #1162392: Family Ties: Management of Carney Complex Across the Lifespan

Carney Complex is a multiple endocrine neoplasia syndrome caused by a mutation in PRKAR1A gene. Tumor sites include skin (lentigines, blue nevus, cutaneous myxomas, palpebral lentigines), pituitary (somatotroph hyperplasia/adenomas), adrenal (primary pigmented nodular adrenal hyperplasia (PPNAD)), cardiac (myxomas), and testes (large cell calcifying sertoli cell tumor).We will present a family with a variety of distinct conditions related to Carney Complex, who were effectively treated to prevent secondary endocrine complications.

A CASE OF VUVLVAR ANGIOMYXOMA : REPORT AND LITERATUREREVIEW

Superficialangiomyxoma (SMA) is a rare benign skin tumorwith a peak incidence in middle age . The diseaseiscaused by mutations in the PRKAR1A gene. Which, codes for the type of I alpha regulatorysubunit of the enzyme protein kinase A. We report a rare case of vulvarangiomyxomain 19-year-old patient beneficied of large exicion of mass in the leftlabia majora. the diagnostic of SMA retained, afterhistologicalstudy of surgicalspecimen , The evolution has been good withoutrecurrence.

Cardiac myxomas: A narrative review

Cardiac myxomas are common primary neoplasms of the heart. They are biologically benign but “functionally malignant” because of the potential for embolization. They arise most commonly from the left atrium, but no chambers of the heart are immune. They may be sporadic in the majority but also familial as a part of the Carney complex. Two morphological forms exist: polypoid and papillary. Polypoid myxomas often present with obstructive features, while the papillary forms are more prone to embolization. Histogenesis is still controversial; the current view centres around origin from the primitive pluripotent mesenchymal cells. They may be of giant proportion, be calcified or get infected. Clinical presentation typically involves the triad of intracardiac obstruction, embolic events and constitutional symptoms. Precordial examination findings may simulate those of mitral or tricuspid stenosis. The presence of tumour plop and change of the physical findings with changing position may help differentiation between the two. Echocardiography is the investigation of choice. Echogenic polypoid or papillary mobile mass within the atrial cavity remaining attached to the interatrial septum through a stalk are the tell-tale echocardiographic features. Cardiac magnetic resonance and computed tomographic scanning may have incremental diagnostic value. Histopathological examination reveals abundant loose myxoid stroma with scattered round, polygonal or stellate cells with dense irregular nuclei. Genetic testing may detect mutations in the PRKAR1A gene in the familial form of cardiac myxoma, i.e. the Carney complex. Surgical excision is the mainstay of treatment with low operative mortality, excellent postoperative survival and low recurrence rate. The current trend favours minimal-access surgery with or without robotic assistance. Physicians should have appropriate preparedness to make a timely diagnosis and enthusiastic treatment to avoid potentially fatal complications.

In vivo genome-editing screen identifies tumor suppressor genes that cooperate with Trp53 loss during mammary tumorigenesis.

Breast cancer is a heterogeneous disease that comprises multiple histological and molecular subtypes. To gain insight into mutations that drive breast tumorigenesis, we describe a pipeline for the identification and validation of tumor suppressor genes. Based on an in vivo genome‐wide CRISPR/Cas9 screen in Trp53+/– heterozygous mice, we identified tumor suppressor genes that included the scaffold protein Axin1, the protein kinase A regulatory subunit gene Prkar1a, as well as the proof‐of‐concept genes Pten, Nf1, and Trp53 itself. Ex vivo editing of primary mammary epithelial organoids was performed to further interrogate the roles of Axin1 and Prkar1a. Increased proliferation and profound changes in mammary organoid morphology were observed for Axin1/Trp53 and Prkar1a/Trp53 double mutants compared to Pten/Trp53 double mutants. Furthermore, direct in vivo genome editing via intraductal injection of lentiviruses engineered to express dual short‐guide RNAs revealed that mutagenesis of Trp53 and either Prkar1a, Axin1, or Pten markedly accelerated tumor development compared to Trp53‐only mutants. This proof‐of‐principle study highlights the application of in vivo CRISPR/Cas9 editing for uncovering cooperativity between defects in tumor suppressor genes that elicit mammary tumorigenesis.