Familial bilateral macronodular adrenal hyperplasia due to a novel ARMC 5 germline mutation: Clinical status and possible association with other neoplasms.

INTRODUCTION/OBJECTIVES: Mutations in the ARMC5 (armadillo repeat containing 5, OMIM 615549) gene, a putative tumor suppressor gene, have recently been identified as a common cause of sporadic and familial bilateral macronodular adrenal hyperplasia (BMAH). Familial BMAH is thought to be caused by two mutations, one germline and the other somatic, as suggested by the 2-hit theory. The objective is to describe a new mutation and develop its clinical characteristics and implications. METHODS, RESULTS AND CONCLUSIONS: We present an affected family with 11 members carrying a novel mutation of the ARMC5 gene (NM_001288767.1): c.2162T>C p. (Leu721Pro). Two of the carriers developed clinical Cushing's syndrome (CS), two mild autonomous cortisol secretion (MACS) and one presented with autonomous cortisol secretion (ACS). Four patients developed other tumors, three of whom died from this cause. It is not known whether these tumors could be related to the described mutation.

Adipose tissue in cortisol excess: What Cushing's syndrome can teach us?

Endogenous Cushing's syndrome (CS) is a rare condition due to prolonged exposure to elevated circulating cortisol levels that features its typical phenotype characterised by moon face, proximal myopathy, easy bruising, hirsutism in females and a centripetal distribution of body fat. Given the direct and indirect effects of hypercortisolism, CS is a severe disease burdened by increased cardio-metabolic morbidity and mortality in which visceral adiposity plays a leading role. Although not commonly found in clinical setting, endogenous CS is definitely underestimated leading to delayed diagnosis with consequent increased rate of complications and reduced likelihood of their reversal after disease control. Most of all, CS is a unique model for systemic impairment induced by exogenous glucocorticoid therapy that is commonly prescribed for a number of chronic conditions in a relevant proportion of the worldwide population. In this review we aim to summarise on one side, the mechanisms behind visceral adiposity and lipid metabolism impairment in CS during active disease and after remission and on the other explore the potential role of cortisol in promoting adipose tissue accumulation.

Discovery of a Cushing's syndrome protein kinase A mutant that biases signaling through type I AKAPs.

Adrenal Cushing's syndrome is a disease of cortisol hypersecretion often caused by mutations in protein kinase A catalytic subunit (PKAc). Using a personalized medicine screening platform, we discovered a Cushing's driver mutation, PKAc-W196G, in ~20% of patient samples analyzed. Proximity proteomics and photokinetic imaging reveal that PKAcW196G is unexpectedly distinct from other described Cushing's variants, exhibiting retained association with type I regulatory subunits (RI) and their corresponding A kinase anchoring proteins (AKAPs). Molecular dynamics simulations predict that substitution of tryptophan-196 with glycine creates a 653-cubic angstrom cleft between the catalytic core of PKAcW196G and type II regulatory subunits (RII), but only a 395-cubic angstrom cleft with RI. Endocrine measurements show that overexpression of RIα or redistribution of PKAcW196G via AKAP recruitment counteracts stress hormone overproduction. We conclude that a W196G mutation in the kinase catalytic core skews R subunit selectivity and biases AKAP association to drive Cushing's syndrome.

Hypercortisolaemia without clinical stigmata of Cushing syndrome.

A man in his 20s was referred by his general practitioner because of the finding of adrenocorticotropic hormone (ACTH)-dependent hypercortisolaemia, discovered as part of investigation of fatigue and alopecia. The man had no other clinical findings suggestive of Cushing syndrome. Further investigation revealed intact diurnal rhythm in cortisol production, normal bone density and excluded assay interference. Further investigation revealed the man's sibling had been labelled as having Cushing syndrome because of similar biochemical abnormalities. A diagnosis of familial primary generalised glucocorticoid resistance syndrome was made. Testing for mutations in the NR3C1 gene is awaited.

Genetically predicted plasma cortisol and common chronic diseases: A Mendelian randomization study.

OBJECTIVE: Cushing's syndrome is characterized by hypercortisolaemia and is frequently accompanied by comorbidities such as type 2 diabetes, hypertension, osteoporosis, depression and schizophrenia. It is unclear whether moderate but lifelong hypercortisolaemia is causally associated with these diseases in the general population. We aimed to address this research gap using a Mendelian randomization approach. METHODS: We used three cortisol-associated genetic variants in the SERPINA6/SERPINA1 region as genetic instruments in a two-sample, inverse-variance-weighted Mendelian randomization analysis. We obtained summary-level statistics for cortisol and disease outcomes from publicly available genetic consortia, and meta-analysed them as appropriate. We conducted a multivariable Mendelian randomization analysis to assess potential mediating effects. RESULTS: A 1 standard deviation higher genetically predicted plasma cortisol was associated with greater odds of hypertension (odds ratio: 1.12; 95% confidence interval [CI]: 1.05-1.18) as well as higher systolic blood pressure (mean difference [MD]: 0.03 SD change; 95% CI: 0.01-0.05) and diastolic blood pressure (MD: 0.03 SD change; 95% CI: 0.01-0.04). There was no evidence of association with type 2 diabetes, osteoporosis, depression and schizophrenia. The association with hypertension was attenuated upon adjustment for waist circumference, suggesting potential mediation through central obesity. CONCLUSION: There is strong evidence for a causal association between plasma cortisol and greater risk for hypertension, potentially mediated by obesity.

Circulating myomiRNAs as biomarkers in patients with Cushing's syndrome.

PURPOSE: Impairment of skeletal muscle mass and strength affects 40-70% of patients with active Cushing's syndrome (CS). Glucocorticoid excess sustains muscle atrophy and weakness, while muscle-specific microRNAs (myomiRs) level changes were associated with muscle organization and function perturbation. The aim of the current study is to explore changes in circulating myomiRs in CS patients compared to healthy controls and their involvement in IGFI/PI3K/Akt/mTOR pathway regulation in skeletal muscle. METHODS: C2C12, mouse myocytes, were exposed to hydrocortisone (HC), and atrophy-related gene expression was investigated by RT-qPCR, WB and IF to assess HC-mediated atrophic signalling. miRNAs were evaluated in HC-treated C2C12 by PCR Arrays. MyomiRs significantly overexpressed in C2C12 were investigated in 37 CS patients and 24 healthy controls serum by RT-qPCR. The anti-anabolic role of circulating miRNAs significantly upregulated in CS patients was explored in C2C12 by investigating the IGFI/PI3K/Akt/mTOR pathway regulation. RESULTS: HC induced higher expression of atrophy-related genes, miR-133a-3p, miR-122-5p and miR-200b-3p in C2C12 compared to untreated cells. Conversely, the anabolic IGFI/PI3K/Akt/mTOR signalling was reduced and this effect was mediated by miR-133a-3p. In CS patients miR-133a-3p and miR-200b-3p revealed higher circulating levels (p < 0.0001, respectively) compared to controls. ROC curves for miR-133a-3p (AUC 0.823, p < 0.0001) and miR-200b-3p (AUC 0.850, p < 0.0001) demonstrated that both myomiRs represent potential biomarkers to discriminate between CS and healthy subjects. Pearson's correlation analysis revealed that circulating levels of miR-133a-3p are directly correlated with 24 h urinary-free cortisol level (r = 0.468, p = 0.004) in CS patients. CONCLUSIONS: HC induces atrophic signals by miR-133a-3p overexpression in mouse myocytes and humans. Circulating miR-133a-3p is promising biomarkers of hypercortisolism.

Cardiovascular risk assessments in patients with cortisol-producing adenoma: impact of clinical features and genetic characteristics.

The causes of adrenal Cushing's syndrome (CS) encompass a wide spectrum of adrenal cortisol proliferations that exhibit clinical and molecular heterogeneity. The aims of our study were to investigate whether clinical and molecular heterogeneity influences endothelial function and metabolic abnormalities in patients with cortisol-producing adenoma (CPA). We retrospectively enrolled 25 patients with CPA and 45 patients with essential hypertension (EH). All CPAs were studied by direct sequencing of PRKACA. Flow-mediated vasodilation (FMD), an index of vascular endothelial function, was significantly lower in CS and subclinical CS (SCS) groups than in the EH group. FMD impairment did not differ significantly between CS and SCS groups. No differences in FMD were seen between PRKACA mutant and wild-type groups. FMD correlated negatively with hemoglobin A1c (HbA1c) in both PRKACA mutant and wild-type groups, as well as in CS and SCS groups. After adrenalectomy, systolic blood pressure (SBP) and HbA1c decreased significantly from baseline in the CS group, and SBP and low-density lipoprotein cholesterol (LDL-C) decreased significantly from baseline in the SCS group. While SBP and LDL-C decreased significantly from baseline in patients with wild-type PRKACA, only HbA1c decreased from baseline in patients harboring PRKACA mutations. Our data showed that patients with CPA have impaired endothelial function compared with EH patients and suggest the need for strict monitoring of atherosclerosis, even in patients with SCS or without PRKACA mutation.

PPARG dysregulation as a potential molecular target in adrenal Cushing's syndrome.

Background: We performed a transcriptomic analysis of adrenal signaling pathways in various forms of endogenous Cushing's syndrome (CS) to define areas of dysregulated and druggable targets. Methodology: Next-generation sequencing was performed on adrenal samples of patients with primary bilateral macronodular adrenal hyperplasia (PBMAH, n=10) and control adrenal samples (n=8). The validation groups included cortisol-producing adenoma (CPA, n=9) and samples from patients undergoing bilateral adrenalectomy for Cushing's disease (BADX-CD, n=8). In vivo findings were further characterized using three adrenocortical cell-lines (NCI-H295R, CU-ACC2, MUC1). Results: Pathway mapping based on significant expression patterns identified PPARG (peroxisome proliferator-activated receptor gamma) pathway as the top hit. Quantitative PCR (QPCR) confirmed that PPARG (l2fc<-1.5) and related genes - FABP4 (l2fc<-5.5), PLIN1 (l2fc<-4.1) and ADIPOQ (l2fc<-3.3) - were significantly downregulated (p<0.005) in PBMAH. Significant downregulation of PPARG was also found in BADX-CD (l2fc<-1.9, p<0.0001) and CPA (l2fc<-1.4, p<0.0001). In vitro studies demonstrated that the PPARG activator rosiglitazone resulted in decreased cell viability in MUC1 and NCI-H295R (p<0.0001). There was also a significant reduction in the production of aldosterone, cortisol, and cortisone in NCI-H295R and in Dihydrotestosterone (DHT) in MUC1 (p<0.05), respectively. Outcome: This therapeutic effect was independent of the actions of ACTH, postulating a promising application of PPARG activation in endogenous hypercortisolism.

Germline PRKACA amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS). Pediatric patients with PPNAD typically have unusual skin lesions and slow growth with unknown causes. We present a case of a female Chinese patient with PPNAD caused by the germline PRKACA gene copy number gain of chromosome 19. The patient initially presented with kidney stones, short stature, and obesity. After further testing, it was discovered that the patient had diabetes, mild hypertension, low bone mass, a low ACTH level, and hypercortisolemia, and neither the low-dose or high-dose dexamethasone suppression test was able to inhibit hematuric cortisol, which paradoxically increased. PPNAD was pathologically diagnosed after unilateral adrenalectomy. Chromosome microarrays and whole exon sequencing analyses of the peripheral blood, as well as testing of sectioned adrenal tissue, showed a rise in the copy number of the duplication-containing PRKACA gene on chromosome 19p13.13p13.12, a de novo but not heritable gene defect that causes disease. The clinical signs and symptoms supported the diagnosis of Carney complex (CNC). One significant mechanism of CNC pathogenesis may be the rise in germline PRKACA copy number of chromosome 19. When assessing PPNAD patients for CNC, the possibility of PRKACA gene amplification should be considered. The effect of PRKACA gene amplification on the clinical manifestations of CNC needs to be confirmed by more cases.

[Macronodular adrenal hyperplasia causing Cushing's syndrome due to ARMC5 gene mutation.] / Cushing-szindrómát okozó macronodularis mellékvese-hyperplasia ARMC5-génmutáció következtében.

Our 69-year-old female patient was investigated for a 20 kg weight gain over 2 years. The patient's medical history included hypertension, hyperuricemia, bilateral cataract surgery and musculosceletal complaints. Diabetes mellitus was not found. Physical examination revealed abdominal obesity, proximal myopathy and atrophic, vulnerable skin. The "overnight", low-dose and long, low-dose dexamethasone suppression tests indicated autonomous cortisol overproduction (plasma cortisol level: 172.6 and 153.2 nmol/L, cut-off: 50 nmol/L). The suppressed ACTH (<1.11 pmol/L, normal value: 1.12-10.75 pmol/L) suggested ACTH-independent hypercortisolism. Abdominal CT described macronodular enlargement of both adrenals. The size of the largest nodule was 23 × 20 mm in the right, and 24 × 30 mm on the left side (with -33 ± 37 HU density values on native scans). The 131I-cholesterol adrenal scintigraphy and SPECT/CT showed almost equally intensive radiopharmacon uptake on both sides. Based on the clinical results, bilateral macronodular adrenal hyperplasia associated with ACTH-independent hypercortisolism was diagnosed. Genomic DNA was obtained from the peripheral blood leukocytes. Targeted sequencing of 25 genes potentially involved in adrenal tumorigenesis revealed a new disease-causing armadillo repeat-containing 5 (ARMC5) gene mutation (c.1724del28 bp, g.31,476,067-31,476,094). Because of the autosomal dominant inheritance of this genetic alteration, the patient's two children underwent genetic screening for the ARMC5 mutation. The same mutation was found in the younger child of our patient. To the best of our knowledge, this is the first published Hungarian case of ARMC5 mutation with bilateral macronodular adrenal hyperplasia and ACTH-independent Cushing's syndrome. The genetic alteration is present in two generations of the family of the index patient. Orv Hetil. 2023; 164(32): 1271-1277.

Unique Gene Expression Signature in Periadrenal Adipose Tissue Identifies a High Blood Pressure Group in Patients With Cushing Syndrome.

BACKGROUND: Cushing syndrome (CS) is a rare disease caused by excess cortisol levels with high cardiovascular morbidity and mortality. Hypertension in CS promotes hypercortisolism-associated cardiovascular events. Adipose tissue is a highly plastic tissue with most cell types strongly affected by the excess cortisol exposure. We hypothesized that the molecular and cellular changes of periadrenal adipose tissue in response to cortisol excess impact systemic blood pressure levels in patients with CS. METHODS: We investigated gene expression signatures in periadrenal adipose tissue from patients with adrenal CS collected during adrenal surgery. RESULTS: During active CS we observed a downregulation of gene programs associated with inflammation in periadrenal adipose tissue. In addition, we observed a clustering of the patients based on tissue gene expression profiles into 2 groups that differed in blood pressure levels (CS low blood pressure and CS high blood pressure). The 2 clusters showed significant differences in gene expression pattens of the renin-angiotensin-aldosterone-system. Renin was the strongest regulated gene compared with control patients and its expression correlated with increased blood pressure observed in our patients with CS. In the CS high blood pressure group, systemic renin plasma levels were suppressed indicative of an abnormal blood pressure associated with periadrenal adipose tissue renin-angiotensin-aldosterone-system activation. CONCLUSIONS: Here, we show for the first time a relevant association of the local renin-angiotensin-aldosterone-system and systemic blood pressure levels in patients with CS. Patients from the CS high blood pressure group still had increased blood pressure levels after 6 months in remission, highlighting the importance of local tissue effects on long-term systemic effects observed in CS.

Renal neuroendocrine tumors: clinical and molecular pathology with an emphasis on frequent association with ectopic Cushing syndrome.

Renal neuroendocrine tumors (RenNETs) are rare malignancies with largely unknown biology, hormone expression, and genetic abnormalities. This study aims to improve our understanding of the RenNETs with emphasis of functional, hormonal, and genetic features. Surgically resected RenNETs (N = 13) were retrieved, and immunohistochemistry and next-generation sequencing (NGS) were performed in all cases. In addition, all published RenNETs were systematically reviewed. Our cohort (4 men and 9 women, mean age 42, mean tumor size 7.6 cm) included 2 patients with Cushing syndrome (CS). WHO grade (23% G1, 54% G2, and 23% G3) and tumor progression did not correlate. CS-associated RenNETs (CS-RenNETs) showed a solid and eosinophilic histology and stained for ACTH, while the remaining non-functioning tumors had a trabecular pattern and expressed variably hormones somatostatin (91%), pancreatic polypeptide (63%), glucagon (54%), and serotonin (18%). The transcription factors ISL1 and SATB2 were expressed in all non-functioning, but not in CS-RenNETs. NGS revealed no pathogenic alterations or gene fusions. In the literature review (N = 194), 15 (8%) of the patients had hormonal syndromes, in which CS being the most frequent (7/15). Large tumor size and presence of metastasis were associated with shorter patients' survival (p < 0.01). RenNETs present as large tumors with metastases. CS-RenNETs differ through ACTH production and solid-eosinophilic histology from the non-functioning trabecular RenNETs that produce pancreas-related hormones and express ISL1 and SATB2. MEN1 or DAXX/ARTX abnormalities and fusion genes are not detected in RenNETs, indicating a distinct yet unknown molecular pathogenesis.

ARMC5-negative primary bilateral macronodular adrenal hyperplasia.

A woman in her 60s with chronic fatigue, depressed mood and proximal muscle weakness was referred to our endocrinology department. Physical examination revealed facial plethora, atrophic skin and ankle oedema. Adjuvant blood and urine analyses indicated endogenous ACTH-independent Cushing syndrome. Abdominal imaging showed bilateral macronodular adrenals, measuring 58.9 × 29.7 mm on the right and 55.6 × 42.6 mm on the left. Primary bilateral macronodular adrenal hyperplasia was confirmed by pathology after bilateral adrenalectomy. Gradual mental and physical recovery was observed in the months following surgery. Genetic sequencing failed to reveal mutations in the ARMC5 gene.Cushing syndrome is a rare entity that should be suspected when typical clinical signs, including skin atrophy with ecchymosis, muscle weakness or coloured stretch marks, are present. Primary bilateral macronodular adrenal hyperplasia is an uncommon cause of endogenous Cushing syndrome. It is a benign condition characterised by adrenal macronodules exceeding 1 cm and hypercorticism.

Classification of Cushing's syndrome PKAc mutants based upon their ability to bind PKI.

Cushing's syndrome is an endocrine disorder caused by excess production of the stress hormone cortisol. Precision medicine strategies have identified single allele mutations within the PRKACA gene that drive adrenal Cushing's syndrome. These mutations promote perturbations in the catalytic core of protein kinase A (PKAc) that impair autoinhibition by regulatory subunits and compartmentalization via recruitment into AKAP signaling islands. PKAcL205R is found in ∼45% of patients, whereas PKAcE31V, PKAcW196R, and L198insW and C199insV insertion mutants are less prevalent. Mass spectrometry, cellular, and biochemical data indicate that Cushing's PKAc variants fall into two categories: those that interact with the heat-stable protein kinase inhibitor PKI, and those that do not. In vitro activity measurements show that wild-type PKAc and W196R activities are strongly inhibited by PKI (IC50 < 1 nM). In contrast, PKAcL205R activity is not blocked by the inhibitor. Immunofluorescent analyses show that the PKI-binding variants wild-type PKAc, E31V, and W196R are excluded from the nucleus and protected against proteolytic processing. Thermal stability measurements reveal that upon co-incubation with PKI and metal-bound nucleotide, the W196R variant tolerates melting temperatures 10°C higher than PKAcL205. Structural modeling maps PKI-interfering mutations to a ∼20 Šdiameter area at the active site of the catalytic domain that interfaces with the pseudosubstrate of PKI. Thus, Cushing's kinases are individually controlled, compartmentalized, and processed through their differential association with PKI.

Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) patient with ARMC5 mutations.

BACKGROUND: Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a highly heterogeneous disease with divergent manifestations ranging from asymptomatic subclinical Cushing syndrome (CS) to overt Cushing syndrome with severe complications. ARMC5 mutations occur in 20 to 55% PBMAH patients usually with more severe phenotypes. Different ARMC5 mutations might be associated with diverse phenotypes of PBMAH. CASE PRESENTATION: A 39-year-old man was admitted to our hospital with progressive weight gain and severe hypertension. He presented typical CS and its classical metabolic and bone complications like hypertension and osteoporosis. The laboratory results showed high levels of cortisol and low levels of ACTH. Low- and high-dosed dexamethasone suppression tests were negative. Contrast-enhanced computed tomography (CT) revealed multiple bilateral irregular macronodular adrenal masses. Adrenal venous sampling (AVS) confirmed that the right adrenal gland with larger nodules secreted more hormone that the left side did. Right adrenalectomy and subsequent contralateral subtotal resection were conducted. His blood pressure and CS symptoms as well as comorbidities including backache and muscle weakness improved. Whole exome sequencing identified one ARMC5 germline mutation (c.1855C > T, p. R619*), five ARMC5 somatic mutations (four novel mutations) in his right and left adrenal nodules. CONCLUSIONS: This PBMAH patient was identified with one ARMC5 germline mutation and five different somatic ARMC5 mutations (four novel mutations) in the different nodules of the bilateral adrenal masses. AVS combined with CT imagine could be helpful to determine the dominant side for adrenalectomy. Genetic testing is important for the diagnosis and management of the patient with PBMAH.

Genetic Testing for Adrenal Tumors-What the Contemporary Surgeon Should Know.

Surgical diseases of the adrenal gland include pheochromocytoma/paraganglioma, primary hyperaldosteronism, Cushing syndrome, and adrenocortical carcinoma. These conditions may be associated with familial syndromes, and genetic testing is available and recommended in most. For adrenal surgeons to be familiar with these syndromes and know when to consider referral for genetic counseling and genetic testing is important. Identification of patients with familial syndromes allows for the detection and screening of associated syndromic neoplasms, guides surgical planning and operative approach, influences recurrence and malignancy risk assessment, aids in the development of a postoperative surveillance plan, and determines the need for screening family members.

Extensive expertise in endocrinology: glucose-dependent insulinotropic peptide-dependent Cushing's syndrome.

Thirty years ago, we identified that cortisol secretion in some patients with unilateral adenoma or primary bilateral macronodular adrenal hyperplasia (PBMAH) was stimulated by food intake; this was secondary to the abnormal adrenocortical responsiveness to physiological post-prandial increase in glucose-dependent insulinotropic peptide (GIP). This resulted from the ectopic expression of non-mutated GIP receptor in the pathological adrenal tissues of those patients. Although ectopic GIP receptor (GIPR) was confirmed in a relatively limited number of cases to date, its elucidation leads to the identification of a wide diversity of aberrant G-protein-coupled receptors regulating steroidogenesis and cell proliferation in a high proportion of patients with PBMAH or cortisol-secreting adenomas. In addition, ectopic GIPR was identified in other endocrine tumors including somatotroph pituitary tumors with paradoxical growth hormone response to oral glucose, medullary thyroid carcinomas, and other neuroendocrine tumors. The first molecular pathogenic mechanism responsible for ectopic GIPR expression was elucidated in unilateral GIP-dependent adenomas in which somatic duplication and rearrangements in chromosome region 19q13.32 containing the GIPR locus lead to increased expression of GIPR which was enhanced by the activity of a glucocorticoid response element. Recently, germline lysine demythylase 1A (KDMIA) mutations combined with somatic chromosome 1p deletions were found to be specifically responsible for ectopic GIPR in sporadic or familial GIP-dependent PBMAH and can be associated with adrenal myelolipoma, monoclonal gammopathy of unknown significance (MGUS), or multiple myeloma. Screening for ectopic GIPR should be conducted in all patients with PBMAH; genetic studies to identify KDM1A mutations should be offered to such patients in order to detect affected members and provide early detection of PBMAH and other potential associated neoplasias. The elucidation of GIP-dependent Cushing's syndrome (CS) illustrates that careful bedside phenotyping of rare conditions can lead to identification of genetically determined diseases requiring personalized approaches to investigation and therapy.

New pathogenic variants in ARMC5 gene in a series of Italian patients affected by primary bilateral macronodular adrenocortical hyperplasia (PBMAH).

BACKGROUND: To perform genetic screening for ARMC5 gene germline pathogenic variants in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH). SUBJECTS AND METHODS: In a group of 10 PBMAH patients, we performed complete sequencing of the coding region of the ARMC5 gene and MLPA analysis for large deletion detection. In subjects with the ARMC5 variant, we searched ARMC5 gene somatic variants on tumor samples. RESULTS: Among 10 PBMAH patients, we identified four ARMC5 germline variants (40%). One variant, c:174dupC p.Glu59Argfs*44, was already known; one variant p.Gly323Asp, was already reported and classified as likely disease-causing VUS (class 3-4); two variants p.Leu596Arg and p.Arg811Pro, were never reported before. For p.Gly323Asp and p.Arg811Pro, we identified second deleterious variants at the somatic level, enforcing the possible pathogenic effect of germline variants. CONCLUSIONS: Our results underscore the importance of performing genetic testing also in sporadic PBMAH patients and broaden the spectrum of molecular variants involved in PBMAH syndrome.

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.

A 14-Year-Old Saudi Boy with Gynecomastia, Cushing Syndrome, Large-Cell Calcifying Sertoli Cell Tumor of the Testis, and Carney Complex.

BACKGROUND Carney complex (CNC) is a rare multiple neoplasia syndrome with autosomal dominant inheritance. CNC is frequently misdiagnosed owing to its diverse clinical characteristics. We reported the case of a 14-year-old Saudi boy with a history of gynecomastia, Cushing syndrome, large-cell calcifying Sertoli cell tumor of the testis, and CNC. CASE REPORT The patient was referred to the pediatric endocrine clinic for evaluation of bilateral slow progressing gynecomastia for 1-year duration. His clinical examination revealed lentigenes, bilateral diffuse breast enlargement (consistent with Tanner stage III), and asymmetrical testicular enlargement, more on the left side. Other systemic examinations were unremarkable. The initial blood workup showed elevated estradiol level with unsuppressed cortisol after an overnight 1-mg dexamethasone suppression test. Breast ultrasound (US) confirmed true gynecomastia. Testicular US revealed microcalcification and the testicular biopsy confirmed diagnoses of large-cell calcifying Sertoli cell tumor (LCCSCT). A 2-step dexamethasone suppression test showed a paradoxical rise in serum and urine cortisol levels, which are characteristic for PPNAD. LCCSCT and PPNAD are 2 major criteria fulfilling a diagnosis of CNC. The gene test showed heterozygous mutation in the PRKAR1A gene, which is diagnostic for CNC. The patient underwent bilateral mastoplasty and was planned for radical left orchiectomy. CONCLUSIONS Gynecomastia and LCCSCT can be presenting features of CNC, which mandates careful, thorough clinical examination and tailored investigation to reach a diagnosis.