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Context: Data on germline genetics of pituitary adenomas (PAs) using whole-exome sequencing (WES) are limited. Objective: This study investigated the germline genetic variants in patients with PAs using WES. Methods: We studied 134 consecutive functioning (80.6%) and nonfunctioning (19.4%) PAs in 61 female (45.5%) and 73 male patients (54.5%). Their median age was 34 years (range, 11-85 years) and 31 patients had microadenomas (23.0%) and 103 macroadenomas (77%). None of these patients had family history of PA or a known PA-associated syndrome. Peripheral blood DNA was isolated and whole-exome sequenced. We used American College of Medical Genetics and Genomics (ACMG) criteria and a number of in silico analysis tools to characterize genetic variant pathogenicity levels and focused on previously reported PA-associated genes. Results: We identified 35 variants of unknown significance (VUS) in 17 PA-associated genes occurring in 40 patients (29.8%). Although designated VUS by the strict ACGM criteria, they are predicted to be pathogenic by in silico analyses and their extremely low frequencies in 1000 genome, gnomAD, and the Saudi Genome Project databases. Further analysis of these variants by the Alpha Missense analysis tool yielded 8 likely pathogenic variants in 9 patients in the following genes: AIP:c.767C>T (p.S256F), CDH23:c.906G>C (p.E302D), CDH23:c.1096G>A (p.A366T), DICER1:c.620C>T (p.A207V), MLH1:c.955G>A (p.E319K), MSH2:c.148G>A (p.A50T), SDHA:c.869T>C (p.L290P) and USP48 (2 patients): c.2233G>A (p.V745M). Conclusion: This study suggests that about 6.7% of patients with apparently sporadic PAs carry likely pathogenic variants in PA-associated genes. These findings need further studies to confirm them.

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Background: Fibromyalgia is a chronic condition that is characterized by widespread musculoskeletal pain and tenderness of soft tissue. The prevalence of FM in Saudi Arabia is not known. The diagnosis of FM is mainly clinical. The knowledge about fibromyalgia is poor, even among healthcare providers. Aim: To assess the knowledge and prevalence of fibromyalgia among medical students and physicians in the Riyadh region. Materials and Methods: A cross-sectional study was conducted at all medical colleges in Riyadh and Riyadh hospitals. The study was conducted on both medical students and physicians using a questionnaire. The SPSS program was used to analyze the data. Results: A total of 556 participants were involved; 56.5% heard about fibromyalgia, and only 5.6% attended Continuing Medical Education (CME) activity. There were 31.5% had high knowledge, whereas 68.5% had low knowledge. The level of knowledge was associated with the year (P = 0.002), specialty (P = 0.013), hearing about fibromyalgia (P = 0.0001), attending lectures (P = 0.009), and being aware of diagnostic criteria (P = 0.0001). Conclusion: The prevalence of FM was high, and there was poor knowledge among medical students and physicians regarding fibromyalgia.

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Background Gastroesophageal reflux disease (GERD) is a chronic disease mainly characterized by heartburn and acid regurgitation. To our knowledge, there have been a limited number of studies in Saudi Arabia looking at the knowledge level among the general population regarding this disease and its associated factors. Therefore, this study aims to identify the knowledge level of the disease and its associated factors, assess the prevalence of GERD among the Riyadh general population, and assess the need for educational programs for GERD. Methodology A cross-sectional study was conducted among the general public in Riyadh, Saudi Arabia. The degree of GERD knowledge was assessed by translating and editing Jorgen Urnes' 24-item questionnaire into Arabic. In addition, six questions related to the symptoms and complications of GERD were added. Convenience sampling was done by using a Google form to distribute the questionnaire. The questionnaire assesses GERD knowledge by asking about the signs, symptoms, risk factors, predisposing factors, and management of GERD. Statistical analysis was performed using R v. 3.6.3 (https://cran.r-project.org/bin/windows/base/old/3.6.3/). Counts and percentages were used to summarize the distribution of categorical variables. Results The questionnaire was completed by 664 respondents (48.2% males and 51.8% females). The average age of the included respondents was 34.1 ± 12.8 years and Saudis represented 97% of the included respondents. The majority of the respondents had heard of GERD (83%). The average number of correct answers was 12.7 ± 6.1. In total, 40 respondents did not answer any questions correctly. Approximately one-third of respondents answered >50% of the questions correctly (n = 250, 37.6%). Approximately half of the respondents identified all risk factors for GERD. Other common risk factors identified included caffeine (23.6%), fast food (26.8%), and smoking (17.6%). Slightly more than a quarter of the respondents reported being diagnosed with GERD (28.8%). Knowledge was significantly higher among respondents who had received a diagnosis of GERD. A statistically significant positive association was observed between age and knowledge (r = 0.19, p < 0.001). Conclusion The study shows a relatively good knowledge level compared to previously reported figures in Saudi Arabia and worldwide. Educational programs for GERD should be increased in Saudi Arabia and more health conferences and teaching school students of the disease should be highlighted to increase the general knowledge of this disease in the Kingdom of Saudi Arabia (KSA).

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Pituitary carcinoma is a rare disease, defined by the presence of cerebrospinal or distant metastasis of a pituitary neuroendocrine tumor (PitNET). To review our institutional experience of pituitary carcinoma, we searched the database of the UHN Endocrine Oncology Site group and the University Health Network pathology laboratory information system from 2001 to 2016. Among 1055 PitNETs from 1169 transsphenoidal resections, we identified 4 cases of pituitary carcinoma, indicating that pituitary carcinoma represents around 0.4% of PitNETs. All four patients were women. The age at initial presentation ranged from 23 to 54 years. Two patients had Cushing disease with corticotroph tumors; one was initially a densely granulated corticotroph tumor that evolved to become sparsely granulated, while the other was a Crooke cell tumor. One patient had a functioning sparsely granulated lactotroph tumor and one had a clinically silent poorly differentiated PIT1 lineage tumor. Apart from a relatively high Ki67 labeling index (≥ 10%) in three tumors, there were no cytomorphologic features at the time of initial presentation that could predict subsequent metastatic behavior. The time from diagnosis of the pituitary neuroendocrine tumor to the diagnosis of malignancy was 3 to 14 years. Therapies included somatostatin analogs, external beam radiotherapy, chemotherapies including capecitabine/temozolomide, everolimus, sunitinib, bevacizumab, and peptide receptor radionuclide therapy (PRRT). One patient died of disease 18 years after initial diagnosis, underscoring the protracted course of this ultimately fatal neuroendocrine malignancy.

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We report clinicopathological features of a large series of synchronous multiple pituitary neuroendocrine tumors (PitNETs) of different cell lineages. Retrospective review of pathology records from 2001 to 2016 identified 13 synchronous multiple PitNETs from 1055 PitNETs classified using pituitary cell-lineage transcription factors, adenohypohyseal hormones, and other biomarkers. Clinical, radiological, and histopathological features of these tumors were reviewed. The series included seven females and six males. Mean age at diagnosis was 55.23 years (range 36-73). Imaging was unavailable for four patients; among the other nine, mean tumor size was 2.23 cm (range 0.9-3.9). Five patients had acromegaly, four had Cushing disease, and four had clinically non-functional tumors. Twelve had double PitNETs; one had a triple PitNET. The most common tumor type was corticotroph (n = 8; six densely and one sparsely granulated and one Crooke cell; three densely and one sparsely granulated were clinically silent), gonadotroph tumors (n = 8), and somatotroph tumors (n = 5; four sparsely granulated and one densely granulated somatotroph) were followed by lactotroph tumors (n = 4; all sparsely granulated), poorly differentiated Pit-1 lineage tumor (n = 1), and unusual plurihormonal tumor (n = 1). A 54-year-old man with Cushing disease had MEN1-driven Crooke cell and gonadotroph tumors. The triple pitNET consisted of a multilineage plurihormonal tumor associated with a gonadotroph and a sparsely granulated lactotroph tumor. The Ki67 (available from 10 specimens) ranged from 1 to 5% in individual tumors. Radiological and biochemical follow-up was available for 10 and 11 patients, respectively. Radiological tumor persistence/recurrence was identified in three patients with double PitNETs consisting of sparsely granulated lactotroph and gonadotroph tumors (n = 1), sparsely granulated somatotroph and silent corticotroph tumors (n = 1), and gonadotroph and silent corticotroph tumors (n = 1) with cavernous sinus invasion. Biochemical persistence was noted in four patients with double PitNETs consisting of sparsely granulated somatotroph and silent corticotroph tumors (n = 2), gonadotroph and Crooke cell tumors (n = 1), and densely granulated somatotroph and silent corticotroph tumors (n = 1). Multiple PitNETs represent about 1% of PitNETs and usually have hormone excess due to at least one tumor component. Clinical manifestations may be due to the minor component, especially in patients with Cushing disease. Invasive growth and aggressive histological subtypes predicted disease persistence/recurrence. This series also highlights the importance of routine application of pituitary cell lineage transcription factors along with hormones to distinguish and subtype multiple synchronous PitNETs.

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The objective of the study is to report a rare case of pancreatic neuroendocrine tumor (pNET) producing insulin and vasopressin. We describe the clinical presentation and management of a metastatic pNET with refractory hypoglycemia and progressive severe hyponatremia. A 52-year-old patient had abdominal pain leading to the diagnosis of a tumor that was initially presumed to be splenic in origin. Investigations ultimately identified a pancreatic mass that on biopsy proved to be a pNET. Eventually, he developed extensive liver metastases, and with tumor progression, he manifested hypoglycemia and severe hyponatremia. He was managed with multiple therapies including somatostatin analogue, peptide-receptor-radionuclide-therapy (PRRT), diazoxide, and everolimus; none of these therapeutic modalities was successful in controlling functional and structural progression of the tumor. Ultimately, the pNET proved fatal and autopsy confirmed widely metastatic disease that stained strongly and diffusely for vasopressin, a feature not seen in the previous liver biopsy. This case illustrates the challenges of diagnosis and management of aggressive insulin-producing pNETs and highlights the potential concomitant ectopic production of vasopressin leading to refractory hyponatremia.

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[Purpose] The aim of the present study was to investigate the association between sleep duration, quality and obesity in the medical students of Saudi population. [Subjects and Methods] This is a cross-sectional study carried out in 408 medical students from King Khalid University Hospitals, Riyadh, Saudi Arabia, based on well-designed questionnaire study and consent form. [Results] The results of this study revealed 39.9% of subjects perform the exercise on regular basis and 61.5% of them reduced their weight, which may be due to diet plan (52.9%) also. Only 68.6% of the subjects were affected with the weight. The maximum number of subjects was lying down after the lunch (88.2%), sitting and reading (80.1%) are prone to develop obesity in future. [Conclusion] Our study confirms sleep disturbance has affected the weight gain and the maximum number of subjects was lying down after the lunch and sitting and reading will be prone to develop obesity in future.

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Paget disease of the bone is a chronic disease characterized by accelerated bone turnover with abnormal repair leading to expansion, pain and deformities. The disease is common in the West, but little if any information is available on its existence in the Arab world, including Saudi Arabia. We present four cases of Saudi patients with Paget disease with variable presentations. The first case, a 63-year-old woman with a history of papillary thyroid cancer, presented with bone, shoulder and chest wall pain and foci of uptake in the ribs and skull that were thought to be metastases, indicating the possibility of diagnostic difficulty in a patient with history of malignancy. Bone biopsy confirmed the diagnosis of Paget disease. The second case was a 47-year-old asymptomatic woman with an elevated alkaline phosphatase of 427 U/L, a common presentation but at an unusual age. Plain x-rays and bone scan confirmed the diagnosis. The third case was a 43-year-old man who presented with hearing impairment and right knee osteoarthritis, unusual presentations at a young age leading to a delay in diagnosis. The fourth case was a 45-year-old man who presented with sacroiliac pain and normal biochemical values, including a normal alkaline phosphatase. Bone biopsy unexpectedly revealed features of Paget disease, which evolved over time into a classical form. A common feature in all except the first case was the relatively young age. Paget disease does exist in Saudi Arabia, and it should be considered in the differential diagnosis of similar cases.

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CONTEXT: Mutations in the CYP27B1 gene, which encodes vitamin D 1alpha-hydroxylase, are the genetic basis for vitamin D-dependent rickets type 1 (VDDR-I). OBJECTIVE: The aim of this study was to investigate the CYP27B1 mutation in a large family with VDDR-I and characterize the genotype-phenotype correlation. PATIENTS AND METHODS: The index patient was a 23-yr-old female who had a progressive form of rickets and growth retardation since the age of 9 months. Laboratory data showed hypocalcemia, low urine calcium, hypophosphatemia, high serum alkaline phosphatase, elevated PTH, and low serum 1,25-dihydroxyvitamin D(3). Her parents were healthy first-degree cousins, and two of her 12 siblings were affected with similar but milder rickets. Three other siblings were asymptomatic but had biochemical evidence of the disease. The entire coding region of the CYP27B1 gene was sequenced, and the mutation was characterized by functional studies. RESULTS: We found a novel biallelic c.305G>A sequence variation at codon 102, changing amino acid from glycine to glutamic acid (G102E) in the patient and five affected siblings, whereas a monoallelic c.305G>A variation was present in the mother and five nonaffected siblings. This variation was not present in 100 population controls. Expression of this mutant in CHO cells revealed an 80% reduction in the 1alpha-hydroxylase activity as compared to wild-type activity. CONCLUSIONS: A novel mutation in the CYP27B1 gene was found in patients with VDDR-I. This mutation resulted in a significant reduction in 1alpha-hydroxylase activity. The residual enzymatic activity may account for the mild phenotype presentation in some affected members.

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OBJECTIVE: To report a rare cause of ectopic adrenocorticotropic hormone (ACTH) secretion leading to severe Cushing syndrome. METHODS: We describe the clinical presentation and management of a case of Cushing syndrome attributable to ectopic ACTH secretion from small cell cancer of the prostate. RESULTS: In a 70-year-old man with hypertension and diabetes, congestive heart failure developed. He was found to have severe hypokalemia (serum potassium, 1.7 mEq/L) and a huge pelvic mass on a computed tomographic scan performed because of a complaint of urinary retention. Transurethral biopsy of the prostate showed features of small cell prostate cancer. Hormonal evaluation revealed a high urine free cortisol excretion of 6,214.5 microg/d (reference range, 36 to 137), confirming the diagnosis of Cushing syndrome. A serum ACTH level was elevated at 316 ng/dL (reference range, 10 to 52). An overnight high-dose (8 mg orally) dexamethasone suppression test was positive (serum cortisol levels were 43.2 and 41 microg/dL before and after suppression, respectively), and magnetic resonance imaging of the pituitary gland disclosed no abnormalities. A prostate biopsy specimen showed small cell prostate cancer with positive staining for ACTH. The tumor was found to be unresectable, and the poor condition of the patient did not allow for bilateral adrenalectomy. He was treated with ketoconazole and metyrapone, which yielded good temporary control of his Cushing syndrome (24-hour urine free cortisol decreased to 55.2 microg/d). He received 1 cycle of chemotherapy (etoposide and cisplatin), but he died 6 months later as a result of sepsis. CONCLUSION: Small cell prostate cancer is a rare subtype that can be associated with ectopic secretion of ACTH and severe Cushing syndrome. With this subtype of prostate cancer, Cushing syndrome should be considered and appropriately managed.

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