bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tissue-Specific Tumorigenesis in Multiple Endocrine Neoplasia Type I
Authors: Gardiner Juliet C 
Published: May 2021

Abstract
While a germline heterozygous mutation in the MEN1 gene predisposes tumor formation in the endocrine pancreas, parathyroid glands and anterior pituitary, this tissue-specific tumorigenesis is not dependent on MEN1 mutations alone. In fact, a homozygous deletion of Men1 in the entire pancreas of a mouse results in tumor formation only in the endocrine pancreas, not in the exocrine pancreas, suggesting an endocrine tissue-specific mechanism. The MEN1 gene encodes the menin protein, which interacts with chromatin associated protein complexes, therefore engaging in epigenetic control mechanisms. Recognizing menin’s participation in epigenetic regulation led to an investigation of whether the pathogenesis of MEN1 syndrome may be related to epigenetic changes in the affected endocrine tissues. Indeed, MEN1-associated endocrine cell types exhibit various menin-dependent epigenetic mechanisms. In fact, a significant increase in methylated DNA loci was observed in MEN1 human parathyroid tumors when compared to human parathyroid adenomas and carcinomas without known MEN1 mutations. Subsequent studies revealed that loss of menin results in increased activity of DNA methyltransferase 1 (Dnmt1). Our studies have shown that Dnmt1 is transcriptionally regulated by the menin-interacting protein Rbbp5. While menin normally functions to suppress Rbbp5 activity, loss of menin activates Rbbp5, thus upregulating Dnmt1 expression, causing global DNA hypermethylation and subsequent tumorigenesis in MEN1-target endocrine tissues. In order to assess the behavior of Rbbp5 in both MEN1-target tissues and non-target tissues, Rbbp5 protein expression was analyzed in both MEN1-target tissues (endocrine pancreas, anterior pituitary, parathyroid) and non-MEN1-target tissues (kidney, lung, liver, brain, heart) of wild-type (WT) mice. We confirmed that Rbbp5 protein expression is ubiquitous throughout all of these WT mouse tissues. Since Rbbp5 is a transcriptional activator responsible for enhanced Dnmt1 gene expression, and the loss of menin causes Dnmt1 overexpression solely in MEN1-target tissues, we assessed whether Rbbp5 binds preferentially in a tissue-specific manner to the Dnmt1 promoter. We determined the presence of Rbbp5 on the Dnmt1 promoter in MEN1-target tissues (WT mouse endocrine pancreas, normal human parathyroid, WT mouse pituitary) and the absence of Rbbp5 on the Dnmt1 promoter in non-MEN1-target tissues (WT mouse liver, WT mouse kidney, WT mouse lung). These results confirmed that Rbbp5 does exhibit MEN1-target-tissue-specific occupancy at the Dnmt1 promoter. This endocrine-specific localization of Rbbp5 to the Dnmt1 promoter suggests the presence of additional tissue-specific factors (with tissue-specific expression or interactions/activity) that must be validated and tested further.
GH1 C.291 + 34G&gt;C in a Growth Hormone Deficient Pedigree
Authors: Vidal Katherine , Britt Allison D , George Anu , Ray Joseph , Lee Phillip D K 
Published: May 2021

Abstract
Background: Heterozygous loss of function mutations in GH1 are a cause of autosomal dominant isolated growth hormone deficiency (GHD) or IGHD type II. However, this condition is rare and a genotype/phenotype association is often based on single case or pedigree reports.
Clinical Case: The male proband was born at 38 weeks following an uncomplicated pregnancy, birthweight 2585 gm (˗1.3SD), length 43 cm (˗2.7SD). At 20 months old: length ˗3.2SD, weight/length 16%. Peak growth hormone (GH) levels 4.42 ng/mL and 3.2 ng/mL following clonidine and arginine stimulation, respectively; cortrosyn-stimulated cortisol was 41.4 mcg/dL. Prolactin was 61.2 ng/mL (reference range 2.6 to 13.1 ng/mL); T4 and TSH levels were normal. Magnetic resonance imaging showed a flattened anterior pituitary gland, consistent with empty sella, with normal bright spot. He has had an intermittent and variable response to GH treatment due to noncompliance; recent recorded height was ˗3.6SD at 13.9 and he was early pubertal. Father had a history of childhood growth hormone treatment and is 151 cm tall, 2 paternal aunts did not receive treatment and are 145 cm tall, 3 children of these aunts are diagnosed with GHD. There is no maternal family history of GHD; mother is 155 cm. Proband testing revealed heterozygous GH1 c.291 + 34G&gt;C (EGL Genetics), classified as a variant of unknown significance; father was also found to have this variant, mother was negative. Genetic testing for of additional family members is under consideration.
Conclusion: Nine of 96 heterozygous GH1 variants are located in intron 3. Two have been classified as pathogenic and are predicted to cause exon skipping. Our proband’s variant cannot be considered a canonical splice site or in a mutational hot spot but has extremely low frequency in population databases. Functional studies clan clarify if our proband’s variant results in a 17.5 kDa GH isoform and dominant negative effect on full length GH production with potential detrimental effects on other anterior pituitary hormones. We present the second GHD pedigree with GH1 c.291 + 34G&gt;C mutation. As in the previous report (1), no other hormone deficiencies are identified, despite the appearance of an empty sella for our proband.
Reference: (1) Cho SY, Ki, CS, Park, HD, et al. Genetic investigation of patients with undetectable peaks of growth hormone after two provocation tests. Clin Endocrinol 2013; 78: 317-20.
A Case Of Panhypopituitarism, Resembling The Picture Of Syndrome Of Inappropriate Antidiuretic Hormone Secretion
Authors: Jung Andrew , Shahid Novera , Shaaban Noreen , Angueira-Serrano Eugenio 
Published: May 2021

Abstract
Background: Hyponatremia is a common medical condition in the elderly. When encountering hyponatremia in the clinical setting, it is important to start with a broad differential list, and then work through all the different possibilities before arriving at the correct diagnosis. Treatment guidelines recommend starting with broad differentials in order to avoid premature conclusions, reach the correct diagnosis, and avoid suboptimal treatment or inappropriate workup. Clinical Case: 86-year old female presented with one week of general weakness, decreased appetite, sleep, and polyuria. Initial serum sodium was 128 mmol/L (136-146), and plasma and urine osmolarities were 271mOsmol/kg (285-305) and 592 mOsmol/kg (50-1400), respectively. Her urine sodium was elevated at 126 mmol/L (n&lt;20), suggestive of a clinical picture of a syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The patient did not respond to &lt;1L/day fluid restriction alone. The initial dose of furosemide did not improve the sodium level; thus, the dosage was raised and salt tablets were added, which improved sodium level steadily. Meanwhile, her thyroid profile showed TSH 0.07uU/mL (0.3-4.2), free T4 0.9 ng/dL (0.8-1.8), demonstrating central hypothyroidism while taking levothyroxine as a home medication. Further pituitary workup revealed an abnormally low level of FSH 4.95mIU/mL (16.7-113.5) and LH 2.33mIU/mL (10.8-58.6), considering the post-menopausal state. Prolactin was elevated at 39ng/mL (3.3-26.7). The rest of the hormone labs including cortisol, ACTH, and GH were normal. Blood sugar and serum triglyceride levels were within the normal range. Per history and physical, the patient neither exhibited hypervolemic nor hypovolemic features. No home medications would have likely caused SIADH. Her MRI of the brain in 2016 reported a sellar mass uplifting the optic chiasm and its extension of the right cavernous sinus. Latest outpatient record from October 2020 documented pituitary macroadenoma with secondary hypothyroidism, secondary hypogonadism, and hyperprolactinemia due to the stalk effect. Finally, ADH returned as &lt;0.8 pg/mL (0-4.7), ruling out SIADH as the most likely etiology. Conclusion: Treating hyponatremia in the elderly is a challenge. Starting with a broad differential list and effectively ruling out each diagnosis is critical to find the most likely etiology and prevent a premature diagnosis. Instances of such diagnoses and subsequent inappropriate treatments invariably lead to poor patient outcomes. It is, therefore, crucial to keep an open mind and consider all possibilities when approaching a hyponatremic elderly patient. References: Paul Grant, John Ayuk, Pierre-Marc Bouloux. The diagnosis and management of inpatient hyponatraemia and SIADH. Eur J Clin Invest 2015;45(8):888-894.
A Case of Unusual Initial Presentation of Panhypopituitarism From Metastatic Adenocarcinoma of Lungs
Authors: Ahmad Malik Waseem , Becker Susannah 
Published: May 2021

Abstract
Introduction: Metastatic disease of the pituitary gland account for about 1 to 2 percent of the sellar masses with suprasellar extension. Approximately 7 percent of the patients are symptomatic with varying symptoms based on the location and extent of metastases. We present you a case in which patient presented with features of Panhypopituitarism starting with severe hypothyroidism in a previously undiagnosed lung cancer. The Patient also suffered with some serious complications such as diabetes insipidus, adrenal insufficiency and complete vision loss. Clinical Case: A 60 y/o male with a past medical history of Hypertension, Chronic Obstructive Pulmonary Disease, smoking 2 packs of cigarettes per day for 40 years, second-degree heart block requiring a pacemaker, Chronic kidney disease 3b presented to the emergency department with complaints of left ankle pain, swelling, and syncope. The Patient was admitted for further workup and Endocrinology was consulted for concerns of hypothyroidism with severe myxedema and adrenal insufficiency. CT head was done, which showed sellar and suprasellar mass lesion measuring 1.8 x 2.2 x 3.0 cm. Finding were confirmed on MRI. Pertinent labs were PTH 57.7 pg/ml, TSH 0.33 uIU/ml, Free T4 0.4 ng/dl, ACTH 8 pg/ml, Cortisol 2.5 ug/dl, FSH 0.5 MIU/ml, LH 0.1 MIU/ml, testosterone 4 ng/dl, Prolactin 17.7 ng/ml, Insulin-like GFBP-3: 2.1 mg/L. The Patient was started on high dose Hydrocortisone, IV Levothyroxine T4 and desmopressin for Diabetes Insipidus. The Patient complained of peripheral vision loss. Neurosurgery partially resected the sellar mass through the transsphenoidal approach. Histopathology came back with Metastatic adenocarcinoma. Further clinical course was complicated by complete vision loss from increase in the sellar mass size after 8 weeks. Patient received radiation therapy but unfortunately there was no significant improvement in the vision. Conclusion: This case highlights some serious complication from metastatic disease of Pituitary gland from lung cancer. There is a need for continued annual screening for dysfunction of the hypothalamic-pituitary axis to monitor therapy. This case also highlights the importance of widespread screening of smokers in accordance with the standard lungs cancer screening recommendations. This can potentially prevent some of the serious complications of metastatic lung disease. Reference: Ross, D. Cooper, D. Mulder, J. (2020, September) Central Hypothyroidism. https://www.uptodate.com/contents/central-hypothyroidismSnyder, P. Cooper, D. Martin, K. (2020, September) Causes, presentation, and evaluation of sellar masses. https://www.uptodate.com/contents/causes-presentation-and-evaluation-of-sellar-masses
A Case With Adult GH Deficiency Complicated With Osteogenesis Imperfecta: Effect of GH Replacement on Bone Mineral Density
Authors: Taguchi Tomomi , Toki Takuya , Hayashi Akinori , Takano Koji 
Published: May 2021

Abstract
Background: Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with many phenotypic presentations. Bisphosphonates are the mainstay of pharmacologic fracture prevention therapy, although they aren’t officially approved for the treatment of OI.
Clinical Case: The patient was born by breech delivery. After he had multiple fractures at the age of two years, he was diagnosed with osteogenesis imperfecta (OI) type I by genetic analysis (c.1299 + 1G&gt; A mutation in the COL1A1 gene). On the growth curve, his height fell below -2SD at the age of six years. When he was 12 years old, he visited another hospital because of short stature (Hight 119 cm: -2.7SD). Pituitary MRI revealed pituitary stalk disruption and pituitary atrophy. Endocrinological examinations (ITT, TRH, LHRH, arginine stimulation tests) showed severe GH deficiency. Growth hormone replacement therapy was started. At the age of 16 years, he was diagnosed to have central hypothyroidism and central diabetes insipidus, and levothyroxine and DDAVP were started. His bone mineral density of the lumbar spine was 0.546 g/cm2, and alendronate was started. At the age of 17, central hypogonadism was diagnosed by LHRH stimulation test, and HCG injections were initiated. His bone mineral density continued to increase by GH replacement, HCG injections and bisphosphonate and reached 0.820 g/cm2 (Z-score: -0.27) by the age of 18 years. GH replacement was discontinued (final height 180 cm). At that age, his bone mineral density declined to 0.717 g/cm2 at the age of 25 years, although he stayed on an alendronate and HCG injections. At that time, total testosterone 890 ng/dL (142&lt;n&lt;923 ng/dL) was within normal range, but IGF-1 level was below the lower limit (44 ng/mL; -4.6SD, 225&lt;n&lt;337 ng/mL). He was referred to our hospital for transition to adult endocrine care. Endocrinologic evaluation revealed low serum cortisol level in the early morning (2.26 µg/dL, 7.07&lt;n&lt;19.6 μg/dL). GH-releasing peptide-2 stimulation test revealed severe GH deficiency (peak GH 0.18 ng/mL, n&gt; 15 ng/mL (1)) and replacements with GH and hydrocortisone were initiated. After the GH replacement, the bone mineral density started to increase to 0.954 g/cm2 (Z-score: -0.5).
Conclusion: So far as we know, this is the first case report of OI with panhypopituitarism treated with GH and bisphosphonate. This case suggests that bisphosphonate alone is not sufficient to maintain bone mineral density complicated with both OI and severe GHD. GH replacement therapy was inevitable to increase bone mineral density in this patient.
Reference: (1) Kazuo Chihara et al. A simple diagnostic test using GH-releasing peptide-2 in adult GH deficiency. Eur J Endocrinol.2007;157;19-27.
A Rare Case of a Plurihormonal Pituitary Adenoma
Authors: Hossain Alisha , Skutnik Emily , Ahluwalia Arjan , Gelin Lindor , Singh Sonum , Perilli Gretchen , Koshy Sharmilia 
Published: May 2021

Abstract
Background: Pituitary adenomas are usually benign tumors that arise from adenophypophyseal cells and produce one or two types of hormones. Plurihormonal adenomas are a rare subtype that produce two or more hormones and represent less than 1% of all pituitary adenomas.
Clinical Presentation: A 76-year-old female presented for evaluation of abnormal thyroid function test results. She was found to have an elevated free T4 of 1.92 ng/dL and total T4 of 14.4 ug/dL with an inappropriately normal TSH of 2.11 uIU/mL. Physical examination was significant for tachycardia, tremors, diaphoresis, coarse facial features, and enlarged hands. Further biochemical evaluation of her pituitary hormone levels demonstrated an elevated prolactin (PRL) of 237.2 ng/mL, elevated insulin-like growth factor 1 (IGF-1) of 787 ng/mL, normal morning ACTH of 47 pg/mL, normal morning cortisol of 17.0 ug/dL, an inappropriately suppressed FSH of &lt;5.0 mIU/mL, an elevated alpha subunit of pituitary glycoprotein hormones (PGH) of 6.9 ng/mL, and an elevated free T4 of 3.5 ng/dL by equilibrium dialysis. She underwent an MRI of the pituitary and brain which demonstrated a pituitary adenoma measuring 1.2 x 1.3 x 1.8 cm with a portion herniating into the sella turcica with no mass effect of the optic chiasm. A formal visual field examination was normal. The patient underwent workup for Cushing’s Disease with a low dose overnight dexamethasone suppression test, resulting in an appropriate response with an 8 AM cortisol of &lt;1.0 ug/dL. Glucose suppression test confirmed the diagnosis of acromegaly with growth hormone at 120 minutes of 19.90 ng/mL. Neurosurgery performed a trans-sphenoidal pituitary adenoma resection. Thyroid function tests on post-operative day 4 demonstrated a suppressed TSH of 0.01 uIU/mL and an elevated free T4 of 2.30 ng/dL. Histological evaluation revealed dual expression of transcription factors pituitary-specific positive transcription factor 1 (PIT1) and steroidogenic factor 1 (SF1) as well as PRL, GH, TSH and FSH expression. Immunostaining for LH and ACTH were negative. Post-operative IGF-1 and GH levels were 106 ng/mL and 0.51 ng/mL at 17 weeks, respectively. Post-operative TSH normalized to 0.82 uIU/mL, free T4 normalized to 1.04 ng/dL, and PRL normalized to 8.1 ng/mL at 12 weeks. The patient remained symptom free after successful surgical resection.
Discussion: Our case demonstrates the clinical course of a unique patient with clinical and biochemical manifestations of thyroid dysfunction and acromegaly with a pituitary adenoma immunoreactive for GH, TSH, FSH, and PRL. The co-secretion of GH, TSH, PRL, and FSH as well as positivity for the alpha-subunit is extremely unusual. This case emphasizes the importance of considering pituitary abnormalities as a cause for abnormal thyroid function tests.
A Rare Case of Thyrotropin Secreting Pituitary Macroadenoma Primarily Treated With Somatostatin Analogue
Authors: Elsheikh Arwa Mahmoud , Vates G Edward , Shafiq Ismat 
Published: May 2021

Abstract
Introduction/Background: Thyrotropin secreting pituitary adenomas (TSH-oma) are a rare cause of hyperthyroidism. They account for &lt;1% of the cases of hyperthyroidism with a reported incidence of 2.8 per 1 million in Sweden. Diagnosis is suspected by the presence of elevated T4 and T3 in the setting of an unsuppressed TSH level. The presence of large pituitary adenoma is highly suggestive of the diagnosis and can be differentiated from thyroid hormone resistance by elevated alpha subunit and SHBG levels. Trans-sphenoidal surgery is the definitive treatment. Peri-operative medical treatment with somatostatin analogues is indicated to achieve euthyroidism and prevent surgical risks and thyroid storm. The use of somatostatin analogues as a primary treatment for TSH-oma is still under investigation. We hereby report a rare case of TSH-oma where somatostatin analogues successfully resulted in normalization of thyroid function and tumor size reduction.
Clinical Case: A 61 years old gentleman with a history of hypothyroidism diagnosed three years before presentation to the Pituitary clinic. He was treated with Levothyroxine. On clinical examination, he had mild tremor and warm sweaty palms with no stigmata of Grave’s disease. The thyroid function test showed elevated free T4 of 3.6 ng/dl (0.9-1.7), elevated free T3 of 8.6 pg/ml (2.0-4.4), and a high TSH level of 9.10 μIU/ml (0.27-4.20). His prolactin level was mildly elevated at 24.8 ng/ml(4.0-15.2). Testosterone, IGF-1, and cortisol levels were normal. An MRI of his pituitary gland showed large pituitary macroadenoma with supra-sellar extension and mild compression of the optic nerve. He had an elevated alpha subunit of 5.6 ng/ml (&lt;1.37) and a high SHBG level of 198 nmol/l(10-80). TSH adenoma was diagnosed and he was planned for trans-sphenoidal surgery. Pre-operative treatment with somatostatin analogue Lanerotide 90 mg monthly injection was initiated. Interestingly normal thyroid function was observed approximately 1 month after his first injection. Repeat MRI showed a considerable decrease in the size of the pituitary macroadenoma. The patient opted to hold on to surgery and to continue on medical treatment. His thyroid function remains normal 15 months after initiation of treatment and his MRI continues to show stable pituitary adenoma.
Conclusion: Somatostatin analogues can be used as a primary treatment for thyrotropin secreting pituitary adenomas when the patient is unable or unwilling to undergo surgery. It is use is associated with normalization of thyroid function and in some cases with a reduction in the adenoma size.
Spexin as a Satiety Factor in Mouse via Regulatory Actions Within the Hypothalamus
Authors: Wong Matthew K H , Chen Yuan , He Mulan , Lin Chengyuan , Bian Zhaoxiang , Wong Anderson On-Lam 
Published: May 2021

Abstract
Spexin (SPX) is a pleiotropic peptide with highly conserved protein sequence from fish to mammals and its biological actions are mediated by GalR2/GalR3 receptors expressed in target tissues. Recently, SPX was found to be a novel satiety factor in fish models but whether the peptide has a similar function in mammals is still unknown. Using the mouse as a model for mammalian species, the functional role of SPX in feeding control and the mechanisms involved were investigated. After food intake, serum SPX could be up-regulated in mice with parallel elevations of transcript expression and tissue content of SPX in the glandular stomach but not in other tissues examined. As revealed by immunostaining, food intake also intensified SPX signals in different cell types within the gastric mucosa of glandular stomach. Furthermore, IP injection of SPX was effective in reducing food consumption with parallel drops in transcript expression of NPY, AgRP, NPY type 5 receptor (NPY5R) and ghrelin receptor (GHSR) in the hypothalamus, and these inhibitory effects could be blocked by GalR3 but not GalR2 antagonism. In agreement with the central actions of SPX, similar inhibition on food intake and hypothalamic expression of NPY, AgRP, NPY5R and GHSR could be observed with ICV injection of SPX. In the same study, parallel rises of transcript expression of leptin receptor (LepR) and melanocortin 4 receptor (MC4R) were also observed in the hypothalamus. These findings, taken together, suggest that the role of SPX as a satiety factor is well-conserved in the mouse. Probably, food consumption can induce SPX production in glandular stomach and contribute to the postprandial rise of SPX in circulation. Through GalR3 activation, this SPX signal can act within the hypothalamus to trigger feedback inhibition on food intake by differential modulation of the feeding regulators (NPY & AgRP) and their receptors (NPY5R, GHSR, LepR & MC4R) involved in the feeding circuitry of the brain.