bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Germline SUCLG2 Mutations in Patients With Pheochromocytoma and Paraganglioma
Authors: Vanova Katerina Hadrava , Pang Ying , Krobova Linda , Kraus Michal , Nahacka Zuzana , Boukalova Stepana , Pack Svetlana , Zobalova Renata , Zhu Jun , Huynh Thanh , Jochmanova Ivana , Uher Ondrej , Hubackova Sona , Dvorakova Sarka , Garrett Timothy , Ghayee Hans , Schuster Bjoern , Knapp Philip , Frysak Zdenek , Hartmann Igor , Nilubol Naris , Cerny Jiri , Taieb David , Rohlena Jakub , Neuzil Jiri , Yang Chun Zhang , Pacak Karel 
Published: May 2021

Abstract
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest cells that are frequently linked to mutations including those in Krebs cycle enzymes, particularly succinate dehydrogenase (SDH). Succinyl-CoA ligase (SUCL) catalyzes reversible conversion of succinyl-CoA to succinate providing the substrate for SDH. While mitochondrial diseases were documented for the mutations in SUCL subunits G1 and A2, the association of GDP/GTP-specific subunit SUCLG2 mutations with specific pathologies including cancer have not been reported. In our study, 352 patients with apparently sporadic PPGLs underwent genetic testing using a panel of 54 genes developed at the National Institutes of Health. Additionally, human pheochromocytoma (hPheo1) cells were used for gene manipulation to produce SUCLG2 knock-out (KO). Tumor tissues and hPheo1 SUCLG2 KO cells were used for further analysis focusing on mechanism of germline variants effect on mitochondrial functions. We detected eight germline SUCLG2 mutations in 15 patients which represents 4.3% of the cohort. Germline variants together with LOH led to decreased levels of SDH subunit B resulting in aberrant respiration and accumulation of succinate, well recognized oncometabolite. Manipulation of SUCLG2 in hPheo1 cells confirmed decrease in SDHB leading to faulty assembly of mitochondrial complex II and alteration of its respiration and activity. In summary, our study identified an association between SUCLG2 and PPGL. Larger scale sequencing and uncovering additional cases bearing SUCLG2 variants will further clarify the relationship between SUCLG2 and SDHx, particularly SDHB, as well as their role in disease etiology.
A Challenging Case of Vitamin D Toxicity Responding to Cinacalcet
Authors: Addasi Noor , Johnson Jake , Davis Clifton , Bernstein Ilia , Puri Ritika , Neumeister Amy S , Drincic Andjela T , Kotwal Anupam 
Published: May 2021

Abstract
Background: Interest in the role of vitamin D in various physiological processes, the prevalence of its deficiency and importance of replacement has increased significantly over the past few decades. However, many formulations of vitamin D are not regulated and are available to the public without clear guidance on safe administration, which has contributed to the uptrend in the incidence and severity of vitamin D toxicity cases. Clinical Case A 57- year-old man with a medical history significant for amyotrophic lateral sclerosis, cervical myelopathy, and oropharyngeal dysphagia presented with weakness, constipation, polydipsia, polyuria and was found to have hypercalcemia with a total Calcium level of 15.5 mg/dL (n 8.6- 10.4), and albumin 4.2 g/dL (n 3.5–5.1). He soon developed acute hypoxic respiratory failure requiring prolonged intubation followed by tracheostomy. Evaluation of the hypercalcemia revealed an elevated 25-hydroxyvitamin D [25(OH)D] &gt; 392 ng/mL (n 30–80), 1,25- dihydroxyvitamin D [1,25(OH)D] &gt;600 pg/mL (n 19.9 - 79.3), PTH 8 pg/mL (n 12–88), and PTHrP 0.7 pmol/L (n&lt; 4.2). The patient had initially stated that he was taking 5000 IU of vitamin D daily but further discussion with his wife revealed that he had been taking 2 teaspoons of a powder cholecalciferol preparation with 125 mcg (5000 IU of vitamin D) per 50 mg, which would be about 800,000 IU/day. He was treated with aggressive IV hydration, calcitonin and received 2 doses of pamidronate with an initial improvement in his Calcium level down to 10 mg/dL followed by recurrence of hypercalcemia. Work up for granulomatous disease and multiple myeloma revealed latent TB. At significantly elevated [25(OH)D] levels, toxicity is partially caused by the direct action of [25(OH)D] on the vitamin D receptor (VDR), and [25(OH)D] can also cross-react with the [1,25(OH)D] assay causing false elevation. Steroids were avoided because of his recent diagnosis of latent TB; hence he was started on Cinacalcet which was gradually increased to 60 mg twice a day with sustained Calcium normalization. Repeat labs showed improvement in [25(OH)D] to 292, and normalization of [1,25(OH)D] at 69.4. He was discharged on Cinacalcet 30 mg twice a day. Conclusion PTH-independent hypercalcemia is usually treated with hydration, anti-resorptive agents including bisphosphonates, denosumab and calcitonin, in addition to steroids in cases of increased 1 αλπηα-hydroxylase activity. Cinacalcet acts on the Calcium sensing receptor (CaSR) in parathyroid tissue, kidneys, bones and the intestine and was recently shown to improve hypercalcemia of malignancy in a report of 2 cases by Sheehan et al. Cinacalcet has helped our patient and might have a potential role for the prompt treatment of vitamin D toxicity, but more data is needed.
A Case of an Ectopic Parathyroid Adenoma With a Concomitant 99mTc-sestamibi-avid Papillary Thyroid Carcinoma
Authors: Castillo Cruz Maria Nikki , Ramos Celeste Ong 
Published: May 2021

Abstract
Background: The evaluation and management of parathyroid adenomas have improved over the years. Localization of parathyroid adenomas in patients with primary hyperparathyroidism was simplified with the use of 99mTc-sestamibi scintigraphy. In the advent of minimally invasive parathyroid surgery, use of radionuclide probes reduced the need for neck exploration and intraoperative frozen section leading to fewer complications, shorter operative time and hospitalization and rapid postoperative recovery. However, limitations of these techniques should be taken into consideration in certain cases.
Clinical Case: A 60 year-old female diagnosed with primary hyperparathyroidism presented with recurrent nephrolithiasis and osteoporosis. Initial laboratory evaluation showed elevated serum calcium and intact PTH (1.54 mmol/L and 146 pg/mL, respectively). 99mTc-sestamibi scintigraphy showed a sestamibi-avid focus in the inferior aspect of the right lobe suggestive of a parathyroid adenoma or hyperplasia. Pre-operative neck ultrasound showed non-specific thyroid parenchymal changes and nodules on both lobes with benign sonographic features. She underwent radionuclide-guided focused right parathyroidectomy. The identified enlarged right inferior parathyroid gland registered a highest reading of 70 cps on radionuclide probe. Post-operatively, repeat intact PTH level was still elevated (171.2 pg/mL). There was an interval non-demonstration of the sestamibi-avid focus in the inferior aspect of the right thyroid lobe with an increased sestamibi uptake in the left thyroid lobe compared to the previous parathyroid scan. Histopathologic examination showed a normocellular parathyroid gland and a multifocal papillary thyroid carcinoma. She underwent total thyroidectomy with central neck dissection and 4 parathyroid gland exploration with intraoperative parathyroid hormone assay. However, serial PTH monitoring after left inferior parathyroidectomy and after bilateral partial superior parathyroidectomy still showed elevated levels. Histopathologic examination showed mildly enlarged, normocellular parathyroid gland. The bilateral carotid sheath, retropharyngeal region and superior mediastinum were explored but no ectopic parathyroid tissues were seen. Post-operatively, calcium and PTH were still elevated (1.48 mmol/L and 200.5 pg/mL, respectively).
Conclusion: This case highlights the predicaments in the management of parathyroid adenomas, recognizing the possibility of false-positive sestamibi scans due to malignant thyroid nodules and the possibility of the two diseases occurring concurrently, albeit rare.
A Case of Pseudohypoparathyroidism Type 1b in Pregnancy
Authors: Balasubramanian Priyadarshini , Lupsa Beatrice 
Published: May 2021

Abstract
Introduction: Pseudohypoparathyroidism (PHP) type 1b is characterized by target organ resistance to PTH leading to hypocalcemia and hyperphosphatemia in the setting of elevated PTH due to abnormal imprinting that affects the regulatory elements of GNAS1. It poses challenges in management during pregnancy and lactation. We report the case of a patient who was diagnosed with PHP type 1b while pregnant. Case Presentation: A 30 year old woman, 16 weeks pregnant was referred for the evaluation of hypocalcemia. She had a history of traumatic fracture of her lower extremity and hypothyroidism treated with levothyroxine. She was noted to have hypocalcemia 1 year prior during routine labs. Family history was significant for hypothyroidism in her sister. On physical examination, she did not have phenotypic features of Albright hereditary osteodystrophy except for short stature. Before pregnancy her labs were significant for Ca 8.1 mg/dL(8.6–10.2), iCa 4.2 mg/dL(4.8–5.6), iPTH 289 pg/mL (14–64), creatinine 0.6 mg/dL(0.8–1.2), 25 vitamin D 22 ng/mL and 24 hr urine Ca 80 mg/24 hr (65-250mg). She was started on a combination of calcium citrate and carbonate 600 mg daily and vitamin D 1000 units daily. Labs while pregnant showed Ca 8.1 mg/dL, iCa 4.1 mg/dL, iPTH 184 pg/mL, PO4 4.9 mg/dL(2.5–3.5), 1,25 Vitamin D 53 pg/mL(18–72) and 25 Vitamin D 38 ng/mL. She had mild paresthesia and muscle cramps. Calcium supplements were increased to 1800 mg daily. While the urine Ca increased to 315 mg/24 hr, other biochemical parameters did not improve. Given her low Ca, high iPTH, high PO4, normal GFR and 25 vitamin D, PHP was suspected. Genetic testing showed loss of methylation at GNAS locus down to 5% (NL &gt;43%) Diagnosis of PHP type 1b was made. Her Ca decreased the next months to a nadir of 7.9 mg/dL despite increased doses of calcium up to 1200 mg BID. Calcitriol 0.25 mcg BID was added. The rest of her pregnancy the serum Ca stayed between 8.1–8.6 mg/dL. She delivered a boy. At birth his Ca was 8.0 mg/ dL and PTH 81pg/mL. Genetic testing showed 41% methylation of GNAS. While breast feeding her Ca was 9.4 mg/dL, her calcitriol and calcium supplements were decreased. She continues to do well on calcium 630 mg daily and calcitriol 0.25 mcg daily with serum Ca between 8.5–8.8 mg/dL. Conclusion: The literature on PHP in pregnancy is scarce due to its rarity and the management is challenging due to altered calcium and vitamin D metabolism during pregnancy and lactation. The fetus draws calcium from maternal circulation and predisposes mother to hypocalcemia. Some patients may become normocalcemic during pregnancy due to placental secretion of 1,25 Vitamin D and PTHrp. There is also increased demand for calcium with lactation. There are genetic implications on the baby as it is inherited in an autosomal dominant mode. It is important to monitor calcium levels closely as there are multiple factors that could influence calcium metabolism in pregnancy.
A Case Report of Patient With Mysterious Hypercalcemia
Authors: Eldin Randa Sharag , Poku Caroline A , Camacho Pauline M 
Published: May 2021

Abstract
Background: Non-parathyroid hormone related hypercalcemia has a broad differential diagnosis. One of the key diagnosis to exclude is malignancy.
Case: A 41 yo male with paraplegia due to an accident at age 21, b/l BKA, stage 4 sacral pressure ulcer complicated by vesico-cutanous fistula status post ileal conduit and chronic osteomyelitis of the ischia, sacrum and pelvis was admitted with sepsis secondary to infected sacral pressure ulcer. He was noted to be hypercalcemic with corrected calcium of 13.4mg/dl. He had no previous history of hypercalcemia, kidney stones, head or neck radiation. Work up showed appropriately suppressed PTH with normal PTHrp, 1,25-dihydroxy vitamin D, 25-dihydroxy vitamin D, SPEP, UPEP and TSH. Drug induced hypercalcemia was ruled out. CT abdomen/pelvis was done and showed chronic osteomyelitis; destruction of the sacrum, ischia, pubic bones and femoral heads with enlarged inguinal lymph nodes. Review of records showed a NM bone scan done the year prior to admission to evaluate the chronic destruction of pelvic bones was negative for malignancy. Chest imaging was unremarkable. Patient underwent debridement and wash out of sacral and bilateral lower extremity wounds with bone biopsy. Pathology showed necrotic bone, chronic and acute inflammatory tissue. Calcium peaked at 17mg/dl prior to bisphosphonate, calcitonin and IVF becoming effective. Given the severity of hypercalcemia there was concern for malignancy despitethe negative work up thus Interventional Radiology was consulted for lymph node biopsy. Inguinal lymph node FNA was positive for metastatic squamous cell cancer prompting an exam under anesthesia which was negative for anal lesions. He underwent a cystoscopy which showed a large fungating mass involving the bulbar and membranous urethra with biopsies consistent with invasive and moderately differentiated keratinizing squamous cell carcinoma. Hypercalcemia resolved with treatment and he was discharged home to complete an antibiotic course prior to anticipated chemotherapy. Unfortunately, patient died prior to starting chemotherapy.
Conclusion: Hypercalcemia has been found to be associated with 30% of late stage malignancies and is a marker of poor prognosis. It is most commonly associated with hematological malignancies, such as multiple myeloma and leukemias as well solid tumors like breast carcinomas. In Hypercalcemia of malignancy, PTHrp is the causal agent in over 80% of cases with 20% of cases attributed to osteolytic mechanisms mediated by inflammatory cytokines. Less than 1% of hypercalcemia of malignancy is attributed to excess 1,25-dihydroxy vitamin D. High level of suspicion for malignancy should be presentwhen patients present moderate/severe non-PTH mediated hypercalcemia. Workup for malignancy should be pursued even with normal PTHrp.
A Complicated Case of Posterior Reversible Encephalopathy Syndrome (PRES) Secondary to Severe Hypercalcemia
Authors: Alqaisi Sura , Saand Aisha Rasool , Tapryal Neel , Alwakeel Mahmoud , Akbik Bassel 
Published: May 2021

Abstract
Background:PRES is a rare but severe condition with highly variable neurologic manifestations ranging from headaches to seizures, coma and radiologic findings of focal vasogenic edema1. It is commonly caused by hypertension, chronic renal failure, preeclampsia / eclampsia and immunosuppressants. We are reporting a rare presentation of PRES caused by severe hypercalcemia.
Clinical Case: A 29- year old female presented with frontal headaches, visual disturbance, emesis and confusion. Her medical history was relevant for hyperthyroidism treated with partial thyroidectomy (on methimazole) and complicated by iatrogenic hypoparathyroidism. The resulting hypocalcemia was managed with calcitriol and calcium supplementation. On presentation, the patient was awake but disoriented. Physical examination was remarkable for right-sided hemianopsia. Admission blood pressure (BP) was 192/127 suggestive of hypertensive emergency. Initial laboratory tests revealed severe hypercalcemia (calcium: 18.7 mg/dL, ionized: 2.1 mmol/L), acute kidney injury (creatinine of 2.5 mg/dL, (baseline = &lt;1), elevated 1, 25-dihydoxy vitamin D: 65.1 pg/mL, PTH &lt;1 pg/mL, and negative urine toxicology. Head CT without contrast revealed symmetric bilateral parieto-occipital parenchymal hypoattenuation and MRI confirmed the aforementioned findings to be consistent with PRES. The patient was admitted to the ICU and started on Nicardipine intravenous (IV) infusion, IV fluids and calcitonin. Other causes of severe hypercalcemia such as multiple myeloma and hypercalcemia of malignancy were ruled out. Home calcium and calcitriol supplements were discontinued due to suspicion of intoxication. After correction of serum calcium levels her encephalopathy, hypertension and AKI resolved. She was subsequently transferred to the medical floor in stable condition. Calcium supplementation was resumed when serum calcium level normalized and calcitriol was held until further follow up of calcium levels as outpatient.
Conclusion: Severe hypercalcemia is a rare cause of PRES secondary its effect on vascular smooth muscle vasoconstriction and increased vascular resistance leading to severe hypertension. Thus, it is imperative to establish a prompt diagnosis and rule out hypercalcemia in all patients presenting with PRES to prevent its devastating neurologic complications. Reference: Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol. 2015 Sep;14(9):914–925. doi: 10.1016/S1474-4422(15)00111-8. Epub 2015 Jul 13. Erratum in: Lancet Neurol. 2015 Sep;14(9):874. PMID: 26184985.
An Uncommon Cause of Hypomagnesemia With Hypercalciuria and Nephrocalcinosis in a Young Woman
Authors: Rudovich Natalia N , Hahn Kai , Jonczy Malgorzata L , Wille Georg , Zerkiebel Nic 
Published: May 2021

Abstract
Background: Mutations of the calcium-sensing receptor (CaSR) gene resolve in a change of calcium homeostasis with autosomal dominant and/or sporadic hypocalcemia with hypercalciuria (ADH) (gain-of-function) and familial hypocalciuric hypercalcemia (loss-of-function-mutation). Additionally, genetic mutations in renal tubular transporters are also associated with hypomagnesemia, hypercalciuria and nephrocalcinosis. Such,,magnesium-losing-diseases“ are disorders like familiar hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) which shows a mutation in the Claudin 16 gene (CLD16) and the primary hypomagnesemia with secondary hypocalcaemia caused by a genetic defect in the Transient Receptor Potential Cation Channel Subfamily M Member 6 (TRPM6) gene. Clinical Case: A 35- year old woman with a first episode of pyelonephritis presented herself in our emergency unit in January 2020. Kidney ultrasound showed an advanced stage of nephrocalcinosis and normocalcemia, hypomagnesemia, suppressed PTH and hypercalciuria were observed in laboratory analyses. Several family members from her father`s side and her brother have all been diagnosed with nephrocalcinosis developed in young age. A gene sequencing of CASR and CLD16 gene provided no sequence or copy changes. Thiazide diuretic was initiated for correction of hypercalciuria, but the patient developed hypotonic blood pressure and stopped the drug. In November 2020 she unexpectedly died. Conclusions: In our patient ADH due an activating mutation of the CaSR gene was supposed, but no abnormality in gene sequence was detected. Since CaSR are not only expressed in PTH-secreting cells in the parathyroid but also along the nephron, particularly in the thick ascending limp of loop of Henle, activating mutations of CaSR gene will lead to a decreased reabsorption of divalent cations (like calcium and magnesium). Thus, this phenotype results in low or normal PTH, low or normal serum calcium levels, hypomagnesemia, high- normal urinary calcium and magnesium excretion (due to increased activation of the CaSR gene in kidneys) and nephrocalcinosis with recurrent nephrolithiasis. Thiazide diuretics are effective in these patients and vitamin D supplementation should be considered with caution. Therapeutic attempts using CASR antagonists (calcilytics) to treat ADH are currently investigated. However, familiar hypomagnesemia with hypercalciuria and nephrocalcinosis as well as primary hypomagnesemia with secondary hypocalcaemia should also be discussed as differential diagnoses in this case. The teaching point of our case is the need of magnesium testing and additional cardiological observation regarding possibly fatal arrhythmias in these subjects. Also genetic and metabolic phenotyping of all family members in such cases is important.
Bones Versus Teeth
Authors: Mammadova Aytan Siraj , Hodge MaKenzie , Folawewo Kehinde Matilda , Cobbs Elizabeth , Nunlee-Bland Gail Louise , Odonkor Wolali Akua-Sabia , Ganta Vijaya A , Zenebe Anteneh Woldetensay 
Published: May 2021

Abstract
Introduction: A 200% increase in population growth among those over 85 is projected in the United States by 2050. Approximately half of women over 50 will experience an osteoporotic fracture in their lifetime. Osteoporosis disproportionately affects old-old adults (those between 85 and 95) as more than half of those admitted to the hospital for hip fracture are over 80 years of age. Older adults are also likely to need dental care. The American Dental Association guidelines offer preventive recommendations for those over 60 years of age but do not address the nuances of treatment options for nonagenarian persons. This case illustrates the treatment dilemma of nonagenarians wishing to optimize both bone and dental health. Case: We have a 95-year-old performance artist, who seeks to optimize bone health in the face of recommended dental work. She has been physically active her whole life and consumes adequate quantities of calcium and Vitamin D. She doesn’t smoke but has needed periodic glucocorticoids for exacerbations of chronic lung disease. At age 84 she began ibandronate but stopped due to worsening of esophageal reflux. She was then treated with teriparatide for 2 years. DEXA scans have shown declining hip T scores from -2.8 at age 88 to -3.5 at age 94 (osteoporotic bone density: T-score lower than -2.5). Her dentist recommended the extraction of several teeth before beginning zoledronate. She refused tooth extraction and sought treatment options to enhance her bone density. Discussion: Persons of advanced age are likely to have oral health problems requiring dental treatment. Bone health treatments such as bisphosphonates and denosumab are generally safe but can potentially cause osteonecrosis of the jaw even with simple tooth extraction in old-old population. Specific guidelines are lacking for treatment to maintain bone and dental health. The American Association of Oral and Maxillofacial Surgeons suggests that extractions and implants can be conducted as usual in patients who have been treated with oral bisphosphonates for less than four years and lack other clinical risk factors. A delay of two months is suggested for those who have been treated for more than four years or has taken glucocorticoids concomitantly. The approach is uncertain for old-old adults who are taking treatment but develop a need for dental surgery. More research is needed about options for optimizing dental health while enhancing bone density in aging population.