Publication Details > Case Report Type > Insight into disease pathogenesis or mechanism of therapy

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S Ludgate Department of Diabetes and Endocrinology, Ryde Hospital, Eastwood, N ew South Wales, Australia

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M Lin Department of Diabetes and Endocrinology, Ryde Hospital, Eastwood, N ew South Wales, Australia

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M Mayadunne Department of Diabetes and Endocrinology, Ryde Hospital, Eastwood, N ew South Wales, Australia

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J Steen Department of Diabetes and Endocrinology, Ryde Hospital, Eastwood, N ew South Wales, Australia

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K W Ho Department of Diabetes and Endocrinology, Ryde Hospital, Eastwood, N ew South Wales, Australia
Department of Medicine, Macquarie University, Sydney, Australia
Department of Medicine, University of Western Sydney, Sydney, Australia

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Summary

Thyrotoxic periodic paralysis (TPP) is a rare condition characterised by acute onset hypokalaemia and paralysis which most commonly affects men of Asian descent between the ages of 20 and 40 years (1, 2). It has been reported in approximately 2% of patients with thyrotoxicosis in China and Japan (1, 2, 3). Hypokalaemia in TPP results from a massive intracellular shift of potassium induced by the thyroid hormone sensitisation of Na+/K+-ATPase (4). Treatment of TPP includes prevention of this shift by using beta-blockade, rapid potassium replacement and treatment of the underlying hyperthyroidism. We present two cases of TPP with differing outcomes. In the first case, a 33-year-old Filipino gentleman presented to our emergency department (ED) with a 3-month history of recurrent proximal lower limb weakness. Serum potassium was 2.2 mmol/L (3.3–5.1) and he was given i.v. potassium replacement. Thyroid function tests (TFTs) and thyroid antibodies were consistent with Graves thyrotoxicosis. He was discharged home on carbimazole and remains well controlled on long-term medical therapy. In the second case, a 22-year-old Malaysian gentleman presented to our ED with new-onset bilateral lower limb painless paralysis. Serum potassium was 1.9 mmol/L with TFTs demonstrating Graves thyrotoxicosis. He was treated with i.v. potassium replacement and discharged home on carbimazole and propranolol. He represented to the hospital on two further occasions with TPP and was advised to consider total thyroidectomy given his refractory Graves’ disease. These cases highlight the importance of prompt recognition of this rare life-threatening complication of Graves’ disease, especially in patients of Asian descent.

Learning points

  • Thyrotoxic periodic paralysis is a rare condition characterised by hypokalaemia and acute painless muscle weakness in the presence of thyrotoxicosis.

  • The signs and symptoms of thyrotoxicosis can be subtle in these patients.

  • It is most commonly seen in Asian males between the ages of 20 and 40 and is most frequently caused by Graves’ disease.

  • Prompt recognition is essential as it is a life-threatening condition.

  • Urgent i.v. potassium replacement and beta-blockade with a non-selective beta-blocker are the mainstays of treatment.

  • i.v. potassium replacement should not be given in dextrose as this can potentiate hypokalaemia.

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Diana Festas Silva Endocrinology, Diabetes and Metabolism Department, Coimbra Hospital and University Centre, Coimbra, Portugal

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Adriana De Sousa Lages Faculty of Medicine of the University of Coimbra, Coimbra, Portugal
Endocrinology Department, Braga Hospital, Braga, Portugal

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Joana Serra Caetano Pediatric Endocrinology, Diabetes and Growth Department, Coimbra Pediatric Hospital, Coimbra, Portugal

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Rita Cardoso Pediatric Endocrinology, Diabetes and Growth Department, Coimbra Pediatric Hospital, Coimbra, Portugal

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Isabel Dinis Pediatric Endocrinology, Diabetes and Growth Department, Coimbra Pediatric Hospital, Coimbra, Portugal

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Leonor Gomes Endocrinology, Diabetes and Metabolism Department, Coimbra Hospital and University Centre, Coimbra, Portugal
Faculty of Medicine of the University of Coimbra, Coimbra, Portugal

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Isabel Paiva Endocrinology, Diabetes and Metabolism Department, Coimbra Hospital and University Centre, Coimbra, Portugal

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Alice Mirante Pediatric Endocrinology, Diabetes and Growth Department, Coimbra Pediatric Hospital, Coimbra, Portugal

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Summary

Hypoparathyroidism is characterized by low or inappropriately normal parathormone production, hypocalcemia and hyperphosphatemia. Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene. Current treatments for ADH type 1 include supplementation with calcium and active vitamin D. We report a case of hypoparathyroidism in an adolescent affected by syncope without prodrome. The genetic testing revealed a variant in the CASR gene. Due to standard therapy ineffectiveness, the patient was treated with recombinant human parathyroid hormone (1–34), magnesium aspartate and calcitriol. He remained asymptomatic and without neurological sequelae until adulthood. Early diagnosis and treatment are important to achieve clinical stability.

Learning points

  • Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene.

  • The variant c.368T>C (p.Leu123Ser) in heterozygosity in the CASR gene is likely pathogenic and suggests the diagnosis of ADH type 1.

  • Teriparatide (recombinant human parathyroid hormone 1–34) may be a valid treatment option to achieve clinical stability for those individuals whose condition is poorly controlled by current standard therapy.

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Ana Dugic Department for Gastroenterology, Endocrinology and Metabolic Diseases, Bayreuth University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Bayreuth, Germany

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Michael Kryk Department for Gastroenterology, Endocrinology and Metabolic Diseases, Bayreuth University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Bayreuth, Germany

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Claudia Mellenthin Department of Surgery, HFR Fribourg, Fribourg, Switzerland

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Christoph Braig Department for Gastroenterology, Endocrinology and Metabolic Diseases, Bayreuth University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Bayreuth, Germany

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Lorenzo Catanese Department for Nephrology, Angiology and Rheumatology, Bayreuth University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Bayreuth, Germany

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Sandy Petermann Department for Gastroenterology, Endocrinology and Metabolic Diseases, Bayreuth University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Bayreuth, Germany

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Jürgen Kothmann Department for Nephrology, Angiology and Rheumatology, Bayreuth University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Bayreuth, Germany

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Steffen Mühldorfer Department for Gastroenterology, Endocrinology and Metabolic Diseases, Bayreuth University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Bayreuth, Germany

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Summary

Drinking fruit juice is an increasingly popular health trend, as it is widely perceived as a source of vitamins and nutrients. However, high fructose load in fruit beverages can have harmful metabolic effects. When consumed in high amounts, fructose is linked with hypertriglyceridemia, fatty liver and insulin resistance. We present an unusual case of a patient with severe asymptomatic hypertriglyceridemia (triglycerides of 9182 mg/dL) and newly diagnosed type 2 diabetes mellitus, who reported a daily intake of 15 L of fruit juice over several weeks before presentation. The patient was referred to our emergency department with blood glucose of 527 mg/dL and glycated hemoglobin (HbA1c) of 17.3%. Interestingly, features of diabetic ketoacidosis or hyperosmolar hyperglycemic state were absent. The patient was overweight with an otherwise unremarkable physical exam. Lipase levels, liver function tests and inflammatory markers were closely monitored and remained unremarkable. The initial therapeutic approach included i.v. volume resuscitation, insulin and heparin. Additionally, plasmapheresis was performed to prevent potentially fatal complications of hypertriglyceridemia. The patient was counseled on balanced nutrition and detrimental effects of fruit beverages. He was discharged home 6 days after admission. At a 2-week follow-up visit, his triglyceride level was 419 mg/dL, total cholesterol was 221 mg/dL and HbA1c was 12.7%. The present case highlights the role of fructose overconsumption as a contributory factor for severe hypertriglyceridemia in a patient with newly diagnosed diabetes. We discuss metabolic effects of uncontrolled fructose ingestion, as well as the interplay of primary and secondary factors, in the pathogenesis of hypertriglyceridemia accompanied by diabetes.

Learning points

  • Excessive dietary fructose intake can exacerbate hypertriglyceridemia in patients with underlying type 2 diabetes mellitus (T2DM) and absence of diabetic ketoacidosis or hyperosmolar hyperglycemic state.

  • When consumed in large amounts, fructose is considered a highly lipogenic nutrient linked with postprandial hypertriglyceridemia and de novo hepatic lipogenesis (DNL).

  • Severe lipemia (triglyceride plasma level > 9000 mg/dL) could be asymptomatic and not necessarily complicated by acute pancreatitis, although lipase levels should be closely monitored.

  • Plasmapheresis is an effective adjunct treatment option for rapid lowering of high serum lipids, which is paramount to prevent acute complications of severe hypertriglyceridemia.

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Ashwini Maudhoo Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

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Avinaash Maharaj Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

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Federica Buonocore Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK

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Gabriel Angel Martos-Moreno Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain

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Jesús Argente Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
CEI UAM + CSIC, IMDEA Food Institute, Madrid, Spain

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John C Achermann Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK

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Li F Chan Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

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Lou A Metherell Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

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Summary

Congenital isolated ACTH deficiency (IAD) is a rare condition characterised by low plasma ACTH and serum cortisol with normal production of other pituitary hormones. TBX19 (also known as TPIT) is a T-box pituitary restricted transcription factor important for POMC gene transcription and terminal differentiation of POMC-expressing cells. TBX19 gene mutations have been shown to cause neonatal-onset congenital IAD. We report a neonate of Romanian origin, who presented at 15 h of life with respiratory arrest and hypoglycaemia which recurred over the following 2 weeks. Biochemical investigations revealed IAD, with undetectable serum cortisol (cortisol < 1 μg/dL; normal range (NR): 7.8–26.2) and plasma ACTH levels within the normal range (22.1 pg/mL; NR: 4.7–48.8). He responded to hydrocortisone treatment. Patient DNA was analysed by a HaloPlex next-generation sequencing array targeting genes for adrenal insufficiency. A novel homozygous synonymous mutation p.Thr96= (Chr1:168260482; c.288G>A; rs376493164; allele frequency 1 × 10−5, no homozygous) was found in exon 2 of the TBX19 gene. The effect of this was assessed by an in vitro splicing assay, which revealed aberrant splicing of exon 2 giving rise to a mutant mRNA transcript whereas the WT vector spliced exon 2 normally. This was identified as the likely cause of IAD in the patient. The predicted protein product would be non-functional in keeping with the complete loss of cortisol production and early presentation in the patient.

Learning points

  • Synonymous variants (a nucleotide change that does not alter protein sequence) usually thought to be benign may still have detrimental effects on RNA and protein function causing disease. Hence, they should not be ignored, especially if very rare in public databases.

  • In vitro splicing assays can be employed to characterise the consequence of intronic and exonic nucleotide gene changes that may alter splicing.

  • Establishing a diagnosis due to a TBX19 mutation is important as it defines a condition of isolated ACTH deficiency not associated with additional pituitary deficiencies.

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Fiona Melzer Institute of Diabetes and Clinical Metabolic Research, Kiel, Germany

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Corinna Geisler Institute of Diabetes and Clinical Metabolic Research, Kiel, Germany

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Dominik M Schulte Institute of Diabetes and Clinical Metabolic Research, Kiel, Germany
Department of Medicine 1, Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Schleswig-Holstein, Kiel, Germany

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Matthias Laudes Institute of Diabetes and Clinical Metabolic Research, Kiel, Germany
Department of Medicine 1, Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Schleswig-Holstein, Kiel, Germany

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Summary

Familial partial lipodystrophy (FPLD) syndromes are rare heterogeneous disorders especially in women characterized by selective loss of adipose tissue, reduced leptin levels and severe metabolic abnormalities. Here we report a 34-year-old female with a novel heterozygotic c.485 thymine>guanine (T>G) missense variant (p.phenylalanine162cysteine; (Phe162Cys)) in exon 4 of the peroxisome proliferator-activated receptor gamma (PPARG) gene, developing a non-ketotic diabetes and severe hypertriglyceridemia with triglyceride concentrations >50 mmol/L. In this case, a particular interesting feature in comparison to other known PPARG mutations in FPLD is that while glycaemic control could be achieved through standard anti-diabetic medication, hypertriglyceridemia did neither respond to fibrate nor to omega-3-fatty acid therapy. This might suggest a lipid metabolism driven phenotype of the novel PPARG c.485T>G missense variant. Notably, recombinant leptin replacement therapy (metreleptin (Myalepta®)) was initiated showing a rapid and profound effect on triglyceride levels as well as on liver function tests and satiety feeling. Unfortunately, severe allergic skin reactions developed at the side of injection which could be covered by anti-histaminc treatment. We conclude that the heterozygous PPARG c.485T>G variant is a yet undescribed molecular basis underlying FPLD with difficulties predominantly to control hypertriglyceridemia and that recombinant leptin therapy may be effective in affected subjects.

Learning points

  • Heterozygous c.485T>G variant in PPARG is most likely a cause for FPLD in humans.

  • This variant results in a special metabolic phenotype with a predominant dysregulation of triglyceride metabolism not responding to standard lipid lowering therapy.

  • Recombinant leptin therapy is effective in rapidly improving hypertriglyceridemia.

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Gabriele Costanzo Endocrine Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy

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Salvatore Curatolo Dermatology Unit, Garibaldi Hospital, Catania, Italy

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Barbara Busà Pharmacy Unit, Garibaldi-Nesima Hospital, Catania, Italy

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Antonino Belfiore Endocrine Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy

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Damiano Gullo Endocrine Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy

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Summary

Semaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist, approved for the treatment of type 2 diabetes mellitus (T2DM). GLP-1 analogs exert several biological activities connected not only with an insulinotropic effect but also with immunoregulation and reduction of inflammation. A 73-year-old male patient with class III obesity was referred to us for T2DM, which was not controlled with metformin therapy. He had suffered from plaque psoriasis for some years and was treated with topical therapy and adalimumab, without success. The psoriasis area and severity index (PASI) was 33.2 (indicating severe psoriasis), and the dermatology life quality index (DLQI) was 26.0 (indicating an extremely negative effect on the patient's life). Semaglutide (starting with 0.25 mg/week for 4 weeks, increased to 0.50 mg/week for 12 weeks, and then to 1 mg/week) was added to metformin. After 4 months, glycemic parameters had improved, and his body weight decreased. Unexpectedly, skin lesions of plaque psoriasis improved. PASI decreased by 19% compared with baseline and quality of life, assessed with the DLQI, markedly ameliorated. After 10 months, glycemic and obesity parameters, as well as psoriasis, improved further. HbA1c, BMI, and PASI were reduced by 32, 16.3, and 92%, respectively, compared with the baseline. DLQI declined to 0, meaning there was no effect of plaque psoriasis on the patient’s life.

Learning points

  • Psoriasis in patients with type 2 diabetes is often resistant to therapy.

  • We observed an obese patient with type 2 diabetes mellitus who achieved glycemic control and weight loss with the addition of semaglutide to metformin and had a relevant and long-lasting improvement of plaque psoriasis, which was previously resistant to biologic therapy.

  • Therapy with semaglutide may be attempted in eligible patients with difficult to treat plaque psoriasis.

Open access
Amir Babiker College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia
King Abdullah Specialized Children Hospital, Ministry of the National Guard Health Affairs, Riyadh, Saudi Arabia
King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

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Wejdan Al Hamdan College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia

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Sondos Kinani College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia

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Yasser Kazzaz College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia
King Abdullah Specialized Children Hospital, Ministry of the National Guard Health Affairs, Riyadh, Saudi Arabia
King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

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Abdelhadi Habeb Department of Pediatrics, Ministry of the National Guard Health Affairs, Madinah, Saudi Arabia

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Talal Al Harbi College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia
King Abdullah Specialized Children Hospital, Ministry of the National Guard Health Affairs, Riyadh, Saudi Arabia
King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

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Mohammed Al Dubayee College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia
King Abdullah Specialized Children Hospital, Ministry of the National Guard Health Affairs, Riyadh, Saudi Arabia
King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

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M Al Namshan College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia
King Abdullah Specialized Children Hospital, Ministry of the National Guard Health Affairs, Riyadh, Saudi Arabia
King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

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Abdul Aleem Attasi College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia
King Abdullah Specialized Children Hospital, Ministry of the National Guard Health Affairs, Riyadh, Saudi Arabia
King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

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Summary

The use of antihypertensive medications in patients with pheochromocytomas and paragangliomas (PCC/PG) is usually a challenge. We report a case of familial paraganglioma that was successfully treated by esmolol and other antihypertensive medications without associated perioperative complications. Our patient was an 11-year-old girl who presented with classic symptoms and signs of PCC/PG and a CT scan of the abdomen that showed a right-sided paravertebral mass. Her father was diagnosed with paraganglioma a few years ago. Prazosin had been started but she continued to experience uncontrolled paroxysms of blood pressure (BP). She was known to have asthma; hence, she developed serious bronchospasm with atenolol. She was, therefore, switched to esmolol that successfully controlled her BP in addition to prazosin and intermittent doses of hydralazine prior to laparoscopic surgery with no side effects of medications or postoperative complications. Esmolol could be a good alternative to routinely used beta-blockers in children with PCC/PG with labile hypertension and related symptoms in the pre and intra-operative periods. It is titrable, effective, and can be weaned rapidly helping to avoid postoperative complications. Further larger studies on the use of esmolol in children with PCC/PG are needed to confirm our observation.

Learning points

  • In addition to alpha-blockers, esmolol could be a good alternative for routinely used beta-blockers to control paroxysmal hypertension and tachycardia in the pre- and intra-operative periods.

  • Esmolol is titrable and an effective beta-blocker. It can be weaned rapidly helping to avoid postoperative complications in children with PCC/PG.

  • Children with PCC/PG and other comorbidity like asthma may particularly benefit from the use of esmolol due to no or less side effects on airway resistance and the advantage of rapid titration of the medication compared to other beta-blockers.

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Jasmine Jiang Zhu Department of Endocrinology, Austin Health, Victoria, Australia

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William J Naughton Department of Infectious Diseases, Austin Health, Victoria, Australia

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Kim Hay Be Liver Transplant Unit, Austin Health, Victoria, Australia

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Nicholas Ensor Liver Transplant Unit, Austin Health, Victoria, Australia

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Ada S Cheung Department of Endocrinology, Austin Health, Victoria, Australia
Department of Medicine (Austin Health), The University of Melbourne, Victoria, Australia

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Summary

Hypercalcaemia is a very common endocrine condition, yet severe hypercalcaemia as a result of fungal infection is rarely described. There are have only been two reported cases in the literature of hypercalcaemia associated with Cryptococcus infection. Although the mechanism of hypercalcaemia in these infections is not clear, it has been suggested that it could be driven by the extra-renal production of 1-alpha-hydroxylase by macrophages in granulomas. We describe the case of a 55-year-old woman with a 1,25-OH D-mediated refractory hypercalcaemia in the context of a Cryptococcus neoformans infection. She required treatment with antifungals, pamidronate, calcitonin, denosumab and high-dose glucocorticoids. A disseminated fungal infection should be suspected in immunosuppressed individuals presenting with hypercalcaemia.

Learning point

  • In immunocompromised patients with unexplained hypercalcaemia, fungal infections should be considered as the differential diagnoses;

  • Glucocorticoids may be considered to treat 1,25-OH D-driven hypercalcaemia; however, the benefits of lowering the calcium need to be balanced against the risk of exacerbating an underlying infection;

  • Fluconazole might be an effective therapy for both treatment of the hypercalcaemia by lowering 1,25-OH D levels as well as of the fungal infection.

Open access
Laura Marino Department of Service of Endocrinology, Diabetes, and Metabolism, Faculty of Biology and Medicine, University of Lausanne, Lausanne University Hospital, Lausanne, Vaud, Switzerland

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Andrea Messina Department of Service of Endocrinology, Diabetes, and Metabolism, Faculty of Biology and Medicine, University of Lausanne, Lausanne University Hospital, Lausanne, Vaud, Switzerland

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James S Acierno Department of Service of Endocrinology, Diabetes, and Metabolism, Faculty of Biology and Medicine, University of Lausanne, Lausanne University Hospital, Lausanne, Vaud, Switzerland

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Franziska Phan-Hug Department of Service of Endocrinology, Diabetes, and Metabolism, Faculty of Biology and Medicine, University of Lausanne, Lausanne University Hospital, Lausanne, Vaud, Switzerland

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Nicolas J Niederländer Department of Service of Endocrinology, Diabetes, and Metabolism, Faculty of Biology and Medicine, University of Lausanne, Lausanne University Hospital, Lausanne, Vaud, Switzerland

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Federico Santoni Department of Service of Endocrinology, Diabetes, and Metabolism, Faculty of Biology and Medicine, University of Lausanne, Lausanne University Hospital, Lausanne, Vaud, Switzerland

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Stefano La Rosa Department of Laboratory Medicine and Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Vaud, Switzerland

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Nelly Pitteloud Department of Service of Endocrinology, Diabetes, and Metabolism, Faculty of Biology and Medicine, University of Lausanne, Lausanne University Hospital, Lausanne, Vaud, Switzerland

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Summary

Complete androgen-insensitivity syndrome (CAIS), a disorder of sex development (46,XY DSD), is caused primarily by mutations in the androgen receptor (AR). Gonadectomy is recommended due to the increased risk of gonadoblastoma, however, surgical intervention is often followed by loss of libido. We present a 26-year-old patient with CAIS who underwent gonadectomy followed by a significant decrease in libido, which was improved with testosterone treatment but not with estradiol. Genetic testing was performed and followed by molecular characterization. We found that this patient carried a previously unidentified start loss mutation in the androgen receptor. This variant resulted in an N-terminal truncated protein with an intact DNA binding domain and was confirmed to be loss-of-function in vitro. This unique CAIS case and detailed functional studies raise intriguing questions regarding the relative roles of testosterone and estrogen in libido, and in particular, the potential non-genomic actions of androgens.

Learning points

  • N-terminal truncation of androgen receptor can cause androgen-insensitivity syndrome.

  • Surgical removal of testosterone-producing gonads can result in loss of libido.

  • Libido may be improved with testosterone treatment but not with estradiol in some forms of CAIS.

  • A previously unreported AR mutation – p.Glu2_Met190del (c.2T>C) – is found in a CAIS patient and results in blunted AR transcriptional activity under testosterone treatment.

Open access
Kei Ito Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Jun Ito Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Yuki Yamamoto Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Rikako Nakajima Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Masanao Fujii Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Yukino Katakura Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Aiko Muramatsu Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Norio Takayashiki Department of Pathology, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Kazuhiro Toyama Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

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Mineo Kurokawa Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

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Hiroaki Yagyu Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Miyamachi, Mito-shi, Ibaraki, Japan

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Summary

A 61-year-old man developed central diabetes insipidus caused by mixed histiocytosis (MH) representing Langerhans cell histiocytosis overlapping with Erdheim–Chester disease. Bone, skin, vascular, and retroperitoneal involvements were also observed. Dynamic hormonal testing showed normal responses for anterior pituitary hormones, except for impaired secretion of growth hormone (GH). MRI of the brain showed thickening of the pituitary stalk with slightly reduced signal hyperintensity in the posterior pituitary lobe on T1-weighted imaging. During 2 years of follow-up without radical treatment for MH, imaging studies suggested extension of vascular and retroperitoneal involvements. In contrast, brain MRI did not show any particular interval changes, except for the disappearance of hyperintense signalling in the posterior pituitary lobe. Moreover, no other anterior pituitary dysfunctions beyond GH deficiency emerged during the 2 years of follow-up. The natural history of MH in this case is described, focusing on serial assessments of pituitary functions using dynamic tests.

Learning points

  • Erdheim–Chester disease and Langerhans cell histiocytosis overlapping as MH was described, focusing on pituitary functions.

  • MH caused both GH deficiency and central diabetes insipidus.

  • Despite a lack of radical therapy for MH, no other anterior pituitary dysfunctions emerged for 2 years.

  • Radiological images showed no particular interval changes in pituitary stalk lesions, while vascular and retroperitoneal involvements extended.

Open access