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Open access

Insulinoma: a quarter century of dietary control

Hessa Boharoon, Shaunak Navalkissoor, Tu Vinh Luong, Martyn Caplin, and Ashley Grossman

Summary

Insulinomas are rare pancreatic neuroendocrine neoplasms (NENs) that are typically sporadic and solitary, with the majority being <2 cm in diameter at diagnosis. The median duration of symptoms before diagnosis is variable; however, this is usually in the region of 12–18 months. We report on an insulinoma diagnosed some 25 years following initial symptoms, having by that stage attained a diameter of 4 cm. We present a 50-year-old man who was reported with hypoglycaemic symptoms on his wedding 25 years prior to eventual confirmation of an insulinoma. He had since learned to live with the symptoms by eating frequently to manage his hypoglycaemia. However, over recent months, he reported a substantial deterioration in his symptoms, and indeed, had collapsed on two occasions. He had a fasting glucose of 2.9 mmol/L with grossly inappropriate elevated insulin and C-peptide levels. MRI demonstrated a 4.1 cm lesion at the body of pancreas and an indeterminate 9-mm liver lesion with a negative 68Gallium-DOTATATE PET scan. Accordingly, he was initiated on diazoxide and referred to the surgical team for distal pancreatectomy: histology confirmed a 4.4-cm well-differentiated pancreatic NEN of intermediate grade (NEN G2, Grade 2, 2017 World Health Organization (WHO) pancreatic-NEN classification), with positive immunohistochemistry for insulin. His hypoglycaemia episodes have ceased, and he remains under active surveillance. Our case demonstrates the possibility of dietary control of insulinoma-induced hypoglycaemia, and the likelihood that such a prolonged delay in diagnosis has led to the uncommonly large size of the apparently benign tumour which is usually ‘small and indolent’.

Learning points

  • Most patients with insulinomas have lesions that are 1–2 cm in size, with 96% being less than 3 cm.

  • The mean tumour size of insulinomas found in 3 of the largest reported series was 1.5 cm, with a range of 0.1–7.0 cm.

  • It is not uncommon for patients to have symptoms for several months to years before diagnosis; however, no reported cases had the symptoms such long for 25 years, and the large size of the tumour in this case may reflect the very long history.

Open access

Adrenal haemorrhage and infarction in the setting of vaccine-induced immune thrombocytopenia and thrombosis after SARS-CoV-2 (Oxford–AstraZeneca) vaccination

Anneke Graf, Eleni Armeni, Louise Dickinson, Matthew Stubbs, Brian Craven, Umasuthan Srirangalingam, and Teng-Teng Chung

Summary

Rare cases of vaccine-induced Immune thrombocytopenia and thrombosis (VITT) are being identified after vaccination with the SARS-CoV-2 Oxford–AstraZeneca vaccination. We report on two such patients with associated adrenal involvement, which is now being recognised. Both patients presented with abdominal pain, back pain and vomiting. Case 1 was a 46-year-old male who had received the first dose of the Oxford–AstraZeneca vaccination 8 days earlier. Imaging demonstrated a number of serious thrombotic complications including evolving bilateral adrenal haemorrhage (right adrenal haemorrhage identified at presentation, with the left-sided changes only evident on day 4 of the admission). Case 2 was a 38-year-old female who had received the first dose of Oxford–AstraZeneca vaccination 11 days prior. Imaging demonstrated left renal vein thrombosis and left adrenal infarction. VITT was diagnosed in both cases given these changes and other consistent haematological findings. Both patients were treated empirically for adrenal insufficiency, a diagnosis subsequently confirmed in case 1. We report these two cases of VITT presenting with adrenal complications (haemorrhage and infarction) after Oxford–AstraZeneca vaccination to highlight the association and the need for prompt management of co-existing adrenal insufficiency, especially given the potential for evolving adrenal involvement.

Learning points

  • Adrenal complications (thrombosis/infarction/haemorrhage) may develop as a part of vaccine-induced immune thrombocytopenia (VITT) after SARS-CoV-2 Oxford–AstraZeneca vaccination.

  • Evolving adrenal involvement is possible and ongoing assessment is required to identify this promptly.

  • Cortisol levels may be difficult to interpret when assessing for adrenal insufficiency, given high doses of corticosteroids may be used to manage VITT.

  • Clinicians should have a low threshold for starting empirical replacement with corticosteroids until reliable assessment of adrenal function can be performed.

Open access

Non-balanced translocation between the short arms of chromosomes 8 and 6 associated with type 1 diabetes mellitus

Vitor Scalone Netto, Gabriel Bellincanta, Guido de Paula Colares Neto, Nara Michelle de Araujo Evangelista, Carolina Costa Figueiredo, Patricia Salmona, and Vânia de Fátima Tonetto-Fernandes

Summary

We describe a rare case of a girl with an initial diagnostic hypothesis of chromosome 8 trisomy based on clinical findings and karyotyping, which identified a structural change in the short arm of chromosome 8 (46,XX,add(8)(p23)). At the age of 7, she developed type 1 diabetes mellitus and started insulin therapy with multiple daily doses, and then she started to use a continuous insulin infusion system (pump) at 10 years of age. At the age of 12, she underwent a molecular study that identified an unbalanced translocation between the short arms of chromosomes 6 and 8 – 46,XX,add(8)(p23).ish der(8)t(6;8)(GS-196I5+;RP-11338B22−).

Learning points

  • Patients with an unbalanced translocation between the short arms of chromosomes 6 and 8 – 46,XX,add(8)(p23).ish der(8)t(6;8)(GS-196I5+;RP-11338B22-) may present syndromic features suggestive of chromosome 8 trisomy.

  • Main characteristics are a prominent forehead, ocular and breast hypertelorism, ocular, external ear and palate abnormalities, a short neck, heart defects, and developmental delay.

  • Patients with 46,XX,add(8)(p23).ish der(8)t(6;8)(GS-196I5+;RP-11338B22-) may present autoimmune type 1 diabetes mellitus.

  • Karyotyping is an essential tool for the diagnosis of chromosomal changes, but it has some limitations.

  • Multiplex ligation-dependent probe amplification, array-single nucleotide polymorphism and fluorescence in situ hybridization can help diagnose genetic syndromes in patients with atypical evolution.

Open access

Monogenic diabetes due to an INSR mutation in a child with severe insulin resistance

Elaine E Sanderson, Mark Shah, Amanda J Hooper, Damon A Bell, and Catherine S Choong

Summary

We report a case of an 11-year-old girl presenting with a new diagnosis of diabetes associated with a heterozygous missense mutation in the insulin receptor (INSR) gene. This case highlights that INSR gene variants can be a cause for monogenic diabetes in children and adolescents and the need for genetic evaluation in atypical presentations of diabetes. We also describe the possible role of metformin in treating individuals with type A insulin resistance syndrome due to INSR gene variants.

Learning points

  • Insulin receptor (INSR) gene variants can be a cause of monogenic diabetes in children and adolescents.

  • Genetic evaluation should be considered in children and adolescents with type 2 diabetes (T2D), particularly where there is an atypical presentation and/or positive family history.

  • Metformin may have a role in the treatment of type A insulin resistance syndrome due to heterozygous mutation of the INSR gene.

Open access

Pheochromocytoma due to a novel SDHD variant presenting as unilateral visual loss

Clare Miller, Agnieszka Pazderska, John Reynolds, Patricia Gou, Barbara Dunne, Kealan McElhinney, and Lisa Owens

Summary

A 53-year-old female presented to a tertiary ophthalmology referral centre complaining of unilateral painless loss of vision. Subsequent assessment revealed malignant hypertension causing right-sided cystoid macular oedema. During the course of secondary hypertension workup, she was diagnosed with a 7.8 cm phaeochromocytoma which was resected. Testing for a panel of all predisposing phaeochromocytoma-causing variants using next-generation sequencing resulted in the diagnosis of a novel SDHD variant.

Learning points

  • Screening for secondary causes of hypertension is indicated when there is evidence of hypertension-mediated end-organ damage ().

  • Testing for a predisposing variant should be considered in all patients with phaeochromocytoma or paraganglioma due to the high heritability rate and prevalence of somatic variants (, , ).

  • Novel variants are commonly uncovered in the Succinate Dehydrogenase (SDH) subunit; proving pathogenicity is a complex, time-consuming process and one challenge of next-generation sequencing ().

  • SDHB immunohistochemistry as a tool for demonstrating pathogenicity is associated with reduced sensitivity when assessing SDHD variants (, ).

Open access

Immobilization-induced hypercalcemia in a patient with renal failure

Anand Gandhi, Mike Mortensen, Sonie Sunny, Pawarid Techathaveewat, Jerome Targovnik, and Mahmoud Alsayed

Summary

Immobilization-induced hypercalcemia is an uncommon cause of elevated calcium which is usually diagnosed following extensive systemic workup and exclusion of more common etiologies. Previously reported cases have largely described this phenomenon in adolescents and young adults a few weeks to months after the initial onset of immobilization. Metabolic workup tends to demonstrate hypercalcemia, hypercalciuria, and eventual osteoporosis. While the exact mechanism remains largely unclear, a dysregulation between bone resorption and formation is central to the pathogenesis of this disease. Decreased mechanical loading from prolonged bedrest tends to increase osteoclast induced bone resorption while promoting osteocytes to secrete proteins such as sclerostin to reduce osteoblast mediated bone formation. We describe the case of an 18-year-old male who was admitted following intraabdominal trauma. He underwent extensive abdominal surgery including nephrectomy resulting in initiation of dialysis. After 6 months of hospitalization, the patient gradually began developing uptrending calcium levels. Imaging and laboratory workup were unremarkable for any PTH-mediated process, malignancy, thyroid disorder, adrenal disorder, or infection. Workup did reveal significant elevated bone turnover markers which in combination with the clinical history led the physicians to arrive at the diagnosis of immobilization induced hypercalcemia. In order to prevent decreased rates of bone loss, the patient was administered denosumab for treatment. Hypocalcemia followed treatment expectedly and was repleted with supplementation via the patient’s total parenteral nutrition.

Learning points

  • Immobilization-induced hypercalcemia should remain as a differential diagnosis of patients with prolonged hospitalizations with hypercalcemia.

  • Extensive workup of common etiologies of hypercalcemia should be considered prior to arriving at this diagnosis.

  • Denosumab, while off-label for this usage, offers an effective treatment option for immobilization-induced hypercalcemia though it carries a risk of hypocalcemia especially among patients with renal disease.

Open access

Factitious Cushing’s syndrome, hypopituitarism, and self-provoked skin lesions: when the skin mirrors the soul

Salvatore Cannavò and Serafinella Patrizia Cannavò

Summary

Factitious Cushing’s syndrome (CS) is a very rare form of Münchausen syndrome. Its presentation and course are extremely heterogeneous, and diagnosis is generally challenging. We report the case of a 52-year-old woman who was initially investigated because of the occurrence of cushingoid features. Nevertheless, endocrine work-up showed very low morning plasma ACTH and serum cortisol levels. In addition, it also demonstrated central hypopituitarism and hypogonadotropic hypogonadism. Head MRI showed a small pituitary mass. Based on these results, and probably overlooking the initial clinical suspicion, general practitioner (GP) referred the patient to our Endocrine Unit for hypopituitarism. At inspection, moon face, central obesity, and bruising were evident. Multiple ulcerative skin lesions were also concentrated in the right arm and leg. Dermatology evaluation suggested that the lesions were self-provoked. For several days, the patient denied the assumption of corticosteroids, but we finally discovered that the GP’ nurse had prescribed betamethasone without the GP’s knowledge for about 2 years. In conclusion, the surreptitious assumption of corticosteroids is very rare, but the physicians should be aware that pituitary function could be impaired by high doses of corticosteroids, mimicking hypopituitarism. In these patients, a multidisciplinary approach and environmental investigation can be useful to diagnose factitious CS.

Learning points

  • Surreptitious assumption of corticosteroids can cause heterogeneous presentation, ranging from Cushing’s syndrome to multiple hypopituitarism.

  • Suppression of ACTH and cortisol levels in a patient with cushingoid features firstly suggests surreptitious assumption of corticosteroids.

  • A multidisciplinary approach can be extremely useful in patients with suspected factitious Cushing’s syndrome.

  • Sometimes, to prove surreptitious assumption of corticosteroids needs environmental investigation.

Open access

Dual attack: targeting the rare co-occurrence of myasthenia gravis and Graves’ disease with radioactive iodine therapy

Anna Elvira S Arcellana, Karen Joy B Adiao, and Myrna Buenaluz-Sedurante

Summary

Occasionally, autoimmune disorders can come in twos. This double trouble creates unique challenges. Myasthenia gravis co-existing with autoimmune thyroid disease occurs in only about 0.14–0.2% of cases. The patient is a 27-year-old man with a 2-month history of bilateral ptosis, diplopia, with episodes of easy fatigability, palpitations, and heat intolerance. On physical exam, the patient had an enlarged thyroid gland. Myasthenia gravis was established based on the presence of ptosis with weakness of the intraocular muscles, abnormal fatigability, and a repetitive nerve stimulation study indicated neuromuscular junction disease. Episodes of fluctuating right shoulder weakness were also noted. He was also found to have elevated FT3, FT4, and a suppressed TSH. Thyroid ultrasound revealed thyromegaly with diffused parenchymal disease. Thyroid scintigraphy showed increased uptake function at 72.4% uptake at 24 h. TRAb was positive at 4.1 U/L. Patient was started on pyridostigmine which led to a significant reduction in the frequency of ocular muscle weakness. Methimazole was also initiated. Radioactive iodine at 14.9 mci was instituted for the definitive management of hyperthyroidism. After RAI, there was abatement of the hyperthyroid symptoms, as well as improvement in the status of the myasthenia gravis, with ptosis, diplopia, and right arm weakness hardly occurring thereafter despite the reduction of the pyridostigmine dose based on a symptom diary and medication intake record. Two distinct autoimmune conditions displayed a markedly improved clinical course with the institution of radioactive iodine therapy for Graves’ disease.

Learning points

  • The presence of ptosis, diplopia, and fluctuating muscle weakness are atypical in Graves’ disease and should prompt an investigation on the existence of concurrent myasthenia gravis. A prompt diagnosis of both conditions will enable the institution of appropriate management that would target both rare and challenging autoimmune diseases.

  • Selecting the therapeutic options with minimal risk of morbidity and mortality, which could lead to maximal benefit especially in a resource-limited setting is paramount.

  • Targeted non-surgical management can lead to the remission of two autoimmune diseases which can result in patient satisfaction and improved quality of life.

Open access

Oncogenic osteomalacia secondary to glomus tumor

Rishi Raj, Samaneh Hasanzadeh, Mitra Dashtizadeh, Mohammadreza Kalantarhormozi, Katayoun Vahdat, Mohammad Hossein Dabbaghmanesh, Iraj Nabipour, Mohammdreza Ravanbod, Majid Assadi, Basir Hashemi, and Kamyar Asadipooya

Summary

Oncogenic osteomalacia secondary to glomus tumor is extremely rare. Localization of causative tumors is critical as surgical resection can lead to a complete biochemical and clinical cure. We present a case of oncogenic osteomalacia treated with resection of glomus tumor. A 39-year-old woman with a history of chronic sinusitis presented with chronic body ache and muscle weakness. Biochemical evaluation revealed elevated alkaline phosphatase hypophosphatemia, increased urinary phosphate excretion, low calcitriol, and FGF23 was unsuppressed suggestive of oncogenic osteomalacia. Diagnostic studies showed increase uptake in multiple bones. Localization with MRI of paranasal sinuses revealed a sinonasal mass with concurrent uptake in the same area on the octreotide scan. Surgical resection of the sinonasal mass was consistent with the glomus tumor. The patient improved both clinically and biochemically postoperatively. Along with the case of oncogenic osteomalacia secondary to a glomus tumor, we have also discussed in detail the recent development in the diagnosis and management of oncogenic osteomalacia.

Learning points

  • Tumor-induced osteomalacia is a rare cause of osteomalacia caused by the secretion of FGF23 from mesenchymal tumors.

  • Mesenchymal tumors causing TIO are often difficult to localize and treat.

  • Resection of the tumor can result in complete resolution of biochemical and clinical manifestations in a very short span of time.

  • Glomus tumor can lead to tumor induced osteomalacia and should be surgically treated.

Open access

One in a billion: a patient with Marfan syndrome and familial hypocalciuric hypercalcaemia

Su Ann Tee, Paul Brennan, and Anna L Mitchell

Summary

Marfan syndrome is an autosomal dominant multisystem disorder that has an estimated incidence of 1 in 5000. It is caused by mutations in the FBN1 gene, which encodes the extracellular matrix protein type 1 fibrillin. Familial hypocalciuric hypercalcaemia (FHH), also inherited in an autosomal dominant pattern, is a rare benign disorder characterised by hypercalcaemia, hypocalciuria and relative hyperparathyroidism with normal or high plasma PTH levels, with an estimated incidence of between 1 in 10 000 to 1 in 100 000. We report a unique case of a 26-year-old man referred for investigation of hypercalcaemia, who also had clinical features of Marfan syndrome but no previous genetic investigations. Calculated fractional urinary excretion of calcium was low (0.0005) following correction of vitamin D deficiency, raising the possibility of FHH. Genetic testing for Marfan syndrome and FHH, via a hyperparathyroidism multiplex gene panel test, revealed a novel truncating variant in the FBN1 gene (c.8481T>G; p.(Tyr2827Ter)), consistent with Marfan syndrome; and a pathogenic truncating variant in the CaSR gene (c.741dupT; p.[Asp248Ter]), which confirmed the diagnosis of FHH. The patient’s mother was subsequently found to have mild hypercalcaemia (adjusted calcium 2.76 mmol/L) and is also heterozygous for the same CaSR mutation. Genetic testing of his father confirmed the presence of the same FBN1 gene mutation. This case illustrates the importance of making robust diagnoses in the era of modern genomic medicine, confirming FHH as the cause of hypercalcaemia means that no treatment is warranted and the patient can be reassured.

Learning points

  • Familial hypocalciuric hypercalcaemia (FHH) should always be excluded during the investigation of hypercalcaemia by measuring urinary calcium: creatinine clearance ratio.

  • Diagnosing FHH is important as the condition is benign and misdiagnosing patients with primary hyperparathyroidism could potentially lead to unnecessary morbidity from parathyroid surgery.

  • Genetic testing is increasingly available for a variety of inherited conditions including Marfan syndrome and FHH. Patients who present with clinical features suggestive of a particular genetic condition should undergo prompt, appropriate confirmatory testing wherever possible.

  • Taking a thorough family history is vital when assessing patients presenting with endocrine conditions, as this could prompt cascade testing and appropriate genetic counselling where necessary.