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Alessandro Rossini Endocrinology and Diabetes Unit, ASST Papa Giovanni XXIII, Bergamo, Italy

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Francesca Perticone Endocrine Unit, Department of Internal Medicine

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Laura Frosio Endocrine Unit, Department of Internal Medicine

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Marco Schiavo Lena Department of Pathology, San Raffaele Hospital, Milan, Italy

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Roberto Lanzi Endocrine Unit, Department of Internal Medicine

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Summary

ACTH-secreting pheochromocytoma is a very rare cause of Cushing’s syndrome, with a high morbidity and mortality risk due to both cortisol and catecholamines excess. We report the case of a 45-year-old female patient with a 3 cm, high-density, left adrenal mass, diagnosed as an ACTH-secreting pheochromocytoma. The biochemical sensitivity of the tumor to somatostatin analogues was tested by a 100 μg s.c. octreotide administration, which led to an ACTH and cortisol reduction of 50 and 25% respectively. In addition to alpha and beta blockers, preoperative approach to laparoscopic adrenalectomy included octreotide, a somatostatin analogue, together with ketoconazole, in order to achieve an adequate pre-surgical control of cortisol release. Histopathological assessment confirmed an ACTH-secreting pheochromocytoma expressing type 2 and 5 somatostatin receptors (SSTR-2 and -5).

Learning points:

  • ACTH-secreting pheochromocytomas represent a rare and severe condition, characterized by high morbidity and mortality risk.

  • Surgical removal of the adrenal mass is the gold standard treatment, but adequate medical therapy is required preoperatively to improve the surgical outcome and to avoid major complications.

  • Somatostatin analogs, in addition to other medications, may represent a useful therapeutic option for the presurgical management of selected patients.

  • In this sense, the octreotide challenge test is a useful tool to predict favorable therapeutic response to the treatment.

Open access
Sakshi Jhawar Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

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Rahul Lakhotia Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA

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Mari Suzuki Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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James Welch Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Sunita K Agarwal Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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John Sharretts Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Maria Merino Laboratory of Pathology, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA

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Mark Ahlman Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA

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Jenny E Blau Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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William F Simonds Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Jaydira Del Rivero Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA

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Summary

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant condition characterized by parathyroid, anterior pituitary and enteropancreatic endocrine cell tumors. Neuroendocrine tumors occur in approximately in 5–15% of MEN1 patients. Very few cases of ovarian NETs have been reported in association with clinical MEN1 and without genetic testing confirmation. Thirty-three-year-old woman with MEN1 was found to have right adnexal mass on computed tomography (CT). Attempt at laparoscopic removal was unsuccessful, and mass was removed via a minilaparotomy in piecemeal fashion. Pathology showed ovarian NET arising from a teratoma. Four years later, patient presented with recurrence involving the pelvis and anterior abdominal wall. She was treated with debulking surgery and somatostatin analogs (SSAs). Targeted DNA sequencing analysis on the primary adnexal mass as well as the recurrent abdominal wall tumor confirmed loss of heterozygosity (LOH) at the MEN1 gene locus. This case represents to our knowledge, the first genetically confirmed case of ovarian NET arising by a MEN1 mechanism in a patient with MEN1. Extreme caution should be exercised during surgery as failure to remove an ovarian NET en masse can result in peritoneal seeding and recurrence. For patients with advanced ovarian NETs, systemic therapy options include SSAs, peptide receptor radioligand therapy (PRRT) and novel agents targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF).

Learning points:

  • Ovarian NET can arise from a MEN1 mechanism, and any adnexal mass in a MEN1 patient can be considered as a possible malignant NET.

  • Given the rarity of this disease, limited data are available on prognostication and treatment. Management strategies are extrapolated from evidence available in NETs from primaries of other origins.

  • Care should be exercised to remove ovarian NETs en bloc as failure to do so may result in peritoneal seeding and recurrence.

  • Treatment options for advanced disease include debulking surgery, SSAs, TKIs, mTOR inhibitors, PRRT and chemotherapy.

Open access
Sarah W Y Poon Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong

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Karen K Y Leung Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong

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Joanna Y L Tung Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong

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Summary

Severe hypertriglyceridemia is an endocrine emergency and is associated with acute pancreatitis and hyperviscosity syndrome. We describe an infant with lipoprotein lipase deficiency with severe hypertriglyceridemia who presented with acute pancreatitis. She was managed acutely with fasting and intravenous insulin infusion, followed by low-fat diet with no pharmacological agent. Subsequent follow-up until the age of 5 years showed satisfactory lipid profile and she has normal growth and development.

Learning points:

  • Hypertriglyceridemia-induced acute pancreatitis has significant morbidity and mortality, and prompt treatment is imperative.

  • When no secondary causes are readily identified, genetic evaluation should be pursued in hypertriglyceridemia in children.

  • Intravenous insulin is a safe and effective acute treatment for hypertriglyceridemia in children, even in infants.

  • Long-term management with dietary modifications alone could be effective for primary hypertriglyceridemia due to lipoprotein lipase deficiency, at least in early childhood phase.

Open access
Wei Yang Division of Endocrinology, Department of Internal Medicine

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David Pham Department of Radiology, University of California Davis School of Medicine, Sacramento, California, USA

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Aren T Vierra Division of Endocrinology, Department of Internal Medicine

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Sarah Azam Division of Endocrinology, Department of Internal Medicine

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Dorina Gui Department of Pathology, University of California Davis School of Medicine, Sacramento, California, USA

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John C Yoon Division of Endocrinology, Department of Internal Medicine

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Summary

Ectopic ACTH-secreting pulmonary neuroendocrine tumors are rare and account for less than 5% of endogenous Cushing’s syndrome cases. We describe an unusual case of metastatic bronchial carcinoid tumor in a young woman presenting with unprovoked pulmonary emboli, which initially prevented the detection of the primary tumor on imaging. The source of ectopic ACTH was ultimately localized by a Gallium-DOTATATE scan, which demonstrated increased tracer uptake in a right middle lobe lung nodule and multiple liver nodules. The histological diagnosis was established based on a core biopsy of a hepatic lesion and the patient was started on a glucocorticoid receptor antagonist and a somatostatin analog. This case illustrates that hypercogulability can further aggravate the diagnostic challenges in ectopic ACTH syndrome. We discuss the literature on the current diagnosis and management strategies for ectopic ACTH syndrome.

Learning points:

  • In a young patient with concurrent hypokalemia and uncontrolled hypertension on multiple antihypertensive agents, secondary causes of hypertension should be evaluated.

  • Patients with Cushing’s syndrome can develop an acquired hypercoagulable state leading to spontaneous and postoperative venous thromboembolism.

  • Pulmonary emboli may complicate the imaging of the bronchial carcinoid tumor in ectopic ACTH syndrome.

  • Imaging with Gallium-68 DOTATATE PET/CT scan has the highest sensitivity and specificity in detecting ectopic ACTH-secreting tumors.

  • A combination of various noninvasive biochemical tests can enhance the diagnostic accuracy in differentiating Cushing’s disease from ectopic ACTH syndrome provided they have concordant results. Bilateral inferior petrosal sinus sampling remains the gold standard.

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Anne Marie Hannon Departments of Endocrinology and Diabetes, Cork University Hospital, Cork, Ireland

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Isolda Frizelle Departments of Endocrinology and Diabetes, Cork University Hospital, Cork, Ireland

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George Kaar Departments of Neurosurgery, Cork University Hospital, Cork, Ireland

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Steven J Hunter Department of Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, UK

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Mark Sherlock Department of Endocrinology and Diabetes, Beaumont Hospital, Dublin, Ireland

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Christopher J Thompson Department of Endocrinology and Diabetes, Beaumont Hospital, Dublin, Ireland

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Domhnall J O’Halloran Departments of Endocrinology and Diabetes, Cork University Hospital, Cork, Ireland

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the Irish Pituitary Database Group
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Summary

Pregnancy in acromegaly is rare and generally safe, but tumour expansion may occur. Managing tumour expansion during pregnancy is complex, due to the potential complications of surgery and side effects of anti-tumoural medication. A 32-year-old woman was diagnosed with acromegaly at 11-week gestation. She had a large macroadenoma invading the suprasellar cistern. She developed bitemporal hemianopia at 20-week gestation. She declined surgery and was commenced on 100 µg subcutaneous octreotide tds, with normalisation of her visual fields after 2 weeks of therapy. She had a further deterioration in her visual fields at 24-week gestation, which responded to an increase in subcutaneous octreotide to 150 µg tds. Her vision remained stable for the remainder of the pregnancy. She was diagnosed with gestational diabetes at 14/40 and was commenced on basal bolus insulin regimen at 22/40 gestation. She otherwise had no obstetric complications. Foetal growth continued along the 50th centile throughout pregnancy. She underwent an elective caesarean section at 34/40, foetal weight was 3.2 kg at birth with an APGAR score of 9. The neonate was examined by an experienced neonatologist and there were no congenital abnormalities identified. She opted not to breastfeed and she is menstruating regularly post-partum. She was commenced on octreotide LAR 40 mg and referred for surgery. At last follow-up, 2 years post-partum, the infant has been developing normally. In conclusion, our case describes a first presentation of acromegaly in pregnancy and rescue of visual field loss with somatostatin analogue therapy.

Learning points:

  • Tumour expansion may occur in acromegaly during pregnancy.

  • Treatment options for tumour expansion in pregnancy include both medical and surgical options.

  • Somatostatin analogues may be a viable medical alternative to surgery in patients with tumour expansion during pregnancy.

Open access
Saurabh Uppal Departments of Paediatric Endocrinology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

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James Blackburn Departments of Paediatric Endocrinology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

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Mohammed Didi Departments of Paediatric Endocrinology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

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Rajeev Shukla Departments of Pathology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

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James Hayden Departments of Oncology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

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Senthil Senniappan Departments of Paediatric Endocrinology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK
Institute of Child Health, University of Liverpool, Liverpool, UK

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Summary

Beckwith–Wiedemann syndrome (BWS) can be associated with embryonal tumours and congenital hyperinsulinism (CHI). We present an infant with BWS who developed congenital hepatoblastoma and Wilms’ tumour during infancy. The infant presented with recurrent hypoglycaemia requiring high intravenous glucose infusion and was biochemically confirmed to have CHI. He was resistant to diazoxide but responded well to octreotide and was switched to Lanreotide at 1 year of age. Genetic analysis for mutations of ABCC8 and KCNJ11 were negative. He had clinical features suggestive of BWS. Methylation-sensitive multiplex ligation-dependent probe amplification revealed hypomethylation at KCNQ1OT1:TSS-DMR and hypermethylation at H19 /IGF2:IG-DMR consistent with mosaic UPD(11p15). Hepatoblastoma was detected on day 4 of life, which was resistant to chemotherapy, requiring surgical resection. He developed Wilms’ tumour at 3 months of age, which also showed poor response to induction chemotherapy with vincristine and actinomycin D. Surgical resection of Wilms’ tumour was followed by post-operative chemotherapy intensified with cycles containing cyclophosphamide, doxorubicin, carboplatin and etoposide, in addition to receiving flank radiotherapy. We report, for the first time, an uncommon association of hepatoblastoma and Wilms’ tumour in BWS in early infancy. Early onset tumours may show resistance to chemotherapy. UPD(11p15) is likely associated with persistent CHI in BWS.

Learning points:

  • Long-acting somatostatin analogues are effective in managing persistent CHI in BWS.

  • UPD(11)pat genotype may be a pointer to persistent and severe CHI.

  • Hepatoblastoma and Wilms’ tumour may have an onset within early infancy and early tumour surveillance is essential.

  • Tumours associated with earlier onset may be resistant to recognised first-line chemotherapy.

Open access
Sarah Kiff Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK
Department of Endocrinology, Royal Hospital for Sick Children, Edinburgh, UK

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Carolyn Babb Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK

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Maria Guemes Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK
Genetics and Genomic Medicine Programme, Great Institute of Child Health, University College London, London, UK

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Antonia Dastamani Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK

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Clare Gilbert Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK

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Sarah E Flanagan Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK

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Sian Ellard Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK

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John Barton Department of Paediatric Endocrinology, Bristol Royal Hospital for Children, Bristol, UK

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M Dattani Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK
Genetics and Genomic Medicine Programme, Great Institute of Child Health, University College London, London, UK

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Pratik Shah Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK
Genetics and Genomic Medicine Programme, Great Institute of Child Health, University College London, London, UK

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Summary

We report a case of partial diazoxide responsiveness in a child with severe congenital hyperinsulinaemic hypoglycaemia (CHI) due to a homozygous ABCC8 mutation. A term baby, with birth weight 3.8 kg, born to consanguineous parents presented on day 1 of life with hypoglycaemia. Hypoglycaemia screen confirmed CHI. Diazoxide was commenced on day 7 due to ongoing elevated glucose requirements (15 mg/kg/min), but despite escalation to a maximum dose (15 mg/kg/day), intravenous (i.v.) glucose requirement remained high (13 mg/kg/min). Genetic testing demonstrated a homozygous ABCC8 splicing mutation (c.2041-1G>C), consistent with a diffuse form of CHI. Diazoxide treatment was therefore stopped and subcutaneous (s.c.) octreotide infusion commenced. Despite this, s.c. glucagon and i.v. glucose were required to prevent hypoglycaemia. A trial of sirolimus and near-total pancreatectomy were considered, however due to the significant morbidity potentially associated with these, a further trial of diazoxide was commenced at 1.5 months of age. At a dose of 10 mg/kg/day of diazoxide and 40 µg/kg/day of octreotide, both i.v. glucose and s.c. glucagon were stopped as normoglycaemia was achieved. CHI due to homozygous ABCC8 mutation poses management difficulties if the somatostatin analogue octreotide is insufficient to prevent hypoglycaemia. Diazoxide unresponsiveness is often thought to be a hallmark of recessively inherited ABCC8 mutations. This patient was initially thought to be non-responsive, but this case highlights that a further trial of diazoxide is warranted, where other available treatments are associated with significant risk of morbidity.

Learning points:

  • Homozygous ABCC8 mutations are commonly thought to cause diazoxide non-responsive hyperinsulinaemic hypoglycaemia.

  • This case highlights that partial diazoxide responsiveness in homozygous ABCC8 mutations may be present.

  • Trial of diazoxide treatment in combination with octreotide is warranted prior to considering alternative treatments, such as sirolimus or near-total pancreatectomy, which are associated with more significant side effects.

Open access
Xin Chen Division of Internal Medicine, LAC+USC Medical Center, University of Southern California, Los Angeles, California, USA

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Dina Kamel Division of Endocrinology, Diabetes, and Metabolism, Keck School of Medicine, LAC+USC Medical Center, University of Southern California, Los Angeles, California, USA

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Braden Barnett Division of Endocrinology, Diabetes, and Metabolism, Keck School of Medicine, LAC+USC Medical Center, University of Southern California, Los Angeles, California, USA

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Evan Yung Division of Pathology, LAC+USC Medical Center, University of Southern California, Los Angeles, California, USA

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Adrienne Quinn Keck School of Medicine, University of Southern California, Los Angeles, California, USA

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Caroline Nguyen Division of Endocrinology, Diabetes, and Metabolism, Keck School of Medicine, LAC+USC Medical Center, University of Southern California, Los Angeles, California, USA

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Summary

There has been an increasing awareness of post gastric bypass hypoglycemia (PGBH). Histopathologic findings from such patients who underwent partial/total pancreatomy, however, can vary widely from minimal changes to classic nesidioblastosis, making the pathologic diagnosis challenging. PGBH typically presents as postprandial hypoglycemia, as opposed to insulinoma, which presents as fasting hypoglycemia. Herein, we describe an unusual case of a patient with PGBH who initially presented with postprandial hypoglycemia three years after surgery, but later developed fasting hyperinsulinemic hypoglycemia as the disease progressed. Our hypothesis for this phenomenon is that this disease is progressive, and later in its course, the insulin release becomes dissociated from food stimulation and is increased at baseline. Future studies are needed to investigate the prevalence as well as etiology of this progression from postprandial to fasting hypoglycemia.

Learning points:

  • There has been an increasing awareness of post gastric bypass hypoglycemia (PGBH).

  • Histopathologically, PGBH can vary from minimal changes to nesidioblastosis.

  • Although uncommon, patients with PGBH after Roux-en-Y gastric bypass may present with both postprandial and fasting hyperinsulinemic hypoglycemia as disease progresses.

  • Our hypothesis for this phenomenon is that the insulin release becomes dissociated from food stimulation and is increased at baseline with disease progression.

Open access
W K M G Amarawardena Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
Department of Endocrinology, Royal Hallamshire Hospital, University of Sheffield, Sheffield, UK

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K D Liyanarachchi Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
Department of Endocrinology, Royal Hallamshire Hospital, University of Sheffield, Sheffield, UK

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J D C Newell-Price Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
Department of Endocrinology, Royal Hallamshire Hospital, University of Sheffield, Sheffield, UK

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R J M Ross Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK

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D Iacovazzo Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK

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M Debono Department of Endocrinology, Royal Hallamshire Hospital, University of Sheffield, Sheffield, UK

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Summary

The granulation pattern of somatotroph adenomas is well known to be associated with differing clinical and biochemical characteristics, and it has been shown that sparsely granulated tumours respond poorly to commonly used somatostatin receptor ligands (SRLs). We report a challenging case of acromegaly with a sparsely granulated tumour resistant to multiple modalities of treatment, ultimately achieving biochemical control with pasireotide. A 26-year-old lady presented with classical features of acromegaly, which was confirmed by an oral glucose tolerance test. Insulin-like growth factor 1 (IGF1) was 1710 µg/L (103–310 µg/L) and mean growth hormone (GH) was >600 U/L. MRI scan showed a 4 cm pituitary macroadenoma with suprasellar extension and right-sided cavernous sinus invasion. She underwent trans-sphenoidal pituitary surgery. Histology displayed moderate amounts of sparsely granular eosinophilic cytoplasm, staining only for GH. Postoperative investigations showed uncontrolled disease (IGF1:1474 µg/L, mean GH:228 U/L) and residual tumour in the cavernous sinus. She received external beam fractionated radiation. Over the years, she received octreotide LAR (up to 30 mg), lanreotide (up to 120 mg) two weekly, cabergoline, pegvisomant and stereotactic radiosurgery to no avail. Only pegvisomant resulted in an element of disease control; however, this had to be stopped due to abnormal liver function tests. Fifteen years after the diagnosis, she was started on pasireotide 40 mg monthly. Within a month, her IGF1 dropped and has remained within the normal range (103–310 µg/L). Pasireotide has been well tolerated, and there has been significant clinical improvement. Somatostatin receptor subtyping revealed a positivity score of two for both sst5 and sst2a subtypes.

Learning points:

  • Age, size of the tumour, GH levels on presentation, histopathological type and the somatostatin receptor status of the tumour in acromegaly should be reviewed in patients who poorly respond to first-generation somatostatin receptor ligands.

  • Tumours that respond poorly to first-generation somatostatin receptor ligands, especially sparsely granulated somatotroph adenomas, can respond to pasireotide and treatment should be considered early in the management of resistant tumours.

  • Patients with membranous expression of sst5 are likely to be more responsive to pasireotide.

Open access
Alfredo Di Cerbo Endocrinology, ‘Casa Sollievo della Sofferenza’, IRCCS, San Giovanni Rotondo, Foggia, Italy

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Federica Pezzuto Department of Medical, Oral and Biotechnological Sciences, Dental School, University ‘G. d’Annunzio’ of Chieti-Pescara, Chieti, Italy

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Alessandro Di Cerbo Department of Medical, Oral and Biotechnological Sciences, Dental School, University ‘G. d’Annunzio’ of Chieti-Pescara, Chieti, Italy

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Summary

Graves’ disease, the most common form of hyperthyroidism in iodine-replete countries, is associated with the presence of immunoglobulins G (IgGs) that are responsible for thyroid growth and hyperfunction. In this article, we report the unusual case of a patient with acromegaly and a severe form of Graves’ disease. Here, we address the issue concerning the role of growth hormone (GH) and insulin-like growth factor 1 (IGF1) in influencing thyroid function. Severity of Graves’ disease is exacerbated by coexistent acromegaly and both activity indexes and symptoms and signs of Graves’ disease improve after the surgical remission of acromegaly. We also discuss by which signaling pathways GH and IGF1 may play an integrating role in regulating the function of the immune system in Graves’ disease and synergize the stimulatory activity of Graves’ IgGs.

Learning points:

  • Clinical observations have demonstrated an increased prevalence of euthyroid and hyperthyroid goiters in patients with acromegaly.

  • The coexistence of acromegaly and Graves’ disease is a very unusual event, the prevalence being <1%.

  • Previous in vitro studies have showed that IGF1 synergizes the TSH-induced thyroid cell growth-activating pathways independent of TSH/cAMP/PKA cascade.

  • We report the first case of a severe form of Graves’ disease associated with acromegaly and show that surgical remission of acromegaly leads to a better control of symptoms of Graves’ disease.

Open access