POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein and Skin changes) is a rare multisystemic disease. Clinical presentation is variable, the only mandatory criteria being polyneuropathy and monoclonal gammapathy in association with one major and one minor criterion. Primary adrenal insufficiency is rarely reported. We describe a case of a 33-year-old patient, in whom the presenting symptoms were mandibular mass, chronic sensory-motor peripheral polyneuropathy and adrenal insufficiency. The laboratory evaluation revealed thrombocytosis, severe hyperkalemia with normal renal function, normal protein electrophoresis and negative serum immunofixation for monoclonal protein. Endocrinologic laboratory work-up confirmed Addison’s disease and revealed subclinical primary hypothyroidism. Thoracic abdominal CT showed hepatosplenomegaly, multiple sclerotic lesions in thoracic vertebra and ribs. The histopathologic examination of the mandibular mass was nondiagnostic. Bone marrow biopsy revealed plasma cell dyscrasia and confirmed POEMS syndrome. Axillary lymphadenopathy biopsy: Castleman’s disease. Gluco-mineralocorticoid substitution and levothyroxine therapy were started with clinical improvement. Autologous hematopoietic cell transplantation (HCT) was planned, cyclophosphamide induction was started. Meanwhile the patient suffered two ischemic strokes which resulted in aphasia and hemiparesis. Cerebral angiography revealed vascular lesions compatible with vasculitis and stenosis of two cerebral arteries. The patient deceased 14 months after the diagnosis. The young age at presentation, multiplicity of manifestations and difficulties in investigation along with the absence of serum monoclonal protein made the diagnosis challenging. We report this case to highlight the need to consider POEMS syndrome in differential diagnosis of peripheral neuropathy in association with endocrine abnormalities even in young patients.
POEMS syndrome is considered a ‘low tumor burden disease’ and the monoclonal protein in 15% of cases is not found by immunofixation.
Neuropathy is the dominant characteristic of POEMS syndrome and it is peripheral, ascending, symmetric and affecting both sensation and motor function.
Endocrinopathies are a frequent feature of POEMS syndrome, but the cause is unknown.
The most common endocrinopathies are hypogonadism, primary hypothyroidism and abnormalities in glucose metabolism.
There is no standard therapy; however, patients with disseminated bone marrow involvement are treated with chemotherapy with or without HCT.
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.
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.
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.
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.
Thyrotoxicosis is associated with cardiac dysfunction; more commonly, left ventricular dysfunction. However, in recent years, there have been more cases reported on right ventricular dysfunction, often associated with pulmonary hypertension in patients with thyrotoxicosis. Three cases of thyrotoxicosis associated with right ventricular dysfunction were presented. A total of 25 other cases of thyrotoxicosis associated with right ventricular dysfunction published from 1994 to 2017 were reviewed along with the present 3 cases. The mean age was 45 years. Most (82%) of the cases were newly diagnosed thyrotoxicosis. There was a preponderance of female gender (71%) and Graves’ disease (86%) as the underlying aetiology. Common presenting features included dyspnoea, fatigue and ankle oedema. Atrial fibrillation was reported in 50% of the cases. The echocardiography for almost all cases revealed dilated right atrial and or ventricular chambers with elevated pulmonary artery pressure. The abnormal echocardiographic parameters were resolved in most cases after rendering the patients euthyroid. Right ventricular dysfunction and pulmonary hypertension are not well-recognized complications of thyrotoxicosis. They are life-threatening conditions that can be reversed with early recognition and treatment of thyrotoxicosis. Signs and symptoms of right ventricular dysfunction should be sought in all patients with newly diagnosed thyrotoxicosis, and prompt restoration of euthyroidism is warranted in affected patients before the development of overt right heart failure.
Thyrotoxicosis is associated with right ventricular dysfunction and pulmonary hypertension apart from left ventricular dysfunction described in typical thyrotoxic cardiomyopathy.
Symptoms and signs of right ventricular dysfunction and pulmonary hypertension should be sought in all patients with newly diagnosed thyrotoxicosis.
Thyrotoxicosis should be considered in all cases of right ventricular dysfunction or pulmonary hypertension not readily explained by other causes.
Prompt restoration of euthyroidism is warranted in patients with thyrotoxicosis complicated by right ventricular dysfunction with or without pulmonary hypertension to allow timely resolution of the abnormal cardiac parameters before development of overt right heart failure.
Benjamin G ChallisWellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Box 281, Cambridge, CB2 0QQ, UK
Nicolai J Wewer AlbrechtsenDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark
Bolette HartmannDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark
Stephen O'RahillyWellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK Wolfson Diabetes and Endocrinology Clinic, Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Box 281, Cambridge, CB2 0QQ, UK
Jens J HolstDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark
Pancreatic neuroendocrine tumours (pNETs) secreting proglucagon are associated with phenotypic heterogeneity. Here, we describe two patients with pNETs and varied clinical phenotypes due to differential processing and secretion of proglucagon-derived peptides (PGDPs). Case 1, a 57-year-old woman presented with necrolytic migratory erythema, anorexia, constipation and hyperinsulinaemic hypoglycaemia. She was found to have a grade 1 pNET, small bowel mucosal thickening and hyperglucagonaemia. Somatostatin analogue (SSA) therapy improved appetite, abolished hypoglycaemia and improved the rash. Case 2, a 48-year-old male presented with diabetes mellitus, diarrhoea, weight loss, nausea, vomiting and perineal rash due to a grade 1 metastatic pNET and hyperglucagonaemia. In both cases, plasma levels of all measured PGDPs were elevated and attenuated following SSA therapy. In case 1, there was increased production of intact glucagon-like peptide 1 (GLP-1) and GLP-2, similar to that of the enteroendocrine L cell. In case 2, pancreatic glucagon was elevated due to a pancreatic α-cell-like proglucagon processing profile. In summary, we describe two patients with pNETs and heterogeneous clinical phenotypes due to differential processing and secretion of PGDPs. This is the first description of a patient with symptomatic hyperinsulinaemic hypoglycaemia and marked gastrointestinal dysfunction due to, in part, a proglucagon-expressing pNET.
PGDPs exhibit a diverse range of biological activities including critical roles in glucose and amino acid metabolism, energy homeostasis and gastrointestinal physiology.
The clinical manifestations of proglucagon-expressing tumours may exhibit marked phenotypic variation due to the biochemical heterogeneity of their secreted peptide repertoire.
Specific and precise biochemical assessment of individuals with proglucagon-expressing tumours may provide opportunities for improved diagnosis and clinical management.
G K DimitriadisWarwick Institute for the Study of Endocrinology Diabetes and Metabolism (WISDEM Centre), The Arden NET Centre, University Hospitals of Coventry and Warwickshire, UHCW NHS Trust, ENETS CoE, Coventry, UK Division of Experimental Medicine, Faculty of Medicine, Imperial College London, Hammersmith Campus, London, UK Division of Translational and Systems Medicine, Warwick Medical School, University of Warwick, Coventry, UK
R RaoWarwick Institute for the Study of Endocrinology Diabetes and Metabolism (WISDEM Centre), The Arden NET Centre, University Hospitals of Coventry and Warwickshire, UHCW NHS Trust, ENETS CoE, Coventry, UK
D K GrammatopoulosDivision of Translational and Systems Medicine, Warwick Medical School, University of Warwick, Coventry, UK Department of Clinical Biochemistry and Histopathology, Coventry and Warwickshire, Pathology Service, UHCW NHS Trust, Coventry, UK
H S RandevaWarwick Institute for the Study of Endocrinology Diabetes and Metabolism (WISDEM Centre), The Arden NET Centre, University Hospitals of Coventry and Warwickshire, UHCW NHS Trust, ENETS CoE, Coventry, UK Division of Translational and Systems Medicine, Warwick Medical School, University of Warwick, Coventry, UK
M O WeickertWarwick Institute for the Study of Endocrinology Diabetes and Metabolism (WISDEM Centre), The Arden NET Centre, University Hospitals of Coventry and Warwickshire, UHCW NHS Trust, ENETS CoE, Coventry, UK
N MurthyWarwick Institute for the Study of Endocrinology Diabetes and Metabolism (WISDEM Centre), The Arden NET Centre, University Hospitals of Coventry and Warwickshire, UHCW NHS Trust, ENETS CoE, Coventry, UK
We report the case of a 70-year-old previously healthy female who presented acutely to the Accident and Emergency department with left-sided vasomotor symptoms including reduced muscle tone, weakness upon walking and slurred speech. Physical examination confirmed hemiparesis with VIIth nerve palsy and profound hepatomegaly. A random glucose was low at 1.7 mmol/l, which upon correction resolved her symptoms. In hindsight, the patient recalled having had similar episodes periodically over the past 3 months to which she did not give much attention. While hospitalized, she continued having episodes of symptomatic hypoglycaemia during most nights, requiring treatment with i.v. dextrose and/or glucagon. Blood tests including insulin and C-peptide were invariably suppressed, in correlation with low glucose. A Synacthen stimulation test was normal (Cort (0′) 390 nmol/l, Cort (30′) 773 nmol/l). A computed tomography scan showed multiple lobulated masses in the abdomen, liver and pelvis. An ultrasound guided biopsy of one of the pelvic masses was performed. Immunohistochemistry supported the diagnosis of a gastrointestinal stromal tumour (GIST) positive for CD34 and CD117. A diagnosis of a non islet cell tumour hypoglycaemia (NICTH) secondary to an IGF2 secreting GIST was confirmed with further biochemical investigations (IGF2=96.5 nmol/l; IGF2:IGF1 ratio 18.9, ULN <10). Treatment with growth hormone resolved the patient's hypoglycaemic symptoms and subsequent targeted therapy with Imatinib was successful in controlling disease progression over an 8-year observation period.
NICTH can be a rare complication of GISTs that may manifest with severe hypoglycaemia and neuroglucopenic symptoms.
NICTH can masquerade as other pathologies thus causing diagnostic confusion.
Histological confirmation of GIST induced NICTH and exclusion of other conditions causing hypoglycaemia is essential.
Mutational analysis of GISTs should be carried out in all cases as it guides treatment decision.
Tailored management of hypoglycaemia, in this case using growth hormone and targeted cyto-reductive therapy, minimizes the risk of possible life-threatening complications.
Erdheim–Chester disease (ECD) is a potentially fatal condition characterized by infiltration of multiple organs by non-Langerhans histiocytes. Although endocrine dysfunction has been reported in association with ECD, to date, there have been no previous reports of empty sella syndrome (ESS) associated with it. We report the case of a patient with ECD who had symptomatic ESS. A 55-year-old man of Chinese ethnicity initially presented with symptoms of heart failure, fatigue and knee joint pain. Physical examination revealed xanthelasma, gynaecomastia, lung crepitations, hepatomegaly and diminished testicular volumes. He had laboratory evidence of hypogonadotrophic hypogonadism, secondary hypoadrenalism and GH deficiency. Imaging studies showed diffuse osteosclerosis of the long bones on X-ray, a mass in the right atrium and thickening of the pleura and of the thoracic aorta on fusion positron emission tomography–computed tomography. Magnetic resonance imaging (MRI) of the brain showed an empty sella. The diagnosis of ECD was confirmed by bone biopsy.
ECD is a multisystemic disease that can affect the pituitary and other organs. The diagnosis of ECD is based on clinical and radiological features and histology, showing lipid-laden CD68+ CD1a− S100− histiocytes surrounded by fibrosis.
The finding of xanthelasmas especially in the presence of normal lipid levels in the presence of a multisystem infiltrative disorder should raise the suspicion of ECD.
Systemic perturbation of autoimmunity may play a role in the pathogenesis of ECD and is an area that merits further research.
Glycogen storage disease (GSD) type I is characterized by impaired production of glucose from glycogenolysis and gluconeogenesis resulting in severe hypoglycaemia and increased production of lactic acid, triglyceride and uric acid. The most common type, glycogenosis type Ia, demands a balanced, sufficient carbohydrate intake to preserve normal 24-h glycaemia. Insufficient intake of carbohydrates can cause hypoglycaemia, as the missing glucose-6-phosphatase enzyme cannot free the glucose stored as liver glycogen and nor is gluconeogenesis possible. The principle means of handling this disorder is to avoid starving by taking regular meals during the day and night. Such a dietary regimen could lead to obesity. Herein, we present the case of an adult patient with glycogenosis type Ia suffering from hyperuricaemia, dyslipidaemia and arterial hypertension. The accumulation of these cardiovascular risk factors could lead to the early onset of atherosclerosis, which should be postponed by contemporary methods of surveillance and treatment.
Continuous subcutaneous glucose monitoring may be of value in every adult patient with GSD type I to evaluate the actual prevalence of eventual hypoglycaemic and hyperglycaemic episodes.
Good dietary management minimizes the metabolic abnormalities of the disease and decreases the risk of long-term complications.
Treatment of obesity in patients with GSD reduces the risk of earlier atherosclerosis and cardiovascular disease.