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Jenny S W Yun Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

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Chris McCormack Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

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Michelle Goh Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

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Cherie Chiang Department of Internal Medicine, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
University of Melbourne, Parkville, Victoria, Australia

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Summary

Acanthosis nigricans (AN) is a common dermatosis associated with hyperinsulinemia and insulin resistance. However, AN has been rarely reported in patients with insulinoma, a state of persistent hyperinsulinemia. We present a case of metastatic insulinoma, in whom AN manifested after the first cycle of peptide receptor radionuclide therapy (PRRT). A 40-year-old man was diagnosed with metastatic insulinoma after 5 months of symptomatic hypoglycemia. Within 1 month post PRRT, the patient became euglycemic but developed a pigmented, pruritic rash which was confirmed on biopsy as AN. We discuss the rare manifestation of AN in subjects with insulinoma, the role of insulin in the pathogenesis of AN, malignant AN in non-insulin-secreting malignancies and association with other insulin-resistant endocrinopathies such as acromegaly.

Learning points

  • Acanthosis nigricans (AN) is a common dermatosis which is typically asymptomatic and associated with the hyperinsulinemic state.

  • Malignant AN can rapidly spread, cause pruritus and affect mucosa and the oral cavity.

  • AN is extremely rare in patients with insulinoma despite marked hyperinsulinemia.

  • Peptide receptor radionuclide therapy might have triggered TGF-α secretion in this subject which led to malignant AN.

  • Rapid spread or unusual distribution of pruritic AN warrants further investigation to exclude underlying malignancy.

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Pradeep Vasudevan Leicester Clinical Genetics, Women’s and Children’s Services, Leicester Royal Infirmary, Leicester, UK

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Corrina Powell Leicester Clinical Genetics, Women’s and Children’s Services, Leicester Royal Infirmary, Leicester, UK

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Adeline K Nicholas University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK

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Ian Scudamore Department of Obstetrics and Gynaecology, Women’s and Prenatal Services, Leicester General Hospital, Leicester, UK

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James Greening Department of Paediatric Endocrinology, Leicester Royal Infirmary, Leicester, UK

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Soo-Mi Park Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

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Nadia Schoenmakers University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK

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Summary

In the absence of maternal thyroid disease or iodine deficiency, fetal goitre is rare and usually attributable to dyshormonogenesis, for which genetic ascertainment is not always undertaken in the UK. Mechanical complications include tracheal and oesophageal compression with resultant polyhydramnios, malpresentation at delivery and neonatal respiratory distress. We report an Indian kindred in which the proband (first-born son) had congenital hypothyroidism (CH) without obvious neonatal goitre. His mother’s second pregnancy was complicated by fetal hypothyroid goitre and polyhydramnios, prompting amniotic fluid drainage and intraamniotic therapy (with liothyronine, T3 and levothyroxine, T4). Sadly, intrauterine death occurred at 31 weeks. Genetic studies in the proband demonstrated compound heterozygous novel (c.5178delT, p.A1727Hfs*26) and previously described (c.7123G > A, p.G2375R) thyroglobulin (TG) mutations which are the likely cause of fetal goitre in the deceased sibling. TG mutations rarely cause fetal goitre, and management remains controversial due to the potential complications of intrauterine therapy however an amelioration in goitre size may be achieved with intraamniotic T4, and intraamniotic T3/T4 combination has achieved a favourable outcome in one case. A conservative approach, with surveillance, elective delivery and commencement of levothyroxine neonatally may also be justified, although intubation may be required post delivery for respiratory obstruction. Our observations highlight the lethality which may be associated with fetal goitre. Additionally, although this complication may recur in successive pregnancies, our case highlights the possibility of discordance for fetal goitre in siblings harbouring the same dyshormonogenesis-associated genetic mutations. Genetic ascertainment may facilitate prenatal diagnosis and assist management in familial cases.

Learning points:

  • CH due to biallelic, loss-of-function TG mutations is well-described and readily treatable in childhood however mechanical complications from associated fetal goitre may include polyhydramnios, neonatal respiratory compromise and neck hyperextension with dystocia complicating delivery.

  • CH due to TG mutations may manifest with variable phenotypes, even within the same kindred.

  • Treatment options for hypothyroid dyshormogenic fetal goitre in a euthyroid mother include intraamniotic thyroid hormone replacement in cases with polyhydramnios or significant tracheal obstruction. Alternatively, cases may be managed conservatively with radiological surveillance, elective delivery and neonatal levothyroxine treatment, although intubation and ventilation may be required to support neonatal respiratory compromise.

  • Genetic ascertainment in such kindreds may enable prenatal diagnosis and anticipatory planning for antenatal management of further affected offspring.

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Shweta Birla Laboratory of Cyto-Molecular Genetics, Department of Anatomy

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Sameer Aggarwal Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India

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Arundhati Sharma Laboratory of Cyto-Molecular Genetics, Department of Anatomy

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Nikhil Tandon Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India

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Summary

Carney complex (CNC) is a rare autosomal dominant syndrome characterized by pigmented lesions of the skin and mucosae along with cardiac, endocrine, cutaneous, and neural myxomatous tumors. Mutations in the PRKAR1A gene have been identified in ∼70% of the CNC cases reported worldwide. A 30-year-old male was referred to the endocrinology clinic with suspected acromegaly. He had a history of recurrent atrial myxoma for the past 8 years for which he underwent repeated surgeries. Presently, he complained of having headache, excessive snoring, sweating, and also noticed increase in his shoe size. Evaluation for acromegaly revealed elevated levels of GH in random as well as in suppressed condition. Magnetic resonance imaging scan revealed enlarged sella with microadenoma in the left anterior pituitary. Screening of PRKAR1A gene was carried out for the patient, his parents and siblings who were available and willing to undergo the test. The patient was diagnosed to have the rare CNC syndrome characterized by recurrent atrial myxoma and acromegaly due to a novel 22 bp insertion mutation in PRKAR1A which was predicted to be deleterious by in silico analysis. Screening the available family members revealed the absence of this mutation in them except the elder brother who also tested positive for this mutation. The present study reports on a novel PRKAR1A insertion mutation in a patient with acromegaly and left atrial myxoma in CNC.

Learning points

  • Identification of a novel deleterious PRKAR1A insertion mutation causing CNC.

  • It is important that patients with cardiac myxoma be investigated for presence of endocrine overactivity suggestive of CNC.

  • PRKAR1A mutation analysis should be undertaken in such cases to confirm the diagnosis in the patients as well as first degree relatives.

  • This case highlights an important aspect of diagnosis, clinical course, and management of this rare condition.

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Pinaki Dutta Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Anuradha Aggarwal Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Yashpal Gogate Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Uma Nahar Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Viral N Shah Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Mandeep Singla Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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N Khandelwal Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Anil Bhansali Departments of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India

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Summary

We describe the clinical presentation, diagnostic and management issues in five cases of non-islet cell tumor hypoglycemia (NICTH), diagnosed at a tertiary care institute over a period of 15 years. The clinical, laboratory, and histopathological findings of these patients along with diagnostic utility of IGF2:IGF1 ratio are discussed. The mean age of presentation was 52 years, with a male predominance (3:2). Three patients presented with recurrent episodes of fasting hypoglycemia and it was detected in other two patients during hospitalization. Two patients had acromegaloid features that regressed following treatment. One patient had hypokalemia. Low levels of insulin, C-peptide, GH, and IGF1 were invariably found in all. The IGF2 level was elevated in only one patient; however, IGF2:IGF1 ratio was more than 10 in four of the five patients. The mean tumor size was 16.4 cm and mean weight was 3.6 kg. Four patients had mesenchymal tumors and one had epithelial tumor. NICTH is a rare cause of hypoglycemia. Hypoinsulinemic hypoglycemia with low IGF1 and IGF2:IGF1 ratio more than 10 is suggestive of this entity.

Learning points

  • NICTH should be considered in patients presenting with tumor of mesenchymal origin and hypoglycemia.

  • Hypoinsulinemic hypoglycemia with low IGF1 is a strong biochemical evidence of NICTH.

  • IGF2:IGF1 ratio of more than 10 is a complementary investigation in the absence of an assay facility for IGF2.

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