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Open access

A case of early-onset diabetes with impaired insulin secretion carrying a PAX6 gene Gln135* mutation

Motohiro Sekiya, Mikiko Yuhara, Yuki Murayama, Mariko Ohyama Osawa, Rikako Nakajima, Nami Ohuchi, Nako Matsumoto, Daichi Yamazaki, Sayuri Mori, Takaaki Matsuda, Yoko Sugano, Yoshinori Osaki, Hitoshi Iwasaki, Hiroaki Suzuki, and Hitoshi Shimano

Summary

A paired homeodomain transcription factor, PAX6 (paired-box 6), is essential for the development and differentiation of pancreatic endocrine cells as well as ocular cells. Despite the impairment of insulin secretion observed in PAX6-deficient mice, evidence implicating causal association between PAX6 gene mutations and monogenic forms of human diabetes is limited. We herein describe a 33-year-old Japanese woman with congenital aniridia who was referred to our hospital because of her uncontrolled diabetes with elevated hemoglobin A1c (13.1%) and blood glucose (32.5 mmol/L) levels. Our biochemical analysis revealed that her insulin secretory capacity was modestly impaired as represented by decreased 24-h urinary C-peptide levels (38.0 μg/day), primarily explaining her diabetes. Intriguingly, there was a trend toward a reduction in her serum glucagon levels as well. Based on the well-recognized association of PAX6 gene mutations with congenital aniridia, we screened the whole PAX6 coding sequence, leading to an identification of a heterozygous Gln135* mutation. We tested our idea that this mutation may at least in part explain the impaired insulin secretion observed in this patient. In cultured pancreatic β-cells, exogenous expression of the PAX6 Gln135* mutant produced a truncated protein that lacked the transcriptional activity to induce insulin gene expression. Our observation together with preceding reports support the recent attempt to include PAX6 in the growing list of genes causally responsible for monogenic diabetes. In addition, since most cases of congenital aniridia carry PAX6 mutations, we may need to pay more attention to blood glucose levels in these patients.

Learning points

  • PAX6 Gln135* mutation may be causally associated not only with congenital aniridia but also with diabetes.

  • Blood glucose levels may deserve more attention in cases of congenital aniridia with PAX6 mutations.

  • Our case supports the recent attempt to include PAX6 in the list of MODY genes, and Gln135* may be pathogenic.

DOI:
https://doi.org/10.1530/EDM-22-0271
Volume 2022: Issue 1
Open access

An incidental finding behind adrenal incidentaloma

Filippo Crimì, Giulio Barbiero, Irene Tizianel, Laura Evangelista, and Filippo Ceccato

Summary

A 61-year-old man went to the Emergency Department with left upper abdominal quadrant pain and low-grade fever, as well as a loss of weight (3 kg in 6 weeks). A solid-cystic lesion in the left adrenal lodge was discovered by abdominal ultrasonography. A slight increase in the serum amylase with normal lipase was observed, but there were no signs or symptoms of pancreatitis. A contrast-enhanced CT revealed a tumor that was suspected of adrenocortical cancer. Therefore, he was referred to the endocrine unit. The hormonal evaluation revealed no signs of excessive or inadequate adrenal secretion. To characterize the mass, an MRI was performed; the lesion showed an inhomogeneous fluid collection with peripheral wall contrast-enhancement, as well as a minor 18-fluorodeoxyglucose uptake at PET/CT images. The risk of primary adrenal cancer was minimal after the multidisciplinary discussion. An acute necrotic collection after focal pancreatitis was suspected, according to the characteristics of imaging. Both CT-guided drainage of the necrotic accumulation and laboratory analysis of the aspirated fluid confirmed the diagnosis.

Learning points

  • Different types of expansive processes can mimic adrenal incidentalomas.

  • Necrotic collection after acute focal pancreatitis could be misdiagnosed as an adrenal mass, since its CT characteristics could be equivocal.

  • MRI has stronger capacities than CT in differentiating complex lesions of the adrenal lodge.

  • A multidisciplinary approach is fundamental in the management of patients with a newly discovered adrenal incidentaloma and equivocal/suspicious imaging features (low lipid content and size >4 cm).

DOI:
https://doi.org/10.1530/EDM-22-0255
Volume 2022: Issue 1
Open access

Multiple electrolyte disturbances as the presenting feature of multiple endocrine neoplasia type 1 (MEN-1)

Adrian Po Zhu Li, Sheela Sathyanarayan, Salvador Diaz-Cano, Sobia Arshad, Eftychia E Drakou, Royce P Vincent, Ashley B Grossman, Simon J B Aylwin, and Georgios K Dimitriadis

Summary

A 49-year-old teacher presented to his general physician with lethargy and lower limb weakness. He had noticed polydipsia, polyuria, and had experienced weight loss, albeit with an increase in central adiposity. He had no concomitant illnesses and took no regular medications. He had hypercalcaemia (adjusted calcium: 3.34 mmol/L) with hyperparathyroidism (parathyroid hormone: 356 ng/L) and hypokalaemia (K: 2.7 mmol/L) and was admitted for i.v. potassium replacement. A contrast-enhanced CT chest/abdomen/pelvis scan revealed a well-encapsulated anterior mediastinal mass measuring 17 × 11 cm with central necrosis, compressing rather than invading adjacent structures. A neck ultrasound revealed a 2 cm right inferior parathyroid lesion. On review of CT imaging, the adrenals appeared normal, but a pancreatic lesion was noted adjacent to the uncinate process. His serum cortisol was 2612 nmol/L, and adrenocorticotrophic hormone was elevated at 67 ng/L, followed by inadequate cortisol suppression to 575 nmol/L from an overnight dexamethasone suppression test. His pituitary MRI was normal, with unremarkable remaining anterior pituitary biochemistry. His admission was further complicated by increased urine output to 10 L/24 h and despite three precipitating factors for the development of diabetes insipidus including hypercalcaemia, hypokalaemia, and hypercortisolaemia, due to academic interest, a water deprivation test was conducted. An 18flurodeoxyglucose-PET (FDG-PET) scan demonstrated high avidity of the mediastinal mass with additionally active bilateral superior mediastinal nodes. The pancreatic lesion was not FDG avid. On 68Ga DOTATE-PET scan, the mediastinal mass was moderately avid, and the 32 mm pancreatic uncinate process mass showed significant uptake. Genetic testing confirmed multiple endocrine neoplasia type 1.

Learning points

  • In young patients presenting with primary hyperparathyroidism, clinicians should be alerted to the possibility of other underlying endocrinopathies.

    In patients with multiple endocrine neoplasia type 1 (MEN-1) and ectopic adrenocorticotrophic hormone syndrome (EAS), clinicians should be alerted to the possibility of this originating from a neoplasm above or below the diaphragm.

  • Although relatively rare compared with sporadic cases, thymic carcinoids secondary to MEN-1 may also be associated with EAS.

  • Electrolyte derangement, in particular hypokalaemia and hypercalcaemia, can precipitate mild nephrogenic diabetes insipidus.

DOI:
https://doi.org/10.1530/EDM-21-0207
Volume 2022: Issue 1
Open access

Acromegaly caused by a GHRH-producing pancreatic neuroendocrine tumor: a rare manifestation of MEN1 syndrome

Minna Koivikko, Tapani Ebeling, Markus Mäkinen, Juhani Leppäluoto, Antti Raappana, Petteri Ahtiainen, and Pasi Salmela

Summary

Multiple endocrine neoplasia type 1 NM_001370259.2(MEN1):c.466G>C(p.Gly156Arg) is characterized by tumors of various endocrine organs. We report on a rare, growth hormone-releasing hormone (GHRH)-releasing pancreatic tumor in a MEN1 patient with a long-term follow-up after surgery. A 22-year-old male with MEN1 syndrome, primary hyperparathyroidism and an acromegalic habitus was observed to have a pancreatic tumor on abdominal CT scanning, growth hormone (GH) and insulin-like growth factor 1 (IGF1) were elevated and plasma GHRH was exceptionally high. GHRH and GH were measured before the treatment and were followed during the study. During octreotide treatment, IGF1 normalized and the GH curve was near normal. After surgical treatment of primary hyperparathyroidism, a pancreatic tail tumor was enucleated. The tumor cells were positive for GHRH antibody staining. After the operation, acromegaly was cured as judged by laboratory tests. No reactivation of acromegaly has been seen during a 20-year follow-up. In conclusion, an ectopic GHRH-producing, pancreatic endocrine neoplasia may represent a rare manifestation of MEN1 syndrome.

Learning points

  • Clinical suspicion is in a key position in detecting acromegaly.

  • Remember genetic disorders with young individuals having primary hyperparathyroidism.

  • Consider multiple endocrine neoplasia type 1 syndrome when a person has several endocrine neoplasia.

  • Acromegaly may be of ectopic origin with patients showing no abnormalities in radiological imaging of the pituitary gland.

DOI:
https://doi.org/10.1530/EDM-21-0079
Volume 2022: Issue 1
Open access

Fructose-induced severe hypertriglyceridemia and diabetes mellitus: a cautionary tale

Ana Dugic, Michael Kryk, Claudia Mellenthin, Christoph Braig, Lorenzo Catanese, Sandy Petermann, Jürgen Kothmann, and Steffen Mühldorfer

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.

DOI:
https://doi.org/10.1530/EDM-21-0110
Volume 2021: Issue 1
Open access

Effect of once weekly oral levothyroxine therapy

Andrea del Toro-Diez, Ernesto Solá-Sánchez, and Michelle Mangual-García

Summary

Primary hypothyroidism is one of the most common endocrine disorders with widely available treatment. A minority of patients remain with uncontrolled hypothyroidism despite therapy. The objective of this case series was to demonstrate that medication non-adherence, rather than malabsorption, should be sought as the most common cause of unsuppressed TSH levels in patients receiving treatment for this condition. Non-adherence is often considered as a diagnosis of exclusion. Nonetheless, a diagnosis of malabsorption requires a more extensive workup, including imaging and invasive procedures, which increase healthcare costs and burden to the patient. The findings of this study allow for a cost-effective approach to uncontrolled hypothyroidism.

Learning points

  • Medication non-adherence is a common cause of insuppressible TSH levels.

  • Once weekly levothyroxine is an alternative approach to non-compliant patients.

  • Assessing compliance is more cost-effective and less burdensome than testing for malabsorption.

DOI:
https://doi.org/10.1530/EDM-21-0045
Volume 2021: Issue 1
Open access

Over-the-counter protein supplement resulting in impaired thyroxine absorption in a hypothyroid patient

P A D M Kumarathunga, N S Kalupahana, and C N Antonypillai

Summary

Whey protein is a popular dietary supplement that is claimed to provide multiple health benefits. It has been shown to delay gastric emptying and impair ileal nutrient absorption. Additionally, some of the other additives like papain enzyme, soy lecithin in these protein supplements could interfere with L-thyroxine absorption. There is no evidence in the literature for the effects of protein supplements on L-thyroxine absorption. Herein, we describe a case of a 34-year-old lady who was on endocrinology follow up for primary hypothyroidism with stable thyroid-stimulating hormone (TSH) levels within the normal range while on L-thyroxine with a dose of 125 µg daily for the last 3 years, presenting with mild hypothyroid symptoms and elevated TSH level following a recent introduction of a protein supplement by her physical care adviser. Her treatment adherence and ingestion technique were good throughout, she was not on other medications or herbal remedies, there were no other changes in her food pattern or features suggestive of malabsorption, she was not pregnant, was taking the same L-thyroxine brand and TSH test was done from the routine lab. Since the only factor which could have contributed to the deranged TSH levels was the recent introduction of the whey protein supplement, we advised her to stop the protein supplement while continuing the same dose of L-thyroxine. Her TSH level was repeated in 6 weeks and was found to be normal (1.7 mIU/L). Our case report demonstrates that over-the-counter protein supplements could interfere with L-thyroxine absorption. Therefore, patients on L-thyroxine should be cautious when taking them.

Learning points

  • Over-the-counter protein supplements could interfere with oral L-thyroxine absorption.

  • The underlying mechanism could be the effect of whey protein by delaying gastric emptying and reduced responsiveness of organic anion transporters in the ileum, and there may be a contribution from other additives like papain and soy lecithin present in these supplements.

  • When there is an elevation of previously stable thyroid-stimulating hormone (TSH) value in a hypothyroid patient on oral L-thyroxine, the patient's assessment should include inquiring for a recent introduction of protein supplement, in the absence of other well-known risk factors.

  • Discontinuation of protein supplement results in normalization of thyroid function tests.

  • Patients on oral L-thyroxine should be cautious when taking over-the-counter protein supplementation.

DOI:
https://doi.org/10.1530/EDM-21-0070
Volume 2021: Issue 1
Open access

Primary hepatic neuroendocrine tumor

Le Tuan Linh, Nguyen Minh Duc, Hoang Tu Minh, Nguyen Ngoc Cuong, Vuong Thu Ha, Dao-Thi Luan, Thieu-Thi Tra My, and Bui Van Lenh

Summary

Primary hepatic neuroendocrine tumor (PHNET) is a rare type of neuroendocrine tumor (NET) that is also a primary hepatic tumor. Patients are present with almost no specific clinical symptoms and typically present with negative test results and atypical imaging characteristics; therefore, the differentiation of PHNET from other types of primary hepatic masses can be very difficult. In this article, we describe a case of PHNET that mimicked a liver helminth infection in a 57-year-old man. The diagnosis of PHNET in this patient was challenging, and the final diagnosis was based on imaging, histopathology features, and long-term follow-up.

Learning points

  • An uncommon type of neuroendocrine tumor (NET) is a primary hepatic neuroendocrine tumor (PHNET).

  • Primary hepatic neuroendocrine tumors are rare NET lesions found in the liver, characterized by non-specific clinical and imaging results, which can be easily confused with other liver lesions, including HCC and parasitic lesions.

  • To have a conclusive diagnosis and classification, a mixture of many medical assessment techniques, such as imaging, gastrointestinal endoscopy, nuclear medicine, anatomy, including histopathology, and immunohistochemistry, is essential.

DOI:
https://doi.org/10.1530/EDM-20-0220
Volume 2021: Issue 1
Open access

Treatment-resistant hypertension in a post-transplant patient with cystic fibrosis: a rare case of phaeochromocytoma

David Joseph Tansey, Jim John Egan, Michelle Murray, Katie Padfield, John Conneely, and Mensud Hatunic

Summary

Phaeochromocytoma is a rare catecholamine-producing tumour. We present the case of phaeochromocytoma in a young man with a background history of a double-lung transplant for cystic fibrosis (CF). Clinical case: A 25-year-old man, with a background history of CF, CF-related diabetes (CFRD) and a double-lung transplant in 2012 was presented to the emergency department with crampy abdominal pain, nausea and vomiting. He was diagnosed with distal intestinal obstructions syndrome (DIOS). Contrast-enhanced CT imaging of the abdomen and pelvis showed a 3.4 cm right adrenal lesion. This was confirmed by a subsequent MRI of adrenal glands that demonstrated moderate FDG uptake, suggestive of a diagnosis of phaeochromocytoma. The patient was noted to be hypertensive with a blood pressure averaging 170/90 mm/Hg despite treatment with three different anti-hypertensive medications – amlodipine, telmisartan and doxazosin. He had hypertension for the last 3 years and had noted increasingly frequent sweating episodes recently, without palpitations or headache. Laboratory analysis showed elevated plasma normetanephrines (NMN) of 3167 pmol/L (182–867) as well as elevated metanephrines (MN) of 793 pmol/L (61–377) and a high 3-MT of 257 pmol/L (<185). Once cathecholamine excess was identified biochemically, we proceeded to functional imaging to further investigate. MIBG scan showed a mild increase in the uptake of tracer to the right adrenal gland compared to the left. The case was discussed at a multidisciplinary (MDT) meeting at which the diagnosis of phaeochromocytoma was made. Following a challenging period of 4 weeks to control the patient’s blood pressure with an alpha-blocker and beta-blocker, the patient had an elective right adrenalectomy, with normalisation of his blood pressure post-surgery. The histopathology of the excised adrenal gland was consistent with a 3 cm phaeochromocytoma with no adverse features associated with malignant potential.

Learning points

  • Five to ten per cent of patients have a secondary cause for hypertension. Phaeochromocytomas are rare tumours, originating in chromaffin cells and they represent 0.1–1.0% of all secondary hypertension cases.

  • Secondary causes should be investigated in cases where:

  • Patient is presenting <20 years of age or >50 years of age,

  • There is refractory hypertension, or

  • There is serious end-organ damage present.

  • Patients may present with the triad of headache, sweating and palpitations or more vague, non-specific symptoms.

  • Patients with suspected phaeochromocytoma should have 24-h urinary catecholamines measured and if available, plasma metanephrines measured. Those with abnormal biochemical tests should be further investigated with imaging to locate the tumour.

  • Medical treatment involves alpha- and beta-blockade for at least 2 to 3 weeks before surgery as well as rehydration.

  • There is a possibility of relapse so high-risk patients require life-long follow-up.

DOI:
https://doi.org/10.1530/EDM-21-0026
Volume 2021: Issue 1
Open access

Atypical progeroid syndrome (p.E262K LMNA mutation): a rare cause of short stature and osteoporosis

Marina Yukina, Nurana Nuralieva, Ekaterina Sorkina, Ekaterina Troshina, Anatoly Tiulpakov, Zhanna Belaya, and Galina Melnichenko

Summary

Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson–Gilford progeria syndrome, mandibuloacral dysplasia, atypical progeroid syndrome (APS) and generalized lipodystrophy-associated progeroid syndrome (GLPS). All of those syndromes are associated with some progeroid features, lipodystrophy and metabolic complications but vary differently depending on a particular mutation and even patients carrying the same gene variant are known to have clinical heterogeneity. We report a new 30-year-old female patient from Russia with an APS and generalized lipodystrophy (GL) due to the heterozygous de novo LMNA p.E262K mutation and compare her clinical and metabolic features to those of other described patients with APS. Despite many health issues, short stature, skeletal problems, GL and late diagnosis of APS, our patient seems to be relatively metabolically healthy for her age when compared to previously described patients with APS.

Learning points

  • Atypical progeroid syndromes (APS) are rare and heterogenic with different age of onset and degree of metabolic disorders, which makes this diagnosis very challenging for clinicians and may be missed until the adulthood.

  • The clinical picture of the APS depends on a particular mutation in the LMNA gene, but may vary even between the patients with the same mutation.

  • The APS due to a heterozygous LMNA p.E262K mutation, which we report in this patient, seems to have association with the generalized lipodystrophy, short stature and osteoporosis, but otherwise, it seems to cause relatively mild metabolic complications by the age of 30.

  • The patients with APS and lipodystrophy syndromes require a personalized and multidisciplinary approach, and so they should be referred to highly specialized reference-centres for diagnostics and treatment as early as possible.

  • Because of the high heterogeneity of such a rare disease as APS, every patient’s description is noteworthy for a better understanding of this challenging syndrome, including the analysis of genotype-phenotype correlations.

DOI:
https://doi.org/10.1530/EDM-20-0188
Volume 2021: Issue 1