Summary

The most frequent causes of pancreatitis classically have been known to be gallstones or alcohol. However, genetics can also play a key role in predisposing patients to both chronic and acute pancreatitis. The serine protease inhibitor Kazal type 1 (SPINK 1) gene is known to be strongly associated with pancreatitis. Patients with these underlying genetic mutations can have severe diseases with a high morbidity rate and frequent hospitalization. We report an Arab girl who presented with acute pancreatitis at the age of 7 years progressing to recurrent chronic pancreatitis over a few years. She had severe obesity from the age of 4 years and developed type 2 diabetes at the age of 12. She had a normal biliary system anatomy. Genetic analysis showed that she had combined heterozygous mutations in the SPINK1 gene (SPINK1, c.101A>G p.(Asn34Ser) and SPINK1, c.56-37T>C). Her parents were first-degree cousins, but neither had obesity. Mother was detected to have the same mutations. She had type 2 diabetes but never presented with pancreatitis. This case is the first to be reported from the Arab region with these combined mutations leading to recurrent chronic pancreatitis. It illustrates the importance of diagnosing the underlying genetic mutation in the absence of other known causes of pancreatitis. Considering the absence of pancreatitis history in the mother who did not have obesity but harboured the same mutations, we point out that severe obesity might be a triggering factor of pancreatitis in the presence of the mutations in SPINK1 gene in this child. While this is not an assumption from a single patient, we show that not all carriers of this mutation develop the disease even within the same family. Triggering factors like severe obesity might have a role in developing the disease.

Learning points

• Acute recurrent pancreatitis and chronic pancreatitis are uncommon in children but might be underdiagnosed.

• Biliary tract anomalies and dyslipidaemias are known causative factors for pancreatitis, but pancreatitis can be seen in children with intact biliary system.

• Genetic diagnosis should be sought in children with pancreatitis in the absence of known underlying predisposing factors.

• SPINK1 mutations can predispose to an early-onset severe recurrent pancreatitis and acute pancreatitis.

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.

Summary

Biallelic pathological variants in the thyroid stimulating hormone (TSH) subunit β gene (TSHB) result in isolated TSH deficiency and secondary hypothyroidism, a rare form of central congenital hypothyroidism (CCH), with an estimated incidence of 1 in 65 000 births. It is characterised by low levels of free thyroxine and inappropriately low serum TSH and may therefore be missed on routine neonatal screening for hypothyroidism, which relies on elevated TSH. We describe a patient with CCH who developed recurrence of pituitary hyperplasia and symptomatic hypothyroidism due to poor compliance with thyroxine replacement. She was diagnosed with CCH as a neonate and had previously required trans-sphenoidal hypophysectomy surgery for pituitary hyperplasia associated with threatened chiasmal compression at 17 years of age due to variable adherence to thyroxine replacement. Genetic testing of TSHB identified compound heterozygosity with novel variant c.217A>C, p.(Thr73Pro), and a previously reported variant c.373delT, p.(Cys125Valfs*10). Continued variable adherence to treatment as an adult resulted in recurrence of significant pituitary hyperplasia, which subsequently resolved with improved compliance without the need for additional medications or repeat surgery. This case describes a novel TSHB variant associated with CCH and demonstrates the importance of consistent compliance with thyroxine replacement to treat hypothyroidism and prevent pituitary hyperplasia in central hypothyroidism.

Learning points

• Pathogenic variants in the TSH subunit β gene (TSHB) are rare causes of central congenital hypothyroidism (CCH).

• c.217A>C, p.(Thr73Pro), is a novel TSHB variant, presented in association with CCH in this case report.

• Thyroxine replacement is critical to prevent clinical hypothyroidism and pituitary hyperplasia.

• Pituitary hyperplasia can recur post-surgery if adherence to thyroxine replacement is not maintained.

• Pituitary hyperplasia can dramatically reverse if compliance with thyroxine replacement is improved to maintain free thyroxine (FT4) levels in the middle-to-upper normal range, without the need for additional medications or surgeries.

Summary

Pituitary apoplexy (PA) is a medical emergency with complex diagnosis and management. In this study, we describe a case of PA in a 63-year-old male treated with oral anticoagulant therapy for atrial fibrillation. In the patient, PA manifested itself with asthenia and severe headache not responsive to common analgesics. Despite the finding of a pituitary mass through CT, and in anticipation of the endocrinological evaluation and pituitary MRI, the patient’s clinical condition worsened with an escalation of headache and asthenia associated with deterioration of the visual field and impairment of consciousness level. The emergency assessments revealed an adrenal failure, whereas MRI showed a haemorrhagic pituitary macroadenoma with compression of the optic chiasm. Intravenous fluids repletion and high-dose hydrocortisone were started with a rapid improvement of the patient’s health and visual field abnormalities. Hydrocortisone was gradually reduced to a replacement dose. During the follow-up, panhypopituitarism was documented, and replacement therapies with l-thyroxine and testosterone were introduced. Three months later, a pituitary MRI showed a 50% reduction in the pituitary adenoma volume.

Learning points

• Pituitary apoplexy (PA) is a medical emergency that can result in haemodynamic instability and abnormalities in the level of consciousness.

• The management of PA requires a multidisciplinary team that includes endocrinologists, ophthalmologists, neuro-radiologists, and neuro-surgeons.

• Pituitary MRI with gadolinium is the diagnostic gold standard for PA.

• PA therapy aims to improve general conditions and treat compression symptoms, especially visual field abnormalities.

• Adrenocorticotrophic hormone deficiency is a common and severe complication of PA. Thus, all patients with PA must be promptly treated with injective synthetic glucocorticoids (e.g. hydrocortisone 100 mg) and i.v. saline.

• PA must be taken into consideration in case of sudden headache in patients with a pituitary macroadenoma, especially if other risk factors are recognized.

Summary

Treatment of insulinoma can be challenging, while surgical resection is considered the first line. When surgery is contraindicated or is refused, minimally invasive procedures such as selective arterial embolization, local ablative techniques including alcohol ablation, radiofrequency ablation and microwave ablation are being used of late. The world’s first microwave ablation of insulinoma was performed in 2015, after which there have been only a handful of reported cases. A 78-year-old female presented with painful swelling of the left lower limb. She was drowsy and was previously misdiagnosed as epilepsy when she had similar episodes since 2 years ago. She had hypoglycaemia with high serum insulin and C-peptide, and mildly high adjusted calcium, serum prolactin. MRI did not show pituitary adenoma. Lower limb venous duplex scan showed left lower limb deep vein thrombosis for which she was treated with anticoagulation. CT of the abdomen showed a tumour measuring 1.8 cm, located in the antero-superior aspect of the body of the pancreas, with the superior surface being abutted by the splenic artery and the inferior surface being 3 mm above the pancreatic duct, suggestive of an insulinoma. Selective transcatheter arterial embolization of the pancreatic tumour was attempted but was abandoned due to multiple small feeding arteries. Microwave ablation of the tumour was performed successfully. Since there was a possibility of the ablation being compromised due to the heat sink at the splenic artery, 2 mL of 99% alcohol was injected into the rim of the tumour near the artery. She was subsequently normoglycaemic. She defaulted follow up for repeat imaging of pancreas and screening for MEN1 syndrome due to the impact of the COVID-19 pandemic. Minimally invasive procedures are preferred over surgery in selected patients with insulinoma, out of which microwave ablation could be preferentially recommended due to its efficacy and minimal complications. We report the first case of MWA performed in combination with AA in successfully treating insulinoma to our knowledge. This is also the first reported case of DVT associated with isolated insulinoma prior to intervention, though it is rarely reported in MEN1 syndrome.

Learning points

• Novel therapeutic minimally invasive procedures are successful in treating selected cases of insulinoma.

• Microwave ablation could be recommended preferentially over selective trans-arterial embolization, and radiofrequency ablation in treating insulinoma due to its efficacy and minimal complications.

• We report the first case of microwave ablation performed in combination with alcohol ablation in successfully treating insulinoma to our knowledge.

Summary

Von Hippel–Lindau’s disease (VHL) is a hereditary tumor syndrome characterized by its prototype lesions, hemangioblastomas, and renal cell carcinomas. Treatment for renal cell carcinomas can ultimately result in long-term dialysis. Pancreatic neuroendocrine tumors (pNET) can also occur in the course of the disease. Currently, peptide receptor radionuclide therapy (PRRT) is the standard treatment for progressive neuroendocrine tumors. However, little is known about treatment with PRRT in patients on dialysis, an infrequent presentation in patients with VHL. We present a 72-year-old man with VHL on hemodialysis and a progressive pNET. He received four cycles of PRRT with a reduced dose. Only mild thrombopenia was seen during treatments. The patient died 9 months after the last PRRT because of acute bleeding in a hemangioblastoma. Hemodialysis is not a limiting factor for PRRT treatment and it should be considered as it seems a safe short-term treatment option for this specific group.

Learning points

• Von Hippel–Lindau disease (VHL) is a complex disease in which former interventions can limit optimal treatment for following VHL-related tumors later in life.

• Metastasized pancreatic neuroendocrine tumors occur as part of VHL disease.

• Peptide receptor radionuclide therapy seems a safe short-term treatment option in patients on hemodialysis.

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.

Summary

Thyroid eye disease (TED) is the most common extra-thyroidal manifestation in Graves’ disease (GD). Additional/concurrent/synchronous pathologies may be present, especially in elderly patients who present with atypical features such as non-axial (or eccentric) proptosis, absence of lid lag and restricted superior extra-ocular movements. A 70-year-old female presented with progressive proptosis of her left eye and diplopia. She was diagnosed with GD a year prior and initiated on carbimazole. On examination, she had eccentric proptosis, restricted superior extra-ocular movements and a palpable mass in the supero-temporal quadrant of the left eye. Her T3 (1.33 ng/mL) and T4 (8.85 µg/dL) were normal with carbimazole. Thyroid-stimulating hormone (TSH)-receptor antibody was positive (3.15 IU/L, reference range <1.75). MRI revealed an enhancing lesion infiltrating the left superior rectus, with concurrent characteristic muscle belly involvement bilaterally. Orbital biopsy showed atypical lymphoid cells (CD20+), suggesting marginal zone lymphoma. CT thorax and abdomen, fluorodeoxyglucose-positron emission tomography and bone marrow examination were normal. The patient was administered orbital radiotherapy for her localised lymphoma and carbimazole was continued. TED is the most common cause of orbital involvement overall and in GD. However, additional or alternative pathology may be present which requires evaluation. MRI can be a useful adjunct in these patients. Orbital lymphoma needs to be staged with workup for disseminated disease. Radiotherapy is the treatment of choice for localized disease. The index case provides evidence for synchronous presentation of dual pathology and highlights the importance of astute clinical examination as well as keeps a low threshold for MRI in selected cases.

Learning points

• Thyroid eye disease can co-exist with other ocular pathology, especially in elderly individuals.

• Eccentric proptosis, absent lid lag and restriction of eye movements (suggesting tendon involvement) should alert towards the presence of alternative pathology.

• Orbital imaging using MRI not only has greater sensitivity in diagnosing radiologically bilateral disease in patients who have unilateral involvement clinically but is also useful to identify concurrent neoplasms.

Summary

Primary adrenal insufficiency is a rare disease and can masquerade as other conditions; therefore, it is sometimes incorrectly diagnosed. Herein, we reported the case of a 39-year-old Vietnamese male with primary adrenal insufficiency due to bilateral adrenal tuberculosis. The patient presented to the emergency room with acute adrenal crisis and a 3-day history of nausea, vomiting, epigastric pain, and diarrhoea with a background of 6 months of fatigue, weight loss, and anorexia. Abdominal CT revealed bilateral adrenal masses. Biochemically, unequivocal low morning plasma cortisol (<83 nmol/L) and high plasma adrenocorticotropic hormone levels were consistent with primary adrenal insufficiency. There was no evidence of malignancy or lymphoma. As the patient was from a tuberculosis-endemic area, extra-adrenal tuberculosis was excluded during the work up. A retroperitoneal laparoscopic left adrenalectomy was performed, and tuberculous adrenalitis was confirmed by the histopathological results. The patient was started on antituberculous therapy, in addition to glucocorticoid replacement. In conclusion, even without evidence of extra-adrenal tuberculosis, a diagnosis of bilateral adrenal tuberculosis is required. A histopathological examination has a significant role along with clinical judgement and hormonal workup in establishing a definitive diagnosis of adrenal tuberculosis without evidence of active extra-adrenal involvement.

Learning points

• Primary adrenal insufficiency can be misdiagnosed as other mimicking diseases, such as gastrointestinal illness, leading to diagnostic pitfalls.

• Adrenal insufficiency can be confirmed with significantly low morning plasma cortisol levels of <83 nmol/L without a dynamic short cosyntropin stimulation test.

• Tuberculous adrenalitis is an uncommon treatable condition; however, it remains an important cause of primary adrenal insufficiency, especially in developing countries. In the absence of extra-adrenal involvement, adrenal biopsy plays a key role in the diagnostic process. Alternatively, adrenalectomy for histopathological purposes should be considered if CT scan-guided fine needle aspiration is infeasible in cases of small adrenal masses.

Summary

A 32-year-old Caucasian male presented to the emergency department with a one-day history of acute severe bilateral lower limb weakness, three days after competing in a bodybuilding competition. He consumed large quantities of carbohydrate-rich foods following the competition. His past medical history was significant for anxiety, and family history was non-contributory. Examination was normal except for reduced power and hyporeflexia in both legs, despite his muscular physique. He was noted to have severe hypokalaemia (K⁺= 1.9 mmol/L). His thyroid function tests were consistent with thyrotoxicosis. He reported taking thyroxine and several other agents to facilitate muscle mass generation before the bodybuilding competition. His presentation was reminiscent of thyrotoxic periodic paralysis, albeit uncommon with Caucasian ethnicity. He also had transient hyperglycaemia at presentation with concomitant hyperinsulinaemia, which could be attributed to the carbohydrate load and may have exacerbated his hypokalaemia through a transcellular shift. Urine toxicology screen subsequently ruled out the use of diuretics but confirmed the presence of a long-acting beta agonist (clenbuterol) which, along with other substances, may have aggravated the hypokalaemia further. After 12 h of i.v. replacement, the potassium level normalised and leg weakness resolved. The patient agreed to stop taking thyroxine and beta agonists and was well during the clinic visit at one month follow-up. This case highlights the potential for thyrotoxicosis factitia to exacerbate hypokalaemia and muscle weakness from other causes in bodybuilders presenting with acute severe weakness, irrespective of ethnicity.

Learning points

• In patients presenting with muscle weakness and hypokalaemia, early consideration of thyrotoxicosis is essential, even in the absence of a past history of thyroid disease or specific symptoms of thyrotoxicosis, in order to allow prompt initiation of appropriate treatment and to prevent recurrence.

• Bodybuilders may constitute a uniquely ‘at-risk’ group for thyrotoxic periodic paralysis secondary to thyrotoxicosis factitia, especially where there is concomitant use of beta-adrenergic agonists, even in the absence of diuretic use.

• Although rare and usually described in patients of Asian or Polynesian ethnicity, this case highlights that thyrotoxic periodic paralysis secondary to thyrotoxicosis factitia can also occur in patients with Caucasian ethnicity.

• We speculate that consuming large quantities of carbohydrates may induce hyperinsulinaemia, which could theoretically contribute to worse hypokalaemia, though mechanistic studies would be needed to explore this further.