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Xiao Li,1,&ast; Zicheng Xu,1,&ast; Ting Xu,1,&ast; Feng Qi,1 Ninghong Song2 1Department of Urology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, 210009, People’s Republic of China; 2Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feng QiDepartment of Urology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, 210009, People’s Republic of ChinaEmail qf199408@163.comNinghong SongDepartment of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of ChinaEmail songninghong@126.comBackground: To explore the baseline characteristics, pathological and survival outcomes of Asian-American patients with clear cell renal cell carcinoma (ccRCC), and make comparisons with White patients.Materials and Methods: In this study, patients diagnosed with ccRCC between 2010 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Basic characteristics of Asian-American patients were analysed and compared with White patients. Then, proportional mortality ratio (PMR) analyses were performed in Asian population to investigate the proportions of different cause of deaths (CODs), and make comparisons with White patients. Moreover, Kaplan–Meier (KM) analyses were developed to investigate the survival disparities of ccRCC patients between Asian-Americans and White patients. Finally, a competing risk regression model was constructed to identify potential prognostic factors for ccRCC patients in the whole population.Results: A total of 1586 Asian-American patients were eventually identified, and the median age at diagnosis was 61 years old. In Asian patients, those from South Asian had the youngest age at diagnosis (P< 0.001) and the earliest stage of diseases (localized: 76.83%, T1: 70.73%, all P< 0.05) when compared with other ethnicities. No significant differences were detected in tumor characteristics between Asian-Americans and White patients. Older age (P< 0.001), earlier stage (P< 0.001) and the administration of surgery (P=0.050) were tightly associated with a lower risk of dying of RCC in Asian-American patients. Additionally, Asian-American patients had comparable survival outcomes when compared with White patients. Lastly, competing risk regression model revealed that age at diagnosis (P< 0.001), tumor grade (P< 0.001), histological stage (P< 0.001), median household income (P< 0.001) and the administration of surgery (P< 0.001) were prognostic factors for cancer-specific survival (CSS) in ccRCC patients, while died of other causes was regarded as a competing event.Conclusion: Asian-American patients had similar tumor characteristics and survival outcomes with White patients. In Asian patients, those from South Asian had the youngest age at diagnosis and the earliest stage of diseases. Age, grade, histological stage, household income and surgery were identified to be closely related to CSS in ccRCC patients. In the future, prospective and well-designed studies are needed to verify our findings.Keywords: ccRCC, Asian-American, SEER, White, prognosis

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.

Summary Thyroid dysfunction is among the most common immune-related adverse reactions associated with immune checkpoint inhibitors. It most commonly manifests as painless thyroiditis followed by permanent hypothyroidism. This usually causes mild toxicity that does not interfere with oncological treatment. In rare instances, however, a life-threatening form of decompensated hypothyroidism called myxoedema coma may develop. We present a case of myxoedema coma in a woman in her sixties who was treated with a combination of CTLA-4 and PD-1 immune checkpoint inhibitors; for stage four malignant melanoma. She became hypothyroid and required thyroxine replacement after an episode of painless thyroiditis. Six months after the initial diagnosis of malignant melanoma, she presented to the emergency department with abdominal pain, profuse diarrhoea, lethargy and confusion. She was drowsy, hypotensive with a BP of 60/40 mmHg, hyponatraemic and hypoglycaemic. Thyroid function tests (TFTs) indicated profound hypothyroidism with a TSH of 19 mIU/L, and undetectable fT3 and fT4, despite the patient being compliant with thyroxine. She was diagnosed with a myxoedema coma caused by immune-related enteritis and subsequent thyroxine malabsorption. The patient was treated with i.v. triiodothyronine (T3) and methylprednisolone in the ICU. While her clinical status improved with T3 replacement, her enteritis was refractory to steroid therapy. A thyroxine absorption test confirmed persistent malabsorption. Attempts to revert to oral thyroxine were unsuccessful. Unfortunately, the patient’s malignant melanoma progressed significantly and she passed away four months later. This is the first reported case of myxoedema coma that resulted from two distinct immune-related adverse reactions, namely painless thyroiditis and enterocolitis. Learning points Myxoedema coma, a severe form of decompensated hypothyroidism is a rare immunotherapy-related endocrinopathy. Myxedema coma should be treated with either i.v. triiodothyronine (T3) or i.v. thyroxine (T4). Intravenous glucocorticoids should be co-administered with thyroid hormone replacement to avoid precipitating an adrenal crisis. Thyroid function tests (TFTs) should be monitored closely in individuals with hypothyroidism and diarrhoea due to the risk of thyroxine malabsorption. A thyroxine absorption test can be used to confirm thyroxine malabsorption in individuals with persistent hypothyroidism.

Summary Hyponatraemia is the most common electrolyte disturbance in hospitalised patients and is associated with numerous adverse outcomes. Patients with schizophrenia are particularly susceptible to hyponatraemia, in part due to the close association between this condition and primary polydipsia. We report the case of a 57-year-old woman with schizophrenia and primary polydipsia who was receiving inpatient psychiatric care. She became increasingly confused, had multiple episodes of vomiting, and collapsed 1 week after being commenced on quetiapine 300 mg. On examination, she was hypertensive and her Glasgow coma scale was nine. She had a fixed gaze palsy and a rigid, flexed posture. Investigations revealed extreme hyponatraemia with a serum sodium of 97 mmol/L. A CT brain demonstrated diffused cerebral oedema with sulcal and ventricular effacement. A urine sodium and serum osmolality were consistent with SIAD, which was stimulated by the introduction of quetiapine. The antidiuretic effect of vasopressin limited the kidney’s ability to excrete free water in response to the patients' excessive water intake, resulting in extreme, dilutional hyponatraemia. The patient was treated with two 100 mL boluses of hypertonic 3% saline but deteriorated further and required intubation. She had a complicated ICU course but went on to make a full neurological recovery. This is one of the lowest sodium levels attributed to primary polydipsia or second-generation antipsychotics reported in the literature. Learning points The combination of primary polydipsia and SIAD can lead to a life-threatening, extreme hyponatraemia. SIAD is an uncommon side effect of second-generation anti-psychotics. Serum sodium should be monitored in patients with primary polydipsia when commencing or adjusting psychotropic medications. Symptomatic hyponatraemia is a medical emergency that requires treatment with boluses of hypertonic 3% saline. A serum sodium of less than 105 mmol/L is associated with an increased risk of osmotic demyelination syndrome, therefore the correction should not exceed 8 mmol/L over 24 h.

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.

Summary Our objective is to demonstrate the importance of considering microcalcifications even without evidence of nodules as a potential sign of malignancy. Current guidelines, such as those of the British Thyroid Association, acknowledge the clinical significance of microcalcifications only when found within nodules. In this case, they are considered a suspicious feature, classifying the nodules as U5 (i.e. high risk) where fine-needle aspiration biopsy (FNAB) is warranted, following the high likelihood of cancer in these nodules. In addition, there is a dearth of evidence of ultrasound scan (USS) detection of microcalcifications in the thyroid gland outside of nodules, along with their associated clinical implications. Yet, this clinical manifestation is not so infrequent considering that we do encounter patients in the clinic showing these findings upon ultrasound examination. Three patients who presented to our clinic with thyroid-related symptoms were shown to have areas of microcalcifications without a nodule upon sonographic evaluation of their thyroid gland. These incidentally detected hyperechoic foci were later confirmed to correspond to areas of papillary thyroid carcinoma (PTC) on histopathological examination of resected tissue following thyroidectomy. Four more cases were identified with sonographic evidence of microcalcifications without nodules and given their clinical and other sonographic characteristics were managed with active surveillance instead. Learning points Echogenic foci known as microcalcifications may be visible without apparent association to nodular structures. Microcalcifications without nodules may not be an infrequent finding. Microcalcifications are frequently indicative of malignancy within the thyroid gland even without a clearly delineated nodule. Empirically, the usual guidelines for the management of thyroid nodules can be applied to the management of microcalcifications not confined to a nodule, but such a finding per se should be classified as a ‘high-risk’ sign.

Summary A 33-year-old gentleman of Egyptian heritage presented with a 21 years history of unexplained and recurrent hypercalcaemia, nephrolithiasis, nephrocalcinosis, and myocarditis. A similar history was also found in two first-degree relatives. Further investigation into the vitamin D metabolism pathway identified the biochemical hallmarks of infantile hypercalcaemia type 1 (IIH). A homozygous, likely pathogenic, variant in CYP24A1 was found on molecular genetic analysis confirming the diagnosis. Management now focuses on removing excess vitamin D from the metabolic pathway as well as reducing calcium intake to achieve serum-adjusted calcium to the middle of the reference range. If undiagnosed, IIH can cause serious renal complications and metabolic bone disease. Learning points Infantile hypercalcaemia type 1 (IIH) is an autosomal recessive disorder characterised by homozygous mutations in the CYP24A1 gene that encodes the 24-hydroxylase enzyme used to convert active vitamin D metabolites such as 1,25-(OH)2-vitamin D into their inactive form. IIH should be questioned in individuals presenting with a history of unexplained hypercalcaemia, especially if presenting from childhood and/or where there is an accompanying family history of the same in first and/or second degree relatives, causing complications such as nephrocalcinosis, pericarditis, and calcium-based nephrolithiasis. Associated biochemistry of IIH is persistent mild to moderate hypercalcaemia, normal or raised 25-(OH)-vitamin D and elevated 1,25-(OH)2-vitamin D. An elevated ratio of 25-(OH)-vitamin D to 24,25-(OH)2-vitamin D can be a useful marker of defects in the 24-hydroxylase enzyme, whose measurement can be facilitated through the supra-regional assay service. Management should focus on limiting the amount of vitamin D introduced into the body either via sunlight exposure or supplementation in addition to calcium dietary restriction to try and maintain appropriate calcium homeostasis

Summary Insulin autoimmune syndrome (IAS) is a rare cause of non-islet cell hypoglycaemia. Treatment of this condition is complex and typically involves long-term use of glucocorticoids. Immunotherapy may provide an alternative in the management of this autoimmune condition through the suppression of antibodies production by B-lymphocyte depletion. We present a case of a 62-year-old male, with refractory hypoglycaemia initially presenting with hypoglycaemic seizure during an admission for acute psychosis. Biochemical testing revealed hypoglycaemia with an inappropriately elevated insulin and C-peptide level and no evidence of exogenous use of insulin or sulphonylurea. Polyethylene glycol precipitation demonstrated persistently elevated free insulin levels. This was accompanied by markedly elevated anti-insulin antibody (IA) titres. Imaging included CT with contrast, MRI, pancreatic endoscopic ultrasound and Ga 68-DOTATATE position emission tomography (DOTATATE PET) scan did not reveal islet cell aetiology for hyperinsulinaemia. Maintenance of euglycaemia was dependent on oral steroids and dextrose infusion. Complete resolution of hypoglycaemia and dependence on glucose and steroids was only achieved following treatment with plasma exchange and rituximab. Learning points Insulin autoimmune syndrome (IAS) should be considered in patients with recurrent hyperinsulinaemic hypoglycaemia in whom exogenous insulin administration and islet cell pathologies have been excluded. Biochemical techniques play an essential role in establishing high insulin concentration, insulin antibody titres, and eliminating biochemical interference. High insulin antibody concentration can lead to inappropriately elevated serum insulin levels leading to hypoglycaemia. Plasma exchange and B-lymphocyte depletion with rituximab and immunosuppression with high dose glucocorticoids are effective in reducing serum insulin levels and hypoglycaemia in insulin autoimmune syndrome (IAS). Based on our observation, the reduction in serum insulin level may be a better indicator of treatment efficacy compared to anti-insulin antibody (IA) titre as it demonstrated greater correlation to the frequency of hypoglycaemia and to hypoglycaemia resolution.

Summary Marfan syndrome is an autosomal dominant multisystem disorder that has an estimated incidence of 1 in 5000. It is caused by mutations in the FBN1 gene, which encodes the extracellular matrix protein type 1 fibrillin. Familial hypocalciuric hypercalcaemia (FHH), also inherited in an autosomal dominant pattern, is a rare benign disorder characterised by hypercalcaemia, hypocalciuria and relative hyperparathyroidism with normal or high plasma PTH levels, with an estimated incidence of between 1 in 10 000 to 1 in 100 000. We report a unique case of a 26-year-old man referred for investigation of hypercalcaemia, who also had clinical features of Marfan syndrome but no previous genetic investigations. Calculated fractional urinary excretion of calcium was low (0.0005) following correction of vitamin D deficiency, raising the possibility of FHH. Genetic testing for Marfan syndrome and FHH, via a hyperparathyroidism multiplex gene panel test, revealed a novel truncating variant in the FBN1 gene (c.8481T>G; p.(Tyr2827Ter)), consistent with Marfan syndrome; and a pathogenic truncating variant in the CaSR gene (c.741dupT; p.[Asp248Ter]), which confirmed the diagnosis of FHH. The patient’s mother was subsequently found to have mild hypercalcaemia (adjusted calcium 2.76 mmol/L) and is also heterozygous for the same CaSR mutation. Genetic testing of his father confirmed the presence of the same FBN1 gene mutation. This case illustrates the importance of making robust diagnoses in the era of modern genomic medicine, confirming FHH as the cause of hypercalcaemia means that no treatment is warranted and the patient can be reassured. Learning points Familial hypocalciuric hypercalcaemia (FHH) should always be excluded during the investigation of hypercalcaemia by measuring urinary calcium: creatinine clearance ratio. Diagnosing FHH is important as the condition is benign and misdiagnosing patients with primary hyperparathyroidism could potentially lead to unnecessary morbidity from parathyroid surgery. Genetic testing is increasingly available for a variety of inherited conditions including Marfan syndrome and FHH. Patients who present with clinical features suggestive of a particular genetic condition should undergo prompt, appropriate confirmatory testing wherever possible. Taking a thorough family history is vital when assessing patients presenting with endocrine conditions, as this could prompt cascade testing and appropriate genetic counselling where necessary.

The antimicrobial impact of visible violet and blue light has been known for more than a century but hardly been applied for purposeful pathogen reduction or prevention. The disinfecting properties of wide-spread warm-white and cool-white light emitting diodes (LEDs) are investigated by irradiation of staphylococci with different LEDs and varying doses. Additionally, the combination of a white and a violet LED illumination is examined. Both white LEDs exhibit an antimicrobial effect, which seems to be dominated by the blue parts of the LED emissions. Unfortunately, the antimicrobial effect is weak in realistic illumination applications. Additional violet LEDs can significantly enhance this impact without a large change in human color perception. This allows reasonable applications in certain medical and domestic environments without endangering humans.

Summary A phaeochromocytoma is a rare neuroendocrine tumour derived from the chromaffin cells of the adrenal medulla. Tumours can produce excessive amounts of catecholamines. The presenting symptoms can vary but often include the classic triad of episodic headaches, sweating and palpitations. Due to catecholamine excess, patients can develop cardiomyopathy. Bradycardia and collapse could be the result of sinus node dysfunction or transient dysregulation of the autonomic nervous system. Patients with co-existing diabetes can have improvement or resolution of their diabetes after successful adrenalectomy. We report a case of an 87-year-old lady who initially presented with sweating, palpitations and collapse, resulting in a permanent pacemaker insertion. She was later found to have a large adrenal incidentaloma with subsequent markedly elevated plasma metanephrine levels. She later presented with chest pain and in acute pulmonary oedema with normal coronary arteries visualised on coronary angiogram. After surgical excision of her phaeochromocytoma, her diabetes resolved with her HbA1c improving from 68 to 46 mmol/mol, with no further requirement for diabetic medications. Her pulmonary oedema improved with no ongoing need for diuretic therapy. This case highlights that phaeochromocytomas can affect multiple systems and there should be a very high index of suspicion in patients presenting with sweating, palpitations, hypertension and a history of diabetes and even in those with collapse. Learning points There should be a high index of suspicion for phaeochromocytomas in patients with palpitations, diaphoresis, anxiety, hypertension and diabetes. Rarely phaeochromocytomas can present as bradycardia and collapse due to sinus node dysfunction or transient autonomic dysregulation and that should be considered in older patients. Catecholamine cardiomyopathy can occur in phaeochromocytoma with potential resolution after successful surgical excision. Diabetes can resolve after successful surgical treatment of a phaeochromocytoma.

Resistance to thyroid hormone (RTH) is a rare hereditary syndrome with impaired sensitivity to thyroid hormones (TH) and reduced intracellular action of triiodothyronine (T3) caused by genetic variants of TH receptor beta (TRB) or alpha (TRA). RTH type beta (RTHβ) due to dominant negative variants in the TRB gene usually occurs with persistent elevation of circulating free TH, non-suppressed serum TSH levels responding to a thyrotropin-releasing hormone (TRH) test, an absence of typical symptoms of hyperthyroidism and goiter. Here, we present a rare variant in the TRB gene reported for the first time in an Italian patient with generalized RTHβ syndrome. The patient showed elevated TH, with non-suppressed TSH levels and underwent thyroid surgery two different times for multinodular goiter. The genetic test showed a heterozygous mutation in exon 9 of the TRB gene resulting in the replacement of threonine (ACG) with methionine (ATG) at codon 310 (p.M310T). RTHβ syndrome should be considered in patients with elevated TH, non-suppressed TSH levels and goiter. Resistance to thyroid hormone (RTH) is a rare hereditary syndrome with impaired sensitivity to thyroid hormones (TH) and reduced intracellular action of triiodothyronine (T3) caused by genetic variants of TH receptor beta (TRB) or alpha (TRA). RTH type beta (RTHβ) due to dominant negative variants in the TRB gene usually occurs with persistent elevation of circulating free TH, non-suppressed serum TSH levels responding to a thyrotropin-releasing hormone (TRH) test, an absence of typical symptoms of hyperthyroidism and goiter. Here, we present a rare variant in the TRB gene reported for the first time in an Italian patient with generalized RTHβ syndrome. The patient showed elevated TH, with non-suppressed TSH levels and underwent thyroid surgery two different times for multinodular goiter. The genetic test showed a heterozygous mutation in exon 9 of the TRB gene resulting in the replacement of threonine (ACG) with methionine (ATG) at codon 310 (p.M310T). RTHβ syndrome should be considered in patients with elevated TH, non-suppressed TSH levels and goiter.

Previous studies indicate that oxytocin (OT) administration reduces body weight in high-fat diet (HFD)-induced obese (DIO) rodents through both reductions in food intake and increases in energy expenditure. We recently demonstrated that chronic hindbrain [fourth ventricular (4V)] infusions of OT evoke weight loss in DIO rats. Based on these findings, we hypothesized that chronic 4V OT would elicit weight loss in DIO mice. We assessed the effects of 4V infusions of OT (16 nmol/day) or vehicle over 28 days on body weight, food intake, and body composition. OT reduced body weight by approximately 4.5% ± 1.4% in DIO mice relative to OT pretreatment body weight ( P < 0.05). These effects were associated with reduced adiposity and adipocyte size [inguinal white adipose tissue (IWAT)] ( P < 0.05) and attributed, in part, to reduced energy intake ( P < 0.05) at a dose that did not increase kaolin intake ( P = NS). OT tended to increase uncoupling protein-1 expression in IWAT (0.05 < P < 0.1) suggesting that OT stimulates browning of WAT. To assess OT-elicited changes in brown adipose tissue (BAT) thermogenesis, we examined the effects of 4V OT on interscapular BAT temperature ( TIBAT). 4V OT (1 µg) elevated TIBAT at 0.75 ( P = 0.08), 1, and 1.25 h ( P < 0.05) postinjection; a higher dose (5 µg) elevated TIBAT at 0.75-, 1-, 1.25-, 1.5-, 1.75- ( P < 0.05), and 2-h (0.05 < P < 0.1) postinjection. Together, these findings support the hypothesis that chronic hindbrain OT treatment evokes sustained weight loss in DIO mice by reducing energy intake and increasing BAT thermogenesis at a dose that is not associated with evidence of visceral illness.

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.

Familial paraganglioma syndrome type 1 (PGL-1) is maternally imprinted, caused by SDHD mutations on the paternally inherited allele, and presents with paragangliomas and pheochromocytomas that are usually benign. We describe a kindred with a germline c.57delG SDHD mutation that demonstrates an aggressive and possibly expanded phenotype. Eight individuals across four generations were heterozygous for the c.57delG SDHD mutation. The three with known paternal inheritance were clinically affected. The aggressive phenotype was manifested by a neck paraganglioma with distant metastases, and to a lesser degree a neck paraganglioma infiltrating into local connective tissue and a pheochromocytoma presenting at age 8 y. A pulmonary capillary hemangioma may expand the SDHD phenotype. We conclude that the c.57delG SDHD mutation may confer a more aggressive and possibly expanded phenotype than other SDHD mutations. Learning points The c.57delG SDHD mutation may confer a more aggressive phenotype than other mutations associated with familial paraganglioma syndrome type 1. A capillary hemangioma, a component of other pseudohypoxia states, was observed in the lung of a single member of the c.57delG SDHD kindred. This report supports the hypothesis of others that mutations found near the beginning of the SDHD open reading frame are more likely to demonstrate an aggressive phenotype. Patient Demographics: Paediatric, Male, Female, White, United States Clinical Overview: Adrenal, Adrenal Related Disciplines: Oncology Publication Details: Unique/unexpected symptoms or presentations of a disease, March, 2021 Background Pseudohypoxia is a state of dysregulated cellular respiration that contributes to the hypoxic phenotype in the absence of hypoxemia. The pseudohypoxia state is caused by germline mutations in SDHB, SDHD, SDAF2, SDHC, VHL, NF1, HIF1/HIF2A, and IDH1/IDH2, and the phenotype is manifested by pheochromocytomas and paragangliomas (1, 2, 3). SDHD mutations cause the PGL-1 syndrome that is maternally imprinted and presents with sympathetic and parasympathetic paragangliomas of the head, neck, thorax and abdomen, and with pheochromocytomas (4, 5). We describe a kindred with a germline c.57delG SDHD mutation with an aggressive and expanded phenotype.

Summary Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited endocrine disorder with a high rate of penetrance. The incidence of MEN1 is 1/30,000 in the general population; however, it is quite rare for a patient to present for medical attention with MEN1 for the first time in pregnancy. Primary hyperparathyroidism (PHPT) is one of the most common features of MEN1. The incidence of PHPT occurring in pregnancy is 1%. Despite advances in the medical, surgical and obstetric care over the years, management of this condition during pregnancy may be challenging. It can be difficult to identify pregnant women with PHPT requiring intervention and to monitor safely. Hypercalcemia can result in significant maternal and fetal adverse outcomes including: miscarriage, intrauterine growth restriction, preterm delivery, neonatal hypocalcaemia, pre-eclampsia and maternal nephrolithiasis. Herein, we present a case study of a lady with a strong family history of MEN1, who was biochemically proven to have PHPT and evidence of Zollinger Ellison Syndrome (ZE) on endoscopy. This patient delayed her assisted pregnancy plans for in vitro fertilization (IVF) until completion of the MEN1 workup; nevertheless, she spontaneously achieved an unplanned pregnancy. As a result, she required intervention with parathyroidectomy in the second trimester of her pregnancy as her calcium level continued to rise. This case study highlights the workup, follow up and management of MEN1 presenting with PHPT and ZE in pregnancy. Learning points Women of childbearing age who are suspected to have a diagnosis of primary hyperparathyroidism ideally should have genetic testing and avoid pregnancy until definitive plans are in place. Zollinger Ellison syndrome in pregnancy means off-label use of high dose of proton pump inhibitors (PPI). Use of PPI in pregnancy is considered to be safe based on retrospective studies. Omeprazole, however, is FDA class C drug because of lack of large prospective studies or large case series during pregnancy. Calcium supplements in the form of calcium carbonate must be converted to calcium chloride by gastric acid in order to be absorbed, however, patients rendered achlorhydric as a result of PPI use will have impaired absorption of calcium. Therefore, use of calcium citrate might be considered a better option in this case.

Summary Molecular alterations of the transcription factor hepatocyte nuclear factor 1B (HNF1B) are associated with systemic disease, with kidney disease and maturity-onset diabetes of the young (MODY) as the most characteristic manifestations. Other features comprise pancreatic exocrine insufficiency, liver and biliary anomalies, and genital tract malformations. HNF1B-associated disease is clinically heterogeneous, and therefore the diagnosis is challenging. The authors describe the case of a 19-year-old man with new-onset diabetes after kidney transplantation (NODAT). The kidney disease presented during fetal life as bilateral hyperechogenic kidneys. Renal function progressively deteriorated during childhood, and at the age of 19, the patient was submitted to a living-kidney transplant. Two weeks after transplant, NODAT developed. Given the young age and normal body weight, NODAT was unexpected, and the possibility of HNF1B-associated disease was considered. Screening for mutations in HNF1B was undertaken, and a known mutation was found. As this case highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive renal disease. Learning points: HNF1B anomalies are associated with systemic disease, including kidney disease, diabetes mellitus, pancreatic exocrine insufficiency, liver test abnormalities and genital tract malformations. Phenotype is variable and there are no pathognomonic manifestations, but kidney disease appears to be the most common feature and diabetes the most frequent extra-renal phenotype. Spontaneous gene alterations are common, and the lack of family history should not exclude the diagnosis. HNF1B defects should be considered when NODAT develops in a young adult kidney transplant recipient with a suggestive kidney disease and without extensive risk factors for diabetes. The most appropriate treatment for HNF1B-associated diabetes is not established, but immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period. Immunosupressive regimens free of calcineurin inhibitors should be considered in patients with HNF1B-associated disease to minimize the risk of developing NODAT.

Summary An 11-year-old girl presented with acute lower limb weakness, dehydration, hypernatraemia and secondary rhabdomyolysis on a background of an 8-month history of polyuria. Radiological investigations revealed a suprasellar tumour which was diagnosed on biopsy as a non-metastatic germinoma. Further endocrinological investigations confirmed panhypopituitarism and she commenced desmopressin, hydrocortisone and thyroxine. Her chemotherapeutic regime consisted of etoposide, carboplatin and ifosfamide, the latter of which required 4 litres of hyperhydration therapy daily. During the first course of ifosfamide, titration of oral desmopressin was trialled but this resulted in erratic sodium control leading to disorientation. Based on limited literature, we then trialled an arginine-vasopressin (AVP) infusion. A sliding scale was developed to adjust the AVP dose, with an aim to achieve a urine output of 3–4 mL/kg/h. During the second course of ifosamide, AVP infusion was commenced at the outset and tighter control of urine output and sodium levels was achieved. In conclusion, we found that an AVP infusion during hyperhydration therapy was required to achieve eunatraemia in a patient with cranial diabetes insipidus. Developing an AVP sliding scale requires individual variation; further reports/case series are required to underpin practice. Learning points: Certain chemotherapeutic regimens require large fluid volumes of hyperhydration therapy which can result in significant complications secondary to rapid serum sodium shifts in patients with diabetes insipidus. The use of a continuous AVP infusion and titrating with a sliding scale is more effective than oral desmopressin in regulating plasma sodium and fluid balance during hyperhydration therapy. No adverse effects were found in our patient using a continuous AVP infusion. Adjustment of the AVP infusion rate depends on urine output, fluid balance, plasma sodium levels and sensitivity/response of the child to titrated AVP doses.

Summary The authors examine several reports of the literature concerning thyrotoxic dilated cardiomyopathy. In particular, it is pointed out that this clinical manifestation of hyperthyroidism is rare in readily diagnosed and properly treated hyperthyroidism. Case reports are analyzed comparatively. A case deriving from the direct experience of the authors is also presented. Learning points: Dilated cardiomyopathy has been reported as the initial presentation of hyperthyroidism in only 6% of patients although Clinical picture of thyrotoxic dilated cardiomyopathy can degenerate into an overt cardiogenic shock sometimes requiring the use of devices for mechanical assistance to the circulation, or extracorporeal membrane oxygenation. For thyrotoxic dilated cardiomyopathy, evidence-based pharmacologic measures valid for heart failure should always be supplemented by the administration of specific thyroid therapies such as thionamides (methimazole, carbimazole or propylthiouracil), whose relatively long latency of action should be supported by the i.v. administration of small doses of beta-blocker. In cases of cardiogenic shock, the administration of beta-blocker should be carried out only after the restoration of satisfactory blood pressure levels- with the prudent use of synthetic catecholamines, if necessary.

Summary Autoimmune polyglandular syndrome type 1 (APS-1) is a very rare autoimmune entity, accounting for about 400 cases reported worldwide. It is characterized by the presence of at least two of three cardinal components: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism and Addison’s disease. It typically manifests in childhood with CMC and years later with hypoparathyroidism. A 50-year-old man was referred to the Endocrinology outpatient clinic due to irregular follow-up of primary hypoparathyroidism diagnosed at age 7. Previous analysis reported frequent fluctuations of calcium and phosphate levels and persistent hypercalciuria. He presented several comorbidities, including bilateral cataracts, other ocular disorders, transient alopecia and chronic gastritis. Due to weight loss, fatigue, gastrointestinal complaints and the findings at objective examination, Addison’s disease and CMC were investigated and confirmed. Antifungal therapy and hormonal replacement were started with evident clinical improvement. Regarding hypoparathyroidism, calcium-phosphate product decreased and other extraskeletal calcifications were diagnosed, such as nephrolithiasis and in basal ganglia. Further evaluation by genetic analysis revealed homozygosity for a frameshift mutation considered to be a pathogenic variant. It was reported only in two Asian siblings in compound heterozygosity. This case highlights the broad phenotypic spectrum of APS-1 and the significative intra-familial phenotype variability. A complete clinical history taking and high index of suspicion allowed the diagnosis of this rare entity. This case clarifies the need for regular long-term follow-up. In the specific case of hypoparathyroidism and Addison’s disease in combination, the management of APS-1 can be complex. Learning points: Autoimmune polyglandular syndrome type 1 (APS-1) is a deeply heterogeneous genetic entity with a broad spectrum of clinical manifestations and a significant intra-family phenotypic variability. Early diagnosis of APS-1 is challenging but clinically relevant, as endocrine and non-endocrine manifestations may occur during its natural history. APS-1 should be considered in cases of acquired hypoparathyroidism, and even more so with manifestations with early onset, family history and consanguinity. APS-1 diagnosis needs a high index of suspicion. Key information such as all the comorbidities and family aspects would never be valued in the absence of a complete clinical history taking. Especially in hypoparathyroidism and Addison’s disease in combination, the management of APS-1 can be complex and is not a matter of simply approaching individually each condition. Regular long-term monitoring of APS-1 is essential. Intercalary contact by phone calls benefits the control of the disease and the management of complications.

Context and purpose There is an urgent need to develop vitamin D dietary recommendations for dark-skinned populations resident at high latitude. Using data from randomised controlled trials (RCTs) with vitamin D3-supplements/fortified foods, we undertook an individual participant data-level meta-regression (IPD) analysis of the response of wintertime serum 25-hydroxyvitamin (25(OH)D) to total vitamin D intake among dark-skinned children and adults residing at ≥ 40° N and derived dietary requirement values for vitamin D. Methods IPD analysis using data from 677 dark-skinned participants (of Black or South Asian descent; ages 5-86 years) in 10 RCTs with vitamin D supplements/fortified foods identified via a systematic review and predefined eligibility criteria. Outcome measures were vitamin D intake estimates across a range of 25(OH)D thresholds. Results To maintain serum 25(OH)D concentrations ≥ 25 and 30 nmol/L in 97.5% of individuals, 23.9 and 27.3 µg/day of vitamin D, respectively, were required among South Asian and 24.1 and 33.2 µg/day, respectively, among Black participants. Overall, our age-stratified intake estimates did not exceed age-specific Tolerable Upper Intake Levels for vitamin D. The vitamin D intake required by dark-skinned individuals to maintain 97.5% of winter 25(OH)D concentrations ≥ 50 nmol/L was 66.8 µg/day. This intake predicted that the upper 2.5% of individuals could potentially achieve serum 25(OH)D concentrations ≥ 158 nmol/L, which has been linked to potential adverse effects in older adults in supplementation studies. Conclusions Our IPD-derived vitamin D intakes required to maintain 97.5% of winter 25(OH)D concentrations ≥ 25, 30 and 50 nmol/L are substantially higher than the equivalent estimates for White individuals. These requirement estimates are also higher than those currently recommended internationally by several agencies, which are based predominantly on data from Whites and derived from standard meta-regression based on aggregate data. Much more work is needed in dark-skinned populations both in the dose-response relationship and risk characterisation for health outcomes. Trail registration PROSPERO International Prospective Register of Systematic Reviews (Registration Number: CRD42018097260).

Summary Carbimazole is a commonly used antithyroid drug (ATD), which is associated with several well-established side effects. However, Carbimazole-induced rhabdomyolysis is rarely reported in the literature. We report a 27-year-old male who presented with upper limb myalgia and significantly raised creatine kinase elevation, 1-month post commencement of Carbimazole for Graves’ disease. Carbimazole was ceased with subsequent clinical and biochemical improvement. Though the pathophysiology remains unclear, we hope to raise awareness regarding this rare adverse effect with a view to promote early recognition and prompt discontinuation of the offending medication caused by a commonly used medication in endocrinology. Learning points Musculoskeletal complaints can relate to unidentified and untreated hyperthyroidism. However one must be mindful that the treatment for these disorders can too induce myopathies. ATD-induced myopathy should be considered when there is a temporal relationship between introduction of ATDs and the onset of symptoms. If ATD-induced myopathy is being considered, other causes of myopathy should still be outruled. Prompt discontinuation of potentially offending medications may provide resolution of symptoms and avoid significant consequences.

Summary Conventional treatment of hypoparathyroidism relies on oral calcium and calcitriol. Challenges in managing post-parathyroid- and post-thyroidectomy hypocalcaemia in patients with a history of bariatric surgery and malabsorption have been described, but postoperative management of bariatric surgery in patients with established hypoparathyroidism has not. We report the case of a 46-year-old woman who underwent elective sleeve gastrectomy on a background of post-surgical hypoparathyroidism and hypothyroidism. Multiple gastric perforations necessitated an emergency Roux-en-Y gastric bypass. She was transferred to a tertiary ICU and remained nil orally for 4 days, whereupon her ionised calcium level was 0.78 mmol/L (1.11–1.28 mmol/L). Continuous intravenous calcium infusion was required. She remained nil orally for 6 months due to abdominal sepsis and the need for multiple debridements. Intravenous calcium gluconate 4.4 mmol 8 hourly was continued and intravenous calcitriol twice weekly was added. Euthyroidism was achieved with intravenous levothyroxine. Maintaining normocalcaemia was fraught with difficulties in a patient with pre-existing surgical hypoparathyroidism, where oral replacement was impossible. The challenges in managing hypoparathyroidism in the setting of impaired enteral absorption are discussed with analysis of the cost and availability of parenteral treatments. Learning points: Management of hypoparathyroidism is complicated when gastrointestinal absorption is impaired. Careful consideration should be given before bariatric surgery in patients with pre-existing hypoparathyroidism, due to potential difficulty in managing hypocalcaemia, which is exacerbated when complications occur. While oral treatment of hypoparathyroidism is cheap and relatively simple, available parenteral options can carry significant cost and necessitate a more complicated dosing schedule. International guidelines for the management of hypoparathyroidism recommend the use of PTH analogues where large doses of calcium and calcitriol are required, including in gastrointestinal disorders with malabsorption. Approval of subcutaneous recombinant PTH for hypoparathyroidism in Australia will alter future management.

Summary Excess cortisol is associated with hypertrophy and redistribution of adipose tissue leading to central obesity which is classically seen in Cushing’s syndrome. Abnormal accumulation of fatty tissue in the spinal canal is most commonly associated with chronic steroid therapy and rarely reported with endogenous Cushing’s syndrome. Herein, we describe a case of spinal epidural lipomatosis (SEL) associated with Cushing’s disease. A 17-year-old man was referred with lower limb weakness, weight gain, multiple stretch marks, back pain and loss of height. He had clinical and biochemical features of Cushing’s syndrome. MRI and Inferior Petrosal Sinus Sampling (IPSS) confirmed a pituitary adenoma as the source. On day 1 post trans-sphenoidal adenectomy he developed spastic paraparesis with a sensory deficit to the level of T5. MRI spine showed increased fat deposition in the spinal canal from T2 to T9 consistent with a diagnosis of SEL. He was managed conservatively and made a good recovery following restoration of eucortisolism and a period of rehabilitation. Learning points: SEL is a serious complication of glucocorticoid excess and should be considered in any patient presenting with new lower limb neurological symptoms associated with hypercortisolism. It is important to distinguish symptomatic SEL from cortisol-induced proximal myopathy by good history and clinical examination. MRI of the spine is the gold standard investigation for making a diagnosis of SEL. Restoration of eucortisolism can lead to resolution of fat accumulation and good neurological outcome.

Summary We present a 60-year-old woman who underwent successful surgical resection (partial pancreatectomy) for a low grade non-functioning pancreatic neuroendocrine tumour (pNET), with no biochemical or radiological features of recurrence on follow-up visits for 5 years. Fourteen years after the initial surgery, she developed spontaneous severe hypoglycaemic episodes which required hospitalisation, with subsequent investigations confirming the diagnosis of a metastatic insulin-secreting pNET (insulinoma). Medical management of her severe spontaneous hypoglycaemic episodes remained challenging, despite optimum use of diazoxide and somatostatin analogue therapy. Based on a discussion at the regional neuroendocrine tumour multidisciplinary team meeting, she underwent an elective hepatic trans-arterial embolization which was unfortunately unsuccessful. She ended up requiring an emergency right hemihepatectomy and left retroperitoneal mass resection which finally stabilised her clinical condition. Learning points: Ours is only the seventh case report of a previously benign pNET presenting as a functional insulin secreting metastatic tumour. However, it is the first case report, in which the metastatic functional pNET presented after such a long hiatus (14 years). There is currently no clear consensus regarding the length of follow-up of non-functional pNET which are deemed cured post-surgical resection, with most guidelines advocating a median follow up of 5 years (1). The delayed presentation in our case suggests additional considerations should be made regarding optimal post-operative surveillance duration based on the age of the patient, location of the tumour, lymph node spread and Ki-67 index. Hepatic artery embolization and/or partial hepatectomy remains a treatment option for pNET patients with significant hepatic metastasis.

Summary Lymphocytic hypophysitis is a rare neuroendocrine disease characterised by an autoimmune inflammatory disorder of the pituitary gland. We report a 50-year-old woman who presented with headaches and bilateral sixth cranial nerve palsies. MRI of the pituitary revealed extensive fibrosis involving the sellar and extending into both cavernous sinuses causing bilateral occlusion of the internal carotid arteries (ICA). Transphenoidal biopsy confirmed the diagnosis of infiltrative fibrotic lymphocytic hypophysitis. Symptoms resolved with high dose of oral steroids but relapsed on tapering, requiring several treatments of i.v. pulse steroids over 8 months. Rituximab combined with mycophenolate mofetil was required to achieve long-term symptom relief. Serial MRI pituitary imaging showed stabilisation of her disease without reduction in sellar mass or regression of ICA occlusion. The patient’s brain remained perfused solely by her posterior circulation. This case demonstrates an unusual presentation of a rare disease and highlights a successful steroid-sparing regimen in a refractory setting. Learning points: Lymphocytic hypophysitis is a rare inflammatory disorder of the pituitary gland. In exceptional cases, there is infiltration of the cavernous sinus with subsequent occlusion of the internal carotid arteries. First-line treatment of lymphocytic hypophysitis is high-dose glucocorticoids. Relapse after tapering or discontinuation is common and its use is limited by long-term adverse effects. There is a paucity of data for treatment of refractory lymphocytic hypophysitis. Goals of treatment should include improvement in symptoms, correction of hormonal insufficiencies, reduction in lesion size and prevention of recurrence. Steroid-sparing immunosuppressive drugs such as rituximab and mycophenolate mofetil have been successful in case reports. This therapeutic combination represents a viable alternative treatment for refractory disease.

Summary Colorectal poorly differentiated neuroendocrine carcinomas (NECs) are typically associated with poor outcomes. The mechanisms of their aggressiveness are still being investigated. Microsatellite instability (MSI) has recently been found in colorectal NECs showing aberrant methylation of the MLH1 gene and is associated with improved prognosis. We present a 76-year-old lady with an ascending colon tumour showing features of a pT3 N0 R0, large cell NEC (LCNEC) following right hemicolectomy. The adjacent mucosa showed a sessile serrated lesion (SSL) with low-grade dysplasia. Immunohistochemistry showed loss of expression for MLH1 and PMS2 in both the LCNEC and dysplastic SSL. Molecular analysis indicated the sporadic nature of the MLH1 mismatch repair (MMR) protein-deficient status. Our patient did not receive adjuvant therapy and she is alive and disease-free after 34 months follow-up. This finding, similar to early-stage MMR-deficient colorectal adenocarcinoma, is likely practice-changing and will be critical in guiding the appropriate treatment pathway for these patients. We propose that testing of MMR status become routine for early-stage colorectal NECs. Learning points: Colorectal poorly differentiated neuroendocrine carcinomas (NECs) are known to be aggressive and typically associated with poor outcomes. A subset of colorectal NECs can display microsatellite instability (MSI) with mismatch repair (MMR) protein-deficient status. MMR-deficient colorectal NECs have been found to have a better prognosis compared with MMR-proficient NECs. MMR status can be detected using immunohistochemistry. Immunohistochemistry for MMR status is routinely performed for colorectal adenocarcinomas. Immunohistochemical expression of MMR protein and MSI analysis should be performed routinely for early-stage colorectal NECs in order to identify a subgroup of MMR-deficient NECs which are associated with a significantly more favourable prognosis.

Background: Diffusion-weighted 1H magnetic resonance spectroscopy (DW-MRS) allows to quantify creatine-phosphocreatine brain diffusivity (ADC(tCr)), whose reduction in multiple sclerosis (MS) has been proposed as a proxy of energy dysfunction. Objective: To investigate whether thalamic ADC(tCr) changes are associated with thalamo-cortical tract damage in MS. Methods: Twenty patients with MS and 13 healthy controls (HC) were enrolled in a DW-MRS and DW imaging (DWI) study. From DW-MRS, ADC(tCr) and total N-acetyl-aspartate diffusivity (ADC(tNAA)) were extracted in the thalami. Three thalamo-cortical tracts and one non-thalamic control tract were reconstructed from DWI. Fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivity (RD), reflecting microstructural integrity, were extracted for each tract. Associations between thalamic ADC(tCr) and tract metrics were assessed using linear regression models adjusting for age, sex, thalamic volume, thalamic ADC(tNAA), and tract-specific lesion load. Results: Lower thalamic ADC(tCr) was associated with higher MD and RD of thalamo-cortical projections in MS (MD: p = 0.029; RD: p = 0.017), but not in HC (MD: p = 0.625, interaction term between thalamic ADC(tCr) and group = 0.019; RD: p = 0.320, interaction term = 0.05). Thalamic ADC(tCr) was not associated with microstructural changes of the control tract. Conclusion: Reduced thalamic ADC(tCr) correlates with thalamo-cortical tract damage in MS, showing that pathologic changes in thalamic energy metabolism are associated with structural degeneration of connected fibers.

Summary HAIR-AN syndrome, the coexistence of Hirsutism, Insulin Resistance (IR) and Acanthosis Nigricans, constitutes a rare nosologic entity. It is characterized from clinical and biochemical hyperandrogenism accompanied with severe insulin resistance, chronic anovulation and metabolic abnormalities. Literally, HAIR-AN represents an extreme case of polycystic ovary syndrome (PCOS). In everyday practice, the management of HAIR-AN constitutes a therapeutic challenge with the available pharmaceutical agents. Specifically, the degree of IR cannot be significantly ameliorated with metformin administration, whereas oral contraceptives chronic administration is associated with worsening of metabolic profile. Liraglutide and exenatide, in combination with metformin, have been introduced in the management of significantly obese women with PCOS with satisfactory results. Based on this notion, we prescribed liraglutide in five women with HAIR-AN. In all participants a significant improvement regarding the degree of IR, fat depositions, androgen levels and the pattern of menstrual cycle was observed, with minimal weight loss. Furthermore, one woman became pregnant during liraglutide treatment giving birth to a healthy child. Accordingly, we conclude that liraglutide constitutes an effective alternative in the management of women with HAIR-AN. Learning points: HAIR-AN management is challenging and classic therapeutic regimens are ineffective. Literally HAIR-AN syndrome, the coexistence of Hirsutism, Insulin Resistance and Acanthosis Nigricans, represents an extreme case of polycystic ovary syndrome. In cases of HAIR-AN, liraglutide constitutes an effective and safe choice.

Summary Standard treatment of hypoparathyroidism consists of supplementation of calcium and vitamin D analogues, which does not fully restore calcium homeostasis. In some patients, hypoparathyroidism is refractory to standard treatment with persistent low serum calcium levels and associated clinical complications. Here, we report on three patients (58-year-old male, 52-year-old female, and 48-year-old female) suffering from severe treatment-refractory postsurgical hypoparathyroidism. Two patients had persistent hypocalcemia despite oral treatment with up to 4 µg calcitriol and up to 4 g calcium per day necessitating additional i.v. administration of calcium gluconate 2–3 times per week, whereas the third patient presented with high frequencies of hypocalcemic and treatment-associated hypercalcemic episodes. S.c. administration of rhPTH (1–34) twice daily (40 µg/day) or rhPTH (1–84) (100 µg/day) only temporarily increased serum calcium levels but did not lead to long-term stabilization. In all three cases, treatment with rhPTH (1–34) as continuous s.c. infusion via insulin pump was initiated. Normalization of serum calcium and serum phosphate levels was observed within 1 week at daily 1–34 parathyroid hormone doses of 15 µg to 29.4 µg. Oral vitamin D and calcium treatment could be stopped or reduced and regular i.v. calcium administration was no more necessary. Ongoing efficacy of this treatment has been documented for up to 7 years so far. Therefore, we conclude that hypoparathyroidism that is refractory to both conventional treatment and s.c. parathyroid hormone (single or twice daily) may be successfully treated with continuous parathyroid hormone administration via insulin pump. Learning points: Standard treatment of hypoparathyroidism still consists of administration of calcium and active vitamin D. Very few patients with hypoparathyroidism also do not respond sufficiently to standard treatment or administration of s.c. parathyroid hormone once or twice daily. In those cases, continuous s.c. administration of parathyroid hormone via insulin pump may represent a successful treatment alternative.

Summary Brown tumors are osteoclastic, benign lesions characterized by fibrotic stroma, intense vascularization and multinucleated giant cells. They are the terminal expression of the bone remodelling process occurring in advanced hyperparathyroidism. Nowadays, due to earlier diagnosis, primary hyperparathyroidism keeps few of the classical manifestations and brown tumors are definitely unexpected. Thus, it may happen that they are misdiagnosed as primary or metastatic bone cancer. Besides bone imaging, endocrine evaluation including measurement of serum parathyroid hormone and calcium (Ca) levels supports the pathologist to address the diagnosis. Herein, a case of multiple large brown tumors misdiagnosed as a non-treatable osteosarcoma is described, with special regards to diagnostic work-up. After selective parathyroidectomy, treatment with denosumab was initiated and a regular follow-up was established. The central role of multidisciplinary approach involving pathologist, endocrinologist and oncologist in the diagnostic and therapeutic work-up is reported. In our opinion, the discussion of this case would be functional especially for clinicians and pathologists not used to the differential diagnosis in uncommon bone disorders. Learning points: Brown tumors develop during the remodelling process of bone in advanced and long-lasting primary or secondary hyperparathyroidism. Although rare, they should be considered during the challenging diagnostic work-up of giant cell lesions. Coexistence of high parathyroid hormone levels and hypercalcemia in primary hyperparathyroidism is crucial for the diagnosis. A detailed imaging study includes bone X-ray, bone scintiscan and total body CT; to rule out bone malignancy, evaluation of bone lesion biopsy should include immunostaining for neoplastic markers as H3G34W and Ki67 index. If primary hyperparathyroidism is confirmed, selective parathyroidectomy is the first-line treatment. In advanced bone disease, treatment with denosumab should be considered, ensuring a strict control of Ca levels.

Summary Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of ACTH-independent Cushing syndrome (CS). This condition is characterized by glucocorticoid and/or mineralocorticoid excess, and is commonly regulated by aberrant G-protein coupled receptor expression may be subclinical, allowing the disease to progress for years undetected. Inhibin A is a glycoprotein hormone and tumor marker produced by certain endocrine glands including the adrenal cortex, which has not been previously investigated as a potential tumor marker for PBMAH. In the present report, serum inhibin A levels were evaluated in three patients with PBMAH before and after adrenalectomy. In all cases, serum inhibin A was elevated preoperatively and subsequently fell within the normal range after adrenalectomy. Additionally, adrenal tissues stained positive for inhibin A. We conclude that serum inhibin A levels may be a potential tumor marker for PBMAH. Learning points: PBMAH is a rare cause of CS. PBMAH may have an insidious presentation, allowing the disease to progress for years prior to diagnosis. Inhibin A is a heterodimeric glycoprotein hormone expressed in the gonads and adrenal cortex. Inhibin A serum concentrations are elevated in some patients with PBMAH, suggesting the potential use of this hormone as a tumor marker. Further exploration of serum inhibin A concentration, as it relates to PBMAH disease progression, is warranted to determine if this hormone could serve as an early detection marker and/or predictor of successful surgical treatment.

Summary Primary adrenal lymphoma (PAL) is a rare cause of adrenal insufficiency. More than 90% is of B-cell origin. The condition is bilateral in up to 75% of cases, with adrenal insufficiency in two of three patients. We report two cases of adrenal insufficiency presenting at the age of 70 and 79 years, respectively. Both patients had negative 21-hydroxylase antibodies with bilateral adrenal lesions on CT. Biopsy showed B-cell lymphoma. One of the patients experienced intermittent disease regression on replacement dosage of glucocorticoids. Learning points: Primary adrenal lymphoma (PAL) is a rare cause of adrenal insufficiency. Bilateral adrenal masses of unknown origin or in individuals with suspected extra-adrenal malignancy should be biopsied quickly when pheochromocytoma is excluded biochemically. Steroid treatment before biopsy may affect diagnosis. Adrenal insufficiency with negative 21-hydroxylase antibodies should be evaluated radiologically.

Summary A 33-year-old female presented with a right 11.6 cm ovarian cyst. Routine pre-operative thyroid function tests showed thyroid stimulating hormone (TSH) of less than 0.02 mU/L (0.3–3.05) and a free thyroxine (FT4) of 5.5 pmol/L (10–28.2) suggesting either assay interference, triiodothyronine (T3) ingestion or hypopituitary hypothyroidism. A free triiodothyronine (FT3) level was requested which was high normal 6.9 pmol/L (3.1–8.1). Parallel assays on a different platform were similar but with a raised FT3 of 7.2 pmol/L (3.1–6.8). TSH receptor stimulating antibody (TSHAb) and thyroid peroxidase antibodies (TPO) were negative. Antithyroglobulin antibody (TgAb) was positive at 155.6 IU/mL (0–115). She was clinically euthyroid. Thyroid ultrasound showed a normal sized mildly heterogeneous gland with low blood flow and a solitary 1.5 cm U3 (BTA) nodule with higher blood flow. Thyroid Tc99m uptake was very low 0.2% (0.6–3.0) with no nodule uptake. These results demonstrated an extrathyroidal source of excessive autonomous T3 production resulting in the low thyroxine (T4). With carbimazole her TSH rose to 11.9 mU/L, FT4 rose to 7.7 pmol/L and FT3 reduced to 3.6 pmol/L. Histological diagnosis was Struma Ovarii. Her TSH, FT4 and FT3 remained normal thereafter. In conclusion, an extrathyroidal source of high T3 secretion was diagnosed using routine thyroid tests and scans. We believe this is the first description of a Struma Ovarii exclusively secreting T3 hormone characterised by the paradoxical rise of a low FT4 to normal with treatment. Two years later she developed non-secreting peritoneal deposits of highly differentiated follicular carcinoma. Learning points: Abnormally low TSH and FT4 levels suggestive of possible T3 ingestion, or less likely, hypopituitary hypothyroidism should always be followed by an assay of FT3. The diagnosis of an extrathyroidal source of T3 can be made using conventional thyroid tests, thyroid ultrasound scanning and technetium thyroid uptake and scan imaging. In a pre-menopausal patient this avoids a radiation dose to the pelvis. Pelvic radioisotope scanning of a suspected Struma Ovarii causing thyrotoxicosis can be reserved for patients whose thyroid function remains abnormal after initial surgery. Carbimazole is effective in the treatment of extrathyroidal autonomous T3 hormone production from a Struma Ovarii. The pathological appearance of a Struma Ovarii is not a guide to its malignancy. Even with a benign appearance they can disseminate to peritoneum, as highly differentiated follicular carcinoma (previously known as peritoneal strumosis). Hyperthyroid secretion by a Struma Ovarii may not be replicated in the metastatic follicular carcinoma in the peritoneum.

Summary Pituitary infections, particularly with fungus, are rare disorders that usually occur in immunocompromised patients. Cushing’s syndrome predisposes patients to infectious diseases due to their immunosuppression status. We report the case of a 55-year-old woman, working as a poultry farmer, who developed intense headache, palpebral ptosis, anisocoria, prostration and psychomotor agitation 9 months after initial diabetes mellitus diagnosis. Cranioencephalic CT scan showed a pituitary lesion with bleeding, suggesting pituitary apoplexy. Patient underwent transsphenoidal surgery and the neuropathologic study indicated a corticotroph adenoma with apoplexy and fungal infection. Patient had no preoperative Cushing’s syndrome diagnosis. She was evaluated by a multidisciplinary team who decided not to administer anti-fungal treatment. The reported case shows a rare association between a corticotroph adenoma and a pituitary fungal infection. The possible contributing factors were hypercortisolism, uncontrolled diabetes and professional activity. Transsphenoidal surgery is advocated in these infections; however, anti-fungal therapy is still controversial. Learning points: Pituitary infections are rare disorders caused by bacterial, viral, fungal and parasitic infections. Pituitary fungal infections usually occur in immunocompromised patients. Cushing’s syndrome, as immunosuppression factor, predisposes patients to infectious diseases, including fungal infections. Diagnosis of pituitary fungal infection is often achieved during histopathological investigation. Treatment with systemic anti-fungal drugs is controversial. Endocrine evaluation is recommended at the time of initial presentation of pituitary manifestations.

Summary Adrenocortical carcinoma (ACC) is an aggressive cancer that originates in the cortex of the adrenal gland and generally has a poor prognosis. ACC is rare but can be more commonly seen in those with cancer predisposition syndromes (e.g. Li-Fraumeni and Lynch Syndrome). The diagnosis of ACC is sometimes uncertain and it requires the use of precise molecular pathology; the differential diagnosis includes pheochromocytoma, adrenal adenoma, renal carcinoma, or hepatocellular carcinoma. We describe a case of a 57-year-old woman with Lynch Syndrome and metastatic ACC who was initially diagnosed as having pheochromocytoma. The tumor was first identified at 51 years of age by ultrasound followed by a CT scan. She underwent a left adrenalectomy, and the histopathology identified pheochromocytoma. Two years later, she had tumor recurrence with imaging studies showing multiple lung nodules. Following a wedge resection by video-assisted thoracoscopic surgery (VATS), histopathology was read as metastatic pheochromocytoma at one institution and metastatic ACC at another institution. She later presented to the National Institutes of Health (NIH) where the diagnosis of ACC was confirmed. Following her ACC diagnosis, she was treated with mitotane and pembrolizumab which were stopped due to side effects and progression of disease. She is currently receiving etoposide, doxorubicin, and cisplatin (EDP). This case highlights the importance of using a multi-disciplinary approach in patient care. Thorough evaluation of the tumor’s pathology and analysis of the patient’s genetic profile are necessary to obtain the correct diagnosis for the patient and can significantly influence the course of treatment. Learning points: Making the diagnosis of ACC can be difficult as the differential diagnosis includes pheochromocytoma, adrenal adenoma, renal carcinoma, or hepatocellular carcinoma. Patients with Lynch Syndrome should undergo surveillance for ACC as there is evidence of an association between Lynch Syndrome and ACC. Conducting a complete tumor immunoprofile and obtaining a second opinion is very important in cases of suspected ACC in order to confirm the proper diagnosis. A multi-disciplinary approach including genetic testing and a thorough evaluation of the tumor’s pathology is imperative to ensuring that the patient receives an accurate diagnosis and the appropriate treatment.

Summary A 40-year-old woman was hospitalised at 25-week gestation following a diagnosis of severe symptomatic hypercalcaemia (adjusted serum calcium 3.02 mmol/L). A diagnosis of primary hyperparathyroidism (PHP) was made on the basis of elevated parathyroid hormone (PTH) 11.2 pmol/L (reference range 1.5–6.9) and exclusion of familial hypocalciuric hypercalcaemia. Ultrasound examination of the neck did not convincingly demonstrate an abnormal or enlarged parathyroid gland and parathyroid scintigraphy was not performed due to maternal choice relating to perceived radiation risk to the foetus. At neck exploration during the 28th week of pregnancy a right lower pole parathyroid lesion was excised together with two abnormal lymph nodes (largest 1.6 cm). Histology confirmed a parathyroid adenoma and also papillary thyroid carcinoma deposits in the two resected lymph nodes. Post-operatively, levels of adjusted serum calcium normalised and pregnancy progressed uneventfully to term. Total thyroidectomy was performed 2 weeks after delivery revealing two small foci of papillary micro-carcinoma (largest 2.3 mm, one in each thyroid lobe) with no evidence of further metastatic tumour in lymph nodes removed during functional neck dissection. Radioiodine remnant ablation (RRA) was performed 2 months post thyroidectomy to allow for breast involution. The patient remains in full clinical and biochemical remission 9 years later. We present and review the difficult management decisions faced in relation to the investigation and treatment of PHP in pregnancy, further complicated by incidentally discovered locally metastatic pT1aN1aM0 papillary thyroid carcinoma. Learning points: PHP may have serious consequences during pregnancy and usually requires surgical management during pregnancy to reduce the risk of maternal and foetal complications. The indications for and optimal timing of surgical management are discussed. Localisation by parathyroid scintigraphy is controversial during pregnancy: modified dose regimes may be considered in preference as an alternative to unguided neck exploration. Breastfeeding is contraindicated for 6–8 weeks before radioactive-iodine remnant ablation (RRA) to prevent increased breast uptake. Breastfeeding is further contra-indicated until after a subsequent pregnancy. Incidentally discovered differentiated thyroid carcinoma (DTC) in cervical lymph nodes in some cases may be managed expectantly because in one quarter of thyroidectomies the primary tumour remains occult.

Summary This rare case describes the course of a pregnancy in a patient with a disseminated small intestinal neuroendocrine tumor. The patient received treatment with first-generation somatostatin ligand receptor (SLR) every 4 weeks and had stable disease for several years before her pregnancy. First-generation SLR treatment was initially paused after detection of the pregnancy. During pregnancy, the patient experienced moderate gastro-intestinal discomfort and fatigue, which was considered predominantly pregnancy related. However, since symptoms could be linked to the patient’s cancer, treatment was resumed after the first trimester. Chromogranin-A measurements remained stable throughout pregnancy and was paralleled by the absence of diarrhea and only minor flushing. She gave birth by elective caesarean section in week 37 to a healthy baby. Subsequent follow up imaging immediately after and 10 months postpartum showed no disease progression. The safety profile of SLR treatment during pregnancy in the context of disseminated neuroendocrine tumors (NET) is discussed. Learning points Neuroendocrine neoplasms (NEN) are rare cancers often occurring in the gastro-intestinal tract or lungs. Many patients with NEN live for several years with disseminated disease. SLR treatment has been given to pregnant patients before; often patients with acromegaly. Pregnancies are reported uneventful. This patient completed an uneventful pregnancy while receiving SLR treatment for disseminated neuroendocrine disease and gave birth to a healthy baby. More research regarding long term effects and safety signals of SLR treatment during pregnancy are much needed.

Summary We report concurrent metastatic prostatic adenocarcinoma (PC) and functioning androgen-secreting adrenocortical carcinoma (ACC) in a 77-year-old man. The failure to achieve adequate biochemical castration via androgen deprivation therapy (ADT) as treatment for PC metastases, together with elevated DHEA-S, androstenedione, and discordant adrenal tracer uptake on FDG-PET and PSMA-PET, suggested the presence of a concurrent functional primary adrenal malignancy. On histopathological analysis, scant foci of PC were present throughout the ACC specimen. Castration was achieved post adrenalectomy with concurrent drop in prostate-specific antigen. We outline the literature regarding failure of testosterone suppression on ADT and salient points regarding diagnostic workup of functioning adrenal malignancies. Learning points Failure to achieve castration with androgen deprivation therapy is rare and should prompt careful review to identify the underlying cause. All adrenal lesions should be evaluated for hormone production, as well as assessed for risk of malignancy (either primary or secondary). Adrenocortical carcinomas are commonly functional, and can secrete steroid hormones or their precursors (androgens, progestogens, glucocorticoids and mineralocorticoids). In this case, a co-incident, androgen-producing adrenocortical carcinoma was the cause of failure of testosterone suppression from androgen deprivation therapy as treatment for metastatic prostate cancer. Pathological adrenal androgen production contributed to the progression of prostate cancer.

Summary Medullary thyroid carcinoma (MTC) has a varying clinical course; distant metastases are frequently present even at diagnosis. We present two MTC cases with unusual metastatic sites. Two female patients are presented with slow progressive MTC. The first case developed distant metastases 23 years after diagnosis and underwent locoregional therapies. At the same time a breast mass developed representing MTC metastasis. Treatment with vandetanib led to long-term disease stabilization. The second patient is presented with metastases in the pancreas 13 years after diagnosis. Shortly, a painful mass developed in the mandible and metastasis of MTC was diagnosed. Disease progression was recorded 20 months after the initiation of local and systemic therapy. Such cases have only rarely been reported in the literature and highlight the need for prompt recognition of unexpected MTC metastases. Learning points Unusual sites of metastasis may appear in patients with medullary thyroid carcinoma (MTC) years after the initial diagnosis. Although rare, unexpected MTC metastases highlight the need for prompt recognition and appropriate treatment. Local recurrences accompanied by inappropriately low calcitonin levels should prompt further investigation for possible distant metastatic disease. Systemic treatment with tyrosine kinase inhibitors may be effective even in patients with unusual metastases from MTC.

Summary Congenital isolated ACTH deficiency (IAD) is a rare condition characterised by low plasma ACTH and serum cortisol with normal production of other pituitary hormones. TBX19 (also known as TPIT) is a T-box pituitary restricted transcription factor important for POMC gene transcription and terminal differentiation of POMC-expressing cells. TBX19 gene mutations have been shown to cause neonatal-onset congenital IAD. We report a neonate of Romanian origin, who presented at 15 h of life with respiratory arrest and hypoglycaemia which recurred over the following 2 weeks. Biochemical investigations revealed IAD, with undetectable serum cortisol (cortisol < 1 μg/dL; normal range (NR): 7.8–26.2) and plasma ACTH levels within the normal range (22.1 pg/mL; NR: 4.7–48.8). He responded to hydrocortisone treatment. Patient DNA was analysed by a HaloPlex next-generation sequencing array targeting genes for adrenal insufficiency. A novel homozygous synonymous mutation p.Thr96= (Chr1:168260482; c.288G>A; rs376493164; allele frequency 1 × 10−5, no homozygous) was found in exon 2 of the TBX19 gene. The effect of this was assessed by an in vitro splicing assay, which revealed aberrant splicing of exon 2 giving rise to a mutant mRNA transcript whereas the WT vector spliced exon 2 normally. This was identified as the likely cause of IAD in the patient. The predicted protein product would be non-functional in keeping with the complete loss of cortisol production and early presentation in the patient. Learning points Synonymous variants (a nucleotide change that does not alter protein sequence) usually thought to be benign may still have detrimental effects on RNA and protein function causing disease. Hence, they should not be ignored, especially if very rare in public databases. In vitro splicing assays can be employed to characterise the consequence of intronic and exonic nucleotide gene changes that may alter splicing. Establishing a diagnosis due to a TBX19 mutation is important as it defines a condition of isolated ACTH deficiency not associated with additional pituitary deficiencies.

Summary Familial partial lipodystrophy (FPLD) syndromes are rare heterogeneous disorders especially in women characterized by selective loss of adipose tissue, reduced leptin levels and severe metabolic abnormalities. Here we report a 34-year-old female with a novel heterozygotic c.485 thymine>guanine (T>G) missense variant (p.phenylalanine162cysteine; (Phe162Cys)) in exon 4 of the peroxisome proliferator-activated receptor gamma (PPARG) gene, developing a non-ketotic diabetes and severe hypertriglyceridemia with triglyceride concentrations >50 mmol/L. In this case, a particular interesting feature in comparison to other known PPARG mutations in FPLD is that while glycaemic control could be achieved through standard anti-diabetic medication, hypertriglyceridemia did neither respond to fibrate nor to omega-3-fatty acid therapy. This might suggest a lipid metabolism driven phenotype of the novel PPARG c.485T>G missense variant. Notably, recombinant leptin replacement therapy (metreleptin (Myalepta®)) was initiated showing a rapid and profound effect on triglyceride levels as well as on liver function tests and satiety feeling. Unfortunately, severe allergic skin reactions developed at the side of injection which could be covered by anti-histaminc treatment. We conclude that the heterozygous PPARG c.485T>G variant is a yet undescribed molecular basis underlying FPLD with difficulties predominantly to control hypertriglyceridemia and that recombinant leptin therapy may be effective in affected subjects. Learning points Heterozygous c.485T>G variant in PPARG is most likely a cause for FPLD in humans. This variant results in a special metabolic phenotype with a predominant dysregulation of triglyceride metabolism not responding to standard lipid lowering therapy. Recombinant leptin therapy is effective in rapidly improving hypertriglyceridemia.

Summary In July 2017, a 35-year-old woman was referred to our care for treatment of a large pituitary mass with an unusually high growth rate. She presented with right-sided ptosis and diplopia (n. III palsy), increasing retrobulbar pain and vertigo. Although laboratory investigations were consistent with acromegaly, she exhibited no clear phenotypic traits. During transsphenoidal surgery aimed at biopsy, typical adenomatous tissue was encountered, upon which it was decided to proceed to debulking. Histopathological analysis demonstrated a poorly differentiated plurihormonal Pit-1-positive adenoma with focal growth hormone (GH) and prolactin positivity, positive SSTR2 staining and a Ki-67 of 20–30%. Postoperative magnetic resonance imaging (MRI) examination revealed a large tumour remnant within the sella invading the right cavernous sinus with total encasement of the internal carotid artery and displacement of the right temporal lobe. As a consequence, she was treated additionally with radiotherapy, and a long-acting first-generation somatostatin analogue was prescribed. Subsequently, the patient developed secondary hypocortisolism and diabetes mellitus despite adequate suppression of GH levels. In September 2019, her symptoms recurred. Laboratory evaluations indicated a notable loss of biochemical control, and MRI revealed tumour progression. Lanreotide was switched to pasireotide, and successful removal of the tumour remnant and decompression of the right optic nerve was performed. She received adjuvant treatment with temozolomide resulting in excellent biochemical and radiological response after three and six courses. Symptoms of right-sided ptosis and diplopia remained. Evidence for systemic therapy in case of tumour progression after temozolomide is currently limited, although various potential targets can be identified in tumour tissue. Learning points Poorly differentiated plurihormonal Pit-1-positive adenoma is a potentially aggressive subtype of pituitary tumours. This subtype can express somatostatin receptors, allowing treatment with somatostatin analogues. A multidisciplinary approach involving an endocrinologist, neurosurgeon, pituitary pathologist, neuroradiologist, radiation oncologist and medical oncologist is key for the management of patients with aggressive pituitary tumours, allowing the successful application of multimodality treatment. Temozolomide is first-line chemotherapy for aggressive pituitary tumours and carcinomas. Further development of novel targeted therapies, such as peptide receptor radionuclide therapy (PRRT), vascular endothelial growth factor (VEGF) receptor-targeted therapy, tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors and immune checkpoint inhibitors, is needed.

Summary Factitious Cushing’s syndrome (CS) is a very rare form of Münchausen syndrome. Its presentation and course are extremely heterogeneous, and diagnosis is generally challenging. We report the case of a 52-year-old woman who was initially investigated because of the occurrence of cushingoid features. Nevertheless, endocrine work-up showed very low morning plasma ACTH and serum cortisol levels. In addition, it also demonstrated central hypopituitarism and hypogonadotropic hypogonadism. Head MRI showed a small pituitary mass. Based on these results, and probably overlooking the initial clinical suspicion, general practitioner (GP) referred the patient to our Endocrine Unit for hypopituitarism. At inspection, moon face, central obesity, and bruising were evident. Multiple ulcerative skin lesions were also concentrated in the right arm and leg. Dermatology evaluation suggested that the lesions were self-provoked. For several days, the patient denied the assumption of corticosteroids, but we finally discovered that the GP’ nurse had prescribed betamethasone without the GP’s knowledge for about 2 years. In conclusion, the surreptitious assumption of corticosteroids is very rare, but the physicians should be aware that pituitary function could be impaired by high doses of corticosteroids, mimicking hypopituitarism. In these patients, a multidisciplinary approach and environmental investigation can be useful to diagnose factitious CS. Learning points Surreptitious assumption of corticosteroids can cause heterogeneous presentation, ranging from Cushing’s syndrome to multiple hypopituitarism. Suppression of ACTH and cortisol levels in a patient with cushingoid features firstly suggests surreptitious assumption of corticosteroids. A multidisciplinary approach can be extremely useful in patients with suspected factitious Cushing’s syndrome. Sometimes, to prove surreptitious assumption of corticosteroids needs environmental investigation.

Increasing envelope facet albedos considerably reduces solar heat gain, thus yielding building cooling energy savings. Few studies have explored the potential benefits of utilizing cool coatings on building envelopes (“cool-coated buildings”) based on life-cycle cost analysis. A holistic approach integrating the field testing, building energy simulation, and a 20-year life-cycle-based optimization was developed to explore cool-coated building performance and the maximum net savings of optimal building envelope retrofit and design. Experimental results showed that applying cool coatings to a west wall of an office building in Chongqing, China reduced its exterior surface temperature by up to 9.3 °C in summer. Simulation results showed that in Chongqing, making the roof and walls cool could reduce annual HVAC electricity use by up to 11.9% in old buildings (with poorly insulated envelopes) and up to 5.9% in new buildings. Retrofitting old buildings with a cool roof provided the net savings per modified area with present values up to 42.8 CNY/m2; retrofitting a new building with a cool roof or cool walls was not cost-effective. Optimizing both envelope insulation and envelope albedo can achieve 5.6 times the net savings of optimizing the insulation only, and 1.6 times that of optimizing albedo only.

Summary We present a 54-year-old patient admitted to the emergency department due to loss of consciousness. The initial ECG registered monomorphic ventricular extrasystoles and prolonged QT interval (QT corrected (QTc) >500 ms). Sustained ventricular tachycardia (VT) was registered on 24-h Holter ECG monitoring, which clinically was presented as a crisis of consciousness. Coronary angiography and other visualization methods were normal. Implantable cardioverter-defibrillator (ICD) implantation was planned for the purpose of secondary prevention of sudden cardiac death (SCD). Laboratory and hormonal analyzes revealed primary hyperparathyroidism (PHPT), chronic kidney disease, and hypokalemia. Neck ultrasound showed a 25 mm, sharply outlined homogenous tumor mass which was separated from thyroid gland (TG) and exerted a mild impression on lower parts of the left lobe. Dual wash technetium-99m sestamibi parathyroid scintigraphy with single-photon emission CT (SPECT)/CT also showed the uptake of tracer behind the lower half of the left lobe of the TG. Surgical treatment, lower left parathyroidectomy, was performed, and pathohistological analysis verified parathyroid adenoma. The patient was rhythmically and hemodynamically stable for 7 days after surgery, without additional complaints, and was discharged from the hospital. Timely diagnosis of PHPT, correct assessment and surgical treatment, did not lead our patient to unnecessary ICD implantation. Our case suggests an additional intertwining of electrolyte disorders and ventricular arrhythmias in PHPT and more importantly emphasizes the need for caution when indicating ICD, even in patients with the most serious life-threatening arrhythmias. Learning points Electrolyte abnormalities in PHPT can have highly malignant consequences, and the occurrence of hypokalemia in the presence of hypercalcemia is underestimated in PHPT, and the consequences can be life-threatening. Although hypercalcemia causes shortened QT interval, concomitant severe hypokalemia may overcome hypercalcemia and prolong QT interval, even in the absence of structural heart disease or LQTS. Timely diagnosis of PHPT, correct assessment and surgical treatment, do not lead to unnecessary ICD implantation.

Summary Myxedema coma is an important differential diagnosis in critically ill patients. Early diagnosis and treatment are paramount but challenging due to a lack of diagnostic criteria. We report a case about a patient who suffered from untreated hypothyroidism for several years. Before the correct diagnosis was made, he was admitted three times due to severe constipation. Eventually, he developed myxedema coma in connection with a urinary tract infection. The course was complicated by recurrent seizures, and neuroimaging showed bilateral hygromas. Hormone replacement therapy resulted in complete recovery and regression of hygromas. To the best of our knowledge, this is the first time hygroma is reported in association with myxedema coma. Learning points Myxedema coma is a difficult diagnosis to make due to a lack of diagnostic criteria. Cardinal features include hypothermia, bradycardia, gastrointestinal symptoms, pericardial/pleural effusions and affection of CNS. Anemia and hyponatremia are common. In case of suspected myxedema coma, neuroimaging should be a part of the evaluation in most cases. There is a possible association between longstanding/severe hypothyroidism and hygroma.

Summary We observed a novel therapeutic response with cabergoline in a male patient with a dopamine-secreting head and neck paraganglioma (HNPGL), macroprolactinoma and germline succinate dehydrogenase C mutation (SDHC). The macroprolactinoma was treated with cabergoline which gave an excellent response. He was found to have raised plasma 3-methoxytyramine of 1014 pmol/L (NR: 0–180 pmol/L); but it was unclear if this was a drug-induced phenomenon from dopamine agonist (DA) therapy. Cabergoline was stopped for 4 weeks and the 3-methoxytyramine level increased significantly to 2185 pmol/L, suggesting a biochemical response of his HNPGL. Subsequently, Gallium-68 Dotatate PET and MRI (Gallium-68 Dotatate PET/MRI) demonstrated a second lesion in the sacrum. Both the HNPGL and metastatic sacral deposit received external beam radiotherapy with a good biochemical and radiological response. Conclusion Our case report highlights the rare potential of germline SDHC mutations causing metastatic paraganglioma and concurrent pituitary tumours. Cabergoline treatment may lower elevated 3-methoxytyramine levels and, therefore, mask the biochemical evidence of metastatic disease but also may have therapeutic relevance in dopamine-secreting pheochromocytomas/paragangliomas (PPGLs). Learning points Several neuroendocrine tumours (NETs) express dopamine D2 and D4 receptors. In this case report, cabergoline significantly reduced plasma 3-methoxytyramine level in a patient with functional HNPGL. Cabergoline might have therapeutic relevance in dopamine-secreting PPGLs. Paragangliomas associated with SDHC mutation classically present with asymptomatic non-functional HNPGL and have rare metastatic potential. The association of pheochromocytoma or paraganglioma and pituitary adenoma is now a well-described rare association (SDHA and SDHC mutations. Cabergoline treatment may lower elevated 3-methoxytyramine levels and mask the biochemical evidence of metastatic disease. Regular functional imaging with Gallium-68 Dotatate PET/MRI provides better evidence of metastatic disease.

Summary A male patient with a germline mutation in MEN1 presented at the age of 18 with classical features of gigantism. Previously, he had undergone resection of an insulin-secreting pancreatic neuroendocrine tumour (pNET) at the age of 10 years and had subtotal parathyroidectomy due to primary hyperparathyroidism at the age of 15 years. He was found to have significantly elevated serum IGF-1, GH, GHRH and calcitonin levels. Pituitary MRI showed an overall bulky gland with a 3 mm hypoechoic area. Abdominal MRI showed a 27 mm mass in the head of the pancreas and a 6 mm lesion in the tail. Lanreotide-Autogel 120 mg/month reduced GHRH by 45% and IGF-1 by 20%. Following pancreaticoduodenectomy, four NETs were identified with positive GHRH and calcitonin staining and Ki-67 index of 2% in the largest lesion. The pancreas tail lesion was not removed. Post-operatively, GHRH and calcitonin levels were undetectable, IGF-1 levels normalised and GH suppressed normally on glucose challenge. Post-operative fasting glucose and HbA1c levels have remained normal at the last check-up. While adolescent-onset cases of GHRH-secreting pNETs have been described, to the best of our knowledge, this is the first reported case of ectopic GHRH in a paediatric setting leading to gigantism in a patient with MEN1. Our case highlights the importance of distinguishing between pituitary and ectopic causes of gigantism, especially in the setting of MEN1, where paediatric somatotroph adenomas causing gigantism are extremely rare. Learning points It is important to diagnose gigantism and its underlying cause (pituitary vs ectopic) early in order to prevent further growth and avoid unnecessary pituitary surgery. The most common primary tumour sites in ectopic acromegaly include the lung (53%) and the pancreas (34%) (1): 76% of patients with a pNET secreting GHRH showed a MEN1 mutation (1). Plasma GHRH testing is readily available in international laboratories and can be a useful diagnostic tool in distinguishing between pituitary acromegaly mediated by GH and ectopic acromegaly mediated by GHRH. Positive GHRH immunostaining in the NET tissue confirms the diagnosis. Distinguishing between pituitary (somatotroph) hyperplasia secondary to ectopic GHRH and pituitary adenoma is difficult and requires specialist neuroradiology input and consideration, especially in the MEN1 setting. It is important to note that the vast majority of GHRH-secreting tumours (lung, pancreas, phaeochromocytoma) are expected to be visible on cross-sectional imaging (median diameter 55 mm) (1). Therefore, we suggest that a chest X-ray and an abdominal ultrasound checking the adrenal glands and the pancreas should be included in the routine work-up of newly diagnosed acromegaly patients.

Summary Although pituitary macroadenomas often cause mass effects on surrounding structures, it is extremely rare for pituitary lesions to disturb cerebrospinal fluid circulation. Sellar gangliocytoma-pituitary adenomas (SGPAs) are also extremely rare. Here we report the unique case of a man with the unusual combination of acromegaly from an SGPA, who presented with unilateral hydrocephalus. A 60-year-old man presented with rapid neurological deterioration, bitemporal hemianopia, and acromegalic features. Neuroimaging revealed a large sellar lesion extending superiorly into the left foramen of Monro, causing acute obstructive unilateral hydrocephalus. External ventricular drain placement improved consciousness immediately. Biochemical assessment confirmed acromegaly. Following trans-sphenoidal debulking, histology revealed a mixed gangliocytoma/sparsely-granulated somatotrophinoma. Despite the residual disease, his vision recovered remarkably, low-dose cabergoline controlled residual excess growth hormone (GH) secretion, and the residual tumour has remained extremely stable over 2 years. Hydrocephalus is an extremely rare complication of pituitary lesions, and unilateral hydrocephalus has never been reported previously. GH secretion in SGPAs is more common than for pituitary adenomas in general, raising questions regarding the aetiology and therapeutic approach to this rare combination tumour. Learning points Pituitary tumours most commonly present with symptoms related to endocrine disturbance or mass effects upon visual pathways (e.g. optic chiasm, nerves in the lateral cavernous sinus). However, extremely rarely, pituitary masses may disrupt cerebrospinal fluid (CSF) circulation resulting in hydrocephalus. Sellar gangliocytomas are very rare tumours and most of them are hybrid tumours with pituitary adenomas (SGPAs). SGPAs are typically indolent and may be functioning or non-functioning tumours. Growth hormone (GH)-producing SGPAs are less likely to respond to somatostatin agonists than classic somatotrophinomas. Primary surgical debulking via a trans-sphenoidal approach was effective in this individual, leading to the restoration of CSF circulation and improvement in visual disturbance, while also negating the need for permanent CSF diversion despite the residual tumour burden.