Unusual hypocalcaemia in breast cancer relapse with multiple bone metastasis

Severe hypocalcaemia in breast cancer with bone metastasis is a rare finding usually associated with an advanced stage of the disease. We report a case of a 45-year-old woman with a history of local ductal carcinoma in situ (DCIS) of the breast, who presented with muscle tremors and general weakness. Hypocalcaemia was evident, with a positive Chvostek sign and a serum calcium level of 5.9 mg/dL (1.47 mmol/L), phosphorus 5.9 mg/dL (normal range: 2.3–4.7 mg/dL) with normal levels of albumin, magnesium and parathyroid hormone. High oral doses of alpha calcitriol and calcium with i.v. infusion of high calcium doses were instituted, altogether sufficient to maintain only mild hypocalcaemia. A whole-body CT revealed bone lesions along the axial skeleton. A biopsy from a bone lesion revealed a metastasis of breast carcinoma. With this pathological finding, leuprolide (GNRH analogue) and chlorambucil (alkylating agent) were initiated, followed by prompt tapering of infused calcium down to full discontinuation. Serum calcium was kept stable close to the low normal range by high doses of oral alpha calcitriol and calcium. This course raises suspicion that breast metastases to the skeleton caused tumour-induced hypocalcaemia by a unique mechanism. We assume that hypocalcaemia in this case was promoted by a combination of hypoparathyroidism and bone metastasis. Learning points Severe hypocalcaemia can a presenting symptom for breast cancer relapse.

Monogenic diabetes due to an INSR mutation in a child with severe insulin resistance

Summary We report a case of an 11-year-old girl presenting with a new diagnosis of diabetes associated with a heterozygous missense mutation in the insulin receptor (INSR) gene. This case highlights that INSR gene variants can be a cause for monogenic diabetes in children and adolescents and the need for genetic evaluation in atypical presentations of diabetes. We also describe the possible role of metformin in treating individuals with type A insulin resistance syndrome due to INSR gene variants. Learning points Insulin receptor (INSR) gene variants can be a cause of monogenic diabetes in children and adolescents. Genetic evaluation should be considered in children and adolescents with type 2 diabetes (T2D), particularly where there is an atypical presentation and/or positive family history. Metformin may have a role in the treatment of type A insulin resistance syndrome due to heterozygous mutation of the INSR gene.

Juxtaglomerular cell tumour of the kidney: a rare cause of resistant hypertension

Summary Juxtaglomerular cell tumour (JGCT) is an unusually encountered clinical entity. A 33-year-old man with severe long-standing hypertension and hypokalaemia is described. The patient also suffered from polyuria, polydipsia, nocturia and severe headaches. On admission, laboratory investigation revealed hypokalaemia, kaliuresis, high aldosterone and renin levels, and the abdomen CT identified a mass of 4 cm at the right kidney. Kidney function was normal. Following nephrectomy, the histological investigation revealed the presence of a JGCT. Immunostaining was positive for CD34 as well as for smooth muscle actin and vimentin. Following surgery, a marked control of his hypertension with calcium channel blockers and normalization of the serum potassium, renin or aldosterone levels were reached. According to our findings, JGCT could be included in the differential diagnosis of secondary hypertension as it consists of a curable cause. The association of JGCT with hypertension and hypokalaemia focusing on the clinical presentation, diagnostic evaluation and management is herein discussed and a brief review of the existing literature is provided. Learning points Juxtaglomerular cell tumours (JGCT), despite their rarity, should be included in the differential diagnosis of secondary hypertension as they consist of a curable cause of hypertension. JGCT could be presented with resistant hypertension along with hypokalaemia, kaliuresis and metabolic alkalosis. Early recognition and management can help to prevent cardiovascular complications. Imaging (enhanced CT scans) may be considered as the primary diagnostic tool for the detection of renal or JGCT. For the confirmation of the diagnosis, a histopathologic examination is needed.

Pitfalls and progress in adrenocortical carcinoma diagnosis: the utility of a multidisciplinary approach, immunohistochemistry and genomics

Summary Adrenocortical carcinoma is a rare disease with poor prognosis whose clinical heterogeneity can at times present a challenge to accurate and timely diagnosis. We present the case of a patient who presented with extensive pulmonary lesions, mediastinal and hilar lymphadenopathy and an adrenal mass in whom the oncological diagnosis was initially uncertain. Through the use of immunohistochemistry, biochemistry and genomic testing, an accurate diagnosis of adrenocortical carcinoma was ultimately made which resulted in more directed treatment being administered. The use of multidisciplinary input and genomics to aid in diagnosis and prognosis of adrenocortical carcinoma is discussed. Learning points Adrenocortical carcinomas can present a diagnostic challenge to clinicians given it is a rare malignancy with significant clinical heterogeneity. Specialist multidisciplinary team input is vital in the diagnosis and management of adrenocortical carcinomas. Hormonal testing is recommended in the diagnostic workup of adrenal masses, even in the absence of overt clinical signs/symptoms of hormone excess. Immunostaining for the highly sensitive and specific steroidogenic factor-1 is vital for accurate diagnosis. Genomics can provide prognostic utility in management of adrenocortical carcinoma.

Synergistic cortisol suppression by ketoconazole–osilodrostat combination therapy

Summary Here, we describe a case of a patient presenting with adrenocorticotrophic hormone-independent Cushing’s syndrome in a context of primary bilateral macronodular adrenocortical hyperplasia. While initial levels of cortisol were not very high, we could not manage to control hypercortisolism with ketoconazole monotherapy, and could not increase the dose due to side effects. The same result was observed with another steroidogenesis inhibitor, osilodrostat. The patient was finally successfully treated with a well-tolerated synergitic combination of ketoconazole and osilodrostat. We believe this case provides timely and original insights to physicians, who should be aware that this strategy could be considered for any patients with uncontrolled hypercortisolism and delayed or unsuccessful surgery, especially in the context of the COVID-19 pandemic. Learning points Ketoconazole–osilodrostat combination therapy appears to be a safe, efficient and well-tolerated strategy to supress cortisol levels in Cushing syndrome. Ketoconazole and osilodrostat appear to act in a synergistic manner. This strategy could be considered for any patient with uncontrolled hypercortisolism and delayed or unsuccessful surgery, especially in the context of the COVID-19 pandemic. Considering the current cost of newly-released drugs, such a strategy could lower the financial costs for patients and/or society.

Subacute thyroiditis post-Pfizer-BioNTech mRNA vaccination for COVID-19

Summary There is emerging evidence of an association between COVID-19 vaccination and subacute thyroiditis. We present the case of a 42-year-old female healthcare worker who was diagnosed with subacute thyroiditis 4 days after receiving her second dose of Pfizer-BioNTech vaccine. Her clinical course followed the classical pattern for thyroiditis with spontaneous return to euthyroidism at 6 months post-presentation. The autoimmune/inflammatory syndrome induced by adjuvants has been implicated as a cause of autoimmune conditions post-vaccination and is a potential mechanism for subacute thyroiditis in our case. Learning points Subacute thyroiditis should be considered in all patients who receive any kind of vaccine for COVID-19 and subsequently develop symptoms or signs of hyperthyroidism or neck pain. Subacute thyroiditis is a self-limiting condition, and recognising it is important as no specific thyroid treatment (antithyroid drugs or thyroid hormone replacement) is necessary for most patients. The autoimmune/inflammatory syndrome induced by adjuvants may be an under-recognised cause of endocrinopathies and should particularly be considered post-vaccination.

Bilateral adrenal masses due to tuberculosis: how to diagnose without extra-adrenal tuberculosis

Summary Primary adrenal insufficiency is a rare disease and can masquerade as other conditions; therefore, it is sometimes incorrectly diagnosed. Herein, we reported the case of a 39-year-old Vietnamese male with primary adrenal insufficiency due to bilateral adrenal tuberculosis. The patient presented to the emergency room with acute adrenal crisis and a 3-day history of nausea, vomiting, epigastric pain, and diarrhoea with a background of 6 months of fatigue, weight loss, and anorexia. Abdominal CT revealed bilateral adrenal masses. Biochemically, unequivocal low morning plasma cortisol (<83 nmol/L) and high plasma adrenocorticotropic hormone levels were consistent with primary adrenal insufficiency. There was no evidence of malignancy or lymphoma. As the patient was from a tuberculosis-endemic area, extra-adrenal tuberculosis was excluded during the work up. A retroperitoneal laparoscopic left adrenalectomy was performed, and tuberculous adrenalitis was confirmed by the histopathological results. The patient was started on antituberculous therapy, in addition to glucocorticoid replacement. In conclusion, even without evidence of extra-adrenal tuberculosis, a diagnosis of bilateral adrenal tuberculosis is required. A histopathological examination has a significant role along with clinical judgement and hormonal workup in establishing a definitive diagnosis of adrenal tuberculosis without evidence of active extra-adrenal involvement. Learning points Primary adrenal insufficiency can be misdiagnosed as other mimicking diseases, such as gastrointestinal illness, leading to diagnostic pitfalls. Adrenal insufficiency can be confirmed with significantly low morning plasma cortisol levels of <83 nmol/L without a dynamic short cosyntropin stimulation test. Tuberculous adrenalitis is an uncommon treatable condition; however, it remains an important cause of primary adrenal insufficiency, especially in developing countries. In the absence of extra-adrenal involvement, adrenal biopsy plays a key role in the diagnostic process. Alternatively, adrenalectomy for histopathological purposes should be considered if CT scan-guided fine needle aspiration is infeasible in cases of small adrenal masses.

Pheochromocytoma due to a novel SDHD variant presenting as unilateral visual loss

Summary A 53-year-old female presented to a tertiary ophthalmology referral centre complaining of unilateral painless loss of vision. Subsequent assessment revealed malignant hypertension causing right-sided cystoid macular oedema. During the course of secondary hypertension workup, she was diagnosed with a 7.8 cm phaeochromocytoma which was resected. Testing for a panel of all predisposing phaeochromocytoma-causing variants using next-generation sequencing resulted in the diagnosis of a novel SDHD variant. Learning points Screening for secondary causes of hypertension is indicated when there is evidence of hypertension-mediated end-organ damage (1). Testing for a predisposing variant should be considered in all patients with phaeochromocytoma or paraganglioma due to the high heritability rate and prevalence of somatic variants (2, 3, 4). Novel variants are commonly uncovered in the Succinate Dehydrogenase (SDH) subunit; proving pathogenicity is a complex, time-consuming process and one challenge of next-generation sequencing (3). SDHB immunohistochemistry as a tool for demonstrating pathogenicity is associated with reduced sensitivity when assessing SDHD variants (5, 6).

Report of a family with three generations of undiagnosed familial nonautoimmune hyperthyroidism

Summary Familial nonautoimmune hyperthyroidism (FNAH) is rare and occurs due to a constitutively activating thyroid-stimulating hormone receptor (TSHR) germline mutation. Forty-one families with FNAH have been reported so far. In the study, 17 of 41 families were not diagnosed with FNAH until three generations or more were described with hyperthyroidism. We report a case of FNAH diagnosed in the third generation. The index patient was diagnosed with hyperthyroidism at age 3. Large fluctuations in thyroid hormone levels occurred during anti-thyroid drug treatment, and he developed a goiter. The patient’s mother had similar history, requiring two surgical interventions and radioiodine treatment. The younger brother of the index patient did not experience large thyroid hormone level fluctuations, nor increased thyroid growth. A heterozygous TSHR c.1357A>G mutation, resulting in a M453V amino acid exchange, was detected in all three patients leading to FNAH diagnosis, with complete genotype–phenotype segregation. Based on Sorting intolerant from tolerant (SIFT) and PolyPhen2 scores of 0.01 and 0.99, respectively, an effect on protein function can be assumed. As illustrated by this family with FNAH, total thyr oidectomy is necessary for patients with nonautoimmune hyperthyroidism. Development of goiter is common, anti-thyroid drug treatment is often difficult, and remission of hyperthyroidism does not occur after discontinuation of anti-thyroid drug treatment. Thus, early diagnosis and appropriate treatment of FNAH is necessary to avoid predictable, unnecessary complications and further surgical interventions. Learning points In the study, 19/42 cases of familial nonautoimmune hyperthyroidism (FNAH), including the reported case, were not diagnosed as FNAH until the third generation; this lead to suboptimal treatment and frequent relapses of nonautoimmune hyperthyroidism (NAH). Detection of thyroid-stimulating hormone receptor (TSHR) mutations in patients with suspected FNAH to confirm diagnosis is essential to ensure proper treatment for the patient and further affected family members. NAH will persist without proper treatment by total thyroidectomy. Symptoms and age of onset may vary between family members All family members with a TSHR germline mutation should be monitored with thyroid-stimulating hormone and for symptoms throughout their lives.

A rare case of macroprolactinoma in a patient with Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome

Summary A 17-year-old lady presented with primary amenorrhoea, headache, nausea and lethargy. She had delayed pubertal development that also includes under-developed breast (Tanner Stage 2). Hormonal investigations showed a high serum prolactin level of 1 680 000 mIU/L (normal value: 45–375 mIU/L), with low oestradiol, progesterone, follicular-stimulating hormone and luteinizing hormone. Early morning cortisol level was 206 nmol/L (normal value: >450 nmol/L), thyroxine was 7.5 pmol/L (normal value: 9.0–24.0 pmol/L) with TSH 5.091 mIU/L (normal value: 0.4–4.5 mlU/L). A pituitary MRI showed a 2.7 (AP) × 3.7 (W) × 4.6 cm (CC) macroadenoma, with invasion into the left cavernous sinus and encasement of cavernous portion of the left internal carotid artery. MRI pelvis showed absent uterus, cervix and 2/3 upper vagina confirming Mullerian hypoplasia. Cytogenetics showed 46XX. These findings were suggestive of Mayer–Rokitansky–Kauser–Hauser (MRKH) syndrome with the presence of a pituitary macroprolactinoma and panhypopituitarism. She was treated with hydrocortisone, levothyroxine and cabergoline. Repeated MRI showed a reduction in tumour size by approximately 50%. This case illustrated a rare coexistence of these two conditions, being only the third reported case in the world. In addition, this would be the first case of a functioning pituitary adenoma in a patient with MRKH syndrome. Learning points Comprehensive hormonal and radiological investigations are important in the management of a young patient with primary amenorrhoea. Coexistence pathology of two separate pathologies should be considered in patient presenting with primary amenorrhoea. Early diagnosis of MRKH or any disorders of sex development should be treated early, providing pharmacological, surgical, psychological and emotional support to the patient and reducing risk of associated complications. Abnormal pituitary hormones, particularly panhypopituitarism, would impose greater impact not only psychologically but also metabolically leading to cardiovascular, morbidity and mortality risks in this patient if not treated early. A multidisciplinary approach is necessary for patients presenting with MRKH to ensure appropriate treatments and follow-up across the lifespan of the patient.