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Department of Neurosurgery, Royal Melbourne Hospital, Melbourne, Victoria, Australia
Peter McCallum Cancer Centre, Department of Oncology, Melbourne, Victoria, Australia
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School of Medicine, University of Notre Dame, Sydney, New South Wales, Australia
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Summary
Thyrotropinomas are an uncommon cause of hyperthyroidism and are exceedingly rarely identified during pregnancy, with limited evidence to guide management. Most commonly they present as macroadenomas and may cause symptoms of mass effect including headache, visual field defects and hypopituitarism. We present a case of a 35-year-old woman investigated for headaches in whom a 13 mm thyrotropinoma was found. In the lead-up to planned trans-sphenoidal surgery (TSS), she spontaneously conceived and surgery was deferred, as was pharmacotherapy, at her request. The patient was closely monitored through her pregnancy by a multi-disciplinary team and delivered without complication. Pituitary surgery was performed 6 months post-partum. Isolated secondary hypothyroidism was diagnosed postoperatively and replacement thyroxine was commenced. Histopathology showed a double lesion with predominant pituitary transcription factor-1 positive, steroidogenic factor negative plurihormonal adenoma and co-existent mixed thyroid-stimulating hormone, growth hormone, lactotroph and follicle-stimulating hormone staining with a Ki-67 of 1%. This case demonstrates a conservative approach to thyrotropinoma in pregnancy with a successful outcome. This highlights the need to consider the timing of intervention with careful consideration of risks to mother and fetus.
Learning points
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Thyrotropinomas are a rare cause of secondary hyperthyroidism. Patients may present with hyperthyroidism or symptoms of mass effect, including headaches or visual disturbance.
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Thyrotropinoma in pregnancy presents a number of pituitary-related risks including pituitary apoplexy and compression of local structures.
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Hyperthyroidism in pregnancy raises the risk of complications including spontaneous abortion, preeclampsia, low birthweight and premature labour.
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Timing of medical and surgical therapies must be carefully considered. A conservative approach requires careful monitoring in case emergent intervention is required.
Cancer Diagnosis and Pathology Group, Kolling Institute, Sydney, New South Wales, Australia
Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
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Cancer Diagnosis and Pathology Group, Kolling Institute, Sydney, New South Wales, Australia
Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
Department of Diabetes and Endocrinology, Nepean Hospital, Kingswood, New South Wales, Australia
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Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, New South Wales, Australia
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Cancer Diagnosis and Pathology Group, Kolling Institute, Sydney, New South Wales, Australia
Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
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Summary
Necrobiosis lipoidica (NL) is a rare and chronic disease characterised by yellow-brown, atrophic, telangiectatic plaques usually located on the lower extremities, with pathological features of collagen necrobiosis and dermal inflammation. Most cases are seen in those with diabetes mellitus, particularly type 1 diabetes (T1DM), and many without diabetes have evidence of abnormal glucose tolerance or family history of autoimmune disease. In this study, we describe four patients with NL and T1DM. A common theme is late identification and delay in diagnosis. Hence, we discuss the clinical features, need for clinicopathological correlation, and the management and prognostic implications for this distinctive entity. While most remain relatively asymptomatic, others progress to debilitating disease with pruritus, dysesthesia, and pain. Pain is often intense in the presence of ulcerated plaques, a morbid complication of NL. Diagnosis requires the integration of both clinical and histopathological findings. NL has proven a challenging condition to treat, and despite the numerous therapeutic modalities available, there is no standard of care. Hence, in this study, we provide an overview of current management strategies available for NL.
Learning points
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Necrobiosis lipoidica (NL) is classically seen in patients with type 1 diabetes.
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Koebner phenomenon, defined as the appearance of new skin lesions on previously unaffected skin secondary to trauma, is a well-recognised feature in NL.
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Background skin phototype contributes to variable yellow appearance of lesions in NL.
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Diagnosis of NL requires careful clinicopathological correlation.
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NL is a chronic disease often refractory to treatment leading to significant morbidity for the patient and a management conundrum for the multidisciplinary healthcare team.
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No standard therapeutic regimen has been established for the management of NL.
Department of Endocrinology, Royal North Shore Hospital, Sydney, Australia
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Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, Sydney, Australia
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Department of Endocrinology, Royal North Shore Hospital, Sydney, Australia
Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, Sydney, Australia
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Summary
Biallelic pathological variants in the thyroid stimulating hormone (TSH) subunit β gene (TSHB) result in isolated TSH deficiency and secondary hypothyroidism, a rare form of central congenital hypothyroidism (CCH), with an estimated incidence of 1 in 65 000 births. It is characterised by low levels of free thyroxine and inappropriately low serum TSH and may therefore be missed on routine neonatal screening for hypothyroidism, which relies on elevated TSH. We describe a patient with CCH who developed recurrence of pituitary hyperplasia and symptomatic hypothyroidism due to poor compliance with thyroxine replacement. She was diagnosed with CCH as a neonate and had previously required trans-sphenoidal hypophysectomy surgery for pituitary hyperplasia associated with threatened chiasmal compression at 17 years of age due to variable adherence to thyroxine replacement. Genetic testing of TSHB identified compound heterozygosity with novel variant c.217A>C, p.(Thr73Pro), and a previously reported variant c.373delT, p.(Cys125Valfs*10). Continued variable adherence to treatment as an adult resulted in recurrence of significant pituitary hyperplasia, which subsequently resolved with improved compliance without the need for additional medications or repeat surgery. This case describes a novel TSHB variant associated with CCH and demonstrates the importance of consistent compliance with thyroxine replacement to treat hypothyroidism and prevent pituitary hyperplasia in central hypothyroidism.
Learning points
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Pathogenic variants in the TSH subunit β gene (TSHB) are rare causes of central congenital hypothyroidism (CCH).
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c.217A>C, p.(Thr73Pro), is a novel TSHB variant, presented in association with CCH in this case report.
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Thyroxine replacement is critical to prevent clinical hypothyroidism and pituitary hyperplasia.
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Pituitary hyperplasia can recur post-surgery if adherence to thyroxine replacement is not maintained.
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Pituitary hyperplasia can dramatically reverse if compliance with thyroxine replacement is improved to maintain free thyroxine (FT4) levels in the middle-to-upper normal range, without the need for additional medications or surgeries.
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University of Melbourne, Parkville, Victoria, Australia
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Summary
Acanthosis nigricans (AN) is a common dermatosis associated with hyperinsulinemia and insulin resistance. However, AN has been rarely reported in patients with insulinoma, a state of persistent hyperinsulinemia. We present a case of metastatic insulinoma, in whom AN manifested after the first cycle of peptide receptor radionuclide therapy (PRRT). A 40-year-old man was diagnosed with metastatic insulinoma after 5 months of symptomatic hypoglycemia. Within 1 month post PRRT, the patient became euglycemic but developed a pigmented, pruritic rash which was confirmed on biopsy as AN. We discuss the rare manifestation of AN in subjects with insulinoma, the role of insulin in the pathogenesis of AN, malignant AN in non-insulin-secreting malignancies and association with other insulin-resistant endocrinopathies such as acromegaly.
Learning points
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Acanthosis nigricans (AN) is a common dermatosis which is typically asymptomatic and associated with the hyperinsulinemic state.
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Malignant AN can rapidly spread, cause pruritus and affect mucosa and the oral cavity.
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AN is extremely rare in patients with insulinoma despite marked hyperinsulinemia.
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Peptide receptor radionuclide therapy might have triggered TGF-α secretion in this subject which led to malignant AN.
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Rapid spread or unusual distribution of pruritic AN warrants further investigation to exclude underlying malignancy.
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Department of Medicine, Macquarie University, Sydney, Australia
Department of Medicine, University of Western Sydney, Sydney, Australia
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Summary
Thyrotoxic periodic paralysis (TPP) is a rare condition characterised by acute onset hypokalaemia and paralysis which most commonly affects men of Asian descent between the ages of 20 and 40 years (1, 2). It has been reported in approximately 2% of patients with thyrotoxicosis in China and Japan (1, 2, 3). Hypokalaemia in TPP results from a massive intracellular shift of potassium induced by the thyroid hormone sensitisation of Na+/K+-ATPase (4). Treatment of TPP includes prevention of this shift by using beta-blockade, rapid potassium replacement and treatment of the underlying hyperthyroidism. We present two cases of TPP with differing outcomes. In the first case, a 33-year-old Filipino gentleman presented to our emergency department (ED) with a 3-month history of recurrent proximal lower limb weakness. Serum potassium was 2.2 mmol/L (3.3–5.1) and he was given i.v. potassium replacement. Thyroid function tests (TFTs) and thyroid antibodies were consistent with Graves thyrotoxicosis. He was discharged home on carbimazole and remains well controlled on long-term medical therapy. In the second case, a 22-year-old Malaysian gentleman presented to our ED with new-onset bilateral lower limb painless paralysis. Serum potassium was 1.9 mmol/L with TFTs demonstrating Graves thyrotoxicosis. He was treated with i.v. potassium replacement and discharged home on carbimazole and propranolol. He represented to the hospital on two further occasions with TPP and was advised to consider total thyroidectomy given his refractory Graves’ disease. These cases highlight the importance of prompt recognition of this rare life-threatening complication of Graves’ disease, especially in patients of Asian descent.
Learning points
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Thyrotoxic periodic paralysis is a rare condition characterised by hypokalaemia and acute painless muscle weakness in the presence of thyrotoxicosis.
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The signs and symptoms of thyrotoxicosis can be subtle in these patients.
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It is most commonly seen in Asian males between the ages of 20 and 40 and is most frequently caused by Graves’ disease.
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Prompt recognition is essential as it is a life-threatening condition.
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Urgent i.v. potassium replacement and beta-blockade with a non-selective beta-blocker are the mainstays of treatment.
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i.v. potassium replacement should not be given in dextrose as this can potentiate hypokalaemia.
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Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia
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Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia
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Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia
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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
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Adrenocortical carcinomas can present a diagnostic challenge to clinicians given it is a rare malignancy with significant clinical heterogeneity.
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Specialist multidisciplinary team input is vital in the diagnosis and management of adrenocortical carcinomas.
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Hormonal testing is recommended in the diagnostic workup of adrenal masses, even in the absence of overt clinical signs/symptoms of hormone excess.
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Immunostaining for the highly sensitive and specific steroidogenic factor-1 is vital for accurate diagnosis.
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Genomics can provide prognostic utility in management of adrenocortical carcinoma.
Faculty of Medicine and Health, University of Sydney, Sydney, Australia
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Faculty of Medicine, University of New South Wales, Sydney, Australia
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Faculty of Medicine and Health, University of Sydney, Sydney, Australia
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Faculty of Medicine and Health, University of Sydney, Sydney, Australia
Charles Perkins Centre, University of Sydney, Sydney, Australia
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Summary
Maturity-onset diabetes of the young type 3 (MODY3) accounts for approximately 50% of cases of MODY. First-line treatment with sulfonylureas has been well established for individuals with MODY3. In contrast, the use of sodium-glucose co-transporter 2 (SGLT2) inhibitors in the treatment of individuals with MODY3 remains unclear. This case illustrates the in vivo effect of an SGLT2 inhibitor in a 30-year-old woman with MODY3 with poor glycaemic control despite the treatment with supramaximal doses of sulfonylurea and metformin. The addition of a SGLT2 inhibitor resulted in a rapid improvement in glycaemic control without any hypoglycaemic episodes. This case suggests that SGLT2 inhibitors may be an effective and potent treatment option in addition to sulfonylureas for individuals with MODY3.
Learning points
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Maturity-onset diabetes of the young type 3 (MODY3) arises from mutations in the hepatocyte nuclear factor-1alpha gene, which controls the expression of sodium-glucose co-transporter 2 (SGLT2) in the kidneys.
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Paradoxically, despite individuals with MODY3 having reduced expression of SGLT2, SGLT2 inhibitors induce higher glycosuria in individuals with MODY3 compared to individuals with type 2 diabetes mellitus.
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SGLT2 inhibitors may be an effective treatment for achieving glycaemic control in individuals with MODY3.
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School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia
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Surgical Services, John Hunter Hospital, Newcastle, New South Wales, Australia
University of Newcastle, Newcastle, New South Wales, Australia
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Department of Endocrinology, John Hunter Hospital, Newcastle, New South Wales, Australia
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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
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Failure to achieve castration with androgen deprivation therapy is rare and should prompt careful review to identify the underlying cause.
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All adrenal lesions should be evaluated for hormone production, as well as assessed for risk of malignancy (either primary or secondary).
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Adrenocortical carcinomas are commonly functional, and can secrete steroid hormones or their precursors (androgens, progestogens, glucocorticoids and mineralocorticoids).
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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.
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
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Department of Medicine, Monash University, Victoria, Australia
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Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
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Summary
Primary aldosteronism is one of the most common (affecting up to 10%) yet treatable causes of hypertension in our community, notable due to an associated elevated risk of atrial fibrillation, stroke and myocardial infarction compared to essential hypertension. Guidelines have focussed on improving case detection due to significant underdiagnosis in the community. While our case experienced significant delay in diagnosis, we highlight a state of protracted, persistent post-operative hypoaldosteronism which manifested with severe hyponatraemia and hyperkalaemia, necessitating long-term mineralocorticoid replacement. We discuss whether pre-operative mineralocorticoid receptor antagonists to stimulate aldosterone secretion from the contralateral gland may have prevented this complication.
Learning points
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Hypoaldosteronism is an uncommon complication of adrenalectomy for primary aldosteronism, typically manifesting with hyperkalaemia and hyponatraemia. While most cases are transient, it may be persistent, necessitating ongoing mineralocorticoid replacement.
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Routine electrolyte monitoring is recommended post-adrenalectomy.
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Risk factors for hypoaldosteronism include age >50 years, duration of hypertension >10 years, pre-existing renal impairment and adrenal adenoma size >2 cm.
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Mineralocorticoid receptor antagonists may assist in the management of hypokalaemia and hypertension pre-operatively. However, it is unclear whether this reduces the risk of post-operative hypoaldosteronism.
Department of Endocrinology, The Austin Hospital, Heidelberg, Victoria, Australia
Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
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Department of Endocrinology, Monash Health, Clayton, Victoria, Australia
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Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
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Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
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Women’s Health Research Program, School of Public Health and Preventative Medicine, Monash University, Melbourne, Victoria, Australia
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Summary
Hypophosphatasia (HPP) is a rare and under-recognised genetic defect in bone mineralisation. Patients presenting with fragility fractures may be mistakenly diagnosed as having osteoporosis and prescribed antiresorptive therapy, a treatment which may increase fracture risk. Adult-onset HPPhypophosphatasia was identified in a 40-year-old woman who presented with bilateral atypical femoral fractures after 4 years of denosumab therapy. A low serum alkaline phosphatase (ALP) and increased serum vitamin B6 level signalled the diagnosis, which was later confirmed by identification of two recessive mutations of the ALPL gene. The patient was treated with teriparatide given the unavailability of ALP enzyme-replacement therapy (asfotase alfa). Fracture healing occurred, but impaired mobility persisted. HPP predisposes to atypical femoral fracture (AFF) during antiresorptive therapy; hence, bisphosphonates and denosumab are contraindicated in this condition. Screening patients with fracture or ‘osteoporosis’ to identify a low ALP level is recommended.
Learning points
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Hypophosphatasia (HPP) is a rare and under-recognised cause of bone fragility produced by impaired matrix mineralisation that can be misdiagnosed as a fragility fracture due to age-related bone loss.
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Antiresorptive therapy is contraindicated in HPP.
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Low serum alkaline phosphatase (ALP) provides a clue to the diagnosis.
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Elevated serum vitamin B6 (an ALP substrate) is indicative of HPP, while identification of a mutation in the ALPL gene is confirmatory.
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Enzyme therapy with recombinant ALP (asfotase alfa) is currently prohibitively costly.
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Treatment with anabolic bone agents such as teriparatide has been reported, but whether normally mineralized bone is formed requires further study.
