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Open access

Catastrophic ACTH-secreting pheochromocytoma: an uncommon and challenging entity with multifaceted presentation

Luca Foppiani, Maria Gabriella Poeta, Mariangela Rutigliani, Simona Parodi, Ugo Catrambone, Lorenzo Cavalleri, Giancarlo Antonucci, Patrizia Del Monte, and Arnoldo Piccardo

Summary

Cushing’s syndrome due to ectopic adrenocorticotropic hormone (ACTH) secretion (EAS) by a pheochromocytoma is a challenging condition. A woman with hypertension and an anamnestic report of a ‘non-secreting’ left adrenal mass developed uncontrolled blood pressure (BP), hyperglycaemia and severe hypokalaemia. ACTH-dependent severe hypercortisolism was ascertained in the absence of Cushingoid features, and a psycho-organic syndrome developed. Brain imaging revealed a splenial lesion of the corpus callosum and a pituitary microadenoma. The adrenal mass displayed high uptake on both 18F-FDG PET/CT and 68Ga-DOTATOC PET/CT; urinary metanephrine levels were greatly increased. The combination of antihypertensive drugs, high-dose potassium infusion, insulin and steroidogenesis inhibitor normalized BP, metabolic parameters and cortisol levels; laparoscopic left adrenalectomy under intravenous hydrocortisone infusion was performed. On combined histology and immunohistochemistry, an ACTH-secreting pheochromocytoma was diagnosed. The patient's clinical condition improved and remission of both hypercortisolism and catecholamine hypersecretion ensued. Brain magnetic resonance imaging showed a reduction of the splenial lesion. Off-therapy BP and metabolic parameters remained normal. The patient was discharged on cortisone replacement therapy for post-surgical hypocortisolism. EAS due to pheochromocytoma displays multifaceted clinical features and requires prompt diagnosis and multidisciplinary management in order to overcome the related severe clinical derangements.

Learning points

  • A small but significant number of cases of adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome are caused by ectopic ACTH secretion by neuroendocrine tumours, which is usually associated with severe hypercortisolism causing severe clinical and metabolic derangements.

  • Ectopic ACTH secretion by a pheochromocytoma is exceedingly rare but can be life-threatening, owing to the simultaneous excess of both cortisol and catecholamines.

  • The combination of biochemical and hormonal testing and imaging procedures is mandatory for the diagnosis of ectopic ACTH secretion, and in the presence of an adrenal mass, the possibility of an ACTH-secreting pheochromocytoma should be taken into account.

  • Immediate-acting steroidogenesis inhibitors are required for the treatment of hypercortisolism, and catecholamine excess should also be appropriately managed before surgical removal of the tumour.

  • A multidisciplinary approach is required for the treatment of this challenging entity.

DOI:
https://doi.org/10.1530/EDM-22-0308
Volume 2023: Issue 2
Open access

Diagnosis of 17-alpha hydroxylase deficiency performed late in life in a patient with a 46,XY karyotype

Bruno Bouça, Mariana Cascão, Pedro Fiúza, Sara Amaral, Paula Bogalho, and José Silva-Nunes

Summary

17-Alpha-hydroxylase deficiency (17OHD) is a rare autosomal recessive disease, representing 1% of cases of congenital adrenal hyperplasia. A 44-year-old female presented to the emergency department complaining of generalized asthenia and polyarthralgia for about 2 weeks. On examination, she was hypertensive (174/100 mmHg), and laboratory results revealed hypokalemia and hypocortisolism. She had an uncharacteristic morphotype, BMI of 16.7 kg/m2, cutaneous hyperpigmentation, and Tanner stage M1P1, with normal female external genitalia. She reported to have primary amenorrhea. Further analytical evaluations of her hormone levels were performed CT scan revealed adrenal bilateral hyperplasia and absence of female internal genitalia. A nodular lesion was observed in the left inguinal canal with 25 × 10 mm, compatible with a testicular remnant. Genetic analysis identified the c.3G>A p.(Met1?) variant in homozygosity in the CYP17A1 gene, classified as pathogenic, confirming the diagnosis of 17OHD. Karyotype analysis was compatible with 46,XY. The association of severe hypokalemia, hypertension, hypocortisolism, and oligo/amenorrhea and the absence of secondary sexual characteristics favored the diagnosis of 17OHD, confirmed by genetic testing. As in other published clinical cases, diagnosis outside pediatric age is not rare and should be considered when severe hypokalemia occurs in hypertensive adults with a lack of secondary sexual characteristics.

Learning points

  • The association of severe hypokalemia, hypertension, hypocortisolism, and oligo/amenorrhea and the absence of secondary sexual characteristics favor the diagnosis of 17-alpha-hydroxylase deficiency (17OHD).

  • Diagnosis outside pediatric age is not rare.

  • 17OHD should be considered when severe hypokalemia occurs in hypertensive adults with a lack of secondary sexual characteristics.

DOI:
https://doi.org/10.1530/EDM-22-0338
Volume 2023: Issue 2
Open access

Stress-induced severe transient hypercortisolism with reversible bilateral adrenal enlargement after cardiogenic shock

Jairo Arturo Noreña, Medha Joshi, Mandip S Rawla, Elizabeth Jenkins, and Elias S Siraj

Summary

Acute illness-related stress can result in severe hypercortisolism and bilateral adrenal enlargement in certain patients. We report a case of stress-induced hypercortisolism and bilateral adrenal enlargement in a patient admitted for acute respiratory distress and cardiogenic shock. Bilateral adrenal enlargement and hypercortisolism found during hospitalization for acute illness resolved 3 weeks later following the resolution of acute illness. Acute illness can be a precipitating factor for stress-induced hypercortisolism and bilateral adrenal enlargement. We hypothesize that increased adrenocorticotrophic hormone mediated by corticotrophin-releasing hormone from physical stress resulted in significant adrenal hyperplasia and hypercortisolism. This mechanism is downregulated once acute illness resolves.

Learning points

  • Adrenal enlargement with abnormal adrenal function after stress is uncommon in humans; however, if present, it can have self-resolution after the acute illness is resolved.

  • Stress induces enlargement of the adrenals, and the degree of cortisol elevation could be very massive. This process is acute, and the absence of cushingoid features is expected.

  • Treatment efforts should be focused on treating the underlying condition.

DOI:
https://doi.org/10.1530/EDM-22-0329
Volume 2023: Issue 2
Open access

Novel likely pathogenic variant in NR5A1 gene in a Tanzanian child with 46,XY differences of sex development, inherited from the mosaic father

Rahim Karim Damji, Mohamed Zahir Alimohamed, Hedi L Claahsen-van der Grinten, Dineke Westra, and Ben Hamel

Summary

Pathogenic variants in the nuclear receptor subfamily 5 group A member 1 gene (NR5A1), which encodes steroidogenic factor 1 (SF1), result in 46,XY and 46,XX differences of sex development (DSD). In 46,XY individuals with a pathogenic variant in the NR5A1 gene a variable phenotype ranging from mild to severe is seen, including adrenal failure, testis dysgenesis, androgen synthesis defects, hypospadias and anorchia with microphallus and infertility. We report the clinical, endocrinological and genetic characteristics of a patient with 46,XY DSD with a novel likely pathogenic missense variant in the NR5A1 gene. A retrospective evaluation of the medical history, physical examination, limited endocrinological laboratory analysis and genetic analysis with DSD gene panel testing was performed. A 1.5-month-old individual was referred with ambiguous genitalia. The karyotype was 46,XY. The endocrinological analyses were within normal male reference including a normal response of cortisol within an adrenocorticotropic hormone test. A novel heterozygous missense variant c.206G>C p.(Arg69Pro) in the NR5A1 gene was detected. This variant was present in mosaic form (~20%) in his unaffected father. Because another missense variant at the same position and other missense variants involving the same highly conserved codon have been reported, we consider this NR5A1 variant in this 46,XY DSD patient as likely pathogenic in accordance with the ACMG/AMP 2015 guidelines causing ambiguous genitalia but no adrenal insufficiency. This variant was inherited from the apparently unaffected mosaic father, which might have implications for the recurrence risk in this family.

Learning points

  • The importance of performing trio (patient and parents) sequencing is crucial in pointing out the origin of inheritance.

  • In a 46,XY differences of sex development patient, a normal adrenal function does not rule out an NR5A1 mutation.

  • With the support of a dedicated overseas institute partnership, we could solve this complex clinical case by molecular diagnosis in a resource-limited setting.

DOI:
https://doi.org/10.1530/EDM-22-0384
Volume 2023: Issue 2
Open access

Extreme hyperferritinemia in restrictive type anorexia nervosa

Christine Hvolby Amanoal, Lene Kongsgaard Nielsen, and Henrik Holm Thomsen

Summary

Iron metabolism and markers hereof are altered in anorexia nervosa (AN) but far from completely understood. We report a case of extreme hyperferritinemia in a patient with AN and discuss the possible mechanisms and current knowledge about the association between hyperferritinemia and AN. A 20-year-old woman with a history of AN presented with bradycardia, weariness, and malaise in addition to an incidentally very high ferritin level. The symptoms disappeared spontaneously after a short admission. There were no signs suggestive of systemic, hematological, or malignant disease causing the very high concentration of ferritin. Her body weight was in decline, leading up to admission, but did initially increase after discharge accompanied by declining ferritin concentration. However, a clear association between ferritin dynamics and weight changes or physical activity was not identified and neither were other causes of the hyperferritinemia. Around one in four patients with AN have increased ferritin concentrations. Our case represents the highest ferritin concentration reported in a patient with AN without other underlying causes or comorbidities.

Learning points

  • Perturbed iron metabolism is frequent in restrictive type anorexia nervosa but incompletely understood.

  • Altered ferritin in anorexia nervosa may be linked to nutritional status.

DOI:
https://doi.org/10.1530/EDM-22-0405
Volume 2023: Issue 1
Open access

False-positive 123I-metaiodobenzylguanidine scintigraphy in a patient with a gastrointestinal stromal tumor presenting as a left adrenal incidentaloma

Erika Sugito, Akiyo Tanabe, Koji Maruyama, Kyoko Nohara, Naoki Enomoto, Ryotaro Bouchi, Mitsuru Ohsugi, Kohjiro Ueki, Kazuhiko Yamada, and Hiroshi Kajio

Summary

A 47-year-old man was diagnosed with a left adrenal incidentaloma at 40 years of age. The tumor had irregular margins and grew from 18 mm to 30 mm in maximum diameter over 7 years. On computed tomography scan, the mass appeared to localize within the tip of the lateral limb of the left adrenal gland, and between the left adrenal gland and the posterior wall of the stomach. The plasma corticotropin and cortisol concentrations and the 24-h urine fractionated metanephrine levels were normal. 123I-metaiodobenzylguanidine scintigraphy showed tumor avidity consistent with a hormonally inactive pheochromocytoma. A laparoscopic left adrenalectomy was performed; however, no tumor was present in the resected specimen. Abdominal computed tomography postoperatively showed that the tumor remained intact and appeared to connect to the posterior wall of the stomach. A laparotomy was performed and the tumor was removed. The tumor was localized to the intraperitoneal space and isolated from the posterior wall of the stomach. The pathological diagnosis was a gastrointestinal stromal tumor. Clinicians need to be aware of the limitations of diagnostic imaging studies in diagnosing non-functioning adrenal incidentalomas, which require a pathological analysis for the final diagnosis. Moreover, clinicians need to provide patients with sufficient informed consent when deciding on treatment strategies.

Learning points

  • Anatomic structures and tumors that develop in neighboring tissues to the adrenal glands may be confused with primary adrenal tumors.

  • 123I- metaiodobenzylguanidine (MIBG) scintigraphy is specific for diagnosing pheochromocytomas and paragangliomas; however, it has been reported that 123I-MIBG may accumulate in neuroendocrine tumors as well as other tumors.

  • Clinicians should recognize the limitations of imaging studies and the uncertainty of an imaging-based preoperative diagnosis.

DOI:
https://doi.org/10.1530/EDM-22-0390
Volume 2023: Issue 1
Open access

Ectopic adrenocorticotrophic hormone syndrome secondary to treatment-related neuroendocrine differentiation of metastatic castrate-resistant prostate cancer

Chelsea Tan and Jessica Triay

Summary

A 64-year-old man with progressive metastatic castrate-resistant prostate adenocarcinoma presented with recurrent fluid overload, severe hypokalaemia with metabolic alkalosis and loss of glycaemic control. Clinical features were facial plethora, skin bruising and proximal myopathy. Plasma adrenocorticotrophic hormone (ACTH), serum cortisol and 24-h urinary cortisol levels were elevated. Low-dose dexamethasone failed to suppress cortisol. Pituitary MRI was normal and 68Gallium-DOTATATE PET–CT scan showed only features of metastatic prostate cancer. He was diagnosed with ectopic ACTH syndrome secondary to treatment-related neuroendocrine prostate cancer differentiation. Medical management was limited by clinical deterioration, accessibility of medications and cancer progression. Ketoconazole and cabergoline were utilised, but cortisol remained uncontrolled. He succumbed 5 months following diagnosis. Treatment-related neuroendocrine differentiation of prostate adenocarcinoma is a rare cause of ectopic ACTH syndrome.

Learning points

  • Neuroendocrine differentiation following prostate adenocarcinoma treatment with androgen deprivation has been described.

  • Ectopic adrenocorticotrophic hormone (ACTH) syndrome should be considered where patients with metastatic prostate cancer develop acute electrolyte disturbance or fluid overload.

  • Ketoconazole interferes with adrenal and gonadal steroidogenesis and can be used in ectopic ACTH syndrome, but the impact may be insufficient. Inhibition of gonadal steroidogenesis is favourable in prostate cancer.

  • More data are required to evaluate the use of cabergoline in ectopic ACTH syndrome.

  • Ectopic ACTH syndrome requires prompt management and is challenging in the face of metastatic cancer.

DOI:
https://doi.org/10.1530/EDM-22-0347
Volume 2023: Issue 1
Open access

Hypercalcaemia secondary to hypophysitis and cortisol deficiency: another immunotherapy-related adverse event

Samuel R Miller, Shejil Kumar, Alexander Yuile, and Alexander M Menzies

Summary

Hypercalcaemia is a common complication seen in malignancy, frequently due to paraneoplastic parathyroid hormone-related peptide production or osteolytic bony metastases. We present a 58-year-old female with immunotherapy-mediated hypophysitis causing secondary cortisol deficiency resulting in severe glucocorticoid-responsive hypercalcaemia. Whilst hypophysitis is a well recognised adverse event in those receiving immunotherapy for advanced malignancy, it does not typically present with hypercalcaemia. The mechanism responsible for hypercalcaemia due to hypocortisolaemia has not been fully elucidated although hypotheses include the effects of volume depletion and thyroxine’s action on bone. Prompt treatment with glucocorticoids caused an improvement in the patient’s symptoms and corrected her hypercalcaemia which later returned after an attempted glucocorticoid wean. With the increasing uptake of immunotherapy, clinicians should be aware of this unusual presentation of immunotherapy-related hypophysitis and secondary hypocortisolaemia which can be life-threatening if the diagnosis is delayed.

Learning points

  • Immunotherapy can cause inflammation of the pituitary gland resulting in secondary hypocortisolaemia, which can, though rarely, present as hypercalcaemia.

  • Secondary hypocortisolaemia requires prompt recognition and treatment with glucocorticoids. Glucocorticoid replacement leads to rapid clinical and biochemical improvement in these patients.

  • The differential diagnosis for glucocorticoid-responsive hypercalcaemia extends beyond granulomatous disorders (e.g. sarcoidosis, tuberculosis) to adrenocorticotrophic hormone and cortisol deficiency, particularly in patients receiving immunotherapy.

  • Hypocortisolaemia can lead to hypercalcaemia through various proposed mechanisms. Low serum glucocorticoids are associated with reduced blood volume, thus reducing renal calcium excretion. In addition, without glucocorticoid’s inhibitory action, thyroxine appears to drive calcium mobilisation from bone.

DOI:
https://doi.org/10.1530/EDM-22-0375
Volume 2023: Issue 1
Open access

A case of unilateral post-COVID-19 adrenal haemorrhage and follow-up during pregnancies

Alessandra Mangone, Quratulain Yousuf, Wiebke Arlt, Alessandro Prete, Fozia Shaheen, Senthil-kumar Krishnasamy, Yasir S Elhassan, and Cristina L Ronchi

Summary

The spectrum of endocrine-related complications of COVID-19 infection is expanding; one of the most concerning of which is adrenal haemorrhage due to the risk of catastrophic adrenal crisis. In this study, we present a case that highlights the challenging management of a large, indeterminate unilateral adrenal mass during pregnancy and draws attention to a rare yet probably underestimated complication of COVID-19. During hospitalization for severe COVID-19 pneumonia, a 26-year-old woman was incidentally found to have a 12.5 cm heterogeneous left adrenal mass. Soon after the discovery, she became pregnant and upon referral, she was in the seventh week of gestation, without clinical or biochemical features of hormonal excess. The uncertainty of the diagnosis and the risks of malignancy and surgical intervention were discussed with the patient, and a period of radiological surveillance was agreed upon. An MRI scan performed 3 months later showed a size reduction of the adrenal lesion to 7.9 cm, which was against malignancy. A Doppler ultrasound showed a non-vascular, well-defined round lesion consistent with an adrenal haematoma, likely a complication of the recent COVID-19 infection. The multidisciplinary team recommended further radiological follow-up. The patient then spontaneously had miscarriage at 12 weeks gestation. Subsequent radiological surveillance showed a further size reduction of the adrenal lesion to 5.5 cm. The patient conceived again during follow-up, and the repeated Doppler ultrasound showed stable appearances of the adrenal mass, and thus, it was agreed to continue radiological monitoring after delivery. The pregnancy was uneventful, and the patient delivered a healthy baby. An MRI scan performed after delivery showed a stable but persistent lesion consistent with a likely underlying adrenal lesion.

Learning points

  • Unilateral adrenal haemorrhage can occur as a complication of COVID-19 and should be considered in the differential diagnosis of heterogeneous adrenal masses if there is a history of recent infection.

  • Management of large indeterminate adrenal masses during pregnancy poses several challenges and should be led by an experienced multidisciplinary team.

  • Underlying adrenal tumours may trigger non-traumatic haemorrhages, especially if exacerbated by stressful illness.

DOI:
https://doi.org/10.1530/EDM-22-0337
Volume 2022: Issue 1
Open access

De novo purely prostatic large-cell neuroendocrine carcinoma with thyroid and adrenal metastases

Evangelos Karvounis, Ioannis Zoupas, Dimitra Bantouna, Rodis D Paparodis, Roxani Efthymiadou, Christina Ioakimidou, and Christos Panopoulos

Summary

Large-cell neuroendocrine carcinoma (LCNEC) is a rare neuroendocrine prostatic malignancy. It usually arises after androgen deprivation therapy (ADT), while de novo cases are even more infrequent, with only six cases described. The patient was a 78-year-old man with no history of ADT who presented with cervical lymphadenopathy. Diagnostic approaches included PET/CT, MRI, CT scans, ultrasonography, biopsies, and cytological and immunohistochemical evaluations. Results showed a poorly differentiated carcinoma in the thyroid gland accompanied by cervical lymph node enlargement. Thyroid surgery revealed LCNEC metastasis to the thyroid gland. Additional metastases were identified in both the adrenal glands. Despite appropriate treatment, the patient died of the disease. De novo LCNEC of the prostate is a rare, highly aggressive tumor with a poor prognosis. It is resistant to most therapeutic agents, has a high metastatic potential, and is usually diagnosed at an advanced stage. Further studies are required to characterize this tumor.

Learning points

  • De novo LCNECs of the prostate gland can metastasize almost anywhere in the body, including the thyroid and adrenal glands.

  • LCNECs of the prostate are usually associated with androgen-depriving therapy, but de novo cases are also notable and should be accounted for.

  • Further studies are required to fully understand and treat LCNECs more effectively.

DOI:
https://doi.org/10.1530/EDM-22-0301
Volume 2022: Issue 1