Significant barriers to diagnosis and management of adrenal insufficiency in Africa.

BACKGROUND: The burden and management of primary adrenal insufficiency (PAI) in Africa have not been well documented. We aimed to identify specific disease characteristics, patient demographics, and patterns of clinical management in established PAI in Africa. METHODS: An online survey of physicians' experience relating to PAI. RESULTS: There were 1334 responses received, 589 were complete, and 332 respondents reported managing patients with hypoadrenalism. The described responses were related to a calculated pool of 5787 patients with hypoadrenalism (2746 females, 3041 males), of whom 2302 had PAI. The likely causes of PAI in Sub-Saharan Africa (SSA) vs the Middle East and North Africa (MENA) regions included autoimmune disease (20% vs 60.3%; P < 0.001), tuberculosis (34% vs 4.1%; P < 0.001), AIDS (29.8% vs 1%; P < 0.001), malignancy, and genetic conditions. Sixteen percent of AD patients (376/2302) presented in an adrenal crisis. Medical emergency identification was not used by 1233 (83.6%) SSA vs 330 (40.4%) MENA patients (P < 0.001), respectively. Relative non-availability of diagnostic tests across both regions included adrenal antibodies 63% vs 69.6% (P = 0.328), s-cortisol 49.4 % vs 26.7% (P = 0.004), s-ACTH 55.7% vs 53.3% (P = 0.217), and adrenal CT scans 52.4% vs 31.8% (P = 0.017) in the SSA and MENA region, respectively. Across the entire cohort, the overall hydrocortisone use and extrapolated proportion of synacthen use were 59.4% and 50.7%, respectively. CONCLUSIONS: Through the perception and practice of healthcare professionals, we identified significant challenges in the diagnosis and management of PAI which may herald high mortality. Differences between regions may reflect the allocation of healthcare resources.

Fatal high-grade skull osteosarcoma 30 years following radiotherapy for Cushing's disease.

SUMMARY: Cushing's disease is a rare disorder characterised by excessive cortisol production as a consequence of a corticotroph pituitary tumour. While the primary treatment is surgical resection, post-operative radiation therapy may be used in cases of ongoing inadequate hormonal control or residual or progressive structural disease. Despite improved outcomes, radiotherapy for pituitary tumours is associated with hypopituitarism, visual deficits and, rarely, secondary malignancies. We describe an unusual case of a 67-year-old female with presumed Cushing's disease diagnosed at the age of 37, treated with transsphenoidal resection of a pituitary tumour with post-operative external beam radiotherapy (EBRT), ketoconazole for steroidogenesis inhibition, and finally bilateral adrenalectomy for refractory disease. She presented 30 years after her treatment with a witnessed generalised tonic-clonic seizure. Radiological investigations confirmed an extracranial mass infiltrating through the temporal bone and into brain parenchyma. Due to recurrent generalised seizures, the patient was intubated and commenced on dexamethasone and anti-epileptic therapy. Resection of the tumour revealed a high-grade osteoblastic osteosarcoma. Unfortunately, the patient deteriorated in intensive care and suffered a fatal cardiac arrest following a likely aspiration event. We describe the risk factors, prevalence and treatment of radiation-induced osteosarcoma, an exceedingly rare and late complication of pituitary irradiation. To our knowledge, this is the longest reported latency period between pituitary irradiation and the development of an osteosarcoma of the skull. LEARNING POINTS: Cushing's disease is treated with transsphenoidal resection as first-line therapy, with radiotherapy used in cases of incomplete resection, disease recurrence or persistent hypercortisolism. The most common long-term adverse outcome of pituitary tumour irradiation is hypopituitarism occurring in 30-60% of patients at 10 years, and less commonly, vision loss and oculomotor nerve palsies, radiation-induced brain tumours and sarcomas. Currently proposed characteristics of radiation-induced osteosarcomas include: the finding of a different histological type to the primary tumour, has developed within or adjacent to the path of the radiation beam, and a latency period of at least 3 years. Treatment of osteosarcoma of the skull include complete surgical excision, followed by systemic chemotherapy and/or radiotherapy. Overall prognosis in radiation-induced sarcoma of bone is poor. Newer techniques such as stereotactic radiosurgery may reduce the incidence of radiation-induced malignancies.

Pregnancy during the course of Cushing's syndrome: a case report and literature review.

SUMMARY: Cushing's syndrome is an endocrine disorder that causes anovulatory infertility secondary to hypercortisolism; therefore, pregnancy rarely occurs during its course. We present the case of a 24-year-old, 16-week pregnant female with a 10-month history of unintentional weight gain, dorsal gibbus, nonpruritic comedones, hirsutism and hair loss. Initial biochemical, hormonal and ultrasound investigations revealed hypokalemia, increased nocturnal cortisolemia and a right adrenal mass. The patient had persistent high blood pressure, hyperglycemia and hypercortisolemia. She was initially treated with antihypertensive medications and insulin therapy. Endogenous Cushing's syndrome was confirmed by an abdominal MRI that demonstrated a right adrenal adenoma. The patient underwent right laparoscopic adrenalectomy and anatomopathological examination revealed an adrenal adenoma with areas of oncocytic changes. Finally, antihypertensive medication was progressively reduced and glycemic control and hypokalemia reversal were achieved. Long-term therapy consisted of low-dose daily prednisone. During follow-up, despite favorable outcomes regarding the patient's Cushing's syndrome, stillbirth was confirmed at 28 weeks of pregnancy. We discuss the importance of early diagnosis and treatment of Cushing's syndrome to prevent severe maternal and fetal complications. LEARNING POINTS: Pregnancy can occur, though rarely, during the course of Cushing's syndrome. Pregnancy is a transient physiological state of hypercortisolism and it must be differentiated from Cushing's syndrome based on clinical manifestations and laboratory tests. The diagnosis of Cushing's syndrome during pregnancy may be challenging, particularly in the second and third trimesters because of the changes in the maternal hypothalamic-pituitary-adrenal axis. Pregnancy during the course of Cushing's syndrome is associated with severe maternal and fetal complications; therefore, its early diagnosis and treatment is critical.

Multiple endocrinological failures as a clinical presentation of a metastatic lung adenocarcinoma.

SUMMARY: Multiple endocrine metastases are a rare but possible complication of lung adenocarcinoma (LAC). Pituitary metastasis is a rare condition with poor clinical expression. Diabetes insipidus (DI) is its most common presenting symptom. Here we report an original case of a pituitary stalk (PS) metastasis from LAC presenting as central DI followed by adrenal insufficiency (AI) from bilateral adrenal metastasis, without known evidence of the primary malignancy. A 45-year-old woman whose first clinical manifestations were polyuria and polydipsia was admitted. She was completely asymptomatic with no cough, no weight loss or anorexia. Chest radiography was normal. Brain MRI showed a thick pituitary stalk (PS). DI was confirmed by water restriction test and treated with vasopressin with great clinical results. Explorations for systemic and infectious disease were negative. Few months later, an acute AI led to discovering bilateral adrenal mass on abdominal CT. A suspicious 2.3 cm apical lung nodule was found later. Histopathological adrenal biopsy revealed an LAC. The patient received systemic chemotherapy with hormonal replacement for endocrinological failures by both vasopressin and hydrocortisone. We present this rare case of metastatic PS thickness arising from LAC associated with bilateral adrenal metastasis. Screening of patients with DI and stalk thickness for lung and breast cancer must be considered. Multiple endocrine failures as a diagnostic motive of LAC is a rare but possible circumstance. LEARNING POINTS: Adrenal metastasis is a common location in lung adenocarcinoma; however, metastatic involvement of the pituitary stalk remains a rare occurrence, especially as a leading presentation to diagnose lung cancer. The posterior pituitary and the infundibulum are the preferential sites for metastases, as they receive direct arterial blood supply from hypophyseal arteries. Patients diagnosed with diabetes insipidus due to pituitary stalk thickness should be considered as a metastasis, after exclusion of the classical systemic and infectious diseases. The diagnosis of an endocrinological metastatic primary lung adenocarcinoma for patients without respiratory symptoms is often delayed due to a lack of correlation between endocrinological symptoms and lung cancer. The main originality of our case is the concomitant diagnosis of both endocrinological failures, as it was initiated with a diabetes insipidus and followed by an acute adrenal insufficiency.

Osmotic demyelination syndrome in a patient with Noonan syndrome and anterior hypopituitarism.

SUMMARY: Severe hyponatremia and osmotic demyelination syndrome (ODS) are opposite ends of a spectrum of emergency disorders related to sodium concentrations. Management of severe hyponatremia is challenging because of the difficulty in balancing the risk of overcorrection leading to ODS as well as under-correction causing cerebral oedema, particularly in a patient with chronic hypocortisolism and hypothyroidism. We report a case of a patient with Noonan syndrome and untreated anterior hypopituitarism who presented with symptomatic hyponatremia and developed transient ODS. LEARNING POINTS: Patients with severe anterior hypopituitarism with severe hyponatremia are susceptible to the rapid rise of sodium level with a small amount of fluid and hydrocortisone. These patients with chronic anterior hypopituitarism are at high risk of developing ODS and therefore, care should be taken to avoid a rise of more than 4-6 mmol/L per day. Early recognition and rescue desmopressin and i.v. dextrose 5% fluids to reduce serum sodium concentration may be helpful in treating acute ODS.

A rare cause of severe Cushing's syndrome.

SUMMARY: Ectopic adrenocorticotropic hormone (ACTH) production is an uncommon cause of Cushing's syndrome and, rarely, the source can be a phaeochromocytoma. A 55-year-old man presented following an episode of presumed gastroenteritis with vomiting and general malaise. Further episodes of diarrhoea, joint pains and palpitations followed. On examination, he was hypertensive with no clinical features to suggest hypercortisolaemia. He was subsequently found to have raised plasma normetanephrines of 3.98 nmol/L (NR <0.71) and metanephrines of 0.69 nmol/L (NR <0.36). An adrenal CT showed a 3.8 cm right adrenal nodule, which was not MIBG-avid but was clinically and biochemically consistent with a phaeochromocytoma. He was started on alpha blockade and referred for right adrenalectomy. Four weeks later, on the day of admission for adrenalectomy, profound hypokalaemia was noted (serum potassium 2.0 mmol/L) with non-specific ST-segment ECG changes. He was also diagnosed with new-onset diabetes mellitus (capillary blood glucose of 28 mmol/L). He reported to have gained weight and his skin had become darker over the course of the last 4 weeks. Given these findings, he underwent overnight dexamethasone suppression testing, which showed a non-suppressed serum cortisol of 1099 nmol/L. Baseline serum ACTH was 273 ng/L. A preliminary diagnosis of ectopic ACTH secretion from the known right-sided phaeochromocytoma was made and he was started on metyrapone and insulin. Surgery was postponed for 4 weeks. Following uncomplicated laparoscopic adrenalectomy, the patient recovered with full resolution of symptoms. LEARNING POINTS: Phaeochromocytomas are a rare source of ectopic ACTH secretion. A high clinical index of suspicion is therefore required to make the diagnosis. Ectopic ACTH secretion from a phaeochromocytoma can rapidly progress to severe Cushing's syndrome, thus complicating tumour removal. Removal of the primary tumour often leads to full recovery. The limited literature suggests that the presence of ectopic Cushing's syndrome does not appear to have any long-term prognostic implications.

Corticotroph adenoma and pituitary fungal infection: a rare association.

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.

Adrenocortical carcinoma and pulmonary embolism from tumoral extension.

SUMMARY: Adrenococortical carcinoma (ACC) is a rare cancer, occurring at the rate of one case in two million person years. Cushing syndrome or a mixed picture of excess androgen and glucocorticoid production are the most common presentations of ACC. Other uncommon presentations include abdominal pain and adrenal incidentalomas. In the present report, a 71-year-old male presented with abdominal pain and was eventually diagnosed with ACC. He was found to have pulmonary thromboembolism following an investigation for hypoxemia, with the tumor thrombus extending upto the right atrium. This interesting case represents the unique presentation of a rare tumor, which if detected late or left untreated is associated with poor outcomes, highlighting the need for a low index of suspicion for ACC when similar presentations are encountered in clinical practice. LEARNING POINTS: ACC is a rare but aggressive tumor. ACC commonly presents with rapid onset of hypercortisolism, combined hyperandrogenism and hypercortisolism, or uncommonly with compressive symptoms. Clinicians should have a low index of suspicion for ACC in patients presenting with rapid onset of symptoms related to hypercortisolism and/or hyperandrogenism. Venous thromboembolism and extension of the tumor thrombus to the right side of the heart is a very rare but serious complication of ACC that clinicans should be wary of. The increased risk of venous thromboembolism in ACC could be explained by direct tumor invasion, tumor thrombi or hypercoagulability secondary to hypercortisolism. Early diagnosis and prompt treatment can improve the long-term survival of patients with ACC.

Cushing syndrome: uncovering Carney complex due to novel PRKAR1A mutation.

Carney complex (CNC) is a rare multiple neoplasia syndrome characterized by spotty pigmentation of the skin and mucosa in association with various non-endocrine and endocrine tumors, including primary pigmented nodular adrenocortical disease (PPNAD). A 20-year-old woman was referred for suspected Cushing syndrome. She had signs of cortisol excess as well as skin lentigines on physical examination. Biochemical investigation was suggestive of corticotropin (ACTH)-independent Cushing syndrome. Unenhanced computed tomography scan of the abdomen did not reveal an obvious adrenal mass. She subsequently underwent bilateral laparoscopic adrenalectomy, and histopathology was consistent with PPNAD. Genetic testing revealed a novel frameshift pathogenic variant c.488delC/p.Thr163MetfsX2 (ClinVar Variation ID: 424516) in the PRKAR1A gene, consistent with clinical suspicion for CNC. Evaluation for other clinical features of the complex was unrevealing. We present a case of PPNAD-associated Cushing syndrome leading to the diagnosis of CNC due to a novel PRKAR1A pathogenic variant. Learning points: PPNAD should be considered in the differential for ACTH-independent Cushing syndrome, especially when adrenal imaging appears normal. The diagnosis of PPNAD should prompt screening for CNC. CNC is a rare multiple neoplasia syndrome caused by inactivating pathogenic variants in the PRKAR1A gene. Timely diagnosis of CNC and careful surveillance can help prevent potentially fatal complications of the disease.

Etomidate in the management of severe Cushing's disease and MRSA bacteraemia in a district general hospital in the United Kingdom.

SUMMARY: We report our experience on managing a case of florid Cushing's disease with Methicillin-resistant Staphylococcus aureus (MRSA) sepsis using intravenous etomidate in the intensive care unit of a UK district general hospital. LEARNING POINTS: Severe Cushing's syndrome is associated with high morbidity and mortality. Etomidate is a safe and effective medical therapy to rapidly lower cortisol levels even in the context of severe sepsis and immunosuppression. Etomidate should ideally be administered in an intensive care unit but is still feasible in a district general hospital. During treatment with etomidate, accumulation of serum 11ß-deoxycortisol (11DOC) levels can cross-react with laboratory cortisol measurement leading to falsely elevated serum cortisol levels. For this reason, serum cortisol measurement using a mass spectrometry assay should ideally be used to guide etomidate prescription.

Somatostatin analog challenge test in the pre-surgical management of ACTH-secreting pheochromocytoma.

SUMMARY: ACTH-secreting pheochromocytoma is a very rare cause of Cushing's syndrome, with a high morbidity and mortality risk due to both cortisol and catecholamines excess. We report the case of a 45-year-old female patient with a 3 cm, high-density, left adrenal mass, diagnosed as an ACTH-secreting pheochromocytoma. The biochemical sensitivity of the tumor to somatostatin analogues was tested by a 100 µg s.c. octreotide administration, which led to an ACTH and cortisol reduction of 50 and 25% respectively. In addition to alpha and beta blockers, preoperative approach to laparoscopic adrenalectomy included octreotide, a somatostatin analogue, together with ketoconazole, in order to achieve an adequate pre-surgical control of cortisol release. Histopathological assessment confirmed an ACTH-secreting pheochromocytoma expressing type 2 and 5 somatostatin receptors (SSTR-2 and -5). LEARNING POINTS: ACTH-secreting pheochromocytomas represent a rare and severe condition, characterized by high morbidity and mortality risk. Surgical removal of the adrenal mass is the gold standard treatment, but adequate medical therapy is required preoperatively to improve the surgical outcome and to avoid major complications. Somatostatin analogs, in addition to other medications, may represent a useful therapeutic option for the presurgical management of selected patients. In this sense, the octreotide challenge test is a useful tool to predict favorable therapeutic response to the treatment.

Addison's disease in antiphospholipid syndrome: a rare complication.

Addison's disease (AD) is the most common endocrine manifestation of antiphospholipid syndrome (APS), but it remains a very rare complication of the syndrome. It is caused by adrenal venous thrombosis and consequent hemorrhagic infarction or by spontaneous (without thrombosis) adrenal hemorrhage, usually occurring after surgery or anticoagulant therapy. We present a clinical case of a 36-year-old female patient with a previous diagnosis of APS. She presented with multiple thrombotic events, including spontaneous abortions. During evaluation by the third episode of abortion, a CT imaging revealed an adrenal hematoma, but the patient was discharged without further investigation. A few weeks later, she presented in the emergency department with manifestations suggestive of adrenal insufficiency. Based on that assumption, she started therapy with glucocorticoids, with significant clinical improvement. After stabilization, additional investigation confirmed AD and excluded other etiologies; she also started mineralocorticoid replacement. This case illustrates a rare complication of APS that, if misdiagnosed, may be life threatening. A high index of suspicion is necessary for its diagnosis, and prompt treatment is crucial to reduce the morbidity and mortality potentially associated. Learning points: AD is a rare but life-threatening complication of APS. It is important to look for AD in patients with APS and a suggestive clinical scenario. APS must be excluded in patients with primary adrenal insufficiency and adrenal imaging revealing thrombosis/hemorrhage. Glucocorticoid therapy should be promptly initiated when AD is suspected. Mineralocorticoid replacement must be started when there is confirmed aldosterone deficiency. Hypertension is a common feature of APS; in patients with APS and AD, replacement therapy with glucocorticoids and mineralocorticoids may jeopardize hypertension management.