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Rob Gonsalves Division of Endocrinology, Phoenix Children’s Hospital, Phoenix, Arizona, USA

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Kirk Aleck Division of Genetics, Phoenix Children’s Hospital, Phoenix, Arizona, USA

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Dorothee Newbern Division of Endocrinology, Phoenix Children’s Hospital, Phoenix, Arizona, USA

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Gabriel Shaibi Division of Endocrinology, Phoenix Children’s Hospital, Phoenix, Arizona, USA

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Chirag Kapadia Division of Endocrinology, Phoenix Children’s Hospital, Phoenix, Arizona, USA

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Oliver Oatman Division of Endocrinology, Phoenix Children’s Hospital, Phoenix, Arizona, USA

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Summary

Single-minded homolog 1 (SIM1) is a transcription factor that plays a role in the development of both the hypothalamus and pituitary. SIM1 gene mutations are known to cause obesity in humans, and chromosomal deletions encompassing SIM1 and other genes necessary for pituitary development can cause a Prader–Willi-like syndrome with obesity and hypopituitarism. There have been no reported cases of hypopituitarism linked to a single SIM1 mutation. A 21-month-old male presented to endocrinology clinic with excessive weight gain and severe obesity. History was also notable for excessive drinking and urination. Endocrine workup revealed central hypothyroidism, partial diabetes insipidus, and central adrenal insufficiency. Genetic evaluation revealed a novel mutation in the SIM1 gene. No other genetic abnormalities to account for his obesity and hypopituitarism were identified. While we cannot definitively state this mutation is pathogenic, it is notable that SIM1 plays a role in the development of all three of the patient’s affected hormone axes. He is now 6 years old and remains on treatment for his pituitary hormone deficiencies and continues to exhibit excessive weight gain despite lifestyle interventions.

Learning points:

  • Mutations in SIM1 are a well-recognized cause of monogenic human obesity, and there have been case reports of Prader–Willi-like syndrome and hypopituitarism in patients with chromosomal deletions that contain the SIM1 gene.

  • SIM1 is expressed during the development of the hypothalamus, specifically in neuroendocrine lineages that give rise to the hormones oxytocin, arginine vasopressin, thyrotropin-releasing hormone, corticotropin-releasing hormone, and somatostatin.

  • Pituitary testing should be considered in patients with severe obesity and a known genetic abnormality affecting the SIM1 gene, particularly in the pediatric population.

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Rachel Wurth Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development

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Crystal Kamilaris Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development

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Naris Nilubol Surgical Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

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Samira M Sadowski Surgical Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

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Annabel Berthon Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development

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Martha M Quezado Laboratory of Pathology Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

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Fabio R Faucz Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development

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Constantine A Stratakis Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development

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Fady Hannah-Shmouni Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development

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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.

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Sofia Pilar Ildefonso-Najarro Division of Endocrinology, Guillermo Almenara Irigoyen National Hospital, Lima, Peru

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Esteban Alberto Plasencia-Dueñas Division of Endocrinology, Guillermo Almenara Irigoyen National Hospital, Lima, Peru

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Cesar Joel Benites-Moya National University of Trujillo, School of Medicine, Trujillo, Peru

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Jose Carrion-Rojas Metabolism and Reproduction Unit, Division of Endocrinology, Guillermo Almenara Irigoyen National Hospital, Lima, Peru

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Marcio Jose Concepción-Zavaleta Division of Endocrinology, Guillermo Almenara Irigoyen National Hospital, Lima, Peru

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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.

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Shamaila Zaman Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK

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Bijal Patel Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK

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Paul Glynne The Physicians’ Clinic, London, UK

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Mark Vanderpump The Physicians’ Clinic, London, UK

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Ali Alsafi Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK

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Sairah Khan Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK

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Rashpal Flora Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK

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Fausto Palazzo Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK

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Florian Wernig Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK

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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.

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Katta Sai Department of Internal Medicine, Saint Vincent Hospital at Worcester Medical Center, Worcester, Massachusetts, USA

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Amos Lal Department of Internal Medicine, Saint Vincent Hospital at Worcester Medical Center, Worcester, Massachusetts, USA

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Jhansi Lakshmi Maradana Department of Internal Medicine, Saint Vincent Hospital at Worcester Medical Center, Worcester, Massachusetts, USA

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Pruthvi Raj Velamala Department of Internal Medicine, Saint Vincent Hospital at Worcester Medical Center, Worcester, Massachusetts, USA

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Trivedi Nitin Department of Endocrinology, Diabetes, and Metabolism, Saint Vincent Hospital at Worcester Medical Center, Worcester, Massachusetts, USA

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Summary

Mifepristone is a promising option for the management of hypercortisolism associated with hyperglycemia. However, its use may result in serious electrolyte imbalances, especially during dose escalation. In our patient with adrenocorticotropic hormone-independent macro-nodular adrenal hyperplasia, unilateral adrenalectomy resulted in biochemical and clinical improvement, but subclinical hypercortisolism persisted following adrenalectomy. She was started on mifepristone. Unfortunately, she missed her follow-up appointments following dosage escalation and required hospitalization at an intensive care level for severe refractory hypokalemia.

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Sharmin Jahan Department of Endocrinology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh

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M A Hasanat Department of Endocrinology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh

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Tahseen Mahmood Department of Endocrinology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh

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Shahed Morshed Department of Endocrinology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh

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Raziul Haq Department of Neurosurgery, Dhaka Medical College and Hospital (DMCH), Dhaka, Bangladesh

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Md Fariduddin Department of Endocrinology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh

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Summary

Silent corticotroph adenoma (SCA) is an unusual type of nonfunctioning pituitary adenoma (NFA) that is silent both clinically and biochemically and can only be recognized by positive immunostaining for ACTH. Under rare circumstances, it can transform into hormonally active disease presenting with severe Cushing syndrome. It might often produce diagnostic dilemma with difficult management issue if not thoroughly investigated and subtyped accordingly following surgery. Here, we present a 21-year-old male who initially underwent pituitary adenomectomy for presumed NFA with compressive symptoms. However, he developed recurrent and invasive macroadenoma with severe clinical as well as biochemical hypercortisolism during post-surgical follow-up. Repeat pituitary surgery was carried out urgently as there was significant optic chiasmal compression. Immunohistochemical analysis of the tumor tissue obtained on repeat surgery proved it to be an aggressive corticotroph adenoma. Though not cured, he showed marked clinical and biochemical improvement in the immediate postoperative period. Anticipating recurrence from the residual tumor, we referred him for cyber knife radio surgery.

Learning points:

  • Pituitary NFA commonly present with compressive symptoms such as headache and blurred vision.

  • Post-surgical development of Cushing syndrome in such a case could be either drug induced or endogenous.

  • In the presence of recurrent pituitary tumor, ACTH-dependent Cushing syndrome indicates CD.

  • Rarely a SCA presenting initially as NFA can transform into an active corticotroph adenoma.

  • Immunohistochemical marker for ACTH in the resected tumor confirms the diagnosis.

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Marcela Rodríguez Flores Obesity and Eating Disorders Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

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Ruth Carmina Cruz Soto Nutrition and Obesity Center, Centro Médico ABC

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Verónica Vázquez Velázquez Obesity and Eating Disorders Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

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Reina Ruth Soriano Cortés Obesity and Eating Disorders Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

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Carlos Aguilar Salinas Metabolic Diseases Research Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
Endocrinology and Metabolism Department, Instituto Tecnológico de Estudios Superiores de Monterrey Tec Salud, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

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Eduardo García García Obesity and Eating Disorders Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

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Summary

In patients with gastric bypass (GB), high glucose variability (GV) and hypoglycemia have been demonstrated, which could impact the metabolic status and eating behavior. We describe the glucose patterns determined through continuous glucose monitoring (CGM) in two patients with >5 years follow-up after GB and significant weight recovery, who reported hypoglycemic symptoms that interfered with daily activities, and their response to a nutritional and psycho-educative prescription. Case 1: A 40-year-old woman without pre-surgical type 2 diabetes (T2DM) and normal HbA1c, in whom CGM showed high GV and hypoglycemic episodes that did not correlate with the time of hypoglycemic symptoms. Her GV reduced after prescription of a diet with low glycemic index and modification of meal patterns. Case 2: A 48-year-old male with pre-surgical diagnosis of T2DM and current normal HbA1c, reported skipping meals. The CGM showed high GV, 15% of time in hypoglycemia and hyperglycemic spikes. After prescription of a low glycemic index diet, his GV increased and time in hypoglycemia decreased. Through the detailed self-monitoring needed for CGM, we discovered severe anxiety symptoms, consumption of simple carbohydrates and lack of meal structure. He was referred for more intensive psychological counseling. In conclusion, CGM can detect disorders in glucose homeostasis derived both from the mechanisms of bariatric surgery, as well as the patient’s behaviors and mental health, improving decision-making during follow-up.

Learning points:

  • High glycemic variability is frequent in patients operated with gastric bypass.

  • Diverse eating patterns, such as prolonged fasting and simple carbohydrate ingestion, and mental health disorders, including anxiety, can promote and be confused with worsened hypoglycemia.

  • CGM requires a detailed record of food ingested that can be accompanied by associated factors (circumstances, eating patterns, emotional symptoms). This allows the detection of particular behaviors and amount of dietary simple carbohydrates to guide recommendations provided within clinical care of these patients.

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Jose León Mengíbar Endocrinology and Nutrition Department, Parc Taulí University Hospital, Sabadell, Barcelona, Spain

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Ismael Capel Endocrinology and Nutrition Department, Parc Taulí University Hospital, Sabadell, Barcelona, Spain

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Teresa Bonfill Medical Oncology Department, Parc Taulí University Hospital, Sabadell, Barcelona, Spain

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Isabel Mazarico Endocrinology and Nutrition Department, Parc Taulí University Hospital, Sabadell, Barcelona, Spain

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Laia Casamitjana Espuña Endocrinology and Nutrition Department, Parc Taulí University Hospital, Sabadell, Barcelona, Spain

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Assumpta Caixàs Endocrinology and Nutrition Department, Parc Taulí University Hospital, Sabadell, Barcelona, Spain

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Mercedes Rigla Endocrinology and Nutrition Department, Parc Taulí University Hospital, Sabadell, Barcelona, Spain

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Summary

Durvalumab, a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) with the PD-1 and CD80 (B7.1) molecules, is increasingly used in advanced neoplasias. Durvalumab use is associated with increased immune-related adverse events. We report a case of a 55-year-old man who presented to our emergency room with hyperglycaemia after receiving durvalumab for urothelial high-grade non-muscle-invasive bladder cancer. On presentation, he had polyuria, polyphagia, nausea and vomiting, and laboratory test revealed diabetic ketoacidosis (DKA). Other than durvalumab, no precipitating factors were identified. Pre-durvalumab blood glucose was normal. The patient responded to treatment with intravenous fluids, insulin and electrolyte replacement. Simultaneously, he presented a thyroid hormone pattern that evolved in 10 weeks from subclinical hyperthyroidism (initially attributed to iodinated contrast used in a previous computerised tomography) to overt hyperthyroidism and then to severe primary hypothyroidism (TSH: 34.40 µU/mL, free thyroxine (FT4): <0.23 ng/dL and free tri-iodothyronine (FT3): 0.57 pg/mL). Replacement therapy with levothyroxine was initiated. Finally, he was tested positive for anti-glutamic acid decarboxylase (GAD65), anti-thyroglobulin (Tg) and antithyroid peroxidase (TPO) antibodies (Abs) and diagnosed with type 1 diabetes mellitus (DM) and silent thyroiditis caused by durvalumab. When durvalumab was stopped, he maintained the treatment of multiple daily insulin doses and levothyroxine. Clinicians need to be alerted about the development of endocrinopathies, such as DM, DKA and primary hypothyroidism in the patients receiving durvalumab.

Learning points:

  • Patients treated with anti-PD-L1 should be screened for the most common immune-related adverse events (irAEs).

  • Glucose levels and thyroid function should be monitored before and during the treatment.

  • Durvalumab is mainly associated with thyroid and endocrine pancreas dysfunction.

  • In the patients with significant autoimmune background, risk–benefit balance of antineoplastic immunotherapy should be accurately assessed.

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Catherine D Zhang Departments of Internal Medicine, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA

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Pavel N Pichurin Departments of Clinical Genomics, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA

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Aleh Bobr Departments of Laboratory Medicine and Pathology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA

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Melanie L Lyden Departments of Surgery, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA

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William F Young Jr Departments of Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA

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Irina Bancos Departments of Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA

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Summary

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.

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Lima Lawrence Departments of Endocrinology, Diabetes & Metabolism, Cleveland Clinic, Cleveland, Ohio, USA

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Peng Zhang Departments of Pulmonary Medicine & Critical Care, Cleveland Clinic, Cleveland, Ohio, USA

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Humberto Choi Departments of Pulmonary Medicine & Critical Care, Cleveland Clinic, Cleveland, Ohio, USA

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Usman Ahmad Departments of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, Ohio, USA

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Valeria Arrossi Departments of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio, USA

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Andrei Purysko Departments of Diagnostic Radiology, Cleveland Clinic, Cleveland, Ohio, USA

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Vinni Makin Departments of Endocrinology, Diabetes & Metabolism, Cleveland Clinic, Cleveland, Ohio, USA

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Summary

Ectopic adrenocorticotropic hormone (ACTH) production leading to ectopic ACTH syndrome accounts for a small proportion of all Cushing’s syndrome (CS) cases. Thymic neuroendocrine tumors are rare neoplasms that may secrete ACTH leading to rapid development of hypercortisolism causing electrolyte and metabolic abnormalities, uncontrolled hypertension and an increased risk for opportunistic infections. We present a unique case of a patient who presented with a mediastinal mass, revealed to be an ACTH-secreting thymic neuroendocrine tumor (NET) causing ectopic CS. As the diagnosis of CS from ectopic ACTH syndrome (EAS) remains challenging, we emphasize the necessity for high clinical suspicion in the appropriate setting, concordance between biochemical, imaging and pathology findings, along with continued vigilant monitoring for recurrence after definitive treatment.

Learning points:

  • Functional thymic neuroendocrine tumors are exceedingly rare.

  • Ectopic Cushing’s syndrome secondary to thymic neuroendocrine tumors secreting ACTH present with features of hypercortisolism including electrolyte and metabolic abnormalities, uncontrolled hypertension and hyperglycemia, and opportunistic infections.

  • The ability to undergo surgery and completeness of resection are the strongest prognostic factors for improved overall survival; however, the recurrence rate remains high.

  • A high degree of initial clinical suspicion followed by vigilant monitoring is required for patients with this challenging disease.

Open access