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Evangelos Karvounis Department of Endocrine Surgery, ‘Euroclinic’ Hospital, Athens, Greece

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Ioannis Zoupas Department of Endocrine Surgery, ‘Euroclinic’ Hospital, Athens, Greece

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Dimitra Bantouna Private Practice, Patras, Greece

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Rodis D Paparodis Private Practice, Patras, Greece
Center for Diabetes and Endocrine Research, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA

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Roxani Efthymiadou PET-CT Department, Hygeia Hospital, Athens, Greece

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Christina Ioakimidou Department of Pathology

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Christos Panopoulos Department of Medical Oncology, ‘Euroclinic’ Hospital, Athens, Greece

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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.

Open access
Simone Antonini Endocrinology, Diabetology and andrology Unit, IRCCS Humanitas Research Hospital, Rozzano (MI), Italy

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Alessandro Brunetti Endocrinology, Diabetology and andrology Unit, IRCCS Humanitas Research Hospital, Rozzano (MI), Italy

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Benedetta Zampetti ASST Grande Ospedale Metropolitano Niguarda, Endocrinology Department, Milan (MI), Italy

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Davide Boeris ASST Grande Ospedale Metropolitano Niguarda, Neurosurgery Department, Milan (MI), Italy

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Andrea Saladino Fondazione IRCCS Istituto Neurologico Carlo Besta, Unit of Neurosurgery, Milan, (MI) Italy

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Renato Cesare Cozzi ASST Grande Ospedale Metropolitano Niguarda, Endocrinology Department, Milan (MI), Italy

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Summary

Osilodrostat is a novel, orally administered cortisol synthesis inhibitor, approved in 2020 by the European Medicines Agency (EMA) for the treatment of Cushing’s syndrome in adults. A significant amount of the studies currently available in the literature focus on treatment in patients with Cushing’s disease. However, data collected from patients treated with osilodrostat in real-life settings still represents a small entity. For this reason, in this article, we will discuss two real-life cases of patients with Cushing’s disease treated with this drug. The first report is about a 35-year-old woman with an adrenocorticotrophic hormone (ACTH)-secreting adenoma. After non-curative trans-nasal-sphenoidal (TNS) surgery, due to a small remnant of the adenoma, medical therapy with osilodrostat achieved fast and effective biochemical and clinical response. During treatment, progressive increase of ACTH levels and an enlargement of the pituitary remnant were documented, with planned radiosurgical treatment. The second case reports a 32-year-old man diagnosed with Cushing’s disease in 2020, who, after surgery refusal, started osilodrostat at progressively up-titrated doses, according to 24 h urinary free cortisol levels, up to 5 mg twice a day. With osilodrostat, the patient reached biochemical and clinical control of disease until TNS surgery in October 2021, with complete remission. The first post-surgical biochemical assessment was equivocal in spite of a transient clinical hypoadrenalism, reverted after 2 months with the restoration of physiological hypothalamic-pituitary-adrenal axis (HPA) function.

Learning points

  • Osilodrostat is a potent oral drug viable for Cushing’s disease as medical therapy when surgery is not feasible or remission cannot be reached.

  • Osilodrostat proves to be a safe drug and its main adverse effect is hypoadrenalism, due to the adrenolytic action of the compound.

  • Osilodrostat needs a very tailored approach in its clinical use because there is no correlation between the level of hypercortisolism pre-treatment and the dose required to reach disease control.

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S M Constantinescu Department of Endocrinology, Cliniques Universitaires Saint-Luc, Brussels, Belgium

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G Wilms Department of Radiology, Cliniques Universitaires Saint-Luc, Brussels, Belgium

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R M Furnica Department of Endocrinology, Cliniques Universitaires Saint-Luc, Brussels, Belgium

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T Duprez Department of Radiology, Cliniques Universitaires Saint-Luc, Brussels, Belgium

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D Maiter Department of Endocrinology, Cliniques Universitaires Saint-Luc, Brussels, Belgium

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Summary

Complicated Rathke’s cleft cyst (RCC) is a rare occurrence of symptomatic bleeding or growth of a previously asymptomatic (and often undiagnosed) intrasellar cyst derived from remnants of Rathke’s pouch, situated on the midline between the adeno- and neurohypophysis. Symptoms may be identical to those of pituitary apoplexy: acute onset of headache, hypopituitarism, and neurological disturbances. Both syndromes may also exhibit a similar appearance of a large haemorrhagic sellar mass at initial radiological evaluation. We report on two patients who presented with headache and complete hypopituitarism. Based on the initial MRI, they were first diagnosed with pituitary apoplexy but managed conservatively with hormone therapy alone because of the absence of severe visual or neurological threat. Upon follow-up at 4 months, clinical evolution was good in both patients but their pituitary mass had not reduced in size and, after careful radiologic reviewing, was more indicative of a large midline complicated RCC. In conclusion, the diagnosis of complicated RCC is challenging because it can mimic pituitary apoplexy clinically, biologically, and radiologically. Clinicians should distinguish between the two entities using specific radiological signs or evolution of the mass at MRI if the patient does not undergo surgery. To our knowledge, we report conservative management of this rare condition for the first time, though it seems appropriate in the absence of neurological compromise or visual compression. Long-term follow-up is however mandatory.

Learning points

  • Complicated Rathke’s cleft cyst can mimic pituitary apoplexy, presenting with sudden onset of headache, hypopituitarism, and visual and neurological compromise in the most severe cases.

  • At diagnosis, pituitary MRI may not be able to differentiate between the two entities, showing a large haemorrhagic mass inside the sella, with little or no normal pituitary tissue visible. Patients are often diagnosed with apoplexy at this stage and may undergo pituitary surgery.

  • When surgery has not been performed initially in these patients, repeat imaging at 3–6 months is unchanged and does not show the expected involution usually seen after adenoma apoplexy.

  • Conservative management with hormonal replacement seems a valid option in the absence of visual or neurological deficits that would require trans-sphenoidal surgery.

Open access
Carolina Chaves Department of Endocrinology and Nutrition, Hospital Divino Espírito Santo de Ponta Delgada, EPER, Azores Islands, Portugal

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Teresa Kay Department of Medical Genetics, Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, EPE, Lisbon, Portugal

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João Anselmo Department of Endocrinology and Nutrition, Hospital Divino Espírito Santo de Ponta Delgada, EPER, Azores Islands, Portugal

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Summary

Leptin is secreted by adipocytes in response to fat storage and binds to its receptor (LEPR), which is ubiquitously expressed throughout the body. Leptin regulates energy expenditure and is anorexigenic. In this study, we describe the clinical and hormonal findings of three siblings with a personal history of rapid weight gain during the first months of life. They had delayed puberty, high levels of FSH (15.6 ± 3.7 mUI/mL; reference: 1.5–12.4) and LH (12.3 ± 2.2 mUI/mL; reference: 1.7–8.6), normal oestradiol and total testosterone and successful fertility. None of the patients had dyslipidemia, diabetes or thyroid disease. Next-generation sequencing identified a pathogenic homozygous variant c.2357T>C, p.(Leu786Pro) in LEPR. Their parents and children were heterozygous for this mutation. We compared clinical and biochemical findings of homozygous carriers with first-degree heterozygous family members and ten randomly selected patients with adult-onset morbid obesity. Homozygous carriers of the mutation had significantly higher BMI (32.2 ± 1.7 kg/m2 vs 44.5 ± 7.1 kg/m2, P = 0.023) and increased serum levels of leptin (26.3 ± 9.3 ng/mL vs 80 ± 36.4 ng/mL, P = 0.028) than their heterozygous relatives. Compared with the ten patients with adult-onset morbid obesity, serum levels of leptin were not significantly higher in homozygous carriers (53.8 ± 24.1 ng/mL vs 80 ± 36.4 ng/mL, P = 0.149), and thus serum levels of leptin were not a useful discriminative marker of LEPR mutations. We described a rare three-generation family with monogenic obesity due to a mutation in LEPR. Patients with early onset obesity should be considered for genetic screening, as the identification of mutations may allow personalized treatment options (e.g. MC4R-agonists) and targeted successful weight loss.

Learning points

  • The early diagnosis of monogenic forms of obesity can be of great interest since new treatments for these conditions are becoming available.

  • Since BMI and leptin levels in patients with leptin receptor mutations are not significantly different from those found in randomly selected morbid obese patients, a careful medical history is mandatory to suspect this condition.

  • Loss of leptin receptor function has been associated with infertility. However, our patients were able to conceive, emphasizing the need for genetic counselling in affected patients with this condition.

Open access
George Brown Department of Hepatobiliary & Pancreatic Surgery, University Hospital Southampton, Southampton, UK

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Anthony Mark Monaghan Department of Hepatobiliary & Pancreatic Surgery, University Hospital Southampton, Southampton, UK

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Richard Fristedt Department of Hepatobiliary & Pancreatic Surgery, University Hospital Southampton, Southampton, UK

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Emma Ramsey Department of Hepatobiliary & Pancreatic Surgery, University Hospital Southampton, Southampton, UK

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Ma’en Al-Mrayat Department of Endocrinology, University Hospital Southampton, Southampton, UK

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Rushda Rajak Department of Cellular Pathology, University Hospital Southampton, Southampton, UK

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Thomas Armstrong Department of Hepatobiliary & Pancreatic Surgery, University Hospital Southampton, Southampton, UK

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Arjun Takhar Department of Hepatobiliary & Pancreatic Surgery, University Hospital Southampton, Southampton, UK

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