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Background Several human monoclonal antibodies directed against immune checkpoints, including T lymphocyte antigen 4 and programmed cell death protein 1, have been implemented for cancer treatment in order to promote effector T cell response to tumors. Despite the antitumor activity of these agents, a significant number of patients demonstrated immune-related adverse events that affected the functions of multiple organs, including the endocrine system. We report the first case of immune checkpoint inhibitor–induced simultaneous diabetic ketoacidosis and isolated adrenocorticotropic hormone deficiency following combination treatment with immune checkpoint inhibitors. Case presentation A 70-year-old Thai man with no previous history of diabetes mellitus was diagnosed with stage IVB non–small cell lung with pleural and liver metastases. After 14 weeks of combination treatment with pembrolizumab and ipilimumab, he presented with fatigue, nausea, and vomiting. Laboratory investigation revealed random plasma glucose 794 mg/dl, serum ketone 6.3 mmol/L, bicarbonate 13 mmol/L, and high anion gap 24 mmol/L. New-onset diabetes mellitus and diabetic ketoacidosis were diagnosed. Insulin therapy was initiated a favorable outcome within 10 hours. Despite improvement of hyperglycemia, the patient had persistent nausea and hyponatremia. Further investigation revealed cortisol 0.8 μg/dl and adrenocorticotropic hormone 21.7 pg/ml. His other pituitary hormone levels were normal, except for mild elevation of gonadotropin hormone. Magnetic resonance imaging of the pituitary showed a normal pituitary gland. Isolated adrenocorticotropic hormone deficiency was diagnosed, and corticosteroid replacement therapy was administered, resulting in an improvement of his symptoms. Conclusion Our patient developed new-onset diabetes mellitus, diabetic ketoacidosis, and isolated adrenocorticotropic hormone deficiency during cancer treatment with pembrolizumab and ipilimumab. The present case highlights the need for physicians to be aware that immune-related adverse events can occur in multiple organs at the same time.

Objective Mutations of the genes encoding transcription factors which play important roles in pituitary morphogenesis, differentiation and maturation may lead to combined pituitary hormone deficiency (CPHD). PROP1 gene mutations are reported as the most frequent genetic aetiology of CHPD. The aim of this study was to describe the phenotypes of Turkish CPHD patients and define the frequency of PROP1 mutations. Methods Fifty-seven CPHD patients from 50 families were screened for PROP1 mutations. The patients were affected by growth hormone (GH) and additional anterior pituitary hormone deficiencies. Results All patients had GH deficiency. In addition, 98.2% had central hypothyroidism, 45.6% had hypogonadotropic hypogonadism, 43.8% had adrenocorticotropic hormone deficiency and 7.1% had prolactin deficiency. Parental consanguinity rate was 50.9% and 14 cases were familial. Mean height standard deviation score (SDS) and weight SDS were -3.8±1.4 and -3.1±2.0, respectively. Of 53 patients with available pituitary imaging, 32 (60.4%) showed abnormalities. None had extra-pituitary abnormalities. Eight index patients had PROP1 gene mutations. Five sporadic patients were homozygous for c.301_302delAG (p.Leu102CysfsTer8) mutation, two siblings had exon 2 deletion, two siblings had complete gene deletion and two siblings were homozygous for the novel c.353A>G (p.Q118R) mutation. The frequency of the PROP1 mutations was 16% in our cohort. Mutation rate was significantly higher in familial cases compared to sporadic cases (42.8% vs 11.6%; p Conclusion Phenotype of patients regarding hormonal deficiencies, pituitary morphology, presence of extra-pituitary findings, family history of CPHD and parental consanguinity are important for deciding which pituitary transcription factor deficiency should be investigated. PROP1 mutation frequencies vary in different populations and its prevalence is high in Turkish CPHD patients.

Background The programmed cell death 1 (PD-1) inhibitor pembrolizumab is a promising agent for treatment of several different malignancies, but as with all immunotherapy there is a potential risk of immune-related adverse events. Adrenocorticotropic hormone (ACTH) deficiency and hypophysitis have been reported in patients treated with a different PD-1 inhibitor, nivolumab. However, clinical characteristics of these side effects associated with pembrolizumab have yet to be described in detail. Case presentation An 85-year-old Japanese woman was diagnosed with advanced squamous cell lung cancer. The patient was treated with 200 mg pembrolizumab every three weeks as first-line therapy. Routine examination including thyroid function, complete blood count, serum cortisol and sodium levels before each pembrolizumab infusion had shown no significant changes up to the eighth cycle. However, 8 days after the eighth cycle of single-agent pembrolizumab, she presented with rapidly worsening general fatigue and appetite loss over two days. Laboratory data revealed a low serum cortisol level (0.92 μg/dL) with inappropriately low ACTH (8.3 pg/mL), hyponatremia (122 mmol/L) and hypoglycemia (68 mg/dL). Standard-dose short ACTH testing showed an unsatisfactory cortisol response, indicating adrenal insufficiency. Pituitary magnetic resonance imaging showed diffuse substantial gadolinium enhancement, T2 hyperintensity, loss of pituitary bright spot, but no pituitary enlargement. Serum cortisol and ACTH levels were low throughout the day, and urinary free cortisol excretion fell below the lower normal limit. There was no ACTH and cortisol response in the corticotropin-releasing hormone test, despite significant responses of other anterior pituitary hormones to their corresponding challenge tests. Thus, isolated ACTH deficiency was diagnosed, and hypophysitis was suspected as the etiology. After administration of 15 mg/day hydrocortisone, the patient’s debilitation, hyponatremia, and hypoglycemia swiftly disappeared. Conclusion This is a case of isolated ACTH deficiency possibly due to hypophysitis in a patient with advanced lung cancer, in whom recent routine examinations had shown unremarkable results. We therefore conclude that isolated ACTH deficiency can suddenly arise during pembrolizumab monotherapy, albeit probably only rarely. Caution should be exercised to make sure that adrenal insufficiency is recognized immediately in order to achieve swift recovery by steroid replacement.

Background Immune checkpoint inhibitors significantly increase survival in some malignant tumors, but they also lead to a variety of immune-related adverse events that affect multiple organs, including the liver, lung and endocrine system. Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is a rare pituitary disorder characterized by secondary adrenal insufficiency with low or absent cortisol production but the normal secretion of pituitary hormones other than ACTH. IAD caused by atezolizumab, pembrolizumab and nivolumab therapy had been reported, but none is reported in camrelizumab, a new immune checkpoint inhibitor (ICI). Clinicians may not be aware of this unusual side effect. Case presentation: Here, we describe a 70-year-old male patient who had lung sarcoma and was treated with camrelizumab. After nine months of treatment, he developed immune-related pneumonia and hepatitis associated with camrelizumab. The patient discontinued the drug and recovered soon after administration of glucocorticoids. But he subsequently appeared severe hyponatremia, and was diagnosed with late-onset IAD induced by camrelizumab. His symptoms alleviated after glucocorticoid replacement therapy. Conclusion Regular monitoring serum sodium levels and testing endocrine function should be beneficial for cancer patients not only during the treatment of camrelizumab but also after discontinuation of the ICI. Clinicians should consider IAD induced by ICIs when hyponatremia occurs in the patients.

Pembrolizumab, an anti-programmed death-1 specific monoclonal antibody is a second-line treatment for metastatic urothelial carcinoma. Physicians should be aware of adverse immune-related events associated with the use of immune checkpoint inhibitors, particularly adrenocortical insufficiency, which poses a risk of death. We report a case of secondary adrenocortical insufficiency due to isolated adrenocorticotropic hormone deficiency with empty sella syndrome after pembrolizumab treatment in a patient with metastatic renal pelvic cancer. Fortunately, a therapeutic effect was observed 4 months after discontinuation of pembrolizumab, and a durable antitumor response has persisted for 5 months.

Anti-programmed death-1 (anti-PD-1) monoclonal antibodies, such as nivolumab, have been used for the treatment of various types of cancers, and excellent efficacy has been shown in some patients. The adverse effects of anti-PD-1 antibodies relating to autoimmunity are different from traditional chemotherapeutic drugs and may involve many organs including the endocrine system. We herein describe a case of adrenocorticotropic hormone deficiency during the treatment of advanced small-cell lung cancer, probably caused by nivolumab-induced hypophysitis. The case showed nonspecific, insidious, as well as potentially life-threatening characters of immune-related adverse effects. It is important for physicians to acknowledge clinical features of the rare side effect and take appropriate and prompt treatment.

Background: Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is an adrenal insufficiency caused by a decrease in ACTH alone among the anterior pituitary hormones. IAD is often overlooked because it causes nonspecific symptoms. We report a case of IAD diagnosed after the appearance of mild cognitive impairment (MCI).Case presentation: Our department was consulted on a case of a 46-year-old man for whom dementia was suspected because he was speaking incoherently, wiped his nose with his hands and showed mild brain atrophy on MRI. He was previously diagnosed with some psychiatric diseases, such as narcolepsy and adjustment disorder. He could not continue working due to somnolence, general fatigue and appetite loss. At the examination, he had difficulty concentrating and sustaining attention, exhibited restlessness, and scored 25 points on the Mini Mental State Examination-Japanese (MMSE-J); MCI was observed. Blood tests showed decreased ACTH, cortisol and free thyroxine and increased thyroid-stimulating hormone levels. He received further evaluation, and he was diagnosed with IAD and primary hypothyroidism. Hydrocortisone (15 mg) was started, after which his physical problems and his difficulty concentrating disappeared. His MMSE-J score also increased to 30. His cognitive functions completely recovered. He returned to work and continued to work stably.Conclusion: This patient was diagnosed with IAD and treated with adrenocortical hormone replacement therapy. His cognitive functions recovered, his physical and mental disorders were alleviated, and he returned to society. It is important not to miss neurological and psychiatric symptoms that can be cured by physical treatment.

Patient: Female, 78-year-old Final Diagnosis: Isolated adrenocorticotropic hormone deficiency Symptoms: Anorexia • general weakness • muscle pain Medication: Hydrocortisone Clinical Procedure: Endocrine test Specialty: Endocrinology and Metabolic Objective: Unusual clinical course Background: Immune checkpoint inhibitors (ICIs) are anticancer medications that enhance the antitumor immune response. The clinical benefit afforded by ICIs, however, can be accompanied by immune-related adverse events (IRAEs). One of the common endocrine IRAEs is hypophysitis, which often causes hypopituitarism with secondary adrenal insufficiency (AI). Secondary AI, including isolated adrenocorticotropic hormone (ACTH) deficiency (IAD), is often associated with hyponatremia. Here, we report an unusual case of ICI-related IAD associated with severe hyperkalemia. Case Report: A 78-year-old woman who had an ileal conduit, chronic kidney disease, type 2 diabetes mellitus, and hyper-tension and was taking an angiotensin II receptor blocker began treatment for advanced ureteral cancer with the anti-programmed cell death protein 1 inhibitor pembrolizumab. The therapy effectively controlled the cancer, but 4 1/2 months after starting it, the patient developed anorexia, general weakness, and muscle pain and was diagnosed with IAD associated with severe hyperkalemia and hyperchloremic metabolic acidosis. She recovered after prompt administration of corticosteroids and treatment with sodium bicarbonate, glucose/insulin, and cation exchange resins. Conclusions: Hyperkalemia is a common symptom of primary AI but is less common in patients with central AI because a lack of ACTH does not cause aldosterone deficiency and mineralocorticoid action is preserved. The present case demonstrates the need for physicians to be aware of severe hyperkalemia as a life-threatening complication of secondary AI induced by ICIs, particularly in patients with predisposing factors, such as kidney dysfunction, diabetes mellitus, an ileal conduit, and renin-angiotensin-aldosterone system inhibitor use.

Pembrolizumab is an immune checkpoint inhibitor that targets the programmed cell death protein 1 antigen to stimulate an immune response against tumor cells. It has successfully induced remission in patients with severe metastatic disease, including those refractory to other chemotherapeutic regimens. Immune checkpoint inhibitors may result in immune-related adverse events affecting multiple organs, including endocrine organs, leading to thyroiditis and hypophysitis, among others. Isolated adrenocorticotropic hormone deficiency and hypophysitis have been reported in patients treated with nivolumab, another programmed cell death protein 1 inhibitor. However, clinical characteristics of these side effects associated with pembrolizumab have yet to be described in detail. We describe a case of an 85-year-old Caucasian male undergoing treatment of metastatic urothelial carcinoma with pembrolizumab, who abruptly developed hypophysitis requiring emergent intervention.

BackgroundPituitary dysfunction is a life-threatening immune-related adverse event (irAE) induced by immune checkpoint inhibitors (ICIs). To date, it is not possible to identify patients who may develop pituitary irAEs prior to ICI treatment. The aim of this study was to characterize the predisposition for ICI-induced pituitary irAEs by analyzing anti-pituitary antibodies (APAs) and human leukocyte antigens (HLAs).MethodsIn this case–control study, APAs and HLA alleles were analyzed in 62 patients (17 who developed ICI-induced isolated adrenocorticotropic hormone deficiency (ICI-IAD), 5 who developed ICI-induced hypophysitis (ICI-H) and 40 who did not develop pituitary irAEs) treated with ICIs between November 2, 2015, and March 31, 2020, at Nagoya University Hospital. The main outcome measures in this study were the association between the development of pituitary irAEs with APAs at baseline and after treatment and HLA alleles.ResultsEleven of 17 (64.7%) patients who developed ICI-IAD had APAs at baseline, whereas APAs were positive only in 1 of 40 (2.5%) control patients. Although APAs were negative at baseline in all patients who developed ICI-H, they had become positive before the onset of ICI-H in 3 of 4 patients several weeks after ipilimumab administration. At the onset of ICI-IAD and ICI-H, APAs were positive in 15 of 17 (88.2%) and 4 of 5 (80%) patients, respectively. The prevalence of HLA-Cw12, HLA-DR15, HLA-DQ7, and HLA-DPw9 was significantly higher in patients with ICI-IAD, whereas that of HLA-Cw12 and HLA-DR15 was significantly higher in patients with ICI-H than in controls.ConclusionsThis study showed distinct and overlapped patterns of APAs and HLA alleles between ICI-IAD and ICI-H. Our findings also showed that positive APAs at baseline and after treatment, together with susceptible HLA alleles, could become predictive biomarkers for ICI-IAD and ICI-H, respectively.Trial registration numberUMIN000019024.

Background Nivolumab is an anti-programmed cell death protein 1 antibody, typically used as cancer immunotherapy agent. Despite multiple clinical benefits it might cause autoimmune-related side-effects, often involving the endocrine system. To our knowledge, this is the first case of nivolumab-induced hypophysitis manifesting several months after treatment discontinuation. Case presentation We, herein, report a 53-year-old patient with hypophysitis and isolated adrenocorticotropic hormone deficiency, who presented with recurring syncopal episodes and persistent mild hyponatremia. The performed challenged tests were consistent with secondary adrenal insufficiency, while responses of other anterior pituitary hormones were preserved. Magnetic resonance imaging revealed thickened pituitary stalk, consistent with hypophysitis. The patient’s condition gradually improved after administration of hydrocortisone, with normalization of sodium and glucose-levels. The related literature is discussed. Conclusions We conclude that even after discontinuation of nivolumab, isolated adrenal insufficiency can occur. Therefore, in case of administration of such agents, clinical assessment, and routine monitoring of blood pressure, sodium-, glucose-levels, pituitary hormones as well as magnetic resonance imaging are needed to identify such conditions and prevent an adrenal crisis.

Isolated adrenocorticotropic hormone (ACTH) deficiency is a rare immune-related adverse event associated with immunotherapy using immune checkpoint inhibitors for malignant tumors. A 68-year-old man had previously undergone a complete gastrectomy with regional lymph-node dissection for remnant gastric cancer, with a final diagnosis of T4aN2M1, Stage IV. Because he developed lymph-node metastases during postoperative chemotherapy using S-1 plus oxaliplatin, he was treated with ramucirumab plus nab-paclitaxel. Eight months after the operation, the patient developed multiple liver metastases and was treated with nivolumab (3 mg/kg, every 2 weeks). After four cycles of nivolumab treatment, the cortisol level decreased, and the patient reported general fatigue and appetite loss. Pituitary stimulation testing using a combination of corticotropin-releasing hormone, luteinizing hormone-releasing hormone, and thyrotropin-releasing hormone revealed markedly low ACTH and cortisol responses. Magnetic resonance imaging revealed no enlargement of the pituitary gland or thickening of the stalk. After steroid replacement therapy using hydrocortisone, the patient's symptoms of general fatigue improved. After discharge, nivolumab and steroid replacement were continued. During the subsequent 6 months, the clinical course of the patient was mostly uneventful. Abdominal computed tomography revealed a marked shrinkage of liver and lymph-node metastases, which indicated a partial response with a 95.0% decrease in target lesions compared with baseline. To the best of our knowledge, this is the first case reported in the English literature of a patient who developed isolated ACTH deficiency during nivolumab treatment for a metastatic advanced gastric cancer.

Background Severe pulmonary arterial hypertension (PAH) is generally treated with multiple PAH-specific vasodilators. If these agents are unsuccessful, additional treatment options are scarce, and the prognosis is poor due to right-sided heart failure. Some of these severe cases are also accompanied by endocrinological side effects. The most common side effect of prostacyclin is thyroid dysfunction, but in very few cases, adrenocorticotropic hormone (ACTH) deficiency may occur. Case summary A 35-year-old woman was diagnosed with hereditary PAH 2 years ago. Since her mean pulmonary arterial pressure was high, combination therapy of vasodilators, including prostacyclin, was introduced. Several months later, she was hospitalized with a persistent fever. Laboratory tests showed no findings suggestive of infection. However, hypereosinophilia and decreased secretion of ACTH and cortisol were noted, which led to the diagnosis of ACTH deficiency. A multimodal diagnostic approach, including pituitary magnetic resonance imaging and axillary lymph node biopsy, indicated that the aetiology of the ACTH deficiency was likely autoimmune hypophysitis. She was treated with hydrocortisone supplementation, which significantly relieved her condition. Discussion Endocrinological side effects in PAH patients using prostacyclin should be carefully addressed. If right-sided heart failure worsens during the administration of prostacyclin, it is essential to determine whether it is due to progression of pulmonary hypertension or endocrinological side effects. Careful diagnosis and treatment are important for managing the haemodynamics and symptoms of PAH patients given prostacyclin.

Pituitary tumors are discovered either incidentally by imaging studies (incidentalomas) or via evaluation of certain clinical symptoms (symptomatic tumors). In this study, we first surveyed patients with incidentalomas who underwent surgery. Cases included 62.3% non-functioning adenomas (NFPAs), 14.5% functioning adenomas, and 13.8% Rathke's cleft cysts. Next, we compared the clinical features and surgical outcomes of 145 patients whose preoperative diagnosis was NFPA (incidentalomas [n = 79] vs. symptomatic tumors [n = 66]). The patients with incidentalomas were older (59.9 vs. 55.3 years, p < 0.05) and had smaller tumors compared with the patients with symptomatic tumors (mean maximum diameter: 23.1 vs. 27.5 mm, p < 0.01). The main reason for undergoing imaging studies was headache (n = 25) in the incidentaloma group and visual disturbance (n = 46) in the symptomatic tumor group. The incidence of preoperative pituitary hormone deficiencies was lower in the incidentaloma than symptomatic tumor group (growth hormone deficiency: 37.7% vs. 66.7%, p < 0.01; gonadotropin deficiency: 19.0% vs. 39.4%, p < 0.01; adrenocorticotropic hormone deficiency: 3.8% vs. 18.2%, p < 0.01; thyroid stimulating hormone deficiency: 6.3% vs. 12.1%, p = 0.25). Postoperative pituitary function was better preserved in the incidentaloma than symptomatic tumor group (no deficiency: 58.2% vs. 28.8%, p < 0.01). The difference in postoperative complications between groups was not statistically significant (incidentalomas vs. symptomatic tumors: 21.5% vs. 19.7%, p = 0.84). In conclusion, incidentalomas were detected while smaller size and lower incidence of hormone deficiency than symptomatic tumors, and the pituitary hormones were also preserved after surgery. It is important to observe incidentalomas carefully and to judge whether to operate appropriately before they become symptomatic tumors.

Hypothalamic-pituitary (HP) dysfunctions are commonly reported complications in survivors of childhood cancer. These include growth hormone deficiency, luteinizing hormone/follicle-stimulating hormone deficiency, thyroid-stimulating hormone deficiency, adrenocorticotropic hormone deficiency, central precocious puberty, hyperprolactinemia, and central diabetes insipidus. Local tumor invasion and surgical or radiation-induced injury represent the highest risk factors. New treatment modalities, such as immunotherapy and molecular targeted therapy have the potential to cause autoimmune hypophysitis. Untreated HP dysfunctions are associated with adverse physical and psychosocial consequences and reduced quality of life. Systematic and periodic endocrine assessments optimize early diagnosis and timely treatment and may improve long-term health outcomes.

Rationale: Pituitary stalk interruption syndrome (PSIS) is a congenital pituitary anatomical defect. It is characterized by the triad of thin or interrupted pituitary stalk, absent or ectopic posterior lobe, and hypoplastic or aplastic anterior lobe. Moreover, this condition is considered rare. Patient concerns: A 23-year-old male patient presented with a history of short stature and hypogonadism. Laboratory assessment revealed low thyroxine, cortisol, and adrenocorticotropic hormone levels, which are consistent with adrenal insufficiency without hypoglycemia. The insulin-induced hypoglycemia tolerance test finding indicated growth hormone (GH) deficiency. Moreover, magnetic resonance imaging revealed an interrupted pituitary stalk, ectopic posterior pituitary, and hypoplastic anterior pituitary. This triad of symptoms was indicative of PSIS. Diagnosis: 1. PSIS; 2. hypopituitarism: secondary hypothyroidism, secondary adrenocortical dysfunction, hypogonadotropic hypogonadism, and GH deficiency; 3. sphenoid sinus cyst; 4. osteoporosis; 5. hyperinsulinism; and 6. dyslipidemia. Interventions: The patient was deficient in adrenaline, thyroxine, gonadal steroid, and GH. Thus, glucocorticoid replacement therapy was initiated, followed by euthyrox, androgen, and human chorionic gonadotropin treatment. Calcium tablets, calcitriol, and alendronate sodium were used for the management of osteoporosis. The patient was 164 cm tall, and his bone age was approximately 15 years old. However, owing to a poor economic condition, the family did not proceed with GH therapy. Outcomes: The patient did not present with adrenal or hypothyroidism crisis after receiving poly-hormonal replacement therapy. His secondary sexual characteristics began to develop. However, owing to a short treatment window period, the patient could not receive the required treatment. Hence, whether the patient would have a normal fertility function needs to be confirmed. Lessons: PSIS is a rare disease with various clinical characteristics. During the neonatal period and infancy, the signs and symptoms of PSIS are often not evident. Therefore, diagnosis is delayed. The early detection of hormone deficiency and treatment initiation can affect both the quality of life and the prognosis of patients with PSIS. Thus, the diagnosis and treatment of this disease must be improved to help patients achieve a better quality of life and to prevent reproductive health problems.

Although opiate use can result in various endocrine disorders, isolated adrenocorticotropic hormone (ACTH) deficiency resulting in secondary adrenal insufficiency remains uncommon. We present a case of a 54-year-old woman with a history of chronic opiate use who presented with a four-month history of worsening fatigue and syncopal episodes. Laboratory workup revealed a low ACTH with low baseline cortisol and normal levels of rest of the anterior pituitary hormones. The imaging study did not reveal any pituitary abnormality. The patient was diagnosed with opiate-induced isolated ACTH deficiency. Her symptoms improved after treatment with hydrocortisone. This case would further improve clinician's awareness towards opiate-induced endocrinopathies, including isolated ACTH deficiency, which can present with nonspecific signs and symptoms, creating a diagnostic challenge.

Background/aim Hypothalamic-pituitary (HT-P) dysfunction is one of the most common endocrine late effects following cranial radiotherapy. However, there are currently no specific data describing this complication in adult-onset cancer patients after whole brain radiotherapy (WBRT). The present cohort study aims to establish the prevalence of HT-P axis dysfunction in this group of patients. Patients and methods Twenty-six cancer patients previously treated with WBRT (median follow-up=20.5 months) received standardized endocrine check-up focusing on HT-P function. Results In 50% of the patients, impaired hypothalamic-pituitary function was detected during follow-up. While functional loss of a single hormonal axis was evident in 34.6% of patients, 7.7% showed an impairment of multiple endocrine axes, and one patient developed adrenocorticotropic hormone deficiency. Hypothalamic-pituitary dysfunction did not directly correlate with the applied WBRT total doses. Conclusion In our cohort, hypothalamic-pituitary dysfunction appeared to be common after WBRT and was diagnosed as early as 6 months following radiation. This finding highlights the need for routine endocrine follow-up even in patients with limited life expectancy.

Context The international GENHYPOPIT network collects phenotypical data and screens genetic causes of non‐acquired hypopituitarism. Aims To describe main phenotype patterns and their evolution through life. Design Patients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2. Results Among 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations. Conclusion This large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long‐term follow‐up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes.

Background: Immune checkpoint inhibitors (ICI’s) are now indicated in the treatment of several solid tumors and have improved the prognosis of patients with advanced malignancy. The expanded use of ICI’s has led to the rise of otherwise rare autoimmune sequelae. The overall incidence of ICI-induced autoimmune hypophysitis has increased to approximately 10%, but is only estimated to be 0.4% with PD-1 inhibitors specifically (1). Isolated ACTH deficiency from immune checkpoint inhibitors is rare, and very few cases secondary to the PD-1 inhibitor pembrolizumab have thus far been reported. Clinical Case: A 75-year old woman with history of Stage IV lung adenocarcinoma presented to oncology clinic in July 2019 with progressive weakness, weight loss, and confusion for several weeks. She was found to be hypotensive and dehydrated in the clinic and subsequently was admitted to the hospital. A comprehensive infectious work-up was non-contributory. History revealed that after treatment failure with carboplatin, she was treated with pembrolizumab from January 2017 to June 2019 with excellent response. Laboratory evaluation on admission demonstrated an undetectable AM cortisol level of < 1 ug/dL (n 5-25 ug/dL) with concomitant ACTH < 5pg/mL (Roche cobas, n 7.2-63 pg/mL), consistent with central adrenal insufficiency. Testing of the remainder of the pituitary axis, including TSH (0.83uU/mL, n 0.4-4.6 uU/mL), FSH (34.7 mIU/mL, n Conclusions: Isolated ACTH deficiency is a very rare but potential consequence of pembrolizumab use. It can be especially difficult to diagnose in patients on chemotherapy who are at higher risk for dehydration and failure to thrive. Duration of pembrolizumab therapy should not preclude the diagnosis of isolated ACTH deficiency, as it can occur even as late as 2.5 years into therapy. Reference: (1) Chang, L., Barroso-Sousa, R., Tolaney S., Hodi F.S., Kaiser, U.B., Min, L. Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints, Endocr Rev. 2019;40;17–65.

Patient: Male, 84-year-old Final Diagnosis: Isolated adrenocorticotropic hormone deficiency Symptoms: Anorexia • fatigue • lethargy Medication: — Clinical Procedure: Dynamic endocrine testing • magnetic resonance imaging Specialty: Endocrinology and metabolic Objective: Rare co-existance of disease or pathology Background: Patients with end-stage renal disease undergoing long-term maintenance hemodialysis are more likely than the general population to exhibit primary hypothyroidism. Only a few cases of isolated adrenocorticotropic hormone deficiency (IAD) among hemodialysis patients have been reported. We herein report an unusual case of a patient undergoing long-term hemodialysis who exhibited both IAD and primary hypothyroidism. Case Report: A 82-year-old male with end-stage renal disease secondary to immunoglobulin A nephropathy, undergoing hemodialysis for 20 years, was found to have primary hypothyroidism without obvious symptoms and consequently began thyroid hormone replacement therapy with oral levothyroxine. At 84 years of age, he developed anorexia, fatigue, and lethargy. A systemic workup using computed tomography and gastrointestinal endos-copy detected no abnormalities. He did not exhibit electrolyte imbalances, such as hyponatremia or hyperkalemia, and had normal morning blood levels of cortisol and adrenocorticotropic hormone. However, he exhibited hypoglycemic coma 4 months later. Detailed endocrinological examinations using dynamic function tests indicated IAD. After commencement of corticosteroid replacement therapy, his symptoms resolved without complications. Conclusions: To our knowledge, this is the first report of a hemodialysis patient with both IAD and primary hypothyroidism. This case highlights the importance of regular assessments of thyroid function for primary hypothyroidism in hemodialysis patients, even when they are asymptomatic. Furthermore, timely dynamic endocrine testing of hypothalamic-pituitary-adrenal function is needed to diagnose possible IAD in hemodialysis patients with symptoms suggestive of adrenal insufficiency, even in the absence of abnormal laboratory findings such as electrolyte imbalances or low morning blood levels of cortisol or adrenocorticotropic hormone.

Introduction: Isolated adrenocorticotropic hormone (ACTH) deficiency is a rare pituitary hormone deficiency defined by secondary adrenal insufficiency and normal secretion of all other pituitary hormones. Patients present with fatigue, weakness, weight loss, anorexia, nausea, low cortisol levels and low ACTH levels. Isolated ACTH deficiency is more common in males and usually presents in the fifth decade of life. Main mechanisms involved in the pathogenesis are genetics and autoimmune causes, traumatic brain injury and infarction of the pituitary postpartum, known as Sheehan’s syndrome. Sheehan’s syndrome is characterized by postpartum hemorrhage, failure to lactate and menstrual irregularities and it can occur from immediate postpartum period to years after delivery. The most common hormone deficiencies are prolactin and growth hormone. Empty sella is the most common finding on brain MRI. We are reporting a case of a woman in her third decade with isolated ACTH deficiency due to Sheehan’s syndrome two years postpartum, able to lactate, with normal menses and normal brain MRI. Clinical Case: A 33-year-old woman G3P3A0 with hypothyroidism who was referred to Endocrinology clinics due to tiredness, fatigue and weakness. She reported postpartum hemorrhage requiring 4 PRBC transfusions and IV steroids after last pregnancy 5 years ago. Patient was able to lactate after pregnancy and continued in her usual state of health until 3 years ago when she referred loss of consciousness with traumatic head injury due to hypoglycemia. At Endocrinology office physical examination and vital signs were unremarkable, including no blood pressure or heart rate variations with positional changes. Despite hypothyroidism being adequately controlled, she continued with extreme fatigue and weakness affecting her quality of life, for which cortisol and ACTH levels were ordered. Laboratories showed normal electrolytes, negative autoantibodies, cortisol 0.20 μg/dL (5-25 μg/dL) and ACTH 22 pg/mL (10-60 pg/mL) suggesting partial isolated ACTH deficiency. ACTH stimulation test was done and noted with suboptimal response. Evaluation of other anterior pituitary hormones was normal. Brain MRI showed normal pituitary gland. She was started on hydrocortisone in AM and PM and symptoms resolved. Conclusion: Immediate recognition of isolated ACTH deficiency due to Sheehan’s syndrome is necessary due to the availability of effective treatment and morbidity and mortality associated with this serious condition. To our knowledge isolated ACTH deficiency due to Sheehan’s syndrome in which the patient was able to lactate and normal findings on brain MRI has not previously been reported.References: Shivaprasad C. Sheehan’s Syndrome: Newer advances. Indian J Endocrinol Metab. 2011 Sep; 15(3): S203-207. DOI:10.4103/2230-8210.84869.

Syndromic congenital ichthyoses (CI) are genetically determined disorders of cornification that are characterized by generalized scaling along with systemic symptoms. Data on congenital syndromic ichthyosis from developing countries are scarce. We aimed to assess the prevalence, phenotype-genotype correlation, and management of syndromic CI patients presenting to our outpatient during the specified period this was a retrospective study of congenital syndromic ichthyosis patients attending a dermatology clinic in a tertiary care center from 2105-2018. We reviewed epidemiological and comorbidities data, phenotype-genotype correlations, and treatments of syndromic congenital ichthyosis patients. Six patients of Syndromic CI were diagnosedamongst 86 patients of CI (8.1%). Amongst these, three patients of Sjogren-Larrson syndrome (SLS), two patients of Netherton syndrome (NS), and one of Chanarin-Dorfman disease (CDD) were reported. Next-generation sequencing (NGS) was performed with novel variants reported in one patient each of SLS, NS, and CDD. An atypical phenotype was observed in a patient with NS with associated growth hormone and adrenocorticotropic hormone deficiency but with favorable clinical response to intravenous immunoglobulin. Our reports point towards the unreported pool of genetic mutations in CI from India. Novel mutations were associated with variable cutaneous and systemic involvement.

Congenital isolated adrenocorticotropic hormone deficiency (CIAD) is a rare disorder that may be conducive to hypoglycemia, cholestasis, and seizures. We reported on two siblings with a homozygous mutation of the TBX19 gene, C.377 (exon2) C>T, p. P126L. Their parents had heterozygous mutations on the same locus. Glucocorticoid supplementary therapy was effective, but the treatment became delayed due to inaccessibility, which resulted in entirely different clinical outcomes for the siblings. The older brother developed subdural hematoma, intractable epilepsy, and developmental delays. In contrast, the younger sister received timely glucocorticoid replacement therapy and had no long-term complications while maintaining a good quality of life. In summary, when CIAD is confirmed, early intervention is essential to achieve the optimal outcome.

Introduction. Sheehan syndrome presents with features of multiple hormone deficiencies including lactation failure and amenorrhoea as well as with features of central hypothyroidism and adrenocorticotropic hormone deficiency. Psychiatric manifestations are mostly limited to cognitive impairment. Psychotic presentations are rare and limited to case reports. Case Presentation. A 32-year-old female was evaluated for fearfulness and delusions for one year. She had persecutory and bizarre delusions, delusion of thought possession, and elementary auditory hallucinations. These began four months after the birth of her third child. The delivery had been complicated with postpartum haemorrhage. Her symptoms caused the functional decline and progressively worsened, resulting in suicidal ideation. Cognitive assessment revealed mild impairment in attention. Further inquiry revealed lethargy, constipation, cold intolerance, and lactation failure. She was slow, having dry skin, puffy face, and bradycardia with a blood pressure of 80/60 mmHg (supine) and 70/50 mmHg (standing). She had hyponatraemia, elevated creatine phosphokinase, low thyroxine, prolactin, FSH, LH, and IGF-1. She had poor cortisol and growth hormone response to the insulin tolerance test. MRI-pituitary showed empty sella. A diagnosis of Sheehan syndrome was made. Her symptoms improved completely after the initiation of levothyroxine and hydrocortisone. Conclusions. Sheehan syndrome can present with psychotic symptoms mimicking schizophrenia with variable involvement of cognition. Detailed reporting of these patients would enhance better characterization of the clinical presentation and risk profile of these patients.

In isolated adrenocorticoropic hormone (ACTH) deficiency (IAD), autoimmunity against corticotrophs has been suggested; however, the pathogenesis remains largely unknown. Large cell neuroendocrine carcinoma (LCNEC) of the lung is a pulmonary tumor of high-grade malignant neuroendocrine tumor and it reportedly caused paraneoplastic syndrome by autoimmunity in several cases. A 42-year-old woman with isolated adrenocorticotropic (ACTH) hormone deficiency (IAD) was diagnosed with large cell neuroendocrine carcinoma (LCNEC) 3 years after being diagnosed with IAD. We hypothesized that the LCNEC played a causal role in the development of IAD as a paraneoplastic syndrome and analyzed the autoimmunity. We also analyzed another case of ectopic ACTH syndrome to prove this hypothesis. The LCNEC tissue revealed an ectopic ACTH expression and lymphocyte infiltration. Interestingly, autoantibody against the proopiomelanocortin (POMC) protein was detected in the peripheral blood. Although, patient’s serum did not show any effects on cell viability, proliferation, nor pomc expression in a corticotroph cell line, AtT20 cells, patient’s lymphocytes in the peripheral blood specifically reacted toward POMC protein, indicating a presence of cytotoxic T lymphocytes (CTLs). In addition, the analysis of another case of ectopic ACTH syndrome showed lymphocyte infiltration not only in the metastatic liver tumors but also in the pituitary. Moreover, most CD8-positive cells resided adjacent to corticotrophs. These data indicate that the ectopic ACTH expression in the tumor evoked the autoimmunity to corticotrophs and caused IAD as a form of paraneoplastic syndrome.

We describe a 58-year-old man with a malignant melanoma metastasis to the liver. After initiation of nivolumab therapy, he developed destructive thyroiditis and subsequently simultaneous isolated adrenocorticotropic hormone (ACTH) deficiency and severe hypercalcemia. Although isolated ACTH deficiency and hypercalcemia due to nivolumab therapy are both rare occurrences, these conditions can often cause a severe clinical course accompanied by a disturbance of consciousness. Therefore, clinicians should pay attention to these possible side effects of nivolumab if the patients have clinical symptoms, such as fatigue and a disturbance of consciousness.