Symptoms Of Diabetes Insipidus Research Articles

GCT-24. ISOLATED PITUITARY STALK THICKENING

Abstract BACKGROUND Few studies have examined predictive factors and outcome of isolated pituitary stalk thickening (iPST) in children. We aim to describe our institutional cohort to determine predictors of future proliferative disease. METHODS A search of the radiology, endocrinology and neuro-oncology databases was performed to identify patients with iPST diagnosed between January 2000 and June 2019. Clinical data was collected along with detailed radiology review of MRIs in a blinded fashion. RESULTS Forty-seven patients were identified, with 40 meeting criteria for inclusion. Median age of baseline MRI was 9.6 years (range 0.9-17.5). Twenty-five (63%) were female. Median follow up time was 5.2 years (range 0.3-18.6). Indication for MRI was symptoms of diabetes insipidus (DI) in 29 patients followed by concerns for anterior endocrine disturbance (6), headache (1) or visual impairment (1). Thirty-four (85%) subjects had pituitary dysfunction, including 31 with DI however DI was not predictive of future development of proliferative disease (69% with presumed hypophysitis vs 93% with proliferative disease, p=0.12). Fourteen (35%) patients developed proliferative disease, with germinoma (8), Langerhans cell histiocytosis (5) and lymphoma (1) at median of 1.3 years (range 0.3-4.0), 2.2 years (range 0.3-9.4) and 1.1 years after initial MRI respectively. Lumbar puncture was performed in 24 patients with elevated white blood cell count (>5 x 106/L) found in 6 (75%) patients with germinoma, 1 (100%) patient with lymphoma, 0 patients with LCH and 3 of 11 (27%) patients with presumed hypophysitis (p=0.015). Thickening of the entire stalk at time of diagnosis and radiographic progression were more likely to be seen in those that developed proliferative disease. CONCLUSION In this cohort 35% of children with PST were eventually diagnosed with a proliferative disease. Importantly, central DI was not associated with risk of proliferative disease. Several radiographic features and elevated CSF WBC were predictive of this outcome.

Physiological Functions of Aquaporin-3 in Mediating Water and Solutes

Aquaporins (AQP), are a family of membrane channel proteins that facilitate the transmembrane diffusion of water and some small non-charged solutes such as glycerol and urea by osmosis or solute gradient. AQP3, an aquaglyceroporin, is expressed in the kidney, skin, and testes, etc. Mice lacking AQP3 have symptoms of diabetes insipidus. In addition, the absence of AQP3 leads to dry skin in mice. AQP4 is permeable to water only. To understand the specific function of the water permeability and small solute transport mediated by AQP3, we generated AQP3 knock-out (AQP3 KO) mice and AQP4 knock-in mice (AQP4 KI) with AQP4 replacing AQP3 in situ. In the basal condition, knock-out of AQP3 in mice led to increased urine volume, decreased urine osmolality and tubule dilation. Interestingly, in AQP4 KI mice, these phenomena were reversed, showing improved urine concentration and tubular morphology. However, there was no significant difference in non-urea solute concentrations between both genotypes. Subsequently, we conducted acute urea loading tests and high-protein diet experiments to further increase the production and excretion of urea in mice. The experimental results showed that both urea loading and high-protein diet had little impact on urine osmolality and urinary urea concentration in AQP3 KO mice. But the urine osmolality and urinary urea concentration in AQP4 KI mice were altered by exogenous administration of urea. Our data indicates that the absence of AQP3 prevents urea accumulation in the kidney, disrupting urine concentration mechanism. The knock-in of AQP4 can restore AQP3 mediated water channel function and help to regulate the urine concentration ability. The water permeability, other than solute transport, of AQP3 plays important role in urine concentrating mechanism. AQP3 KO mice exhibited significant epidermal thickening, excessive keratinization, decreased skin hydration and elasticity. The replacement of AQP4 in situ did not improve these phenomena, indicating that solute transport mediated by AQP3 may play a role in maintaining normal skin function. Therefore, we constructed a mouse model of psoriasis induced by imiquimod (IMQ). It was found that AQP3 expression was reduced in the lesional skin of wildtype (WT) mice, while AQP3 KO mice and AQP4 KI mice exhibited dry skin, excessive epidermal proliferation, and increased inflammatory response. Local treatment with urea (10%) could alleviate these symptoms. These experimental results confirmed the important role of AQP3 in the pathogenesis of psoriasis and the potential role of urea in the treatment of psoriasis. Our study suggests the diverse physiological functions of AQP3 in different tissues. This research was supported by Beijing Natural Science Foundation (7232249). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Diabetes Insipidus: Types, Diagnosis and Management

Diabetes insipidus (DI) is an acquired or hereditary water imbalance disorder characterized by polydipsia and polyuria. It is a condition that involves the excretion of dilute urine in large volumes. The illness can strike at any age, with males and females have identical rates of occurrence of the disease. The two main mechanisms responsible for diabetes insipidus are either insufficient release or production of ADH (antidiuretic hormone) from the hypothalamus (central diabetes insipidus) or ADH resistance in which the kidneys are unable to respond to ADH (nephrogenic diabetes insipidus). Another form of DI is transient diabetes insipidus commonly known as gestational diabetes insipidus that occurs in the second/third trimester of pregnancy due to increased levels of placental vasopressinase that occurs progressively during pregnancy and increases metabolic clearance of vasopressin. The fourth type of DI is primary polydipsia, characterized by elevated levels of water intake that physiologically lower vasopressin and may be psychogenic, iatrogenic or dipsogenic. Signs and symptoms of DI often include water electrolyte-imbalance, excessive or severe thirst, frequent and excessive urination, fatigue, dehydration, and weight loss. Diabetes insipidus (DI) should be distinguished from primary polydipsia, and whether it is caused by a central, nephrogenic, or gestational cause. This distinction is critical since incorrect treatment can result in serious repercussions. Diagnosis of DI includes measurement of plasma sodium and osmolality, baseline copeptin, hypertonic saline stimulation and arginine stimulation test. The treatment for DI includes the use of drugs such as desmopressin, thiazide diuretics, indomethacin and amiloride.

Abstract #1411935: A Radiographic Diagnosis: IgG4-Related Hypophysitis Presenting with Hypopituitarism and Central Diabetes Insipidus

Hypophysitis is defined as inflammation of the pituitary gland. IgG4-related hypophysitis is a rare form and isolated IgG4-related hypophysitis is even more rare. Here, we discuss an interesting patient who presented with symptoms of diabetes insipidus and was found to have panhypopituitarism with suspicious MRI findings of a suprasellar mass and a thickened pituitary stalk, suggestive of IgG4-related hypophysitis. A 69-year-old male with past medical history of lung adenocarcinoma status-post right pneumonectomy, chronic obstructive pulmonary disease, orthostatic hypotension, and poor oral intake due to esophageal compression presented with acute encephalopathy and sepsis secondary to pneumonia. CT head scan done for encephalopathy showed a 1.2 cm suprasellar mass. On consultation, the patient was found to be hypernatremic. Upon further questioning, the patient reported experiencing polydipsia, nocturia, chronic cold intolerance, fatigue, and impotence for several weeks to months. He denied any vision changes, breast tenderness, or galactorrhea. Laboratory testing revealed a sodium level of 157 mmol/L (n.135-145 mmol/L) with plasma osmolality elevated at 332 mOsm/kg (n.275-295 mosm/kg). Urine sodium was low at < 20 mmol/L. Desmopressin (DDAVP) 0.1mg nightly was started given concern for diabetes insipidus. Peak cortisol after performed Cosyntropin stimulation test resulted at 13.5mcg/dL with an ACTH 6 pg/mL (n.6-50 pg/mL). TSH was < 0.01 mU/L, free T4 1.79 ng/dL, and free T3 4.9 nmol/L. The elevated free T3 was felt to be from heparin displacement. Total testosterone was 84 ng/dL with suppressed FSH and LH. Elevated prolactin of 39 ng/mL was thought to be from stalk-effect. MRI of the pituitary gland revealed a 1.3cm enhancing suprasellar mass in the region of the optic chiasm and a smaller 9mm intra-sellar mass, with a thickened pituitary stalk. Given these radiologic findings and the patient's age and gender, the possibility of IgG4 hypophysitis was suspected. CT chest, abdomen, and pelvis were unremarkable. In addition to the DDAVP, he was started on high-dose hydrocortisone, thyroxine replacement, and testosterone replacement. Serum IgG4 level was 23.6 mg/dL (n. 4-86 mg/dL). A six week repeat pituitary MRI is pending; however, the patient is clinically improving and doing well. Specific radiologic findings, such as thickened pituitary stalk and pituitary enlargement with suprasellar mass, led us to strongly consider IgG4-related hypophysitis in our differential for this patient. Clinical presentation of panhypopituitarism, along with patient age and gender, also supported the diagnosis of IgG4-related hypophysitis. Although this patient does not meet all Leporati diagnostic criteria for IgG4-related hypophysitis, the high degree of suspicion led to prompt treatment with high dose steroids. High dose steroids have been shown to revert symptoms and prevent irreversible fibrosis. This case highlights the need for radiologists and endocrinologists to work together in the early recognition of the diagnosis and treatment of IgG4-related hypophysitis.

Mineralocorticoids induce polyuria by reducing apical aquaporin-2 expression of the kidney in partial vasopressin deficiency.

The symptoms of diabetes insipidus may be masked by the concurrence of adrenal insufficiency and emerge after the administration of hydrocortisone, occasionally at high doses. To elucidate the mechanism underlying polyuria induced by the administration of high-dose corticosteroids in the deficiency of arginine vasopressin (AVP), we first examined the secretion of AVP in three patients in whom polyuria was observed only after the administration of high-dose corticosteroids. Next, we examined the effects of dexamethasone or aldosterone on water balance in wild-type and familial neurohypophyseal diabetes insipidus (FNDI) model mice. A hypertonic saline test showed that AVP secretion was partially impaired in all patients. In one patient, there were no apparent changes in AVP secretion before and after the administration of high-dose corticosteroids. In FNDI mice, unlike dexamethasone, the administration of aldosterone increased urine volumes and decreased urine osmolality. Immunohistochemical analyses showed that, after the administration of aldosterone in FNDI mice, aquaporin-2 expression was decreased in the apical membrane and increased in the basolateral membrane in the collecting duct. These changes were not observed in wild-type mice. The present data suggest that treatment with mineralocorticoids induces polyuria by reducing aquaporin-2 expression in the apical membrane of the kidney in partial AVP deficiency.

LBMON135 Diffuse Large B-cell Lymphoma Affecting The Pituitary Gland: A Case Report

Abstract Introduction Diffuse large B-cell lymphoma is a common manifestation of non-Hodgkin lymphoma, representing approximately 25% of non-Hodgkin lymphoma cases. Patients typically present with an enlarging lymph node that is painless and associated with constitutional symptoms. For the pituitary to be involved is extremely uncommon with approximately 10 previously reported cases. We present a 51-year-old Caucasian female who initially presented with nausea, vomiting, polyuria, and polydipsia and was found to have a pituitary mass diagnosed as diffuse large B-cell lymphoma upon surgical resection. Case Presentation A 51-year-old female presented with nausea, vomiting, polydipsia, and polyuria. She had no history of lithium use. She was found to have an initial serum osmolarity of 324 mOsm/kg (280-300mOsm/kg), urine sodium of &amp;lt;20mmol/L, and urine osmolality of 191 mOsm/kg (390-1,090 mOsm/kg). She was initially diagnosed with primary polydipsia, however, her symptoms did not improve with appropriate treatment. An MRI was performed demonstrating a 13mm lobulated, homogeneously enhancing hypothalamic mass with adjacent thickening of the pituitary stalk and pituitary. Subsequent lab work demonstrated deficiencies in ACTH, TSH, cortisol, FSH, LH, and GH. She was initiated on DDAVP, levothyroxine, and hydrocortisone. A repeat MRI several months later revealed that the pituitary mass had enlarged to 2.4cm×2.3cm×1.5cm. She underwent surgical removal of the mass via right frontal craniotomy, and histopathology demonstrated diffuse large B-cell lymphoma. She underwent chemotherapy with high dose methotrexate and cytarabine for 3 cycles. Subsequent MRIs demonstrated stable intracranial findings. Her pituitary function did not recover, and she remains on hormonal replacement with levothyroxine, hydrocortisone, and desmopressin. The patient continues to follow with endocrinology and oncology in the outpatient setting. Conclusion This is a rare instance of diffuse large B-cell lymphoma affecting the pituitary gland. In a patient presenting with symptoms of diabetes insipidus, it is prudent to evaluate for other signs of pituitary involvement. This patient was found to have a pituitary mass on MRI that did not have an appropriate response to medical therapy. Thus, surgical management was performed, and histopathology elucidated the etiology of her symptoms. Reference: Kenchaiah, M., Hyer, S. L. Diffuse large B-cell non Hodgkin's lymphoma in a 65-year-old woman presenting with hypopituitarism and recovering after chemotherapy: a case report. J Med Case Reports 5, 498 (2011). https://doi.org/10.1186/1752-1947-5-498 Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PMON96 A Curious Case of Isolated Oculomotor Nerve Palsy From a Non-Functional Gonadotroph Adenoma

Abstract Introduction Pituitary adenoma typically presents with signs and symptoms of hormone hypersecretion and only 30% of cases present clinically as nonfunctioning adenomas. Furthermore, amongst these less than 5% are associated with ocular nerve palsies. We report a rare case of isolated, unilateral oculomotor nerve palsy due to a non-functional gonadotroph adenoma expanding into the left cavernous sinus. Case 48 years old male with a pertinent medical history of Type 2 Diabetes Mellitus presented to the ER with 3 days of intractable generalized headache associated with double vision, nausea, and increased lethargy. On initial examination, he had findings of oculomotor nerve palsy on the left eye (ptosis, the eye being down and out, and non-reactive pupil to direct or consensual light stimulation) while the rest of his examination was normal. His initial blood work was non-revealing and normal. He underwent extensive imaging including an initial CT scan showing a pituitary macroadenoma, followed by a pituitary-focused MRI brain revealing a hyperplastic pituitary lesion measuring 17.8 mm×22.5 mm in axial axis and 16.4 mm×14.4 mm in sagittal axis with extension into the left cavernous sinus. Biochemical workup was done to evaluate the pituitary function and it revealed a low total testosterone level (95 ng/ml) with a suppressed LH (2.1IU/l) and FSH (1.76 mIU/ml), a low fT4 (0.58 ng/dl) with a suppressed TSH (0.68 mIU/l), low cortisol (1.2 mcg/dl) with a suppressed ACTH of &amp;lt; 5 pg/ml and normal IGF-1 and prolactin levels. He was given stress dose steroids and underwent transsphenoidal resection of the pituitary mass. Pathology of the specimen showed immunoreactivity for SF1 and ASU which was suggestive of a gonadotroph adenoma. The patient showed no signs or symptoms of diabetes insipidus post-operatively, however, was managed for secondary adrenal insufficiency, hypothyroidism, and hypogonadism. He was discharged home on hydrocortisone, levothyroxine, and metformin. He followed up at the Neuroendocrine clinic within a week of discharge and maintained a regular outpatient follow-up where he showed gradual improvement in his symptoms. Conclusion Visual impairment from a non-secreting pituitary adenoma is usually from chiasmal compression. Very rarely, pituitary macroadenoma expands laterally into the cavernous sinus and compresses the oculomotor nerve causing signs and symptoms of third nerve palsy. This case highlights the importance of recognizing different presentations of nonfunctional pituitary adenoma early as this could improve both the morbidity and mortality associated with them. Reference Choong, K., Lee, S L. Pituitary Macroadenoma with invasion into the cavernous sinus, cranial nerve palsies (Endocrine Today) Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

A Novel Missense Mutation of Arginine Vasopressin Receptor 2 in a Chinese Family with Congenital Nephrogenic Diabetes Insipidus: X-Chromosome Inactivation in Female CNDI Patients with Heterozygote 814A>G Mutation.

Background To identify novel clinical phenotypic signatures of congenital nephrogenic diabetes insipidus (CNDI). Methods A Chinese family with CNDI was recruited for participation in this study. The proband and one of his uncles suffered from polydipsia and polyuria since infancy. The results of clinical testing indicated the diagnosis of CNDI. 10 family members had similar symptoms but did not seek medical advice. Genetic testing of mutations in the coding region of the aquaporin 2 (AQP2) gene and the arginine vasopressin receptor 2 (AVPR2) gene were carried out in 11 family members. Somatic DNA from 5 female family members was used to test for methylation of polymorphic CAG repeats in the human androgen receptor (AR) gene, as an index for X-chromosome inactivation pattern (XCIP). Results AQP2 gene mutations were not found in any family members, but a novel missense mutation (814th base A>G) in exon 2 of the AVPR2 gene was identified in 10 individuals. This mutation leads to a Met 272 Val (GAT-GGT) amino acid substitution. Skewed X-chromosome inactivation patterns of the normal X allele were observed in 4 females with the AVPR2 gene mutation and symptoms of diabetes insipidus, but not in an asymptomatic female with the AVPR2 gene mutation. Conclusions Met 272 Val mutation of the AVPR2 gene was identified as a novel genetic risk factor for CDNI. The clinical NDI phenotype of female carriers with heterozygous AVPR2 mutation may be caused by X-chromosome inactivation induced by dominant methylation of the normal allele of AVPR2 gene.

Extended Neuroendoscopic Endonasal Approach for Resection of Craniopharyngioma in Children.

ObjectiveTo explore the surgical approach and technique of neuroendoscopic endonasal resection of pediatric craniopharyngiomas and to further evaluate its safety and effect in children.MethodsThe clinical data of 8 children with craniopharyngiomas who were surgically treated by neuroendoscopy through an extended endonasal approach in our center from 2018 to 2021 were retrospectively analyzed. The related surgical approach and technique were evaluated to improve the surgical results and further reduce the surgical complications when removing craniopharyngioma in children.ResultsAll 8 patients achieved a gross-total resection of the tumor under neuroendoscopy. Postoperatively, 2 cases of transient hyperthermia and 4 cases of transient hyper- and/or hyponatremia occurred within the first 2 weeks, all of which were quickly controlled. Seven patients had symptoms of diabetes insipidus to varying degrees after the operation, and 4 of them improved within 1–3 months after surgery, but 3 cases still needed oral pituitrin. There were no cases of coma or death, leakage of cerebrospinal fluid, or severe electrolyte imbalance after surgery. During the postoperative follow-up of 3 months to 2 years, no tumor recurrence was found. Among the 7 patients who suffered postoperative neuroendocrine deficiencies, 3 patients were found to be temporary during the follow-up, but 4 patients still required hormone replacement therapy. Particularly, postoperative visual deterioration and olfactory defect that occurred in patients were all improved during follow-up periods. In addition, 4 cases of obesity were noted at the last follow-up.ConclusionsExtended neuroendoscopic endonasal resection of craniopharyngiomas may be used as a safe and effective approach for children. Due to the poor pneumatization of the sphenoid sinus and worse compliance of treatment in children, surgical techniques of exposing the sellar region, removing the tumor, and reconstructing the skull base, as well as postoperative management of patients was proposed. However, due to the limited surgical cases in the study, the surgical safety and effects of the extended neuroendoscopic endonasal approach for children with craniopharyngiomas need to be further studied in the future.

Masked diabetes insipidus in pituitary metastasis from breast cancer after thalamic biopsy: a case report

BackgroundSymptomatic pituitary metastasis is rare; furthermore, it can result in diabetes insipidus and panhypopituitarism. Since diabetes insipidus is masked by concurrent panhypopituitarism, it can impede the diagnosis of pituitary dysfunction.Case presentationA 68-year-old Japanese female suffering from pituitary and thalamic metastases caused by untreated breast cancer, underwent a biopsy targeting the thalamus, not the pituitary. She lacked prebiopsy pituitary dysfunction symptoms; however, these symptoms unexpectedly occurred after biopsy. Diabetes insipidus was masked by corticosteroid insufficiency, and she showed normal urinary output and plasma sodium levels. Upon commencement of glucocorticoid replacement therapy, the symptoms of diabetes insipidus appeared.ConclusionsIn this case, thalamic biopsy, as opposed to pituitary biopsy, was performed to preserve pituitary function. However, pituitary dysfunction could not be avoided. Caution is necessary for asymptomatic patients with pituitary metastases as invasive interventions, such as surgery, may induce pituitary dysfunction. Moreover, with respect to masked diabetes insipidus, there is a need to carefully consider pituitary dysfunction to avoid misdiagnosis and delayed treatment.

Unmasking of Neurosarcoidosis

Abstract Introduction: Central diabetes insipidus is a rare complication of neurosarcoidosis. In patients with concomitant adrenal insufficiency (AI), the symptoms of Diabetes Insipidus (DI) can be masked. Case: A 55-year-old female with past medical history of sarcoidosis presented to the hospital with hematemesis, nausea and dizziness. She has a past medical history of cardiac sarcoidosis that was revealed on a PET scan done before 10 years for which she was being treated with methotrexate and prednisone. She was off prednisone for a year prior to hospitalization. She underwent an upper endoscopy that showed diffusely erythematous gastric mucosa in the antrum. She was also hypotensive on admission, and she received packed red blood transfusions after which her sodium increased from 145mmol/L to 165mmol/L (Normal: 135-145mmol/L) in 48 hours. Further workup revealed persistent hypernatremia and urine osmolality was 75mOsm/kg H2O. (Normal: 50-1200mOsm/kg H2O). She was also hypoglycemic and hypotensive requiring multiple fluid boluses throughout her hospitalization. This prompted us to perform a random cortisol that came back at 2.1ug/dl (Normal: 3-23ug/dl) and 1.8ug/dl on two occasions. Cortisol Stimulation test was subsequently ordered, but was done only at 30 minutes, and Cortisol increased from 1.8ug/dl to 6.3ug/dl. Free thyroxine was 0.5 ng/dl (Normal: 0.9-1.8 ng/dl) and her TSH was 7.58uIU/ml (Normal: 0.55-4.78uIU/ml). MRI of the brain revealed extensive areas of extra-axial supra-sellar/infundibular nodular homogeneous intense enhancement that is most consistent with neuro-sarcoid. She was started on prednisone 40 mg daily, Desmopressin 0.05 mg twice daily, and levothyroxine as well. Her sodium level normalized and was 137mmol/L at discharge. She followed up later with outpatient Endocrinology and reported around 90lbs weight gain and no more episodes of nausea or vomiting or epistaxis or lightheadedness. Conclusion: The involvement of the hypothalamic-pituitary axis in sarcoidosis is extremely rare and attributes to &amp;lt; 1% of patients with a sellar mass. Small case series have shown that hypogonadism is the most common endocrine abnormality followed by DI. Our patient had a long-standing history of sarcoidosis with her pituitary dysfunction unmasked only on admission for other causes. She did not manifest any symptoms of DI or AI. There have been case reports where the symptoms of DI are masked due to underlying glucocorticoid deficiency. There have been theories that glucocorticoid deficiency impairs renal water excretion by both ADH (Anti-diuretic hormone) dependent and ADH independent pathways. Another notable feature in our case is that our patient presented with primary hypothyroidism. In fact, sarcoidosis has been commonly implicated in auto-immune polyglandular syndromes type 3, which can present with auto-immune thyroiditis more so in females.

A very rare case of pituitary metastasis infiltrating a non-secretory gonadotroph adenoma

Pituitary adenomas are the commonest sellar tumours. Pituitary metastases are very rare, with the most common primaries being breast and lung cancers. We report the case of an 83-year-old man with a history of breast carcinoma who presented with recent-onset headaches and progressive deterioration of visual acuity. MRI brain showed a large sellar and suprasellar mass compressing the optic chiasm and involving the pituitary stalk. Transsphenoidal debulking resulted in symptomatic relief and visual recovery. Specimen examination revealed a combination of a gonadotroph pituitary adenoma that was infiltrated by metastatic breast carcinoma. He had no symptoms of diabetes insipidus. He was subsequently treated with pituitary radiotherapy. This is a very rare presentation of a pituitary mass with mixed pathology. To our knowledge, this is the third description of a breast carcinoma metastasis into a gonadotroph cell pituitary adenoma.Highlight points:Infiltrating metastases into pituitary adenomas are very rare but do occur.To our knowledge this is the third case of breast adenocarcinoma metastasising to a gonadotroph pituitary adenoma.Pituitary metastases should always be considered in rapidly evolving pituitary symptoms in a cancer patient.Not all complex pituitary lesions are associated with panhypopituitarism.Early invasive local management (TSS and post TSS radiotherapy) can provide rapid satisfactory outcomes.

GCT-75. ISOLATED PITUITARY STALK THICKENING

OBJECTIVESOnly few studies have examined the predictive factors and outcome of isolated pituitary stalk thickening (PST) in children. We aim to describe our institutional cohort to determine predictors of future malignancy.METHODSA search of the radiology, endocrinology and neuro-oncology databases was performed to identify patients with isolated PST diagnosed between January 2000 and June 2019. Clinical data was collected. A detailed radiology review of baseline and follow up magnetic resonance imaging (MRI) was undertaken in a blinded fashion by two examiners.RESULTSForty-four patients were identified, with 37 meeting criteria for isolated PST and adequate imaging. Median age of baseline MRI was 9.9 years (range 0.9–17.5). Twenty-three were female (62%). Median follow up time was 5 (0.31–18.6) years. Indication for MRI was symptoms of diabetes insipidus (DI) in 28 patients with the remainder having other concerns for endocrine disturbance (7), headache (1) or visual impairment (1). Thirty-five subjects had pituitary dysfunction (95%), including 30 with diabetes insipidus (81%). Nine patients developed a malignancy (24%), with germinoma (5), Langerhans cell histiocytosis (3) and lymphoma (1) at a median of 0.36 years, 0.63 years and 1.1 years respectively. Elevated white blood cell count (>5 x 106/L) in initial cerebrospinal fluid analysis was predictive of future diagnosis of germinoma or lymphoma (p=0.027).CONCLUSIONIn this cohort 24% of children with PST were eventually diagnosed with a neoplasia after a median of 0.63 years. Pleocytosis in initial CSF samples was predictive for future development of germinoma or lymphoma.

MON-263 Renal Cell Cancer Metastasis to the Pituitary Masquerading as a Non-Functioning Adenoma

A 47 yr. old male with history of RCC and hypertension was seen in pituitary clinic for management of a pituitary mass. He initially presented to an outside hospital with persistent headaches, unintentional weight loss, severe fatigue, dizziness, cold intolerance, low libido and difficulty with erections. CT head showed a pituitary mass. Lab work revealed pan-hypopituitarism with adrenal insufficiency [random cortisol 0.7 ug/dL (4- 19 ug/dL); ACTH 13 pg/mL (7-63 pg/mL)], hypothyroidism [T4 0.52 ng/dL (0.7-1.5 ng/dL); TSH 0.1 mIU/L (0.45-4.5 mIU/L)] and hypogonadism [total testosterone 15 ng/dL (200-1000 ng/dL); LH of 0.6 mIU/mL (1.5-9.3 mIU/mL); FSH of 3.5 mIU/mL (1.6- 8.0 mIU/mL)]. Prolactin was slightly elevated at 34 ng/mL (2- 18 ng/mL) from stalk compression. IGF-1 was 78 ng/mL (Z score -1.2).When we saw him, he was already on hormone replacement with significant improvement in symptoms. He had no visual field defects or symptoms of diabetes insipidus (DI). As for his history of RCC, he underwent a partial left nephrectomy in 2015, followed by a completion nephrectomy shortly after. Pathology was consistent with clear cell RCC. He did not receive any adjuvant therapy; Follow up imaging studies were reportedly negative for recurrence. Pituitary MRI showed a 1.6 X 1.4 X 1.5 cm enhancing sellar and suprasellar mass without compression of optic chiasm. He was thought to have a presumed non-functioning adenoma, and chose to proceed with trans-spenoidal surgery (TSS). Intra operatively, a very vascular tumor was encountered, which could only be debulked safely. Pathology was consistent with metastatic clear cell RCC. A follow up CT showed innumerable lung nodules and a 3.2 cm right adrenal nodule consistent with metastases. He completed stereotactic radiation to the sella and is currently on Ipilimumab and Nivolumab for immunotherapy.MP is uncommon, and seen in 1-4% of patients with cancer in autopsy studies. Breast (40%) and Lung cancer (25%) are the most common tumors causing MP in women and men respectively, with very few case reports of RCC MP (2.6%). DI is the most common symptom of MP, which is thought to be due to direct vascular supply from hypophyseal arteries to the posterior pituitary. Interestingly in RCC MP, anterior pituitary dysfunction is more prevalent (90%) compared to DI (24%). There is also a tendency for suprasellar extension, causing vision loss. Radiologic features that could help distinguish MP from an adenoma include a rapidly enhancing sellar mass, erosion of sellar floor or posterior clinoid process, infundibular thickening, and the presence of intra-tumoral vascular flow voids. There reportedly is no benefit to using FDG- PET to diagnose MP from RCC. There are no standardized treatment guidelines and the choice of treatment is also influenced by the extent of systemic disease.

An Unexpected Combination of Prolactinoma and Septo-Optic Dysplasia

To describe the unusual finding of pituitary adenoma in a patient with septo-optic dysplasia (SOD). We describe the clinical presentation, biochemical and radiological evaluation, treatment, and outcomes of a patient with macroprolactinoma and previously undiagnosed SOD. A 41-year-old woman with optic nerve hypoplasia and growth hormone deficiency presented with new-onset galactorrhea, polyuria, and polydipsia. Physical exam was notable for bilateral galactorrhea. Laboratory workup showed a prolactin level of 176 μg/L (reference range is 6 to 20 μg/L), serum cortisol of 7.7 μg/dL (reference range is 5.0 to 20.0 μg/dL), and adrenocorticotropic hormone of 54 pg/mL (reference range is 0 to 46 pg/mL). Thyroid function and pituitary-gonadal axis testing were normal. Low-dose cosyntropin test showed a borderline cortisol response and persistently low adrenal androgens, suggestive of partial secondary adrenal insufficiency. A water deprivation test showed evidence of diabetes insipidus (DI). Magnetic resonance imaging of the sella showed a 1.0 × 1.0 × 1.5-cm mass compatible with pituitary adenoma, absence of septum pellucidum, and atrophy of the optic nerves.The patient was diagnosed with SOD with partial hypopituitarism and a concomitant macroprolactinoma of more recent onset resulting in DI. The patient was treated with cabergoline with good clinical and biochemical response including resolution of DI symptoms. Subsequent magnetic resonance imaging of the sella showed near resolution of the prolactinoma. We conclude that a diagnosis of SOD should not exclude the possibility of a pituitary adenoma in the appropriate clinical context, and that the pattern of hormonal deficits in such a combination may be uncharacteristic of the deficits expected with pituitary adenoma alone.

Viral rescue of magnocellular vasopressin cells in adolescent Brattleboro rats ameliorates diabetes insipidus, but not the hypoaroused phenotype

Dysregulated arousal often accompanies neurodevelopmental disorders such as attention deficit hyperactivity disorder and autism spectrum disorder. Recently, we have found that adolescent homozygous Brattleboro (Hom) rats, which contain a mutation in the arginine vasopressin (AVP) gene, exhibit lower behavioral arousal than their heterozygous (Het) littermates in the open field test. This hypoaroused phenotype could be due to loss of AVP in magnocellular cells that supply AVP to the peripheral circulation and project to limbic structures or parvocellular cells that regulate the stress axis and other central targets. Alternatively, hypoarousal could be a side effect of diabetes insipidus – polydipsia and polyuria seen in Hom rats due to loss of AVP facilitation of water reabsorption in the kidney. We developed a viral-rescue approach to “cure” magnocellular AVP cells of their Brattleboro mutation. Infusion of a recombinant adeno-associated virus (rAAV) containing a functional Avp gene and promoter (rAAV-AVP) rescued AVP within magnocellular cells and fiber projections of the paraventricular nucleus of the hypothalamus (PVN) of male and female adolescent Hom rats. Furthermore, water intake was markedly reduced, ameliorating the symptoms of diabetes insipidus. In contrast, open field activity was unaffected. These findings indicate that the hyporaoused phenotype of adolescent Hom rats is not due to the loss of AVP function in magnocellular cells or a side effect of diabetes insipidus, but favors the hypothesis that central, parvocellular AVP mechanisms underlie the regulation of arousal during adolescence.

Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor

The extracellular domain of the (pro)renin receptor (PRR) is cleaved to produce a soluble (pro)renin receptor (sPRR) that is detected in biological fluid and elevated under certain pathological conditions. The present study was performed to define the antidiuretic action of sPRR and its potential interaction with liver X receptors (LXRs), which are known regulators of urine-concentrating capability. Water deprivation consistently elevated urinary sPRR excretion in mice and humans. A template-based algorithm for protein-protein interaction predicted the interaction between sPRR and frizzled-8 (FZD8), which subsequently was confirmed by coimmunoprecipitation. A recombinant histidine-tagged sPRR (sPRR-His) in the nanomolar range induced a remarkable increase in the abundance of renal aquaporin 2 (AQP2) protein in primary rat inner medullary collecting duct cells. The AQP2 up-regulation relied on sequential activation of FZD8-dependent β-catenin signaling and cAMP-PKA pathways. Inhibition of FZD8 or tankyrase in rats induced polyuria, polydipsia, and hyperosmotic urine. Administration of sPRR-His alleviated the symptoms of diabetes insipidus induced in mice by vasopressin 2 receptor antagonism. Administration of the LXR agonist TO901317 to C57/BL6 mice induced polyuria and suppressed renal AQP2 expression associated with reduced renal PRR expression and urinary sPRR excretion. Administration of sPRR-His reversed most of the effects of TO901317. In cultured collecting duct cells, TO901317 suppressed PRR protein expression, sPRR release, and PRR transcriptional activity. Overall we demonstrate, for the first time to our knowledge, that sPRR exerts antidiuretic action via FZD8-dependent stimulation of AQP2 expression and that inhibition of this pathway contributes to the pathogenesis of diabetes insipidus induced by LXR agonism.

Partial nephrogenic diabetes insipidus caused by a novel AQP2 variation impairing trafficking of the aquaporin-2 water channel.

BackgroundAutosomal dominant inheritance of congenital nephrogenic diabetes insipidus (CNDI) is rare and usually caused by variations in the AQP2 gene. We have investigated the genetic and molecular background underlying symptoms of diabetes insipidus (DI) in a Swedish family with autosomal dominant inheritance of the condition.MethodsThe proband and her father were subjected to water deprivation testing and direct DNA sequencing of the coding regions of the AQP2 and AVP genes. Madin-Darby canine kidney (MDCK) cells stably expressing AQP2 variant proteins were generated by lentiviral gene delivery. Localization of AQP2 variant proteins in the cells under stimulated and unstimulated conditions was analyzed by means of immunostaining and confocal laser scanning microscopy. Intracellular trafficking of AQP2 variant proteins was studied using transient expression of mutant dynamin2-K44A-GFP protein and AQP2 variant protein phosphorylation levels were assessed by Western blotting analysis.ResultsClinical and genetic data suggest that the proband and her father suffer from partial nephrogenic DI due to a variation (g.4807C > T) in the AQP2 gene. The variation results in substitution of arginine-254 to tryptophan (p.R254W) in AQP2. Analysis of MDCK cells stably expressing AQP2 variant proteins revealed disabled phosphorylation, impaired trafficking and intracellular accumulation of AQP2-R254W protein. Notably, blocking of the endocytic pathway demonstrated impairment of AQP2-R254W to reach the cell surface.ConclusionsPartial CNDI in the Swedish family is caused by an AQP2 variation that seems to disable the encoded AQP2-R254W protein to reach the subapical vesicle population as well as impairing its phosphorylation at S256. The AQP2-R254W protein is thus unable to reach the plasma membrane to facilitate AVP mediated urine concentration.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-015-0213-3) contains supplementary material, which is available to authorized users.

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Objective: Familial hyperaldosteronism type III (FH-III) is a rare autosomal dominant and clinically heterogeneous condition, that can display mild as well as severe phenotypes. Point mutations in the KCNJ5 gene, affecting the ion selectivity of the inward rectifier K+ channel 4 (Kir3.4), represent the molecular basis of FH-III. So far, five germline mu- tations in the KCNJ5 gene have been identified and functionally characterized in patients with FH-III. Objective of the present study was to characterized the effect of a de novo KCNJ5 germline substitution in vitro. Design and method: We describe the case of a girl affected by severe hyperaldosteronism. KCNJ5 gene was PCR amplified from peripheral blood and sequenced. Electrophysiological and gene expression studies were performed to establish the functional effects of the new mutation on the membrane potential and adrenal cell CYP11B2 (aldosterone synthase) expression. Results: The index case is a Caucasian girl born to nonconsanguineous parents. She came to medical attention at the age of two years because of polydipsia, polyuria and failure to thrive. The patient, affected by hypertension and hypokalemia, was diagnosed with primary aldosteronism on the basis of extremely high aldosterone levels and suppressed plasma renin activity. At the age of 19 she was on four antihypertensive medications and potassium supplements; transthoracic echocardiography revealed mildly dilated aortic root and ascending aorta without left ventricular hypertrophy. The patient consented to bilateral adrenalectomy which was performed laparoscopically. KCNJ5 sequencing in the index case and her parents revealed a de novo p.Glu145Gln germline mutation. The substitution resulted in Na+-dependent depolarization of adrenal cells and increased intracellular calcium concentration, which activated the transcription of NR4A2 and, in turn, CYP11B2. Pharmacological studies revealed that the mutant channel was insensitive to tertiapin-Q and calcium-channel blocker verapamil. Conclusions: Herein we report on the identification of a novel KCNJ5 germline mutation responsible for severe hyperaldosteronism that presented in infancy with symptoms of diabetes insipidus. The findings of this study further elucidate the etiology of FH-III and expand our knowledge of this rare condition.

Diabetes insipidus in pediatric germinomas of the suprasellar region: characteristic features and significance of the pituitary bright spot.

The pituitary bright spot is acknowledged to indicate functional integrity of the posterior pituitary gland, whilst its absence supports a diagnosis of central diabetes insipidus (DI). This feature was evaluated, together with the incidence and clinical characteristics of DI in children with suprasellar/neurohypophyseal germinomas. We performed a review of all suprasellar (SS) or bifocal (BF) germinoma pediatric patients treated in Toronto since 2000. Demographics, symptomatology, treatment outcome and imaging were evaluated. Nineteen patients fulfilled inclusion criteria (10 SS, 9 BF; median age 12.5 years (6.2-16.8 years)). All remained alive at 6.4 years median follow-up (1.2-13.7 years) after receiving chemotherapy and radiotherapy (13 focal/ventricular, four whole brain, two neuraxis), with only one progression. All had symptoms of DI at presentation with a symptom interval above one year in eight cases (42 %). Desmopressin was commenced and maintained in 16 patients (84 %). The pituitary bright spot was lost in most diagnostic interpretable cases, but was appreciated in three patients (18 %) who had normal serum sodium values compared to 'absent' cases (p = 0.013). For two such cases, spots remained visible until last follow-up (range 0.4-3.3 years), with one still receiving desmopressin. No case of bright spot recovery was observed following therapy. Protracted symptom intervals for germinoma-induced central DI may reflect poor clinical awareness. Explanations for persistence of the pituitary bright spot in symptomatic patients remain elusive. Desmopressin seldom reverses the clinical features of germinoma-induced DI to allow discontinuation, nor does treatment cause bright spot recovery.