bluuebunny/crossref_metadata_2025 huggingface dataset:
8209 Silent Somatotroph Adenoma Unmasked as Pituitary Apoplexy, Disguised as Subarachnoid Hemorrhage
Authors: Vemparala Pranathi , Challagulla Sabita
Published: October 2024

Disclosure: P. Vemparala: None. S. Challagulla: None.

Introduction - Pituitary apoplexy is a rare and potentially life-threatening complication associated with pituitary adenomas, particularly in cases of nonfunctioning macroadenomas. Silent somatotroph adenomas, characterized by the presence of growth hormone (GH) immunoreactivity without manifesting signs and symptoms of acromegaly, are uncommon. This case report presents a distinctive instance where pituitary apoplexy served as the initial manifestation of a GH-immunoreactive tumor. CASE PRESENTATION- A 45-year-old male with a medical history of hypertension, sleep apnea, and hypogonadism sought emergency medical attention following a syncopal episode. Post-syncope, he reported severe headache and neck pain, with no other associated symptoms. Imaging revealed a subarachnoid hemorrhage and a sellar/suprasellar mass measuring approximately 2.8 x 3.6 x 4.2 cm. CT angiography ruled out an aneurysm or vascular malformation. The subarachnoid hemorrhage was attributed to hemorrhage within the sellar mass. Treatment with Nimodipine and levetiracetam was initiated. Laboratory investigations indicated normal insulin-like growth factor 1 (IGF-1) levels. Brain MRI revealed a 4.2 x 2.3 x 2.6 cm heterogeneous enhancing cystic sellar/suprasellar lesion causing mass effect on the hypothalamus and third ventricle. The patient underwent endoscopic transsphenoidal hypophysectomy, revealing a tumor that was diffusely positive for GH and synaptophysin immunostaining and negative for prolactin and ACTH. Ki67 was less than 5%, with no apparent mitotic activity, atypia, or tumor necrosis. The postoperative course was uneventful, and the patient was discharged on oral steroids. Conclusion- Silent somatotroph adenomas constitute a small percentage (2-4.2%) of pituitary adenomas. In contrast to silent gonadotroph adenomas, these tumors are more prevalent in women, tend to present earlier and exhibit higher recurrence rates. This case emphasizes the potential of silent somatotroph adenomas to manifest initially as pituitary apoplexy. It underscores the importance of vigilant post-surgical follow-up due to the possibility of recurrence. Additionally, recognizing pituitary apoplexy as subarachnoid hemorrhage is crucial for timely intervention and appropriate management.

Presentation: 6/2/2024
7248 Spliceosome component TCERG1 regulates the aggressiveness of somatotroph adenoma
Authors: Kim Kyungwon , Shin Hye Ju , Kang Chan Woo , Lee Eun Jig , Ku Cheol Ryong
Published: October 2024

Disclosure: K. Kim: None.

The role of the spliceosome in the development of pituitary tumors is not well understood, despite preliminary studies indicating abnormal expression of oncogenic splicing variants in these neuroendocrine tumors. We aimed to identify differentially expressed spliceosome components in growth hormone (GH)-secreting pituitary tumors and investigate their roles in pathogenesis.We performed transcriptome analysis of 20 somatotroph adenomas and 6 normal pituitary tissues to select dysregulated spliceosome components. Clinical characteristics were analyzed based on gene expression in 64 patients with acromegaly. GH secreting pituitary adenomas were confirmed by 75 g oral glucose tolerance and immunohistochemical staining. Proliferation, invasion, and hormonal activity of GH secreting pituitary adenoma cells were investigated after modulating gene expression.TCERG1 expression was significantly higher in somatotroph adenomas than in normal cells (log2 fold change 0.59, adjusted P=0.0002*). Genotype-phenotype analysis revealed that patients with higher TCERG1 expression had lower surgical remission rates than those with lower expression (63.64% vs. 95.45%, P=0.009*). TCERG1 expression was significantly higher in groups with cavernous sinus (CS) invasion or Ki67 index over 1.5 (2.06 vs. 1.65, P=0.011*; 2.02 vs. 1.66, P=0.043*). TCERG1 overexpression led to a 16.91% increase in proliferation after 72 h (P<0.001*) and a 249.47% increase in invasion after 48 h in GH3 cells (P=0.026*). Conversely, TCERG1 silencing significantly decreased cell proliferation (10.15% at 72 h, P<0.001*) and invasion (96.87% at 48 h, P=0.029*). Vimentin was increased, but E-cadherin was decreased in both TCERG1 overexpressed GH3 cells and somatotroph adenomas. And TCERG1 silence reversed the expression of the genes (CDH2, SNAI1, ZEB2, and VIM) in GH3 cells. Additionally, GH secretion increased when TCERG1 was overexpressed in GH3 cells. Spliceosome machinery provide novel insights into the pathogenesis of GH-secreting pituitary tumor and highlight the potential role of TCERG1 as a therapeutic target.

Presentation: 6/2/2024
8442 Successful Pregnancy in the Setting of Medically Untreated Acromegaly
Authors: Chlebek Sylvia , Guerra Yannis Sergio
Published: October 2024

Disclosure: S. Chlebek: None. Y.S. Guerra: None.

Background: Acromegaly is a rare disease due to excessive GH secretion, usually from a benign pituitary adenoma. Gonadal dysfunction and infertility are common in acromegalic women within reproductive age [1]. Effective treatment typically improves fertility. Minimal data, mostly in the form of isolated cases, is available on pregnancy in acromegaly. Clinical Case: A 39-year-old woman presented to outpatient Endocrinology for management of acromegaly. Past medical history was notable for a GH secreting pituitary adenoma, of unknown size, which was initially found in Mexico during work-up for progressive, chronic headaches and gradual enlargement of her facial features, feet, and hands. The patient subsequently underwent trans-sphenoidal resection of the pituitary adenoma. A post-operative MRI revealed a residual adenoma with a 94% decrease in size. She declined further therapy at that time. The patient reported improvement in her symptoms, however, these gradually recurred over two years. She traveled to the U.S. from Mexico and sought Endocrine evaluation. Clinically, the patient exhibited features of acromegaly: coarse facial features and acanthosis nigricans at the nape. She was found to have biochemical persistence: GH at the upper limit of normal (3.479 ng/mL, normal 0.010-3.607 ng/mL) and IGF-1 elevation (573 ng/mL, normal 53-331 ng/mL). The remainder of the results were unremarkable, and an MRI was scheduled. The patient returned to clinic, 3-months later, 11-weeks pregnant. While pregnant, the MRI Brain revealed a macroadenoma without optic chiasm compression. Furthermore, there were no visual field defects on Ophthalmology evaluation. The patient decided to forego medical therapy for acromegaly during pregnancy. Notably, she was diagnosed with gestational diabetes and preeclampsia. She delivered a healthy baby without complications and with no fetal malformations. Post-partum, the patient was initiated on a somatostatin analog with a plan for repeat biochemical testing at her next appointment. Conclusion: As pregnancy is rare in women with acromegaly, few case reports have been published on this clinical presentation. Pregnancy warrants consideration of adenoma growth and the impact of hormone hypersecretion on the patient and fetus. Failure to achieve biochemical control may increase the risk of gestational diabetes and hypertension, as seen in this patient. Post-partum treatment and regular follow-up are important for managing acromegaly and associated complications. Reference:1.Pirchio et al. Fertility in Acromegaly: A Single-Center Experience of Female Patients During Active Disease and After Disease Remission, The Journal of Clinical Endocrinology & Metabolism, Volume 108, Issue 8, August 2023, Pages e583–e593, https://doi.org/10.1210/clinem/dgad042

Presentation: 6/2/2024
6444 The Cortisol Conundrum: A Case of Cushing’s Disease Masked by Cabergoline
Authors: Khan Aysha , Vedere Tarunya
Published: October 2024

Disclosure: A. Khan: None. T. Vedere: None.

Introduction: The most common cause of endogenous hypercortisolism is Cushing’s disease (CD) accounting for 70% of the cases. We describe a case where the diagnosis of CD was delayed due to cabergoline (CBG) use. Case A 25-year-old male with history of OSA, multiple sclerosis, obesity, recurrent kidney stones, and a pituitary microadenoma, presumed to be a prolactinoma, presented with gynecomastia and erectile dysfunction (ED). He had developed gynecomastia in his teenage years. Workup showed elevated prolactin level (PRL) and MRI pituitary showed a 5mm pituitary adenoma. Patient was started on CBG 0.5 mg once a week and had been on it for 4 years at presentation. Most recent PRL had normalized to 13.7 (12.0-18.0) ng/ml and MRI pituitary showed stable size of the adenoma. He reported generalized weakness with proximal muscle weakness, weight gain, easy bruising, ED, decreased libido, and persistent gynecomastia for a few years. Interestingly, he had noted a 50 lb weight gain, low mood, and worsening striae when he was taken off CBG for 3 months in the past. Physical exam was significant for obese male with dorsocervical and supraclavicular fat pads, facial plethora, reduced motor power in proximal upper extremities and prominent wide purple striae on the abdomen. In the past, while on CBG, 24-hour urine free cortisol levels were 85.9 and 40.9 (4.0-50.0) mcg/24hrs in two collections. While briefly off CBG, 24-hour urine cortisol level was 254.2 mcg/24hrs. We obtained salivary cortisol levels which were elevated at 0.666 (<0.308) mcg/dL and 1.005 mcg/dL on two samples and ACTH was 67.6 (7.2-63.3) pg/ml while on CBG. IPSS results pointed to a pituitary source. Patient underwent transsphenoidal hypophysectomy and was discharged on hydrocortisone (HC). Pathology showed minute pituitary tissue, possible pituitary adenoma. Specimen was too small to perform staining for ACTH and PRL. Postoperatively, he has done well off HC with significant clinical improvement and normalization of salivary cortisol levels. Discussion Dopamine agonist such a CBG is the first line treatment of prolactinomas. The evidence for CBG use in CD has been controversial; some studies show almost a 40% decrease of cortisol levels. Given that CBG suppresses ACTH secretion by acting on dopamine receptor subtype 2, it would also mask CD by reducing cortisol levels in urine and serum. Our patient had equivocal results for 24-hour urine cortisol level for CD. While CBG adds to the armamentarium for these ACTH-PRL secreting pituitary adenomas, its use interferes with work up in patients with pituitary adenoma who are still undergoing diagnostic tests for pituitary function evaluation. Our case highlights a unique diagnostic challenge in the work up of CD.

Presentation: 6/3/2024
7089 The Effects of Asprosin on Reproductive Parameters in the Rats
Authors: Kelestimur Haluk , Oz Zeynep Dila , Ozdede Mehmet Ridvan , Serhatlioglu İhsan , Kacar Emine , Yilmaz Bayram
Published: October 2024

Disclosure: H. Kelestimur: None. Z. Oz: None. M. Ozdede: None. &. Serhatlioglu: None. E. Kacar: None. B. Yilmaz: None.

Purpose: Asprosin, a novel glucogenic adipokine produced by the fibrillin 1 (FBN1) gene, is integral to the body's energy regulation processes. Generated and released by white adipose tissue during fasting, asprosin affects the hypothalamic-pituitary-gonadal (HPG) axis, impacting reproduction. While its effects on metabolic parameters are well established, the understanding of its impact on reproductive health and functionality is still emerging. This study investigates the effects of exogenous asprosin administration on the reproductive capabilities of male and female rats. Materials and Methods: Forty-eight Sprague-Dawley rats, 21 days old and weighing 35±2 grams, were divided into control and asprosin-treated groups (n = 12 per group, for both genders). This approach allowed direct comparison between treated and untreated groups. From postnatal day 21, treatment groups received daily intraperitoneal injections of asprosin (500 ng/kg) for ten weeks (male) and eight weeks (female), while control groups received only saline (1 ml/kg). The study examined various reproductive parameters, including those related to pubertal maturation and sexual behavior, and conducted hormonal analyses on blood samples collected at the experiment's conclusion. Results: Asprosin administration did not alter puberty onset or weight in either gender. However, asprosin-treated rats showed significantly earlier sperm formation in males and earlier estrus in females compared to controls. In male sexual behavior, asprosin reduced intromission latency and increased ejaculation frequency. While interaction with females remained unchanged, asprosin notably increased time near males and male preference ratio. The rate of male investigation preference and the activity index (frequency of passing through the test device's center) also significantly increased in the asprosin-treated group. Conclusion: These findings suggest that asprosin may stimulate the reproductive system in both male and female rats. They highlight the potential role of asprosin in reproductive biology and underscore the need for further research to fully understand the mechanisms by which asprosin influences reproduction. Such studies could significantly advance our knowledge in endocrine regulation. Acknowledgement: This study was supported by TUBITAK (Project No: 220S744).

Presentation: 6/1/2024
6529 The Risk of Hypophysitis Following Treatment With Relatlimab+Nivolumab Appears Higher Than Expected
Authors: Chamorro-Pareja Natalia , Faje Alexander Terence , Miller Karen Klahr
Published: October 2024

Disclosure: N. Chamorro-Pareja: None. A.T. Faje: None. K.K. Miller: Stock Owner; Self; Bristol-Myers Squibb.

Hypophysitis is a recognized complication of immune checkpoint inhibitor therapy; the risk of developing hypophysitis in patients receiving nivolumab (an anti-programmed death-ligand 1 [anti-PD-1]) is estimated to be < 1%. Relatlimab is a human monoclonal antibody targeting lymphocyte activation gene 3 (LAG-3) recently approved in combination with nivolumab for the treatment of unresectable or metastatic melanoma. The risk of hypophysitis as a complication of relatlimab therapy is not well-defined. Objective: To examine the prevalence, identify risk factors, and characterize the clinical presentation of hypophysitis in patients receiving relatlimab+nivolumab. Methods: 159 patients received relatlimab+nivolumab at the Mass General Brigham health care system between 6/2015 and 11/2023. Twenty-seven patients were excluded because they were either diagnosed with adrenal insufficiency (AI) before receiving relatlimab+nivolumab or AI was secondary to other factors, primarily exogenous glucocorticoid administration, leaving a total of 122 patients. The medical records of these patients, including provider encounters, laboratory results, medication records, and radiologic images were reviewed. Data are presented as mean ± SD. Results: Central AI was diagnosed in 10 patients (7.5% of the cohort) after relatlimab+nivolumab administration. The mean age was 64.5±13.8 vs. 67.1±14.4 in patients with AI vs. patients without AI (p= 0.58). Sixty percent of patients in the AI group were male compared to 53% of patients without AI (p= 0.68). The development of AI was not related to the cumulative dose of relatlimab+nivolumab (mean number of cycles 6.4±3.2 vs. 4.9±5.0, p=0.35). The most common presenting symptoms of AI were fatigue, anorexia, nausea, and vomiting. No patients were diagnosed with additional anterior pituitary hormone deficiencies, though not all patients were evaluated for these diagnoses; none had diabetes insipidus. Nine patients had MRIs performed after the diagnosis of central AI; 7 of these patients had pre-treatment MRIs for comparison. Diffuse pituitary enlargement was seen on MRI after initiation of relatlimab+nivolumab in 3 patients up to 8 weeks prior to the diagnosis of hypopituitarism. All patients had persistent hypopituitarism at the most recent evaluation. Conclusions: This study is the first cohort analysis of hypophysitis in patients treated with relatlimab+nivolumab. A significant portion of patients were diagnosed with central AI, presumptively due to hypophysitis given the lack of an identifiable alternative etiology. Although the clinical phenotype of these patients paralleled published studies analyzing anti-PD-1 monotherapy, combination treatment with relatlimab+nivolumab appeared to confer a significantly higher risk of developing hypophysitis.

Presentation: 6/3/2024
7559 TRIM21 Regulates Activation of ERK1/2 to Promote Growth and Drug Resistance in Pituitary Neuroendocrine Tumors
Authors: Liu Yanting , Liu Fang , Li Chuanbao , Zhang Tao , Xue Li , Wu Zhe Bao
Published: October 2024

Disclosure: Y. Liu: None. F. Liu: None. C. Li: None. T. Zhang: None. L. Xue: None. Z. Wu: None.

Objective: To investigate the role of the TRIM family genes in pituitary neuroendocrine tumors (PitNETs) and provide new targets and strategies for the clinical treatment of these tumors. Methods: A CRISPR screening system targeting the TRIM family was constructed and validated using next-generation sequencing. Stable cell lines overexpressing or knocking out TRIM21 were generated, and functional validation was performed using assays such as CCK-8, colony formation, and xenograft tumor growth in nude mice. RNA-seq, mass spectrometry, immunohistochemistry, and immunoblotting were employed to explore the signaling pathways and mechanisms underlying TRIM21's actions. Immunoprecipitation, immunofluorescence, GST-pulldown, NanoBiT assays, and ubiquitination experiments were conducted to investigate the effects of TRIM21 on ERK1/2. Immunohistochemistry and immunoblotting were used to explore the role of TRIM21 in drug- resistant prolactinomas and the correlation between TRIM21 and p-ERK. Results: Through screening the proliferative and drug-resistant effects of the TRIM family in MMQ and GH3 cells, we found that knocking out TRIM21 may inhibit cell growth and enhance drug sensitivity. Subsequently, stable cell lines overexpressing or knocking out TRIM21 were generated in MMQ and GH3 cells, revealing that TRIM21 overexpression promotes pituitary tumor cell growth and resistance to drug treatment, while TRIM21 knockout inhibits cell growth and enhances drug sensitivity. Cell-derived xenograft models showed that TRIM21 overexpression promoted growth of GH3 cells in vivo and resistance to cabergoline (CAB), while TRIM21 knockout suppressed growth of MMQ cells in vivo. Further exploration of the signaling pathways influenced by TRIM21 revealed that TRIM21 knockout downregulates the MAPK signaling pathway, while TRIM21 overexpression upregulates it. TRIM21 overexpression upregulates p-ERK1/2 in the MAPK pathway, while TRIM21 knockout decreases p-ERK. However, there is no significant influence on ERK1/2, JNK, p-JNK, p38, or p-p38. Mechanically, TRIM21 interacted with ERK1/2, enhancing the K27-linked ubiquitination of ERK1/2 and promoting their interaction with MEK1/2. In addition, the TRIM21 with D-docking mutant or ERK1/2 with CD-domain mutant resulted in the loss of their interaction. Furthermore, TRIM21 and p-ERK levels were significantly elevated in drug-resistant prolactinomas and immunohistochemical semi-quantitative analysis demonstrated a positive correlation between TRIM21 and p-ERK. Conclusion: The ubiquitin ligase TRIM21 catalyzes K27-linked ubiquitination of ERK1/2, enhancing its interaction with MEK1/2 and activation, thereby promoting growth and drug resistance in pituitary neuroendocrine tumors. TRIM21 may serve as a potential target for the treatment of pituitary neuroendocrine tumors.

Presentation: 6/3/2024
7521 Unmasking of PCOS after Microprolactinoma Treatment
Authors: Erenler Feyza , Mathyk Begum Aydogan
Published: October 2024

Disclosure: F. Erenler: None. B. Aydogan Mathyk: None.

Background: PCOS and prolactinomas are two of the leading causes of secondary amenorrhea. Hirsutism is a common finding for both diagnosis and can be the presenting symptom. We are presenting a case of secondary amenorrhea, initially diagnosed with microprolactinoma without signs of hyperandrogenism, which progressed to overt PCOS after prolactinoma treatment. Case: A 22-year-old female with history of Hashimoto’s hypothyroidism presented with secondary amenorrhea. Patient was on combined oral contraception pills (COC) for menstrual regulation and discontinued them with a desire of natural cycles. After the discontinuation of COC, her menstrual cycles did not return for four months and patient was subsequently found to have a microprolactinoma with prolactin (PRL) level 70.6 ng/mL - high (nl: 2.8-29.2 ng/mL), LH 6.1 mIU/mL (follicular phase: 1.9-12.5 mIU/mL), FSH 2.4 mIU/mL - low (follicular phase: 2.5-10.2 mIU/mL), androstenedione 132 ng/mL (follicular phase: 51-213 ng/mL), testosterone 36 ng/mL (nl: 2-45 ng/mL), AMH 33 ng/mL - high (nl: 1.02-14.63 ng/mL), DHEA-S 241 mcg/dL (nl: 44-286 mcg/dL), HCG neg. MR Sella showed a 0.5 cm hypoenchancing pituitary lesion, confirming the diagnosis of prolactinoma. Patient was started treatment with cabergoline 0.25 mg twice a week and PRL level trended down to 3.9 ng/mL. With normalization of PRL, patient started complaining of new onset hirsutism without return of her menses. Ferriman Gallway score was 8. Further workup showed elevated androgen markers: LH 25.7 mIU/mL - high (follicular phase: 1.9-12.5 mIU/mL), FSH 5.0 mIU/mL (follicular phase: 2.5-10.2 mIU/mL), PRL 4.7 ng/mL -low (nl: 4.8-23.2 ng/mL), androstenedione 341 ng/mL -high (41-262 ng/mL), E2 63.4 pg/mL (nl: 12.5-160 pg/mL), AMH 22.3 ng/mL – high (nl: 1.23-11.61 ng/mL), testosterone 94.7 ng/mL - high (nl: 10-55 ng/mL), DHEA-S 261 mcg/dL (nl:110-431.7 mcg/dL). ACTH stimulation test pursued to rule out NCAH and17-OH progesterone levels were within normal range after stimulation. Pelvis US obtained due to high suspicion for PCOS and was consistent with polycystic ovaries. The diagnosis of PCOS confirmed by Rotterdam criteria. Patient has phenotype A PCOS by the definition of NIH 2012 consensus. Conclusion: Hyperprolactinemia and pituitary adenomas can cause secondary amenorrhea. In our case, the treatment of hyperprolactinemia with cabergoline unmasked the underlying PCOS. The clinical and biochemical manifestation of PCOS became apparent following the removal of prolactin’s suppressive effect on GnRH.

Presentation: 6/2/2024
7534 Characterizing The Presentation Of Non-Classical Congenital Adrenal Hyperplasia
Authors: Patel Sruti , Skamagas Maria , Levine Alice C , Yau Mabel
Published: October 2024

Disclosure: S. Patel: None. M. Skamagas: None. A.C. Levine: None. M. Yau: None.

Introduction: 21-hydroxylase deficiency, due to CYP21A2 gene mutations, is the most common steroidogenic enzymatic defect causing congenital adrenal hyperplasia (CAH). Disease severity is categorized into the classical and milder, non-classical (NCAH) form. Many patients go undiagnosed due to variable presentation and delayed onset. We aim to investigate the specific presenting concerns, age of onset, and genotypes associated with NCAH. Methods: A retrospective chart review of 285 patients with CAH seen over the past 2 years at our academic pediatric and adult endocrine clinics was performed. Records were reviewed for presenting concerns and age of symptom onset. CYP21A2 gene analysis was performed commercially via multiplex ligation-dependent probe amplification or next generation sequencing. Results: Of the 165 patients classified with NCAH, genotypes were available for 124 patients. Of the patients with a V281L allele, 43 were homozygous and 49 were heterozygous. 7 patients had the P30L allele and 7 had other allele combinations. The overall most common presenting concerns were early pubarche (29%), hirsutism (28%), and irregular menses (26%). In V281L homozygotes, family history most commonly led to diagnosis (30%). In patients with V281L heterozygosity or the P30L allele, the predominant concern was early pubarche (37% and 43% respectively). 15% of patients were screened prenatally or only due to family history and were asymptomatic at diagnosis. Patients’ age at diagnosis ranged from 0-40 years, with the mean age at diagnosis for the total group being 13.3 ± 8.9 years. Mean age of onset in symptomatic V281L homozygotes (15.4 ± 7.9 years) trended toward an older age compared to symptomatic V281L heterozygotes (15.1 ± 10.5 years) (P value = 0.90). Those who were heterozygous for V281L/P30L or undetermined whether homozygous for V281L or heterozygous with a deletion were excluded from age of onset comparisons. Discussion: The mean age of symptom onset was in adolescence and did not differ significantly between V281L homozygotes and heterozygotes. Early pubarche is a frequent presenting symptom in children with NCAH, and our data support this finding. P30L has been associated with a more severe phenotype than V281L, and in our cohort, the only patient presenting in adrenal crisis had a genotype with a P30L mutation. As NCAH is one of the most common autosomal recessive disorders in humans and there is an allelic predominance of V281L in NCAH patients, it is not surprising that a large percentage of V281L homozygotes were diagnosed due to family history prior to developing symptoms. Such patients need to be followed clinically and our data describing symptom onset could be useful in counseling these families and those with prenatal diagnoses.

Presentation: 6/1/2024
6640 Utility of bilateral inferior petrosal sinus sampling for diagnosis and management of Cushing's disease in children ; a case report
Authors: Leal V , Socha L , Awadalla S S
Published: October 2024

Disclosure: V. leal: None. L. Socha: None. S.S. Awadalla: None.

The causes of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) are Cushing's disease (CD) and ectopic ACTH syndrome (EAS). The differential diagnosis of CS and the localization of lesions in CD and EAS are often challenging. The utility of bilateral inferior petrosal sinus sampling (BIPSS), an important test in adults, is less defined in children.A 16-year-old girl was referred for evaluation and treatment of Cushing syndrome she experienced weight gain, secondary amenorrhea, and back pain. 24-hour urinary free cortisol and low-dose dexamethasone suppression tests suggested Cushing syndrome. Adrenocorticotropic hormone (ACTH) level and high-dose dexamethasone suppression test confirmed Cushing disease. Pituitary magnetic resonance reported a microadenoma. To rule ectopic ACTH syndrome, and localize the pituitary tumor, bilateral inferior petrosal sinus sampling (BIPSS) was performed with desmopressin to stimulate ACTH. Finally, the patient was diagnosed with Cushing disease due to right ACTH-secreting pituitary microadenoma and underwent endoscopic endo-nasal transsphenoidal surgery.In conclusion , BIPSS can be a valuable tool not only for discriminating between pituitary origin and ectopic ACTH-secreting Cushing syndrome, but also for providing precise localization of pituitary adenomas, thereby facilitating appropriate treatment.

Presentation: 6/1/2024
6545 Weekly Somapacitan Reduces Serum C-reactive Protein Levels in Adult Patients with Growth Hormone Deficiency
Authors: Seki Y , Morimoto S , Ikemoto M , Takano N , Yamashita K , Bokuda K , Watanabe D , Ichihara A
Published: October 2024

Disclosure: Y. Seki: None. S. Morimoto: None. M. Ikemoto: None. N. Takano: None. K. Yamashita: None. K. Bokuda: None. D. Watanabe: None. A. Ichihara: None.

Background: Adult growth hormone deficiency (GHD) is known to be associated with increased inflammation. Our previous research revealed a significant association between GHD and elevated serum C-reactive protein (CRP) levels. Limited studies have demonstrated a significant association between GH replacement therapies and CRP levels; only two reports showed a significant reduction in serum CRP levels with daily somatropin. This study aimed to investigate the effects of weekly somapacitan on serum CRP levels in adult patients with GHD. Methods: We prospectively observed serum CRP levels as the primary outcome before and 6 months after somapacitan treatment in adult patients with GHD with no history of GH supplementation therapy within the past 6 months. Secondary outcomes included anthropometric data, IGF-1 levels, and kidney and liver functions. The somapacitan dose was titrated based on IGF-1 levels during the 6-month treatment period. Results: Eight adult patients (mean age 50±17, male 4 [50%]) with GHD received weekly somapacitan treatment. Of the patients, 2 (25%) had ACTH deficiency, 2 (25%) had TSH deficiency, and 2 (25%) had gonadotropin deficiency. Two patients (25%) were on glucocorticoid replacement. The somapacitan dose at 6 months was 1.9 (1.5-2.6) mg/week. Weekly somapacitan significantly increased serum IGF-1 level (48 [29-122] to 125 [63-205] ng/mL, P = 0.001) and IGF-1 SD score (-3.3 [-5.3-0.9] to -0.7 [-3.0-0.8], P = 0.008) and significantly decreased serum CRP level (0.243 [0.056-0.464] to 0.093 [0.036-0.290] ng/mL, P = 0.008). However, it did not affect body weight (80.6±11.6 to 79.8±10.5 kg, P = 0.67) or serum creatinine (0.74±0.13 to 0.68±0.21 mg/dL, P = 0.35) and alanine aminotransferase (60 [20-99] to 48 [21-85] U/L, P = 0.23) levels. Changes in CRP levels were significantly correlated with changes in IGF-1 levels (rs = -0.83, P = 0.010) and IGF-1 SD scores (rs = -0.79, P = 0.021). Conclusion: GH supplementation therapy with weekly somapacitan reduced serum CRP levels in adult patients with GHD without affecting body composition or kidney and liver functions.

Presentation: 6/3/2024
7418 Xanthoma Disseminatum - A Rare cause of Diabetes Insipidus
Authors: Balasubramanian Priyadarshini , Cohen Jeffrey , Corbin Zachary , Panse Gauri , Inzucchi Silvio E
Published: October 2024

Disclosure: P. Balasubramanian: None. J. Cohen: None. Z. Corbin: None. G. Panse: None. S.E. Inzucchi: None.

Background: Xanthoma disseminatum is a rare non-Langerhans cell-derived benign histiocytosis of unknown etiology, characterized by mucocutaneous xanthomatosis. Systemic involvement occurs in a subset of patients, the most common manifestation being central diabetes insipidus in the setting of hypothalamic-pituitary- infundibulum infiltration, occurring in about 30-50% of the patients. We present the case of a man with biopsy proven cutaneous xanthoma disseminatum who developed central diabetes insipidus due to pituitary stalk involvement. Case Presentation: A 69-year-old male presented with a 2-year history of symmetrically distributed, erythematous to hyperpigmented macules and papules in the axillae and inguinal folds. He did not have any mucosal lesions. Skin biopsy revealed histiocytic infiltrate consistent with non-Langerhans cell histiocytosis, likely xanthoma disseminatum. He developed symptoms of polyuria and nocturia around the same time of the eruption, resulting in a large daily fluid intake of 100-120 ounces/day for several months. Laboratory evaluation revealed normal electrolytes. After an overnight water deprivation test, serum osmolality was 299mOsm/kg, serum sodium was 144mmol/L and urine osmolality was 280mOsm/kg, consistent with partial central diabetes insipidus. MRI pituitary with and without IV contrast showed thickening and hyperenhancement of the pituitary stalk. Anterior pituitary function was intact except for mild hypogonadotropic hypogonadism. He was started on DDAVP with good response and resolution of symptoms. Conclusion: Xanthoma disseminatum is characterized by extensive mucocutaneous xanthomatosis with occasional systemic involvement. The natural history of xanthoma disseminatum is usually benign, indolent, and slowly progressive with spontaneous regression described in a few cases. Hypothalamic and pituitary involvement may cause hyperprolactinemia, central diabetes insipidus, and variable degrees of hypopituitarism. Diabetes insipidus is often mild and sometimes transient. Occasionally, central diabetes insipidus can precede the skin lesions. Prognosis is generally good. Central nervous system involvement outside the hypothalamus/pituitary carries a poor prognosis.

Presentation: 6/2/2024
9293 Do Obesity-Associated MRAP2 Variants Modulate MC4R and GHSR Signaling?
Authors: Rondon Alejandra Virginia Rodriguez , Volker Femke , Welling Mila Sofie , de Groot Corjan , van Haelst Mieke M , van den Akker Erica L T , van Rossum Elisabeth F C , Delhanty Patric John , Visser Jenny A
Published: October 2024

Disclosure: A.V. Rodriguez Rondon: None. F. Volker: None. M.S. Welling: None. C. de Groot: None. M.M. van Haelst: None. E.L. van den Akker: None. E.F. van Rossum: None. P.J. Delhanty: None. J.A. Visser: None.

Melanocortin 2 receptor accessory protein 2 (MRAP2) is a membrane-bound protein expressed on hypothalamic neurons that modulate the function of appetite-regulating receptors, including melanocortin-4 receptor (MC4R) and growth hormone secretagogue receptor (GHSR). While pathogenic variants in the MRAP2 gene are associated with obesity, the mechanism for this remains unclear. The aim of this study is to investigate the functional impact of wildtype (WT) MRAP2 and MRAP2 variants on MC4R and GHSR signaling. Four MRAP2 variants (S80F, R125C, P167A and Q174X) were identified in patients with obesity by obesity gene panel analysis. The functional effects of these variants were analyzed by co-transfecting HEK293 cells with expression plasmids encoding WT or variant MRAP2 and WT MC4R or WT GHSR. Endpoint analyses included cell surface expression, and ligand-induced second messenger responses (α-MSH-induced cAMP response for MC4R and ghrelin-induced Ca2+ mobilization for GHSR), β-arrestin-2 recruitment, and internalization. WT MRAP2 significantly decreased basal MC4R cell surface expression by 68.1±4.3% (p<0.001). In the absence of MRAP2, α-MSH induced MC4R internalization. However, in the presence of WT MRAP2, MC4R cell surface expression was increased by 89.4±6.9% upon α-MSH stimulation (p<0.001). GHSR cell surface expression and ghrelin-induced internalization were not affected by WT MRAP2. Furthermore, in the cells expressing MC4R with WT MRAP2, the maximal α-MSH-induced cAMP and β-arrestin-2 recruitment responses were increased by 29.8±5.2% and 81.3±4.2% respectively (p<0.001), compared with those lacking MRAP2. We also investigated GHSR ghrelin-induced Ca2+ mobilization and found that, in the presence of WT MRAP2, this increased significantly by 95.37±21.9%, (p<0.0003). However, ghrelin-induced β-arrestin-2 recruitment was suppressed by 69.8±7.6%, (p<0.001). Using these endpoints we found no effect of the variants on the ability of MRAP2 to modulate ligand-induced signaling by MC4R and GHSR. Our results indicate that WT MRAP2 enhances the cAMP response by increasing MC4R cell membrane expression upon α-MSH stimulation, and enhances GHSR Ca2+ mobilization by decreasing β-arrestin-2 recruitment upon ghrelin stimulation. The MRAP2 variants assessed in this study behaved as WT MRAP2 in α-MSH-induced MC4R and ghrelin-induced GHSR signaling, suggesting that these may be benign variants. However, since MRAP2 can modulate multiple receptors, we cannot rule out that these MRAP2 variants affect other appetite-regulating receptors and thereby influence body weight regulation via other pathways.

Presentation: 6/3/2024
7354 A Case of Continuous Glucose Monitoring in Children with Glutamate Dehydrogenase Hyperinsulinism
Authors: Kim Kyung Hee , Mun Eunji , Eun Choi Jung , Lee Rosie , Soon Kim Hae
Published: October 2024

Disclosure: K. Kim: None. E. Mun: None. C. Jung Eun: None. R. Lee: None. K. Hae Soon: None.

A Case of Continuous Glucose Monitoring in Children with Glutamate Dehydrogenase(GLUD1) Hyperinsulinism Background: Continuous glucose monitoring (CGM) is increasingly being used in pediatric patients with diabetes. CGM can help prevent hypoglycemia and support the management of hypoglycemic problems. Congenital hyperinsulinism is a rare condition in which hypoglycemia occurs due to hyperinsulinemia caused by the dysregulation of insulin secretion, and it can lead to complications such as developmental delay and seizures. Case presentation: A 14 months years old, male infant was referred to the pediatric emergency room representing symptoms of GTC type seizure during 2-3 minutes and hypoglycemia. He had no perinatal problems with no significant family history. During seizure, He was found to have a blood glucose of 39mg/dL, ammonia of 183μmol/L, insulin of 28.3 mcg/mL and ketone 203.4μmol/L. C-peptide was 1.4 ng/mL (≥ 0.5ng/mL) and free fatty acid was 0.492mmol/L (<1.7mmol/L) for evaluation. He was thought to have GDH hyperinsulinism. Blood glucose level was followed up with feeding frequency and protein restricted diet. Congenital hyperinsulinism genetic test was requested. Brain CT showed normal. EEG revealed no focal abnormalities, no persistent asymmetries. CGM was used in patient. Diazoxide was started with 5mg/kg/day in 2 divided doses and then blood glucose level was observed below 60mg/dL 3-4 times for day. Complete blood counts and uric acid levels were measured at baseline and 5 days after starting diazoxide therapy, and thereafter increase to 6.25mg/kg/day Conclusions: In children with GDH hyperinsulinism, the utilization of CGM can serve as a tool to assess the impact of treatment before and after medication therapy, as well as also aiding in hypoglycemia prevention.

Presentation: 6/2/2024
9296 A Novel LC-MS/MS Salivary Fludrocortisone Method With Potential for Monitoring in Adrenal Insufficiency Patients
Authors: Dolan Megan , Marshall David , Hawley James , Reisch Nicole , Keevil Brian G
Published: October 2024

Disclosure: M. Dolan: None. D. Marshall: None. J. Hawley: None. N. Reisch: None. B.G. Keevil: None.

Fludrocortisone (FC) is a fluorinated exogenous mineralocorticoid used to treat conditions associated with adrenal insufficiency including Addison’s disease and classic congenital adrenal hyperplasia (CAH). The mineralocorticoid action of FC allows the drug to compensate for aldosterone deficiency, thus helping to maintain blood pressure and other homeostatic mechanisms. Optimising FC replacement is vital as under-replacement can cause dizziness and hypotension, whereas over-replacement can lead to cardiometabolic disturbances. Treatment in classic CAH patients, who are typically diagnosed as new-borns, is even more complex as the requirement for mineralocorticoid replacement decreases with age. Endocrine Society guidelines recommend that FC monitoring should involve the clinical assessment of symptoms, which can be non-specific, and regular blood pressure measurements. Plasma renin activity (PRA) should be measured if clinical changes occur, aiming towards the upper end of the reference range. The utility of PRA is debated due to methodological issues and the inherent variability of the analyte itself, which may not always represent FC replacement status. Therefore, investigation into alternative biochemical markers of FC replacement is required. Here we aimed to facilitate this by developing an LC-MS/MS method for the measurement of salivary FC. Method: A salivary FC LC-MS/MS assay has been developed and validated for use according to FDA and EMA guidelines. Passive drool samples from 10 clinical trial patients with classic CAH were collected on two separate occasions at select time points throughout the day (0800, 1200, 1600, 2000 and 2300h). In most patients the 0800h sample was taken pre-FC dose. Once in the laboratory the patient samples were extracted and analysed using the FC method to produce a FC concentration day curve. Results: The method analysis time was 2.1 minutes, with a mean recovery of 102% and limit of quantification of 5 pmol/L (2.1 pg/mL). No analytical interference was identified. Analysis of patient samples using the method showed the presence of FC allowing the production of day curves. In most patients, the pre-dose sample contained no FC, with the subsequent samples showing a peak FC concentration corresponding to the Cmax. After this the FC concentration gradually tapered off throughout the remainder of the day. Conclusions: We have developed a novel assay for the measurement of salivary FC, which may allow the calculation of the area under the curve. As an optimal FC dose has yet to be determined this method may facilitate more in-depth pharmacokinetic studies into FC metabolism and blood pressure control. Thereby identifying patients that are fast metabolisers or poor absorbers of the medication, enabling a non-invasive strategy to optimise patient care.

Presentation: 6/1/2024
12212 A Rare Case Of Central Precocious Puberty In A Male Infant With Adrenal Hypoplasia Congenita
Authors: Mastoropoulou Aikaterini , Lane Andrew Harry
Published: October 2024

Disclosure: A. Mastoropoulou: None. A.H. Lane: None.

Introduction: We describe a male with Adrenal Hypoplasia Congenita (AHC) caused by a novel mutation in NR0B1, who was noted at 9 months of age to have central precocious puberty (CPP). Clinical case: A 3 week-old full-term male presented with hypothermia and lethargy, and a 0.3 kg weight loss since birth. Labs were consistent with adrenal crisis: Na 109 mmol/L, K 10.4 mmol/L, Ca 12.2 mg/dL, glucose 43 mg/dL. He was stabilized with stress dose hydrocortisone (HC), insulin and antibiotics, and was admitted. Subsequent labs revealed cortisol 3.5 ug/dL (4.6-23), ACTH 1,123 pg/mL (7.2-63), 17OHP 181 ng/dL (<199), and a renin of 180 ng/mL/h (1.7-11.2) with aldosterone 14.9 ng/dL (6-179). Abdominal ultrasound was remarkable for non-visualization of the adrenal glands. The patient was discharged with HC, fludrocortisone and sodium supplementation with good tolerance and interval weight gain and normal electrolytes. Genetic testing identified a novel pathogenic c.707G>A [p.Trp236Ter] nonsense variant in the DNA-binding domain of NR0B1 (DAX-1). At 9 months of age, penile enlargement with prepubertal testes was noted. Testosterone was 318 ng/dL (Tanner stage I: 0-18), LH 3.2 mIU/mL (prepubertal: 0-0.3), DHEA-S 2 ug/dL (0-33), FSH 1.1 mIU/mL (prepubertal: 0-1), consistent with hypothalamic pituitary gonadal (HPG) axis activation. Given previous reports of prolonged but self-resolving “mini-puberty of infancy” in AHC, observation was initially chosen. At 12 months of age the bone age was consistent with the Greulich and Pyle 17 months standard. At 13 months of age testosterone remained elevated, therefore based on others’ reported experiences we increased HC from 8 to 15 mg/m2/day and noted a decrease in testosterone to 104 ng/dL within 5 days. HC was further increased to 18 mg/m2/day for 15 days, however testosterone increased to 270 ng/dL, therefore decision was made to treat with Lupron Depot. Conclusions: Historically, hypogonadotropic hypogonadism has been observed in 76% of adolescent patients with AHC who have alterations in NR0B1. CPP has been infrequently described in AHC, and the natural history and management of CPP in this setting is not established. CPP in AHC does not seem to correlate with any particular functional domain of DAX1, because previously reported NR0B1 variants associated with CPP, and this case’s, are dispersed across the gene. The course of our patient suggests multiple underlying mechanisms, including early HPG axis activation as well as the possibility of ACTH dependent precocious puberty. Our observations may contribute to the understanding of factors influencing normal and abnormal puberty in infants. Increased awareness of the possibility of CPP in AHC will aid clinicians in the earlier clinical and laboratory detection of this complication.

Presentation: 6/1/2024
8450 Accelerometer-based Sedentary Time and Physical Activity with the Risk of Severe Liver Steatosis and Liver Cirrhosis in 2684 Children: A 13-Year Longitudinal and Mediation Study
Authors: Agbaje A O
Published: October 2024

Disclosure: A.O. Agbaje: None.

Background: Non-alcoholic fatty liver diseases have been associated with physical inactivity in adults. However, long-term evidence on the prospective relationship of accelerometer-measured sedentary time (ST), light physical activity (LPA), and moderate-to-vigorous PA (MVPA) with liver steatosis and fibrosis and changes in liver enzymes in a large paediatric population is scarce. Hypothesis: It was hypothesized that increased ST from childhood through young adulthood would increase the risk of severe liver steatosis and cirrhosis and worsen liver enzymes, whereas engaging in LPA and MVPA would reduce the risk. Methods: From the Avon Longitudinal Study of Parents and Children (ALSPAC), UK birth cohort, 2684 children aged 11 years who had at least one follow-up time-point accelerometer-measured ST, LPA, and MVPA over a period of 13 years, and liver indices and enzymes measures at age 24 years clinic visit were included. Liver steatosis and fibrosis were assessed by transient elastography (FibroScan 502 Touch) and categorized as fibrosis stage F0-F4 and steatosis grade (S0-S3) at age 24 years. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transferase (GGT) were assayed at ages 17 and 24 years. Longitudinal associations were examined using generalized linear mixed-effect models, while mediation analyses were conducted with structural equation models. Results: Among 2684 children (mean [SD] age, 11.75 [0.24] years; 1537 [57.3%] females]), ST increased from 6 hours/day in childhood to 9 hours/day in young adulthood, while LPA decreased from 6 hours/day to 3 hours/day and MVPA was relatively stable at 50 minutes/day. The prevalence of liver cirrhosis [F4, ≥11·7 kPa] and severe liver steatosis [S3, controlled attenuation parameter value ≥280 dB/m] is 0.3 and 10%, respectively. Cumulative 1-minute/day increase in ST from ages 11-24 years was associated with higher odds of liver cirrhosis (odds ratio 1.004 [95% CI 1.002 - 1.005] p<0.001) and severe liver steatosis (1.001 [1.001 - 1.002] p=0.002) at age 24 years. Increased ST from childhood was directly associated with increased ALT, AST, and GGT from ages 17 - 24 years. Cumulative 1-minute/day LPA was associated with lower odds of liver cirrhosis (0.990 [0.990 - 0.991] p<0.001) and severe liver steatosis (0.999 [0.998 - 0.999] p<0.001) at age 24 years, as well as decreased liver enzymes. Cumulative 1-minute/day MVPA was associated with associated with lower odds of severe liver steatosis (0.996 [0.994 - 0.998] p<0.001) but not liver cirrhosis at age 24 years. MVPA effect on lowering liver steatosis was significantly suppressed (64% suppression) by increased fat mass. Conclusions: Increasing LPA, sustaining MVPA, and decreasing ST from childhood may independently attenuate and reverse the risk of severe liver steatosis and cirrhosis by young adulthood.

Presentation: 6/1/2024