bluuebunny/crossref_metadata_2025 huggingface dataset:
TMPRSS6 gene polymorphisms associated with iron deficiency anaemia among global population
Authors: Mohd Atan Farah Nur Elina , Wan Mohd Saman Wan Asmuni , Kamsani Yuhaniza Shafinie , Khalid Zalizah , Abdul Rahman Amirah
Published: November 2022

Iron deficiency anaemia (IDA) has been recognised as a common global health problem that affects more than 1.2 billion people worldwide, particularly in high-risk individuals such as young children, pre-menopausal women, and pregnant women. In most cases, IDA arises due to the prolonged effect of iron deficiency (ID). On the other hand, it has been estimated that iron deficiency without anaemia is more frequent nowadays. Apart from the lack of nutrients, infections and inflammatory diseases, genetic factors can also be another factor that drives iron instability in the blood, leading to IDA. Previous studies, including genome-wide association studies, have identified multipletransmembrane protease serine 6 (TMPRSS6)genetic variants associated with different iron parameters, especially variants contributing to an increase in hepcidin level, low blood, and iron status. Despite multiple studies onTMPRSS6gene polymorphisms, fewer studies are reported among the Asian population. Thus, further association studies ofTMPRSS6genetic polymorphisms between ID and IDA are warranted among the Asian population. This review provides a comprehensive summary of the causativeTMPRSS6genetic variants and their roles associated with iron deficiency among the global population.
Mammalian Target of Rapamycin Inhibition Decreases Angiotensin II-Induced Steroidogenesis in HAC15 Human Adrenocortical Carcinoma Cells
Authors: Ali Yusuf , Gomez-Sanchez Elise P , Gomez-Sanchez Celso E
Published: November 2022

Background

Mammalian target of rapamycin (mTOR) inhibitors suppress adrenal cortical carcinoma cell proliferation and cortisol production; the relationship between mTOR and aldosterone production has not been examined.

Methods

HAC15 cells were incubated with an mTOR activator and several inhibitors including AZD8055 (AZD) in the presence and absence of angiotensin II (AngII). The expression of rapamycin-sensitive adapter protein of mTOR (Raptor) and rapamycin-insensitive companion of mTOR (Rictor), adaptor proteins of mTOR complex 1 and 2, respectively, were studied in the HAC15 cells and deleted by CRISPR/gRNA.

Results

The mTOR inhibitors decreased aldosterone induced by AngII. Inhibition of mTOR by AZD significantly suppressed AngII-induced aldosterone and cortisol formation in a dose-dependent manner, whereas the mTOR activator MHY had no effect. AZD did not alter forskolin-induced aldosterone production showing that it is specific to the AngII signaling pathway. AngII-mediated ERK and mTOR activation were suppressed by AZD, along with a concomitant dose-dependent reduction of AngII-induced steroidogenic enzymes including steroidogenic acute regulatory protein, 3β-hydroxysteroid dehydrogenase-type 2, CYP17A1, and aldosterone synthase protein. Furthermore, mTOR components ribosomal protein S6 kinase (P70S6K) and protein kinase B phosphorylation levels were decreased by AZD. As mTOR exerts its main effects by forming complexes with adaptor proteins Raptor and Rictor, the roles of these individual complexes were studied. We found an increase in the phosphorylation of Raptor and Rictor by AngII and that their CRISPR/gRNA-mediated knockdown significantly attenuated AngII-induced aldosterone and cortisol production.

Conclusion

mTOR signaling has a critical role in transducing the AngII signal initiating aldosterone and cortisol synthesis in HAC15 cells and that inhibition of mTOR could be a therapeutic option for conditions associated with excessive renin–angiotensin system-mediated steroid synthesis.
ODP017 A case of an infected pheochromocytoma presenting as an acute abdomen: case report.
Authors: Sutharsan Shamila , Singarayar Dr Carolina , Foo Dr Siew Hui
Published: November 2022

This is a case of a 41 years old gentleman who had presented with a 3 day history of severe left sided abdominal pain associated with vomiting 6 years prior in 2015. He had a CT abdomen at that time which showed acute cholecystitis and a left adrenal lesion arising from the lateral limb with a size of 2.8×2.9cm with a HU of 139 and less than 60% washout. He was treated with antibiotics for 3 days however he took an AOR discharge once he felt better. A 24 hour urine cathecolamines were sent during that admission. Subsequently he had defaulted his follow up and presented again 6 years later in May 2021 to another hospital with severe sharp left hypochondriac pain of 2 weeks duration with a pain score of 6/10 associated with vomiting. He was hypertensive at 190/100mmHg, tachycardic at 117 beats/min, febrile at 40 degrees Celcius and had associated hyperglycemia with a blood glucose of 28mmol/L with no metabolic acidosis. His blood investigations revealed a raised white cell count of14.7×10 9 /L with a normal renal and liver profile. He was started on a intravenous antibiotics, variable rate insulin infusion and kept nil by mouth. An urgent CT abdomen done showed a large mass of 9.8×10.1×12.5cm with a mean HU of 25 suggestive of solid cystic mass arising from the left adrenal. His previous cathecolamines from year 2015 was traced and the epinephrine level was 2x elevated at 46mcg/day. He was started on oral Phenoxybenzamine 10mg BD and further titrated to 10mg TDS. Propanolol 40mg BD was given as well. He was only given oral Phenoxybenzamine for 3 days (usually needing 1 week) as an emergency left adrenalectomy was done due to worsening pain not relieved by analgesics and ileus. He had an open left adrenalectomy, splenectomy and distal pancreatectomy. Intraoperative findings weregeneralized pus contamination, stomach, small and large bowel grossly dilated without any perforation, infected left adrenal tumour 10×8cm with no clear plane with distal pancreas including splenic vein due to desmoplastic reaction. During surgery his blood pressure was ranging between 110-140mmHg (systolic) and 60-80mmHg (diastolic). Intra – op, his blood pressure was supported by a low dose noradrenaline which was discontinued within a few hours post surgery. Histopathalogy examination showed neutrophilic infiltrates forming microabscesses with necrosis amounting 60% of the total tumour. The ragged area of the adrenal gland shows mainly inflammation and fibrosis with no evidence of tumour. A final diagnosis of infected pheochromocytoma was given. After surgery, he recovered well and did not need antihypertensives and was discharged with oral glucose lowering agents.

Presentation: No date and time listed
ODP020 A Challenging Case of Poorly Differentiated Carcinoma with Neuroendocrine Differentiation and Adrenal Mass
Authors: Mosquera Jorge , Oo Yin , Milburn Joseph
Published: November 2022

Background

Neuroendocrine tumors (NETs) account for about 0.5% of all newly diagnosed malignancies. The most frequent primary sites are the gastrointestinal tract or pancreatic (62%-67%) and the lung (22%-27%). All poorly differentiated NETs have a Ki-67 index of greater than 20% and WHO grade of 3. The determination of the site of origin can be challenging in widely metastatic poorly differentiated NETs.

Clinical Case

A 51-year man with a history of hypertension and type 2 diabetes mellitus presented with angioedema while on lisinopril for years. Apart from a month's history of bilateral flank pain, he denied diarrhea, flushing, stridor, or shortness of breath. CT abdomen showed an 8.2×8. 0×7.9 cm right adrenal mass with a few punctate calcifications, hepatomegaly with multiple liver metastases, multiple retroperitoneal, hepatoduodenal, retrocrural adenopathy, and T4 metastatic lesion. CT chest showed bulky mediastinal and supraclavicular lymph nodes with trachea narrowing. All those lesions were FDG avid on PET/CT scan. Core biopsy of right supraclavicular lymph node revealed a poorly differentiated carcinoma with neuroendocrine differentiation and high proliferative index (25-50%). On cell block, it was negative for (AE1/AE3 (-), CAM5.2 (-), CK7, CK20, vimentin, desmin, CEA, EMA, CD45, CD20, and TTF-1 but positive for CK903 (focal +), synaptophysin (+), chromogranin (+), calretinin (focally +), inhibin (focally +). Based on the immunohistochemical stain, it was concluded as a metastatic small cell carcinoma of unknown origin. He was treated with carboplatin, etoposide, and atezolizumab and received 5 cycles. Endocrine was consulted two months after his initial presentation. Urine normetanephrine was > 4-fold elevated. Blood pressure was controlled on Doxazosin at 4 mg bid. The 10 gene-panel for hereditary pheochromocytoma and Paraganglioma (PGL) was negative. There was a progression of mediastinal adenopathy while on treatment with narrowing of proximal intrathoracic trachea requiring elective tracheostomy. Based on imaging findings and elevated normetanephrine, we believe he has metastatic pheochromocytoma and PGL. His chemo regimen was switched to Cyclophosphamide, Vincristine, and Dacarbazine (CVD). He finished 8 cycles of CVD with an overall reduction in the size of lymph nodes (both above and below the diaphragm) and right adrenal mass. His plasma normetanephrine level was also significantly improved.

Presentation: No date and time listed
ODP603 Impact of CME at Improving Knowledge, Competence and Confidence Related to Management of Cushing Disease
Authors: Larkin Amy , Maeglin John
Published: November 2022

Introduction

We sought to determine if an online continuing medical education (CME) activity could improve knowledge, competence and confidence of primary care physicians (PCPs) and endocrinologists (endos) related to management of patients with Cushing disease (CD).

Methods

Educational design included a "test, then teach" approach to elicit cognitive dissonance, with evidence-based feedback provided following each learner response. A repeated pairs pre-/post-assessment study design was used and McNemar's test (5% significance level, P .8 large). The activity posted June 22, 2021, and data were collected through August 27, 2021.

Results

Overall, 74% of PCP learners (N=468, Cohen's d=.96) and 75% of endo learners (N=81, Cohen's d=1.14) improved their knowledge/competence(both P

Presentation: No date and time listed
PMON154 Cardiovascular Complications in Acromegaly-A National Inpatient Sample Analysis
Authors: Thota Geethika , Raj Kavin , Dewan Sandesh
Published: November 2022

Introduction

Cardiovascular complications are the frequent cause of death in Acromegaly. Most of the prior studies on the epidemiology of cardiovascular complications in Acromegaly had a small sample size due to the rarity of Acromegaly. We wanted to investigate the prevalence of cardiovascular risk factors and cardiovascular diseases in patients with Acromegaly in a large sample size using the NIS (National inpatient sample)

Methods

We utilized the National inpatient sample (NIS) 2016, 2017, and 2018 for our analysis. All patients with Acromegaly were included. The frequency of different cardiovascular risk factors and cardiovascular diseases was estimated.

Results

A total of weighted 5654 weighted hospitalizations (95% CI 5220-6089) with Acromegaly were included. Out of these, 15% had heart failure, 20% had cardiac arrhythmias, 7% had valvular diseases, 3% had pulmonary circulation disorders, 6.9% had peripheral vascular diseases. 42.1% had hypertension with no complications, 13.9% had hypertension with complications, 2% had paralysis, 17.7% had Diabetes mellitus without complications, 15.2% had Diabetes mellitus with complications, 20.9% had obesity, 33% had dyslipidemia, 11.6% had nicotine dependence, and 4.7% had a family history of myocardial infarction. The mean elixhauser comorbidity score was 2.9. A total of 33% of patients had pituitary surgery at the time of hospitalization.

Discussion

Cardiovascular risk factors and cardiovascular diseases remain a significant issue in acromegaly patients. Hypertension was the most common cardiovascular risk factor, and cardiac arrhythmias were the most common cardiovascular disease. Acromegaly patients have a higher risk for mortality than the general population due to cardiovascular complications. This is directly correlated with increased IGF-1 levels which can be eliminated with surgery. However, 80-90% of patients do not cure despite surgery. Hence, aggressive control of the cardiovascular risk factors and strict biochemical control is necessary to reduce cardiovascular mortality in acromegaly patients. Acromegaly patients should be regularly screened for cardiovascular risk factors, and they should receive guideline-directed management of these conditions. Potential limitations of our study include the retrospective nature, lack of documentation of pituitary resection, and the exact treatment received in the outpatient for Acromegaly in NIS.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
PMON157 Evidence For Locally Produced Cortisol in Pituitary Tissue
Authors: Tsai Karen , Bergsneider Marvin , Vinters Harry , Wang Marilene , Zhang Dongyun , Heaney Anthony
Published: November 2022

Double or multiple pituitary adenomas are rare and account for only 1.6-3.3% of all corticotroph tumors. We describe 2 distinct pituitary corticotroph adenomas in a 43-year-old female presenting with ACTH-dependent Cushing disease (CD). Although pre-operative pituitary MRI noted a single 8×6mm left sided pituitary microadenoma, which was confirmed at trans-nasal trans-sphenoidal surgery, she was found to an additional 7mm right sided microadenoma. Histopathology confirmed 2 separate corticotroph adenomas and she exhibited immediate remission of her CD with nadir cortisol of 1mcg/dL. Whole exome sequencing demonstrated a somatic mutation in the 21-alpha-hydroxylase (CYP21A2) gene in both tumors. CYP21A2 transcript and protein expression were absent in the index case but both CYP21A2 transcript and protein were demonstrated in a series of 9 other pituitary corticotroph adenomas and 12 normal pituitary tissues. This unusual case which prompted us to examine CYP21A2 expression in the pituitary allows us to describe for the first time evidence of locally generated pituitary-derived cortisol and indicate this could play a paracrine role on the corticotroph and may contribute to growth of ACTH pituitary adenomas in some instances.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
PMON71 Evaluation of a new transition organization for young adults with endocrine or metabolic diseases
Authors: Roux Enora L , Touraine Pr Philippe
Published: November 2022

Objective

To evaluate the effect of a new care organisation on outcomes of transition success Design. Non-randomized controlled trial in a French University Hospital.

Methods

Patients transferred to adult care during the control period (04/2014-08/2016) and the intervention period (09/2016-06/2018) were included. The intervention is based on case management involving liaising with pediatric services, personalising care pathways, and liaising with structures outside hospital (general practitioner, educational and social sector).

Results

202 patients were included (101 per period), the most represented pathologies were congenital and non-congenital hypopituitarism (respectively n=34 (17%) and n=45 (22%)) and thyroid diseases (n=21, 10%). Patients were aged 22.5 in median at 24 months post transfer where 12 were lost to follow up in the control group versus 9 with the intervention (p=0.49). The percentage of honoured consultation among those planned during 24 months was higher with intervention (p=0.0065). Patient satisfaction, physician trust, transfer delay did not differ between the groups. The incremental cost-effectiveness ratio was €179 per patient not lost to follow-up.

Conclusions

At 24 months post transfer the rate of lost to follow-up does not differ significantly, but indicators of a steadier follow-up are increased and the intervention appears to be cost-effective.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
PMON89 Nephrogenic Diabetes Insipidus in a Patient on Temozolomide
Authors: Moll Teresa , Lott David , Wright Virginia , Lien Lillian , Subauste Jose
Published: November 2022

A 54-year-old female admitted for nausea and vomiting found to have hypernatremia. Four months prior to this admission, patient had undergone emergent craniotomy for an intraparenchymal hemorrhage. Found to have a 7.8 cm hemorrhagic and partially necrotic mass. Pathology consistent with anaplastic oligodendroglioma. She began radiation and temozolomide 2 months after surgery. On this admission for nausea and vomiting, sodium noted to be elevated at 154 mmol/L (136-145 mmol/L). Initially thought to be due to dehydration and started on intravenous fluids. Urine output noted to increase to 2-3 liters/day with persistently elevated sodium. Urine studies and labs collected while sodium 155 mmol/L significant for urine osmolality 128 mOsm/kg (50-1200 mOsm/kg), serum osmolality 330 mOsm/kg (280-295), and urine sodium 34 mmol/L. Given patient's history of prior craniotomy, radiation, and temozolomide, suspected central diabetes insipidus but DDAVP challenge with 4 mcg did not result in a lower urine output and urine osmolality remained <300 mOsm/kg. Repeat DDAVP challenge produced similar results. Evaluation of other central axis deficiencies revealed normal Free T4 (1.21 ng/dL). Unable to assess for adrenal insufficiency due to patient already on high-dose steroids for malignancy. Workup was turned to potential nephrogenic etiology as patient had been started on pantoprazole during her initial diagnosis 4 months prior. Co-peptin while sodium 148 mmol/L returned at 27.6 pmol/L (<13.1 pmol/L), indicative for nephrogenic diabetes insipidus. Patient was started on amiloride 5 mg twice a day and hydrochlorothiazide 25 mg twice a day with improvement noted in both sodium and urine output. Did discuss renal biopsy to rule-out interstitial nephritis from pantoprazole but given patient was on anti-coagulation for sub-massive pulmonary embolism, biopsy was deferred. Ultimately patient was discharged on amiloride 10 mg and hydrochlorothiazide 25 mg daily with sodium 142 mmol/L. She continued to receive temozolomide but eventually both amiloride and hydrochlorothiazide were held during a subsequent admission about a month later due to hyponatremia from poor oral intake. Sodium remained stable for about 5 months off medication at which time patient was re-started on amiloride for hypernatremia. Unfortunately patient passed due to complications from thrombosis. Review of PubMed revealed only 1 additional case report of a patient on temozolomide who developed nephrogenic diabetes insipidus but that patient was also on sulfamethoxazole-trimethoprim which was most likely the cause.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
PMON91 Late Presentation of Pituitary Apoplexy Following Gonadotropin-Releasing Hormone Agonist for Prostate Cancer Treatment
Authors: Raj Rishi , Elshimy Ghada , Owen Douglas
Published: November 2022

Background

Pituitary apoplexy (PA) is characterized by sudden increase in pituitary gland volume secondary to ischemia and/or necrosis. Certain predisposing factors can result in PA and use of gonadotropin-releasing hormone (GnRH) agonist for prostate cancer (PCa) is one such condition. We present a case of 59-year-old male who had insidious onset of PA following leuprolide administration, resulting in late presentation of PA.

Case Presentation

A 59-years old male was referred to the endocrinology clinic for evaluation of pituitary enlargement found on MRI brain in June 2021. He complained of fatigue, anorexia, unintentional weight loss, diplopia, and blurry vision, which developed insidiously and gradually worsened over six months. In 2014, he was diagnosed with stage 4 PCa (Gleason Score=8) with metastasis to the lymph nodes, ribs, and pelvic bones and underwent palliative radiation for bone metastasis and androgen deprivation with intramuscular leuprolide 22.5 mg every 3 months between July 2014 till July 2020. On presentation, he was hemodynamically stable and visual field testing was negative. Anterior pituitary hormone evaluation revealed panhypopituitarism with low serum ACTH 5 pg/ml (7.2-63.3 pg/ml), cortisol 2.9 mcg/dl (5-15 mcg/dl), TSH 0.53 mclIU/ml (0.6-4.7 mclIU/ml), Free T4 0.27 ng/dl (0.58-1.76 ng/dl), IGF-1 58 ng/ml (54-258 ng/ml), LH 0.3 mIU/ml (1.5-9.3 mIU/ml), FSH 1 mIU/ml (1.4-18 mIU/ml) and testosterone < 3 ng/dl (1.5-9.3 ng/dl). Pituitary MRI July 2021 demonstrated subacute hemorrhage inside the pituitary gland which was not present in prior MRI in September 2020. Based on laboratory work up showing secondary adrenal insufficiency and central hypothyroidism, as well as pituitary imaging confirming apoplectic event, he was diagnosed with PA secondary to GnRH agonist use. He was initially treated with stress dose of steroids followed by prednisone 5 mg daily and levothyroxine 75 mcg daily. He had significant improvement of symptoms over next few weeks including near complete resolution of visual symptoms.

Conclusion

Given high prevalence of PCa and increased use of GnRH agonists, more patients will develop PA, which was once thought to be extremely rare. Furthermore, it is critical that patients receiving GnRH agonists should be evaluated for possible PA, even in the absence of acute symptoms, which is classically seen in PA.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
PMON94 Collision tumor with Rathke cleft cyst and co existing Cushing's disease
Authors: Mittal Ashima , Jaiswal Gayatri
Published: November 2022

Introduction

- Collision tumors, i.e., co-occurring distinct histopathological lesions are rare. We present a case of a 48-year-old female present with co-existing Rathke cleft cyst (RCC) and pituitary adenoma with Cushing disease.

Case

- 48-year-old female presented for evaluation of an incidental sellar mass with enlarged pituitary noted on MRI brain. The patient complained of symptoms of mental fogginess, confusion, intermittent dizziness for the last 1 year. The patient had complained of easy bruising with no reported weight gain, change in facial appearance, proximal muscle weakness. MRI brain showed mildly enlarged pituitary measuring 13 mm with RCC.Past medical history was significant for recent-onset Type 2 Diabetes and Hypertension. The examination was unremarkable with no signs of Cushing's syndrome. Lab work showed elevated ACTH of 51 pg/ml (10-48) with AM cortisol level of 14.7 mcg/dl (6- 18.4). IGF-1 levels elevated at 307 ng/ml (77- 220). LH, FSH, FT4, prolactin levels were normal. Given elevated ACTH levels, further testing showed elevated midnight salivary cortisol at 0.22 and 0.239 mcg/dl (0.010-0.090), elevated 24-hour urine cortisol 141 ug/ 24 hrs. (6- 44), absence of suppression with 1 mg dexamethasone with cortisol 12.4 mcg/dl (< 1.8), ACTH 123 pg/ml (10-48) with dexamethasone levels 432 ng/dl (140- 295). Lab work was consistent with ACTH-dependent hypercortisolism. MRI pituitary showed 7.5×7.8 mm RCC.8 mg dexamethasone suppression test and CT chest, abdomen, and pelvis were performed to differentiate between ectopic Cushing's and Cushing's disease. Cortisol levels suppressed greater than 50% after 8 mg dexamethasone from baseline cortisol – 17.7 mcg/dl and ACTH 67 pg/ml to cortisol 3.4 mcg/dl and ACTH – 34 pg/ml with dexamethasone levels of 3120 ng/dl (1600–2850). CT chest abdomen, pelvis showed no evidence of bronchial carcinoid or other potential lesions. With neuroimaging findings and biochemical confirmation of Cushing's disease, the patient underwent transsphenoidal resection.

Discussion

– The association between RCC and pituitary adenoma was found in 0.5–1.9% cases per literature review1, co-occurrence with ACTH producing pituitary adenoma being rarer. The diagnosis of collision tumors can be challenging as the most common presentation on imaging is a cystic mass. Appropriate biochemical testing is indicated based on clinical presentation, initial laboratory testing, and level of suspicion. Elevated ACTH levels along with diabetes and hypertension led to a diagnosis of Cushing's disease in our patient with the initial presentation of an incidental RCC. The knowledge about collision tumors is important, especially in unusual presentations as in our case.

References

Sagan KP et al. Cushing's Syndrome in a patient with Rathke's cleft cyst and ACTH cell hyperplasia detected by 11C-Methionine PET Imaging-A Case Presentation. Front Endocrinol (Lausanne). 2020; 11: 460. Published 2020 Jul 22.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
OR08-5 Associations Between Signal Transducer and Activator of Transcription (STAT) Mutations and Galactorrhea
Authors: Al-Naqeeb Ghadah , Cypess Aaron , Zenno Anna , Jumani Sanjay
Published: November 2022

Background

Prolactin (PRL) is responsible for the development of mammary glands and milk production. STAT1 and STAT3 are genes that express transcription factors that mediate PRL's intracellular signaling, but an association between their function and galactorrhea has not yet been identified. Here we describe three patients with somatic STAT mutations and galactorrhea.

A 27-year-old woman with hyper-IgE syndrome (Job's Syndrome) due to a STAT3 deletion mutation (p.Val463del) associated with recurrent infections reported thin, white, bilateral discharge with breast manipulation beginning in adolescence. She did not have spontaneous leakage or pain. At presentation, PRL was slightly elevated to 27.9 (ref. 2.0-25.0 mcg/L) with otherwise normal levels of anterior pituitary hormones. She was not on any drugs known to cause hyperprolactinemia. MRI showed a 5×4 mm microadenoma without any mass effect.

A 32-year-old woman also with Job's syndrome due to a heterozygous loss-of-function STAT3 mutation (p.R382Q) associated with recurrent infections and papillary thyroid cancer described unilateral, chronic, thin, white nipple discharge with light touch of her right breast for "as long as she could remember." She had a history of breast abscesses, but at presentation there was no evidence of abscess or infection. PRL was 15.1 mcg/L, and other anterior pituitary hormones were normal. MRI showed a structurally normal pituitary.

A 22-year-old woman with a STAT1 activating mutation (p.E235A) associated with recurrent infections, autoimmune hypothyroidism, T1DM, and hypogonadotropic hypogonadism requiring pubertal induction at age 12y reported bilateral galactorrhea starting at age 18y. A white, milky discharge could be expressed with light manipulation, but no discharge was produced spontaneously. PRL was 16.2 mcg/L with serial dilution and has consistently been in the reference range. Anterior pituitary evaluation was normal except for elevated TSH of 12.5 (ref. 0.27-4.2) consistent with autoimmune hypothyroidism. MRI revealed a diffusely enlarged pituitary gland (12mm in the cranio-caudal dimension) without focal hypo-enhancement.

Conclusions

It is known that PRL signaling involves the JAK/STAT pathway, and an analysis of human milk cells showed upregulated STAT3 and downregulated STAT1 during lactation (PMID 26909879). These three cases provide clinical evidence for a mechanistic connection between STAT signaling and galactorrhea and suggest that STAT3 and STAT1 function in opposite directions to regulate lactation. In our cases, increased STAT1 or decreased STAT3 activity are associated with normal-PRL, inducible galactorrhea. Beyond understanding the specific intracellular signaling pathways leading to galactorrhea, these observations may be utilized for developing therapies for those with impaired lactation.

Presentation: Saturday, June 11, 2022 12:30 p.m. - 12:45 p.m.
ODP042 Hereditary Pheochromocytoma with a Novel Mutation in the Succinate Dehydrogenase Subunit A gene
Authors: Karuppasamy Gowri , Farooqi Amer , Sajid Sadia , Elouzi Elhadi
Published: November 2022

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumorswith a diverse clinical presentation. Pathogenic variants in the genes encoding different subunits of the succinate dehydrogenaseenzyme complex that plays a central role in energy metabolism,have been linked to hereditary PPGL syndromes. Here wereport a rare case of hereditary pheochromocytoma with a novel mutation in the succinate dehydrogenase subunit A (SDHA) gene. A middle aged woman presented with left sided abdominal pain and was incidentally found to have bilateral adrenal lesions on abdominal imaging. She denied any symptoms of catecholamine excess but her plasma metanephrines level was elevated. Family history was significant for breast cancer in her motherand sister. Computed tomography (CT) scan of the abdomen showed bilateralbulky adrenal glands with a lesion in theleft adrenal gland. Magnetic resonance imaging (MRI) abdomen was performed for further characterization, the lesion measured approximately 2.8×2.6 cm with imaging characteristics suggestive of pheochromocytoma. Iodine-131 Metaiodobenzylguanidine (MIBG) whole body scan showed abnormal focal radiotracer uptake at the left adrenal gland, and she then underwentleft sided robotic adrenalectomy. Following surgery, the patient had symptomatic relief. Histopathology confirmed the diagnosis of pheochromocytoma measuring 2×2×1.5 cm with PASS (Pheochromocytoma of the Adrenal gland Scaled Score) score of 1/10, due to cellular monotony. Genetic testing revealed that she was positive for a pathogenic mutation in the SDHA gene consistent with the diagnosis of hereditary PPGL syndrome. Genetic testing was performed for the patient due to her presentation with bilateral adrenal masses and family history of cancers. Guidelines recommend genetic testing for patients with features that indicate a high likelihood of a hereditary cause for PPGL, including positive family history, syndromic features, and multifocal, bilateral, or metastatic disease. SDHA mutated PPGLs have diverse phenotypes and may be at high risk of metastasis. They are also associated with extra-adrenal tumors, include gastrointestinal stromal tumours (GIST), pituitary adenomas, papillary thyroid carcinoma, renal carcinoma and breast carcinoma. The detection of susceptibility genes for hereditary PPGL syndromes has key implications, for surveillance to detectextra-adrenal disease and recurrent tumors, as well as for consideration of genetic testing forfamily members.

Presentation: No date and time listed
PMON181 RGS4 Is Essential For The Sympathetic Regulation of The Short-chain Fatty Acid Receptor FFAR3 In The Heart
Authors: Carbone Alexandra , Cora Natalie , Desimine Victoria , Ghandour Jennifer , Goldberger Jeffrey , Iacobellis Gianluca , Suster Malka , Valiente Rachel , Wang Gaofeng , Lymperopoulos Anastasios
Published: November 2022

Background

Free fatty acids (FFAs) are essential cell nutrients but also important signaling molecules regulating various cellular processes. Short-chain fatty acids (SCFAs), like propionate and butyrate, activate two different types of G protein-coupled receptors (GPCRs), FFAR2 and FFAR3. FFAR3 (also known as GPR41) couples to Gi/o proteins lowering cyclic 3', 5'-adenosine monophosphate (cAMP) levels and activating mitogen-activated protein kinases (MAPKs). In addition to adipose tissue, FFAR3 is highly expressed in peripheral sympathetic ganglia augmenting sympathetic nervous system (SNS) outflow. Regulator of G protein Signaling (RGS)-4 belongs to the RGS superfamily of proteins and inactivates (terminates) both Gi/o- and Gq-protein signaling. Cardiac RGS4 has been implicated in atrial fibrillation (AFib) prevention via calcium signaling attenuation. Finally, β-adrenergic receptors (ARs), the major mediators of catecholaminergic and SNS actions in cardiac myocytes, stimulate cAMP synthesis and activate protein kinase A (PKA), which is known to activate RGS4 via phosphorylation.

Objective

We examined whether RGS4 regulates cardiac FFAR3 signaling.

Methods

We used H9c2 cardiomyocytes transfected to express the human FFAR3. After treatment with catecholaminergic agonists and/or propionic acid plus various pharmacological inhibitors and siRNA to deplete RGS4, we performed signaling assays (western blotting, cAMP accumulation, GTP binding, ELISA) to delineate the precise involvement of RGS4 in the cardiac βAR-FFAR3 signaling crosstalk.

Results

RGS4 is essential for the dampening of propionate/FFAR3-dependent signaling in H9c2 cardiomyocytes since siRNA-mediated RGS4 depletion significantly enhances the effect of propionic acid on cAMP lowering, Gi/o activation, and p38 MAPK activation. Notably, concomitant isoproterenol or salbutamol treatment blocks propionic acid-induced signaling via the FFAR3 in H9c2 cardiomyocytes, indicating negative regulation of FFAR3 by catecholamines via the β2AR. Mechanistically, this is mediated by RGS4, since neither isoproterenol, nor salbutamol can inhibit propionate signaling upon siRNA-mediated RGS4 depletion. Finally, β2AR inhibition of FFAR3 signaling via RGS4 is dependent on β2AR-activated PKA, because pre-treatment with the PKA inhibitor H89 abrogates the catecholaminergic inhibition of FFAR3 signaling in H9c2 cardiomyocytes, as measured by cAMP lowering, downstream p38 MAPK activation, and interleukin (IL)-6 production.

Conclusion

Catecholamine-activated RGS4 abrogates SCFA/FFAR3 signaling and function in cardiac myocytes. This may represent part of the mechanism via which RGS4 protects against both AFib pathogenesis and FFAR3-promoted SNS hyperactivity and inflammation in the myocardium.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
ODP372 A Rare Case Of Cornelia de Lange Syndrome With Hyperinsulinism And Hypopituitarism
Authors: Greve Katherynne , Chang Eric
Published: November 2022

Background

Cornelia de Lange syndrome (CdLS) is characterized by slow growth with short stature, intellectual disability with developmental delays, distinctive facial features, and limb defects. Various genetic mutations have been associated with CdLS, with approximately 60% of cases having a mutation in the NIPBL gene. There are few published reports of endocrine disorders in individuals affected by CdLS.

Clinical Case

A four month old female was admitted for hypoglycemic seizures. She had previously undergone workup for CHARGE syndrome. Physical exam was remarkable for acrocephaly, malar hypoplasia, hypertelorism with downslanting eyes, hirsutism, and bradydactyly. During her hospitalization, she remained persistently hypoglycemic despite repeated dextrose boluses, prompting a scheduled fasting test. Results indicated severe hypoglycemia (37 mg/dL) with inappropriate suppression of beta-hydroxybutyrate (0. 08 mmol/L) and negative urine ketones. Her glucagon stimulation test result showed an exaggerated increase of the glucose greater than 30 mg/dL after glucagon administration (glucose was 31 mg/dL at the start of the test; peak glucose was 77 mg/dL after receiving 0. 03 mg/kg of glucagon), indicating excessive glycogen stores. These findings were consistent with hyperinsulinism. Furthermore, she was found to have an undetectable cortisol (<1. 0 ug/dL) with hypoglycemia, prompting a low dose ACTH stimulation test with results consistent with central adrenal insufficiency (baseline ACTH: <5 pg/mL, baseline cortisol: <1. 0 ug/dL, peak cortisol after receiving 10 micrograms of cosyntropin was 1.1 ug/dL). Additional evaluation revealed a low free T4 (0.5 ng/dL). Interestingly, the initial TSH was 6.46 uIU/mL, which later became undetectable (<0. 05 uIU/mL), consistent with central hypothyroidism. Ultimately, a brain MRI showed sella turcica hypoplasia with absence of the dorsum sella as well as corpus callosum hypoplasia and a thin pituitary infundibulum. The child was treated with diazoxide, hydrocortisone, and levothyroxine with improvement in clinical course. Genetic testing eventually confirmed CdLS, showing a heterozygous variant mutation (c.8077_8079dupGAC: p. D2693dup) in exon 47 of NIPBL gene, classified as autosomal dominant.

Conclusion

There are very few clinical reports that mention either hyperinsulinism or hypopituitarism in an individual affected by CdLS. This patient is a rare documented case of CdLS presenting with both hyperinsulinism and hypopituitarism. Further understanding of the different genetic mutations seen with CdLS could help identify atypical forms of CdLS associated with endocrinopathies and more clearly direct unifying treatment.

Presentation: No date and time listed
ODP378 Biliary Sludge in a Neonate with Congenital Hypothyroidism
Authors: Dorado Juan Pablo Hayes , ALACA Fortunato Amachuy , Vargas Gerben Justiniano , Ortiz Alexis Bellot , Ayala Marco Antonio Calla , Tapia Emilene Coca
Published: November 2022

Background

Most cases of congenital hypothyroidism are asymptomatic. When signs are evident, they are nonspecific. Characteristic clinical findings, including prolonged jaundice are seen in less than 5% of affected neonates.

Clinical Case

Female newborn, full term, appropriate weight for gestational age, five days old, Kramer zone 3 jaundice. The laboratory ruled out hemolysis, blood group incompatibility and TORCH infections. Hepatobiliary ultrasound showed biliary sludge. The screening for congenital hypothyroidism reported a TSH value of 38 mlU/L; the free T4 value was analyzed and was low. With the diagnosis of congenital hypothyroidism, levothyroxine therapy was started. The biliary sludge disappeared two weeks after initiation of hormone therapy.

Conclusion

It is important to exclude other causes of biliary sludge formation, such as sepsis, parenteral nutrition, hemolytic disease, metabolic diseases, some drugs and pyloric stenosis. Congenital hypothyroidism may be associated with biliary sludge formation; thyroid hormones have an inhibitory effect on the contractility of the sphincter of Oddi.

Presentation: No date and time listed
ODP383 Clinical Presentation and Management of Diabetes Mellitus in Youth with Prader-Willi Syndrome
Authors: Paprocki Emily , Eickhoff Paige , Sweeney Brooke , Halpin Kelsee
Published: November 2022

Background

Diabetes mellitus (DM) is reported in 7–24% of adults with PWS. It is thought that abnormal glucose metabolism develops as a consequence of severe obesity and/or insulin resistance. Given obesity and insulin resistance often develop in childhood in children with PWS, DM occurs in youth as well. There are limited data detailing the clinical presentation of DM, diabetes complications, and therapies used in pediatric patients with PWS.

Methods

A retrospective chart review of patients less than 21 years of age with genetically confirmed PWS seen July 2014 through July 2021 was performed. Patients were included if they also had a diagnosis of DM based on a single value meeting American Diabetes Association criteria: fasting blood glucose of ≥ 126 mg/dL, HbA1c ≥ 6.5%, 2-hour blood glucose of ≥ 200 mg/dL on oral glucose tolerance test, or random blood glucose of ≥ 200 mg/dL with symptoms of hyperglycemia.

Results

Of the 88 patients identified with PWS, nine (10%) were found to have DM. Means and range sat diabetes diagnosis were age 11.4 years (7–16), HbA1c8.2% (6.6– 12.4), BMI 38.7 kg/m2 (23.1–73.6),and BMI z-score2.4 (1.3–3.1). Five patients were female. Six patients were non-Hispanic white, two non-Hispanic black, and one Hispanic. Of these nine patients with DM, six had at least three diabetes autoantibodies assessed. All antibodies were negative in three patients, two patients had a weakly positive islet cell antibody only, and one patient had all four autoantibodies positive. Most patients were identified incidentally on screening laboratory evaluation in clinic, two patients had polyuria, and one patient was admitted with vomiting and mixed diabetic ketoacidosis/hyperosmolar hyperglycemic syndrome (DKA/HHS). Diabetes treatment methods included one patient on metformin only; four on metformin and insulin; three on metformin, insulin, and GLP1 receptor agonist; and one patient on insulin only. Of the six patients on insulin, only two were using short acting insulin with meals. No patients were treated using insulin pumps or continuous glucose monitors. No patients underwent bariatric surgery. Only one patient had hypertension requiring treatment with medication. No patients had nephropathy, dyslipidemia, neuropathy, or retinopathy.

Conclusions

DM is seen in children with PWS and often diagnosed incidentally. Regular screening is important as development of DKA/HHS is possible if diabetes goes unrecognized. While type 2 diabetes is more common than type 1 diabetes, diabetes antibodies should be measured. Standards of care for treatment are lacking resulting in variability in therapeutic regimens. Fortunately, despite markedly elevated BMI at DM diagnosis, diabetes comorbidities are not commonly seen.

Presentation: No date and time listed
OR18-6 Tracking the Diagnosis and Progression of Madelung Deformity in Pediatric Turner Syndrome Patients
Authors: Backeljauw Philippe F , Gutmark-Little Iris , Little Kevin , Huron Alex
Published: November 2022

Background

Turner syndrome (TS) is a chromosomal anomaly occurring in females which presents with numerous medical and developmental manifestations including skeletal deformities. A specific developmental skeletal dyplasia seen in TS patients is Madelung deformity (MD), characterized by a growth deficiency of the distal radial physis that causes excessive radial inclination and volar tilt, with resultant ulnocarpal impaction. Surgical intervention, particularly in early stages, can halt progression of or reverse MD. Despite a considerable body of literature highlighting the presence of MD in TS, it is often underdiagnosed, in part due to a lack of data documenting the epidemiology and natural history.

Objective

Analyze the frequency of diagnosis of MD in patients meeting key radiographic threshold criteria and document the time course of the deformity in these patients using these parameters.

Methods

From a database of 264 patients with a confirmed diagnosis of TS, bone age radiographs for 187 (71%) were retrospectively measured against generally accepted cutoffs for MD using two parameters: ulnar tilt = UT and lunate subsidence = LS. For patients meeting general inclusion criteria of UT > 33° or LS < 0 mm, historical measurements of UT and LS were obtained using past bone ages and patients’ charts were reviewed to determine if a clinical diagnosis of MD was made.

Results

7 patients (7/187 = 3.7%) met overall inclusion criteria and had radiographs consistent with Madelung Deformity. Of these 7, only one clinical diagnosis (14%) of MD was made; this patient underwent subsequent surgical intervention. The 6 undiagnosed patients had an average UT and LS of 40.5 degrees and -4.4 mm at the time of most recent bone age (∼16.3 years old). The time-courses for 4 (UT) and 3 (LS) of the 6 non-surgical patients were plotted over time from 7.2–18.9 years of age. Patients crossed threshold at an average age of 15.3 and 13.6 years for UT and LS, respectively. Average maximum read-to-read growth rates of 5.3 degrees and 3.5 mm occurred at an average age of 15.3 (UT) and 14.2 years (LS).

Conclusion

Our results suggest MD is significantly underdiagnosed in patients with TS, highlighting the need for better screening tools to make this diagnosis. This would include physical examination looking for the characteristic wrist deformity and careful analysis of bone age radiographs at an earlier age, when corrective surgery is more likely to succeed. We recommend careful scrutiny of yearly bone age radiographs from 10-15 years of age to ensure that the diagnosis of MD is not missed, and obtaining bilateral wrist radiographs (PA and Lateral views) for verification. Future research should focus on documenting disease progression using radiographic trends, as well as assessing how onset and progression are affected by therapeutic interventions such as growth hormone.

Presentation: Monday, June 13, 2022 12:15 p.m. - 12:30 p.m.
PMON188 Frequency of Hemoglobin A1c and Body Mass Index Increase in Youth at Risk for Developing Type 2 Diabetes Mellitus During the COVID-19 Pandemic
Authors: Wee Erica , Sherman Ashley K , Clements Mark A , Halpin Kelsee , Yan Yun
Published: November 2022

BACKGROUND: Childhood obesity rates continue to increase and have progressed with the COVID-19 pandemic. Obesity is associated with comorbidities, including prediabetes and type 2 diabetes mellitus (T2D). The frequency of HbA1c progression in overweight/obese children during the COVID-19 pandemic is not well reported.

OBJECTIVES: To investigate the frequency of HbA1c and BMI increase in overweight/obese youth at risk of developing T2D during the COVID-19 pandemic.

METHODOLOGY: A retrospective chart review of patients followed in a pediatric endocrinology clinic with overweight/obesity and concern of developing T2D was conducted. We included patients who were seen pre-pandemic (June 2019 to May 2020) and again after the pandemic onset (June 2020 to May 2021). We chose June 2020 as the pandemic onset since our clinic resumed in-person visits at this time. Demographic and clinical data, including BMI and HbA1c, were collected in the pre-pandemic and pandemic periods for each patient. We evaluated change in HbA1c using the following categories: Category 1: <5.7%, Category 2: 5.7-6%, Category 3: 6.1-6.4%, Category 4: 6.5-8.4%, and Category 5: >8.4%. HbA1c progression defined as increase in the HbA1c category. BMI progression defined as a z-score increase of at least 0.2 and we only included patients with 6-18 months between visits for this analysis. Chi-square or Fisher's exact test and t-test were used to evaluate HbA1c and BMI progression.

RESULTS: A total of 64 patients (mean age 12.6 years, 58% female, 31% Black) were evaluated and had available HbA1c data. HbA1c progression was found in 18.8% (12 of 64) of patients during the pandemic. Based on pre-pandemic age, those with HbA1c progression had a mean (SD) age of 14.1 (2.3) years while those whose HbA1c did not progress had a mean (SD) age of 12.3 (2.7) years (p=0.04). Other characteristics including birth sex (p=0.18), race (p=0.54), and insurance (public/private/self-pay) (p=0.83) were not significantly different between those with and without HbA1c progression. We found that 9.1% of patients with HbA1c progression also had BMI progression compared to 6.7% without HbA1c progression (p= 1.0).

SUMMARY: We found that 18.8% of overweight/obese youth with risk of developing T2D had HbA1c progression during the COVID-19 pandemic and that older age was a risk factor for HbA1c progression. Significant BMI increase was not associated with HbA1c progression. Further studies are needed to evaluate the impact of COVID-19 pandemic on HbA1c and BMI progression in youth at risk for T2D.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
PMON190 Characterization Of Lymphedema With Respect To Phenotype and Karyotype in Patients With Turner Syndrome
Authors: Law Jennifer , Ross Judith , Ikomi Chijioke , Blatt Julie , Truxon Alyssa , Lawler Corinne
Published: November 2022

We characterize karyotypic and phenotypic features of a cohort of patients with Turner syndrome (TS) and lymphedema (LD).

Medical records from two large TS specialized pediatric clinics were reviewed retrospectively. Seventy-one patients with TS and history of LD were identified, mean age 15.9 ± 7.71 years. Reported LD onset was in infancy in 72% of patients, with 56% (40/71) reporting LD present at birth. LD affected hands in 29% of patients, feet in 57%, and both hands and feet in 25%. 46% reported LD was a current problem, with 11% stating it was present but not a problem. 73% (52/71) of children in this cohort had the 45,X karyotype. The remainder had mosaic/complex karyotypes. 55% of children had congenital heart disease and 10% had renal anomalies. 76% were on growth hormone treatment, 52% had a history of estrogen replacement.

Lymphedema is a frequently under-documented comorbidity in Turner syndrome, with limited data currently available. Analysis of a larger cohort comparing patients with TS with and without LD is underway including the role of growth hormone and estrogen replacement in LD. Given that new therapies are being developed for LD in other genetic conditions, a better understanding of LD in Turner syndrome is important for management considerations.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.