Evaluation For Secondary Causes Research Articles

Polymorphic ventricular tachycardia and cardiac arrest from abiraterone-induced hypokalemia: a case report

BackgroundPolymorphic ventricular tachycardia (PMVT) is an unstable and often fatal cardiac tachyarrhythmia. While there are many causes of this rhythm, including electrolyte imbalances, ischemia, and genetic disorders, iatrogenic etiologies are important to recognize. Abiraterone is an androgen synthesis antagonist effective in treating prostate cancer, but here we describe a case of severe hypokalemia secondary to abiraterone resulting in polymorphic ventricular tachycardia and cardiac arrest. While this is a potential adverse effect of the medication, severe hypokalemia causing polymorphic ventricular tachycardia and cardiac arrest, as seen in our patient’s case, has not been described.Case presentationA 78-year-old African-American man with history of prostate cancer presents with polymorphic ventricular tachycardia and cardiac arrest. After resuscitation, he was found to be severely hypokalemic and refractory to large doses of repletion. Evaluation of secondary causes of hypokalemia identified the likely culprit to be adverse effects from prostate cancer treatment.ConclusionA broad differential diagnosis for polymorphic ventricular tachycardia is essential in identifying and treating patients presenting in this rhythm. Here we present a case of iatrogenic polymorphic ventricular tachycardia secondary to oncologic treatment.

World Health Organization and International Consensus Classification of eosinophilic disorders: 2024 update on diagnosis, risk stratification, and management.

The eosinophilias encompass a broad range of non-hematologic (secondary or reactive) and hematologic (primary or clonal) disorders with the potential for end-organ damage. Hypereosinophilia (HE) has generally been defined as a peripheral blood eosinophil count greater than 1.5 × 109/L, and may be associated with tissue damage. After the exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of various tests. They include morphologic review of the blood and marrow, standard cytogenetics, fluorescence in situ hybridization, molecular testing and flow immunophenotyping to detect histopathologic or clonal evidence for an acute or chronic hematolymphoid neoplasm. Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2022 World Health Organization and International Consensus Classification endorse a semi-molecular classification scheme of disease subtypes. This includes the major category "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions" (MLN-eo-TK), and the MPN subtype, "chronic eosinophilic leukemia" (CEL). Lymphocyte-variant HE is an aberrant T-cell clone-driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion. The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., <1.5 × 109/L) without symptoms or signs of organ involvement, a watch and wait approach with close follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Pemigatinib was recently approved for patients with relapsed or refractory FGFR1-rearranged neoplasms. Corticosteroids are first-line therapy for patients with lymphocyte-variant HE and HES. Hydroxyurea and interferon-α have demonstrated efficacy as initial treatment and in steroid-refractory cases of HES. Mepolizumab, an interleukin-5 (IL-5) antagonist monoclonal antibody, is approved by the U.S Food and Drug Administration for patients with idiopathic HES. Cytotoxic chemotherapy agents, and hematopoietic stem cell transplantation have been used for aggressive forms of HES and CEL, with outcomes reported for limited numbers of patients. Targeted therapies such as the IL-5 receptor antibody benralizumab, IL-5 monoclonal antibody depemokimab, and various tyrosine kinase inhibitors for MLN-eo-TK, are under active investigation.

Intracranial Hypertension as a rare presentation of Sjögren's Syndrome: a case report

Introduction. A rare extraglandular manifestation of Sjögren's syndrome is presented, mimicking idiopathic intracranial hypertension. Case Report. A young eutrophic female, complained of persistent headache, followed by diplopia and bilateral sixth nerve paresis. Neuroimaging investigation showed classic signs of intracranial hypertension. As the patient had a normal weight, prompted evaluation of secondary causes, which revealed positive anti-SSA/Ro and anti-La/SSB antibodies. A salivary gland biopsy later confirmed the diagnosis of Sjögren's syndrome. Xerostomia and dysphagia developed weeks later. Conclusion. This case report is important to raise awareness about an atypical neurological manifestation of Sjögren's syndrome.

THU438 A Case Of Pregnancy Associated Osteoporosis

Abstract Disclosure: S. Maradana: None. F. Iqbal: None. M. Safran: None. Background: Pregnancy associated osteoporosis (PAO) is a rare form of osteoporosis that is seen in late pregnancy and early post-partum period. Hip and vertebral body are most involved in PAO. Common clinical manifestation is back pain, and many patients suffer from vertebral fractures and kyphosis causing great physiologic burden and negative impact on quality of life. We report a case of PAO with good response to teriparatide. Clinical case: A 27-year-old female with no significant past medical history presented with severe acute back pain two months after delivery of her second child, whilst still breast feeding. Imaging studies demonstrated acute compression fractures of T12, L1, L2 and L3 vertebrae. She had regular monthly menstrual cycles prior to pregnancy with no previous history of fractures. Her pre pregnancy weight was 135 lbs and she had been physically active, while caring for her older son. Family history is notable for osteoporosis in multiple paternal aunts and maternal grandmother with no family history of fractures. There were no other identifiable risk factors. Evaluation for secondary causes of osteoporosis showed 25-OH vitamin D levels of 23 ng/mL (NL 30-100 ng/mL), TSH 1.72 uIU/mL (NL 0.28-3.8 uIU/mL), PTH 19 pg/mL (NL 14-64 pg/mL), calcium 9.7 mg/dL (NL 8.7-10.7 mg/dL), phosphorus 4 mg/dL (NL 2.5-4.5 mg/dL), tryptase 4 mcg/L (NL &amp;lt;11 mcg/L), alkaline phosphatase 111 U/L (NL 30-115 U/L) and 24-hour urine calcium 168 mg (NL 100-300 mg). Urine immune electrophoresis and serum immunofixation did not show any evidence of monoclonal gammopathy. DEXA scan showed low BMD with Z-score of −4.4 SD in lumbar spine -3.1 in femoral neck. She was diagnosed with PAO. She stopped breast feeding after the diagnosis. As the bone mineral density was very low, she was started on teriparatide along with calcium and vitamin D supplementation. One year after treatment initiation, her DEXA scan showed improved bone mineral density with Z-score of −3.5 in lumbar spine and −1.9 in femoral neck. Her osteoporosis is currently being managed with teriparatide with plan to continue for a total duration of 24 months. Conclusion: PAO is under-recognized and under-reported, with limited available evidence on the management. Spontaneous improvement in BMD is known to occur in 6-12 months after pregnancy and lactation have been completed, although, the addition of anti-resorptive treatment in this setting may result in superior BMD gain compared with calcium and vitamin D supplementation alone. Use of teriparatide has shown to have significant increase in BMD and help with pain relief in PAO. Teriparatide has helped with improving the BMD in our patient. Nevertheless, controlled trials are lacking, and the optimal timing of teriparatide use in these women remains uncertain. Presentation: Thursday, June 15, 2023

FRI149 Internal Medicine Residents Knowledge On Testing For Treatment Resistant Hypertension With The Focus On Primary Aldosteronism - Interim Analysis

Abstract Disclosure: N. Markovic: None. M. Brankovic: None. A. Palani: None. D. Matassa: None. Studies have shown that primary aldosteronism (PA) is an underlying cause in up to 23% of patients diagnosed with treatment-resistant hypertension (TRH).1 However, recent data have suggested that less than 2% of TRH patients would undergo testing for PA despite strong guideline recommendations.2 Given that PA is an easily diagnosed and treatable cause of TRH, our goal was to identify modifiable factors that can increase diagnosis of secondary causes of TRH. Therefore, we aimed to investigate the residents’ knowledge on diagnosis and evaluation of TRH with the focus on PA. This anonymous survey included Internal Medicine residents during their Ambulatory Clinic Rotation. The response rate was 66% with equal distribution across PGY 1-3. Total of 75% of residents defined TRH correctly, but only 66% of all residents would pursue additional testing to identify the secondary causes of TRH in patients who meet criteria for TRH. On average, only 45% of all residents reported having at least one patient with TRH in the past six months. Upon stratification, this percentage increased among PGY-3 residents (61%). Most residents (96%) knew that the renin-to-aldosterone ratio is an appropriate screening method for PA. Appropriately when listed possible options for evaluation of secondary causes of TRH 93% of residents would order plasma renin activity, and 87% would order plasma aldosterone concentration. Among other tests that residents would perform are: TSH (87%), renal ultrasound with arterial Doppler (75%), CBC (34%), and almost one third of residents (27%) would order transthoracic echocardiogram. Furthermore, 43% of residents would discontinue both ACE/ARB and spironolactone, whereas 25% would discontinue only spironolactone for 6 weeks before testing. Sixty percent of residents were interested in learning more about TRH.The most striking finding of this study is that despite most of the residents appropriately identified tests for secondary causes of TRH, only two thirds of residents would investigate secondary causes of TRH in their practice. This may be the contributing factor for underdiagnosis of PA. Additional guidance on therapy that does not interfere with screening tests for PA is needed. In phase 2 of this study, we plan to provide more education in this area to improve the blood pressure control and decrease the risk of cardiovascular morbidity and mortality in TRH patients.

Case report: malignant hypertension associated with catecholamine excess in a patient with Leigh syndrome

BackgroundLeigh syndrome is a progressive neurodegenerative mitochondrial disorder caused by multiple genetic etiologies with multisystemic involvement that mostly affecting the central nervous system with high rate of premature mortality.Case presentationWe present a 3-year, 10 month-old female patient with Leigh syndrome complicated by renal tubular acidosis, hypertension, gross motor delay, who presented with hypertensive emergency, persistent tachycardia, insomnia and irritability. Her previous genetic workup revealed a pathogenic variant in the MT-ND5 gene designated as m.13513G > A;p.Asp393Asn with a heteroplasmy of 69%. She presented acutely with malignant hypertension requiring intensive care unit admission. Her acute evaluation revealed elevated serum and urine catecholamines, without an identifiable catecholamine-secreting tumor. After extensive evaluation for secondary causes, she was ultimately found to have progression of her disease with new infarctions in her medulla, pons, and basal ganglia as the most likely etiology of her hypertension. She was discharged home with clonidine, amlodipine and atenolol for hypertension management. This report highlights the need to recognize possible autonomic dysfunction in mitochondrial disease and illustrates the challenges for accurate and prompt diagnosis and subsequent management of the associated manifestations. This association between catecholamine induced autonomic dysfunction and Leigh syndrome has been previously reported only once with MT-ND5 mutation.ConclusionsElevated catecholamines with malignant secondary hypertension may be unique to this specific mutation or may be a previously unrecognized feature of Leigh syndrome and other mitochondrial complex I deficient syndromes. As such, patients with Leigh syndrome who present with malignant hypertension should be treated without the need for extensive work-up for catecholamine-secreting tumors.

Approach to dysmenorrhoea in primary care.

Approach to dysmenorrhoea in primary care.

PMON101 Fluctuating Insulin Requirements in Untreated Acromegaly: From 200-to-0

Abstract Introduction Acromegaly is a clinical disorder that occurs from autonomous production of growth hormone (GH). Diabetic ketoacidosis (DKA) is an uncommon and late complication of acromegaly. Acromegaly presenting in DKA prognosticates glycemic management with insulin-based regimens. Cessation of insulin therapy, however, can be achieved in patients with acromegaly after proper medical and/or surgical interventions. Our case highlights a unique outcome in a patient with newly-diagnosed acromegaly that initially presented in DKA with very high insulin requirements and was ultimately de-escalated off all anti-hyperglycemic therapy with significant glycemic improvement prior to any treatment for acromegaly. Clinical Case A 32 year-old male with a past medical history of colorectal cancer and no known history of diabetes presented to the emergency department for evaluation of generalized weakness, epigastric pain, nausea, and vomiting and was admitted for DKA. Hemoglobin A1c was 11.6% (reference range &amp;lt; 5.7%), confirming the diagnosis of newly-diagnosed diabetes. C-peptide was 1.4 ng/mL (reference range 0.5-3.3 ng/mL) and anti-glutamic acid decarboxylase, anti-islet cell, and anti-zinc transporter 8 antibodies were all negative. He was initiated on intravenous insulin infusion, with rates achieving &amp;gt; 200 units of insulin per day. Given severe insulin resistance in conjunction with acromegalic features on physical exam and a unique history of colorectal cancer at a young age without any family history, evaluation for acromegaly was initiated. Human GH level was 68.60 ng/mL (reference range 0.05-3.00 ng/mL) and insulin-like growth factor-1 (IGF-1) level was 1,036 ng/mL (reference range 82-242 ng/mL). MRI brain revealed a hypoenhancing 1.3 cm lesion enlarging the left lateral pituitary gland. Diagnosis of acromegaly due to a GH-secreting macroadenoma was established. The patient was discharged on a high-dose insulin regimen in addition to metformin therapy with de-escalation off of all anti-glycemic therapy within a few weeks of diagnosis; at his 3 month follow-up visit, his repeat hemoglobin A1c was 6.1 with repeat GH level of 28.8 ng/mL and IGF-1 level of 1602 ng/mL, despite not yet undergoing any treatment for the underlying condition. Conclusion DKA as an initial presentation of acromegaly has been previously reported in literature, however, not with a concomitant history of colon cancer. Moreover, no previous cases of acromegaly have reported glycemic normalization off of anti-hyperglycemic therapy prior to any treatment for acromegaly. Our case highlights that evaluation for secondary causes, including acromegaly, should be considered in patients with severe insulin resistance and emphasizes the dramatic range of insulin requirements that patients with acromegaly may have. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PSAT016 Deoxycorticosterone-Producing Adrenocortical Carcinoma: A Rare Cause of Resistant Hypertension

Abstract Background Rare causes of secondary hypertension should be considered after negative initial evaluation for more common conditions. 11-Deoxycorticosterone-secreting tumors are one such rare cause. Clinical Case A 38-year-old male with two-year history of resistant hypertension on four antihypertensive medications (amlodipine, hydrochlorothiazide, lisinopril, spironolactone) presented to the emergency room with one-day history of headaches and hypertension. Initial vitals were blood pressure of 179/117, heart rate 68, respiratory rate 18, and SpO2 of 100% on room air. Labs were notable for hypokalemia of 2.2, normal creatinine of 1.03, and troponin elevation of 0.08. EKG showed no ischemic changes. During the hospital admission, spironolactone dose was increased, amiloride was added, hydrochlorothiazide was discontinued, and potassium was supplemented. The patient's blood pressure stabilized, and troponin normalized. Evaluation for secondary causes was also initiated, including plasma renin, aldosterone, and metanephrines, with results pending on discharge. Outpatient CT abdomen and pelvis was also ordered. The patient was discharged on the third day of admission on an increased dose of spironolactone 100mg daily, amiloride 5mg daily, amlodipine 10mg daily, lisinopril 40mg daily, and potassium 20meq twice daily. Laboratory studies and outpatient endocrinology evaluation revealed suppressed plasma renin activity 0.1 ng/mL/hr, low aldosterone &amp;lt;3.0 ng/dL, elevated 11-deoxycorticosterone (DOC) 869 ng/dL (reference range ≤19 ng/dL), and elevated 11-deoxycortisol 719 ng/dL (reference range ≤49 ng/dL). Plasma and urine metanephrines, 24-hour urinary free cortisol, and plasma DHEAS were normal. CT revealed a large 9.7×10.0×10.7cm heterogeneously enhancing right adrenal mass and several subcentimeter bilateral pulmonary nodules. FDG PET-CT showed mild heterogeneous uptake of the adrenal mass with SUVmax of 5.1 and hepatic SUVmean of 2.5, without convincing metabolic evidence of metastasis. Mild uptake was noted in the mediastinal, hilar and left axillary lymph nodes, which were not suspiciously hypermetabolic and favored to be reactive, perhaps related to recent COVID-19 vaccination administered to the left upper extremity. The subcentimeter pulmonary nodules did not have increased avidity. The patient underwent open right adrenalectomy without complications. Pathology revealed 11.5cm low-grade adrenocortical carcinoma with clear margins and angioinvasion, Ki67 proliferation index of 1-2%, and without necrosis, lymphovascular invasion, or extra-adrenal extension. 11-deoxycortisol normalized and DOC was undetectable at one and three months postoperatively. Blood pressure improved significantly, and all antihypertensives were discontinued except amlodipine 10mg daily. On surveillance CT scan six months after surgery, there was no evidence of residual disease in the adrenalectomy bed and pulmonary nodules appeared stable. Conclusions Adrenocortical carcinomas rarely produce aldosterone and even less commonly produce DOC as the major steroid product. DOC should be evaluated in the setting of hypertension with hypokalemia, suppressed renin and aldosterone. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PSAT015 A Rare Case of Incidental Massive Pheochromocytoma with Ectopic Parathyroid Hormone Secretion

Abstract Background Pheochromocytoma (PC) is a rare neuroendocrine tumor with an annual incidence of 2 to 8 cases per million that can secrete excess catecholamines precipitating hyper-adrenergic symptoms. In rarer instances, PCs can also secrete substances other than catecholamines. Case A 51-year-old female underwent MRI lumbar spine that demonstrated an incidental 13 cm right adrenal mass. History was significant for newly diagnosed hypertension and a five-year history of episodic headaches, diaphoresis, palpitations and anxiety. A previous cardiac evaluation including Holter monitor, echocardiogram, and stress test was unrevealing. Physical exam was significant only for chronic back pain and BMI 20.4. Labs revealed elevated serum catecholamines with metanephrines and normetanephrines &amp;gt;40x and &amp;gt;65x the upper limit of normal respectively, elevated urine catecholamines and elevated chromogranin A suggestive of PC. Labs also demonstrated mild hypercalcemia &amp;gt;10.3 mg/dL (8.6-10.4 mg/dL) with elevated PTH 78 pg/mL (14-64 pg/mL) and low vitamin D 25-OH 25 ng/mL (30-100 ng/mL). Calcitonin, albumin and phosphorus were normal. She was treated with non-competitive alpha and beta-blockade and metyrosine before undergoing successful right adrenalectomy. Post-operative labs demonstrated normalization of catecholamines, PTH and calcium. Surgical pathology confirmed the diagnosis of PC and demonstrated tumor cells which stained for PTH confirming ectopic PTH secretion, a rare phenomenon. The PC was very large with an elevated PASS (Pheochromocytoma of the Adrenal Gland Scaled Score) indicating increased risk for malignancy/recurrence; however, there was low Ki-67 activity and no capsular involvement, which suggested benign behavior. Furthermore, an MIBG scan was negative for metastatic disease, and an extensive genetic workup for familial PC/PGL (including MEN, RET, SDHx) was negative. Conclusion PC is a rare neuroendocrine tumor that can secrete excess catecholamines precipitating hyper-adrenergic symptoms and potentially fatal complications including hypertensive crises, cardiovascular disease, ischemia and multi-organ failure if untreated. Consequently, early recognition of PCs is imperative. The patient in this case had a five-year history of symptoms seen with PC and newly diagnosed hypertension despite normal BMI and negative cardiac workup. However, she had no evaluation for secondary causes of hypertension. Despite the large tumor size and significantly elevated catecholamines, she functioned without significant morbidity potentially due to adrenergic receptor desensitization. This case also highlights the rare phenomenon of ectopic secretion in PCs, specifically ectopic PTH secretion. A 2019 systemic review identified only 150 cases of pheochromocytomas/paragangliomas with ectopic hormone secretion – of those, only 17 secreted PTH or PTH-related peptide [1]. It is important to consider ectopic secretion in patients with PCs as they may have additional clinical manifestations associated with the hormone or substance secreted. Fortunately, this patient had no overt manifestations of hyperparathyroidism or hypercalcemia.

ODP291 A Series of COVID Reinfections in a Vaccinated Patient leading to Development of Neurogenic Orthostatic Hypotension and Postural Orthostatic Tachycardia

Abstract The recently recognized 'long COVID' syndrome, encompasses symptoms of shortness of breath, chest pain, palpitations and orthostatic intolerance which can last for weeks or more following even mild illness. 'Long COVID' is postulated to be related to a virus- or immune-mediated disruption of the autonomic nervous system resulting in orthostatic intolerance syndromes. We report a 32-yr old female nurse who presented to the endocrinology clinic for symptoms of orthostatic hypotension following two COVID 19 infections. She had received 1 dose of Moderna vaccine in February and March of 2021 respectively. She was hospitalized for COVID June and September of 2021. Following the first hospitalization, she developed severe orthostatic hypotension, chest pain, shortness of breath, fatigue, anxiety, memory, concentration and word finding difficulty. Blood pressure ranged from 110/78 to 124/82 while lying and from 85/45 to 103/59 while standing. HR ranged from 88 to 96 while lying and from 130 to 42 while standing. She was started on midodrine 10 mg three times daily which was discontinued due to patient intolerance. She followed a regimen of adequate hydration, adequate salt intake, fall precautions, physical and speech therapy and high protein/low carb diet with frequent snacks, which improved her symptoms of dizziness and orthostasis, but without complete resolution. However, symptoms of anxiety, dizziness, chest pain and palpitations became even worse after the second hospitalization. She was started on Propranolol 20 mg 2-3 times daily depending on symptoms, and she felt better with this intervention. Evaluation for secondary causes of hypotension were all negative [Cortisol of 19 ug/dL (n=5.3-22.5); ACTH 20 pg/mL (n=0-47); TSH 2.36 uIU/mL (n=0.358 -3.74); Free T4 0.97 ng/dL (n=0.76-1.46); B12 480 pg/mL (n=193-986); Hba1c 4.9%; 25 OH Vitamin D 24.3 ng/mL; tryptase 3.7 mcg/L (n= &amp;lt;11); Sed rate 4 mm/HR (n=0-20). CBC, CMP, TPO and Tg abs, troponin levels, iron studies, ANA panel, Rheumatoid factor, anti-CCP abs, myasthenia gravis panel], CT head and MRI brain, EKG and QTc interval. Echocardiogram= small PFO. 'Post-acute COVID' refers to persistent symptoms 3 weeks after COVID-19 infection, while 'Chronic COVID' describes symptoms lasting more than 12 weeks. Symptoms include fatigue, dyspnea, chest pain, palpitations, dizziness, body aches, presyncope and orthostatic intolerance. Individuals may even develop post-traumatic stress disorder, panic attacks and irritable bowel syndrome. Orthostatic intolerance occurs due to release of epinephrine and norepinephrine leading to development of palpitations, breathlessness, and chest pain. It has been well described that orthostatic intolerance is preceded by viral infections and is associated with the development of autoantibodies α-/β-adrenoceptors and muscarinic receptors. COVID 19 itself can affect the autonomic nervous system through the release of a cytokine storm leading to sympathetic activation. It is crucial to consider the diagnosis of orthostatic intolerance syndromes post COVID infection. Presentation: No date and time listed

Subarachnoid Hemorrhage due to Ruptured Anterior Communicating Artery Aneurysm in a Child with Coarctation of Aorta

Intracranial aneurysms are sometimes associated with other vascular anomalies in extracranial location. Coarctation of aorta, a congenital vascular lesion can be associated with intracranial aneurysms. In patients with coarctation, evaluation of intracranial vasculature is essential. We encountered a 12-year kid with subarachnoid hemorrhage. On further evaluation, she had anterior communicating artery aneurysm. On further evaluation for secondary causes of aneurysm, she had coarctation of aorta. She was surgically managed successfully by clipping of the aneurysm.

Abstract #1178966: A Rare Case of Idiopathic Osteoporosis with COL10A1 and COL27A1 Genetic Mutations in a Premenopausal Woman

The association between bone mineral density (BMD) and fracture differs in premenopausal women when compared to the postmenopausal women. Irrespective of the BMD, any fragility fracture in those aged 20-50 requires evaluation for secondary causes of osteoporosis. In the absence of secondary causes, idiopathic osteoporosis (IOP) is considered. We present a case of a premenopausal woman with IOP whose mutational analysis revealed variants in COL10A1 and COL27A1. These genetic mutations are found in Schmid-type metaphyseal chondrodysplasia (SMCD) and Steel syndrome, respectively. To our knowledge, this is the first case report establishing a linkage between these specific mutations and IOP. A 36-year-old Hispanic woman with a history of fragility fracture of the lumbar spine at age 23 was referred to Endocrinology for further evaluation. Dual-energy x-ray absorptiometry (DEXA) reported a Z-score of -3.0 in L1-L4, consistent with osteoporosis of the lumbar spine. A careful history, physical examination, and laboratory evaluation ruled out secondary causes of osteoporosis. In the interim, the patient presented a recurrent fragility fracture of the left proximal humerus requiring surgical intervention where bone marrow (BM) was obtained for cytology. BM cytology was found normocellular without increase in blasts or lymphocytes. Notably, the mutational analysis revealed heterozygous variants of uncertain significance (VUS) in COL10A1 [variant c682 c >T (p.Pro228Ser)] and COL27A1 [variant c.1814 c >T (p.Thr 6605 Met)]. Whole exome sequencing was not able to be performed due to insurance issues. The most common secondary causes of premenopausal bone loss include estrogen deficiency as seen in hypogonadism, drug exposure such as glucocorticoids, malabsorption disorders like celiac disease, hyperthyroidism, hypercalciuria, hyperparathyroidism, and disturbances in calcium and vitamin D metabolism. Osteoporosis with no known secondary causes is known as IOP. IOP is a disorder with multiple proposed mechanisms including impairment in growth hormone and insulin like growth factor axis, osteoblast dysfunction, and genetic mutations. Mutational analysis in selected IOP cases, have shown pathogenic variants and VUS in LRP5, LRP6, COL1A1, COL1A2, PLS3, WNT1, DKK1, FKBP10, HGD, SLC34A3. Our patient was found with heterozygous VUS in COL10A1 and COL27A1. These genetic mutations are found in (SMCD) and Steel syndrome, respectively. These rare osteochondrodysplasias, more commonly found in childhood, are associated with skeletal abnormalities including scoliosis, congenital hip dislocations, short stature, and characteristic facial features. More importantly, COL10A1 encodes the alpha 1 chain of collagen type X which is involved in growth plate function, and COL27A1 gene encodes a member of the fibrillar collagen family involved in the calcification of cartilage and the transition of cartilage to bone. To our knowledge, COL10A1 and COL27A1 mutations have not been yet associated as primary causes of IOP. We report this case aiming for further research to identify additional genetic etiologies of IOP.

Abstract 71: Preserved beta cell function in long standing type 1 diabetes mellitus

Background: Maturity onset diabetes of young (MODY) may be misdiagnosed as type 1 or type 2 diabetes mellitus and there may be an overlap between MODY and type 1 diabetes. The presence of persistent endogenous insulin, after the “honey-moon period” has ended, should lead to evaluation of secondary causes of diabetes including MODY.Aim: To identify subjects with preserved beta cell function; utilizing urinary C-peptide/creatinine ratio (UCPCR) in those, who have been diagnosed and treated as Type 1 diabetes mellitus.Methodology: Hospital based cross sectional study, between February 2019 and February 2021 in 100 Subjects diagnosed as Type 1 DM for more than 3 years.Results: Mean age and duration of DM 14.17 years and 5.3years respectively. Among 18 who had family history of D.M, 7 subjects had 3 generation involvement. GAD antibodies (68%) were more prevalent compared to IA 2 antibodies (56%). 49% had presence of both Anti GAD and IA2 auto antibodies. Mean UCPCR was 0.17. UCPCR >0.2 (suggestive of preserved endogenous insulin secretion) was present in 8 subjects among study population. Among these 8 subjects, 4 subjects had history of DKA episodes, 3 subjects had family history of D.M. 3 subjects did not have either of the auto antibodies. Compared to UCPCR <0.2, subjects with UCPCR >0.2 had statistically significant lower Hba1c (p=0.005), high UCPCR values (p=0.001), high MODY probability scores (p=0.004).Conclusions: UCPCR can be used as a screening tool to identify cases who need further evaluation for secondary causes, including genetic testing for MODY.

Single Centre Analysis of JAK2 V617F and Exon 12 Negative Idiopathic Erythrocytosis

▪IntroductionThe molecular categorisation of myeloproliferative neoplasms (MPNs) has changed the landscape of diagnosis and treatment. Polycythaemia vera (PV) is characterised by red blood cell proliferation and JAK2 V617F or Exon 12 mutations in up to 98% of patients 1. However, some patients without such mutations have an arduous diagnostic course with varying management and prognostic outcomes 2. We present our experience in managing this challenging cohort and aim to illuminate a potential diagnostic pathway for patients.MethodWe searched electronic records of patients attending haematology clinics over the last 20 years at University College Hospital with a prior diagnosis of PV / erythrocytosis (presenting with raised Haemoglobin (Hb) &/ Haematocrit (Hct)) with no evidence of JAK2 exon 12 or 14 mutations on bone marrow or peripheral blood molecular analysis (multiplex PCR sensitivity 0.1%). We reviewed their diagnostic workup, which included full blood count & where available, bone marrow myeloid (Illumina TruSight Myeloid) & erythroid next generation sequencing (NGS) panels.Results37 patients with JAK2 V617F & Exon 12 mutation negative erythrocytosis were identified. Patients were categorised in to 3 groups 2; idiopathic erythrocytosis (IE), secondary polycythaemia (SP) & high affinity haemoglobinopathies (HAH); patient characteristics are summarised in Table 1. The median age of IE & HAH was younger, their presenting Hb/Hct levels was higher compared to SP, with a male predominance. Constitutional symptoms were only reported in the IE cohort. Erythropoietin (EPO) was elevated in HAH & IE patients but within normal range in SP. Thrombotic events occurred in all cohorts, most frequently in IE. Splenomegaly was reported in 4/21 IE, 1/13 SP, but was not a feature in HAH patients. When performed, IE red cell mass (RCM) studies were raised but within normal range in SP patients. Table 2 details IE cohort erythroid mutations. Myeloid NGS only identified MPL and BCOR mutations of pathogenic significance and multiple single nucleotide polymorphisms of no known significance. No abnormalities were demonstrated in 15% of SP patients that underwent bone marrow myeloid mutational analysis. Venesections (VS) were instigated in 95% of the IE cohort, antiplatelets (AP) in 52%, anticoagulation (AC) in 14% and cytoreductive therapy (CT) in 19% due to intolerance/failure of VS. VS programme was instigated in 46% of SP patients, AP in 7% and AC in 47%.DiscussionThe median age of our IE cohort was 48 yrs with a 19% incidence of thrombosis. Where performed, bone marrow histology demonstrated hypercellularity but was not consistent with MPN diagnostic criteria. Myeloid NGS panel mutations such as BCOR may represent clonal haematopoieis of indeterminate potential. Heterozygous VHL C598T & C376A mutations, in keeping with Chuvash polycythaemia, were demonstrated. Mutations in EGLN1 &BPGM,were detected in our patients, however there was an absence of correlating haematological parameters or family history to support a diagnosis of congenital erythrocytosis (2). Variants of unknown significance were also detected in SH2B3, BMP6 &EGLN3 gene duplication. SP patients were older (median age 68 years) and where performed had normal RCM and no myeloid mutations identified.The initial approach adopted at our centre for diagnosing and managing JAK2 V617F & Exon 12 negative erythocytosis begins with clinical evaluation for secondary causes. This is followed by assessment of EPO level, RCM study, extended molecular mutational analysis involving screening for high affinity haemoglobins, congenital erythrocytosis and bone marrow histology. Where patients are symptomatic or considered at high risk for thrombosis, we venesect to a personalised target and patients are offered AP and/or AC. CT is instigated where VS is not tolerated or ineffective, however this approach is not corroborated in the literature. Our experience highlights the clinical heterogeneity of JAK2 negative erythrocytosis and the need to develop a robust and systematic diagnostic and treatment algorithm with further clarification of the role of molecular profiling.1. William W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017 Feb; 129(6):667-6792. McMullin MF. Idiopathic erythrocytosis: a disappearing entity. Hematology Am Soc Educ Program. 2009; 2009(1):629-635 [Display omitted] DisclosuresSekhar: Novartis: Consultancy, Research Funding.

Bridging the gaps in secondary fracture prevention at a single center in Pakistan—compliance with the IOF best practice framework

The International Osteoporosis Foundation (IOF) formulated a set of best practice framework as an international benchmark for secondary fracture prevention (SFP) and fracture liaison services (FLS), delineating essential elements of service delivery. The aim of this audit was to assess compliance with the IOF standards for patients ≥ 50years presenting with fragility hip fractures at a tertiary care center in Pakistan. A retrospective sample of hip fracture cases from Jan 2019 to Dec 2019, treated at the section of Orthopedic Surgery, Aga Khan University, Karachi, was conducted. After excluding high energy trauma cases and patients younger than 50years of age, medical records were audited, using a pre-structured Performa based on IOF standards. Compliance level of 0, 1, 2, and 3 was recorded as defined by IOF. Microsoft excel was used for data analysis. A compliance level of 3 was recorded for patient identification and fall prevention services, whereas level 1 was attained for database maintenance for 25 (100%) cases. For medication initiation, level 0 was recorded for all the cases; however, 8 (32%) cases were prescribed calcium and vitamin D supplements. For the standards, including post-fracture assessment timing, evaluation of secondary causes of osteoporosis, multifaceted assessment, medication review, communication strategy, and long-term management, a level 0 was noted for 25 (100%) cases. Moreover, no recommended assessment guidelines were followed uniformly. The care gaps identified require substantial efforts to ensure adequate implementation of the overall best practice standards for SFP, necessitating the need for FLS initiation and establishment of fracture care pathway.

World Health Organization-defined eosinophilic disorders: 2022 update on diagnosis, risk stratification, and management.

The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary or clonal) disorders with potential for end-organ damage. Hypereosinophilia (HE) has generally been defined as a peripheral blood eosinophil count greater than 1.5 × 109 /L. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on morphologic review of the blood and marrow, standard cytogenetics, fluorescence in situ hybridization, next generation sequencing gene assays, and flow immunophenotyping to detect histopathologic or clonal evidence for an acute or chronic hematolymphoid neoplasm. Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semi-molecular classification scheme of disease subtypes. This includes the major category "myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2", and the myeloproliferative neoplasm subtype, "chronic eosinophilic leukemia, not otherwise specified" (CEL, NOS). Lymphocyte-variant HE is an aberrant T-cell clone-driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion. The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (eg, < 1.5 × 109 /L) without symptoms or signs of organ involvement, a watch and wait approach with close follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant HE and HES. Hydroxyurea and interferon-α have demonstrated efficacy as initial treatment and in steroid-refractory cases of HES. Mepolizumab, an interleukin-5 (IL-5) antagonist monoclonal antibody, was recently approved by the US Food and Drug Administration for patients with idiopathic HES. The use of the IL-5 receptor antibody benralizumab, as well as other targeted therapies such as JAK2 and FGFR1 inhibitors, is under active investigation.

Renal denervation in hypertension patients: Proceedings from an expert consensus roundtable cosponsored by SCAI and NKF.

Renal denervation in hypertension patients: Proceedings from an expert consensus roundtable cosponsored by SCAI and NKF.

Neuroinfundibulitis: Pituitary Stalk Thickening Presenting as Diabetes Insipidus

Background: Isolated pituitary stalk thickening (PST) from neuroinfundibulitis is a rare entity that requires thorough evaluation of secondary causes and understanding of treatment options. Clinical Case: A 55-year-old male presented with progressive polyuria and polydipsia over several months. He had no significant head injuries, headache, weight loss, fatigue or inability to exercise. His serum sodium level was 148 (135 - 145 mmol/L) with a serum osmolality 310 (275-305 mOsm/kg), and urine osmolality was 246 (40-1200 mOsm/kg) suggestive of partial diabetes insipidus (DI). A 24-hour urine collection had a volume of 9.2 liters. He had a normal hemoglobin A1c. Hormonal work-up was unremarkable with normal range his prolactin, IGF-1, and a.m. cortisol (19 mcg/dl). He was already on levothyroxine with normal thyroid function tests and negative thyroid antibodies. Water deprivation testing confirmed a diagnosis of central DI and he was started on desmopressin. Magnetic resonance imaging (MRI) of the pituitary demonstrated diffuse PST with T2 hyperintensity and loss of normal T1 hyperintensity (“bright spot”) of the posterior pituitary. Repeat imaging 3 months later showed progressive thickening. He underwent full body positron emission tomography-computerized tomography (PET-CT) which demonstrated increased metabolism of the pituitary stalk, but no other suspicious uptake in other areas. Chest X-ray, tuberculin screen, angiotensin converting enzyme, and calcium were all normal. Patient underwent transsphenoidal stalk biopsy. Pathology demonstrated fibrosis and chronic inflammation without malignancy but otherwise was nondiagnostic. Based on these findings, he was presumed to have neuroinfundibulitis and is being actively followed with MRIs and labs. Conclusion: Isolated PST is exceedingly rare, especially in adults. The differential diagnosis includes neoplastic (germinomas, lymphoma, metastatic disease), autoimmune, and infiltrative disease (sarcoidosis, histiocytosis). One review of 38 adult patients with central DI and PST showed that almost half had neuroinfundibulitis. Of those, 4 were treated with corticosteroids and 7 were not. All patients showed reduction or resolution of PST on subsequent MRIs indicating that resolution of thickening can be spontaneous without steroid use, and can be followed by MRI and with hormone replacement for deficiencies (1). Because of the rarity of isolated neuroinfundibulitis, it is important that neoplastic and systemic diseases be ruled out in all patients with PST, as in the case of our patient.1.Devuyst F, Kazakou P, Baleriaux D, Alexopoulou O, Burniat A, Salenave S, et al. Central diabetes insipidus and pituitary stalk thickening in adults: distinction of neoplastic from non-neoplastic lesions. European Journal of Endocrinology. 2020;183(1):95-105.

A Case of Hypolipidemia and Hypocholesterolemia; Cause and Consequences

Background: Hypolipidemia and hypocholesterolemia are uncommon and because of the established risk of hypercholesterolemia for cardiovascular disease, reduced lipids and total cholesterol levels are often clinically desired and/or deemed clinically inconsequential. A finding of persistently low lipid levels and total cholesterol may however not be innocuous nor desirable. We describe the case of a 46 yr old man with persistently low total cholesterol levels <70mg/dl and the associated complications and comorbidities identified. Clinical Case: A 46 yr old Hispanic man with non-alcoholic fatty liver disease (NAFLD) was referred for evaluation of hyperhidrosis in the setting of persistent hypolipidemia and hypocholesterolemia. Review of the patient’s clinical and biochemical history showed persistently low total cholesterol (mean 58mg/dl), hypotriglyceridemia, and low LDL-C (mean 13.4mg/dl) over the prior 7 yrs in addition to undetectable serum lipoprotein A. Evaluation for secondary causes of hypolipidemia, such as multiple myeloma, was unremarkable. He was found to have low carotene, borderline vitamin A and low vitamin E levels while the rest of his serum fat-soluble vitamins were normal. His mother who had presumed Alzheimer’s dementia also had a history of very low cholesterol levels. The degree and persistence of his hypolipidemia and hypocholesterolemia raised the possibility of a genetic etiology of his hypolipidemia. Genetic testing confirmed that the patient was heterozygous for a pathogenic variant in the APOB gene, consistent with familial hypobetalipoproteinemia (FHBL) which is autosomal recessive linked. Subsequent close review of his clinical history revealed other potential complications and comorbidities of FHBL including NAFLD with prediabetes, hypogonadism, progressive cognitive and memory decline, peripheral neuropathy and multiple neuropsychiatric syndromes including adult ADHD, borderline personality disorder, bipolar disorder and chronic anxiety. He is presently on vitamin E and A supplementation and being followed by neurology and psychiatry in addition to ongoing endocrine and metabolic clinical surveillance. In addition, in view of his maternal history and several biologic children he has undergone formal genetic and family counselling. Conclusions: While lipid panels are ubiquitous in clinical care, clinicians need to be vigilant in settings of severe persistent hypolipidemia and/or hypocholesterolemia to evaluate for possible genetic basis for this and to also screen for possible associated complications and comorbidities.