Persistent Hypoglycemia Research Articles

Syndromic forms of congenital hyperinsulinism.

Congenital hyperinsulinism (CHI), also called hyperinsulinemic hypoglycemia (HH), is a very heterogeneous condition and represents the most common cause of severe and persistent hypoglycemia in infancy and childhood. The majority of cases in which a genetic cause can be identified have monogenic defects affecting pancreatic β-cells and their glucose-sensing system that regulates insulin secretion. However, CHI/HH has also been observed in a variety of syndromic disorders. The major categories of syndromes that have been found to be associated with CHI include overgrowth syndromes (e.g. Beckwith-Wiedemann and Sotos syndromes), chromosomal and monogenic developmental syndromes with postnatal growth failure (e.g. Turner, Kabuki, and Costello syndromes), congenital disorders of glycosylation, and syndromic channelopathies (e.g. Timothy syndrome). This article reviews syndromic conditions that have been asserted by the literature to be associated with CHI. We assess the evidence of the association, as well as the prevalence of CHI, its possible pathophysiology and its natural course in the respective conditions. In many of the CHI-associated syndromic conditions, the mechanism of dysregulation of glucose-sensing and insulin secretion is not completely understood and not directly related to known CHI genes. Moreover, in most of those syndromes the association seems to be inconsistent and the metabolic disturbance is transient. However, since neonatal hypoglycemia is an early sign of possible compromise in the newborn, which requires immediate diagnostic efforts and intervention, this symptom may be the first to bring a patient to medical attention. As a consequence, HH in a newborn or infant with associated congenital anomalies or additional medical issues remains a differential diagnostic challenge and may require a broad genetic workup.

KATP channel mutations in congenital hyperinsulinism: Progress and challenges towards mechanism-based therapies.

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infancy/childhood and is a serious condition associated with severe recurrent attacks of hypoglycemia due to dysregulated insulin secretion. Timely diagnosis and effective treatment are crucial to prevent severe hypoglycemia that may lead to life-long neurological complications. In pancreatic β-cells, adenosine triphosphate (ATP)-sensitive K+ (KATP) channels are a central regulator of insulin secretion vital for glucose homeostasis. Genetic defects that lead to loss of expression or function of KATP channels are the most common cause of HI (KATP-HI). Much progress has been made in our understanding of the molecular genetics and pathophysiology of KATP-HI in the past decades; however, treatment remains challenging, in particular for patients with diffuse disease who do not respond to the KATP channel activator diazoxide. In this review, we discuss current approaches and limitations on the diagnosis and treatment of KATP-HI, and offer perspectives on alternative therapeutic strategies.

New approaches to screening and management of neonatal hypoglycemia based on improved understanding of the molecular mechanism of hypoglycemia.

For the past 70 years, controversy about hypoglycemia in newborn infants has focused on a numerical "definition of neonatal hypoglycemia", without regard to its mechanism. This ignores the purpose of screening newborns for hypoglycemia, which is to identify those with pathological forms of hypoglycemia and to prevent hypoglycemic brain injury. Recent clinical and basic research indicates that the three major forms of neonatal hypoglycemia are caused by hyperinsulinism (recognizing also that other rare hormonal or metabolic conditions may also present during this time frame). These include transitional hypoglycemia, which affects all normal newborns in the first few days after birth; perinatal stress-induced hypoglycemia in high-risk newborns, which afflicts ∼1 in 1,200 newborns; and genetic forms of congenital hyperinsulinism which afflict ∼1 in 10,000-40,000 newborns. (1) Transitional hyperinsulinism in normal newborns reflects persistence of the low glucose threshold for insulin secretion during fetal life into the first few postnatal days. Recent data indicate that the underlying mechanism is decreased trafficking of ATP-sensitive potassium channels to the beta-cell plasma membrane, likely a result of the hypoxemic state of fetal life. (2) Perinatal stress-induced hyperinsulinism in high-risk infants appears to reflect an exaggeration of this normal low fetal glucose threshold for insulin release due to more severe and prolonged exposure to perinatal hypoxemia. (3) Genetic hyperinsulinism, in contrast, reflects permanent genetic defects in various steps controlling beta-cell insulin release, such as inactivating mutations of the K ATP-channel genes. The purpose of this report is to review our current knowledge of these three major forms of neonatal hyperinsulinism as a foundation for the diagnosis and management of hypoglycemia in newborn infants. This includes selection of appropriate interventions based on underlying disease mechanism; combined monitoring of both plasma glucose and ketone levels to improve screening for infants with persistent forms of hypoglycemia; and ultimately to ensure that infants at risk of persistent hyperinsulinemic hypoglycemia are recognized prior to discharge from the nursery.

Electroencephalogram features in children with congenital hyperinsulinism treated according to the international protocol in Russian Federation

Congenital hyperinsulinism (CHI) is a rare life-threatening disease characterised by persistent hypoglycaemia as a result of inappropriate insulin secretion, which can lead to irreversible neurological defects in infants. To evaluate neurophysiological characteristics of central nervous system in children with congenital hyperinsulinism treated according to the international protocol in Russian Federation. Our retrospective, prospective cohort study included 73 patients who received treatment for CHI according to the current international protocol at different departments of the Almazov National Medical Research Centre from 2017 to 2022. All patients underwent a comprehensive examination, including electroencephalography (EEG). Among 73 patients with CHI, 35% (23) had focal form of the disease, 65% had non-focal form (49% (39) - diffuse form, 16% (11) - atypical form). All patients with focal form of CHI had a recovery as an outcome.Analysing the EEG data we found that paroxysmal activity was recorded in 23 patients (32%), 50 patients did not have paroxysmal activity (68%). Diffuse changes were observed in 47 patients (64%), whereas 26 patients (36%) were absent of it. By constructing Kaplan-Meier curves we found that the alpha rhythm is formed significantly (p=0.026) earlier in patients with a focal form of CHI. CHI patients treated according to the international guidelines in Russian Federation show rather positive neurological outcome. We established that alpha rhythm earliest formation is associated with focal form of CHI.

CLINICAL CASE OF CONGENITAL HYPERINSULINISM

Introduction. Congenital hyperinsulinism (HI) is a hereditary disease characterized by inadequate insulin hypersecretion by pancreatic beta-cells and leading to hypoglycemia. The prevalence of HI in European countries is on average 1:30,000 - 1:50,000 live births. Despite its low prevalence, HI is one of the main causes of persistent hypoglycemia in children of the first year of life.The aim of the study is to demonstrate the current clinical experience of observation and treatment of a child with HI in the conditions of limited experience of work with similar rare pathologies in children.Material and methods of research. The study is based on the analysis of examination and treatment of a child diagnosed with HI. The set of diagnostic measures included: clinical and laboratory studies, ultrasound, magnetic resonance imaging, molecular genetic studies.Results of the research. Seeing the presence of elevated insulin levels (blood insulin more than 2.0 μIU / ml) on the background of hypoglycemia (blood glucose less than 3.0 mmol / l), the child was diagnosed with congenital hyperinsulinism.Considering the possible etiological and pathogenic factors of HI in children, hereditary metabolic diseases (deficiency of fatty acid dehydrogenase, maple leaf disease, etc.), adrenal insufficiency, thyroid disease, panhypopituitarism were excluded.Conservative glucose treatment in a child with HI did not show the desired results. Additional examination included a molecular genetic study of genes and a heterozygous mutation of the ABCC8 gene was detected, which indicates a focal form of HI.The only effective method of treatment of this pathology is partial resection of the pancreas with removal of the pathological locus. The child was operated at the Danish Children's Clinic, where enucleation of the lesion in the pancreas was performed, which was detected by position-emission (PET) and computed tomography (CT).Conclusions. 1. In case of detection of hypoglycemia in a child, timely diagnosis of the disease is necessary, which reduces the risk of neurological complications of HI. 2. Conservative treatment of focal forms of HI in children does not give significant results and is not appropriate. 3. Partial pancreatectomy is a pathogenic method of treatment of focal form of HI.

La Neonatologia… caso per caso

Neonatal hypotonia, bronchopulmonary dysplasia, necrotizing enterocolitis and persistent hypoglycemia are some of the main topics in neonatology. This work aims to summarize these four neonatal conditions through illustrative clinical cases. The first issue concerns neonatal hypotonia, which can constitute a pivotal sign in the diagnosis of hypoxic ischemic encephalopathy. However, neonatal hypotonia can be present in several other conditions, such as sepsis and neurological or neuromuscular diseases. The second issue is about bronchopulmonary dysplasia, a disease that mainly affects extremely premature infants. Many therapeutic strategies have been proposed to prevent this disease, such as less invasive ventilation and an early use of inhaled and systemic corticosteroids. Long-term respiratory sequelae in infants with bronchopulmonary dysplasia remain one of the main causes of hospitalization in these children in their early years of life. The third issue is necrotizing enterocolitis, a disease that can affect both term and preterm newborns. Multiple risk factors are involved in the pathogenesis of this disease such as an abnormal peripheral perfusion due to congenital heart diseases, small for gestational age (SGA), sepsis, hypoxic-ischemic encephalopathy, chorioamnionitis, intrauterine growth restriction (IUGR). On the other hand, breastfeeding can play as a preventive factor. Finally, the last topic is about the management of persistent hypoglycaemia, a condition that can be caused by the combination of one of the following mechanisms: inadequate glucose supply in an infant with low glycogen stores (preterm, IUGR, SGA); excessive insulin production (maternal diabetes, large for gestational age); failure of counter-regulatory response to hy-poglycaemia (pituitary or adrenal deficiency

Phosphomannomutase 2 hyperinsulinemia: Recent advances of genetic pathogenesis, diagnosis, and management.

Congenital hyperinsulinemia (CHI), is a clinically heterogeneous disorder that presents as a major cause of persistent and recurrent hypoglycemia during infancy and childhood. There are 16 subtypes of CHI-related genes. Phosphomannomutase 2 hyperinsulinemia (PMM2-HI) is an extremely rare subtype which is first reported in 2017, with only 18 families reported so far. This review provides a structured description of the genetic pathogenesis, and current diagnostic and therapeutic advances of PMM2-HI to increase clinicians' awareness of PMM2-HI.

ALGORITMO DE INDICAÇÃO DE ACESSO VENOSO PARA RECÉM-NASCIDOS EM UNIDADE DE TERAPIA INTENSIVA NEONATAL

ABSTRACT Objective: to present an algorithm for the indication of venous accesses for newborns in Neonatal Intensive Care Unit. Development: descriptive study conducted in a Neonatal Intensive Care Unit in southern Brazil, in the period from 2017 to 2020 in two stages of idealization: design of the algorithm; and the adequacy based on the application according to observations made by the nurses involved. The developed algorithm contemplated the prediction of venous access for patients with indication for abdominal and other surgeries, premature infants stratified in gestational age higher and lower than 30 weeks, heart diseases with dependence or not on arterial channel and persistent neonatal hypoglycemia. According to the venous network, number of prescribed therapies, fasting, antibiotic therapy and vasoactive drugs, there is an initial indication for one type of catheter that may be followed by another according to need. Conclusion: the participation of nurses in the indication of venous access integrates interprofessional practices and increases neonatal care.

A case of persistent refractory hypoglycemia from polysubstance recreational drug use.

A case of persistent refractory hypoglycemia from polysubstance recreational drug use.

Successful Treatment of Congenital Hyperinsulinism Due to KJNJ11 Gene Mutation with Long-Acting Release Octreotide: A Case Report from the Arab Region

AbstractCongenital hyperinsulinism is a rare hereditary condition that is caused by various gene mutations related to the function of the pancreatic β-cells. It is characterized by dysregulation of insulin secretion leading to profound and recurrent hypoglycemia. Its clinical presentation, histology, response to treatment, and underlying genetic defects are variable making it a heterogeneous condition. Pancreatectomy is indicated in diazoxide un-responsive cases. However, surgical treatment is associated with the possibility of persistent hypoglycemia and iatrogenic diabetes. We report a 3 months old girl who presented with hyperinsulinemic hypoglycemia. She was born to consanguineous parents and had a history of four neonatal deaths in siblings. Whole exome sequencing detected a KCNJ11 variant c.350_352del p.(Phe117del) in a homozygous state. Pancreatic scan (positron emission tomography/computed tomography) showed a diffusely increased radioisotope uptake in the head and tail of the pancreas. She was resistant to diazoxide and nifedipine and was shifted to octreotide treatment through multiple daily subcutaneous injections initially. Treatment was changed to monthly depot injection of octreotide that resulted in euglycemia. She kept a normal rate of growth, insulin-like growth factor-1, and liver function. This case is an example of an alternative effective medical therapy that avoids major surgical intervention and prevents long-term complication of recurrent hypoglycemia and iatrogenic diabetes resulting after surgery.

A Neonate with a Rare Presentation of Persistent Hypoglycemia and Prolonged Jaundice

A Neonate with a Rare Presentation of Persistent Hypoglycemia and Prolonged Jaundice

Diazoxide for Neonatal Hyperinsulinemic Hypoglycemia and Pulmonary Hypertension.

Hypoglycemia in neonates is associated with long-term neurodevelopmental effects. Hyperinsulinemic hypoglycemia (HH) is the most common cause of persistent hypoglycemia in neonatal intensive care units. Diazoxide is the only medication that is currently recommended for treatment of HH in neonates. However, the use of diazoxide in neonates is associated with pulmonary hypertension as an adverse effect. In this article, we review the literature on the mechanism of action and adverse effects with the use of diazoxide in neonatal hyperinsulinism. We then present a case series of neonates treated with diazoxide in our neonatal intensive care unit over a 5-year period. Among 23 neonates who received diazoxide, 4 developed pulmonary hypertension and 1 died. All infants who developed pulmonary hypertension were born preterm at less than 36 weeks gestation and had pre-existing risk factors for pulmonary hypertension. HH in preterm neonates, with pre-existing pulmonary hypertension or with risk factors for pulmonary hypertension requires thoughtful management.

214: HYPOGLYCEMIA: COMMON BUT UNCOMMONLY IRREVERSIBLE

Introduction: Whipple’s Triad is comprised of symptomatic low blood glucose (< 55 mg/dL) and resolution of symptoms after correction of glucose level, indicating the presence of hypoglycemic disorder. Hypoglycemia is often easily reversed with standardized treatment, however; in few cases, hypoglycemia is refractory to standard treatment, requiring further investigation. Hypoglycemia can be associated with prolonged hospitalizations as well as higher morbidity and mortality. Description: 86-year-old white female was admitted to the intensive care unit (ICU) with sepsis. Patient presenting symptoms included: worsening of baseline confusion, generalized weakness, and diaphoresis. Patient arrived to ICU with tremors and a blood glucose level of 50mg/dL (74-99mg/dL). She had no insulin or oral glycemic agents prior to admission. The hypoglycemia protocol was initiated, which included dextrose containing fluids and glucagon. Octreotide and steroids were added, and dextrose fluid concentration increased due to persistent hypoglycemia. Her lack of response led to further evaluation. Differential diagnoses included: cortisol deficiency, insulinoma, insulin autoimmune syndrome and beta cell hypertrophy. Laboratory studies during hypoglycemic episode were obtained which revealed: random cortisol 13.2 mcg/dL, proinsulin greater than 700 pmol/L (3.6-22 pmol/L), insulin level 103 uIU/mL (2.6-24.9 uIU/mL), C-peptide 22.8 ng/mL (1.1-4.4 ng/mL), and insulin antibody (Ab) level zero. Absence of gastric bypass history made beta cell hypertrophy unlikely. Elevated proinsulin levels as well as an insulin and C-peptide ratio of less than one, both present in this patient, are highly suggestive of insulinoma in the absence of oral hypoglycemic use. No further investigation was pursued due to family wishes to focus on comfort care. Discussion: Hypoglycemia is prevalent in critical care. One should keep an open mind when investigating causes of hypoglycemia when standard treatment does not lead to resolution. A detailed history is important when hypoglycemia persists. Insulin, proinsulin, C-peptide levels, and appropriate imaging should be checked during hypoglycemic episode to determine correct diagnosis and management.

A Rare Case of Amyloid Light Chain Amyloidosis with Extensive Hepatic Involvement

Abstract Introduction/Objective Amyloid light chain (AL) amyloidosis is a life-threatening disease entity, with an incidence of 10–15 per million per year in the USA. Amyloidosis is caused by the extracellular deposition of insoluble fibrillary amyloid protein resulting in multiorgan damage. Though amyloidosis is primarily a systemic disease, 10%-20% of cases can be localized. Methods/Case Report We present a case of a 37-year-old male admitted with predominant hepatic manifestations, whose liver biopsy led to the diagnosis of amyloidosis. The patient presented with intermittent abdominal pain, weight loss, persistent hypoglycemia, hepatomegaly, and raised liver enzymes. Imaging studies showed hepatomegaly with a heterogeneous lace like appearance of the liver parenchyma. Liver biopsy revealed an extensive deposition of amyloid protein in peri-sinusoidal spaces. The amyloid protein is highlighted by crystal violet stain and revealed apple- green birefringence on polarized microscopy after Congo red staining. On further evaluation, elevated kappa and lambda free light chains with increased kappa-lambda ratio were identified by serum protein electrophoresis. Subsequent bone marrow aspirate and biopsy identified a monoclonal kappa positive plasma cell neoplasm with an amorphous eosinophilic infiltrate. Liquid chromatography-tandem mass spectrometry on bone marrow biopsy detected a peptide profile consistent with AL (kappa) type amyloid deposition. Results (if a Case Study enter NA) NA. Conclusion AL amyloidosis patients with predominant hepatic involvement have a worse prognosis. Rapid diagnosis and prompt clinical intervention prevents further organ damage. This case study aims to promote awareness of the unusual presentations of amyloidosis.

Abstract 15313: Hypoglycemia: The Forgotten "H&amp;T" in Cardiac Arrest

Introduction: Hypoglycemia is known to cause cardiac arrhythmias and even sudden cardiac death by inducing oxidative stress, QT prolongation, and myocardial injury. Chromosomal deletion of 1p36 is associated with learning difficulty, progressive renal disease, and cardiomyopathy. To our knowledge, this is the first case of a patient with 1p36 deletion syndrome and end-stage renal disease (ESRD) who developed cardiac arrest due to hypoglycemia. Case Presentation: A 26-year-old female presented to the emergency department with generalized itching, weakness, and progressive dyspnea after missing multiple hemodialysis (HD) sessions. She was admitted for HD and her stay was complicated by an episode of coffee-ground emesis and she was nil per oral (NPO) for an endoscopy. That night, the patient became bradycardic and had a cardiac arrest with pulseless electrical activity (PEA). Fingerstick blood glucose was undetectable during resuscitation and ROSC was achieved instantaneously after dextrose administration. The patient had no history of diabetes and was refusing glucose checks while NPO. She had a remarkable neurological recovery post-cardiac arrest. However, her glucose levels remained persistently low despite maximally tolerated feeds. An extensive workup for persistent hypoglycemia including peptide C levels, hba1c, and insulin level were within normal limits. Her cortisol level was appropriately raised. CT scan of the head performed was normal. Cardiac catheterization revealed no coronary artery disease. Discussions: Hypoglycemia was removed from the Advanced Cardiovascular Life Support (ACLS) algorithm as a reversible cause of cardiac arrest in 2010. Our case is a reminder of a life-threatening yet quickly reversible cause of cardiac arrest. Conclusions: ESRD increases the risk of hypoglycemia due to decreased insulin clearance and must be carefully monitored while NPO. Physicians have to be aware that routine dextrose administration during cardiac resuscitation does not improve survival and neurological outcomes.

ODP580 A Case of New Onset Primary Adrenal Insufficiency in COVID Infection

Abstract Background Accumulating body of evidence shows that SARS-CoV-2 infection in COVID-19 is linked to a variety of autoimmune complications including autoimmune endocrinopathies. Here we report a case of newly diagnosed Addison's disease post-COVID-19 infection. Case Description A 23-year-old male with a history of three episodes of acute disseminated encephalomyelitis (ADEM) in childhood, was brought into the emergency department (ED) by EMS after being found down with a blood glucose of 28 at the field. Prior to presentation, he reported 3 days of sore throat, nausea, vomiting, fatigue, and chills. He takes no home medications, and is not vaccinated against COVID-19. In the ED, the physical exam is notable for temperature 39°C, pulse 145, BP 80/42, RR 39, and no mucocutaneous hyperpigmentation. Labs revealed a positive COVID test, serum sodium 125 mmol/L (135-145), potassium 3.1 mmol/L (3.5-4.1), and persistent hypoglycemia. TSH 1.89 μIU/mL (0.45-4.12). A morning baseline cortisol was 4 mcg/dl (ref: &amp;gt;18) with ACTH level of &amp;gt;1250 pg/ml (0-45). A high-dose 250 mcg ACTH stimulation test followed; with cortisol levels of 3, and 3 mcg/dl (ref: &amp;gt;18) at 30, and 60 minutes; respectively. Aldosterone &amp;lt;3. 0 ng/dl (4. 0-31. 0), and anti-21-hydroxylase antibody was positive (ref: negative). A CT scan of the abdomen with contrast demonstrated mildly atrophied bilateral adrenal glands. The hypotension and hyponatremia resolved after initiation of intravenous hydrocortisone, and he was discharged on hydrocortisone and fludrocortisone. Conclusion The patient's symptoms, elevated ACTH, low cortisol, and presence of 21-hydroxylase antibodies, are consistent with autoimmune Addison's disease. Since ADEM is an autoimmune condition, it is likely that the patient had underlying undiagnosed Addison's disease and COVID-19 triggered an adrenal crisis. There is also a possibility that SARS-CoV-2 infection may have induced a higher titer of adrenal antibody, leading to the exacerbation of Addison's disease. The case highlights the importance of considering adrenal insufficiency as a diagnostic differential in hemodynamically unstable COVID-19 patients, especially those with underlying autoimmune conditions. Presentation: No date and time listed

ODP631 Infectious Disease Causing Damage Of The Adrenal Glands, A Life Threating Event

Abstract Introduction Primary Adrenal Insufficiency (PAI) is not a common cause of adrenal insufficiency. The most common cause is Addison disease that is an autoimmune condition. Other causes include hemorrhage, infiltration, infections, necrosis and metastasis. We present a rare case of primary adrenal insufficiency caused by disseminated histoplasmosis. Case presentation 87 yo male from the Midwest with a history of HTN, HLD, CAD s/p CABG was admitted to our hospital for fatigue and 15 lbs weight loss. In the ED, he was found to have persistent hypoglycemia (BG in the 50s mg/dl after several vials of D50%). He was admitted to ICU for continuous D10% infusion. His laboratory showed Na 137mmol/L, K 3.7mmol/L. Further work up for hypoglycemia showed BG of 53 mg/dl with C-peptide of 0.92ng/ml and Insulin &amp;lt;1uIU/ml. Due to the concern of non-insulin dependent hypoglycemia, AM cortisol was done which was low7ug/dl. Immediately, he was started on high dose hydrocortisone. Head CT was negative for pituitary lesions. CT showed lung nodules and bilateral peripherally calcified adrenal lesions 3.6 &amp; 2.6 cm homogenous, well defined borders (HU 20-30). Adrenal hormones work up showed normal metanephrines, Aldosterone &amp;lt;1ng/dl and PRA 1.35ng/ml/h (0.25-5.82). ACTH stim test revealed cortisol level of 9. 0 ug/dl, 9.4 ug/dl, and 9.2 ug/dl at baseline, 30min and 1hr respectively with a baseline ACTH of 539. Lung biopsy showed necrotizing granuloma and fungal spores compatible with histoplasmosis. He was started on amphotericin then transition to itraconazole for 1 year. Additionally, the dose of HC was decrease and Fludrocortisone 0.1mg daily was added. He refused adrenal biopsy at that point and wanted to continue current treatment with a plan to repeat imaging in 3 months and possible adrenal biopsy depending on CT results. On follow-up, patient regained weight and hypoglycemia resolved. Repeated adrenal CT showed shrinkage of the adrenal nodules bilateral. He was continued on PAI replacement. Discussion Histoplasmosis is a fungal infection caused by (H. capsulatum), found in soil contaminated with bird or bat droppings. Infection usually limited to respiratory disease in immunocompetent host but may cause disseminated infection in immunocompromised patient which can involve any organ system. Less commonly, disseminated type may occur in an immunocompetent host with the adrenal gland being the most common infected organ. Treatment involves systemic antifungal therapy; ketoconazole or itraconazole for mild-moderate forms and amphotericin B for 12-18 months for severe ones. Relapse rate is high; ∼ 7.5% and most patients require long-term glucocorticoid replacement. Because unrecognized disseminated histoplasmosis accompanying PAI usually results in a high mortality rate, considerable suspicion and appropriate investigations are necessary for correct diagnosis of this rare but treatable disease. Presentation: No date and time listed

PSUN09 An Unusual Presentation of Pheochromocytoma with Persistent Hypoglycemia, A Case Report

Abstract Introduction Pheochromocytoma is a rare chromaffin cells tumor of the adrenal medulla characterized by excessive catecholamines production. It can be manifested by various clinical presentations, ranging from being asymptomatic to having sustained or paroxysmal hypertension, or the classical triad of paroxysmal headache, palpitations, and sweating. It may be sporadic or inherited as part of other familial syndromes, including hereditary paraganglioma syndromes, and multiple endocrine neoplasia 2. This case report shows an unusual presentation of pheochromocytoma in a patient with neurofibromatosis type 1. Case Presentation A 27-year-old normotensive woman with a past medical history significant for neurofibromatosis type 1 diagnosed at age 16 was involved in a single-vehicle rollover collision. She experienced a sudden episode of dizziness and presyncope associated with nausea while she was driving. She was found with altered mental status and a serum glucose level of 31 mg/dl (reference value 70-99mg/dL), indicating hypoglycemia which remained persistent after administering a glucose drip. The patient denied any recent febrile illness, previous episodes of dizziness, vertigo, syncope, or known hypoglycemia. Her CT abdomen with intravenous contrast showed a 4.8 cm lobulated heterogeneous mass involving the right adrenal glands concerning for pheochromocytoma. Her laboratory workup revealed HbA1C of 4.9%, serum-free insulin of 6 mcU/mL (reference range &amp;lt;17mcU/mL), C-peptide of 1 ng/mL (reference value 0.5-2 ng/mL), insulin autoantibodies of &amp;lt;0.4 nU/mL (reference value &amp;lt;95 nU/mL), random cortisol of 38.4 mcg/dL (reference value 5-25 mcg/dL), ACTH of &amp;lt;5 pmol/L (reference value 10-60 pmol/L), and a normal cosyntropin stimulation test. Further investigations showed high serum levels of normetanephrine of 8.02 nmol/L (reference range 0-0.89 nmol/L), metanephrines of 0.69 nmol/L (reference range 0-0.49 nmol/L), and chromogranin A of 300 ng/mL (reference range 0-95 ng/mL) which confirmed the diagnosis of pheochromocytoma. Conclusion Hypoglycemia is an unusual presentation of pheochromocytoma, which is usually associated with impaired glucose tolerance and hyperglycemia. Our case shows that pheochromocytoma associated with neurofibromatosis type 1 can present with persistent hypoglycemia. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

PSUN339 Persistent Hypoglycemia and Hyperinsulinism in a Patient With Kabuki Syndrome Type 1.

Abstract Background Transient neonatal hypoglycemia typically resolves within the first few days of life. Persistence of neonatal hypoglycemia is a more significant finding that warrants further investigation. Clinical case A 2-year-old female born at 37 weeks of gestation via C-section due to a history of maternal preeclampsia. Delivery was complicated by meconium aspiration syndrome for which the patient was admitted to the NICU where she had a prolonged course. Patient was initially depressed at birth with APGARs of 3/6/8 at 1, 5 and 10 minutes of life, respectively. During the neonatal period, she had multiple complications including GERD, FTT (G-tube was placed), recurrent UTIs, congenital heart disease (mild RVH and ASD) and hypoglycemia. Regarding her hypoglycemia, the initial work up was suggestive of hyperinsulinism with a critical sample remarkable for a BG: 57 mg/dl (60-100mg/dl), Insulin level: 8.3 uUm/mL Subsequent glucagon challenge test confirmed hyperinsulinism. She initially required a continuous glucose infusion and Diazoxide was started. She was discharged home on Diazoxide and Diuril. Subsequently, Diazoxide was successfully discontinued at the age of 2 months. A Congenital Hyperinsulinism genetic panel was negative for the most frequent mutations. At 11 months old, she presented to our clinic due to persistent hypoglycemia when enteral feeds were attempted to be spaced. Patient was started on cornstarch which was discontinued secondary to frequent diarrhea. SolCarb was started with enteral feeds with good tolerance and response, maintaining target blood glucose levels. On physical examination, she had some dysmorphic features that were suggestive of a syndromic condition: prominent ear lobes, broad and flat nasal bridge, a single prominent tooth at the center of the bottom gum line, long palpebral fissures with upward curvature at the lateral edges, prominent finger pads and neurodevelopmental delay. Since she had features suggestive of Kabuki syndrome, WES was ordered which was remarkable for a pathogenic mutation in KMT2D (Autosomal dominant, Heterozygous, variant c.5269C&amp;gt;T and p.R1757X). Conclusion Persistent hypoglycemia beyond the neonatal period is a rare finding in Kabuki syndrome. In addition, it is a more common finding in Kabuki Syndrome type 2 (Mutations in the KDM6A gene). Our patient presents a rare case of a 2-year-old female with persistent hypoglycemia and hyperinsulinism secondary to KS1. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

PSUN304 CRN04777 an Oral, Nonpeptide SST5-selective Somatostatin Agonist Dose Dependently Suppresses Basal and Stimulated Insulin Secretion

Abstract Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in neonates, infants, and children, and is caused by genetic mutations in the insulin secretion pathway in pancreatic beta-cells. Current medical and surgical treatments are often highly burdensome, only partially effective, and associated with significant morbidity. CRN04777 is a potent orally bioavailable SST5 agonist (EC50=0.41 nM) that is &amp;gt;1300 fold selective over other SST receptor subtypes. CRN04777 has been shown to suppress both glucose- and sulfonylurea (SU)-induced insulin secretion in rats. The latter is a model for the most common known monogenic form of human congenital HI. We report initial results from a randomized, double-blinded, placebo-controlled single ascending dose study evaluating the safety, pharmacokinetics and pharmacodynamics of CRN04777 in 74 healthy volunteers. Endogenous insulin secretion was stimulated using intravenous glucose tolerance tests (IVGTT) or SU challenges in separate cohorts of volunteers. In the IVGTT cohorts, single doses of CRN04777 (0.5-120 mg) were administered after an overnight fast and 1 hour prior to an IV bolus of 300 mg/kg glucose, followed by serial measurements of blood glucose and insulin over 180 minutes. The SU-challenge cohorts received single doses of CRN04777 (30 and 60 mg) one hour after SU administration (5 mg of glibenclamide/glyburide), followed by measurement of the IV glucose infusion rate (GIR) over 8 hours under automated euglycemic clamp conditions (ClampArt®). CRN04777 was orally absorbed (Tmax 1-3 hours) and demonstrated a dose dependent increase in systemic exposures with an apparent terminal elimination t1/2 of approximately 40 hours. Basal insulin secretion was reduced dose-dependently, with a 73% reduction following 120 mg of CRN04777. Likewise, glucose stimulated insulin secretion during the IVGTT (plasma insulin AUC) was reduced dose-dependently by approximately 50% with a parallel doubling of plasma glucose AUC following 120 mg of CRN04777. CRN04777 resulted in dose-dependent reversal of SU-induced insulin secretion, with 79% and 90% reductions in insulin AUC5-180min, respectively, at 30 and 60 mg doses. At the 60 mg dose of CRN04777, no exogenous glucose infusion was needed to prevent SU-induced hypoglycemia. CRN04777 was well tolerated across the dose range evaluated. All adverse events (AEs) were considered mild or moderate and there were no serious AEs. The data from this single-dose, proof-of-concept study show that the selective SST5 agonist CRN04777 is well tolerated after oral administration in healthy volunteers, is suitable for once daily dosing and suppresses insulin secretion under basal and stimulated conditions, including in a pharmacologic model of congenital HI. Multiple ascending dose evaluations in healthy volunteers are underway to support future studies in congenital HI patients. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.