Browsing by Author "Wilson, Don"
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Item A Novel Mutation of APOB in Two Siblings with Hypercholesterolemia(2019-03-05) Hamilton, Luke; Hamby, Tyler; Wilson, Don; Sprunger, AbigailA Novel Mutation of APOB in Two Siblings with Hypercholesterolemia 1 Abigail Sprunger, BS; 2L. Hamilton, MS; 3T. Hamby, PhD; and 2D. P. Wilson, MD, FNLA 1University of North Texas Health Science Center, Ft Worth, TX, and the Departments of 2Pediatric Endocrinology and Diabetes and 3Research Administration, Cook Children’s Medical Center, Ft Worth, TX, USA. Abstract Background: Familial hypercholesterolemia (FH) is a common genetic disorder cause of premature atherosclerosis due to chronically elevated low-density lipoprotein cholesterol (LDL-C) levels from birth. Individuals with FH experience an increased risk of premature cardiovascular disease (CVD), and lack of early identification and treatment increases the risk of CVD-related coronary events later in life. We report two siblings with FH caused by a novel mutation in APOB. Methods: Electronic medical records were reviewed for two patients with FH. Case Information: Two biologically related siblings (male age 9, female age 11) were found to have LDL-C levels [greater than] 95th centile for respective age and gender. Neither sibling had preexisting medical conditions nor a history of chronic medications. Both siblings were found to have the same missense variant in the APOB gene, a novel mutation causing hypercholesterolemia. Because of parental concerns regarding use of statins, both were treated with a cholesterol absorption inhibitor. Conclusions: Despite the benefits of early identification of those at moderate-to-severe risk, several knowledge gaps impede successful cholesterol screening of children: misunderstanding goals of screening, the best screening method, and ideal age for screening and for intervention. Current guidelines recommend universal cholesterol screening and selective screening starting at 10 and 2 years of age, respectively. Although not routinely preformed, identification of a genetic mutation helps to 1) confirm the diagnosis of FH; and 2) serves as an additional risk factor for CVD, aids risk stratification and clinical-decision making, and helps determine the timing and intensity of treatment that would provide the best long-term health benefits. In addition to lipid-lowering medications, treatment should include global reduction of all CVD risk factors through health education, and adoption of life-long, heart-healthy living with a goal to reduce LDL-C levels toItem A PROCESS IMPROVEMENT TOOL TO ENHANCE AND MONITOR THE TREATMENT OF CHILDREN AND ADOLESCENTS WITH DIABETIC KETOACIDOSIS (DKA)(2014-03) Wilson, Don; Nelson, Ashley; Bowman, W. PaulDiabetic ketoacidosis remains a significant cause of morbidity and mortality in children with diabetes mellitus with complications ranging from severe dehydration, electrolyte imbalance, hypercoagulability, pulmonary aspiration, and cerebral edema. Hourly monitoring of laboratory values, especially glucose and sodium [Na+], and fluid status of patients is utilized in many treatments. These values are generally recorded on static sheets next to the patient’s bedside or in an electronic medical record. Such static measures provide limited tools to evaluate trends in treatment and deviations from standard treatment protocols, therefore a process improvement tool was developed to enhance and monitor the treatment of children with DKA. A retrospective chart analysis from fifteen (15) children who were previously admitted to the pediatric intensive care unit (PICU) for treatment of DKA at Cook Children’s Medical Center was conducted. The data previously obtained during the child’s inpatient hospital course was used to assess the functionality of a newly developed computer monitoring tool. Purpose (a): The purpose of this research is to conduct a proof of concept study to determine the ability of a novel process improvement tool to enhance the treatment of children < 18 years of age with diabetic ketoacidosis (DKA). Methods (b): A process improvement tool was developed using an Excel platform. A retrospective study of fifteen patients admitted to the pediatric intensive care unit (PICU) at Cook Children's Medical Center for the treatment of DKA was used to evaluate the functionality of the process improvement tool. Results (c):The process improvement tool enables visual assessment of treatment trends and outcomes along with immediate feedback on the treatment course upon discharge from the PICU. Conclusions (d): A process improvement tool with visual monitoring and tracking of treatment trends is desirable in the treatment if DKA.Item An 11-Year-Old Female with Short Stature, Developmental Delay, and Bilateral Cataracts(2018-03-14) Swanson, Larry; Hamby, Tyler; Hamilton, Luke; Wilson, Don; Tran, MartinPseudohypoparathyroidism (PHP) is a rare, autosomal dominant disorder characterized by an end-organ insensitivity to parathyroid hormone (PTH). 1,2,3 Children with PHP typically present with symptoms of hypocalcemia, such as tetany and seizures. The most common form of PHP is 1A, caused by a loss of function mutation in the GNAS gene, which primarily affects PTH and possibly other hormones that share the same signal transduction. 3,4 In addition to symptoms of hypocalcemia and hormonal resistance, patients with PHP1A present with one or more features of Albright hereditary osteodystrophy (AHO), including short stature, subcutaneous ossifications, obesity, rounded face, mental deficit, and brachydactyly of either the 4th or 5th phalanges of the hands, feet, or both. We report a child who presented with features of PHP1A, discuss the diagnosis, and current recommendation of this rare condition.Item AN ACADEMIC-COMMUNITY-CLINIC PARTNERSHIP TO REDUCE WEIGHT IN HISPANIC YOUTH: FIT FOR HEALTH(2014-03) Nguyen, Dawn; Waverka, Rachael; Kitzman-Ulrich, Heather; Wilson, DonFIT for Health is a family-based weight management program taught by medical and graduate students delivered in a neighborhood clinic that includes behavioral skills, self-monitoring and a social networking website. Purpose (a): To develop an academic-community partnership, FIT for Health, to deliver a weight management program to low-income underserved communities who experience obesity related health disparities. Methods (b): Families with an overweight child (N=12; mean age = 11.8 (SD=2.1) years, 83% female, 100% Hispanic, mean BMI% = 96.3) were recruited by medical staff in a neighborhood clinic. Results (c): Youth maintained their weight over the 9-week program and demonstrated a small decrease in BMI percentile (96.3 to 96.0). The program demonstrated high satisfaction with an 84% attendance rate and 100% of families reporting enjoyment of the program, 89% were happy with their progress, and 100% felt they did a good job getting healthier. In addition, 78% of volunteer students reported an increase in knowledge about delivering community-based health promotion programs. Conclusions (d): The FIT academic-community-clinic model is a novel, cost-effective, and promising health promotion program that can provide resources to underserved low-income, ethnic minority families along with opportunities for students to participate in community-based health promotion.Item Are Patients with Adrenal Insufficiency and X-linked Adrenoleukodystrophy Substrate-Limited?(2018-03-14) Hamilton, Luke; Hamby, Tyler; Wilson, Don; Jack, BenjaminBACKGROUND X-linked adrenoleukodystrophy (X-ALD) results from inherited defects in the ATP-Binding Cassette Subfamily D Member 1 gene (ABCD1), which encodes adrenoleukodystrophy protein (ALDP), a peroxisomal protein involved in intracellular lipid transport. X-ALD phenotypes include various combinations of cerebral, neurological, and adrenal abnormalities, with up to 70% of affected males demonstrating primary adrenocortical insufficiency (AI). The pathogenesis of X-ALD is largely attributed to the accumulation of very long chain fatty acids (VLCFAs). It has been suggested that impaired intracellular transport of cholesterol may also play a role in the pathogenesis of AI in X-ALD. The objective of this case study is to review the mechanisms of cholesterol transport and availability in steroidogenic cells in patients with X-ALD who develop AI. CASE INFORMATION A 27-month-old male was referred for evaluation of adrenal function following a diagnosis of X-ALD. Serial laboratory results revealed progressive decline of both baseline and stimulated adrenal function. DISCUSSION In steroidogenic cells, cytosolic free cholesterol is incorporated into the outer mitochondrial membrane (OMM) by a complex of proteins, including mitochondrial transport protein TSPO. Steroidogenic acute regulatory protein transports cholesterol from the OMM to the inner mitochondrial membrane (IMM) where the initial steps of steroidogenesis occur. If cholesterol isn’t available at the IMM, no steroid hormones are produced. Because cholesterol is critical for steroid hormone synthesis, adrenal cortical cells have redundant mechanisms of cholesterol acquisition to ensure an adequate supply, including from circulating lipoproteins, intracellular stores, and de novo synthesis. Disorders affecting lipid and lipoprotein metabolism—as well as lipid lowering treatments, such as use of statins—could potentially alter adrenocortical function. However, there are few reports of AI in these disorders. CONCLUSION Because cortisol is essential for health and the body’s response to stress, redundant mechanisms of acquiring cholesterol allow steroidogenic cells to acquire cholesterol in spite of ALDP deficiency. The inability to process VLCFAs and accumulation of lipids in X-ALD, however, appears to overwhelm the adrenal cortical cells, resulting in cell death and primary AI.Item Atherogenic Cholesterol in 2 Siblings with Congenital Generalized Lipodystrophy(2016-03-23) Wilson, Don; Torre, Alejandro; Brautbar, Ariel; Hamilton, Luke; Ali, MirCongenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near total absence of body fat from birth, with predisposition to insulin resistance, diabetes, hypertriglyceridemia and hepatic steatosis.1 This clustering of risk factors is often associated with increased atherogenic cholesterol, increasing risk of premature atherosclerotic cardiovascular disease (ASCVD)-related events. We describe two Mexican-American siblings, a 17 yr old male and a 6 yr old female, with congenital generalized lipodystrophy type 4, a variant of CGL, due to null mutations in polymerase I and transcript release factor (PTRF).1 Both siblings had characteristic findings of near lack of total body fat with very low levels of serum leptin, insulin resistance, hepatic steatosis, dyslipidemia and myopathy with elevated CPK. Leptin (ref range 1.4-16.5): 0.8 ng/mL. Measurement of fasting lipid and lipoproteins revealed severe hypertriglyceridemia and low HDL-C. Elevated levels of atherogenic cholesterol (non-HDL-C and LDL-C) are causally related to the development of atherosclerosis, the key underlying process contributing to most clinical ASCVD events. Measurements of atherogenic cholesterol in our two siblings with CGL-4, appeared to increase with age. Lipid profiles in children with CGL-4 are similar to those described in metabolic syndrome, i.e. moderate to severe hypertriglyceridemia with low HDL-C and increased small dense LDL-C. Although CVD risk is increased, children with CGL-4 are prone to sudden cardiac death, the latter most likely a result of the cardiomyocyte dysfunction.Item Cardiovascular Screening in Youth(2015-03) Mou, Margaret; Wilson, DonThe objective of this project is to understand general providers’ screening and treatment processes and treatment options in children with a variety of cardiovascular disease risk factors. Currently, the national standard is to screen for hyperlipidemia and hypercholesterolemia every child within the ranges of 9 to 11 years old. Studies have shown this age to be a critical time that could possibly prevent the development of coronary artery disease as adults. With our study, we aimed to understand current knowledge and the practice patterns of practicing providers for cholesterol screening and treatment in children. Our study created opportunities to understand the knowledge gaps and barriers for universal screening in children ages 9-11 in order to develop improved screening processes and treatment interventions in children with cardiovascular disease risk factors to prevent the future escalation of atherosclerotic heart disease. We created an electronic questionnaire, which was advertised both through the NIH website and through NIH members’ emails, asking what current physicians are doing for cardiovascular screening and follow-up. Results showed that about 80% of providers agreed to screen all children ages 9-11, but there are still barriers to improve screening and treatment, including poor reimbursement and families’ opposition.Item Care of Children with Diabetic Ketoacidosis in Hospital Emergency Departments(2015-03) Mou, Margaret; Pickard, Brenna; Hsieh, Susan; Thornton, Paul; Wilson, DonBackground: Although preventable, diabetic ketoacidosis (DKA) remains a frequent and life-threatening complication of diabetes mellitus. Emergency Departments (ED) are the initial point of treatment for most children with DKA, which emphasizes the critical need for EDs to tailor therapy for their pediatric population. Understanding the evaluation, treatment, and disposition of such patients are critical to improving care and outcomes. Purpose: To conduct a survey of pediatric ED providers to better understand approaches to treating children with DKA. Subjects and Methods: An anonymous electronic survey was distributed to pediatric ED physicians in 6 pediatric emergency departments located in major metropolitan areas. Each of the EDs was part of a pediatric hospital that provides undergraduate and graduate medical education. Data and Conclusions: The majority of emergency department physicians correctly identified published criteria for diagnosis of DKA in children. While 89% either strongly agreed or agreed that children with DKA have ketonuria, only 43% strongly agreed or agreed that children with DKA had a BOBH >3. Reasons for admitting a child with DKA to the hospital included altered mental status, persistent vomiting, and lack of adult supervision. In the past 6 months, of all children treated in the ED with DKA approximately 70% were thought to be autoimmune (i.e. Type 1). The majority of children (91%) who presented to the ED with DKA were admitted; very few were discharged home (6.2%) or admitted to a short stay unit (2.8%). Aside from the pediatric ICU, use of a continuous IV insulin drip was not used either during emergency transport or while a child was admitted to the inpatient pediatric floor. However, 73.2% of respondents stated they used continuous IV insulin drip in the ED to treat DKA. Except for glucose and electrolytes, point of care testing was not available for hemoglobin or BOHB acid testing. Barriers to treating children with DKA in the ED included lack of familiarity with DKA treatment guidelines and lack of adequate inpatient facilities. Suggestions for enhancing knowledge of DKA treatment in the ED included education programs, educational materials, evidence based guidelines for treatment of DKA and a hospital or department sponsored DKA quality improvement initiative.Item CLASSIFICATION OF CHILDREN WITH NEWLY DIAGNOSED DIABETES MELLITUS(2014-03) Prakash, Sameer; Leung-Pineda, Van; Suzuki, Sumihiro; Radack, Jill A.; Dallas, John; Thornton, Paul; Wilson, DonPurpose (a): Historically the diagnosis of Type 2 Diabetes Mellitus (T2DM) has relied on a well described clinical phenotype. The reliability of this clinical phenotype in classifying children with diabetes is, however, not clear. The ability of experienced clinicians to correctly classify the type of diabetes based upon the clinical phenotype has recently been challenged. According to the American Diabetes Association, the diagnosis of T2DM requires a fasting plasma glucose of 126 mg/dL or higher, a 2-hour glucose level of 200 mg/dl or higher during a 75-g oral glucose tolerance test, or a random plasma glucose of 200 mg/dL or higher in a patient with classic symptoms of hyperglycemia or hyperglycemia crisis. In addition, those with T2DM should demonstrate the absence of diabetes auto-antibodies. Since the appropriate classification of a child's diabetes has important implications with regard to treatment options, expected outcomes and genetic counseling, a systematic, cost-effective algorithm to assist in the initial classification of diabetes mellitus is needed. Methods (b): We propose a retrospective analysis of diabetes related autoantibody tests (GAD, IA-2, Tg, Gliadin Peptide IGA, Gliadin Peptide IGG) in children (< 18 yrs of age) seen for evaluation of newly diagnosed diabetes mellitus in the Pediatric Endocrine Clinic hospitalized at Cook Children’s Medical Center for Jan 2010-June 2012.Following IRB approval, children and adolescents. Results (c): Following IRB approval, we conducted a retrospective chart review of 348 children(178 males; 170 females) hospitalized at Cook’s Children’s Medical Center from Jan 2010 – Jun 2012 with new onset diabetes mellitus to determine the frequency of antibody positive vs. antibody negative diabetes mellitus. In addition the frequency and test results for other diabetes-associated conditions (i.e. thyroid and celiac disease) were summarized. As expected the majority of patients were positive for one or more diabetes related antibodies. A much smaller number of patients were also tested for diabetes-associated conditions. Conclusions (d): We conclude that the majority of children < 18 years of age with new onset diabetes are positive for diabetes antibodies at the time of presentation. Those that are antibody negative need further evaluation to 1) determine whether these patients may have T2DM, a genetic form of DM (i.e. MODY) or some other form of diabetes and 2) to provide appropriate therapeutic and genetic counseling. Given the complexity of diagnosing diabetes mellitus and the rising cost of healthcare, a systematic algorithm may be useful in providing a cost-effective means of classifying children with new onset diabetes mellitus.Item Compound Heterozygous Familial Hypercholesterolemia Detected by Cascade Screening(2024-03-21) Nagaram, Sumedha; Hamilton, Luke; Wilson, DonThis report outlines the case of a 13-year-old non-Hispanic White male diagnosed with compound heterozygous Familial Hypercholesterolemia (FH) with a biallelic mutation in the LDLR gene. Notable clinical manifestations of the disease were observed such as: tendon xanthomas, total LDL-C and non-HDL that were all greater than or equal to the 95th percentile for age and sex. The patient received diagnosis for compound heterozygous FH through cascade screening by identification of his sister who had been diagnosed with heterozygous FH. However, given the patient’s family history of hypercholesterolemia and adverse cardiovascular events, both patients should have been screened by the age of 2. This paper urges healthcare systems to consider stricter implementation of universal screening protocols for FH as these patients have a significantly higher risk for adverse cardiovascular events early in life without early intervention.Item Congenital Hypothyroidism(2016-03-23) Hamby, Tyler; Dallas, John; Hamilton, Luke; Wilson, Don; Cielonko, Luke A.Introduction Congenital hypothyroidism (CH) is common, affecting between 1:3,000 and 4,000 newborn infants. Unrecognized or inadequately treated, CH leads to mental retardation. Newborn screening has made it possible to identify affected infants at a very early age, allowing thyroid therapy to be initiated usually within two weeks of birth. As a result of early diagnosis and appropriate treatment, many children with CH have normal cognitive development. The American Academy of Pediatrics (AAP) and the European Society for Pediatric Endocrinology (ESPE) have published guidelines to assist physicians in the appropriate evaluation and treatment of children with CH. Although early detection, correct diagnosis and timely treatment are critical to facilitate the best outcomes, little is known about provider practices when confronted with infants with congenital hypothyroidism. We, therefore, conducted a survey of pediatric endocrine providers to categorize beliefs and clinical practices. Methods An on-line survey was conducted of pediatric endocrine providers in a four state region (Texas, Oklahoma, Arkansas and Louisiana). All responses were anonymous and participation voluntary. The survey was conducted from January 15th to February 15th, 2016. Results The survey consisted of two clinical scenarios of infants with elevated thyroid-stimulating hormone (TSH) levels in the first two weeks of life. Other than a difference in the initial TSH, Scenario 1 (50 mU/L) vs. Scenario 2 (150 mU/L), the two scenarios were identical. Survey questions were designed to explore variation in clinical practice in several key areas, including physical examination, thyroid imaging, laboratory testing and treatment/follow-up. Analysis of variance (ANOVA) was used to examine how responses to these 14 items were impacted by the differences between practitioners based on years of experience ( 15 years), the differences within practitioners’ responses, and the interaction between these two predictors. At least one of the three predictors was significant, p Conclusions Our survey indicates that endocrine providers who completed the survey appear to understand and adhere to CH guidelines irrespective of the level of TSH elevation. Significant differences (pItem Do autopsies and perimortem testing still have a place in today's world of medicine?(2020) Wilson, Don; Hamilton, Luke; Eng, RyanBackground: Autopsies and perimortem testing have previously been a staple for improving patient care and expanding the field of medicine. In recent decades, autopsy rates have dropped dramatically, with current estimates of autopsy rates at 5%, yet data shows that clinical diagnoses are significantly less accurate than autopsy findings. In this case report, we aim to demonstrate the continued importance of autopsies using the case of a boy who passed away due to undiagnosed adrenoleukodystrophy (ALD). Case Information: An 8-year old male with a long history of severe headaches, emesis, and dehydration presented to Cook Children's Medical Center ICU after undergoing cardiac arrest. Workup of the patient did not find an etiology of these symptoms and the patient expired. Prior to expiration, a discussion was had with the parents about collecting samples for peri-mortem testing to determine cause of death. Whole exome sequencing (WES) of a peri-mortem blood sample revealed an ABCD1 variant, allowing the diagnosis of ALD. The patient's family members were recommended for genetic testing. Conclusions: Autopsy and perimortem testing were necessary to determine the patient's cause of death, which was not detected by routine pediatric screening or workup upon admission to the ICU. The patient's diagnosis proved especially important as it allowed family members to be referred to genetic counseling. Despite advances in diagnostic techniques, perimortem testing remains beneficial in cases of unknown or uncertain diagnoses, as seen in this case report.Item Does Cholesterol Screening in Prader Willi Syndrome Represent an Opportunity to Reduce Cardiovascular Disease Risk?(2022) Topham, Emily; Roy, Sani; Hamilton, Luke; Wilson, DonIntroduction: Hypercholesterolemia is a significant cause of cardiovascular disease (CVD) worldwide. Hypercholesterolemia screening guidelines include an initial lipid panel starting at 2 years-of-age with risk factors and 10 years-of-age for all children, regardless of risk status (3). Children with PWS develop a variety of health conditions, increasing their risk of premature CVD. Thus, this population should undergo global risk factor assessment, including cholesterol screening, starting at 2 years. In 2019, the American Academy of Pediatrics management guidelines for PWS included an initial lipid panel from ages 1-5 years (2,4). Case Presentation Case 1: A full-term male infant was admitted to the NICU for hypotonia and difficulty feeding. PWS was diagnosed by microarray paternal deletion of 15q11.2-q13. At age 3 months, growth hormone was started. He developed significant hypercholesterolemia with LDL-C of 236 mg/dL at 3.5 years (BMI < 5th percentile, TC 319, HDL-C 65, TG 71, Non-HDL-C 254). His father has hypercholesterolemia. Familial hypercholesterolemia (FH) genetic screening was negative. Renal, hepatic function and HbA1c were normal. At 3.5 years, a low normal T4 with inappropriately normal TSH was found and consistent with partial central hypothyroidism. He was treated with levothyroxine which normalized his T4; while the LDL-C improved but remained elevated (LDL-C 161). Statin therapy was deferred due to young age. Case 2: A male infant was admitted to the NICU for hypotonia and difficulty feeding. Methylation study confirmed PWS. At 5.5 years, he had hypercholesterolemia with LDL-C of 198 mg/dL (BMI >99th percentile, TC 274, HDL-C 41, TG 176, Non-HDL-C 233). Neither parent is known to have hypercholesterolemia. FH genetic screening was negative. Thyroid and renal function were normal; however, transaminases were very elevated without cholestasis. At 7.5 years, a statin was recommended but the family opted for ezetimibe. At age 9 years, he developed HbA1c of 11.1%, and had negative Type 1 diabetes antibodies, consistent with Type 2 Diabetes Mellitus (T2D). He was treated with diet, insulin, and metformin. As HbA1c normalized (5.5%), the medications were discontinued. Discussion & Conclusion: The development of CVD in individuals with PWS is complex and risk factors are often underdiagnosed. Inherent to PWS are hypotonia and decreased muscle mass, leading to a 20% lower basal metabolic rate and decreased exercise tolerance. Combined with the development of insatiable appetite and hyperphagia, these factors often lead to cardiovascular disease risk (5). In adults with PWS, hypercholesterolemia was undiagnosed in 6%, T2D in 5%, hypertension in 3% (5). Risk factors associated with PWS contribute to premature mortality in this population and 70% die at a young age (29 ± 16 years) (1). The presence of hypercholesterolemia or other risk factors, especially those present from an early age, greatly enhance future CVD-related risk, and represents a need for screening.Item Evaluating the Diagnostic Criteria for NAFLD(2017-03-14) Keng, Jane; Ogunmola, Nicholas; O'Reilly, Crystal; Gonzalez, Jose; Hamilton, Luke; Wilson, Don; Zangla, EmilyPurpose: Nonalcoholic Fatty Liver Disease (NAFLD) is the most prevalent chronic liver disease in American children and adolescents, thought to involve hepatic fat deposition and inflammatory changes secondary to insulin resistance. Methods: Diagnosis is currently based on elevated ALT levels and subsequent liver ultrasound. Ultrasound, however, has proven to be less accurate in pediatrics than adults. Due to these limitations of utilizing ultrasound, liver biopsy remains the gold-standard of NAFLD diagnosis on children. Although biopsy is the most definitive diagnostic method, non-invasive biomarkers need to be further investigated for their diagnostic value to children. A retrospective chart review was completed to describe the clinical parameters of patients with NAFLD. Results: 45 patients (56% male) had a primary diagnosis relating to NAFLD; mean age 9.8 years (range 0‒18 years). Mean BMI percentile was 84% (90% males; 79% females). Median ALT 79; 82.5 males; 79 females; range 25‒1823 (ref 7‒55 U/L males; 7‒45 U/L females). Median AST 59; 60 males; 55 females; range 18‒2353 (ref 8‒60 U/L males 1‒13 years; 8‒50 females 1‒13 years). These results allow us to study the profile of patients evaluated for NAFLD at Cook Children’s. Conclusions: A better understanding of the criteria used by physicians can potentially help with early identification, prevention of disease progression, and improve care of children with NAFLD.Item Growth Hormone Treatment in Rapadilino/Rothmund-Thomson Syndrome(2016-03-23) Hsieh, Susan; Drummond-Borg, Margaret; Hamilton, Luke; Wilson, Don; McKee, DarylINTRODUCTION/CASE PRESENTATION We describe two female Caucasian siblings with compound heterozygous mutations in the RECQL4 gene. Both were referred to the Endocrine clinic for severe short stature. The 4 year old has talipes equinovarus, bilateral radial reduction defects, small palpebral fissures, small mouth, and skin changes. She was found to be growth hormone (GH) deficient, with a small pituitary gland on MRI scan, and was treated with biosynthetic GH. Her 22 month old sibling was born with bilaterally absence of her tibias, bilateral radial ray reduction defects, small mouth, and small palpebral fissures, but normal GH. DISCUSSION The RECQL4 gene encodes helicases that are important in DNA replication and repair. Clinically RECQL4 mutations are found in three rare conditions: 1) Rapadilino syndrome (RS), 2) Rothmund Thomson syndrome (RTS) and 3) Baller Gerold syndrome (BGS). These three autosomal recessive conditions have similar characteristics of skeletal abnormalities, and an increase prevalence of cancer, such as osteosarcoma, particularly in RTS and RS. Osteosarcoma development has been reported in growth hormone treated RS and RTS patients. The DNA helicase activity of RECQL4 has been shown to be critical in skeletal development. Animal models of mutated RECQL4 deregulate p53 activity that can possibly explain the predisposition to osteosarcoma. CONCLUSION We report two siblings with a rare disorder due to the RECQL4 gene mutation associated with multiple skeletal abnormalities and predisposition cancer, such as osteosarcoma. In individuals who are deficient, GH has been shown to significantly improve linear growth and quality of life. Although the older sibling has shown a favorable response, because of its mitogenic effects GH should be used with caution in children predisposed to cancer. A better understanding of the pathophysiology of the diseases associated with mutations in the RECQL4 gene is needed to help develop a more effective treatment program.Item Gynecomastia and Partial Androgen Insensitivity Syndrome (PAIS)(2017-03-14) Thornton, Paul; Hamilton, Luke; Ahmad, Zahid; Wilson, Don; Ahn, SamPurpose: Partial androgen insensitivity syndrome (PAIS) is a rare genetic disorder, with a prevalence of 1:130,000. Caused by a loss-of-function mutation in the androgen receptor (AR) gene located on the X-chromosome, PAIS is clinically characterized by hypospadias, gynecomastia, and infertility due to azoospermia.Phenotypic manifestations often overlap with other genetic disorders. Therefore, genetic screening can not only help provide a definitive diagnosis, but can also assure accurate genetic counseling – especially for female carriers. Case Presentation: A 13-year-old male Caucasian was referred for gynecomastia. His past medical history was unremarkable, except for attention deficit hyperactivity disorder. Family history included cancer, cardiovascular disease, and obesity. On physical exam, his penis was underdeveloped while his pubic hair was Tanner 3. He had large well-formed breasts similar to Tanner 4 in females. His testicles were 6 mls. Laboratory testing revealed elevated serum testosterone of 1610 ng/dL, LH 4.75 mIU/mL, FSH 0.57 mIU/mL and estradiol 17 pg/mL. His initial lab results were consistent with (partial) androgen insensitivity syndrome. Following 10 mg/d of tamoxifen, his breast tissue dissappeared completely and the drug was discontinued. Within a year, significant breast hypertrophy was again noted and tamoxifen was resumed. With further treatment, his gynecomastia once again resolved. F-up lab results showed continued elevation of serum testosterone of 1678 ng/dL with LH levels of 20.24 mIU/mL, and estradiol of 73 pg/m. FSH levels remained normal (2.66 mIU/mL). Genetic testing confirmed a known mutation for PAIS. The patient was advised to continue tamoxifen. Whole exome sequencing was completed (illumina HiSeq 2000, McDermott Center Sequencing Core at UT Southwestern Medical Center, Dallas, TX) from DNA isolated from peripheral blood. The patient harbored a missense mutation (A700D) in the AR gene. Sanger sequencing was completed to confirm the mutation. His mother was heterozygous for the mutation while his father and unaffected brother lacked the mutation. Summary: Gynecomastia, the proliferation of male breast tissue, may occur as a consequence of physiologic or pathologic causes. Although physiologic gynecomastia commonly associated with male puberty resolves spontaneously, pathologic causes often result in persistent breast enlargement, accompanied by tenderness and, in some, galactorrhea. Further diagnostic testing is recommended in those with persistent, unexplained gynecomastia. Current treatment options for PAIS are limited to symptomatic management. Genetic and psychological counseling, and hormone replacement therapy should be proved.4,5 Affected males with hypospadias may benefit from assistance with sex assignment, genitoplasty and gonadectomy. Conclusions: Overall, PAIS is often overlooked due its rarity and may be confused with other genetic disorders with similar clinical presentations. As such, PAIS should be included in differential diagnosis of children who present with abnormal secondary sexual organ development or ambiguous genitalia. Individuals with PAIS should be managed by a multidisciplinary team to assure the best outcomes.Item HbA1c vs FPG and 2-Hour OGTT Glucose in Identifying Dysglycemia in Youth(2016-03-23) de la Torre, Alejandro; Hamilton, Luke; Wilson, Don; Huynh, NganINTRODUCTION In recent years, there has been an increased incidence of pre‑diabetes and type 2 diabetes mellitus in youth 10 years of age and older.1 Dysglycemia has been shown to be a continuous risk factor for cardiovascular disease and thus offers a compelling reason for evidence-based screening and management.2 Current ADA guidelines for the diagnosis and management of pre-diabetes in youth are based upon extrapolation from adult studies and may not be valid in the pediatric population.1, 3 EXPERIMENTAL METHODS To evaluate the utility of HbA1c in identifying dysglycemia in youth, results of the HbA1c, fasting plasma glucose (FPG), and 2-h oral glucose tolerance test (OGTT) were collected retrospectively from a multiethnic cohort of 390 youth seen in a preventive cardiology clinic from 2012 to 2015. Results of the HbA1c were compared to the FPG and 2-h glucose following a standard OGTT. RESULTS Table 1. Comparison between HbA1c and FPG values Table 2. Comparison between HbA1c and OGTT 2-h glucose values Of the patients with a HbA1c DISCUSSION HbA1c is frequently used to identify dysglycemia in at‑risk youth. Although it is a convenient screening tool, the results may be discordant with other measures of dysglycemia. Results from the 2005‑2010 Yale Pathophysiology of Type 2 Diabetes in Obese Youth Study indicate that the optimal A1c threshold for identifying T2DM was 5.8% and that the best predictor of 2-h glucose at a 2-year follow-up was the combination of the subject’s baseline A1c and 2‑h glucose.4 A cross-sectional study compared results of OGTT and HbA1c to measurement of glycemia via continuous glucose monitoring. The OGTT and HbA1c each predicted different patterns of dysglycemia, with the former providing a greater correlation with peak glucose and variability and the latter providing a greater correlation with average and overnight glucose values.5 CONCLUSION Diagnostic tests for pre-diabetes and diabetes in youth are often discrepant. It would appear that HbA1c is a convenient but imperfect screening tool in youth. The cutoff for the different categories of glycemia may need to be modified, and the HbA1c may need to be paired with the OGTT to increase the sensitivity of pre-diabetes screening in at-risk youth. More studies are needed to evaluate diagnostic markers of dysglycemia and effective management of pre-diabetes in this vulnerable population.Item Hypercholesterolemia Induced by a High-Fat, Low-Carbohydrate Diet in a 16-year-old Male and 6-year-old Female.(2024-03-21) Snyder, Alyssa; Hamilton, Luke; Wilson, DonBackground: The ketogenic diet is a high-fat, low-carbohydrate (HFLC) diet that has been linked to hypercholesterolemia. There are ongoing studies on the connection between hypercholesterolemia and adherence to the ketogenic diet. Medically supervised HFLC ketogenic diets with up to 90% fat have been used successfully in children as an alternative treatment for epilepsy. Although safety and efficacy data are limited in children, this high-fat diet has also been used for weight loss. Case information: Patient 1:A 16-year-old previously healthy African American male was concerned about his weight and his mother started him on a ketogenic diet. Before diet implementation, he weighed 93.2 kg (BMI of 31.6 kg/m2; 99%) and had a low-density lipoprotein cholesterol (LDL-C) of 114 mg/dL (normal LDL-C is below 110 mg/dL). During the following months, the patient lost weight and his LDL-C levels continuously increased and peaked at 348 mg/dL after losing 59lbs on the ketogenic diet. The patient was offered pharmacotherapy but the parents declined. During his most recent follow-up appointment, the patient stopped adhering to the ketogenic diet and increased his weight to 79.2 kg (BMI of 26.2 kg/m2; 87.5%), and his LDL-C level dropped to 182 mg/dL. Throughout appointments, triglycerides remained normal. No pathological variants for APOB, LDLR, LDLRAP1, and PCSK9were found on genetic testing. Patient 2: A 6-year-old female with a history of idiopathic ketotic hypoglycemia and growth hormone deficiency was started on the ketogenic diet as a way to help control hypoglycemic episodes. The diet helped keep her blood glucose levels stable but she demonstrated severe hypercholesterolemia on her lipid screening. Her LDL-C levels were significantly elevated at 310 mg/dL 37 months after her first appointment. She was taken off the ketogenic diet for 6-8 weeks with significant improvement in her LDL-C dropping down to 116 mg/dL. At 42 months, the patient was admitted to the hospital for hypoglycemia. It was noted that the mother had started the patient on the ketogenic diet again due to recurrent episodes of hypoglycemia. On lipid screening, her LDL-C was back up to 397 mg/dL. Genetic testing for APOB, LDLR, LDLRAP1, and PCSK9 were all negative. Conclusions: Several mechanisms have been proposed to explain the adverse effect of hypercholesterolemia in individuals participating in the ketogenic diet. This includes increased saturated fatty acid intake causing downregulation of LDL receptors, genetic polymorphisms, and cholesterol mobilization associated with weight loss. Although there is ongoing research regarding the mechanism behind hypercholesterolemia associated with HFLC diets, there is no clear, definitive explanation yet. Our case study and other case series in adults on the ketogenic diet for weight loss show the importance of ruling out HFLC diets when patients present with hypercholesterolemia and have no known genetic mutations suggesting familial hypercholesterolemia (FH).Item Hyperinsulinism Secondary to Congenital Disorder of Glycosylation Type 1a(2016-03-23) Thornton, Paul; Basinger, Alice; Caldwell, James; Hamilton, Luke; Wilson, Don; Choi, WoongsoonPurpose Congenital disorders of glycosylation (CDG) are a group of rare genetic disorders caused by defects in enzymes responsible for a series of post-transcriptional glycosylation reactions. The most well known subtype of these disorders is CDG type 1a. More than 700 cases have been reported worldwide. Its clinical spectrum and severity are widely variable; common symptoms include seizure, ataxia, hypotonia, developmental delay, liver dysfunction, and cardiomegaly, but hypoglycemia secondary to hyperinsulinism has rarely been reported. A closely related subtype of CDG is CDG type 1b. CDG type 1b is characterized by protein-losing enteropathy and diarrhea, as well as endocrine-related symptoms, such as hypoglycemia. Methods A 2-month-old male was admitted for severe hypoglycemia and liver dysfunction. Because of his concomitant liver disease, enzymatic testing and gene sequencing for a disorder of glycosylation were requested. He was found to have a mutation of the gene for CDG type 1a. Over the subsequent 2 years, the child was noted to have ataxia and hypotonia. An MRI scan of the brain demonstrated a hypoplastic cerebellum and vermis. He experienced multiple seizures. Hypoglycemia, secondarily to hyperinsulinism, was controlled with diazoxide. The hypoglycemia resolved by 2 yrs of age when he was able to fast for >24 hours while maintaining a glucose >50mg/dL and beta-hydroxybutyrate>3mmol/L. Therefore, the diazoxide was discontinued. Results The most common presenting symptoms of CDG type 1a are neurological. In addition to hypotonia and seizures, our patient has persistent hypoglycemia associated with hyperinsulinemia, an unusual presentation of CDG type 1a as opposed to CDG type 1b. The proposed mechanism hyperinsulinemia is secondary to constitutively closed ATP-sensitive K+ channel, producing unregulated release of insulin. Given its ability to open the ATP-sensitive K+ channel, diazoxide is a reasonable treatment option. Our patient’s hypoglycemia responded well to diazoxide. Conclusion Currently, there is no cure for disorders of glycosylation. Mortality within the first year of life is as high as 20%. Treatment options are being explored to facilitate glycosylation with either a membrane-permeable mannose-1-phosphate treatment or enzyme replacement therapy. Additional research is needed to find more effective treatments to improve morbidity and reduce mortality in affected patients.Item Iodine: a Catalyst for Transient Congenital Hypothyroidism(2015-03) Wilson, Don; Dallas, John; Baby, NayanaAbstract Introduction: Iodine plays a key role in thyroid hormone metabolism. Excess iodine is an unusual cause of hypothyroidism. We report an infant with iodine induced abnormal newborn screen for congenital hypothyroidism. Case report: A Korean infant female was found to have an abnormal newborn screen for congenital hypothyroidism (CH) at 2 weeks of age. Investigation revealed markedly elevated urinary iodine. The infant’s diet consisted of breast milk alone, and her mother admitted to a diet rich in seaweed soup. It was recommended that the mother discontinue use of seaweed soup. The infant was initially treated with thyroid hormone replacement. Following withdrawal of the thyroid hormone replacement, the child remained euthyroid and developmentally normal. Discussion: Seaweed: a dietary staple of certain cultures is rich in iodine and maternal consumption of products with high iodine content while breastfeeding has been associated with congenital hypothyroidism. In the present case, the infant’s initial New Born Screen (NBS) was normal. The second newborn screen showed an elevated TSH with normal free T4. Conclusion: Iodine excess should be considered as a cause of an abnormal newborn congenital hypothyroidism screen, especially in the Asian culture.
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