Browsing by Author "Hamilton, Luke"
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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 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 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 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 Is Adrenal Insufficiency of Concern in Children with Disorders of Lipid and Lipoprotein Metabolism?(2020) Wilson, Don; Hamilton, Luke; Lammers, CaraBackground: Genetic mutations and newer lipid-lowering medications often result in very low plasma levels of LDL cholesterol. Low plasma cholesterol has the potential to negatively impact physiological processes, including steroidogenesis, but the adrenal employs several redundant mechanisms to minimize disparities. Although the likelihood of very low cholesterol impairing production of adrenocortical steroids is unlikely, our knowledge of adrenal function in affected patients is limited. Several genetic diseases including X-linked adrenoleukodystrophy have been reported to impact cholesterol metabolism leading to altered adrenal function. The case outlined below raises the question as to what extent impaired cholesterol transport could affect steroid hormone synthesis. We consider this question in the context of other disorders of cholesterol metabolism and their potential implications in adrenal insufficiency. Case Information: A 27-month-old male was referred to Endocrinology for evaluation of adrenal function following his diagnosis of X-linked adrenoleukodystrophy. Several labs were obtained including plasma ACTH, baseline cortisol, and peak cortisol. Monitoring over several years revealed impaired cholesterol metabolism and confirmed progressive failure of the adrenal cortex. Conclusions: Decreased intracellular cholesterol impaired adrenal function leading to decreased cortisol production. Several genetic disorders are characterized by abnormalities in cholesterol synthesis or metabolism, potentially limiting this key metabolite in providing proper adrenal hormone production and release. Due to the redundant mechanisms for utilizing cholesterol, it seems unlikely that hypocholesterolemia, secondary to genetic disorders and use of lipid-lowering medication that result in very low levels of LDL cholesterol, is of major concern.Item Mucolipidosis Type II (I-Cell Disease)(2016-03-23) Brautbar, Ariel; Hamilton, Luke; Wilson, Don; Dehbozorgi, Hangameh1. Our case is unusual because ML II does not generally present with fractures. This case demonstrates the importance of considering ML II in infants presenting with in-utero fractures. 2. Athena was used to access the patient's medical chart to collect information on this case presentation. 3. We describe a 10-month-old, Hispanic male of non-consanguineous parents with a history of in- utero fractures. In addition to multiple fractures, osteopenia, congenital heart defect, and jaundice were also present. The infant’s clinical presentation initially suggested osteogenesis imperfecta (OI), however genetic testing found no evidence of known mutations of OI. A careful review of the skeletal survey was suspicious for ML II, and further genetic sequencing at approximately 5 months of age confirmed the diagnosis. 4. Currently, there is no cure for ML II. Treatment focuses on palliative care including physical therapy to alleviate joint stiffness, speech therapy to assist in language acquisition, and surgery to correct conductive deafness. Continued research is needed to reduce morbidity and improve mortality.Item Neonatal Diabetic Ketoacidosis - A Case Report(2023) Bommakanti, Maalini; Borrego, Natali; Radack, Jill; Hamilton, Luke; Wilson, DonBackground: Neonatal diabetes mellitus (NDM) is a rare condition (1 in 400,000 live births). It generally presents within the first 6 months of life and may be transient or permanent. The transient form is commonly associated with paternal isodisomy and monogenic variants, such as KCNJ11 and ABCC8, located on chromosome 6. The permanent form is also associated with monogenic variants, most commonly KCNJ11 and ABCC8. Diabetic ketoacidosis (DKA), which is common in older children and teens with autoimmune diabetes mellitus (T1D), is rare in NDM and often overlooked. Case Study: A 1-day-old female with low birthweight (2.520 kg) was referred to Cook Children’s Medical Center for tachypnea (78 to 84 bpm) and hyperglycemia. Her blood pH was 7.22 (7.29 – 7.24), pCO2 <12 (27- 40 mmHg), pO2 122 (54-95 mmHg), and HCO3 of 4.1 (19.0-24.0 mmol/L). Blood glucose levels were >200 mg/dL. Due to persistent respiratory symptoms, she was suspected of being septic and was treated with ampicillin and gentamicin. She was on the cutoff for SGA. Within the initial 48 hours of admission, her lab test results were consistent with DKA - blood glucose of 305 mg/dL (50-96 normal), lactic acid of 2.3 mmol/L (0.5-2.0 normal), anion gap of 21 (10-16 normal) and B-hydroxybutyrate of 9 mmol/L (0.4-0.5 normal). Genetic testing showed a variant of unknown significance in HNF1a. Following stabilization, the parents underwent diabetes education, and the infant was discharged on daily insulin therapy for follow-up in the Endocrine clinic. By 5 years-of-age, she continued to require daily injections of insulin for glucose control. This case is unique in that the infant was found to have a variant of unknown significance for HNF1a, a monogenic mutation that is typically seen in maturity-onset diabetes of the young (MODY). In general, MODY is not typically associated with DKA. Therefore, while our finding is intriguing, we cannot state that this variant is causative in the case we presented. Further reports of HNF1 variants are needed to help determine if there is an association with NDM and DKA. Conclusions: In infants, NDM and DKA are rare and present with nonspecific symptoms, which often delays the diagnosis. Although rare, it is imperative that NDM and DKA be considered in order to avoid adverse consequences, including death.Item Perceived Fatigue May Be an Overlooked Barrier to Successful Therapeutic Lifestyle Change(2019-03-05) Hamby, Tyler; Jarvis, Todd; Wilson, Don; Hamilton, Luke; Bopp, BenPurpose Children and adolescents at-risk of developing premature cardiovascular disease (CVD) due to genetic disorders and acquired conditions, such as obesity and insulin resistance, are often referred to a pediatric lipid clinic. While adoption of a lifelong, heart-hearty lifestyle is encouraged, those with genetic disorders may benefit from lipid-lowering medications. Recommendations for therapeutic lifestyle change in those who are obese, especially the need for less sedentary time and 30-60 min/d of moderate-to-vigorous physical activity, may be hindered by a perception of fatigue. An increased perception of fatigue in obese youth vs healthy controls has previously been reported in those referred to an obesity clinic. The purpose of this study was to examine perceived fatigue in a sample of obese youth (age; BMI ³95th percentile) with acquired CVD risk factors, who were referred to a pediatric lipid clinic. METHODS This study was a retrospective chart review of 237 youth referred to the Risk Evaluation to Achieve Cardiovascular Health (REACH) clinic at Cook Children’s Medical Center between January 1, 2014 and August 31, 2018. During the initial clinic visit, each subject and the child’s parent independently completed the PedsQL Multidimensional Fatigue Scale, a validated survey with 18 items divided into 3 subscales – General, Sleep/Rest, and Cognitive – each containing 6 questions. A total score was computed, the range of possible scores ranging from 0 to 100 for each subscale. Higher scores indicate less perception of fatigue. A t-test was used to compare study subjects to previously reported obese youth (N=43) referred to an obesity clinic and normal weight, healthy controls (N=157). A p-value RESULTS The study population consisted of 200 subjects, 50.5% of whom were morbidly obese (³99th percentile). Study subjects had statistically significantly more perception of fatigue for each sub- and total scale for both self- and parent-reported scales (p CONCLUSION Obese youth with and without reported acquired CVD risk-factors experience greater perceived fatigue than healthy controls. It is important to consider barriers to implementation, such as perception of fatigue, when recommending lifestyle modification.Item Polyglandular Autoimmunity: Two Cases of Type 1 diabetes (T1D) accompanied by Addison’s disease (AD)(2023) Borrego, Natali; Bommakanti, Maalini; Radack, Jill; Hamilton, Luke; Wilson, DonBackground: Type 1 diabetes (T1D), present in ~1:500 children, is often accompanied by other autoimmune conditions, notably chronic lymphocytic thyroiditis. Involvement of other endocrine organs, however, is rare. Autoimmune impairment of more than one endocrine system is referred to as an autoimmune polyglandular syndrome (APS), categorized as type 1 (APS-1) or type 2 (APS-2). In addition to T1D, APS-1 is characterized by 1 or more of the following: candidiasis, hypoparathyroidism, and/or AD; while APS-2 involves AD and/or chronic thyroiditis2. The lifetime risk of developing a 2nd endocrine autoimmune condition in individuals with T1D is ~1:5, and usually occurs during adulthood. While children may be affected, such reports are unusual and generally limited to case studies. APS-2 is rare in childhood, with a prevalence of ~ 1:100,0004. We present two children with APS-2. Case Information: Case 1: A 6-year-old Caucasian male, who was diagnosed with T1D at 3 years-of-age, presented with persistent vomiting which required hospitalization. Although his diabetes was reasonably well controlled prior to his hospitalization, the child was noted to be overly sensitive to insulin during this admission, during which he experienced several episodes of hypoglycemia. Laboratory testing revealed metabolic acidosis, hyponatremia, and hypocortisolemia. Appropriate testing confirmed primary adrenal insufficiency; the latter, along with his T1D, being consistent with APS-2. Case 2: A 15-year-old Caucasian male experienced an unexplained 20 lb. weight loss. After developing fever, routine laboratory tests were reported to be characteristic of diabetic ketoacidosis (DKA) - hyponatremia, metabolic acidosis and hyperglycemia. With treatment, his DKA resolved, and he began conventional insulin therapy. However, follow-up laboratory tests demonstrated persistent hyponatremia. Additional studies confirmed the presence of AD, consistent with APS-2. Conclusion: These previously healthy children developed T1D accompanied by AD, characteristic of APS-2. The presence of both conditions significantly increases the risk of potential life-threatening complications in affected children5. Individuals with both T1D and AD have a 2.5-fold increased risk of adrenal crises, compared to those with isolated AD6. Timely diagnosis of polyglandular autoimmunity is critical to help inform clinical decision-making, and to avoid adverse outcomes. The diagnosis of APS is often hampered by common symptoms such as: fatigue and weakness, unexplained weight loss, increased thirst, frequent urination, irritability, nausea and abdominal pain, and changes in appetite2. Management is complicated by the effects of glucocorticoid levels on insulin sensitivity. For example, these patients have a risk of increased insulin sensitivity and hypoglycemia in the early morning hours prior to the next glucocorticoid dose1. Patient education is key for understanding the interactions between the two conditions as well as the effects of diet, physical activity, and emotional stress2. While the onset of APS is variable, most patients tend to develop autoimmunity sequentially over a period of many years2. APS-2 has been linked primarily to genes coding for major histocompatibility complex, particularly DR3-DQ2 and DR4-DQ8 variants6. Physicians should be vigilant in assessing children with autoimmune-related conditions, such as T1D, and although rare, aware of the potential for additional autoimmune-mediated organ failure in some.Item Relationship of Lipoprotein (A) with Other Measures of Atherogenic Cholesterol(2016-03-23) Brautbar, Ariel; Hamilton, Luke; De La Torre, Alejandro; Leung-Pineda, Van; Hamby, Tyler; Wilson, Don; Prakash, SameerPurpose: Lipoprotein (a) [LP(a)] represents a class of lipoproteins with structural similarity to low density lipoprotein (LDL). Lp(a) consists of a cholesterol-laden LDL–like particle bound to a plasminogen-like glycoprotein [apolipoprotein(a)], making it capable of contributing to both atherosclerosis and thrombosis. Indeed Lp (a) has been shown to be an independent risk factor in the development of CVD and causative of CVD-related events. Nonetheless, questions remain about screening and treatment of individual with elevated levels, especially youth ( Methods This is a retrospective chart review of youth (age) referred to the Cardiovascular Health and Risk Reduction Program at Cook Children’s Medical Center between Jan 2012 and Feb 2015. Records were reviewed and de-identified data collected of those routinely tested for risk factors associated with premature CVD, including total and LDL-C, HDL-C, TG and Lp(a). Non HDL-C was calculated as: Total cholesterol – HDL-C. Since fasting has little effect on levels of HDL-C, LDL-C, and non HDL-C, blood samples were collected with and without fasting. Pearson’s correlations and non-parametric Spearman’s rho (Ρ) were calculated between Lipoprotein (a) and each individual risk factor. Results The two sets of correlations produced similar results. Lp(a) was positively and significantly, though modestly, correlated with total cholesterol, non HDL-C and LDL-C. However, Lp(a) was not significantly correlated with HDL-C or TG. Conclusions Lp (a) is associated with increased risk for premature cardiovascular disease, such as myocardial infarction and stroke. While moderate correlations to Lp (a) were observed between non HDL-C and LDL-C, Lp (a) seemingly remains an independent risk factor.