Charles A Stanley

The Children's Hospital of Philadelphia, Filadelfia, Pennsylvania, United States

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Publications (246)1542.48 Total impact

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    ABSTRACT: Context: Acquired insulinomas are rare causes of hyperinsulinemic hypoglycemia in children and are much less common than focal lesions of congenital hyperinsulinism. The latter are known to be associated with isodisomy for paternally-transmitted KATP mutations on 11p15; however, the molecular basis for pediatric insulinomas is not well characterized. Objective: The purpose of this study was to characterize the histopathologic and molecular defects in a large group of 12 pediatric insulinomas seen at The Children's Hospital of Philadelphia. Results: Twelve children with insulinomas were seen between 1971-2013, compared to 201 cases with focal congenital hyperinsulinism seen between 1997-2014. The age of insulinoma patients ranged from 4-16 years at the time of surgery. Features of MEN1 syndrome were present in 5 of the 12, including 4 cases with heterozygous mutations of MEN1 on 11q. Immunohistochemical analysis revealed nuclear loss of p57 staining consistent with loss of the maternal 11p15 allele in 11 of the 12 insulinomas, including all 5 MEN1-associated tumors. Imbalance of the paternal 11p allele was confirmed by SNP genotyping and methylation assays of the 11p imprinting control loci in 4 of 5 MEN1-associated tumors and 6 of 7 sporadic insulinomas. In addition, SNP genotyping revealed extensive tumor aneuploidy beyond chromosome 11. Conclusions: These data indicate that MEN1 mutations are more common in insulinomas in children than in adults. Aneuploidy of chromosome 11 and other chromosomes is common in both MEN1 and non-MEN1 insulinomas. The novel observation of a paternal parent-of-origin effect in all MEN1 and most non-MEN1 tumors suggests a critical role for imprinted growth-regulatory genes in the 11p region in the genesis of β-cell endocrine tumors in children.
    No preview · Article · Jan 2016 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: Background: Congenital hyperinsulinism (HI) can have monogenic or syndromic causes. Although HI has long been recognised to be common in children with Beckwith-Wiedemann syndrome (BWS), the underlying mechanism is not known. Methods: We characterised the clinical features of children with both HI and BWS/11p overgrowth spectrum, evaluated the contribution of KATP channel mutations to the molecular pathogenesis of their HI and assessed molecular pathogenesis associated with features of BWS. Results: We identified 28 children with HI and BWS/11p overgrowth from 1997 to 2014. Mosaic paternal uniparental isodisomy for chromosome 11p (pUPD11p) was noted in 26/28 cases. Most were refractory to diazoxide treatment and half required subtotal pancreatectomies. Patients displayed a wide range of clinical features from classical BWS to only mild hemihypertrophy (11p overgrowth spectrum). Four of the cases had a paternally transmitted KATP mutation and had a much more severe HI course than patients with pUPD11p alone. Conclusions: We found that patients with pUPD11p-associated HI have a persistent and severe HI phenotype compared with transient hypoglycaemia of BWS/11p overgrowth patients caused by other aetiologies. Testing for pUPD11p should be considered in all patients with persistent congenital HI, especially for those without an identified HI gene mutation.
    No preview · Article · Nov 2015 · Journal of Medical Genetics
  • Christine Ferrara · Payal Patel · Susan Becker · Charles A Stanley · Andrea Kelly
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    ABSTRACT: Objective: To evaluate thresholds of various biomarkers for defining excess insulin activity to recognize congenital hyperinsulinism. Study design: This was a retrospective chart review of diagnostic fasting tests in children with ketotic hypoglycemia (n = 30) and genetically/pathology confirmed congenital hyperinsulinism (n = 28). Sensitivity and specificity for congenital hyperinsulinism were determined for plasma insulin, β-hydroxybutyrate, free fatty acids (FFA), C-peptide, insulin-like growth factor binding protein-1 (IGFBP-1), and the glycemic response to glucagon (through the glucagon stimulation test [GST]) at the time of hypoglycemia. Results: Only 23 of the 28 subjects with congenital hyperinsulinism had detectable insulin (median, 6.7 μIU/mL), and insulin was undetectable in all subjects with ketotic hypoglycemia. Compared with ketotic hypoglycemia, subjects with congenital hyperinsulinism had higher GST values (57 vs 13 mg/dL; ΔGST ≥30 mg/dL in 24 of 27 subjects with congenital hyperinsulinism vs 0 of 30 subjects with ketotic hypoglycemia) and C-peptide levels (1.55 vs 0.11 ng/mL), with lower levels of FFA (0.82 vs 2.51 mM) and IGFBP-1 (59.5 vs 634 ng/mL). At the time of hypoglycemia, the upper limits of β-hydroxybutyrate and FFA in subjects with congenital hyperinsulinism were higher than reported previously (β-hydroxybutyrate <1.8 mM and FFA <1.7 mM), providing the best sensitivity for congenital hyperinsulinism vs ketotic hypoglycemia. A C-peptide level ≥0.5 ng/mL was 89% sensitive and 100% specific, and an IGFBP-1 level ≤110 ng/mL was 85% sensitive and 96.6% specific. Conclusion: Because low or undetectable insulin level during hypoglycemia does not exclude the diagnosis of hyperinsulinism, C-peptide and IGFBP-1 may inform the diagnosis of congenital hyperinsulinism. In this group of children with well-defined congenital hyperinsulinism, thresholds for "suppressed" β-hydroxybutyrate and FFA are higher than previously reported levels.
    No preview · Article · Oct 2015 · The Journal of pediatrics
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    ABSTRACT: Children with the most common and severe type of congenital hyperinsulinism (HI) frequently require pancreatectomy to control the hypoglycemia. Pancreatectomy increases the risk for diabetes, while recurrent hypoglycemia places children at risk of neurocognitive dysfunction. The prevalence of these complications is not well-defined. To determine the prevalence of diabetes and neurobehavioral deficits in surgically treated HI. A cross-sectional study of individuals who underwent pancreatectomy for HI between 1960 and 2008. Diabetes outcomes were assessed through patient interview and medical record review. Neurobehavioral outcomes were assessed through the Adaptive Behavior Assessment System - second Ed. (ABAS-II) and the Child Behavior Checklist (CBCL). One hundred and twenty one subjects were enrolled in the study at a median age of 8.9 years (range 3.5-50.7 years). Thirty-six percent (44 of 121) of subjects had diabetes. Nine subjects developed diabetes immediately post-pancreatectomy. Of the remaining 35 subjects who developed diabetes, the median age at diabetes diagnosis was 7.7 years (range 8 months-43 years). In subjects with diabetes, the median hemoglobin A1c was 7.4% (range 6.5-12.6%) and 38 (86%) required insulin. Subjects with diabetes had a greater percent pancreatectomy than those subjects without diabetes (95% [range 65-98] vs. 65% [1-98]). Neurobehavioral abnormalities were reported in 58 (48%) subjects. Nineteen (28%) subjects had abnormal ABAS-II scores and 10 (16%) subjects had abnormal CBCL scores. Children, who undergo near-total pancreatectomy, are at high risk of developing diabetes. Neurobehavioral deficits are common and developmental assessment is essential for children with HI.
    No preview · Article · Sep 2015 · The Journal of Clinical Endocrinology and Metabolism

  • No preview · Article · Aug 2015 · Cancer Research
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    Full-text · Article · May 2015 · The Journal of pediatrics
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    ABSTRACT: A Committee of the Pediatric Endocrine Society was recently formed to develop guidelines for evaluation and management of hypoglycemia in neonates, infants, and children. To aid in formulating recommendations for neonates, in this review, we analyzed available data on the brief period of hypoglycemia, which commonly is observed in normal newborns during the transition from fetal to extrauterine life, hereafter referred to as transitional neonatal hypoglycemia in normal newborns. The goal was to better understand the mechanism underlying this phenomenon in order to formulate recommendations for recognizing neonates requiring diagnosis and treatment during the first days of life for disorders causing severe and persistent hypoglycemia.
    Full-text · Article · Mar 2015 · The Journal of pediatrics
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    ABSTRACT: Mitochondrial GTP (mtGTP)-insensitive mutations in glutamate dehydrogenase (GDH(H454Y)) result in fasting and amino acid-induced hypoglycemia in Hyperinsulinemia Hyperammonemia (HI/HA). Surprisingly, hypoglycemia may occur in this disorder despite appropriately suppressed insulin. To better understand the islet-specific contribution transgenic mice expressing the human activating mutation in beta-cells (H454Y mice) were characterized in vivo. As in the humans with HI/HA, H454Y mice had fasting hypoglycemia but plasma insulin concentrations were similar to the controls. Paradoxically, both glucose- and glutamine-stimulated insulin secretion were severely impaired in H454Y mice. Instead, lack of a glucagon response during hypoglycemic clamps identified impaired counter regulation. Moreover, both insulin and glucagon secretion were impaired in perifused islets. Acute pharmacologic inhibition of GDH restored both insulin and glucagon secretion and normalized glucose tolerance in vivo. These studies support the presence of a mtGTP-dependent signal generated via beta-cell GDH that inhibits alpha-cells. As such, in children with activating GDH mutations of HI/HA this insulin-independent glucagon suppression may contribute importantly to symptomatic hypoglycemia. The identification of a human mutation causing congenital hypoglucagonemic hypoglycemia highlights a central role of the mtGTP-GDH-glucagon axis in glucose homeostasis.
    Preview · Article · Jul 2014 · Diabetes
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    Colin P. Hawkes · Charles A. Stanley

    Full-text · Article · Jun 2014 · Journal of Pediatrics
  • D.D. De León · P.S. Thornton · C.A. Stanley · M.A. Sperling

    No preview · Article · Mar 2014
  • D.R. Langdon · C.A. Stanley · M.A. Sperling

    No preview · Article · Mar 2014
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    ABSTRACT: Congenital disorders of glycosylation are genetic syndromes that result in impaired glycoprotein production. We evaluated patients who had a novel recessive disorder of glycosylation, with a range of clinical manifestations that included hepatopathy, bifid uvula, malignant hyperthermia, hypogonadotropic hypogonadism, growth retardation, hypoglycemia, myopathy, dilated cardiomyopathy, and cardiac arrest. Homozygosity mapping followed by whole-exome sequencing was used to identify a mutation in the gene for phosphoglucomutase 1 (PGM1) in two siblings. Sequencing identified additional mutations in 15 other families. Phosphoglucomutase 1 enzyme activity was assayed on cell extracts. Analyses of glycosylation efficiency and quantitative studies of sugar metabolites were performed. Galactose supplementation in fibroblast cultures and dietary supplementation in the patients were studied to determine the effect on glycosylation. Phosphoglucomutase 1 enzyme activity was markedly diminished in all patients. Mass spectrometry of transferrin showed a loss of complete N-glycans and the presence of truncated glycans lacking galactose. Fibroblasts supplemented with galactose showed restoration of protein glycosylation and no evidence of glycogen accumulation. Dietary supplementation with galactose in six patients resulted in changes suggestive of clinical improvement. A new screening test showed good discrimination between patients and controls. Phosphoglucomutase 1 deficiency, previously identified as a glycogenosis, is also a congenital disorder of glycosylation. Supplementation with galactose leads to biochemical improvement in indexes of glycosylation in cells and patients, and supplementation with complex carbohydrates stabilizes blood glucose. A new screening test has been developed but has not yet been validated. (Funded by the Netherlands Organization for Scientific Research and others.).
    Full-text · Article · Feb 2014 · New England Journal of Medicine
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    ABSTRACT: β cell failure in type 2 diabetes (T2D) is associated with hyperglycemia, but the mechanisms are not fully understood. Congenital hyperinsulinism caused by glucokinase mutations (GCK-CHI) is associated with β cell replication and apoptosis. Here, we show that genetic activation of β cell glucokinase, initially triggering replication, causes apoptosis associated with DNA double-strand breaks and activation of the tumor suppressor p53. ATP-sensitive potassium channels (KATP channels) and calcineurin mediate this toxic effect. Toxicity of long-term glucokinase overactivity was confirmed by finding late-onset diabetes in older members of a GCK-CHI family. Glucagon-like peptide-1 (GLP-1) mimetic treatment or p53 deletion rescues β cells from glucokinase-induced death, but only GLP-1 analog rescues β cell function. DNA damage and p53 activity in T2D suggest shared mechanisms of β cell failure in hyperglycemia and CHI. Our results reveal membrane depolarization via KATP channels, calcineurin signaling, DNA breaks, and p53 as determinants of β cell glucotoxicity and suggest pharmacological approaches to enhance β cell survival in diabetes.
    No preview · Article · Dec 2013 · Cell metabolism
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    ABSTRACT: Insulinomas are rare pediatric tumors for which optimal localization studies and management remain undetermined. We present our experience with surgical management of insulinomas during childhood. A retrospective review was performed of patients who underwent surgical management for an insulinoma from 1999 to 2012. The study included eight patients. Preoperative localization was successful with abdominal ultrasound, abdominal CT, endoscopic ultrasound, or MRI in only 20%, 28.6%, 40%, and 50% of patients, respectively. Octreotide scan was non-diagnostic in 4 patients. For diagnostic failure, selective utilization of 18-Fluoro-DOPA PET/CT scanning, arterial stimulation/venous sampling, or transhepatic portal venous sampling were successful in insulinoma localization. Intraoperatively, all lesions were identified by palpation or with the assistance of intraoperative ultrasound. Surgical resection using pancreas sparing techniques (enucleation or distal pancreatectomy) resulted in a cure in all patients. Postoperative complications included a pancreatic fistula in two patients and an additional missed insulinoma in a patient with MEN-1 requiring successful reoperation. Preoperative tumor localization may require many imaging modalities to avoid unsuccessful blind pancreatectomy. Intraoperative palpation with the assistance of ultrasound offers a reliable method to precisely locate the insulinoma. Complete surgical resection results in a cure. Recurrent symptoms warrant evaluation for additional lesions.
    No preview · Article · Dec 2013 · Journal of Pediatric Surgery
  • Diva D De León · Charles A Stanley
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    ABSTRACT: Hyperinsulinemic hypoglycemia is the most common cause of persistent hypoglycemia in children and adults. The diagnosis of hyperinsulinemic hypoglycemia relies on the evaluation of the biochemical profile at the time of hypoglycemia, however, contrary to common perception, plasma insulin is not always elevated. Thus, the diagnosis must often be based on the examination of other physiologic manifestations of excessive insulin secretion, such as suppression of glycogenolysis, lipolysis and ketogenesis, which can be inferred by the finding of a glycemic response to glucagon, and the suppression of plasma free fatty acids and beta-hydroxybutyrate concentrations during hypoglycemia.
    No preview · Article · Dec 2013
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    ABSTRACT: To present our experience in the care of infants with Beckwith-Wiedemann syndrome (BWS) who required pancreatectomy for the management of severe Congenital Hyperinsulinism (HI). We did a retrospective chart review of patients with BWS who underwent pancreatectomy between 2009 and 2012. Four patients with BWS and severe HI underwent pancreatectomy, 3 females and one male. Eight other BWS patients with HI could be managed medically. The diagnosis of BWS was established by the presence of mosaic 11p15 loss of heterozygosity and uniparental disomy in peripheral blood and/or pancreatic tissue. All patients had hypoglycemia since birth that did not respond to medical management with diazoxide or octreotide, and required glucose infusion rates of up to 30mg/kg/min. Preoperative 18-F-DOPA PET/CT scans showed diffuse uptake of the radiotracer throughout an enlarged pancreas in three patients and a normal sized pancreas with a large area of focal uptake in the pancreatic body in one patient. None of the patients had mutations in the ABCC8 or KCNJ1 genes that are typically associated with diazoxide-resistant HI. Age at surgery was 1, 2, 4, and 12months and the procedures were 85%, 95%, 90%, and 75% pancreatectomy, respectively, with the pancreatectomy extent tailored to HI severity. Pathologic analysis revealed marked diffuse endocrine proliferation throughout the pancreas that occupied up to 80% of the parenchyma with scattered islet cell nucleomegaly. One patient had a small pancreatoblastoma in the pancreatectomy specimen. The HI improved in all cases after the pancreatectomy, with patients being able to fast safely for more than 8h. All patients are under close surveillance for embryonal tumors. One patient developed a hepatoblastoma at age 2. The pathophysiology of HI in BWS patients is likely multifactorial and is associated with a dramatic increase in pancreatic endocrine tissue. Severe cases of HI that do not respond to medical therapy improve when the mass of endocrine tissue is reduced by subtotal or near-total pancreatectomy.
    No preview · Article · Dec 2013 · Journal of Pediatric Surgery
  • Ming Li · Changhong Li · Aron Allen · Charles A Stanley · Thomas J Smith
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    ABSTRACT: Glutamate dehydrogenase (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of L-glutamate to 2-oxoglutarate. Only in the animal kingdom is this enzyme heavily allosterically regulated by a wide array of metabolites. The major activators are ADP and leucine and inhibitors include GTP, palmitoyl CoA, and ATP. Spontaneous mutations in the GTP inhibitory site that lead to the hyperinsulinism/hyperammonemia (HHS) syndrome have shed light as to why mammalian GDH is so tightly regulated. Patients with HHS exhibit hypersecretion of insulin upon consumption of protein and concomitantly extremely high levels of ammonium in the serum. The atomic structures of four new inhibitors complexed with GDH complexes have identified three different allosteric binding sites. Using a transgenic mouse model expressing the human HHS form of GDH, at least three of these compounds blocked the dysregulated form of GDH in pancreatic tissue. EGCG from green tea prevented the hyper-response to amino acids in whole animals and improved basal serum glucose levels. The atomic structure of the ECG-GDH complex and mutagenesis studies is directing structure-based drug design using these polyphenols as a base scaffold. In addition, all of these allosteric inhibitors are elucidating the atomic mechanisms of allostery in this complex enzyme.
    No preview · Article · Oct 2013 · Neurochemical Research
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    ABSTRACT: Background/aims: In a family with congenital hyperinsulinism (HI), first described in the 1950s by McQuarrie, we examined the genetic locus and clinical phenotype of a novel form of dominant HI. Methods: We surveyed 25 affected individuals, 7 of whom participated in tests of insulin dysregulation (24-hour fasting, oral glucose and protein tolerance tests). To identify the disease locus and potential disease-associated mutations we performed linkage analysis, whole transcriptome sequencing, whole genome sequencing, gene capture, and next generation sequencing. Results: Most affecteds were diagnosed with HI before age one and 40% presented with a seizure. All affecteds responded well to diazoxide. Affecteds failed to adequately suppress insulin secretion following oral glucose tolerance test or prolonged fasting; none had protein-sensitive hypoglycemia. Linkage analysis mapped the HI locus to Chr10q21-22, a region containing 48 genes. Three novel noncoding variants were found in hexokinase 1 (HK1) and one missense variant in the coding region of DNA2. Conclusion: Dominant, diazoxide-responsive HI in this family maps to a novel locus on Chr10q21-22. HK1 is the more attractive disease gene candidate since a mutation interfering with the normal suppression of HK1 expression in beta-cells could readily explain the hypoglycemia phenotype of this pedigree.
    No preview · Article · Jul 2013 · Hormone Research in Paediatrics
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    ABSTRACT: Abstract Insulin autoimmune syndrome (IAS) or Hirata's disease is a rare cause of hyperinsulinemic hypoglycemia. We report the case of a child with a mild, atypical presentation of IAS. A previously healthy girl, aged 7 years old, developed non-ketotic fasting hypoglycemia during treatment for pneumonia. Laboratory evaluation during hypoglycemia showed the following results: serum glucose, 32 mg/dL (1.8 mmol/L); insulin, 5.6 μIU/mL (38.9 pmol/L); C-peptide, 1.4 ng/mL (0.47 nmol/L); anti-insulin antibody, 6.2% (normal, <2.4%); absence of ketonuria; and positive glucagon stimulation test result. Search for mutation in genes ABCC8, KCNJ11, GLUD1 and MEN1 was negative. Human leukocyte antigen (HLA) typing was HLA-DRB1*1104. Computed tomography scan of the abdomen showed a normal result. The patient evolved with spontaneous resolution of the hypoglycemia, within 30 days, with normalization of serum anti-insulin titers. The serum levels of insulin and anti-insulin antibodies in the patient of this report were not extremely high as previously reported. This novel, mild, or forme fruste presentation of IAS expands the previously reported spectrum of this disease.
    No preview · Article · Jul 2013 · Journal of pediatric endocrinology & metabolism: JPEM
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    ABSTRACT: The purpose of the study was to determine the sensitivity of the (18)fluoro-dihydroxyphenylalanine positron emission tomography/computed tomography scan (18F-PET/CT) in the diagnosis of focal congenital hyperinsulinism (HI). A retrospective review of children with HI who underwent a preoperative 18F-PET/CT scan was performed. Between 1/2008 and 2/2012 we performed 105 consecutive 18F-PET/CT scans on infants with HI. Fifty-three patients had focal HI. Of those fifty-three patients, eight had a preoperative 18F-PET/CT scan read as "diffuse disease". The sensitivity of the study in the diagnosis of focal HI was 85%. The location of the eight missed focal lesions was: head (3), body (2), and tail (3). The 18F-PET/CT of the missed head lesions showed homogeneous tracer uptake (n =2) or heterogeneous uptake throughout the pancreas (n=1). The 18F-PET/CT of the 2 missed body lesions and 1 missed tail lesion showed heterogeneous uptake throughout the pancreas. The 18F-PET/CT of the other 2 missed tail lesions showed lesions adjacent to and obscured by the signal of the upper renal pole, identified retrospectively by closer observation. Fifty-two of the 105 patients had diffuse HI. Two of them had 18F-PET/CT studies read as "focal disease". Therefore, the specificity of the study was 96%. Of the forty-seven 18F-PET/CT studies read as "focal disease", forty-five had true focal HI. Therefore, the positive predictive value of the study in the diagnosis of focal HI was 96%. The sensitivity and specificity of 18 F-PET/CT can be affected by certain anatomic features of the pancreas, by the location of the lesion, and by the reader's experience.
    No preview · Article · Feb 2013 · Journal of Pediatric Surgery

Publication Stats

10k Citations
1,542.48 Total Impact Points


  • 1978-2015
    • The Children's Hospital of Philadelphia
      • • Division of Neonatology
      • • Division of Endocrinology and Diabetes
      • • Department of Pediatrics
      Filadelfia, Pennsylvania, United States
  • 1979-2013
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 1979-2012
    • University of Pennsylvania
      • Department of Pediatrics
      Philadelphia, Pennsylvania, United States
  • 2006
    • Oregon Health and Science University
      • Center for Research on Occupational and Environmental Toxicology (CROET)
      Portland, OR, United States
  • 2000
    • Park Nicollet Health Services
      Minneapolis, Minnesota, United States
  • 1999
    • Hadassah Medical Center
      • Department of Endocrinology and Metabolism
      Yerushalayim, Jerusalem District, Israel
  • 1998
    • University of Florence
      Florens, Tuscany, Italy
    • University of Chicago
      Chicago, Illinois, United States
  • 1993
    • Baylor University
      Waco, Texas, United States
  • 1989-1991
    • Hartford Hospital
      • Department of Pediatrics
      Hartford, Connecticut, United States
    • Childrens Hospital of Pittsburgh
      • Department of Pediatrics
      Pittsburgh, Pennsylvania, United States