RESUMO
Persistent congenital hyperinsulinism (HI) is a rare genetically heterogeneous condition characterised by dysregulated insulin secretion leading to life-threatening hypoglycaemia. For up to 50% of affected individuals screening of the known HI genes does not identify a disease-causing variant. Large deletions have previously been used to identify novel regulatory regions causing HI. Here, we used genome sequencing to search for novel large (>1 Mb) deletions in 180 probands with HI of unknown cause and replicated our findings in a large cohort of 883 genetically unsolved individuals with HI using off-target copy number variant calling from targeted gene panels. We identified overlapping heterozygous deletions in five individuals (range 3-8 Mb) spanning chromosome 20p11.2. The pancreatic beta-cell transcription factor gene, FOXA2, a known cause of HI was deleted in two of the five individuals. In the remaining three, we found a minimal deleted region of 2.4 Mb adjacent to FOXA2 that encompasses multiple non-coding regulatory elements that are in conformational contact with FOXA2. Our data suggests that the deletions in these three children may cause disease through the dysregulation of FOXA2 expression. These findings provide new insights into the regulation of FOXA2 in the beta-cell and confirm an aetiological role for chromosome 20p11.2 deletions in syndromic HI.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 20 , Hiperinsulinismo Congênito , Fator 3-beta Nuclear de Hepatócito , Humanos , Fator 3-beta Nuclear de Hepatócito/genética , Fator 3-beta Nuclear de Hepatócito/metabolismo , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/patologia , Cromossomos Humanos Par 20/genética , Feminino , Masculino , Sequências Reguladoras de Ácido NucleicoRESUMO
Congenital hyperinsulinism is the most common cause of recurrent hypoglycemia in newborns and children. Early diagnosis and rapid management are essential to avoid hypoglycaemic brain injury and later neurological complications. Management of those patients involves biological evaluation, molecular genetics, imaging techniques and surgical advances. We report the case of a newborn with recurrent hypoglycemia due to congenital hyperinsulinism (CHI) caused by a new variant in the ABCC8 gene. Fluorine 18-L-3,4 Dihydroxyphenylalanine Positron Emission Tomography (18F-DOPA PET/CT scan) reported a focal lesion at the isthmus of the pancreas which has been removed by laparoscopic surgery with a complete recovery for the patient.
L'hyperinsulinisme congénital est la cause la plus fréquente d'hypoglycémies récidivantes chez le nouveau-né et l'enfant. Un diagnostic et une prise en charge précoces sont primordiaux pour éviter les conséquences potentielles sur le développement neurologique. Ces derniers reposent sur la conjonction d'éléments biologiques, génétiques et d'imagerie. Nous rapportons le cas d'un nouveau-né présentant des hypoglycémies récidivantes. La mise au point mettra en évidence un hyperinsulinisme congénital (CHI) lié à un variant non encore décrit au sein du gène ABCC8. L'imagerie par Fluorine 18-L-3,4 Dihydroxyphenylalanine Positron Emission Tomography/Computed Tomography-scanner (18F-DOPA PET/CT scan) a mis en évidence une forme focale de l'hyperinsulinisme justifiant une prise en charge chirurgicale amenant à une guérison complète et à l'arrêt de tout traitement médicamenteux.
Assuntos
Hiperinsulinismo Congênito , Laparoscopia , Criança , Humanos , Recém-Nascido , Lactente , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Hiperinsulinismo Congênito/diagnóstico por imagem , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/patologia , Pâncreas/patologia , Pâncreas/cirurgia , Tomografia por Emissão de Pósitrons/métodosRESUMO
Hyperinsulinemic hypoglycemia (HH) of pancreatic origin includes congenital hyperinsulinism (CHI), insulinoma, insulinomatosis, and adult-onset non-insulinoma persistent hyperinsulinemic hypoglycemia syndrome (NI-PHHS). In this review, we describe the genotype-histotype-phenotype correlations in HH and their therapeutic implications. CHI can occur from birth or later on in life. Histologically, diffuse CHI shows diffuse beta cell hypertrophy with a few giant nuclei per islet of Langerhans, most frequently caused by loss-of-function mutations in ABCC8 or KCNJ11. Focal CHI is histologically characterized by focal adenomatous hyperplasia consisting of confluent hyperplastic islets, caused by a paternal ABCC8/KCNJ11 mutation combined with paternal uniparental disomy of 11p15. CHI in Beckwith-Wiedemann syndrome is caused by mosaic changes in the imprinting region 11p15.4-11p15.5, leading to segmental or diffuse overgrowth of endocrine tissue in the pancreas. Morphological mosaicism of pancreatic islets is characterized by occurence of hyperplastic (type 1) islets in one or a few lobules and small (type 2) islets in the entire pancreas. Other rare genetic causes of CHI show less characteristic or unspecific histology. HH with a predominant adult onset includes insulinomas, which are pancreatic insulin-producing endocrine neoplasms, in some cases with metastatic potential. Insulinomas occur sporadically or as part of multiple endocrine neoplasia type 1 due to MEN1 mutations. MAFA mutations may histologically lead to insulinomatosis with insulin-producing neuroendocrine microadenomas or neuroendocrine neoplasms. NI-PHHS is mainly seen in adults and shows slight histological changes in some patients, which have been defined as major and minor criteria. The genetic cause is unknown in most cases. The diagnosis of HH, as defined by genetic, histological, and phenotypic features, has important implications for patient management and outcome.
Assuntos
Hiperinsulinismo Congênito , Humanos , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/patologia , Fenótipo , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Hiperinsulinismo/genética , Hiperinsulinismo/patologia , Insulinoma/genética , Insulinoma/patologia , Hipoglicemia/genética , Genótipo , Estudos de Associação GenéticaRESUMO
Nesidioblastoma and nesidioblastosis were terms given to neoplastic and non-neoplastic lesions of the pancreas associated with pancreatogenous hyperinsulinaemic hypoglycaemia. While nesidioblastoma was rapidly replaced by islet cell tumour, nesidioblastosis, defined as the proliferation of islet cells budding off from pancreatic ducts, was the diagnostic term associated with congenital hyperinsulinism of infancy (CHI) and adult non-neoplastic hyperinsulinaemic hypoglycaemia (ANHH). When it was shown that nesidioblastosis was not specific for CHI or ANHH, it was no longer applied to CHI but kept for the morphological diagnosis of ANHH. In severe CHI cases, a diffuse form with hypertrophic ß-cells in all islets can be distinguished from a focal form with hyperactive ß-cells changes in a limited adenomatoid hyperplastic area. Genetically, mutations were identified in several ß-cell genes involved in insulin secretion. Most common are mutations in the ABCC8 or KCNJ11 genes, solely affected in the diffuse form and associated with a focal maternal allelic loss on 11p15.5 in the focal form. Focal CHI can be localized by 18F-DOPA-PET and is thus curable by targeted resection. Diffuse CHI that fails medical treatment requires subtotal pancreatectomy. In ANHH, an idiopathic form can be distinguished from a form associated with gastric bypass, in whom GLP1-induced stimulation of the ß-cells is discussed. While the ß-cells in idiopathic ANHH are diffusely affected and are either hypertrophic or show only little changes, it is controversial whether there is a ß-cell increase or ß-cell hyperactivity in patients with gastric bypass. Recognizing morphological signs of ß-cell hyperactivity needs a good knowledge of the non-neoplastic endocrine pancreas across all ages.
Assuntos
Adenoma de Células das Ilhotas Pancreáticas , Hiperinsulinismo Congênito , Hiperinsulinismo , Nesidioblastose , Neoplasias Pancreáticas , Humanos , Adulto , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/patologia , Nesidioblastose/diagnóstico , Nesidioblastose/patologia , Nesidioblastose/cirurgia , Hiperinsulinismo/genética , Pâncreas/patologiaRESUMO
Background: The focal form of CHI is caused by an autosomal recessive pathogenic variant affecting the paternal homologue of genes ABCC8 or KCNJ11 and a second somatic event specifically occurring in the affected islet of Langerhans. The approach of this study was to integrate the genetic changes occurring in pancreatic focal lesions of CHI at the genomic and transcriptional level. Research Design and Methods: Patients receiving therapeutic surgery and with proven ABCC8 or KCNJ11 pathogenic variants were selected and analyzed for loss of heterozygosity (LOH), changes in copy number and uniparental disomy (UPD) on the short am of chromosome 11 by molecular microarray analysis and methylation-specific MLPA. Gene expression was analyzed by RT-PCR and Massive Analysis of cDNA Ends (MACE). Results: Both genes, ABCC8 and KCNJ11, are located in proximity to the Beckwith-Wiedemann (BWS) imprinting control region on chromosome 11p15. Somatic paternal uniparental isodisomy (UPD) at chromosome 11p was identified as second genetic event in focal lesions resulting in LOH and monoallelic expression of the mutated ABCC8/KCNJ11 alleles. Of five patients with samples available for microarray analysis, the breakpoints of UPD on chromosome 11p were different. Samples of two patients were analyzed further for changes in gene expression. Profound downregulation of growth suppressing genes CDKN1 and H19 was detected in focal lesions whereas growth promoting gene ASCL2 and pancreatic transcription factors of the endocrine cell lineage were upregulated. Conclusions: Paternal UPD on the short arm of chromosome 11 appears to be the major second genetic event specifically within focal lesions of CHI but no common breakpoint for UDP can be delineated. We show for the first time upregulation of growth promoting ASCL2 (achaete-scute homolog 2) suggestive of a driving factor in postnatal focal expansion in addition to downregulation of growth suppressing genes CDKN1C and H19.
Assuntos
Hiperinsulinismo Congênito , Canais de Potássio Corretores do Fluxo de Internalização , Humanos , Canais de Potássio Corretores do Fluxo de Internalização/genética , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/patologia , Dissomia Uniparental/genética , Perda de Heterozigosidade , Genômica , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Receptores de Sulfonilureias/genéticaRESUMO
OBJECTIVES: Congenital hyperinsulinism (CHI) is a group of rare genetic disorders characterized by insulin overproduction. CHI causes life-threatening hypoglycemia in neonates and infants. Bloom syndrome is a rare autosomal recessive disorder caused by mutations in the BLM gene resulting in genetic instability and an elevated rate of spontaneous sister chromatid exchanges. It leads to insulin resistance, early-onset diabetes, dyslipidemia, growth delay, immune deficiency and cancer predisposition. Recent studies demonstrate that the BLM gene is highly expressed in pancreatic islet cells and its mutations can alter the expression of other genes which are associated with apoptosis control and cell proliferation. CASE PRESENTATION: A 5-month-old female patient from consanguineous parents presented with drug-resistant CHI and dysmorphic features. Genetic testing revealed a homozygous mutation in the KCNJ11 gene and an additional homozygous mutation in the BLM gene. While 18F-DOPA PET scan images were consistent with a focal CHI form and intraoperative frozen-section histopathology was consistent with diffuse CHI form, postoperative histopathological examination revealed features of an atypical form. CONCLUSIONS: In our case, the patient carries two distinct diseases with opposite metabolic phenotypes.
Assuntos
Síndrome de Bloom , Hiperinsulinismo Congênito , Hiperinsulinismo , Síndrome de Bloom/complicações , Síndrome de Bloom/genética , Hiperinsulinismo Congênito/complicações , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/patologia , Feminino , Humanos , Hiperinsulinismo/complicações , Hiperinsulinismo/genética , Lactente , Mutação , Fenótipo , Doenças Raras , Receptores de Sulfonilureias/genéticaRESUMO
Familial Hyperinsulinemic Hypoglycemia (FHH) is a very rare disease with heterogeneous clinical manifestations. There are only a few reports of heterozygous activating mutations of glucokinase (GCK) attributable to FHH, with no reports describing effects in the course in pregnancy with affected mother/affected child. A large kindred with FHH and GCK:c.295T>C (p.Trp99Arg) pathogenic variant was identified in which four family members from three generations were affected. The clinical follow up in one clinical center lasted up to 30 years, with different times of diagnosis ranging from neonate period to adulthood. The severity of hypoglycemia was mild/severe and fasting was the trigger for hypoglycemia. Response to diazoxide varied from good, in the neonate, to moderate/poor, in childhood/adulthood; however, this was biased by poor compliance. Treatment with somatostatin analogues was discontinued due to side effects. Over time, patients developed clinical adaptation to very low glucose levels. During pregnancy, episodes of severe hypoglycemia in the first trimester were observed, which responded very well to steroids. The clinical course of the GCK:c.295T>C (p.Trp99Arg) mutation varied in the same family, with the development of clinical adaptation to very low glucose levels over time. Treatment with steroids might prevent hypoglycemia during pregnancy in an affected mother.
Assuntos
Hiperinsulinismo Congênito/genética , Mutação com Ganho de Função/genética , Predisposição Genética para Doença , Glucoquinase/genética , Adulto , Pré-Escolar , Hiperinsulinismo Congênito/tratamento farmacológico , Hiperinsulinismo Congênito/patologia , Feminino , Glucose/metabolismo , Heterozigoto , Humanos , Recém-Nascido , Masculino , Linhagem , Esteroides/uso terapêutico , Adulto JovemRESUMO
Introduction: Congenital hyperinsulinism (CHI) has diffuse (CHI-D), focal (CHI-F) and atypical (CHI-A) forms. Surgical management depends on preoperative [18F]-DOPA PET/CT and intraoperative morphological differential diagnosis of CHI forms. Objective: to improve differential diagnosis of CHI forms by comparative analysis [18F]-DOPA PET/CT data, as well as cytological, histological and immunohistochemical analysis (CHIA). Materials and Methods: The study included 35 CHI patients aged 3.2 ± 2.0 months; 10 patients who died from congenital heart disease at the age of 3.2 ± 2.9 months (control group). We used PET/CT, CHIA of pancreas with antibodies to ChrA, insulin, Isl1, Nkx2.2, SST, NeuroD1, SSTR2, SSTR5, DR1, DR2, DR5; fluorescence microscopy with NeuroD1/ChrA, Isl1/insulin, insulin/SSTR2, DR2/NeuroD1 cocktails. Results: Intraoperative examination of pancreatic smears showed the presence of large nuclei, on average, in: 14.5 ± 3.5 cells of CHI-F; 8.4 ± 1.1 of CHI-D; and 4.5 ± 0.7 of control group (from 10 fields of view, x400). The percentage of Isl1+ and NeuroD1+endocrinocytes significantly differed from that in the control for all forms of CHI. The percentage of NeuroD1+exocrinocytes was also significantly higher than in the control. The proportion of ChrA+ and DR2+endocrinocytes was higher in CHI-D than in CHI-F, while the proportion of insulin+cells was higher in CHI-A. The number of SST+cells was significantly higher in CHI-D and CHI-F than in CHI-A. Conclusion: For intraoperative differential diagnosis of CHI forms, in addition to frozen sections, quantitative cytological analysis can be used. In quantitative immunohistochemistry, CHI forms differ in the expression of ChrA, insulin, SST and DR2. The development of a NeuroD1 inhibitor would be advisable for targeted therapy of CHI.
Assuntos
Hiperinsulinismo Congênito/patologia , Diagnóstico Diferencial , Adenoma/patologia , Adenoma de Células das Ilhotas Pancreáticas/patologia , Hiperinsulinismo Congênito/cirurgia , Di-Hidroxifenilalanina/análogos & derivados , Imunofluorescência , Humanos , Hiperplasia , Imuno-Histoquímica , Lactente , Recém-Nascido , Período Intraoperatório , Microscopia Confocal , Pâncreas/patologia , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia ComputadorizadaRESUMO
BACKGROUND: In congenital hyperinsulinism (CHI), preoperative prediction of the histological subtype (focal, diffuse, or atypical) relies on genetics and 6-[18F]fluoro-l-3,4-dihydroxyphenylalanine (18F-DOPA) PET-CT. The scan also guides the localization of a potential focal lesion along with perioperative frozen sections. Intraoperative decision-making is still challenging. This study aimed to describe the characteristics and potential clinical impact of intraoperative ultrasound imaging (IOUS) during CHI surgery. METHODS: This was a prospective, observational study undertaken at an expert centre over a 2-year interval. IOUS was performed blinded to preoperative diagnostic test results (genetics and 18F-DOPA PET-CT), followed by unblinding and continued IOUS during pancreatic resection. Characteristics and clinical impact were assessed using predefined criteria. RESULTS: Eighteen consecutive, surgically treated patients with CHI, with a median age of 5.5 months, were included (focal 12, diffuse 3, atypical 3). Focal lesions presented as predominantly hypoechoic, oval lesions with demarcated or blurred margins. Patients with diffuse and atypical disease had varying echogenicity featuring stranding and non-shadowing hyperechoic foci in three of six, whereas these characteristics were absent from those with focal lesions. The blinded IOUS-based subclassification was correct in 17 of 18 patients; one diffuse lesion was misclassified as focal. IOUS had an impact on the surgical approach in most patients with focal lesions (9 of 12), and in those with diffuse (2 of 3) and atypical (2 of 3) disease when the resection site was close to the bile or pancreatic duct. CONCLUSION: Uniform IOUS characteristics made all focal lesions identifiable. IOUS had a clinical impact in 13 of 18 patients by being a useful real-time supplementary modality in terms of localizing focal lesions, reducing the need for frozen sections, and preserving healthy tissue and delicate structures.
Assuntos
Hiperinsulinismo Congênito/diagnóstico por imagem , Hiperinsulinismo Congênito/cirurgia , Pâncreas/diagnóstico por imagem , Tomada de Decisão Clínica , Hiperinsulinismo Congênito/patologia , Feminino , Humanos , Lactente , Período Intraoperatório , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Masculino , Pâncreas/patologia , Pâncreas/cirurgia , Estudos Prospectivos , Método Simples-Cego , UltrassonografiaRESUMO
AIMS/HYPOTHESIS: Acute hyperglycaemia stimulates pancreatic beta cell proliferation in the mouse whereas chronic hyperglycaemia appears to be toxic. We hypothesise that this toxic effect is mediated by increased beta cell workload, unrelated to hyperglycaemia per se. METHODS: To test this hypothesis, we developed a novel mouse model of cell-autonomous increased beta cell glycolytic flux caused by a conditional heterozygous beta cell-specific mutation that activates glucokinase (GCK), mimicking key aspects of the rare human genetic disease GCK-congenital hyperinsulinism. RESULTS: In the mutant mice, we observed random and fasting hypoglycaemia (random 4.5-5.4 mmol/l and fasting 3.6 mmol/l) that persisted for 15 months. GCK activation led to increased beta cell proliferation as measured by Ki67 expression (2.7% vs 1.5%, mutant and wild-type (WT), respectively, p < 0.01) that resulted in a 62% increase in beta cell mass in young mice. However, by 8 months of age, mutant mice developed impaired glucose tolerance, which was associated with decreased absolute beta cell mass from 2.9 mg at 1.5 months to 1.8 mg at 8 months of age, with preservation of individual beta cell function. Impaired glucose tolerance was further exacerbated by a high-fat/high-sucrose diet (AUC 1796 vs 966 mmol/l × min, mutant and WT, respectively, p < 0.05). Activation of GCK was associated with an increased DNA damage response and an elevated expression of Chop, suggesting metabolic stress as a contributor to beta cell death. CONCLUSIONS/INTERPRETATION: We propose that increased workload-driven biphasic beta cell dynamics contribute to decreased beta cell function observed in long-standing congenital hyperinsulinism and type 2 diabetes.
Assuntos
Hiperinsulinismo Congênito/patologia , Glucoquinase/genética , Células Secretoras de Insulina/patologia , Animais , Contagem de Células , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Feminino , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Tamanho do ÓrgãoRESUMO
AIMS/HYPOTHESIS: Congenital hyperinsulinism caused by mutations in the KATP-channel-encoding genes (KATPHI) is a potentially life-threatening disorder of the pancreatic beta cells. No optimal medical treatment is available for patients with diazoxide-unresponsive diffuse KATPHI. Therefore, we aimed to create a model of KATPHI using patient induced pluripotent stem cell (iPSC)-derived islets. METHODS: We derived iPSCs from a patient carrying a homozygous ABCC8V187D mutation, which inactivates the sulfonylurea receptor 1 (SUR1) subunit of the KATP-channel. CRISPR-Cas9 mutation-corrected iPSCs were used as controls. Both were differentiated to stem cell-derived islet-like clusters (SC-islets) and implanted into NOD-SCID gamma mice. RESULTS: SUR1-mutant and -corrected iPSC lines both differentiated towards the endocrine lineage, but SUR1-mutant stem cells generated 32% more beta-like cells (SC-beta cells) (64.6% vs 49.0%, p = 0.02) and 26% fewer alpha-like cells (16.1% vs 21.8% p = 0.01). SUR1-mutant SC-beta cells were 61% more proliferative (1.23% vs 0.76%, p = 0.006), and this phenotype could be induced in SUR1-corrected cells with pharmacological KATP-channel inactivation. The SUR1-mutant SC-islets secreted 3.2-fold more insulin in low glucose conditions (0.0174% vs 0.0054%/min, p = 0.0021) and did not respond to KATP-channel-acting drugs in vitro. Mice carrying grafts of SUR1-mutant SC-islets presented with 38% lower fasting blood glucose (4.8 vs 7.7 mmol/l, p = 0.009) and their grafts failed to efficiently shut down insulin secretion during induced hypoglycaemia. Explanted SUR1-mutant grafts displayed an increase in SC-beta cell proportion and SC-beta cell nucleomegaly, which was independent of proliferation. CONCLUSIONS/INTERPRETATION: We have created a model recapitulating the known pathophysiology of KATPHI both in vitro and in vivo. We have also identified a novel role for KATP-channel activity during human islet development. This model will enable further studies for the improved understanding and clinical management of KATPHI without the need for primary patient tissue.
Assuntos
Hiperinsulinismo Congênito/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Ilhotas Pancreáticas/metabolismo , Receptores de Sulfonilureias/metabolismo , Animais , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/patologia , Hiperinsulinismo Congênito/fisiopatologia , Feminino , Predisposição Genética para Doença , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Células-Tronco Pluripotentes Induzidas/transplante , Secreção de Insulina , Ilhotas Pancreáticas/patologia , Ilhotas Pancreáticas/fisiopatologia , Transplante das Ilhotas Pancreáticas , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Fenótipo , Receptores de Sulfonilureias/genéticaRESUMO
Background: Congenital hyperinsulinism (CHI), a rare disease of excessive and dysregulated insulin secretion, can lead to prolonged and severe hypoglycemia. Dextrose infusions are a mainstay of therapy to restore normal glycemia, but can be associated with volume overload, especially in infants. By releasing intrahepatic glucose stores, glucagon infusions can reduce dependency on dextrose infusions. Recent studies have reported positive outcomes with glucagon infusions in patients with CHI; however, to date, there are no reports describing the clinical utility of titrated doses of infused glucagon to achieve glycemic stability. Objective: To assess the potential clinical utility of dose-titrated glucagon infusions in stabilizing glycemic status in pediatric patients with CHI, who were managed by medical and/or surgical approaches. Methods: Patients with CHI (N = 33), with or without mutations in the ATP-sensitive K+ channel genes, ABCC8, and KCNJ11 requiring glucagon by dose titration in addition to intravenous dextrose and medical therapy with diazoxide/octreotide to achieve glycemic stability were recruited. Following glucagon titration and a 24-h glucose stable period, glucose infusion rate (GIR) was reduced over a 24-h period. Achievement of glycemic stability and decrease in GIR were considered end points of the study. Results: All patients achieved glycemic stability with glucagon infusion, demonstrating clinical benefit. GIR reduced from 15.6 (4.5) to 13.4 (4.6) mg/kg/min mean (SD) (p = 0.00019 for difference; n = 32; paired t-test) over 24 h. By univariate analysis, no individual baseline characteristic was associated with changes in the GIR. However, by baseline-adjusted modeling, mutational status of the patient (p = 0.011) was inversely associated with a reduction in GIR. Adverse events were infrequent with diarrhea possibly attributed to glucagon treatment in 1 patient. With long-term treatment following GIR reduction, necrolytic migratory erythema was observed in another patient. Conclusion: These data suggest that dose-titrated glucagon infusion therapy aids hypoglycemia prevention and reduction in GIR in the clinical management of patients with CHI.
Assuntos
Glicemia/análise , Hiperinsulinismo Congênito/tratamento farmacológico , Fármacos Gastrointestinais/administração & dosagem , Glucagon/administração & dosagem , Secreção de Insulina , Hiperinsulinismo Congênito/sangue , Hiperinsulinismo Congênito/patologia , Gerenciamento Clínico , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Recém-Nascido , Infusões Intravenosas , Masculino , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Objectives Hyperinsulinemic hypoglucemia (HH) is characterized by a dysregulation of insulin secretion from pancreatic ß cells. Congenital hyperinsulinism has been associated with specific genes in monogenic forms and also with other diseases with a yet unknown genetic cause. In 2017, Rubio Cabezas et al. described the association of HH and autosomal recessive polycystic kidney disease (ARPKD) with a promoter mutation in the PMM2 gene. They found that all the patients carried a promoter mutation (c-167G>T) in PMM2, either homozygous or in trans with a second PMM2 coding mutation. Methods We performed the study of the PMM2 gene in six patients from four unrelated families, previously diagnosed with ARPKD and HH. Results All these patients had in common the heterozygous variant c-167G>T in the promoter region for PMM2. Additionally, each patient carried a compound heterozygote for a second missense mutation in this gene (p.Arg141His, p.Asp148Asn or p.Phe157Ser), previously reported as pathogenic for congenital disorder of glycosylation type Ia, with an autosomal recessive inheritance pattern. Unlike the previous published article, two of our patients showed altered type 1 pattern and one of them with rectal bleeding that could be a sign of PMM2-congenital disorders of glycosylation. Conclusion We propose the study of this gene when carrying out the diagnosis of patients with HH, especially in the neonatal period and when a recessive polycystic kidney disease without alterations in PKDH1 is diagnosed.
Assuntos
Biomarcadores/análise , Hiperinsulinismo Congênito/genética , Mutação , Fosfotransferases (Fosfomutases)/genética , Doenças Renais Policísticas/genética , Regiões Promotoras Genéticas , Pré-Escolar , Hiperinsulinismo Congênito/complicações , Hiperinsulinismo Congênito/patologia , Família , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Renais Policísticas/complicações , Doenças Renais Policísticas/patologia , Prognóstico , EspanhaRESUMO
Kabuki syndrome (KS) is a rare heterogeneous phenotypic genetic syndrome, characterized by hypotonia, developmental delay and/or intellectual disability with typical facial features. It is challenging to diagnose KS in newborn and young infant. We report a Thai girl who presented with two rare co-occurrence phenotypes, hyperinsulinemic hypoglycemia and midgut malrotation. She had not have distinctive facial dysmorphism during neonatal period. At 4 months of age, she had poor weight gain with some facial features suggestive KS. Singleton whole exome sequencing (WES) was carried out followed by Sanger sequencing of the supposed variant. The result indicated a novel de novo heterozygous KMT2D mutation, c.15364A>T (p.Lys5122*), confirming KS. Our patient revealed rare clinical manifestations from the diverse population and address the benefit of WES in establishing early diagnosis of KS before typical facial gestalt exhibited, which allows timely and appropriate management to maximize developmental achievement.
Assuntos
Anormalidades Múltiplas/genética , Hiperinsulinismo Congênito/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Doenças Hematológicas/genética , Deficiência Intelectual/genética , Proteínas de Neoplasias/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/patologia , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/epidemiologia , Hiperinsulinismo Congênito/patologia , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Face/patologia , Feminino , Predisposição Genética para Doença , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/epidemiologia , Doenças Hematológicas/patologia , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/patologia , Tailândia/epidemiologia , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/epidemiologia , Doenças Vestibulares/patologia , Sequenciamento do ExomaRESUMO
A multidisciplinary approach to patients with congenital hyperinsulinism (HI) can distinguish focal from diffuse HI, localize focal lesions, and permit partial pancreatectomy with cure in almost all focal patients. Surgery does not cure diffuse disease but can help prevent severe hypoglycemia and brain damage. Surgery can be curative for insulinoma and for some cases of atypical HI.
Assuntos
Hiperinsulinismo Congênito/cirurgia , Pancreatectomia/métodos , Assistência ao Convalescente/métodos , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Laparoscopia , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Cuidados Pós-Operatórios/métodos , Resultado do TratamentoRESUMO
Congenital hyperinsulinism is a rare but significant cause of severe and persistent hypoglycaemia in infancy. Although a biphasic phenotype of congenital hyperinsulinism in infancy followed by Maturity-Onset Diabetes of the Young (MODY) in later life has been established for HNF4A, the existence of a similar phenotype for a related MODY gene, HNF1A, is less clear. We describe two cases of congenital hyperinsulinism in association with dominantly inherited variants in HNF1A. They presented in the early neonatal period with unequivocal biochemical evidence of congenital hyperinsulinism and persistence into childhood with ongoing need for medical therapy. Both cases inherited HNF1A variants from a parent with a diabetes phenotype consistent with MODY, without obesity, insulin resistance or other metabolic syndrome features. In the first case, a paternally inherited novel c.-230_-101del variant was found that deletes the minimal promoter region presumably required for HNF1A expression. In the second case, a maternally inherited missense variant (c.713G>T, p.(Arg238Met)) was identified. This variant is predicted to cause haploinsufficiency via aberrant splicing and has previously been associated with MODY but not congenital hyperinsulinism. Our cases further strengthen the evidence for HNF1A as a CHI-causing gene requiring long-term follow-up.
Assuntos
Hiperinsulinismo Congênito/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Criança , Pré-Escolar , Hiperinsulinismo Congênito/patologia , Feminino , Humanos , Mutação INDEL , Masculino , Mutação de Sentido Incorreto , LinhagemRESUMO
Nonketotic-hypoinsulinemic hypoglycemia (NkHH) is a very rare problem charcterized by increase in glucose consumption without hyperinsulinism. This disorder has mainly been reported in cases with AKT2 mutation and rarely in cases with PTEN mutation. In cases with PTEN or AKT2 mutation, there is no effective therapy other than frequent feeding to counter hypoglycemia. The mammalian target of rapamicin (mTOR) inhibitor, sirolimus, has been used in hyperinsulinemic hypoglycemia that was unresponsive to other medical treatment. In the insulin signaling pathway, both AKT2 and PTEN function upstream of mTOR. However, the role of Sirolimus on hypoglycemia in AKT2 and PTEN mutations is unknown. Case 1: Six month-old female with AKT2 mutation [c.49G>A (p.E17K)] and evidence of NkHH. Frequent feeding was unsuccesful in correcting hypoglycemia and her proptosis continued to worsen. Sirolimus treatment was started at three years of age. Subsequently, blood glucose (BG) levels increased to normal levels. Case 2: In a male with PTEN mutation (p.G132V (c.395G>T), persistent NkHH started at 16 years of age (fasting BG: 27 mg/dL, fasting insulin 1.5 mmol/L, while ketone negative). Sirolimus treatment was started and hypoglycemia was succesfully controlled. NkHH is a very rare and serious disorder which is challenging, both for diagnosis and treatment. Additionally, AKT2 and PTEN mutations may result in NkHH. Sirolimus treatment, through mTOR inhibition, appeared to be effectively controlling the peristent hypoglycemia and may be a life-saving therapy in this NkHH due to AKT2 and PTEN mutations.
Assuntos
Hiperinsulinismo Congênito/tratamento farmacológico , Hipoglicemia/tratamento farmacológico , Imunossupressores/uso terapêutico , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Adolescente , Hiperinsulinismo Congênito/metabolismo , Hiperinsulinismo Congênito/patologia , Feminino , Humanos , Hipoglicemia/metabolismo , Hipoglicemia/patologia , Lactente , Masculino , Prognóstico , Transdução de SinaisRESUMO
CONTEXT: Major advances have been made in the genetics and classification of congenital hyperinsulinism (CHI). OBJECTIVE: To examine the genetics and clinical characteristics of patients with persistent and transient CHI. DESIGN: A cross-sectional study with the register data and targeted sequencing of 104 genes affecting glucose metabolism. PATIENTS: Genetic and phenotypic data were collected from 153 patients with persistent (n = 95) and transient (n = 58) CHI diagnosed between 1972 and 2015. Of these, 86 patients with persistent and 58 with transient CHI participated in the analysis of the selected 104 genes affecting glucose metabolism, including 10 CHI-associated genes, and 9 patients with persistent CHI were included because of their previously confirmed genetic diagnosis. MAIN OUTCOME MEASURES: Targeted next-generation sequencing results and genotype-phenotype associations. RESULTS: Five novel and 21 previously reported pathogenic or likely pathogenic variants in ABCC8, KCNJ11, GLUD1, GCK, HNF4A, and SLC16A1 genes were found in 68% (n = 65) and 0% of the patients with persistent and transient CHI, respectively. KATP channel mutations explained 82% of the mutation positive cases. CONCLUSIONS: The genetic variants found in this nationwide CHI cohort are in agreement with previous studies, mutations in the KATP channel genes being the major causes of the disease. Pathogenic CHI-associated variants were not identified in patients who were both diazoxide responsive and able to discontinue medication within the first 4 months. Therefore, our results support the notion that genetic testing should be focused on patients with inadequate response or prolonged need for medication.
Assuntos
Biomarcadores/análise , Hiperinsulinismo Congênito/patologia , Estudos de Associação Genética , Mutação , Criança , Pré-Escolar , Hiperinsulinismo Congênito/epidemiologia , Hiperinsulinismo Congênito/genética , Estudos Transversais , Feminino , Finlândia , Seguimentos , Quinases do Centro Germinativo/genética , Glutamato Desidrogenase/genética , Fator 4 Nuclear de Hepatócito/genética , Humanos , Lactente , Recém-Nascido , Masculino , Transportadores de Ácidos Monocarboxílicos/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Prognóstico , Estudos Retrospectivos , Receptores de Sulfonilureias/genética , Simportadores/genéticaRESUMO
Mutations in the insulin receptor (INSR) gene are associated with insulin resistance and hyperglycaemia. Various autosomal dominant heterozygous INSR mutations leading to hyperinsulinemic hypoglycaemia (HH) have been described in adults and children (more than 3 years of age) but not in the neonatal period. Family 1: A small for gestational age (SGA) child born to a mother with gestational diabetes presented with persistent hypoglycaemia, was diagnosed with HH and responded well to diazoxide treatment. Diazoxide was gradually weaned and discontinued by 8 months of age. Later, the younger sibling had a similar course of illness. On genetic analysis a heterozygous INSR missense variant p.(Met1180Lys) was found in the siblings, mother and grandfather but not in the father. Family 2: A twin preterm and SGA baby presented with persistent hypoglycaemia, which was confirmed as HH. He responded to diazoxide, which was subsequently discontinued by 10 weeks of life. Genetic analysis revealed a novel heterozygous INSR missense variant p.(Arg1119Gln) in the affected twin and the mother. Family 3: An SGA child presented with diazoxide responsive HH. Diazoxide was gradually weaned and discontinued by 9 weeks of age. Genetic analysis revealed a novel heterozygous INSR p.(Arg1191Gln) variant in the proband and her father. We report, for the first time, an association of INSR mutation with neonatal HH responsive to diazoxide therapy that resolved subsequently. Our case series emphasizes the need for genetic analysis and long-term follow up of these patients.
Assuntos
Antígenos CD/genética , Hiperinsulinismo Congênito/patologia , Diabetes Mellitus/patologia , Hipoglicemia/patologia , Mutação , Receptor de Insulina/genética , Gêmeos/genética , Adulto , Idade de Início , Hiperinsulinismo Congênito/complicações , Hiperinsulinismo Congênito/genética , Diabetes Mellitus/genética , Feminino , Humanos , Hipoglicemia/complicações , Hipoglicemia/genética , Recém-Nascido , Resistência à Insulina , Masculino , Linhagem , PrognósticoRESUMO
Congenital hyperinsulinism (CHI) causes dysregulated insulin secretion which can lead to life-threatening hypoglycaemia if not effectively managed. CHI can be sub-classified into three distinct groups: diffuse, focal and mosaic pancreatic disease. Whilst the underlying causes of diffuse and focal disease have been widely characterised, the genetic basis of mosaic pancreatic disease is not known. To gain new insights into the underlying disease processes of mosaic-CHI we studied the islet tissue histopathology derived from limited surgical resection from the tail of the pancreas in a patient with CHI. The underlying genetic aetiology was investigated using a combination of high depth next-generation sequencing, microsatellite analysis and p57kip2 immunostaining. Histopathology of the pancreatic tissue confirmed the presence of a defined area associated with marked islet hypertrophy and a cytoarchitecture distinct from focal CHI but compatible with mosaic CHI localised to a discrete region within the pancreas. Analysis of DNA extracted from the lesion identified a de novo mosaic ABCC8 mutation and mosaic paternal uniparental disomy which were not present in leukocyte DNA or the surrounding unaffected pancreatic tissue. This study provides the first description of two independent disease-causing somatic genetic events occurring within the pancreas of an individual with localised mosaic CHI. Our findings increase knowledge of the genetic causes of islet disease and provide further insights into the underlying developmental changes associated with ß-cell expansion in CHI.