Syndromic Forms of Hyperinsulinaemic Hypoglycaemia—A 15‐year follow‐up Study

Kostopoulou, Eirini; Dastamani, Antonia; Güemes, María; Clement, Emma; Caiulo, Silvana; Shanmugananda, Prateek; Dattani, Mehul; Gilbert, Clare; Hurst, Jane A.; Shah, Pratik

doi:10.1111/cen.14393

Cited by 13 publications

(12 citation statements)

References 34 publications

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“…Over 28 different syndromes which feature HI have been reported with the most common being Beckwith-Wiedemann syndrome (BWS) and Kabuki syndrome ( 33 ) ( Table 2 ). The proportion of individuals with syndromic disease who present with HI varies between genetic subgroups.…”

Section: Genetic Types Of Congenital Hyperinsulinismmentioning

confidence: 99%

Congenital Hyperinsulinism: Current Laboratory-Based Approaches to the Genetic Diagnosis of a Heterogeneous Disease

2022

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Congenital hyperinsulinism is characterised by the inappropriate release of insulin during hypoglycaemia. This potentially life-threatening disorder can occur in isolation, or present as a feature of syndromic disease. Establishing the underlying aetiology of the hyperinsulinism is critical for guiding medical management of this condition especially in children with diazoxide-unresponsive hyperinsulinism where the underlying genetics determines whether focal or diffuse pancreatic disease is present. Disease-causing single nucleotide variants affecting over 30 genes are known to cause persistent hyperinsulinism with mutations in the KATP channel genes (ABCC8 and KCNJ11) most commonly identified in children with severe persistent disease. Defects in methylation, changes in chromosome number, and large deletions and duplications disrupting multiple genes are also well described in congenital hyperinsulinism, further highlighting the genetic heterogeneity of this condition. Next-generation sequencing has revolutionised the approach to genetic testing for congenital hyperinsulinism with targeted gene panels, exome, and genome sequencing being highly sensitive methods for the analysis of multiple disease genes in a single reaction. It should though be recognised that limitations remain with next-generation sequencing with no single application able to detect all reported forms of genetic variation. This is an important consideration for hyperinsulinism genetic testing as comprehensive screening may require multiple investigations.

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Section: Genetic Types Of Congenital Hyperinsulinismmentioning

confidence: 99%

Congenital Hyperinsulinism: Current Laboratory-Based Approaches to the Genetic Diagnosis of a Heterogeneous Disease

2022

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“…Diazoxide choline controlled-release tablets have been reported to be useful in controlling hyperphagia, obesity and aggressive behaviors in cases with Prader-Willi syndrome [ 210 , 211 ]. This drug has also been reported to prevent the aggravation of the pre-existing ID/GDD for the cases with syndromes known to be accompanied with hyperinsulinaemic hypoglycaemia such as Beckwith-Wiedemann, Sotos, Kabuki and Turner [ 212 ]. The early initiation of the diazoxide within 3 months of the onset of symptoms is associated with normal intelligence [ 213 ].…”

Section: Summary Of the Clinical Featuresmentioning

confidence: 99%

Calcium channelopathies and intellectual disability: a systematic review

Kessi

Chen

Peng

et al. 2021

Orphanet J Rare Dis

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Background Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel. Main body A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro. Conclusion Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.

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“…However, in a minority of cases with BWS, hypoglycemia is more severe and persistent, showing the characteristics of CHI. Some patients are responsive to diazoxide ( 12 ) and some may even require pancreatic surgery ( 12 – 14 ). The overall prevalence of clinically significant and persistent CHI in BWS has not been determined, but is probably less than 10% ( 11 ).…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported that most of the patUPD11p patients without a paternally inherited K ATP channel mutation do not require treatment beyond 2 years of age ( 12 , 14 ). This might be related to the shift of KCNQ1 expression from monoallelic fetal to biallelic adult expression ( 21 ).…”

Section: Resultsmentioning

confidence: 99%

Syndromic forms of congenital hyperinsulinism

2023

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

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Syndromic Forms of Hyperinsulinaemic Hypoglycaemia—A 15‐year follow‐up Study

Cited by 13 publications

References 34 publications

Congenital Hyperinsulinism: Current Laboratory-Based Approaches to the Genetic Diagnosis of a Heterogeneous Disease

Congenital Hyperinsulinism: Current Laboratory-Based Approaches to the Genetic Diagnosis of a Heterogeneous Disease

Calcium channelopathies and intellectual disability: a systematic review

Syndromic forms of congenital hyperinsulinism

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