Hyperinsulinemic hypoglycemia in seven patients with de novo <i>NSD1</i> mutations

Grand, Katheryn; Gonzalez-Gandolfi, Christina X; Ackermann, Amanda M.; Aljeaid, Deema; Bedoukian, Emma; Bird, Lynne M.; León, Diva D. De; Diaz, Jullianne; Hopkin, Robert J.; Kadakia, Sejal P.; Keena, Beth; Klein, Karen Oerter; Krantz, Ian D.; Leon, Eyby; Lord, Katherine; McDougall, Carey; Medne, Līvija; Skraban, Cara; Stanley, Charles A.; Tarpinian, Jennifer; Zackai, Elaine H.; Deardorff, Matthew A.; Kalish, Jennifer M.

doi:10.1002/ajmg.a.61062

Cited by 17 publications

(12 citation statements)

References 17 publications

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“…The precise mechanism of dysregulated insulin secretion in Sotos syndrome is unknown. Notably, the gene product of NSD1 is a histone methyltransferase that is known to be involved in the regulation of chromatin and gene expression, and circumstantial evidence exists that NSD1 may thereby also regulate islet cell insulin expression ( 30 ).…”

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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Section: Resultsmentioning

confidence: 99%

Syndromic forms of congenital hyperinsulinism

2023

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“…However, one of the hypotheses proposed is that the 5q35 region may also include additional genes that could be implicated in HH 21‐23 . It has been reported that major anomalies are associated more frequently with 5q35 deletions compared to point mutations in NSD1 24 . NSD1 gene encodes a histone methyltransferase that is involved in the opening and closing of chromatin.…”

Section: Discussionmentioning

confidence: 99%

“…NSD1 gene encodes a histone methyltransferase that is involved in the opening and closing of chromatin. Disrupted interaction between NSD1 and cofactors or histones could lead to abnormal expression of insulin, or perhaps the association of NSD1 and certain β‐cell transcription factors could suppress the expression of the insulin gene 24,25 …”

Section: Discussionmentioning

confidence: 99%

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

Kostopoulou

Dastamani

Güemes

et al. 2021

Clinical Endocrinology

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Objective Hyperinsulinaemic hypoglycaemia (HH) is one of the commonest causes of hypoglycaemia in children. The molecular basis includes defects in pathways that regulate insulin release. Syndromic conditions like Beckwith‐Wiedemann (BWS), Kabuki (KS) and Turner (TS) are known to be associated with a higher risk for HH. This systematic review of children with HH referred to a tertiary centre aims at estimating the frequency of a syndromic/multisystem condition to help address stratification of genetic analysis in infants with HH. Methods We performed a retrospective study of 69 patients with syndromic features and hypoglycaemia in a specialist centre from 2004 to 2018. Results Biochemical investigations confirmed HH in all the cases and several genetic diagnoses were established. Responsiveness to medications and the final outcome following medical treatment or surgery were studied. Conclusions This study highlights the association of HH with a wide spectrum of syndromic diagnoses and that children with features suggestive of HH‐associated syndromes should be monitored for hypoglycaemia. If hypoglycaemia is documented, they should also be screened for possible HH. Our data indicate that most syndromic forms of HH are diazoxide‐responsive and that HH resolves over time; however, a significant percentage continues to require medications years after the onset of the disease. Early diagnosis of hyperinsulinism and initiation of treatment is important for preventing hypoglycaemic brain injury and intellectual disability.

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“…Ayrıca, prenatal başlangıçlı teratomların postnatal başlangıçlı teratomlara göre daha kötü prognozlu olduğu (7,8), literatürde; Sotos sendromu ve sakrokoksigeal teratomun birlikte görüldüğü 2000 yılında iki (13), 2019 yılında iki vaka olmak üzere, toplam 4 vaka bildirilmiştir. Bu tür tümörlerin rastlantısal olabileceği gibi, aşırı büyümenin tümör gelişimini uyarıcı etkisine bağlı olarak da gelişebileceği belirtilmektedir (14). SONUÇ Sonuç olarak; Sotos sendromu tanısı konulan olgumuzda NSD1 geninde tespit edilen heterozigot değişim de novo olup patojenik varyant olarak kabul edildi.…”

Section: Introductionunclassified

A Case of Sotos Syndrome With Congenital Sacrococcygeal Teratoma

Alay

Yiğin

Özdemir

et al. 2019

Phoenix Medical Journal

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Sotos syndrome is one of the most common overgrowth syndromes. It was first described by Juan Sotos in 1964. The incidence has been reported 1: 14,000. Major findings of the diseases include overgrowth associated with advanced bone age, learning disability, and specific facial dysmorphism. Although most of the cases are sporadic, cases with autosomal dominant inheritance have also been reported. The NSD1 gene associated with the disease is localized to the q35 region of chromosome 5. The likelihood of symptoms, such as tumors, hypermetropia, strabismus, and hypoglycemic attacks are quite unlikely. However, it is recommended that all patients be monitored for tumors such as teratoma and neuroblastoma. In this article, we present a rare case of Sacrococcygeal teratoma diagnosed with Sotos syndrome in our center.

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Hyperinsulinemic hypoglycemia in seven patients with de novo NSD1 mutations

Cited by 17 publications

References 17 publications

Syndromic forms of congenital hyperinsulinism

Syndromic forms of congenital hyperinsulinism

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

A Case of Sotos Syndrome With Congenital Sacrococcygeal Teratoma

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