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Hyperinsulinemic hypoglycemia in seven patients with de novo NSD1 mutations.

ABSTRACT: Sotos syndrome is an overgrowth syndrome characterized by distinctive facial features and intellectual disability caused by haploinsufficiency of the NSD1 gene. Genotype-phenotype correlations have been observed, with major anomalies seen more frequently in patients with 5q35 deletions than those with point mutations in NSD1. Though endocrine features have rarely been described, transient hyperinsulinemic hypoglycemia (HI) of the neonatal period has been reported as an uncommon presentation of Sotos syndrome. Eight cases of 5q35 deletions and one patient with an intragenic NSD1 mutation with transient HI have been reported. Here, we describe seven individuals with HI caused by NSD1 gene mutations with three having persistent hyperinsulinemic hypoglycemia. These patients with persistent HI and Sotos syndrome caused by NSD1 mutations, further dispel the hypothesis that HI is due to the deletion of other genes in the deleted 5q35 region. These patients emphasize that NSD1 haploinsufficiency is sufficient to cause HI, and suggest that Sotos syndrome should be considered in patients presenting with neonatal HI. Lastly, these patients help extend the phenotypic spectrum of Sotos syndrome to include HI as a significant feature.

SUBMITTER: Grand K

PROVIDER: S-EPMC6454923 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Hyperinsulinemic hypoglycemia in seven patients with de novo NSD1 mutations.

Grand Katheryn K Gonzalez-Gandolfi Christina C Ackermann Amanda M AM Aljeaid Deema D Bedoukian Emma E Bird Lynne M LM De Leon Diva D DD Diaz Jullianne J Hopkin Robert J RJ Kadakia Sejal P SP Keena Beth B Klein Karen O KO Krantz Ian I Leon Eyby E Lord Katherine K McDougall Carey C Medne Livija L Skraban Cara M CM Stanley Charles A CA Tarpinian Jennifer J Zackai Elaine E Deardorff Matthew A MA Kalish Jennifer M JM

American journal of medical genetics. Part A 20190204 4

Sotos syndrome is an overgrowth syndrome characterized by distinctive facial features and intellectual disability caused by haploinsufficiency of the NSD1 gene. Genotype-phenotype correlations have been observed, with major anomalies seen more frequently in patients with 5q35 deletions than those with point mutations in NSD1. Though endocrine features have rarely been described, transient hyperinsulinemic hypoglycemia (HI) of the neonatal period has been reported as an uncommon presentation of S ...[more]

PMID: 30719864

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Project description:BackgroundIn addition to inborn metabolic disorders, altered metabolic profiles were reported to be associated with the risk and prognosis of some non-metabolic diseases, while as a rare metabolic disease, the overall secondary metabolic spectrum in congenital hyperinsulinemic hypoglycemia (HH) is largely undetermined. Therefore, we investigated metabolic profiles in HH patients and used ketotic hypoglycemia (KH) patients as a control cohort to unveil their distinct metabolic features.MethodsA total of 97 hypoglycemia children, including 74 with hyperinsulinemic hypoglycemia and 23 with ketotic hypoglycemia, and 170 euglycemia control subjects were studied retrospectively. Clinical and biochemical data were collected. The normoglycemic spectra of amino acids and acylcarnitines were determined by liquid chromatography tandem mass spectrometry. The serum insulin and fatty acid concentrations during standardized fasting tests in hypoglycemia patients were also collected. Receiver operating characteristic curve analysis was performed to screen potential biomarkers.ResultsAmong the normoglycemic spectra of amino acids, blood valine (p < 0.001), arginine (p < 0.001), threonine (p = 0.001), glutamate (p = 0.002), methionine (p = 0.005), ornithine (p = 0.008), leucine (p = 0.014), alanine (p = 0.017), proline (p = 0.031), citrulline (p = 0.042), aspartate (p = 0.046), and glycine (p = 0.048) levels differed significantly among the three groups. Significantly decreased levels of long- (C14:1, p < 0.001; C18, p < 0.001), medium- (C8, p < 0.001; C10, p < 0.001; C10:1, p < 0.001), and short-chain (C4-OH, p < 0.001; C5OH, p < 0.001) acylcarnitines were found in the hyperinsulinemic hypoglycemia group. Hyperinsulinemic hypoglycemia children with focal lesions and diffuse lesions had similar amino acid and acylcarnitine spectra. C10:1 < 0.09 μmol/L, threonine > 35 μmol/L, and threonine/C10:1 > 440 showed sensitivities of 81.1, 66.2, and 81.1% and specificities of 72.7, 78.3, and 81.8%, respectively, in distinguishing HH from KH.ConclusionsWe found significantly different altered serum amino acid and acylcarnitine profiles at normoglycemia, especially decreased C10:1 and increased threonine levels, between HH and KH children, which may reflect the insulin ketogenesis inhibition effect in HH patients; however, the detailed mechanisms and physiological roles remain to be studied in the future.

Dataset Information

Hyperinsulinemic hypoglycemia in seven patients with de novo NSD1 mutations.

Publications

Hyperinsulinemic hypoglycemia in seven patients with de novo NSD1 mutations.

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