ESPEYB16 2. Antenatal and Neonatal Endocrinology Neonatal Hypoglycaemia (5 abstracts)
2.1. Congenital hyperinsulinism in infants with turner syndrome: possible association with monosomy X and KDM6A haploinsufficiency
Gibson CE , Boodhansingh KE , Li C , Conlin L , Chen P , Becker SA , Bhatti T , Bamba V , Adzick NS , De Leon DD , Ganguly A & Stanley CA
To read the full abstract: Horm Res Paediatr: 2018;89(6):413–422.
This study examined the clinical and molecular aspects of girls with Turner syndrome and hyperinsulinaemic hypoglycemia (HH). Records of girls with hyperinsulinism and Turner syndrome were reviewed.
The findings expand on previous observations suggesting a link between Turner syndrome and hyperinsulinaemic hypoglycemia (HH). Some of the patients described in this study had severe HH which was unresponsive to treatment with diazoxide and required pancreatectomy despite having no mutations in the pancreatic KATP channel genes. All the cases in this study were found to have monosomy X, suggesting that haploinsufficiency for an X chromosome gene, rather than an over-dosage of X chromosome material due to the presence of a ring X chromosome, may be responsible for the HH in Turner syndrome.
The authors suggest that haploinsufficiency for the gene KDM6A located on the X chromosome is an attractive explanation for the HH in Turner syndrome. KDM6A escapes X-inactivation and is associated with Kabuki syndrome. KDM6A regulates transcriptionally active chromatin through epigenetic modification of histone H3. KDM6A is a lysine-specific histone H3 demethylase that controls tissue specific expression of genes involved in development as well as the cell cycle. The proportion of beta cells with monosomy X in different girls with Turner syndrome is likely to be highly variable and could affect the severity of their HH.
In one patient who underwent pancreatectomy, the authors were able to study the dynamics of insulin secretion. The islets from this patient showed altered fuel sensing, with increased sensitivity to amino acids and elevated basal cytosolic calcium concentrations. These findings are similar to patients with pancreatic KATP channel defects. Studies of mouse islets exposed to an inhibitor of KDM6A reproduced some of the islet phenotype seen in the case of Turner syndrome, supporting the suggestion that haploinsufficiency of KDM6A might be responsible for HH in Turner syndrome. The mechanisms involved in dysregulated insulin secretion in Turner syndrome and in KDM6A deficiency warrant further investigation and should give further insights into the role of KDM6A in the pancreatic beta-cell. Clearly, Turner syndrome patients have an increased frequency of HH.
Volume 16
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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