Dataset Information

Congenital Hyperinsulinism in Infants with Turner Syndrome: Possible Association with Monosomy X and KDM6A Haploinsufficiency.

ABSTRACT: BACKGROUND:Previous case reports have suggested a possible association of congenital hyperinsulinism with Turner syndrome. OBJECTIVE:We examined the clinical and molecular features in girls with both congenital hyperinsulinism and Turner syndrome seen at The Children's Hospital of Philadelphia (CHOP) between 1974 and 2017. METHODS:Records of girls with hyperinsulinism and Turner syndrome were reviewed. Insulin secretion was studied in pancreatic islets and in mouse islets treated with an inhibitor of KDM6A, an X chromosome gene associated with hyperinsulinism in Kabuki syndrome. RESULTS:Hyperinsulinism was diagnosed in 12 girls with Turner syndrome. Six were diazoxide-unresponsive; 3 had pancreatectomies. The incidence of Turner syndrome among CHOP patients with hyperinsulinism (10 of 1,050 from 1997 to 2017) was 48 times more frequent than expected. The only consistent chromosomal anomaly in these girls was the presence of a 45,X cell line. Studies of isolated islets from 1 case showed abnormal elevated cytosolic calcium and heightened sensitivity to amino acid-stimulated insulin release; similar alterations were demonstrated in mouse islets treated with a KDM6A inhibitor. CONCLUSION:These results demonstrate a higher than expected frequency of Turner syndrome among children with hyperinsulinism. Our data suggest that haploinsufficiency for KDM6A due to mosaic X chromosome monosomy may be responsible for hyperinsulinism in Turner syndrome.

SUBMITTER: Gibson CE

PROVIDER: S-EPMC6067979 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Congenital Hyperinsulinism in Infants with Turner Syndrome: Possible Association with Monosomy X and KDM6A Haploinsufficiency.

Gibson Christopher E CE Boodhansingh Kara E KE Li Changhong C Conlin Laura L Chen Pan P Becker Susan A SA Bhatti Tricia T Bamba Vaneeta V Adzick N Scott NS De Leon Diva D DD Ganguly Arupa A Stanley Charles A CA

Hormone research in paediatrics 20180614 6

<h4>Background</h4>Previous case reports have suggested a possible association of congenital hyperinsulinism with Turner syndrome.<h4>Objective</h4>We examined the clinical and molecular features in girls with both congenital hyperinsulinism and Turner syndrome seen at The Children's Hospital of Philadelphia (CHOP) between 1974 and 2017.<h4>Methods</h4>Records of girls with hyperinsulinism and Turner syndrome were reviewed. Insulin secretion was studied in pancreatic islets and in mouse islets t ...[more]

PMID: 29902804

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Project description:IntroductionCongenital hyperinsulinism is a rare inherited disease caused by mutations in genes responsible for β-cell's function in glucose hemostasis leading to profound and recurrent hypoglycemia. The incidence of the disease is about 1 in 50000 newborns. Mutations in at least 8 genes have been reported to cause congenital hyperinsulinism. Mutations in ABCC8 gene are the most common cause of the disease that account for approximately 40% of cases. Less frequently KCNJ11 gene mutations are responsible for the disease. Mutations in other genes such as HADH account for smaller fractions of cases. In nearly half of the cases the cause remains unknown.Case presentationDuring the period between 2005 and 2010, a total of six patients with persistent hyperinsulinism were investigated at Mofid Children's Hospital. In this study all of the patients had early onset hyperinsulinemia. Five patients had consanguineous parents. After failure of medical treatment in three patients, They were undergone pancreatectomy. Two diffuse types and one focal type had been recognized in pathological analysis of intra-operative frozen specimens of pancreas in these patients. Genetic analysis was performed using polymerase chain reaction followed by Sanger sequencing for ABCC8, KCNJ11and HADH genes. In five patients homozygous mutations in these genes were identified that indicated an autosomal recessive pattern of inheritance. In one patient a heterozygous mutation in ABCC8 was identified, indicating possible autosomal dominant inheritance of the disease.ConclusionsCongenital hyperinsulinism can have different inheritance pattern. Autosomal recessive inheritance is more common but less frequently autosomal dominant inheritance can be seen. It appears that mutations in ABCC8 gene can show both autosomal recessive and autosomal dominant inheritance of the disease. PCR followed by Sanger sequencing proved to be an efficient method for mutation detection in three investigated genes. Despite early diagnosis, psychomotor retardation was seen in two patients.

Project description:Background: Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome. A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown. Methods: We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion. Results: In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. In silico analysis of these genes highlighted SMARCA2 and RFX3 as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region. Conclusions: This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated. Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.

Dataset Information

Congenital Hyperinsulinism in Infants with Turner Syndrome: Possible Association with Monosomy X and KDM6A Haploinsufficiency.

Publications

Congenital Hyperinsulinism in Infants with Turner Syndrome: Possible Association with Monosomy X and KDM6A Haploinsufficiency.

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