Paternally inherited ABCC8 mutation causing diffuse congenital hyperinsulinism

Summary background: Congenital hyperinsulinism (CHI) is a rare genetic disorder characterised by inappropriate insulin secretion in the face of severe hypoglycaemia. There are two histological subtypes of CHI namely diffuse and focal. Diffuse CHI is most common due to recessive mutations in ABCC8/KCNJ11 (which encode the SUR/KIR6.2 components of the pancreatic β-cell KATP channel) whereas focal CHI is due to a paternally inherited ABCC8/KCNJ11 mutation and somatic loss of heterozygosity for the 11p allele inside the focal lesion. Fluorine-18-l-dihydroxyphenylalanine positron emission tomography/computed tomography (18F-DOPA-PET/CT) is used in the pre-operative localisation of focal lesions prior to surgery. Diffuse CHI if medically unresponsive will require a near total pancreatectomy whereas focal CHI will only require a limited lesionectomy, thus curing the patient from the hypoglycaemia. Aims: To report the first case of genetically confirmed CHI in Singapore from a heterozygous paternally inherited ABCC8 mutation. Methods/Results: A term male infant presented with severe hyperinsulinaemic hypoglycaemia (HH) after birth and failed medical treatment with diazoxide and octreotide. Genetic testing (paternally inherited mutation in ABCC8/p.D1472N) suggested focal disease, but due to the unavailability of 18F-DOPA-PET/CT to confirm focal disease, a partial pancreatectomy was performed. Interestingly, histology of the resected pancreatic tissue showed changes typical of diffuse disease. Conclusion: Heterozygous paternally inherited ABCC8/KCNJ11 mutations can lead to diffuse or focal CHI. Learning points HH is a cause of severe hypoglycaemia in the newborn period. Paternal mutations in ABCC8/KCNJ11 can lead to diffuse or focal disease. 18F-DOPA-PET/CT scan is the current imaging of choice for localising focal lesions. Gallium-68 tetra-aza-cyclododecane-N N′N″N-‴-tetra-acetate octreotate PET scan is not a useful imaging tool for localising focal lesions. The molecular mechanism by which a heterozygous ABCC8 mutation leads to diffuse disease is currently unclear. Focal lesions are curable by lesionectomy and so genetic studies in patients with HH must be followed by imaging using 18F-DOPA-PET/CT scan.

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A compound heterozygous mutation of ABCC8 gene causing a diazoxide-unresponsive congenital hyperinsulinism with an atypical form: Not a focal lesion in the pancreas reported by 18F-DOPA-PET/CT scan

Gene ◽

10.1016/j.gene.2015.07.012 ◽

2015 ◽

Vol 572 (2) ◽

pp. 222-226 ◽

Cited By ~ 1

Author(s):

Wen Zhang ◽

Li Liu ◽

Zhe Wen ◽

Jing Cheng ◽

Cuiling Li ◽

...

Keyword(s):

Ct Scan ◽

Compound Heterozygous Mutation ◽

Focal Lesion ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Congenital Hyperinsulinism ◽

Atypical Form ◽

Abcc8 Gene ◽

Pet Ct ◽

Pet Ct Scan

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A36 PET/CT scan with 18F-FDOPA in the diagnosis of congenital hyperinsulinism in children

Nuclear Medicine Communications ◽

10.1097/00006231-200603000-00047 ◽

2006 ◽

Vol 27 (3) ◽

pp. 290

Author(s):

A. Zonoozi ◽

P.A. Beaumont ◽

G. Plant ◽

K. Hussain ◽

J.R.W. Hall

Keyword(s):

Ct Scan ◽

Congenital Hyperinsulinism ◽

Pet Ct ◽

Pet Ct Scan

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The Use of a Long-Acting Somatostatin Analogue (Lanreotide) in Three Children with Focal Forms of Congenital Hyperinsulinaemic Hypoglycaemia

Hormone Research in Paediatrics ◽

10.1159/000491101 ◽

2018 ◽

Vol 91 (1) ◽

pp. 56-61 ◽

Cited By ~ 5

Author(s):

Antonia Dastamani ◽

Maria Güemes ◽

Catherine Pitfield ◽

Kate Morgan ◽

Mansoor Rajab ◽

...

Keyword(s):

Ct Scan ◽

Gene Mutation ◽

Pancreatic Head ◽

Somatostatin Analogue ◽

Close Monitoring ◽

Hyperinsulinaemic Hypoglycaemia ◽

Abcc8 Gene ◽

Pet Ct ◽

Long Acting ◽

Pet Ct Scan

Background: A long-acting somatostatin analogue (lanreotide) is used in the management of a diazoxide-unresponsive diffuse form of congenital hyperinsulinism (CHI). However, no reports of its use in patients with the focal form of CHI exist. Case 1: A 1-month-old boy diagnosed with diazoxide-unresponsive CHI due to a paternal heterozygous ABCC8 gene mutation showed partial response to octreotide. 18F-DOPA-PET/CT scan revealed a focal lesion in the pancreatic head. Surgical removal of the lesion was unsuccessful. He was switched to monthly lanreotide treatment at the age of 11 months, which stabilised his blood glucose over a 12-month period. Case 2: A 1-month-old boy with diazoxide-unresponsive CHI due to a paternal heterozygous KCNJ11 gene mutation was partially responsive to octreotide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. Over 6 months, he underwent 3 lesionectomies and afterwards responded to octreotide. At the age of 9 months, treatment was switched to monthly lanreotide. Currently, he is aged 3, with stable glycaemia, and improved fasting tolerance. Case 3: A 3-week-old girl with a paternal heterozygous ABCC8 gene mutation was unresponsive to diazoxide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. She responded to octreotide, and her parents preferred to avoid pancreatic surgery. At the age of 20 months, treatment was switched to monthly lanreotide, resulting in euglycaemia over the last 7 months. Conclusion: CHI patients with focal pancreatic head lesions are challenging, especially if not surgically amenable. Conservative treatment is preferable, and lanreotide might be an option. The therapeutic impact of lanreotide treatment in patients with the focal forms of CHI should be confirmed in prospective studies with close monitoring of the side effects.

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