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Persistent Hyperinsulinemic Hypoglycemia and Maturity-Onset Diabetes of the Young Due to Heterozygous HNF4A Mutations Ritika R

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Persistent Hyperinsulinemic Hypoglycemia and Maturity-Onset Diabetes of the Young Due to Heterozygous HNF4A Mutations Ritika R BRIEF REPORT Persistent Hyperinsulinemic Hypoglycemia and Maturity-Onset Diabetes of the Young Due to Heterozygous HNF4A Mutations Ritika R. Kapoor,1 Jonathan Locke,2 Kevin Colclough,3 Jerry Wales,4 Jennifer J. Conn,5 Andrew T. Hattersley,2 Sian Ellard,2,3 and Khalid Hussain1 OBJECTIVE—Mutations in the human HNF4A gene encoding the hepatocyte nuclear factor (HNF)-4␣ are known to cause maturity-onset diabetes of the young (MODY), which is charac- yperinsulinemic hypoglycemia is characterized terized by autosomal-dominant inheritance and impaired glu- by the inappropriate secretion of insulin in cose-stimulated insulin secretion from pancreatic ␤-cells. relation to the blood glucose concentration and HNF-4␣ has a key role in regulating the multiple transcriptional Hcan be transient or persistent. Recent studies factor networks in the islet. Recently, heterozygous mutations in established that heterozygous mutations in the transcrip- the HNF4A gene were reported to cause transient hyperinsuline- tion factor hepatocyte nuclear factor (HNF)-4␣ (encoded mic hypoglycemia associated with macrosomia. by the HNF4A gene) are associated with a mild form of RESEARCH DESIGN AND METHODS—Three infants pre- transient hyperinsulinemic hypoglycemia and consider- sented with macrosomia and severe hypoglycemia with a posi- able risk of macrosomia (1,2). HNF-4␣ is a transcription tive family history of MODY. The hypoglycemia was confirmed to factor of the nuclear hormone receptor superfamily and is be due to hyperinsulinism, and all three patients required diazox- expressed in liver, kidney, gut, and pancreatic islets (3). It ide therapy to maintain normoglycemia. Two of the three infants plays a key role in the regulation of pancreatic insulin are still requiring diazoxide therapy at 8 and 18 months, whereas secretion. Loss-of-function HNF4A mutations have been one of them had resolution of hyperinsulinemic hypoglycemia at identified in maturity-onset diabetes of the young (MODY) 32 months of age. families in both coding and regulatory regions of the gene, RESULTS—Sequencing of the HNF4A gene identified heterozy- including the P2 promoter region, which is suggested to be gous mutations in all three families. In family 1, a frameshift the primary transcriptional start site used in ␤-cells (4,5). mutation L330fsdel17ins9 (c.987 1003del17ins9; p.Leu330fs) MODY is characterized by an autosomal-dominant inheri- was present in the proband; a mutation affecting the conserved A tance pattern and impaired glucose-stimulated insulin nucleotide of the intron 2 branch site (c.264–21AϾG) was secretion from pancreatic ␤-cells (4). identified in the proband of family 2; and finally a nonsense The finding of transient mild hyperinsulinemic hypogly- mutation, Y16X (c.48CϾG, p.Tyr16X), was found in the proband cemia is unexpected, since heterozygous mutations in the of family 3. HNF4A gene lead to loss of glucose-induced insulin secre- CONCLUSIONS—Heterozygous HNF4A mutations can there- tion with glucose intolerance in these patients. We now fore cause both transient and persistent hyperinsulinemic hypo- extend the observations of two previous studies (1,2) and glycemia associated with macrosomia. We recommend that report that heterozygous HNF4A mutations can cause macrosomic infants with transient or persistent hyperinsuline- macrosomia with severe and persistent hyperinsulinemic mic hypoglycemia should be screened for HNF4A mutations if hypoglycemia as well as MODY in three families. there is a family history of youth-onset diabetes. Diabetes 57: 1659–1663, 2008 RESEARCH DESIGN AND METHODS Patient 1. Patient 1 was born at 39 weeks’ gestation with a birth weight of 5.9 kg after a vaginal delivery. The From the 1London Centre for Paediatric Endocrinology and Metabolism, Great Ormond Street Hospital for Children NHS Trust, and The Institute of Child delivery was complicated with a prolonged second stage Health, University College London, London, U.K.; the 2Institute of Biomedical and shoulder dystocia. After delivery, the baby developed and Clinical Science, Peninsula Medical School, Exeter, U.K.; the 3Department severe symptomatic hypoglycemia (jitteriness and irrita- of Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, U.K.; the 4Department of Paediatric Endocrinology, Sheffield Children’s Hos- bility with a blood glucose concentration of 0.8 mmol/l). pital, Sheffield, U.K.; and the 5Royal Women’s Hospital, Carlton, Victoria, He required a continuous infusion of 25% dextrose deliv- Australia. ering 25 mg ⅐ kgϪ1 ⅐ minϪ1 glucose, as well as an infusion Corresonding author: Dr. K. Hussain, Developmental Endocrinology Re- search Group, Molecular Genetics Unit, Institute of Child Health, University of glucagon to maintain normoglycemia. Biochemical anal- College London, 30 Guilford St., London WC1N 1EH. E-mail: k.hussain@ ysis showed an inappropriately raised level of insulin (103 ich.ucl.ac.uk. mU/l) during hypoglycemia (glucose 1.6 mmol/l) along Received for publication 23 November 2007 and accepted in revised form 21 with undetectable serum ketone bodies and fatty acids. January 2008. Ϫ1 Ϫ1 Published ahead of print at http://diabetes.diabetesjournals.org on 11 Feb- The hypoglycemia was responsive to 10 mg ⅐ kg ⅐ day ruary 2008. DOI: 10.2337/db07-1657. of diazoxide. An 18fluoro-L-Dopa positron emission tomog- 18F-DOPA-PET, 18fluoro-L-Dopa positron emission tomography; HNF, hepa- raphy (18F-DOPA-PET) scan showed intense uptake of tocyte nuclear factor; MODY, maturity-onset diabetes of the young; PPAR, peroxisome proliferator–activated receptor. tracer throughout the pancreas consistent with increased © 2008 by the American Diabetes Association. metabolic activity of the islets (Fig. 1). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance The child was admitted again at 7 months for a trial off with 18 U.S.C. Section 1734 solely to indicate this fact. medications. During the 24-h profile, several hypoglycemic DIABETES, VOL. 57, JUNE 2008 1659 HETEROZYGOUS HNF4A MUTATIONS AND PERSISTENT HYPOGLYCEMIA TABLE 1 Clinical characteristics of patients with hyperinsulinism Patient 1 Patient 2 Patient 3 Birth weight (g) 5,900 4,200 4,055 Gestational age (weeks) 39/40 37/40 36/40 Age of presentation (days) 1 2 1 Maximum glucose infusion rate (mg ⅐ kgϪ1 ⅐ minϪ1) 25 12.5 11 Glucagon infusion required Yes Yes Yes Diazoxide responsive dose (mg ⅐ kgϪ1 ⅐ dayϪ1) 10 10 6 Family history of diabetes Yes Yes Yes Attempted withdrawal of diazoxide Not successful Not successful Successful at at 7 months at 18 months 32 months (blood glucose levels down to 2.1 mmol/l) episodes were nosis of hyperinsulinemic hypoglycemia was made and her documented, and therefore therapy was reinitiated with a hypoglycemia responded well to 10 mg ⅐ kgϪ1 ⅐ dayϪ1 good response. At the age of 8 months, the child remains diazoxide and 10 mg ⅐ kgϪ1 ⅐ dayϪ1 chlorothiazide. An on8mg⅐ kgϪ1 ⅐ dayϪ1 diazoxide and 5 mg ⅐ kgϪ1 ⅐ dayϪ1 attempt at stopping the diazoxide at 18 months of age chlorothiazide with normoglycemia. resulted in further hypoglycemic episodes, and therapy Family history. Our patient is the first child born to had to be reinitiated. nonconsanguineous parents. There is a strong family his- Family history. There was a strong family history of tory of diabetes, which is summarized in Fig. 2 (pedigree young-onset diabetes (Fig. 2, pedigree 2). At age 23 years, 1). The patient’s father was diagnosed with diabetes at age the child’s father was diagnosed with diabetes, which was 26 years and was treated with oral hypoglycemic agents. initially controlled by diet. He was started on oral hypo- Interestingly, he was born macrosomic at 26 weeks’ ges- glycemic agents at age 25 years and had been on subcuta- tation with a birth weight of 2.79 kg. The paternal grand- neous insulin since age 37 years. Two of the paternal mother was diagnosed with diabetes at age 17 years and uncles and the paternal grandfather were also diagnosed was started on subcutaneous insulin therapy. with diabetes in their 20s. Interestingly, one of the uncles Patient 2. Patient 2 was born at 37 weeks’ gestation with had a birth weight of Ͼ5.4 kg. The father and both the a birth weight of 4.2 kg via a ventouse delivery. Delivery uncles required neonatal intensive care, but further details was difficult and associated with a right-sided Erb’s palsy. were not available. There is further history of youth-onset She developed hypoglycemia (blood glucose 2.5 mmol/l) at diabetes in the extended family shown in Fig. 2 (pedigree 2 days of age with a seizure. The child required a contin- 2). An HNF4A mutation, Y16X, had previously been iden- uous intravenous infusion of 20% glucose solution deliver- tified in the proband’s cousin (1). ing 12.5 mg ⅐ kgϪ1 ⅐ minϪ1 glucose and an intravenous Patient 3. Patient 3 was born at 36 weeks’ gestation via infusion of glucagon to maintain normoglycemia. A diag- vacuum extraction, with a birth weight of 4.05 kg. Delivery Body Head Tail FIG. 1. 18F-DOPA-PET/CT scan showing uptake of the 18F-L-Dopa throughout the whole of the pancreas in patient 1. The principle of this test is that pancreatic islets take up L-3,4-dihydroxyphenylalanine (L-DOPA) and convert it to dopamine by Dopa decarboxylase, present in the islet cells. The standard uptake value (SUV) reflects the intensity of uptake of DOPA. The 18F-DOPA-PET/CT scan in this patient shows uniformly (in the head, body, and tail of the pancreas) increased uptake of 18F-L-Dopa, reflecting increased metabolic activity of the islets. The intensity of ؉ 18 uptake of the F-L-Dopa by the islets was equivalent to that observed in patients with defects in pancreatic ATP-sensitive K (KATP) channels (7). This fits in with the clinical observation of severe hyperinsulinemic hypoglycemia. 1660 DIABETES, VOL. 57, JUNE 2008 R.R.
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