Laparoscopic Diagnosis and Cure of Hyperinsulinism in Two Cases of Focal Adenomatous Hyperplasia in Infancy

Monique De Vroede, MD, PhD*; N.M.A. Bax, MD, PhD‡; Klaus Brusgaard, MSc, PhD§; Mark J. Dunne, PhD࿣; and Floris Groenendaal, MD, PhD¶

ABSTRACT. Persistent hyperinsulinemic hypoglycemia ward normoglycemia, through provision of ade- of infancy or congenital hyperinsulinism of the neonate is quate carbohydrate coverage and the use of drugs a rare condition that may cause severe neurologic damage if that interact with the ion channels to lower insulin the disease is unrecognized or inadequately treated. Cur- secretion.4 Diazoxide, octreotide, and calcium chan- rent treatment aims to restore normal blood glucose levels nel blockers are available, but diazoxide is the drug by providing a carbohydrate-enriched diet and drugs that of choice. PHHI is a heterogeneous disease; in a few inhibit insulin secretion. If medical treatment fails, then surgery is required. Because congenital hyperinsulinism cases, it may be transient and mild, requiring only may be caused either by diffuse involvement of pancreatic short-term medical treatment. In other cases, includ- ␤-cells or by a focal cluster of abnormal ␤-cells, the extent of ing those involving mutations in glucokinase, gluta- pancreatectomy varies. We report on 2 patients with a focal mate dehydrogenase, and short-chain hydroxyacyl- form of the disease for whom diagnosis was made with coenzyme A dehydrogenase genes, diazoxide and laparoscopy. Laparoscopic enucleation of the lesion was appropriate diet are required for a longer time but curative. Pediatrics 2004;114:e520–e522. URL: www. are very effective in controlling hypoglycemia.2,3,5,6 pediatrics.org/cgi/doi/10.1542/peds.2003-1180-L; congeni- However, almost 80% of neonates with congenital tal hyperinsulinism, pancreatectomy, laparoscopy, neuro- hyperinsulinism fail to respond to medical treatment developmental outcome. and require near-total pancreatectomy.5 This proce- dure leads to important digestive and endocrine ABBREVIATIONS. PHHI, persistent hyperinsulinemic hypoglyce- morbidities, whereas removal of insufficient amounts mia of infancy; PVS, pancreatic venous sampling; KATP channel, of the pancreas increases the duration of hypoglyce- adenosine triphosphate-sensitive potassium channel; SUR, sul- fonylurea receptor; Kir, potassium inward rectifier. mia, necessitates reintervention, and enhances the risk of hypoglycemic neuronal injury. The observations in 19757 and then in 19898 that ersistent hyperinsulinemic hypoglycemia of in- PHHI may be caused by either diffuse or focal ab- fancy (PHHI), or congenital hyperinsulinism, normalities of ␤-cells changed the surgical approach Pis a rare disease characterized by inappropriate and led to the development of radiologic procedures insulin secretion in the presence of hypoglycemia. to identify these focal forms. We now report on 2 Severe neurodevelopmental morbidity among these children with PHHI for whom a focal lesion was patients is reportedly attributable to late diagnosis diagnosed during laparoscopy and for whom lapa- and/or inability to control the profound hypoglyce- roscopic enucleation was curative. mia. Most cases are attributable to mutations in the genes coding for the subunits of the adenosine CASE REPORTS triphosphate-sensitive potassium (KATP) channels Patient 1 found in pancreatic ␤-cells, sulfonylurea receptor Patient 1 is the third child of healthy unrelated parents. He was (SUR)1 (ABCC8) and potassium inward rectifier born after an uneventful pregnancy, with a birth weight of 3980 g. (Kir)6.2 (KCNJ11).1 In rarer cases of PHHI, mutations During the first day of life, he became cyanotic and lethargic and was admitted to the hospital. The blood glucose level was 10.8 in the glucokinase gene (GCK), glutamate dehydro- mg/dL (0.6 mmol/L). Glucose was administered intravenously, genase gene (GLUD1), and short-chain hydroxyacyl- and evaluation for hypoglycemia was performed. The diagnosis of coenzyme A dehydrogenase (HADHSC) gene are PHHI was established quickly because of several high serum pathogenic and act mainly by subverting the opera- insulin measurements in the presence of blood sugar levels of Ͻ36 Ͻ tion of K channels.2,3 Treatment is directed to- mg/dL ( 2 mmol/L). Pancreatic sonographic findings were nor- ATP mal. Frequent carbohydrate feedings were administered, and high concentrations of glucose were infused intravenously through a From the Departments of *Pediatric Endocrinology, ‡Pediatric Surgery, and central catheter. Diazoxide (10 mg/kg) and hydrochlorothiazide ¶Perinatology, Wilhelmina Children’s Hospital, University Medical Center (2 mg/kg) administration was initiated, but asymptomatic hypo- Utrecht, Utrecht, Netherlands; §Department of Clinical Genetics, Odense glycemia persisted. Nifedipine (1.1 mg/kg) and octreotide (up to University Hospital, Odense, Denmark; and ࿣School of Biological Sciences, 10 ␮g/kg) were added. Octreotide administration was soon dis- University of Manchester, Manchester, United Kingdom. continued because of ileus. The patientЈs weight increased to 5.5 Accepted for publication May 18, 2004. kg at 1 month of age, and the glucose requirement was increased doi:10.1542/peds.2003-1180-L to 31 mg/kg per minute. At the age of 31 days, a diagnostic Address correspondence to Monique De Vroede, MD, PhD, Department of laparoscopy was performed. After mobilization of the lower bor- Pediatric Endocrinology, Room KC.03.063.0, PO Box 85090, 3508 AB Utre- der of the pancreas, a small round lesion of 5-mm diameter was cht, Netherlands. E-mail: [email protected] observed close to the incisura pancreatis. The lesion was excised. PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- After laparoscopy, blood glucose levels remained stable, medica- emy of Pediatrics. tion was discontinued, and the patient was discharged with nor-

e520 PEDIATRICS Vol.Downloaded 114 No. 4 from October www.aappublications.org/news 2004 www.pediatrics.org/cgi/doi/10.1542/peds.2003-1180-L by guest on September 23, 2021 mal bottle feeding. At the age of 13 months, his glucose metabo- tive for focal lesions, techniques were developed that lism is still normal and his neurologic development is excellent. might help identify these focal pancreatic lesions. The histologic examination revealed a rich proliferation of islet cells, most of which stained positive for insulin. Cultured islet cells Unfortunately, standard radiologic techniques, such were prepared with standard methods, and patch-clamp experi- as ultrasonography, computed tomography, and ments were undertaken to show that KATP channels in PHHI magnetic resonance imaging, are not helpful. In 1989, ␤-cells were defective and there were no functional responses to French interventional radiologists and surgeons de- diazoxide. DNA analysis of peripheral blood lymphocytes re- veloped the technique of pancreatic venous sampling vealed a heterozygous mutation in SUR1 gene exon 12 (1792C3T, resulting in the amino acid substitution R598X), which was also (PVS), using percutaneous transhepatic catheteriza- found for the father. tion of the portal vein.10,12 In these diagnostic stud- ies, the distinction between focal and diffuse hyper- Patient 2 insulinism is made on the basis of the finding of high Patient 2 is the third child of unrelated parents. She was born insulin levels in venous blood collected from a single after an uneventful pregnancy, with a birth weight of 3700 g. During the first day of life, she became irritable and subsequently pancreatic area, as opposed to high insulin levels in lethargic and was admitted to the hospital, where a blood glucose all pancreatic veins. An alternative method involves level of 18 mg/dL (1.0 mmol/L) was measured. Despite glucose the calcium infusion test, whereby calcium is selec- administration, new episodes of hypoglycemia occurred, followed tively infused in the gastroduodenal, superior mes- by seizures. The finding of inappropriately high serum insulin enteric, and splenic arteries and hepatic venous levels in the presence of hypoglycemia established the diagnosis 13 of PHHI. Intravenous glucose administration and frequent feed- blood is sampled for insulin measurements. Both ings were necessary, bringing the glucose requirement to 16 procedures require intensive radiologic investiga- mg/kg per minute. Diazoxide, hydrochlorothiazide, and nifedi- tion, radiation, and anesthesia. PVS seems to be the pine were administered, without improvement of glucose levels. most accurate method13 but has proved to be diffi- Sonographic findings for the pancreas were normal. On day 29, cult to implement in most pediatric centers.14 Re- diagnostic laparoscopy was performed. A lesion in the head of the 15 pancreas (8 mm ϫ 5 mm) was identified and enucleated. Except cently, Otonkoski et al presented preliminary data for transient hyperglycemia, the patient was well after discontin- suggesting the usefulness of positron emission to- uation of all medication and was fed with a normal infant feeding mography with [18F]fluoro-l-dopa for localization of regimen. At the age of 12 months, glucose metabolism is still focal lesions. normal and the child is developing normally. The histologic examination of the lesion showed adenomatous Laparoscopy is a new diagnostic approach for the cell proliferation of predominantly insulin-staining islet cells. Elec- identification of focal lesions. The technical aspects trophysiologic studies of the cultured islets revealed defects in the were discussed previously.16 The combination of mag- electrical activity of KATP channels. DNA analysis of peripheral nification (up to 18-fold when the 5-mm scope is at a blood lymphocytes revealed a heterozygous mutation in exon 3 of the SUR1 gene (331G3A, resulting in the amino acid substitution distance from the object of 2 cm) and the “palpation” of G111R), which was also found for the father. the pancreatic tissue with a suction cannula allows identification of lesions in the entire pancreas. After DISCUSSION detachment of the lower border of the pancreas, the We report on 2 infants with PHHI for whom focal posterior part of the pancreas can also be well visual- lesions of the pancreas were diagnosed during laparos- ized and searched with a palpating probe. The focal copy and laparoscopically enucleated. Both children lesions are variable in size, ranging from microscopic were cured at the age of 1 month. One year after lesions (measuring Ͻ10 mm17) to lesions that are visi- surgery, both patients are well and normoglycemic. ble with the naked eye or magnifying loupes with Functional data from patient tissue analyses and geno- 3.5-fold enlargement.12 The lower limit of detection of typing in both cases revealed that PHHI was a conse- lesions with laparoscopy is not known, and it is logical ␤ quence of defects in -cell KATP channels. For both to assume that microscopic lesions may be missed. children, mutations in the SUR1 gene were found; the However, such lesions may also remain undetected mutations were of paternal origin in both cases, as with PVS, which has success rates of 71% to 89%.10,12 reported for focal hyperinsulinism. The focal origins of Another potential problem is the presence of multiple PHHI were confirmed with histologic diagnoses. small lesions. However, multifocality appears to be Focal adenomatous hyperplasia as a cause of unusual,17 with multiple nodules being 5 times less PHHI was observed first by Kloppel et al7 in 1975 frequent than single lesions.18 Finally, complete visual- and was noted by Goossens et al8 in 1989 in a large ization of the pancreas and identification of lesion(s) study of 24 pancreata from surgically treated pa- should prevent the unfortunate situation of persisting tients with PHHI. Since those observations, focal le- hypoglycemia after blind, near-total pancreatectomy, sions as a cause of intractable hyperinsulinism have with 1 or more lesions being left in the pancreatic been consistently reported. The presumed incidence remnant.14,19 The laparoscopic approach offers other may be as high as 30% to 60% of cases of congenital advantages. This procedure is safe and quick, and se- hyperinsulinism.6,9,10 Diffuse hyperinsulinism and rum glucose levels can be maintained within a safe focal hyperinsulinism have the same clinical presen- range during the procedure with the continuation of tations but differ in their genetic origins and treat- medical treatment. This is a major advantage in com- ment. Diffuse congenital hyperinsulinism is predom- parison with the continuous PVS technique, which re- inantly an autosomal recessive disease, arising from quires medical treatment to be stopped for 5 days and homozygous mutations in the Kir6.2 or SUR1 genes. blood glucose levels to be maintained between 36 Focal forms of congenital hyperinsulinism result mg/dL (2 mmol/L) and 54 mg/dL (3 mmol/L) during from a paternally inherited Kir6.2 or SUR1 mutation the sampling procedure.10 Also, no radiation is in- and loss of maternal 11p15 material in the lesion.11 volved in our approach and no insertion of catheters Because limited pancreatectomy is potentially cura- into the main vessels or arteriography is necessary.

Downloaded from www.aappublications.org/newswww.pediatrics.org/cgi/doi/10.1542/peds.2003-1180-L by guest on September 23, 2021 e521 Laparoscopic exploration can be performed at any age, examination results for the biopsies are inconclusive whereas PVS is generally not performed before age 30 during the operation, then the procedure should be days. aborted. Reexploration should be conducted after The recognition by pathologists of focal lesions has definitive results have become available. The contri- changed the current treatment approach for patients bution of laparoscopy to both diagnosis and treat- with PHHI. For patients with diffuse hyperinsulin- ment will require additional evaluation, but the tech- ism, a near-total pancreatectomy is required to con- nique is likely to be highly valuable for the early trol hypoglycemia, whereas elective partial pancrea- diagnosis and cure of PHHI and improvement of the tectomy is sufficient for the treatment of patients long-term outcomes for hyperinsulinism in infancy. with focal disease, which eliminates the risk of sig- REFERENCES nificant morbidity for a large number of patients. Indeed, de Lonlay-Debeney et al10 reported normo- 1. Dunne MJ, Cosgrove KE, Shepherd RM, Lindley KJ, Aynsley-Green A. Hyperinsulinism in infancy: from basic science to clinical disease. glycemia among 21 neonates with focal hyperinsu- Physiol Rev. 2004;84:893–935 linism who underwent partial pancreatectomy, 2. Aynsley-Green A, Hussain K, Hall J, et al. Practical management of hyper- whereas 15 of the 30 neonates with diffuse hyperin- insulinism in infancy. 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Downloaded from www.aappublications.org/news by guest on September 23, 2021 Laparoscopic Diagnosis and Cure of Hyperinsulinism in Two Cases of Focal Adenomatous Hyperplasia in Infancy Monique De Vroede, N.M.A. Bax, Klaus Brusgaard, Mark J. Dunne and Floris Groenendaal Pediatrics 2004;114;e520 DOI: 10.1542/peds.2003-1180-L

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