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Early brain atrophy in persistent hyperinsulinemic hypoglycemia of infancy
C LINICAL AND L ABORATORY O BSERVATIONS
Early brain atrophy in persistent hyperinsulinemic hypoglycemia of infancy Zohar Nachum, MD, Izhar Ben-Shlomo, MD, Yardena Rakover, MD, Ehud Weiner, MD, and Eliezer Shalev, MD We present two siblings with persistent hyperinsulinemic hypoglycemia of infancy, accelerated intrauterine growth and early neonatal brain atrophy. Fetal plasma glucose and insulin levels in the second sibling revealed normoglycemia despite hyperinsulinemia. The absence of intrauterine hypoglycemia suggests that the brain damage is not secondary to hypoglycemia and other etiologies must be considered. (J Pediatr 2002;141:706-9) Persistent hyperinsulinemic hypoglycemia of infancy (PHHI, also known as nesidioblastosis) is a rare disorder in which insulin secretion in the neonatal period is excessive and glucose-independent, resulting in severe bouts of hypoglycemia. 1 The disease appears to have autosomal recessive and autosomal dominant variants.2,3 The underlying genetic defect has been located to chromosome 11p14-15.1, where the sulphonyl urea receptor (SUR) element of the potassium pump is encoded.4 Several mutations have been described, all leading to loss of function of the
adenosine triphosphate-dependent potassium pump in pancreatic islet β cells.5-7 The disease is often associated with brain atrophy and permanent brain damage,8-10 which have been attributed to periods of hypoglycemia.1 There is no documentation correlating the brain damage to the frequency, severity, and duration of hypoglycemic events or the morphologic correlates in the brain. In cases involving accelerated intrauterine growth, there are reports of high insulin and low glucose levels in the amniotic fluid,11,12 suggesting that brain damage may occur during fetal life.
From the Department of Obstetrics and Gynecology, The Pediatric Endocrine Unit and Endocrine Laboratory, HaEmek Medical Center, Afula, the Rappaport School of Medicine, Technion, Institute of Technology, Haifa, Israel.
Submitted for publication July 31, 2001; revisions received Mar 20, 2002, and July 1, 2002; accepted July 16, 2002. Reprint requests: Prof E. Shalev, MD, Chairman, Department of Obstetrics and Gynecology, Haemek Medical Center, Afula, 18101, Israel. Copyright © 2002, Mosby, Inc. All rights reserved. 0022-3476/2002/$35.00 + 0 9/22/128546 doi:10.1067/mpd.2002.128546
706
We present two siblings in whom accelerated intrauterine growth and early neonatal brain atrophy were documented by ultrasound (US) and computed tomography (CT). Fetal plasma glucose and insulin levels in the second sibling revealed normoglycemia despite hyperinsulinemia. The first newborn died from the complications of repeated hypoglycemic episodes. The second fared better because of an early, aggressive, multiple-drug approach, combined with subsequent pancreatectomy. Our findings suggest that early brain atrophy in PHHI is not caused by intrauterine hypoglycemia and will not lead to neurologic deficit if neonatal hypoglycemia is effectively treated. CT PHHI SUR US
Computed tomography Persistent hyperinsulinemic hypoglycemia of infancy Sulphonyl urea receptor Ultrasound
CASE REPORT A 33-year-old Arab woman was admitted in the 33rd week of her 5th pregnancy because of premature uterine contractions. Her obstetric history included 4 normal pregnancies and deliveries at term of healthy children, weighing 3880 g to 4250 g. Her husband, who is her first cousin, has a late-onset muscular dystrophy. A sono-
NACHUM ET AL
THE JOURNAL OF PEDIATRICS
VOLUME 141, NUMBER 5 graphic examination revealed polyhydramnios and an extremely large-forgestational-age fetus with an estimated fetal weight of 3724 g, which is 7.2 SD above the mean. The head-to-abdomen circumference ratio was 0.92, which is below the 5th percentile, indicating “asymmetry” of growth.13 The fetus also had increased subcutaneous fat, an enlarged liver, and puffy cheeks. No anatomic malformations were detected. An oral glucose tolerance test was normal. Amniocentesis was done at 34.5 weeks and 36 weeks gestational age to measure insulin levels, to confirm a diagnosis of PHHI. Amniotic insulin levels (enzyme-linked immunosorbent assay, Axsym, Abbott Laboratories, Abbott Park, Ill) were 14 mU/L and 15 mU/L, respectively, indicating fetal hyperinsulinism (normal values: for weeks 33 to 34 = 1.9-12.8 mU/L; weeks 35 to 36 = 1.8-13.5 mU/L).14 Lung maturity was confirmed at 36 weeks and an elective cesarean delivery was performed at 36 weeks + 4 days. The newborn male weighed 5690 g, and the Apgar score was 9 at both 1 and 5 minutes. Immediately after birth, the infant had repeated, profound hypoglycemic episodes despite intensive medical treatment. The treatments included intravenous and enteral high-glucose intake (14 mg/kg/minute), diazoxide 10 mg/kg/day and octreotide 40 µg/kg/day (Sandostatin, Sandoz, Basel, Switzerland). The plasma insulin level was 45 mU/L (<10 mU/L is normal with hypoglycemia),1 with a concomitant glucose level of 1.2 mmol/L, establishing a diagnosis of PHHI. No ketones were detected in urine samples, and metabolic workup was normal. Physical examination revealed generalized hypotonia without muscle dystrophy, a systolic murmur, weak femoral pulses, enlarged liver and hypospadias. Echocardiography demonstrated hypertrophic cardiomyopathy and coarctation of the aorta distal to the left brachial artery origin. Cardiac failure developed on the second day of life and was treated with furosemide and β-blockers. A CT of the
Figure. Serial axial CT views of the brain at the level of the 3rd and lateral ventricles in two siblings with persistent hyperinsulinemic hypoglycemia of infancy. A, First child at age 2 weeks: marked atrophic appearance of the brain parenchyma, which is particularly emphasized in the frontal lobes (arrows); B, First child at age 12 weeks: the atrophy is more advanced compared with the first image; C, Second child at age 1 day: atrophic appearance of the brain parenchyma (arrows); D, Second child at age 7 months: noticeable improvement in the appearance of the brain atrophy.
brain at 2 weeks showed marked brain atrophy (Figure, A). At 3 weeks, mechanical ventilation was initiated because of respiratory failure. Because the hypoglycemic episodes had not abated, the infant underwent a near total pancreatectomy at 5 weeks. Histology was consistent with diffuse islet-cell hyperplasia.15 Hypoglycemic episodes persisted, and at 11 weeks he underwent a
subtotal pancreatectomy, after which he remained euglycemic without any medication. A second CT scan revealed extreme atrophy of the brain (Figure, B). The infant could not be weaned off the mechanical ventilation, and died from sepsis at 16 weeks. A year later the mother consulted us again for a pregnancy in the 15th gestational week. US examinations at 15 and 707
NACHUM ET AL
THE JOURNAL OF PEDIATRICS NOVEMBER 2002
Table. Cord blood and amniotic fluid values measured in a fetus with intrauterine manifestations of persistent hyperinsulinemic hypoglycemia of infancy
Gestational week Origin 34 35 37
CB AF CB AF CB AF
Glucose (mmol/L) (normal) 2.8 (2.4-5.2) 0.9 (0.6-2.7) 4.4 (2.3-5.1) 1.0 (0.3-2.7) 4.1 (2.2-5.0) 0.6 (0.4-2.4)
Insulin (µU/mL) (normal)
C-peptide Maternal (pmol/mL) glucose (normal) (mmol/L)
137 (2.6-11.2) 8.33 (0.5-2.2) 4.3 15.4 (1.9-12.8) 137 (2.8-11.6) 7.6 (0.5-2.2) 5.0 16.3 (1.8-13.5) 6.63 (1.74 ± 1.35) 200 (3.0-12.0) 7.3 15.4 (1.5-14.9)
AF, Amniotic fluid; CB, cord blood. Normal values from references 14, 17-19.
20 weeks did not disclose any malformations, and the fetal size was appropriate for gestational age. An oral glucose tolerance test was positive at 26 weeks.16 Glycemic control was achieved by dietary measures alone. Intrauterine growth accelerated (4.4-7.7 SDs above the mean) and was asymmetrical on repeated US examinations from 29 weeks onwards. Our concern that the early brain atrophy in the former child might have been caused by intrauterine hypoglycemia prompted us to obtain fetal blood samplings. After obtaining parental consent, umbilical venous and amniotic fluid samples were taken 3 times to measure glucose, insulin, and C-peptide levels (radioimmunoassay, Diagnostic Products Corporation, Los Angeles, Calif), and to evaluate fetal lung maturity (Table). Fetal plasma glucose levels were normal despite extremely high insulin levels, diagnostic of PHHI. Because fetal blood glucose levels were normal, the pregnancy was allowed to continue until the indicators showed lung maturity. A cesarean delivery was performed at 37 weeks and a female infant weighing 6140 g was delivered in good condition. Umbilical plasma glucose was 2.4 mmol/L and pH was 7.33. Intensive medical treatment was initiated, including glucose intake of 17 mg/kg/minute and intravenous glucagon, later combined with diazox708
ide and subcutaneous Sandostatin (Sandoz). This treatment kept the plasma glucose above 2.5 mmol/L. On the first day of life, US examination of the head revealed brain atrophy. A CT scan one week later was consistent with atrophy (Figure, C). Because of continuing, though infrequent, hypoglycemic episodes, the baby underwent a near total pancreatectomy at two weeks, after which euglycemia was maintained with Sandostatin 20 µg 4 times daily. A CT scan at 7 weeks demonstrated improvement of the brain findings. A trial of treatment with nifedipine instead of Sandostatin failed to maintain blood glucose at the desired levels. The infant was discharged from the hospital at 3 months receiving Sandostatin therapy. At 7 months, a brain CT scan showed continued improvement, although atrophy was still apparent (Figure, D). The neurodevelopmental state of the child at 5 years was normal. Genomic DNA analysis did not reveal any of the 27 known mutations in the sulfonylurea receptor region SUR1. To test whether the defect in the sulphonylurea receptor element of the potassium pump also affected synaptic activity and nerve conductivity, at one year of age the child underwent a brain stem auditory evoked response test, somatosensory peripheral nerve conductivity test, and electromyogram. The results of all 3 tests were normal.
DISCUSSION We describe two siblings affected by PHHI; the first was diagnosed in utero without a family history. In the only two reported cases where prenatal diagnosis was accomplished, the propositus was a previously affected child diagnosed after birth.11,12 Based on previous publications,14 it is notable that whereas amniotic fluid insulin levels in our case and the other cases, were elevated to various extents, up to 4 times normal values, cord blood levels reached 15 times normal values, suggesting that the diagnosis and the possible treatment of intrauterine onset of PHHI should rely on fetal cord blood, rather than amniotic fluid levels of insulin. Cord blood can also be used for genetic analysis. The two consecutive pregnancies complicated by the same condition allowed us to address two questions. First, is there intrauterine hypoglycemia in severe, early onset PHHI? Second, is there a cause and effect relationship between hypoglycemia and what appears by CT to be brain atrophy in this disease? Our initial impression that brain atrophy may be a consequence of intrauterine glucose deprivation resulted from its very early appearance in the first child. In support of this, we found an earlier publication that reported low amniotic fluid glucose, which was assumed to reflect fetal blood levels.12 Previous reports described two stages in brain appearance after hypoglycemic damage to the brain. Edematous brain would have been expected at 2 weeks of age if the initial insult appeared immediately after birth, whereas we found an atrophic brain at this age. Moreover, the parts of the brain found to be affected after hypoglycemia were mainly the parietal and occipital lobes,8 whereas in the two children we treated, the frontal lobes were the most severely affected. The apparent deviation from a typical appearance of the brain in the first
NACHUM ET AL
THE JOURNAL OF PEDIATRICS
VOLUME 141, NUMBER 5 child, if hypoglycemia occurred for the first time after birth, prompted us to address glucose blood levels during fetal life. Our findings, which are novel in this respect, do not support the existence of intrauterine hypoglycemia in PHHI cases, which are already hyperinsulinemic during fetal life. This in turn suggests that the early appearance of brain atrophy may not be caused by intrauterine glucose deprivation. There may be an intrinsic neurologic defect in PHHI, which underlies early brain atrophy. Indeed, the possibility of such an intrinsic defect was proposed by Philipson and Steiner, based on the role of the SUR in the maintenance of transmembrane potentials in several cell types, including neurons.20 A caveat here is the possibility that this family, in whom the mutation was not similar to the 27 known variations, has a disorder different from previous cases. Of note, hypoglycemia-induced brain damage is predominantly of the upper motor neuron type (spastic),9,10 whereas our patients were hypotonic. The finding of normal nerve conductivity and electromyogram was not consistent with hypotonia being caused by peripheral nervous or muscular dysfunction. Timely and adequate intensive management of neonatal hypoglycemia may prevent the progression of brain atrophy, which appears to improve with time. The mechanism underlying the improvement remains unclear, but a prolonged state of euglycemia may enable spontaneous neural development. We thank Benjamin Glaser, MD, from the Department of Endocrinology and Metabolism, Hadassah University Hospital, and Ein Karem, Jerusalem, Israel, for expert genomic analysis.
REFERENCES 1. Aynsley-Green A, Polak JM, Bloom SR, Gough MH, Keeling J, Ashcroft SJ, et al. Nesidioblastosis of the pancreas: definition of the syndrome and the management of the severe neonatal hyperinsulinemic hypoglycemia. Arch Dis Child 1981;56:496-508. 2. Glaser B, Phillip M, Carmi R, Lieberman E, Landau H. Persistent hyperinsulinemic hypoglycemia of infancy (“nesidioblastosis”): autosomal recessive inheritance in 7 pedigrees. Am J Med Genet 1990;37:511-5. 3. Thorenton PS, Satin-Smith MS, Herold K, Glaser B, Chiu KC, Nestorowicz A, et al. Familial hyperinsulinism with apparent autosomal inheritance: clinical and genetic differences from autosomal recesive variant. J Pediatr 1998;132:9-14. 4. Thomas PM, Cote GJ, Hallman DM, Mathew PM. Homozygosity mapping, to chromosome 11p, of the gene for familial persistent hyperinsulinemic hypoglycemia of infancy. Am J Hum Genet 1995;56:416-21. 5. Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, et al. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 1995;268:426-9. 6. Thomas PM, Wohllk N, Huang E, Kuhnle U, Rabl W, Gagel RF, et al. Inactivation of the first nucleotide-binding fold of the sulfanylurea receptor, and familial persistent hyperinsulinemic hypoglycemia of infancy. Am J Hum Genet 1996;59:510-8. 7. Dunne MJ, Kane C, Shepherd RM, Sanchez JA, James RF, Johnson PR, et al. Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor. N Engl J Med 1997;336:703-6. 8. Destructive brain disorders of childhood. In: Barkovich AJ, editor. Pediatric neuroimaging. 2nd ed. Philadelphia (PA): Lippincott-Raven; 1996. p. 171-3. 9. Anderson JM, Milner RDG, Strich SJ. Effect of neonatal hypoglycemia on the nervous system: a pathological
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20.
study. J Neurol Neurosurg Psychiatry 1967;30:295-310. Banker BQ. The neuropathological effect of anoxia and hypoglycemia in the newborn. Dev Med Child Neurol 1967;9:544-50. Bianchi C, Corbella E, Beccaria L, Bolla P, Chiumello G. A case of familial nesidioblastosis: prenatal diagnosis of fetal hyperinsulinism. Acta Pediatr 1992;81:853-5. Aparicio L, Carpenter MW, Schwartz R, Gruppuso PA. Prenatal diagnosis of familial neonatal hyperinsulinemia. Acta Pediatr 1993;82:683-6. Hadlock FP, Harrist RB, MartinezPoyer J. In utero analysis of fetal growth: a sonographic weight standard. Radiology 1991;181:129-33. Weiss PA, Pürstner P, Winter R, Lichtenegger W. Insulin levels in amniotic fluid of normal and abnormal pregnancies. Obstet Gynecol 1984; 63:371-5. Sempoux C, Guiot Y, Lefevre A, NihoulFekete C, Jaubert F, Saudubray JM, et al. Neonatal hyperinsulinemic hypoglycemia: heterogeneity of the syndrome and keys for differential diagnosis. J Clin Endocrinol Metab 1998;83:1455-61. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. National Diabetes Data Group. Diabetes 1979; 28:1039-57. Marconi AM, Paolini C, Buscaglia M, Zerba G, Battaglia FC, Pardi G. The impact of gestational age and fetal growth on the maternal-fetal glucose concentration difference. Obstet Gynecol 1996;87:937-42. Weiss PA, Hofman H, Winter R, Pürstner P, Lichtenegger W. Amniotic fluid glucose values in normal and abnormal pregnancies. Obstet Gynecol 1985; 65:333-9. Fallucca F, Gariulo P, Troili P, Zicari D, Pimpinella G, Maldonato A, et al. Amniotic fluid insulin, C-peptide concentrations, and fetal morbidity in infants of diabetic mothers. Am J Obstet Gynecol 1985;153:534-40. Philipson LH, Steiner DF. Pas de deux or more: the sulfonylurea receptor and K+ channels. Science 1995;268:372-3.
709
Early brain atrophy in persistent hyperinsulinemic hypoglycemia of infancy Zohar Nachum, MD, Izhar Ben-Shlomo, MD, Yardena Rakover, MD, Ehud Weiner, MD, and Eliezer Shalev, MD We present two siblings with persistent hyperinsulinemic hypoglycemia of infancy, accelerated intrauterine growth and early neonatal brain atrophy. Fetal plasma glucose and insulin levels in the second sibling revealed normoglycemia despite hyperinsulinemia. The absence of intrauterine hypoglycemia suggests that the brain damage is not secondary to hypoglycemia and other etiologies must be considered. (J Pediatr 2002;141:706-9) Persistent hyperinsulinemic hypoglycemia of infancy (PHHI, also known as nesidioblastosis) is a rare disorder in which insulin secretion in the neonatal period is excessive and glucose-independent, resulting in severe bouts of hypoglycemia. 1 The disease appears to have autosomal recessive and autosomal dominant variants.2,3 The underlying genetic defect has been located to chromosome 11p14-15.1, where the sulphonyl urea receptor (SUR) element of the potassium pump is encoded.4 Several mutations have been described, all leading to loss of function of the
adenosine triphosphate-dependent potassium pump in pancreatic islet β cells.5-7 The disease is often associated with brain atrophy and permanent brain damage,8-10 which have been attributed to periods of hypoglycemia.1 There is no documentation correlating the brain damage to the frequency, severity, and duration of hypoglycemic events or the morphologic correlates in the brain. In cases involving accelerated intrauterine growth, there are reports of high insulin and low glucose levels in the amniotic fluid,11,12 suggesting that brain damage may occur during fetal life.
From the Department of Obstetrics and Gynecology, The Pediatric Endocrine Unit and Endocrine Laboratory, HaEmek Medical Center, Afula, the Rappaport School of Medicine, Technion, Institute of Technology, Haifa, Israel.
Submitted for publication July 31, 2001; revisions received Mar 20, 2002, and July 1, 2002; accepted July 16, 2002. Reprint requests: Prof E. Shalev, MD, Chairman, Department of Obstetrics and Gynecology, Haemek Medical Center, Afula, 18101, Israel. Copyright © 2002, Mosby, Inc. All rights reserved. 0022-3476/2002/$35.00 + 0 9/22/128546 doi:10.1067/mpd.2002.128546
706
We present two siblings in whom accelerated intrauterine growth and early neonatal brain atrophy were documented by ultrasound (US) and computed tomography (CT). Fetal plasma glucose and insulin levels in the second sibling revealed normoglycemia despite hyperinsulinemia. The first newborn died from the complications of repeated hypoglycemic episodes. The second fared better because of an early, aggressive, multiple-drug approach, combined with subsequent pancreatectomy. Our findings suggest that early brain atrophy in PHHI is not caused by intrauterine hypoglycemia and will not lead to neurologic deficit if neonatal hypoglycemia is effectively treated. CT PHHI SUR US
Computed tomography Persistent hyperinsulinemic hypoglycemia of infancy Sulphonyl urea receptor Ultrasound
CASE REPORT A 33-year-old Arab woman was admitted in the 33rd week of her 5th pregnancy because of premature uterine contractions. Her obstetric history included 4 normal pregnancies and deliveries at term of healthy children, weighing 3880 g to 4250 g. Her husband, who is her first cousin, has a late-onset muscular dystrophy. A sono-
NACHUM ET AL
THE JOURNAL OF PEDIATRICS
VOLUME 141, NUMBER 5 graphic examination revealed polyhydramnios and an extremely large-forgestational-age fetus with an estimated fetal weight of 3724 g, which is 7.2 SD above the mean. The head-to-abdomen circumference ratio was 0.92, which is below the 5th percentile, indicating “asymmetry” of growth.13 The fetus also had increased subcutaneous fat, an enlarged liver, and puffy cheeks. No anatomic malformations were detected. An oral glucose tolerance test was normal. Amniocentesis was done at 34.5 weeks and 36 weeks gestational age to measure insulin levels, to confirm a diagnosis of PHHI. Amniotic insulin levels (enzyme-linked immunosorbent assay, Axsym, Abbott Laboratories, Abbott Park, Ill) were 14 mU/L and 15 mU/L, respectively, indicating fetal hyperinsulinism (normal values: for weeks 33 to 34 = 1.9-12.8 mU/L; weeks 35 to 36 = 1.8-13.5 mU/L).14 Lung maturity was confirmed at 36 weeks and an elective cesarean delivery was performed at 36 weeks + 4 days. The newborn male weighed 5690 g, and the Apgar score was 9 at both 1 and 5 minutes. Immediately after birth, the infant had repeated, profound hypoglycemic episodes despite intensive medical treatment. The treatments included intravenous and enteral high-glucose intake (14 mg/kg/minute), diazoxide 10 mg/kg/day and octreotide 40 µg/kg/day (Sandostatin, Sandoz, Basel, Switzerland). The plasma insulin level was 45 mU/L (<10 mU/L is normal with hypoglycemia),1 with a concomitant glucose level of 1.2 mmol/L, establishing a diagnosis of PHHI. No ketones were detected in urine samples, and metabolic workup was normal. Physical examination revealed generalized hypotonia without muscle dystrophy, a systolic murmur, weak femoral pulses, enlarged liver and hypospadias. Echocardiography demonstrated hypertrophic cardiomyopathy and coarctation of the aorta distal to the left brachial artery origin. Cardiac failure developed on the second day of life and was treated with furosemide and β-blockers. A CT of the
Figure. Serial axial CT views of the brain at the level of the 3rd and lateral ventricles in two siblings with persistent hyperinsulinemic hypoglycemia of infancy. A, First child at age 2 weeks: marked atrophic appearance of the brain parenchyma, which is particularly emphasized in the frontal lobes (arrows); B, First child at age 12 weeks: the atrophy is more advanced compared with the first image; C, Second child at age 1 day: atrophic appearance of the brain parenchyma (arrows); D, Second child at age 7 months: noticeable improvement in the appearance of the brain atrophy.
brain at 2 weeks showed marked brain atrophy (Figure, A). At 3 weeks, mechanical ventilation was initiated because of respiratory failure. Because the hypoglycemic episodes had not abated, the infant underwent a near total pancreatectomy at 5 weeks. Histology was consistent with diffuse islet-cell hyperplasia.15 Hypoglycemic episodes persisted, and at 11 weeks he underwent a
subtotal pancreatectomy, after which he remained euglycemic without any medication. A second CT scan revealed extreme atrophy of the brain (Figure, B). The infant could not be weaned off the mechanical ventilation, and died from sepsis at 16 weeks. A year later the mother consulted us again for a pregnancy in the 15th gestational week. US examinations at 15 and 707
NACHUM ET AL
THE JOURNAL OF PEDIATRICS NOVEMBER 2002
Table. Cord blood and amniotic fluid values measured in a fetus with intrauterine manifestations of persistent hyperinsulinemic hypoglycemia of infancy
Gestational week Origin 34 35 37
CB AF CB AF CB AF
Glucose (mmol/L) (normal) 2.8 (2.4-5.2) 0.9 (0.6-2.7) 4.4 (2.3-5.1) 1.0 (0.3-2.7) 4.1 (2.2-5.0) 0.6 (0.4-2.4)
Insulin (µU/mL) (normal)
C-peptide Maternal (pmol/mL) glucose (normal) (mmol/L)
137 (2.6-11.2) 8.33 (0.5-2.2) 4.3 15.4 (1.9-12.8) 137 (2.8-11.6) 7.6 (0.5-2.2) 5.0 16.3 (1.8-13.5) 6.63 (1.74 ± 1.35) 200 (3.0-12.0) 7.3 15.4 (1.5-14.9)
AF, Amniotic fluid; CB, cord blood. Normal values from references 14, 17-19.
20 weeks did not disclose any malformations, and the fetal size was appropriate for gestational age. An oral glucose tolerance test was positive at 26 weeks.16 Glycemic control was achieved by dietary measures alone. Intrauterine growth accelerated (4.4-7.7 SDs above the mean) and was asymmetrical on repeated US examinations from 29 weeks onwards. Our concern that the early brain atrophy in the former child might have been caused by intrauterine hypoglycemia prompted us to obtain fetal blood samplings. After obtaining parental consent, umbilical venous and amniotic fluid samples were taken 3 times to measure glucose, insulin, and C-peptide levels (radioimmunoassay, Diagnostic Products Corporation, Los Angeles, Calif), and to evaluate fetal lung maturity (Table). Fetal plasma glucose levels were normal despite extremely high insulin levels, diagnostic of PHHI. Because fetal blood glucose levels were normal, the pregnancy was allowed to continue until the indicators showed lung maturity. A cesarean delivery was performed at 37 weeks and a female infant weighing 6140 g was delivered in good condition. Umbilical plasma glucose was 2.4 mmol/L and pH was 7.33. Intensive medical treatment was initiated, including glucose intake of 17 mg/kg/minute and intravenous glucagon, later combined with diazox708
ide and subcutaneous Sandostatin (Sandoz). This treatment kept the plasma glucose above 2.5 mmol/L. On the first day of life, US examination of the head revealed brain atrophy. A CT scan one week later was consistent with atrophy (Figure, C). Because of continuing, though infrequent, hypoglycemic episodes, the baby underwent a near total pancreatectomy at two weeks, after which euglycemia was maintained with Sandostatin 20 µg 4 times daily. A CT scan at 7 weeks demonstrated improvement of the brain findings. A trial of treatment with nifedipine instead of Sandostatin failed to maintain blood glucose at the desired levels. The infant was discharged from the hospital at 3 months receiving Sandostatin therapy. At 7 months, a brain CT scan showed continued improvement, although atrophy was still apparent (Figure, D). The neurodevelopmental state of the child at 5 years was normal. Genomic DNA analysis did not reveal any of the 27 known mutations in the sulfonylurea receptor region SUR1. To test whether the defect in the sulphonylurea receptor element of the potassium pump also affected synaptic activity and nerve conductivity, at one year of age the child underwent a brain stem auditory evoked response test, somatosensory peripheral nerve conductivity test, and electromyogram. The results of all 3 tests were normal.
DISCUSSION We describe two siblings affected by PHHI; the first was diagnosed in utero without a family history. In the only two reported cases where prenatal diagnosis was accomplished, the propositus was a previously affected child diagnosed after birth.11,12 Based on previous publications,14 it is notable that whereas amniotic fluid insulin levels in our case and the other cases, were elevated to various extents, up to 4 times normal values, cord blood levels reached 15 times normal values, suggesting that the diagnosis and the possible treatment of intrauterine onset of PHHI should rely on fetal cord blood, rather than amniotic fluid levels of insulin. Cord blood can also be used for genetic analysis. The two consecutive pregnancies complicated by the same condition allowed us to address two questions. First, is there intrauterine hypoglycemia in severe, early onset PHHI? Second, is there a cause and effect relationship between hypoglycemia and what appears by CT to be brain atrophy in this disease? Our initial impression that brain atrophy may be a consequence of intrauterine glucose deprivation resulted from its very early appearance in the first child. In support of this, we found an earlier publication that reported low amniotic fluid glucose, which was assumed to reflect fetal blood levels.12 Previous reports described two stages in brain appearance after hypoglycemic damage to the brain. Edematous brain would have been expected at 2 weeks of age if the initial insult appeared immediately after birth, whereas we found an atrophic brain at this age. Moreover, the parts of the brain found to be affected after hypoglycemia were mainly the parietal and occipital lobes,8 whereas in the two children we treated, the frontal lobes were the most severely affected. The apparent deviation from a typical appearance of the brain in the first
NACHUM ET AL
THE JOURNAL OF PEDIATRICS
VOLUME 141, NUMBER 5 child, if hypoglycemia occurred for the first time after birth, prompted us to address glucose blood levels during fetal life. Our findings, which are novel in this respect, do not support the existence of intrauterine hypoglycemia in PHHI cases, which are already hyperinsulinemic during fetal life. This in turn suggests that the early appearance of brain atrophy may not be caused by intrauterine glucose deprivation. There may be an intrinsic neurologic defect in PHHI, which underlies early brain atrophy. Indeed, the possibility of such an intrinsic defect was proposed by Philipson and Steiner, based on the role of the SUR in the maintenance of transmembrane potentials in several cell types, including neurons.20 A caveat here is the possibility that this family, in whom the mutation was not similar to the 27 known variations, has a disorder different from previous cases. Of note, hypoglycemia-induced brain damage is predominantly of the upper motor neuron type (spastic),9,10 whereas our patients were hypotonic. The finding of normal nerve conductivity and electromyogram was not consistent with hypotonia being caused by peripheral nervous or muscular dysfunction. Timely and adequate intensive management of neonatal hypoglycemia may prevent the progression of brain atrophy, which appears to improve with time. The mechanism underlying the improvement remains unclear, but a prolonged state of euglycemia may enable spontaneous neural development. We thank Benjamin Glaser, MD, from the Department of Endocrinology and Metabolism, Hadassah University Hospital, and Ein Karem, Jerusalem, Israel, for expert genomic analysis.
REFERENCES 1. Aynsley-Green A, Polak JM, Bloom SR, Gough MH, Keeling J, Ashcroft SJ, et al. Nesidioblastosis of the pancreas: definition of the syndrome and the management of the severe neonatal hyperinsulinemic hypoglycemia. Arch Dis Child 1981;56:496-508. 2. Glaser B, Phillip M, Carmi R, Lieberman E, Landau H. Persistent hyperinsulinemic hypoglycemia of infancy (“nesidioblastosis”): autosomal recessive inheritance in 7 pedigrees. Am J Med Genet 1990;37:511-5. 3. Thorenton PS, Satin-Smith MS, Herold K, Glaser B, Chiu KC, Nestorowicz A, et al. Familial hyperinsulinism with apparent autosomal inheritance: clinical and genetic differences from autosomal recesive variant. J Pediatr 1998;132:9-14. 4. Thomas PM, Cote GJ, Hallman DM, Mathew PM. Homozygosity mapping, to chromosome 11p, of the gene for familial persistent hyperinsulinemic hypoglycemia of infancy. Am J Hum Genet 1995;56:416-21. 5. Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, et al. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 1995;268:426-9. 6. Thomas PM, Wohllk N, Huang E, Kuhnle U, Rabl W, Gagel RF, et al. Inactivation of the first nucleotide-binding fold of the sulfanylurea receptor, and familial persistent hyperinsulinemic hypoglycemia of infancy. Am J Hum Genet 1996;59:510-8. 7. Dunne MJ, Kane C, Shepherd RM, Sanchez JA, James RF, Johnson PR, et al. Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor. N Engl J Med 1997;336:703-6. 8. Destructive brain disorders of childhood. In: Barkovich AJ, editor. Pediatric neuroimaging. 2nd ed. Philadelphia (PA): Lippincott-Raven; 1996. p. 171-3. 9. Anderson JM, Milner RDG, Strich SJ. Effect of neonatal hypoglycemia on the nervous system: a pathological
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