Topiol et al. International Journal of Pediatric Endocrinology 2012, 2012:21 http://www.ijpeonline.com/content/2012/1/21 CASE REPORT Open Access Neonatal diabetes mellitus and congenital diaphragmatic hernia: coincidence or concurrent etiology? Emmanuelle S Topiol1, Laurie A Minarich1, Charles A Williams2, Roberto T Zori2, David W Kays3 and Michael J Haller1* Abstract Neonatal diabetes mellitus (NDM) is a rare metabolic disorder, affecting approximately 1 in 500,000 live births. The management of NDM is challenging, as the benefits of controlling hyperglycemia must be balanced with the risks of iatrogenic hypoglycemia. NDM occurs in both permanent and transient forms, which have been genetically and phenotypically well characterized. Herein, we present the previously unreported combination of transient NDM (TNDM) and congenital diaphragmatic hernia (CDH). In addition to reviewing the management and genetics of NDM we discuss the potential for overlapping genetic or embryologic abnormalities to explain the concurrence of CDH and NDM. Keywords: Neonatal diabetes mellitus, Congenital diaphragmatic hernia, PLAGL1, Imprinting, Duplication Background Congenital diaphragmatic hernia (CDH) occurs in ap- Neonatal diabetes mellitus (NDM) is a rare disorder of proximately 1 in 2,500 children and results from a devel- glucose metabolism (affecting 1 in 500,000 live births) opmental defect in the diaphragm that allows abdominal and may be either transient or permanent [1]. Affected viscera to penetrate the chest [4]. Because the herniating neonates frequently present with hyperglycemia, intra- spleen, liver, and intestines may compress lung tissue uterine growth retardation, and variable degrees of dehy- during critical periods of lung organogenesis, CHD dration. Despite the relative severity of insulin results in varying degrees of irreversible pulmonary deficiency, ketoacidosis is uncommon. Treatment with hypoplasia. Approximately 50% of CDH cases are asso- exogenous insulin is required to promote normal growth ciated with chromosomal abnormalities or congenital and avoid acute and sub-acute complications associated malformations including gut malrotation, umbilical her- with severe hyperglycemia. nia, hydronephrosis, cardiac defects, and type 1 diabetes Transient NDM (TNDM) is associated with over- [2,4,5]. However, the combination of CDH and TNDM expression of paternal genes on chromosome 6 that re- has not previously been reported. duce the capacity of the β cell to release insulin. TNDM Given the unlikely coincidence of CDH and TNDM is characterized by resolution of hyperglycemia by we explore the potential for a common genetic or em- 18 months of age though 40-50% of patients with bryologic etiology of these two diagnoses. TNDM experience a recurrence of diabetes in adoles- cence or early adulthood [1,2]. Permanent NDM Case presentation (PNDM) is associated with mutations of the β cell ATP- β ’ A 2.4 kg female infant was born at 38 weeks gestation to sensitive potassium channel which disable the cell s a 28-year-old primigravida via elective cesarean section. ability to depolarize and release insulin [3]. Birth weight was 2401 grams (2nd percentile), length was 48 cm (29th percentile), and head circumference * Correspondence: [email protected] was 34 cm (32nd percentile). The baby was diagnosed 1University of Florida, Department of Pediatrics, Division of Endocrinology, PO Box 100296, Gainesville, FL 32610, USA with a left sided CDH at 14 weeks gestation by routine Full list of author information is available at the end of the article prenatal ultrasound. Due to the prenatally diagnosed © 2012 Topiol et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Topiol et al. International Journal of Pediatric Endocrinology 2012, 2012:21 Page 2 of 4 http://www.ijpeonline.com/content/2012/1/21 CDH, the baby was intubated at birth, made nothing per In preparation for discharge home, our patient was os, and placed on intravenous hyperalimentation provid- transitioned to continuous subcutaneous insulin infusion ing a glucose infusion rate (GIR) of 8 mg/kg/min. Al- (SCII) therapy with rapid-acting analog diluted 10-fold. though her blood glucose concentration was normal at A single basal rate of 0.5 units/hr of U-10 insulin was birth (103 mg/dl), she developed marked hyperglycemia programmed in the pump (total daily dose 1.2 units). (493 mg/dl) at 9 hours of life. Blood glucose was monitored every 3 hours (typically Family history was notable for neonatal diabetes in the before breastfeeding) and a correction bolus of insulin paternal grandmother that resolved within 2 months. was given for blood glucose values greater than 350 mg/dL. She developed adult-onset diabetes in the 4th decade of Use of a continuous glucose monitoring system was consid- life despite a lean body habitus. ered, but our patient had so little subcutaneous fat that sen- Pertinent physical findings in our patient included shal- sor placement was deemed impossible. Upon discharge, her low supraorbital ridges, relatively prominent eyes, a mildly insulin requirement quickly waned, and the insulin was dis- protruding tongue with micrognathia, mild pectus excava- continued at 7 weeks of age. tum, and bilateral accessory nipples. She had a normal At her three-month visit, she was thriving, with a cranial shape, no central forehead nevus flammeus, nor- weight of 4004 grams, and a hemoglobin A1c of 4.7%. mal ears without pits, and no evidence of limb asymmetry. Comparative genomic hybridization microarray analysis She had normally developed female genitalia and an using a 180 K oligonucleotide array platform revealed a otherwise normal skin exam (See Additional file 1). 389 K micro-duplication in region 6q24.2, which Initial laboratory evaluation revealed negative urine includes the paternally expressed PLAGL1 (pleomorphic ketones, undetectable serum insulin concentration (< 0.5 adenoma of the salivary gland gene like 1) and HYMAI mcIU/ml), and a low serum C-peptide concentration (hydatidiform mole associated and imprinted [non- (0.2 ng/mL). Arterial blood gas and electrolyte mea- protein coding]) genes known to be associated with surements demonstrated a non-anion gap metabolic TNDM. An additional gene, PHACTR2 (phosphatase acidosis with an elevated serum lactate (2.47 mmol/L). and actin regulator 2), also maps within the same de- A thoracoabdominal ultrasound performed on day of letion boundary, though presumably it is not related life 2 revealed a pancreas without definite abnormality, to the problems in our patient. The same duplication but bowel gas prevented optimal delineation of the was found in her father, who did not have neonatal organ. diabetes and who does not have considerable hyper- Initial management included decreasing the GIR, but a glycemia, as evidenced by a normal HbA1c (personal concomitant decrease in blood glucose was not observed. communication, MJ Haller). Over the next 6 hours, she was treated with 3 subcutane- The same micro-duplication in region 6q24.2 was dis- ous injections of 0.5 units rapid-acting insulin analog, covered in our patient’s paternal uncle and his unborn which failed to normalize her blood glucose concentra- child. Amniocentesis demonstrated the presence of the tion. A continuous intravenous infusion of regular insulin mutation in our patient’s first cousin. At birth, the baby was started with an initial rate 0.04 units/kg/hour. Six boy followed a very similar course to our patient. He hours after initiating the insulin infusion, her blood glu- was small at birth, weighing 1710 grams at 34 weeks ges- cose concentration fell below 200 mg/dl and insulin was tation (5th percentile). Hyperglycemia developed in the briefly discontinued. Her blood glucose concentration first 24 hours of life, and insulin therapy was required gradually increased to 230 mg/dl over the next 6 hours, for 6 weeks before resolution occurred. and a simultaneous serum insulin level was <0.5 mcIU/ml. Therapy with continuous intravenous insulin was resumed Discussion at 0.03 units/kg/hour. The rate of the infusion was then The management of infants with NDM remains challen- titrated to achieve blood glucose concentrations between ging, given the need to balance the benefits of normal 200–300 mg/dl. The maximum rate of insulin administra- glycemia with the risks of recurrent hypoglycemia in tion was 0.12 units/kg/hour. infants. In our experience, continuous subcutaneous in- On day of life 4, blood glucose concentrations were sulin infusion (CSII) therapy provides optimal equipoise stable on 0.02-0.05 units of insulin per kg per hour and in managing children with NDM. While there are lim- our patient underwent surgical repair of her CDH. At ited outcomes data to drive evidence based treatment repair she had a moderately severe hernia with small recommendations for NDM, several case series have bowel, colon, stomach, and spleen in the left chest. Her been published. Tubina-Rufi et al. reported on their CDH was associated with a 50% loss of normal dia- experiences in managing NDM over 18 years, and found phragm and was repaired with a patch. Her left lung was CSII therapy to be most effective in safely managing dia- approximately 30% of normal size. She transitioned to betes in newborns requiring insulin for more