Neonatal diabetes mellitus and congenital diaphragmatic hernia: coincidence or concurrent etiology?

MISSING IMAGE

Material Information

Title:
Neonatal diabetes mellitus and congenital diaphragmatic hernia: coincidence or concurrent etiology?
Series Title:
International Journal of Pediatric Endocrinology
Physical Description:
Book
Language:
English
Creator:
Topiol, Emmanuelle S.
Minarich, Laurie A.
Williams, Charles A.
Zori, Roberto T.
Kays, David W.
Haller, Michael J.
Publisher:
BioMed Central
Publication Date:

Subjects

Subjects / Keywords:
Neonatal diabetes mellitus
Congenital diaphragmatic hernia
PLAGL1
Imprinting
Duplication

Notes

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.

Record Information

Source Institution:
University of Florida
Holding Location:
University of Florida
Rights Management:
All rights reserved by the source institution.
Resource Identifier:
doi - 10.1186/1687-9856-2012-21
System ID:
AA00012403:00001


This item is only available as the following downloads:


Full Text
xml version 1.0 encoding utf-8 standalone no
mets ID sort-mets_mets OBJID sword-mets LABEL DSpace SWORD Item PROFILE METS SIP Profile xmlns http:www.loc.govMETS
xmlns:xlink http:www.w3.org1999xlink xmlns:xsi http:www.w3.org2001XMLSchema-instance
xsi:schemaLocation http:www.loc.govstandardsmetsmets.xsd
metsHdr CREATEDATE 2012-07-30T04:06:39
agent ROLE CUSTODIAN TYPE ORGANIZATION
name BioMed Central
dmdSec sword-mets-dmd-1 GROUPID sword-mets-dmd-1_group-1
mdWrap SWAP Metadata MDTYPE OTHER OTHERMDTYPE EPDCX MIMETYPE textxml
xmlData
epdcx:descriptionSet xmlns:epdcx http:purl.orgeprintepdcx2006-11-16 xmlns:MIOJAVI
http:purl.orgeprintepdcxxsd2006-11-16epdcx.xsd
epdcx:description epdcx:resourceId sword-mets-epdcx-1
epdcx:statement epdcx:propertyURI http:purl.orgdcelements1.1type epdcx:valueURI http:purl.orgeprintentityTypeScholarlyWork
http:purl.orgdcelements1.1title
epdcx:valueString Neonatal diabetes mellitus and congenital diaphragmatic hernia: coincidence or concurrent etiology?
http:purl.orgdctermsabstract
AbstractNeonatal 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.
http:purl.orgdcelements1.1creator
Topiol, Emmanuelle S
Minarich, Laurie A
Williams, Charles A
Zori, Roberto T
Kays, David W
Haller, Michael J
http:purl.orgeprinttermsisExpressedAs epdcx:valueRef sword-mets-expr-1
http:purl.orgeprintentityTypeExpression
http:purl.orgdcelements1.1language epdcx:vesURI http:purl.orgdctermsRFC3066
en
http:purl.orgeprinttermsType
http:purl.orgeprinttypeJournalArticle
http:purl.orgdctermsavailable
epdcx:sesURI http:purl.orgdctermsW3CDTF 2012-07-10
http:purl.orgdcelements1.1publisher
BioMed Central Ltd
http:purl.orgeprinttermsstatus http:purl.orgeprinttermsStatus
http:purl.orgeprintstatusPeerReviewed
http:purl.orgeprinttermscopyrightHolder
Emmanuelle S Topiol et al.; licensee BioMed Central Ltd.
http:purl.orgdctermslicense
http://creativecommons.org/licenses/by/2.0
http:purl.orgdctermsaccessRights http:purl.orgeprinttermsAccessRights
http:purl.orgeprintaccessRightsOpenAccess
http:purl.orgeprinttermsbibliographicCitation
International Journal of Pediatric Endocrinology. 2012 Jul 10;2012(1):21
http:purl.orgdcelements1.1identifier
http:purl.orgdctermsURI http://dx.doi.org/10.1186/1687-9856-2012-21
fileSec
fileGrp sword-mets-fgrp-1 USE CONTENT
file sword-mets-fgid-0 sword-mets-file-1
FLocat LOCTYPE URL xlink:href 1687-9856-2012-21.xml
sword-mets-fgid-1 sword-mets-file-2 applicationpdf
1687-9856-2012-21.pdf
sword-mets-fgid-3 sword-mets-file-3 imagejpeg
1687-9856-2012-21-S1.JPEG
structMap sword-mets-struct-1 structure LOGICAL
div sword-mets-div-1 DMDID Object
sword-mets-div-2 File
fptr FILEID
sword-mets-div-3
sword-mets-div-4


!DOCTYPE art SYSTEM 'http:www.biomedcentral.comxmlarticle.dtd'
ui 1687-9856-2012-21ji 1687-9856fm dochead Case reportbibl title p Neonatal diabetes mellitus and congenital diaphragmatic hernia: coincidence or concurrent etiology?aug au id A1 snm Topiolmi Sfnm Emmanuelleinsr iid I1 email etopiol@ufl.eduA2 MinarichALaurielminarich@ufl.eduA3 WilliamsACharlesI2 willicx@peds.ufl.eduA4 ZoriTRobertozorirt@peds.ufl.eduA5 KaysWDavidI3 david.kays@surgery.ufl.eduA6 ca yes HallerJMichaelhallemj@peds.ufl.eduinsg ins University of Florida, Department of Pediatrics, Division of Endocrinology, PO Box 100296, Gainesville, FL, 32610, USAUniversity of Florida, Department of Pediatrics, Division of Genetics, PO Box 100296, Gainesville, FL, 32610, USAUniversity of Florida, Department of Surgery, Division of Pediatric Surgery, PO Box 100119, Gainesville, FL, 32610, USAsource International Journal of Pediatric Endocrinologyissn 1687-9856pubdate 2012volume 2012issue 1fpage 21url http://www.ijpeonline.com/content/2012/1/21xrefbib pubidlist pubid idtype doi 10.1186/1687-9856-2012-21pmpid 22781086history rec date day 9month 5year 2012acc 1072012pub 1072012cpyrt 2012collab Topiol et al.; licensee BioMed Central Ltd.note 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.kwdg kwd Neonatal diabetes mellitusCongenital diaphragmatic herniaPLAGL1ImprintingDuplicationabs sec st AbstractNeonatal 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.bdy BackgroundNeonatal diabetes mellitus (NDM) is a rare disorder of glucose metabolism (affecting 1 in 500,000 live births) and may be either transient or permanent abbrgrp abbr bid B1 1. Affected neonates frequently present with hyperglycemia, intrauterine growth retardation, and variable degrees of dehydration. Despite the relative severity of insulin deficiency, ketoacidosis is uncommon. Treatment with exogenous insulin is required to promote normal growth and avoid acute and sub-acute complications associated with severe hyperglycemia.Transient NDM (TNDM) is associated with over-expression of paternal genes on chromosome 6 that reduce the capacity of the β cell to release insulin. TNDM is characterized by resolution of hyperglycemia by 18 months of age though 40-50% of patients with TNDM experience a recurrence of diabetes in adolescence or early adulthood 1B2 2. Permanent NDM (PNDM) is associated with mutations of the β cell ATP-sensitive potassium channel which disable the β cell’s ability to depolarize and release insulin B3 3.Congenital diaphragmatic hernia (CDH) occurs in approximately 1 in 2,500 children and results from a developmental defect in the diaphragm that allows abdominal viscera to penetrate the chest B4 4. Because the herniating spleen, liver, and intestines may compress lung tissue during critical periods of lung organogenesis, CHD results in varying degrees of irreversible pulmonary hypoplasia. Approximately 50% of CDH cases are associated with chromosomal abnormalities or congenital malformations including gut malrotation, umbilical hernia, hydronephrosis, cardiac defects, and type 1 diabetes 24B5 5. However, the combination of CDH and TNDM has it not previously been reported.Given the unlikely coincidence of CDH and TNDM we explore the potential for a common genetic or embryologic etiology of these two diagnoses.Case presentationA 2.4 kg female infant was born at 38 weeks gestation to a 28-year-old primigravida via elective cesarean section. Birth weight was 2401 grams (2nd percentile), length was 48 cm (29th percentile), and head circumference was 34 cm (32nd percentile). The baby was diagnosed with a left sided CDH at 14 weeks gestation by routine prenatal ultrasound. Due to the prenatally diagnosed CDH, the baby was intubated at birth, made nothing per os, and placed on intravenous hyperalimentation providing a glucose infusion rate (GIR) of 8 mg/kg/min. Although her blood glucose concentration was normal at birth (103 mg/dl), she developed marked hyperglycemia (493 mg/dl) at 9 hours of life.Family history was notable for neonatal diabetes in the paternal grandmother that resolved within 2 months. She developed adult-onset diabetes in the 4sup th decade of life despite a lean body habitus.Pertinent physical findings in our patient included shallow supraorbital ridges, relatively prominent eyes, a mildly protruding tongue with micrognathia, mild pectus excavatum, and bilateral accessory nipples. She had a normal cranial shape, no central forehead nevus flammeus, normal ears without pits, and no evidence of limb asymmetry. She had normally developed female genitalia and an otherwise normal skin exam (See Additional file supplr sid S1 1).suppl Additional file 1text Pertinent physical findings in our patient included shallow supraorbital ridges, relatively prominent eyes, a mildly protruding tongue with micrognathia, mild pectus excavatum, and bilateral accessory nipples. She had a normal cranial shape, no central forehead nevus flammeus, normal ears without pits, and no evidence of limb asymmetry.file name 1687-9856-2012-21-S1.jpeg
Click here for file
Initial laboratory evaluation revealed negative urine ketones, undetectable serum insulin concentration (< 0.5 mcIU/ml), and a low serum C-peptide concentration (0.2 ng/mL). Arterial blood gas and electrolyte measurements demonstrated a non-anion gap metabolic acidosis with an elevated serum lactate (2.47 mmol/L). A thoracoabdominal ultrasound performed on day of life 2 revealed a pancreas without definite abnormality, but bowel gas prevented optimal delineation of the organ.Initial management included decreasing the GIR, but a concomitant decrease in blood glucose was not observed. Over the next 6 hours, she was treated with 3 subcutaneous injections of 0.5 units rapid-acting insulin analog, which failed to normalize her blood glucose concentration. A continuous intravenous infusion of regular insulin was started with an initial rate 0.04 units/kg/hour. Six hours after initiating the insulin infusion, her blood glucose concentration fell below 200 mg/dl and insulin was briefly discontinued. Her blood glucose concentration gradually increased to 230 mg/dl over the next 6 hours, and a simultaneous serum insulin level was <0.5 mcIU/ml. Therapy with continuous intravenous insulin was resumed at 0.03 units/kg/hour. The rate of the infusion was then titrated to achieve blood glucose concentrations between 200–300 mg/dl. The maximum rate of insulin administration was 0.12 units/kg/hour.On day of life 4, blood glucose concentrations were stable on 0.02-0.05 units of insulin per kg per hour and our patient underwent surgical repair of her CDH. At repair she had a moderately severe hernia with small bowel, colon, stomach, and spleen in the left chest. Her CDH was associated with a 50% loss of normal diaphragm and was repaired with a patch. Her left lung was approximately 30% of normal size. She transitioned to oral feeds approximately one week after the operation.In preparation for discharge home, our patient was transitioned to continuous subcutaneous insulin infusion (SCII) therapy with rapid-acting analog diluted 10-fold. A single basal rate of 0.5 units/hr of U-10 insulin was programmed in the pump (total daily dose 1.2 units). Blood glucose was monitored every 3 hours (typically before breastfeeding) and a correction bolus of insulin was given for blood glucose values greater than 350 mg/dL. Use of a continuous glucose monitoring system was considered, but our patient had so little subcutaneous fat that sensor placement was deemed impossible. Upon discharge, her insulin requirement quickly waned, and the insulin was discontinued at 7 weeks of age.At her three-month visit, she was thriving, with a weight of 4004 grams, and a hemoglobin A1c of 4.7%. Comparative genomic hybridization microarray analysis using a 180 K oligonucleotide array platform revealed a 389 K micro-duplication in region 6q24.2, which includes the paternally expressed PLAGL1 (pleomorphic adenoma of the salivary gland gene like 1) and HYMAI (hydatidiform mole associated and imprinted [non-protein coding]) genes known to be associated with TNDM. An additional gene, PHACTR2 (phosphatase and actin regulator 2), also maps within the same deletion boundary, though presumably it is not related to the problems in our patient. The same duplication was found in her father, who did not have neonatal diabetes and who does not have considerable hyperglycemia, as evidenced by a normal HbA1c (personal communication, MJ Haller).The same micro-duplication in region 6q24.2 was discovered in our patient’s paternal uncle and his unborn child. Amniocentesis demonstrated the presence of the mutation in our patient’s first cousin. At birth, the baby boy followed a very similar course to our patient. He was small at birth, weighing 1710 grams at 34 weeks gestation (5th percentile). Hyperglycemia developed in the first 24 hours of life, and insulin therapy was required for 6 weeks before resolution occurred.DiscussionThe management of infants with NDM remains challenging, given the need to balance the benefits of normal glycemia with the risks of recurrent hypoglycemia in infants. In our experience, continuous subcutaneous insulin infusion (CSII) therapy provides optimal equipoise in managing children with NDM. While there are limited outcomes data to drive evidence based treatment recommendations for NDM, several case series have been published. Tubina-Rufi et al. reported on their experiences in managing NDM over 18 years, and found CSII therapy to be most effective in safely managing diabetes in newborns requiring insulin for more than 15 days B6 6.TNDM is most commonly associated with over-expression of the paternally inherited PLAGL1 and HYMAI genes at the 6q24 locus. PLAGL1 is a zinc finger DNA binding protein with tumor suppressor activity, and overexpression of this gene has been shown to arrest β cell division and induce apoptosis. HYMAI shares a promoter region with PLAGL1, and methylation of this promoter on the maternal allele results in sole expression of the paternally inherited allele in most tissues; HYMAI is a non-coding RNA gene whose function is unknown. Over-expression of these genes can occur as a result of uniparental disomy of chromosome 6, duplication of 6q24 of the paternal allele, or hypomethylation of the maternal PLAGL1/HYMAI differentially methylated region B7 7B8 8.PNDM is most commonly caused by mutations in the KCNJ11 and ABCC8 genes, which encode the Kir6.2, and SUR1 subunits of the β cell ATP-sensitive potassium channel, respectively 3. This potassium channel is constitutively open, but closes in response to increased intracellular ATP levels that occur as a consequence of hyperglycemia. When the channel closes, β cell depolarization occurs, and insulin is released. A gain-of-function mutation in this channel prevents closure, so that the β cell remains hyperpolarized and unable to secrete insulin. Evaluation of the specific mutations resulting in PNDM is imperative, as patients with KCNJ11 mutations can be safely and effectively managed with oral sulfonylurea therapy B9 9. Failure to appropriately diagnose these patients may result in unnecessary lifelong therapy with subcutaneous insulin.Emerging knowledge of the mutations underlying PNDM and TNDM has improved our capacity to provide genetic counseling to affected families. While most mutations causing PLAGL1 overexpression are due to de novo events such as methylation defects or segmental uniparental disomy, microduplications can be inherited in an autosomal dominant, imprinting-type, manner 7B10 10B11 11. In families with this imprinting type of NDM, like our case, overexpression of PLAGL1 only occurs when the microduplication is passed through the male germ line, since passage through the maternal germ line will inactivate both copies of PLAGL1 via methylation of its promoter B12 12B13 13. Dominant imprinting inheritance was supported in our family by the observation that the patient’s father and his brother (the paternal uncle) both carried the duplication but were asymptomatic. However, in the grandparental generation, the paternal grandmother had neonatal DM, presumably indicating that she carried the duplication.Despite improved understanding of the genetic basis for NDM, diagnosis of NDM has historically been a post-partum event based on the unexpected development of persistent hyperglycemia in a neonate. Genetic testing is typically performed well after initiation of insulin, with results often reported after discharge from the nursery. The potential to diagnose these mutations prenatally, as occurred with our patient’s cousin, may greatly improve the management of TNDM by allowing families and physicians to be optimally prepared for the development of hyperglycemia. Only recently has uniparental disomy of paternal chromosome 6 been detected through amniocentesis B14 14.Finally, the combination of CDH and TNDM has not previously been reported. A review of diaphragmatic hernia genomic etiologies did not implicate the 6q24.2 locus B15 15. However, CDH has been reported in association with numerous extra-diaphragmatic abnormalities including gut malrotation, umbilical hernia, hydronephrosis, cardiac defects, and type 1 diabetes. CDH is also a common feature of Beckwith-Wiedemann syndrome (BWS), another imprinted genetic disorder that, like TND, may be associated with macroglossia and umbilical hernia B16 16. The known association of CDH and extra-diaphragmatic abnormalities suggests that a common genetic or embryologic etiology might underlie CDH and TNDM.ConclusionsThis case provided the opportunity to demonstrate the successful use of CSII in the management of TNDM complicated by a concurrent congenital anomaly. In addition, this case models the potential value of genetic counseling and prenatal diagnosis in families affected by NDM. Given the incidence of TNDM and CDH, the likelihood of a child presenting with both CDH and TNDM is approximately 1 in 1,250,000,000. While a review a review of diaphragmatic hernia genomic etiologies did not implicate the 6q24.2 locus, our case either represents the observation of an extremely rare coincidental event or indicates that there is a potential link between TNDM and CDH. Further examination of loci neighboring the 6q24 region, and their role in organogenesis, may provide insights toward explaining our patient’s development of two uncommon diagnoses.ConsentWritten informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.AbbreviationsBWS, Beckwith-Wiedemann syndrome; CDH, Congenital diaphragmatic hernia; CSII, Continuous subcutaneous insulin infusion; HYMAI, Hydatidiform mole associated and imprinted [non-protein coding]) genes; NDM, Neonatal diabetes mellitus; PHACTR2, Phosphatase and actin regulator 2; PLAGL1, Pleomorphic adenoma of the salivary gland gene like 1; PNDM, Permanent neonatal diabetes mellitus; TNDM, Transient neonatal diabetes mellitus.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsMJH, LM, CAW, and DAK managed the patient during hospitalization. EST, LM, and MJH drafted the manuscript. CAW and RTZ edited the manuscript and contributed to the discussion. All authors read and approved the final manuscript.bm refgrp Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetesTempleIKGardnerRJMackayDJBarberJCRobinsonDOShieldJPDiabetes2000491359lpage 136610.2337/diabetes.49.8.1359link fulltext 10923638Molecular genetics of congenital diaphragmatic defectsBielinskaMJayPYErlichJMMannistoSUrbanZHeikinheimoMWilsonDBAnn Med20073926127410.1080/07853890701326883pmcid 217462117558598An ATP-binding mutation (G334D) in KCNJ11 is associated with a sulfonylurea-insensitive form of developmental delay, epilepsy, and neonatal diabetesMasiaRKosterJCTuminiSChiarelliFColomboCNicholsCGBarbettiFDiabetes20075632833610.2337/db06-127517259376Congenital diaphragmatic herniaKotechaSBarbatoABushAClausFDavenportMDelacourtCDeprestJEberEFrencknerBGreenoughAetal Eur Respir J20123982082910.1183/09031936.0006651122034651Associated malformations in delayed presentation of congenital diaphragmatic herniaHosgorMKaracaIKarkinerAUcanBTemirGErdagGFescekogluOJ Pediatr Surg2004391073107610.1016/j.jpedsurg.2004.03.05015213902Insulin pump therapy in neonatal diabetesTubiana-RufiNEndocr Dev200712677417923770Diabetes Mellitus, 6q24-Related Transient NeonatalTempleIKMackayDJGGeneReviews™ [Internet]publisher University of Washington, Seattle, Seattle (WA)editor Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP19931993-2005 Oct 10 [updated 2010 Dec 23]21324824Aetiopathology and genetic basis of neonatal diabetesShieldJPGardnerRJWadsworthEJWhitefordMLJamesRSRobinsonDOBaumJDTempleIKArch Dis Child Fetal Neonatal Ed199776F394210.1136/fn.76.1.F3917206189059185Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findingsCajaibaMMWitchelSMadan-KhetarpalSHooverJHoffnerLMacphersonTSurtiUAm J Med Genet A201115581996200210.1002/ajmg.a.34106Partial paternal uniparental disomy of chromosome 6 in an infant with neonatal diabetes, macroglossia, and craniofacial abnormalitiesDasSLeseCMSongMJensenJLWellsLABarnoskiBLRoseberryJACamachoJMLedbetterDHSchnurREAm J Hum Genet2000671586159110.1086/316897128793611038325Transient neonatal diabetes mellitus in an infant with paternal uniparental disomy of chromosome 6 including heterodisomy for 6q24MilenkovicTMarticJRobinsonDOMackayDJPetrovicKZdravkovicDJ Pediatr Endocrinol Metab2006191353135717220064Partial paternal uniparental disomy of chromosome 6 in monozygotic twins with transient neonatal diabetes mellitus and macroglossiaSuzukiSFujisawaDHashimotoKAsanoTMaimaitiMMatsuoKTanahashiYMukaiTFujiedaKClin Genet20107858058410.1111/j.1399-0004.2010.01433.x20412110Genetic and epigenetic defects at the 6q24 imprinted locus in a cohort of 13 patients with transient neonatal diabetes: new hypothesis raised by the finding of a unique case with hemizygotic deletion in the critical regionDiatloff-ZitoCNicoleAMarcelinGLabitHMarquisEBellanne-ChantelotCRobertJJJ Med Genet2007443137259792016971482Management of diabetes mellitus in infantsKargesBMeissnerTIcksAKapellenTHollRWNat Rev Endocrinol2012820121110.1038/nrendo.2011.204Developmental and genetic aspects of congenital diaphragmatic herniaVeenmaDCde KleinATibboelDPediatr Pulmonol20124765344510.1002/ppul.2255322467525Imprinting in Human Disease with Special Reference to Transient Neonatal Diabetes and Beckwith-Wiedemann SyndromeTempleIDevelopment of the Pancreas and Neonatal Diabetes. Endocr DevKarger, BaselScharfmann R, Shield Jedition 122007113123



PAGE 1

CASEREPORTOpenAccessNeonataldiabetesmellitusandcongenital diaphragmatichernia:coincidenceorconcurrent etiology?EmmanuelleSTopiol1,LaurieAMinarich1,CharlesAWilliams2,RobertoTZori2,DavidWKays3and MichaelJHaller1*AbstractNeonataldiabetesmellitus(NDM)isararemetabolicdisorder,affectingapproximately1in500,000livebirths.The managementofNDMischallenging,asthebenefitsofcontrollinghyperglycemiamustbebalancedwiththerisks ofiatrogenichypoglycemia.NDMoccursinbothpermanentandtransientforms,whichhavebeengeneticallyand phenotypicallywellcharacterized.Herein,wepresentthepreviouslyunreportedcombinationoftransientNDM (TNDM)andcongenitaldiaphragmatichernia(CDH).Inadditiontoreviewingthemanagementandgeneticsof NDMwediscussthepotentialforoverlappinggeneticorembryologicabnormalitiestoexplaintheconcurrenceof CDHandNDM. Keywords: Neonataldiabetesmellitus,Congenitaldiaphragmatichernia,PLAGL1,Imprinting,DuplicationBackgroundNeonataldiabetesmellitus(NDM)isararedisorderof glucosemetabolism(affecting1in500,000livebirths) andmaybeeithertransientorpermanent[1].Affected neonatesfrequentlypresentwithhyperglycemia,intrauterinegrowthretardation,andvariabledegreesofdehydration.Despitetherelativeseverityofinsulin deficiency,ketoacidosisisuncommon.Treatmentwith exogenousinsulinisrequiredtopromotenormalgrowth andavoidacuteandsub-acutecomplicationsassociated withseverehyperglycemia. TransientNDM(TNDM)isassociatedwithoverexpressionofpaternalgenesonchromosome6thatreducethecapacityofthe celltoreleaseinsulin.TNDM ischaracterizedbyresolutionofhyperglycemiaby 18monthsofagethough40-50%ofpatientswith TNDMexperiencearecurrenceofdiabetesinadolescenceorearlyadulthood[1,2].PermanentNDM (PNDM)isassociatedwithmutationsofthe cellATPsensitivepotassiumchannelwhichdisablethe cell ’ s abilitytodepolarizeandreleaseinsulin[3]. Congenitaldiaphragmatichernia(CDH)occursinapproximately1in2,500childrenandresultsfromadevelopmentaldefectinthediaphragmthatallowsabdominal visceratopenetratethechest[4].Becausetheherniating spleen,liver,andintestinesmaycompresslungtissue duringcriticalperiodsoflungorganogenesis,CHD resultsinvaryingdegreesofirreversiblepulmonary hypoplasia.Approximately50%ofCDHcasesareassociatedwithchromosomalabnormalitiesorcongenital malformationsincludinggutmalrotation,umbilicalhernia,hydronephrosis,cardiacdefects,andtype1diabetes [2,4,5].However,thecombinationofCDHandTNDM has not previouslybeenreported. GiventheunlikelycoincidenceofCDHandTNDM weexplorethepotentialforacommongeneticorembryologicetiologyofthesetwodiagnoses.CasepresentationA2.4kgfemaleinfantwasbornat38weeksgestationto a28-year-oldprimigravidaviaelectivecesareansection. Birthweightwas2401grams(2ndpercentile),length was48cm(29thpercentile),andheadcircumference was34cm(32ndpercentile).Thebabywasdiagnosed withaleftsidedCDHat14weeksgestationbyroutine prenatalultrasound.Duetotheprenatallydiagnosed *Correspondence: hallemj@peds.ufl.edu1UniversityofFlorida,DepartmentofPediatrics,DivisionofEndocrinology, POBox100296,Gainesville,FL32610,USA Fulllistofauthorinformationisavailableattheendofthearticle 2012Topioletal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycited.Topiol etal.InternationalJournalofPediatricEndocrinology 2012, 2012 :21 http://www.ijpeonline.com/content/2012/1/21

PAGE 2

CDH,thebabywasintubatedatbirth,madenothingper os,andplacedonintravenoushyperalimentationprovidingaglucoseinfusionrate(GIR)of8mg/kg/min.Althoughherbloodglucoseconcentrationwasnormalat birth(103mg/dl),shedevelopedmarkedhyperglycemia (493mg/dl)at9hoursoflife. Familyhistorywasnotableforneonataldiabetesinthe paternalgrandmotherthatresolvedwithin2months. Shedevelopedadult-onsetdiabetesinthe4thdecadeof lifedespitealeanbodyhabitus. Pertinentphysicalfindingsinourpatientincludedshallowsupraorbitalridges,relativelyprominenteyes,amildly protrudingtonguewithmicrognathia,mildpectusexcavatum,andbilateralaccessorynipples.Shehadanormal cranialshape,nocentralforeheadnevusflammeus,normalearswithoutpits,andnoevidenceoflimbasymmetry. Shehadnormallydevelopedfemalegenitaliaandan otherwisenormalskinexam(SeeAdditionalfile1). Initiallaboratoryevaluationrevealednegativeurine ketones,undetectableseruminsulinconcentration( < 0.5 mcIU/ml),andalowserumC-peptideconcentration (0.2ng/mL).Arterialbloodgasandelectrolytemeasurementsdemonstratedanon-aniongapmetabolic acidosiswithanelevatedserumlactate(2.47mmol/L). Athoracoabdominalultrasoundperformedondayof life2revealedapancreaswithoutdefiniteabnormality, butbowelgaspreventedoptimaldelineationofthe organ. InitialmanagementincludeddecreasingtheGIR,buta concomitantdecreaseinbloodglucosewasnotobserved. Overthenext6hours,shewastreatedwith3subcutaneousinjectionsof0.5unitsrapid-actinginsulinanalog, whichfailedtonormalizeherbloodglucoseconcentration.Acontinuousintravenousinfusionofregularinsulin wasstartedwithaninitialrate0.04units/kg/hour.Six hoursafterinitiatingtheinsulininfusion,herbloodglucoseconcentrationfellbelow200mg/dlandinsulinwas brieflydiscontinued.Herbloodglucoseconcentration graduallyincreasedto230mg/dloverthenext6hours, andasimultaneousseruminsulinlevelwas < 0.5mcIU/ml. Therapywithcontinuousintravenousinsulinwasresumed at0.03units/kg/hour.Therateoftheinfusionwasthen titratedtoachievebloodglucoseconcentrationsbetween 200 – 300mg/dl.Themaximumrateofinsulinadministrationwas0.12units/kg/hour. Ondayoflife4,bloodglucoseconcentrationswere stableon0.02-0.05unitsofinsulinperkgperhourand ourpatientunderwentsurgicalrepairofherCDH.At repairshehadamoderatelysevereherniawithsmall bowel,colon,stomach,andspleenintheleftchest.Her CDHwasassociatedwitha50%lossofnormaldiaphragmandwasrepairedwithapatch.Herleftlungwas approximately30%ofnormalsize.Shetransitionedto oralfeedsapproximatelyoneweekaftertheoperation. Inpreparationfordischargehome,ourpatientwas transitionedtocontinuoussubcutaneousinsulininfusion (SCII)therapywithrapid-actinganalogdiluted10-fold. Asinglebasalrateof0.5units/hrofU-10insulinwas programmedinthepump(totaldailydose1.2units). Bloodglucosewasmonitoredevery3hours(typically beforebreastfeeding)andacorrectionbolusofinsulin wasgivenforbloodglucosevaluesgreaterthan350mg/dL. Useofacontinuousglucosemonitoringsystemwasconsidered,butourpatienthadsolittlesubcutaneousfatthatsensorplacementwasdeemedimpossible.Upondischarge,her insulinrequirementquicklywaned,andtheinsulinwasdiscontinuedat7weeksofage. Atherthree-monthvisit,shewasthriving,witha weightof4004grams,andahemoglobinA1cof4.7%. Comparativegenomichybridizationmicroarrayanalysis usinga180Koligonucleotidearrayplatformrevealeda 389Kmicro-duplicationinregion6q24.2,which includesthepaternallyexpressedPLAGL1(pleomorphic adenomaofthesalivaryglandgenelike1)andHYMAI (hydatidiformmoleassociatedandimprinted[nonproteincoding])genesknowntobeassociatedwith TNDM.Anadditionalgene,PHACTR2(phosphatase andactinregulator2),alsomapswithinthesamedeletionboundary,thoughpresumablyitisnotrelated totheproblemsinourpatient.Thesameduplication wasfoundinherfather,whodidnothaveneonatal diabetesandwhodoesnothaveconsiderablehyperglycemia,asevidencedbyanormalHbA1c(personal communication,MJHaller). Thesamemicro-duplicationinregion6q24.2wasdiscoveredinourpatient ’ spaternaluncleandhisunborn child.Amniocentesisdemonstratedthepresenceofthe mutationinourpatient ’ sfirstcousin.Atbirth,thebaby boyfollowedaverysimilarcoursetoourpatient.He wassmallatbirth,weighing1710gramsat34weeksgestation(5thpercentile).Hyperglycemiadevelopedinthe first24hoursoflife,andinsulintherapywasrequired for6weeksbeforeresolutionoccurred.DiscussionThemanagementofinfantswithNDMremainschallenging,giventheneedtobalancethebenefitsofnormal glycemiawiththerisksofrecurrenthypoglycemiain infants.Inourexperience,continuoussubcutaneousinsulininfusion(CSII)therapyprovidesoptimalequipoise inmanagingchildrenwithNDM.Whiletherearelimitedoutcomesdatatodriveevidencebasedtreatment recommendationsforNDM,severalcaseserieshave beenpublished.Tubina-Rufietal.reportedontheir experiencesinmanagingNDMover18years,andfound CSIItherapytobemosteffectiveinsafelymanagingdiabetesinnewbornsrequiringinsulinformorethan 15days[6].Topiol etal.InternationalJournalofPediatricEndocrinology 2012, 2012 :21Page2of4 http://www.ijpeonline.com/content/2012/1/21

PAGE 3

TNDMismostcommonlyassociatedwithoverexpressionofthepaternallyinheritedPLAGL1and HYMAIgenesatthe6q24locus.PLAGL1isazincfingerDNAbindingproteinwithtumorsuppressoractivity, andoverexpressionofthisgenehasbeenshowntoarrest celldivisionandinduceapoptosis.HYMAIshares apromoterregionwithPLAGL1,andmethylationof thispromoteronthematernalalleleresultsinsoleexpressionofthepaternallyinheritedalleleinmosttissues; HYMAIisanon-codingRNAgenewhosefunctionis unknown.Over-expressionofthesegenescanoccurasa resultofuniparentaldisomyofchromosome6,duplicationof6q24ofthepaternalallele,orhypomethylationof thematernalPLAGL1/HYMAIdifferentiallymethylated region[7,8]. PNDMismostcommonlycausedbymutationsinthe KCNJ11 and ABCC8 genes,whichencodetheKir6.2, andSUR1subunitsofthe cellATP-sensitivepotassium channel,respectively[3].Thispotassiumchannelisconstitutivelyopen,butclosesinresponsetoincreased intracellularATPlevelsthatoccurasaconsequenceof hyperglycemia.Whenthechannelcloses, cell depolarizationoccurs,andinsulinisreleased.Againof-functionmutationinthischannelpreventsclosure, sothatthe cellremainshyperpolarizedandunableto secreteinsulin.Evaluationofthespecificmutations resultinginPNDMisimperative,aspatientswith KCNJ11mutationscanbesafelyandeffectivelymanagedwithoralsulfonylureatherapy[9].Failuretoappropriatelydiagnosethesepatientsmayresultin unnecessarylifelongtherapywithsubcutaneousinsulin. Emergingknowledgeofthemutationsunderlying PNDMandTNDMhasimprovedourcapacitytoprovidegeneticcounselingtoaffectedfamilies.Whilemost mutationscausingPLAGL1overexpressionaredueto denovoeventssuchasmethylationdefectsorsegmental uniparentaldisomy,microduplicationscanbeinherited inanautosomaldominant,imprinting-type,manner [7,10,11].InfamilieswiththisimprintingtypeofNDM, likeourcase,overexpressionofPLAGL1onlyoccurs whenthemicroduplicationispassedthroughthemale germline,sincepassagethroughthematernalgermline willinactivatebothcopiesofPLAGL1viamethylationof itspromoter[12,13].Dominantimprintinginheritance wassupportedinourfamilybytheobservationthatthe patient ’ sfatherandhisbrother(thepaternaluncle)both carriedtheduplicationbutwereasymptomatic.However,inthegrandparentalgeneration,thepaternal grandmotherhadneonatalDM,presumablyindicating thatshecarriedtheduplication. Despiteimprovedunderstandingofthegeneticbasis forNDM,diagnosisofNDMhashistoricallybeena post-partumeventbasedontheunexpecteddevelopmentofpersistenthyperglycemiainaneonate.Genetic testingistypicallyperformedwellafterinitiationofinsulin,withresultsoftenreportedafterdischargefromthe nursery.Thepotentialtodiagnosethesemutationsprenatally,asoccurredwithourpatient ’ scousin,may greatlyimprovethemanagementofTNDMbyallowing familiesandphysicianstobeoptimallypreparedforthe developmentofhyperglycemia.Onlyrecentlyhasuniparentaldisomyofpaternalchromosome6been detectedthroughamniocentesis[14]. Finally,thecombinationofCDHandTNDMhas not previouslybeenreported.Areviewofdiaphragmatic herniagenomicetiologiesdidnotimplicatethe6q24.2 locus[15].However,CDHhasbeenreportedinassociationwithnumerousextra-diaphragmaticabnormalities includinggutmalrotation,umbilicalhernia,hydronephrosis,cardiacdefects,andtype1diabetes.CDHisalso acommonfeatureofBeckwith-Wiedemannsyndrome (BWS),anotherimprintedgeneticdisorderthat,like TND,maybeassociatedwithmacroglossiaandumbilicalhernia[16].TheknownassociationofCDHand extra-diaphragmaticabnormalitiessuggeststhatacommongeneticorembryologicetiologymightunderlie CDHandTNDM.ConclusionsThiscaseprovidedtheopportunitytodemonstratethe successfuluseofCSIIinthemanagementofTNDM complicatedbyaconcurrentcongenitalanomaly.In addition,thiscasemodelsthepotentialvalueofgenetic counselingandprenataldiagnosisinfamiliesaffectedby NDM.GiventheincidenceofTNDMandCDH,the likelihoodofachildpresentingwithbothCDHand TNDMisapproximately1in1,250,000,000.Whileareviewareviewofdiaphragmaticherniagenomicetiologiesdidnotimplicatethe6q24.2locus,ourcaseeither representstheobservationofanextremelyrarecoincidentaleventorindicatesthatthereisapotentiallinkbetweenTNDMandCDH.Furtherexaminationofloci neighboringthe6q24region,andtheirroleinorganogenesis,mayprovideinsightstowardexplainingour patient ’ sdevelopmentoftwouncommondiagnoses.ConsentWritteninformedconsentwasobtainedfromthepatient forpublicationofthisCasereportandanyaccompanyingimages.Acopyofthewrittenconsentisavailablefor reviewbytheEditor-in-Chiefofthisjournal.AdditionalfileAdditionalfile1: Pertinentphysicalfindingsinourpatientincluded shallowsupraorbitalridges,relativelyprominenteyes,amildlyprotruding tonguewithmicrognathia,mildpectusexcavatum,andbilateralTopiol etal.InternationalJournalofPediatricEndocrinology 2012, 2012 :21Page3of4 http://www.ijpeonline.com/content/2012/1/21

PAGE 4

accessorynipples.Shehadanormalcranialshape,nocentralforehead nevusflammeus,normalearswithoutpits,andnoevidenceoflimb asymmetry. Abbreviations BWS:Beckwith-Wiedemannsyndrome;CDH:Congenitaldiaphragmatic hernia;CSII:Continuoussubcutaneousinsulininfusion;HYMAI:Hydatidiform moleassociatedandimprinted[non-proteincoding])genes;NDM:Neonatal diabetesmellitus;PHACTR2:Phosphataseandactinregulator2; PLAGL1:Pleomorphicadenomaofthesalivaryglandgenelike1; PNDM:Permanentneonataldiabetesmellitus;TNDM:Transientneonatal diabetesmellitus. Competinginterests Theauthorsdeclarethattheyhavenocompetinginterests. Authordetails1UniversityofFlorida,DepartmentofPediatrics,DivisionofEndocrinology, POBox100296,Gainesville,FL32610,USA.2UniversityofFlorida,Department ofPediatrics,DivisionofGenetics,POBox100296,Gainesville,FL32610,USA.3UniversityofFlorida,DepartmentofSurgery,DivisionofPediatricSurgery, POBox100119,Gainesville,FL32610,USA. Authors ’ contributions MJH,LM,CAW,andDAKmanagedthepatientduringhospitalization.EST, LM,andMJHdraftedthemanuscript.CAWandRTZeditedthemanuscript andcontributedtothediscussion.Allauthorsreadandapprovedthefinal manuscript. Received:9May2012Accepted:10July2012 Published:10July2012 References1.TempleIK,GardnerRJ,MackayDJ,BarberJC,RobinsonDO,ShieldJP: Transientneonataldiabetes:wideningtheunderstandingofthe etiopathogenesisofdiabetes. Diabetes 2000, 49: 1359 – 1366. 2.BielinskaM,JayPY,ErlichJM,MannistoS,UrbanZ,HeikinheimoM,Wilson DB: Moleculargeneticsofcongenitaldiaphragmaticdefects. AnnMed 2007, 39: 261 – 274. 3.MasiaR,KosterJC,TuminiS,ChiarelliF,ColomboC,NicholsCG,BarbettiF: AnATP-bindingmutation(G334D)inKCNJ11isassociatedwitha sulfonylurea-insensitiveformofdevelopmentaldelay,epilepsy,and neonataldiabetes. Diabetes 2007, 56: 328 – 336. 4.KotechaS,BarbatoA,BushA,ClausF,DavenportM,DelacourtC,DeprestJ, EberE,FrencknerB,GreenoughA, etal : Congenitaldiaphragmatichernia. EurRespirJ 2012, 39: 820 – 829. 5.HosgorM,KaracaI,KarkinerA,UcanB,TemirG,ErdagG,FescekogluO: Associatedmalformationsindelayedpresentationofcongenital diaphragmatichernia. JPediatrSurg 2004, 39: 1073 – 1076. 6.Tubiana-RufiN: Insulinpumptherapyinneonataldiabetes. EndocrDev 2007, 12: 67 – 74. 7.TempleIK,MackayDJG: DiabetesMellitus,6q24-RelatedTransient Neonatal .In GeneReviews ™ [Internet] .EditedbyPagonRA,BirdTD,Dolan CR,StephensK,AdamMP.Seattle(WA):UniversityofWashington,Seattle; 1993.1993-2005Oct10[updated2010Dec23]. 8.ShieldJP,GardnerRJ,WadsworthEJ,WhitefordML,JamesRS,RobinsonDO, BaumJD,TempleIK: Aetiopathologyandgeneticbasisofneonatal diabetes. ArchDisChildFetalNeonatalEd 1997, 76: F39 – 42. 9.CajaibaMM,WitchelS,Madan-KhetarpalS,HooverJ,HoffnerL,Macpherson T,SurtiU: Prenataldiagnosisoftrisomy6rescueresultinginpaternal UPD6withnovelplacentalfindings. AmJMedGenetA 2011, 155 (8):1996 – 2002.doi:10.1002/ajmg.a.34106. 10.DasS,LeseCM,SongM,JensenJL,WellsLA,BarnoskiBL,RoseberryJA, CamachoJM,LedbetterDH,SchnurRE: Partialpaternaluniparental disomyofchromosome6inaninfantwithneonataldiabetes, macroglossia,andcraniofacialabnormalities. AmJHumGenet 2000, 67: 1586 – 1591. 11.MilenkovicT,MarticJ,RobinsonDO,MackayDJ,PetrovicK,ZdravkovicD: Transientneonataldiabetesmellitusinaninfantwithpaternal uniparentaldisomyofchromosome6includingheterodisomyfor6q24. JPediatrEndocrinolMetab 2006, 19: 1353– 1357. 12.SuzukiS,FujisawaD,HashimotoK,AsanoT,MaimaitiM,MatsuoK, TanahashiY,MukaiT,FujiedaK: Partialpaternaluniparentaldisomyof chromosome6inmonozygotictwinswithtransientneonataldiabetes mellitusandmacroglossia. ClinGenet 2010, 78: 580 – 584. 13.Diatloff-ZitoC,NicoleA,MarcelinG,LabitH,MarquisE,Bellanne-Chantelot C,RobertJJ: Geneticandepigeneticdefectsatthe6q24imprintedlocus inacohortof13patientswithtransientneonataldiabetes:new hypothesisraisedbythefindingofauniquecasewithhemizygotic deletioninthecriticalregion. JMedGenet 2007, 44: 31 – 37. 14.KargesB,MeissnerT,IcksA,KapellenT,HollRW: Managementofdiabetes mellitusininfants. NatRevEndocrinol 2012, 8: 201 – 211. doi:10.1038/nrendo.2011.204. 15.VeenmaDC,deKleinA,TibboelD: Developmentalandgeneticaspectsof congenitaldiaphragmatichernia. PediatrPulmonol 2012, 47 (6):534 – 45. 16.TempleI: ImprintinginHumanDiseasewithSpecialReferenceto TransientNeonatalDiabetesandBeckwith-WiedemannSyndrome .In DevelopmentofthePancreasandNeonatalDiabetes.EndocrDev .12th edition.EditedbyScharfmannR,ShieldJ.Basel:Karger;2007:113 – 123.doi:10.1186/1687-9856-2012-21 Citethisarticleas: Topiol etal. : Neonataldiabetesmellitusand congenitaldiaphragmatichernia:coincidenceorconcurrentetiology?. InternationalJournalofPediatricEndocrinology 2012 2012 :21. Submit your next manuscript to BioMed Central and take full advantage of: € Convenient online submission € Thorough peer review € No space constraints or color “gure charges € Immediate publication on acceptance € Inclusion in PubMed, CAS, Scopus and Google Scholar € Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Topiol etal.InternationalJournalofPediatricEndocrinology 2012, 2012 :21Page4of4 http://www.ijpeonline.com/content/2012/1/21