REVISTA
PAULISTA
DE
PEDIATRIA
www.rpped.com.br
CASE
REPORT
Congenital
central
hypoventilation
syndrome
associated
with
Hirschsprung’s
Disease:
case
report
and
literature
review
Renata
Lazari
Sandoval
a,b,∗,
Carlos
Moreno
Zaconeta
b,c,
Paulo
Roberto
Margotto
d,
Maria
Teresinha
de
Oliveira
Cardoso
b,e,
Evely
Mirella
Santos
Franc
¸a
c,e,
Cristina
Touguinha
Neves
Medina
e,
Talyta
Matos
Canó
e,
Aline
Saliba
de
Faria
aaHospitaldeBasedoDistritoFederal(HBDF),Brasília,DF,Brazil
bUniversidadedeBrasília(UnB),Brasília,DF,Brazil
cHospitalMaternoInfantildeBrasília(HMIB),Brasília,DF,Brazil
dFaculdadedeMedicina,UniversidadeCatólicadeBrasília(UCB),Brasília,DF,Brazil
eSecretariadeEstadodeSaúdedoDistritoFederal,Brasília,DF,Brazil
Received24June2015;accepted4October2015 Availableonline24March2016
KEYWORDS Congenitalcentral hypoventilation syndrome; Ondinesyndrome; Hirschsprung’s disease;
Haddadsyndrome; PHOX2Bgene
Abstract
Objective: Toreportthecaseofanewbornwithrecurrentepisodesofapnea,diagnosedwith
CongenitalCentral hypoventilationsyndrome (CCHS)associated with Hirschsprung’s disease
(HD),configuringHaddadsyndrome.
Casedescription: Thirdchildbornatfull-termtoanon-consanguineouscouplethrough
nor-maldeliverywithoutcomplications,withappropriateweightandlengthfor gestationalage.
Soonafterbirthhestartedtoshowbradypnea,bradycardiaandcyanosis,beingsubmittedto
trachealintubationandstartedempiricantibiotictherapyforsuspectedearlyneonatalsepsis.
DuringhospitalizationintheNICU,heshoweddifficultytoundergoextubationduetoepisodes
ofdesaturation duringsleep andwakefulness.He had recurrentepisodes ofhypoglycemia,
hyperglycemia,metabolicacidosis,abdominaldistension,leukocytosis,increaseinC-reactive
proteinlevels, withnegativebloodculturesandsuspectedinbornerrorofmetabolism.At2
monthsofagehewasdiagnosedwithlong-segmentHirschsprung’sdiseaseandwassubmitted
tosegmentresectionandcolostomythroughHartmann’sprocedure.A geneticresearchwas
performedbypolymerasechainreactionforCCHSscreening,whichshowedthemutatedallele
ofPHOX2Bgene,confirmingthediagnosis.
Comments: Thisisararegenetic,autosomaldominantdisease,causedbymutationinPHOX2B
gene,locatedinchromosomeband4p12,whichresultsinautonomicnervoussystem
dysfunc-tion.CCHScanalsooccurwithHirschsprung’sdiseaseandtumorsderivedfromtheneuralcrest.
∗Correspondingauthor.
E-mail:[email protected](R.L.Sandoval). http://dx.doi.org/10.1016/j.rppede.2015.10.009
Thereisacorrelationbetweenphenotypeandgenotype,aswellashighintrafamilialphenotypic
variability.Intheneonatalperioditcansimulatecasesofsepsisandinbornerrorsofmetabolism.
©2016SociedadedePediatriadeS˜aoPaulo.PublishedbyElsevierEditoraLtda.Thisisanopen
accessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
PALAVRAS-CHAVE Síndromede hipoventilac¸ão centralcongênita; SíndromedeOndine; Doenc¸ade
Hirschsprung; SíndromedeHaddad;
GenePHOX2B
Síndromedehipoventilac¸ãocentralcongênitaassociadaàdoenc¸adeHirschsprung: relatodecasoerevisãodeliteratura
Resumo
Objetivo: Relatarcasodeneonatocomepisódiosdeapneiasrecorrentes,diagnosticadocom
síndromedehipoventilac¸ãocentralcongênita(SHCC)associadaàdoenc¸adeHirschsprung(DH),
oqueconfigurousíndromedeHaddad.
Descric¸ãodocaso: Terceirofilhodecasalnãoconsanguíneo,nascidoatermo,partonormalsem
intercorrências,pesoecomprimentoadequadosparaidadegestacional.Logoapósonascimento
apresentoubradipneia,bradicardiaecianose,foisubmetidoàintubac¸ãoorotraquealeiniciada
antibioticoterapiaempíricadevidoàsuspeitadesepseneonatalprecoce.Duranteinternac¸ão
em UTI neonatalevoluiu comdificuldadede extubac¸ãodevido aepisódios dedessaturac¸ão
durantesonoevigília.Apresentouquadrosrecorrentesdehipoglicemia,hiperglicemia,acidose
metabólica, distensão abdominal, leucocitose, aumento de proteína Creativa, com
hemo-culturasnegativasesuspeitadeerroinatodometabolismo.Aosdoismesesfoidiagnosticada
doenc¸adeHirschsprungdesegmentolongo,foisubmetidoàressecc¸ãodosegmentoe
colosto-miaàHartmann.Feitapesquisagenéticaporreac¸ãoemcadeiadapolimeraseparapesquisade
SHCC,queevidencioualelomutadodogenePHOX2Beconfirmouodiagnóstico.
Comentários: Trata-se de doenc¸a genética rara, de heranc¸a autossômica dominante,
cau-sada por mutac¸ão no gene PHOX2B, localizado na banda cromossômica 4p12, que resulta
em disfunc¸ão do sistema nervoso autônomo. A SHCC também pode cursar com doenc¸a de
Hirschsprungetumoresderivados dacristaneural.Hácorrelac¸ãoentrefenótipoegenótipo,
alémdegrandevariabilidadefenotípicaintrafamiliar.Noperíodoneonatalpodesimularquadros
desepseeerrosinatosdometabolismo.
©2016SociedadedePediatriadeS˜aoPaulo. PublicadoporElsevier EditoraLtda.Este ´eum
artigoOpenAccesssobumalicenc¸aCCBY(http://creativecommons.org/licenses/by/4.0/).
Introduction
Congenital central hypoventilation syndrome (CCHS) was firstdescribedbyRobertMellinsetal.in1970.1Itis
charac-terizedby centralapnea crises duetoautonomic nervous system dysfunction.2---5 Central nervous system
malforma-tions, as well as lung and heart disease, should be ruled out.Hypoventilation isaccentuated duringsleep, particu-larlyinthenon-REMphase,inwhichtheautonomiccontrol of breathing predominates.6 Forthis reason it wascalled
Ondine’scursesyndrome,basedontheNorsemythofOndine (1811)byFriedrichLaMotteFouque,whichtellsthestory ofanymphwhogivesupimmortalitytoliveahumanlove; however,whensheisbetrayed,shecursesherfaithlesslover toforgettobreathewhilesleeping.7
In 1978, Gabriel Haddad was the first author to describe the association between CCHS, Hirschsprung’s disease and tumors derived from the neural crest, in addition to hypothesize the familial character of the disease.8 Approximately 15---20% of cases of CCHS have
Hirschsprung’s disease; short segment involvement (rec-tosigmoid)ismorecommon,butlong-segmentaganglionosis isalsodescribed.4,9---11Tumorsderivedfromtheneuralcrest
(neuroblastoma, ganglioneuroma, ganglioneuroblastoma) occur in 5---10% of cases, especially in the firsttwo years oflife.12
Initiallyonlycases ofseverelyaffected newbornswere reported in the scientific literature. However, from 1992 on,cohort studies started to be published, which broad-enedthescopeofthesyndromethroughnewevidencesuch asclinical variants of later onset and autonomic nervous system involvement in other organs, which expands the possibilitiesof associated clinical manifestations (cardiac arrhythmias, orthostatic hypotension, abnormal pupillary reflex,esophagealdysmotility,diaphoresis,decreasedheart ratevariability,chronic constipation,excessivedrowsiness afteruseofsedativesandantihistamines).Confirmationof familialrecurrenceemphasizedthegeneticcomponentand thebroadphenotypicspectrum.3,9---11,13---17
In 2003, PHOX2B gene mutations were identified as responsibleforCCHS.ThePHOX2Bgene(paired-like home-obox gene), located on chromosome 4p12, encodes a transcriptionfactorresponsiblefortheregulationofgenes involved in the development of the autonomic nervous system.15Themostfrequentlyfoundmutationisa
mutation due to polyalanine expansion has been demon-strated bymolecular genetictesting bypolymerase chain reaction.Other types of mutations (missense, frameshift) mayoccurandaredemonstratedbygenesequencing.4,11,16
The central breathing control depends on chemore-ceptors expressed in specialized neurons located in the retrotrapezoid nucleus in the brainstem bulbar region, sensitive to carbon dioxide levels in Cerebrospinal Fluid (CSF).2 They are integrated into the neuronal circuitry
thatstimulates thephrenic nerveand,consequently, pro-motes diaphragm movement and controls ventilation in ordertomaintainhomeostasis.Retrotrapezoidnucleus neu-rons(RTNN)expressthePHOX2Bgene.Micemutatedforthe gene,withanincreaseofsevenalanines,show85%reduction ofRTNNandcansurviveonlyonartificialventilation.18
Most of the mutations responsible for CCHS are de novo mutations. Approximately 10---25% of parents are asymptomaticcarriers,responsiblefortransmissiontotheir offspring.15,16,19,20Fourpossibilitiesaredescribedfor
asymp-tomaticcarriers:presence ofminorpolyalanineexpansion (uptothree, i.e.,20/23genotype),20/24 or20/25 geno-types with incomplete penetrance, somatic or germinal mosaicism.11,15,16,19---21 A risk of recurrence of up to 50%
is estimated.20 Recently published studies show extreme
intrafamilialphenotypic variability, fromthe elderly indi-vidual withsleepapnea, chronic constipation and lack of pupillaryresponse toatropine,to theneonate withCCHS thatdependsoncontinuousventilatorysupport.4,5,17,21,22
Thus,theaimofthisstudywastoreportthecase ofa neonatewithrecurrentapneaepisodes,diagnosedwith con-genitalcentralhypoventilationsyndrome(CCHS)associated withHirschsprung’sdisease,configuringHaddadsyndrome.
Case
description
Male neonate, born at term to non-consanguineous par-ents (gestational age of 39 weeks and six days) through vaginaldeliverywithoutcomplications,classifiedas appro-priateforgestationalage(birthweight3390g),hadanApgar scoreof8inthe 1stminute and9inthe 5thminute. The motherwasmultiparous,with6pregnanciesandno miscar-riages,aged34 years;thepregnancywasuneventful.The newbornpresented, inthe firsthour oflife, with bradyp-nea, bradycardia and cyanosis, underwent endotracheal intubationandantibioticsforsuspectedearlyneonatal sep-sis.The echocardiographyshowedapatentforamenovale without hemodynamic repercussions. The transfontanellar ultrasonographyshowednoabnormalitiessuggestiveof cen-tralnervoussystemmalformations.Thepatienthaddelayed meconiumelimination,onthe4thdayoflifeandonlyafter rectalstimulation.Hewasassessedbythestaffofpediatric surgery,whichidentifiedacircularstenosisat3.5cmofthe rectumthroughdigitalrectalexamination.
During hospitalizationin the Neonatal ICU, in thefirst monthoflife,thepatienthaddifficultytoundergo extuba-tion.Severalattemptsweremadetowithdrawmechanical ventilationwiththeuseofnoninvasivepositivepressure ven-tilation,buthepersistedwithdesaturationepisodesduring sleepandwakefulness.Additionally, therewererecurrent episodesofmetabolicacidosisandthreeepisodesof respi-ratoryacidosis duringambient airmaintenance attempts.
Healsodevelopedhypoglycemicepisodesalternatingwith hyperglycemia,recurrentabdominaldistention, leukocyto-sisandfluctuatingincreasedC-reactiveproteinlevelswith negativebloodcultures.Inbornerrorsofmetabolismwere suspected.The bestoption tooffernutritionwasthrough continuousgavage,ashadepisodesofhypoglycemia approx-imatelyonehourafterfeeding.Iftheglucoseinfusionrate wasincreased,hesoonshowedhyperglycemia.
Therewas a familyhistory of a brother witha similar neonatal picture, who died at 10 months from respira-torycomplications,withanundefinedetiologicaldiagnosis, but managed asacarrierof organic acidemia (3-hydroxy-3-methylglutaryl-CoA lyase deficiency). Thus, tests were performed to screen for inborn errors of metabolism (expandedneonatalscreeningtestandresearchoforganic acidsintheurine)andaleucine,isoleucineandvaline-free formula wasinitiated empirically, associatedwiththe use ofhigh-dosevitaminst(biotin,riboflavinandL-carnitine). Therewasnoclinicalimprovementaftertheinstitutionof dietary therapy andmegavitamin. The newborn screening testwithmassspectrometryandresearchofurinaryorganic acidswerenormal.
At twomonths, heunderwent a barium enema, which showed cone-shaped transition zone at the splenic flex-ure and dilatation upstream and Hirschsprung’s disease was diagnosed. He underwent intestinal biopsy, affected segment resection and Hartmann’s colostomy. Anato-mopathologicalexaminationshowedthepresenceofanerve plexus,butabsenceofganglioncellsintherectum,sigmoid, transitionzoneanddescendingcolon;nerveplexuswith gan-glioncellswaspresentonlyinthetransverseandascending colon.
Given the suspicion of congenital central hypoventila-tionsyndrome(CCHS)associatedwithHirschsprung’sdisease and after ruling out the hypothesis of inborn error of metabolism,genetictestingwasperformedusingthe molec-ulartechniqueof polymerasechain reactiontoscreenfor CCHS.
Discussion
Congenital central hypoventilation syndrome (CCHS) is a rare,butprobablyunderdiagnoseddisorder.In1999,there wereapproximately160---180knowncasesworldwide.5The
Frenchregistry,publishedin2005,estimatedanincidence of 1:200,000 live births in France.10 In 2009, there were
1000casesconfirmedbymolecularstudies.3InBrazil,case
reportsofisolatedwerepublished.7,22Thiscasereportaims
toalerthealthprofessionalsabouttheexistenceofthe syn-drome,aswellaspotentialconfounders.
urinewasdemonstratedandtherewasnoaccesstogenetic testing atthe time.However,after reviewingthe case,it is believedthat theincrease in acidmetabolite excretion wasrelatedtothepatient’scriticalconditionandhypoxia.23
Another interesting fact in the brother’s history was the reportofhypoglycemicepisodes,whichwerealsoobserved inthenewborndescribedherein,alternatingwithepisodes ofhyperglycemia.Theoscillationsinglycemiawereinitially attributedtothepresumedinborn errorof metabolismor theadverseeffectsofthespecificdiet.However,thereare studiesshowing liabilitytomaintainnormalblood glucose inpatientswithCCHS.Differentmechanismsarepostulated forthefindingand,amongthem,hyperinsulinism.24,25
ThepresenceofamutatedalleleinthePHOX2Bgenewas demonstrated by the molecular technique of polymerase chain reaction, but thetechnique used does not quantify thenumberof polyalanineexpansions,asitonlyidentifies thepresenceofabovethannormalexpansions.However,it seemstobethemostsevere phenotype,duetotheonset of symptoms in the neonatal period and the association withHirschsprung’sdisease.Approximately87---100%ofthe casescausedbynon-polyalaninerepeatexpansionmutations (NPARM)haveHirschsprung’sdisease.4Incasesofmutation
duetopolyalaninerepeatexpansion,aloweroccurrenceof associationwithHirschsprung’sdiseaseisexpected,ofabout 20%.4Neuralcrestcell-derivedtumorsarefoundin50%of
caseswith NPARMmutations andin only1% of thosewith mutationsduetopolyalaninerepeatexpansion.3,4,11
The parents have not been submitted to mutation screening, but considering the history of familial recur-rence, it is likely that one of them is a carrier. There are no reports of other cases in the family. The mother has postural hypotension and chronic constipation, which mayrepresentmildsymptomsofautonomicnervoussystem dysfunction.3,13,14 Approximately 10---25% of casesof CCHS
areduetoinheritedmutation,transmittedbyasymptomatic carriers.20,21
Central hypoventilation is the cardinal sign of CCHS and the characteristic with the highest morbimortality.4
The genotype is associated with the need for mechani-calventilation. Carriersof the20/25 genotype have later clinical presentation and are rarely depend on ventila-torysupport.4 Ontheotherhand,carriersofthegenotype
20/27 to 20/33 usually depend oncontinuous ventilatory support.4 Mortalityis mainly due tosudden death or
pul-monarycomplications secondary toprolonged mechanical ventilation.Manydeveloppulmonaryhypertension,cor pul-monaleandhypoxic-ischemiclesions,causedbyinadequate ventilatorysupport.4,9,10,13
The diagnosis and management of these patients are quitechallenging.Therarityofthedisease,thebroad dif-ferentialdiagnosis(malformations,sepsis,inbornerrorsof metabolism), restricted access to specific genetic tests, the need for ventilatory support at birth and follow-up with a multidisciplinary team (pediatricians, intensivists, pediatricsurgeons,geneticists,physicaltherapists,nurses, nutritionists)arethebasis oftheprevious statement.The survival and quality of life can be improved through the planning of early tracheostomyand gastrostomy, efficient deinstitutionalization process, access to home care pro-gramsandeventhepossibilityofdiaphragmaticpacemaker implantation.4,9
Funding
Thisstudydidnotreceivefunding.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgements
To Prof. Dr.Gustavo Antônio Moreira, whokindly allowed access to molecular genetic screening for PHOX2B gene mutation,carriedoutby Associac¸ão Fundo deIncentivo à Pesquisa(Afip).
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