94O RIG IN A L A RTIC LE

Received for publication 09/11/2015 - A ccepted for publication 11/12/2015

The authors declare no conflict of interest.

O phthalm ic changes in cleft lip and palate

A lterações oftalm ológicas na fissura lábio palatina

Luciano Sólia N ásser1, D aniella Reis Barbosa M artelli1, M ário Sérgio O liveira Sw erts2, D aniela A raújo Veloso Popoff1,Letízia M onteiro de Barros2, H ercílio M artelli Júnior1,2

1 H ealth Science Program m e, U niversidade Estadual de M ontes C laros, M ontes C laros, M G , Brazil.2 C entre for Rehabilitation of C raniofacial A nom alies, U niversidade José do Rosário Vellano, A lfenas, M G , Brazil.Institution: U niversidade Estadual de M ontes C laros, M ontes C laros, M G , Brazil.

RESU M O

O presente estudo teve com o objetivo analisar evidências de associação entre as alterações oculares e fissuras lábio palatinas nãosindrôm icas (FL /PN S), através de um a revisão da literatura. Foi realizada a revisão da literatura com pesquisa sistem ática, observan-do o protocolo de colaboração com o G rupo C ochrane. PubM ed, Scopus, G oogle A cadêm ico e ISI-W eb of Science. A partir de16estudos acessados, 3 com puseram a am ostra final. Todos os trabalhos da am ostra final relataram alterações oculares em pacientescom FL /PN S. O s artigos relataram respectivam ente alterações oculares em 6,21% , 17,54% e 1,03% dos pacientes. A presença dealterações oculares em pacientes com FL /PN S foi significativa nesta revisão sistem ática, m as todos os três artigos sugerem quefuturos estudos deverão explorar a possibilidade de que haja um aum ento de alterações oculares em indivíduos com FL /PN S.

D escritores:Transtornos da visão; M anifestações oculares; C olobom a; Fissura palatina; Fissura labial

A BSTRA C T

T he current study aim ed to analyze through a literature review evidence of association betw een ocular changes and non-syndrom ic cleftlip and/or palate (N SC L /P ). A literature review w as carried out in accordance w ith the C ochrane C ollaboration G roup protocol.P ubM ed, Scopus, A cadem ic G oogle and ISI W eb of Science databases w ere system atically searched. A total of 16 studies w ere accessed,and three m ade up the final sam ple. A ll three studied ocular abnorm alities in patients w ith N SC L /P. T he articles found ocular abnorm alitiesin 6.21% , 17.54% and 1.03% of patients respectively. T he presence of ocular abnorm alities in patients w ith N SC L /P w as significant in thissystem atic review , but the articles all agreed that future studies should explore the possibility of a greater occurrence of ocular changes inindividuals w ith N SC L /P.

K eyw ords: V ision disorders; E ye m anifestations; C olobom a; C left palate; C left lip

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DOI 10.5935/0034-7280.20160021

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IN TRO D U C TIO N

O rofacial m alform ations are the m ost com m on form ofcongenital anom alies in the w orld(1). A m ong them , them ost prevalent is the cleft lip w ith or w ithout cleft palate

(C L /P)(2-5), w hich m ay occur m ore com m only in an isolated andnon-syndrom ic form as a specific phenotype or, m ore rarely,com posing several associations or syndrom es(6,7). E m bryologically,clefts result from prim ary fusion defects of the craniofacial pro-cesses that form the prim ary and secondary palate in the firstintrauterine trim ester (8). The incidence of C L /P varies accordingto geographical location, racial and ethnic groups, environm entalexposures, and socioeconom ic status, affecting approxim ately 1/700 live births w ith w ide variability across geographic origin.G enerally, A sian and A m erindian populations have the highestreported birth prevalence rates, often as high as 1/500, E uropean-derived populations have interm ediate prevalence rates at about1/1,000, and A frican-derived populations have the low estprevalence rates at about 1/2,500(5,9,10).

A ccording to V ieira(7), the last decade w as crucial inclarifying issues concerning the etiology of C L /P w hen com paredto other defects observed at birth. A s this is a m ultifactorial trait,environm ental risk factors such as sm oking, alcohol, parentalage, m edications, birth order, inter-pregnancy interval, and folicacid deficiency are listed as m odifiers. R isk factor identification isthe first step to better understanding and preventing suchcraniofacial changes(7,11).

C L /P could be associated w ith m any other structuralabnorm alities of the adjacent vital structures of the face like theears, eyes, nose, teeth and brain. C L /P are inherently know n toproduce functional problem s affecting the oropharynx (feedingand breathing), hearing, vision and speech; in addition, they havea negative cosm etic effect(12).A lm ost all skeletal and soft tissuecom ponents of the craniofacial area are unbelievably derivedfrom the neural crest cells (12). B ecause eyes originate as anextension of the forebrain, m alform ations involving ocularstructures invariably accom pany those of the face and brain andvice versa (12).

T he current study aim ed to provide additional evidenceby m eans of review of the literature.

M ETH O D S

T he present review w as carried out in accordance w ith theC ochrane C ollaboration G roup protocol for system aticreview s(13), including a literature search strategy, selection ofpapers through the inclusion and exclusion criteria, dataextraction, and quality assessm ent.

L iterature search strategyO ur review w as perform ed in July 2014 in order to obtain

literature regarding N SC L /P and ocular changes. PubM ed, Scopus,G oogle and ISI - W eb of Science databases w ere system aticallysearched using the follow ing approaches: the search strings “ocu-lar changes” A N D “cleft lip and palate”, “ocular findings” A N D“cleft lip and palate”, “ocular features” A N D “cleft lip and palate”,“ocular disorders” A N D “cleft lip and palate”. The sam e happenedw ith the term s “oral clefts” and “orofacial clefts” for studiespublished up to that tim e.

Selection of papers through the inclusion and exclusion criteriaT he selection of papers is diagram m atically explained in

Figure 1. O f the 16 studies originally found through the literature

search strategy and the references of the potential studiesretrieved, three studies w as excluded (for being in a languageother than E nglish w ith no full text available), and another w asexcluded because it did not describe the ocular abnorm alitiesfound. A further nine studies involving syndrom ic oral cleftsw ere subsequently excluding. A fter w ards, only articles presentingocular changes w ith N SC L /P w ere included in the present study.Thus, three studies w ere selected (Figure 1).

D ata extractionT itle and abstract screening w as perform ed by tw o

review ers (L SN and H M J) w ho w orked independently toidentify potentially relevant papers for w hich full textpublications w ere retrieved. If, how ever, there w as anydiscrepancy of opinion, the review ers reexam ined the papertogether and arrived at a joint final decision. A standardizedform w as used to extract inform ation, such as author and year ofpublication of the paper, origin of participants, study design,sam ple size, type of oral clefts and type of ocular changesassociated w ith non-syndrom ic oral clefts.

RESU LTS

T he initial database search identified 16 citations publishedbetw een 1977 and 2013. A fter screening, nine studies w ereexcluded (because they described ocular changes in patients w ithsyndrom ic C L /P), leaving seven papers. A second screening w asperform ed on the rem aining papers and four studies w ereexcluded (three articles w ere in a language other than E nglishw ith no full text available and one article did not describe theocular changes found). Thus, three papers w ere selected for thesystem atic review.

T he characteristics of the three selected papers arepresented in Table 1. A ll three used a prospective study designand reported the frequency of ocular changes associated to

Figure 1: Flow chart of the studies included and excluded

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O phthalm ic changes in cleft lip and palate

96 N ásser L S, M artelli D R B, Sw erts M SO , Popoff D A V, de B arros L M , M artelli Júnior H

N SC L /P. The sam ple sizes and the population investigated variedconsiderably am ong the studies, not being hom ogeneous: onestudied 322 patients, one studied 57 and the other studied 622patients. C oncerning the country of origin of articles: one w asfrom the U nited States, one from Turkey and one from India(Table 1). E ach study has its ow n classification of cleft type: oneclassified the clefts as unilateral or bilateral, one as C L , C P orC L /P and one did not separate the types of clefts. A ll threestudied ocular abnorm alities in patients w ith N SC L /P. The typeof population studied w as different am ong the three articles:one studied the ocular changes in patients w ith cleft lip andpalate attending the three departm ents of K . S. H egdeC haritable H ospital, nam ely, M axillofacial, O phthalm ology andPediatrics. O ne studied patients w ith cleft lip and/or palate w hosought orthodontic help at the D ental H ospital, Izm ir, Turkeyand one studied children adm itted at the Jubilee M issionM edical C ollege, Trichur for cleft lip or cleft palate repair. Theage of the patients w as sim ilar in the three studies: one studiedpatients over the age of 20, one over 18 and the other over 19.R egarding ocular changes in each article, all classified themaccording to the m odified anatom ical region of the eye and itsannexes (Table 2).

Tw o articles carried out a categorization relating to clefttype w ith associated ocular abnorm alities(12,14). A n article found48.14% of ocular m anifestations in patients w ith bilateral C L /P,18.5% of changes in patients w ith unilateral C L /P, 7.4% in patientsw ith facial clefts, 7.40% in patients w ith clefts w ith alveolus and18.5% in patients w ith recognizable syndrom es(12). The other

article found 64% of ocular m anifestations in patients w ith bila-teral C L /P, 16% in patients w ith unilateral C L /P, 10.5% in patientsw ith isolated cleft palate and 8,7% in isolated cleft lip(14).

A n article(12) found ocular abnorm alities in 6.21% of patients.C hanges in the eyelid w ere the m ost frequent (30% ), follow ed byorbital defects (20% ), abnorm alities of the lacrim al duct (10% ),lim b defects (10% ), cataract (5% ) and retinal colobom a (5% ).Furtherm ore the article found refractive error in 15% of patients.

T he other article(14) found ocular abnorm alities in 17.54%of patients. The m ost frequent ocular disease w as congenitalnasolacrim al duct obstruction (50% ), follow ed by bilateral iriscolobom a (20% ), eyelid (10% ), derm oid tum or (10% ), andesophoria (10% ). The other article(15) found ocular changes in1.03% of patients. The m ost frequent ocular disease w as colobom a(57.14% ), follow ed by eyelid (14.28% ), congenital nasolacrim alduct obstruction (14.28% ) and congenital esotropia (14.28% ).

D ISC U SSIO N

T his literature review assessed available studies describingocular changes in patients w ith non-syndrom ic oral clefts. W edem onstrated that there is a shortage of literature about ocularchanges in patients w ith N SC L /P. O ur results also dem onstratedthat the published studies disagree on the frequency of non-syndrom ic oral clefts. O ne article says: cleft lip and palaterepresents the second m ost frequently occurring congenitaldeform ity after clubfoot deform ity(12). A nother article says: cleft

Table 2

O cular changes in each of the three articles selected.

O cular Total E yelid Squint O rbital N asolacrim al L im bal C ataract C olobom as changes defects abnorm alities derm oids % % % % % % % %

A nchlia et al., 6.21 30 20 20 10 10 5 5 2011

Y am an et al., 17.54 10 10 50 10 20 2011

Shobha et al., 1.03 14.28 14.28 14.28 57.14 2011

A uthor

Table 1

M ain characteristics of the three selected papers

First author, C ountry C left Frequency of ocular Study N um ber of patients A ge of

year of publication of study classification abnorm alities % design evaluated patients

A nchlia et al., E U A B ilateral C L P, 6.21 Prospective 322 U p to 2011 unilateral C L P 20 year

Y am an et al., Turkey C L , C P, C L P 17.54 Prospective 57 U p to 2009 18 years

Shobha et al., India C L P, w ithout 1.03 Prospective 674 6 m onths 2011separating the to 19 years sub-types

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lip and/or cleft palate are am ong the com m on congenitalanom alies of the head and neck region(14). The other article says:cleft lip and palate are com m on birth defects form ed due tofailure of fusion of the m axillary and m andibular processesbetw een the fifth and ninth w eeks of pregnancy. They are foundin one in every 1,000 new borns(15).

O ther studies about C L /P dem onstrated that the studiespublished agree that non-syndrom ic oral clefts are one of them ost com m on hum an m alform ations, w ith an average prevalenceof 1 per 700 or 1,000 live births(2,4,5,7,16), as w ell as that its incidencevaries according to gender: 2:1 being the ratio of m ales to fem alesfor cleft lip and palate and 1:2 the approxim ate ratio of m ales tofem ales for isolated cleft palate(1,10).

O ther com m on inform ation betw een the studies aboutC L /P is the fact that unilateral clefts are m ore com m on thanbilateral clefts, and of the unilateral cases of non-syndrom ic cleftlip and palate, left-sided cleft lips occur m ore frequently thanright-sided cleft lips(4,5,16,17). M any studies have also dem onstratedthat genetic factors m ay play a role in the cause of non-syndrom icoral clefts in addition to certain environm ental and/or stochasticfactors, m eaning that this m alform ation is a m ultifactorialtrait(2,16,18). Sim ilarly, studies have show n that cleft lip, w ith orw ithout cleft palate, is entirely different from isolated cleft palatefrom both em bryological and pathogenetic standpoints(18,19).

T he pathogenesis of the ocular abnorm alities associatedw ith C L /P poses a problem . The m ost probable explanation isdetective organogenesis in the early em bryonic period w hen allof the structures involved are form ing the facial structures, theanterior segm ent of the eye and the eyelids(20). The m echanism sbehind m ovem ent and fusion of m esoderm al processes havebeen studied extensively in experim ental oral clefting, but thefindings m ay apply to other clefting anom alies(21,22). G eneticregulation is critical to successful ocular em bryogenesis. The tw ogenes that have been described as m ost im portant in oculardevelopm ent are the PA X 6 gene (chrom osom e 11p13) and theR x gene (chrom osom e 18). B oth genes belong to a large fam ilyof factors that are related to the hom eodom ain region of theD rosophila paired protein. E arly induction of both genes causesa series of gene activations and depressions w hich are tantam ountto norm al developm ent of the m ature eye. R x and PA X 6 areboth expressed in proliferating cells. M utations of PA X 6 havebeen show n to lead to aniridia, congenital cataract, Peter’sanom aly, and m idline fusion defects. A bsence of the gene leadsto anophthalm ia. R x is associated w ith retinal proliferation(23).

T he defects in the eye m ay be view ed as show ing sim ilardefective m esenchym al m ovem ent and fusion. D uring the periodbetw een 17 and 22 w eeks, three m esoderm al tissue m igrationsnorm ally occur from the rim of the optic cup(24). In turn, theyform the corneal endothelium , the cells of the corneal strom aand the m esoderm al portion of the iris. These m igrations havethe additional effect of separating the developing lens from thecornea. D efective m esoderm al m igrations from the upper rim ofthe optic cup w ould account for lack of corneal developm ent,failure of lens separation and incom plete aniridia superiorly. A tthe sam e tim e, the eyelids are form ing above and below the eyeas a fold of m esoderm al covered by ectoderm and are advancingtow ard their partial fusion over the central cornea. The eyelidcolobom a m ay represent an inappropriate fusion of theepithelium associated w ith cell death and disease characterizedby C L / P, and eyelid colobom a is called oral clefts(20).

A ccording to the C arnegier stages, the m ajor congenitalm alform ations of the eye and its attachm ents occur betw een the

fourth and eighth w eeks of the em bryonic period w hile the cleftlip and palate occur betw een the sixth and eighth w eeks. That is,there is a com m on em bryonic period from the sixth to the eighthw eek in w hich occur both ocular and oral alterations(24).

Tessier’s classification is used for patients w ith congenital cleftsand lid colobom a. Tessier’s num ber 3, 4, 5 affect the eye (Figure 2).

Figure 2: O ro-ocular clefts and the Tessier’s classification.

Source: Shobha M E , Joseph A , A denw alla H S, N arayanan PV,K akkanat C V, O cular findings in cleft lip and cleft palate patient.K erala J O phthalm ol. 2011;23(4):358-60.

There w as not a consensus in the review ed articles regarding thetype of ocular change m ost often related to non-syndrom ic C L /P, asw ell as any article deepened the study relating these changes to C L/P, based on em bryological and genetic concepts.

T hus the hypothesis that there is som e correlation betw eenocular m anifestations and non-syndrom ic C L /P cannot beconfirm ed by this system atic review.

To date, there is no know n genetic or epigenetic explanationfor the ocular changes described in the review ed articles that canbe correlated w ith the causative genes for non-syndrom ic C L /P.T he articles are in agreem ent that future studies should explorethe possibility that there is a preferential occurrence of ocularchanges in individuals w ith non-syndrom ic C L /P and test thehypothesis that com m on genetic and epigenetic m echanism s areplaying a role in both conditions. Through this inform ation, futurestudies m ay be better able to identify the causes of non-syndrom ic orofacial clefts and ultim ately to predict its occurrenceand to facilitate genetic counseling of affected fam ilies(16).

C left lip and palate are usually repaired early in life.H ow ever, the ocular com plications m ay be progressive andthreaten sight. It is therefore im portant that these patients beunder long-term ophthalm ic supervision to try to prevent thesight threatening ocular com plications(25). Thus, w hen oculardisorders associated w ith C L /P are identified, the appropriateeye tracking is essential in the prevention of seriousconsequences, since the loss of vision can be m ore disabling inpatients w ith C L /P.

A CKN O W LED G EM EN TS

T his w ork w as supported by grants from the Fundação deA m paro a Pesquisa do E stado de M inas G erais (FA PE M IG ),M inas G erais, B razil and the C onselho N acional de D esenvolvi-m ento C ientífico e Tecnológico (C N Pq), B rasília, B razil.

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C orresponding authorLuciano Sólia N ásserRua W alter Ferreira Barreto, 57- Zip code: 39401-347M ontesC laros, M inas G erais, BrazilTel: + 55 38 9132:5452E-m ail address: solianasser@ gm ail.com

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N ásser L S, M artelli D R B, Sw erts M SO , Popoff D A V, de B arros L M , M artelli Júnior H