Background Orofacial clefts (ie, cleft lip [CL], cleft lip and palate [CLP], cleft palate [CP] alone, as well as median, lateral [transversal], oblique facial clefts) are among the most common cong enital anomalies !ppro"imatel# $ case of orofacial cleft occurs in ever# %&&'%%& births he prevalence varies b# ethnicit#, countr#, and socioeconomic socioeconomic status ons#ndromic cleft lip and palate, which forms the largest subgroup of craniofacial anomalies, anomalies, occurs in the range of $%'*% cases per $&&& live births +n the nited n ited -tates, *& infants are born with an orofacial cleft on an average da#, or .%&& ever# ever # #ear Children who have an orofacial cleft require several surgical procedures and multidisciplinar# treatment and care/ the conservative estimated lifetime medical cost for each child with an orofacial cleft is 0$&&,&&&, amounting to 0.%& million for all children with orofacial cleft born each #ear in the nited -tates[$] +n addition, these children and their families often e"perience serious ps#chological problems 1ith rapidl# advancing 2nowledge in medical genetics and with new 3! diagnostic technologies, more cleft lip and palate anomalies are diagnosed prenatall# and more orofacial clefts identified as s#ndromic !lthough !lthough the basic rate of clefting c lefting ($4%&& to $4%%&) has not changed since 5ogh'!ndersen performed his pioneering $67* genetic stud# distinguishing * basic categories of orofacial clefts (cleft lip lip with or without cleft palate [CL8P] and cleft palate [*] alone), these clefts can now be more accuratel# classified he correct diagnosis of a cleft anomal# is fundamental for treatment, for further genetic and etiopathological studies, and for preventive measures correctl# targeting the categor# of preventable orofacial clefts clefts
Problem Classification and diagnostics he group of orofacial cleft anomalies is heterogeneous +t comprises t#pical orofacial clefts (eg, cleft lip, cleft lip and palate, cleft palate) and at#pical clefts, including median, transversal, oblique, and other essier essier t#pes of facial clefts[9, 7] # #pical pical and at#pical clefts can both occur as an isolated anomal#, as part of a sequence of a primar# defect, de fect, or as a multiple congenital anomal# (:C!) +n an :C!, the cleft anomal# could be part of a 2nown monogenic s#ndrome, part of a chromosomal aberration, part of an association, or part of a comple" of :C! of un2nown etiolog# (see the image below)
Classification of orofacial clefts
Cleft lip can occur as a unilateral (on the left or right side) or as a bilateral anomal# he line of cleft alwa#s starts on the lateral part of the upper lip and continues through the philtrum to the alveolus between the lateral incisor and the canine tooth, following the line of sutura incisiva up to the foramen incisivum he clefting anterior to the incisive foramen (ie, lip an d alveolus) is also defined as a cleft primar# palate Cleft lip ma# ma # occur with a wide range of severit#, from from a notch located on the left or right side of the lip to the most severe form, bilateral cleft lip and alveolus that separates the philtrum of the upper lip and a nd prema"illa from the rest of the ma"illar# arch (see the image below)
;"amples of cleft lip he mildest form is a microform and is a subtler e"pression of the CL8P phenot#pe and can t#picall# involve small defects as a notch located on the lip, also called forme fruste[%] or congenital healed cleft lip[<] and alveolar arch or as#mmetrical as #mmetrical drooping of the nostril[.] :ost often these cleft lip microforms occur unilaterall# :icroform of cleft lip is a rarel# reported birth defect that occurs in &&< case per $&,&&& live births[<] he phrase =possible carriers> was used to search in families afflicted with orofacial clefts[.] he investigation was carried out in $%9 families of probands with no ns#ndromic cleft lip with or without cleft palate +n possible carriers (individuals in between * affected individuals, ie, a child and mother?s mother are affected with a cleft, so the mother is a possible carrier), there was nearl# alwa#s some microform with a higher incidence in all relatives of the sub@ect/ the as#mmetrical drooping of the nose was the most frequent microform he microforms ma# be used as a prognostic criterion 5amil# prognosis is generall# worse if an# microform has been found in near relatives of the patient +n a famil# without CL8P, CL8P, the the incidence of a microform ma# increase the ris2 for clefting, but the actual probabilit# is low Aowever, in a case of consanguineous marriage, the cleft microforms found in both partners should serve as a warning signal he incidence of microforms in a certain population group (or in a certain area) must be ta2en into account ac count in studies concerning the epidemiolog# in order to prevent erroneous interpretation of the findings [.]
he most recent contribution to the classification cleft lip has been identif#ing and defining cleft lip subphenot#pes :araBita presented evidence that subepithelial (occult) defects of the superior orbicularis oris (OO) muscle represent the mildest form of the lip portion of cleft lip8palate [] he author provided descriptive histolog# of OO muscles from cadavers, assessed assessed the rate of OO defects in unaffected relatives of individuals with cleft lip8palate b# ultrasound, and compared to controls and sequence D:P7 in nonEcleft lip8palate individuals with OO defects onEcleft lip8palate
relatives of individuals with overt cleft lip8palate had a significantl# increased frequenc# of OO defects compared with controls with no famil# histor# of cleft lip8palate his showed a pattern of disorganiBed OO muscle fibers in those individuals with OO discontinuities diagnosed b# ultrasound -equencing of D:P7 found a significant increase in potentiall# damaging mutations in individuals with OO defects versus controls his is significant support for the h#pothesis that subepithelial OO muscle defects are a mild manifestation of the lip portion of the cleft lip8palate phenot#pe -uBu2i et al also used ultrasonograph# to detect a subtle defect of the OO muscle (subepithelial defects)[6] Aistologic studies showed a disorganiBation of the muscle fibers and e"cess connective tissue compared with normal OO muscles he D:P7 mutation frequenc# for overt cleft lip8palate cases alone was not significantl# greater than for controls, but the frequenc# for microform plus OO muscle cases was significantl# greater than for controls 5urthermore, the D:P7 mutation frequenc# in overt cleft lip8palate cases was significantl# less than the frequenc# in microform plus OO muscle cases hese results suggest amino acid alteration in D:P7 results in dela#ed lip closure (resulting in the appearance of a healed scar) or that actual healing of the cleft occurred b# an un2nown mechanism D:P7 has a role in microform and subepithelial clefting that is consistent with the speculation that a genetic pathwa# ma# be involved in both wound healing and cleft lip8palate !nother stud# using ultrasonograph# compared the frequenc# of discontinuities in the OO muscle in %*% unaffected relatives of individuals with nonEcleft lip8palate versus *%. unaffected controls[$&] OO muscle discontinuities were observed in $&F of the non'cleft relatives, compared with %F of the controlsGa statisticall# significant increase ( P H&7) :ale relatives had a higher rate of discontinuities than male controls ($*F vs 9*F, P H&$) 5emale relatives also had a higher rate of discontinuities than female controls but the increase was not statisticall# significant (6F vs .7F/ P H%<) hese data confirm the h#pothesis that subepithelial OO muscle defects are a mild manifestation of the cleft lip phenot#pe +dentification of subepithelial OO muscle d efects ma# be important in a clinical setting as a means of providing more accurate recurrence ris2 estimates to relatives in cleft families 5urthermore, the e"pansion of the nonEcleft lip8palate phenot#pic spectrum should improve the power of genetic studies 1hen cleft lip continues from the foramen incisivum further through the sutura palatina in the middle of the palate, a cleft lip and palate (either unilateral or bilateral) is present (see the image below)
;"amples of cleft lip and palate ! wide range of severit# ma# be observed he cleft line ma# be interrupted b# soft (s2in or mucosa) bridges, hard (bone) bridges, or both, corresponding to a diagnosis of an incomplete cleft his occurs in unilateral and bilateral cleft lip and palate Cleft palate (see the images below) is etiologicall# and embr#ologicall# different from cleft lip with or without cleft palate
;"amples of cleft palate -ubmucous cleft palate -everal subt#pes of cleft palate can be diagnosed based on severit# he uvula is the place where the minimal form of clefting of the palate is observed (Aowever, a relativel# high prevalence of this anomal# in the general population suggests that a certain proportion ma# represent the ver# far end of a normal variabilit#) ! more severe form is a cleft of the soft palate ! complete cleft palate constitutes a cleft of the hard palate, soft palate, and cleft uvula he clefting posterior to the incisive foramen is defined as a cleft of secondar# palate (see the image below)
;"amples of cleft palate +n a significant proportion of patients, the cleft of the h ard palate is covered b# mucosa and continues through the soft palate, forming a so'called submucous cleft palate ! submucous CP ma# occur in the hard palate onl# and continue to the open cleft of the soft palate, or it ma# occur as a submucous cleft of the soft palate with or without a notch into the hard palate Careful clinical e"amination ma# reveal a blue triangle in continuation of the cleft of the soft palate, which represents a cleft of the bone palate underneath mucosa (see the image below)
-ubmucous cleft palate he palate cleft ma# ta2e * distinguishable formsGa I shape, which is most common in isolated clefts, or a shape, which is most common in Jobin sequence (see Pierre Jobin :alformation) and in s#ndromic clefts !s is described below, the cleft palate posterior to the incisive foramen is defined as the cleft of the secondar# palate Cleft lip and cleft of the palate anterior to the incisive foramen (unilateral or bilateral) is defined as the cleft of primar# palate (thus, in bilateral cleft lip, prema"illa is separated from lateral palatal segments) he bifid uvula is a sign that adeno idectom# ma# result in h#pernasal speech if a complete adenoidectom# is done
Embryology +n facial morphogenesis, neural crest cells migrate into the facial region, wh ere the# form the s2eletal and connective tissue and all dental tissues e"cept the enamel Iascular endothelium and muscle are of mesodermal origin[$$] he upper lip is derived from medial nasal and ma"illar# processes 5ailure of merging between the medial nasal and ma"illar# processes at % wee2s? gestation, on one or both sides, results in cleft lip Cleft lip usuall# occurs at the @unction between the central and lateral parts of the upper lip on either side he cleft ma# affect onl# the upper lip, or it ma# e"tend more deepl# into the ma"illa and the primar# palate (Cleft of the primar# palate includes cleft lip and cleft of the alveolus) +f the fusion of palatal shelves is impaired also, the cleft lip is accompanied b# cleft palate, forming the cleft lip and palate abnormalit# Cleft palate is a partial or total lac2 of fusion of palatal shelves +t can occur in numerous wa#s4 •
3efective growth of palatal shelves
•
5ailure of the shelves to attain a horiBontal position
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Lac2 of contact between shelves
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Jupture after fusion of shelves
he secondar# palate develops from the right and left palatal processes 5usion of palatal shelves begins at wee2s? gestation and continues usuall# until $* wee2s? gestation One h#pothesis is that a threshold is noted be#ond which dela#ed movement of palatal shelves does not allow closure to ta2e place, and this results in a cleft palate
Cleft lip can be easil# diagnosed b# performing ultrasonograph# in the second trimester of pregnanc# when the position of the fetal face is located correctl# (see the images below)
Dilateral cleft lip on ultrasound :edian cleft lip on ultrasound suall#, diagnosing a cleft palate with ultrasonograph# is not possible/ however, an e"perienced ph#sician or technician ma# catch an at#pical movement of the fetal tongue in a lateral view +n the case of a large cleft palate, the tongue moves up into an open space (cleft) in the roof of the oral cavit# hree'dimensional imaging has been introduced to prenatal ultrasonograph# diagnostics of cleft anomalies and appears to be promising for recogniBing a cleft palate in a fetus
Frequency Jeported data on the frequenc# of orofacial clefts var# according to the investigator and the countr# +n general, all t#pical orofacial cleft t#pes combined occur in white populations with a frequenc# of $ per %&&'%%& live births !lthough the total combined frequenc# of cleft lip, cleft lip and palate, and cleft palate is often used in statistics, combining the * etiologicall# different groups (cleft lip with or without cleft palate and cleft palate) represents a misclassification bias similar to that of combining clefts with other congenital malformations he se" ratio in patients with clefts varies +n whites, cleft lip and cleft lip and palate occur significantl# more often in males, and cleft palate occurs significantl# more often in females +n cleft lip with or without cleft palate, the se" ratio correlates with the severit# and lateralit# of the cleft ! large stud# of ,6%* orofacial clefts in whites found the male'to'female se" ratio to be $%'$%64$ for cleft lip, $6'*&.4$ for cleft lip and palate, and &.*'&.74$ for cleft palate[$*] he prevalence rate of clefts in different racial groups is considerable he lowest rate is for blac2s ! high prevalence of cleft lip with or without cleft palate was found for the Kapanese population, and the highest prevalence was found for the orth !merican +ndian populations +n contrast, no remar2able variation among races was found in isolated cleft palate +n particular, its prevalence did not significantl# var# between blac2 and white infants or between infants of Kapanese and ;uropean origin in Aawaii Lec2 ($67) considered that such findings ma# reflect a higher etiological heterogeneit# of cleft palate than of cleft lip with or without cleft palate :ethods of ascertainment and classification criteria undoubtedl# have ma@or influence on the prevalence values[9]
+n a large population'based stud# of 7,799 children born with orofacial cleft (ascertained from *,%&6,$ California births), the birth prevalence of nons#ndromic cleft lip with or without cleft palate was &.. per $,&&& births (cleft lip, &*68$,&&&/ cleft palate, &78$,&&&) and prevalence of nons#ndromic cleft palate was &9$ per $,&&& births (see the image below)[$9]
Prevalence of orofacial clefts (olarova and Cerven2a, $66) +n that stud#, the ris2 of cleft lip with or without cleft palate was slightl# lower among the offspring of nonG-'born Chinese women compared to -'born Chinese women and slightl# higher among nonG-'born 5ilipinos relative to their -'born counterparts 5or cleft palate, lower prevalences were observed among blac2s and Aispanics than among whites he ris2 of cleft palate was higher among nonG-'born 5ilipinos compared to -'born 5ilipinos hese prevalence variations ma# reflect differences in both environmental and genetic factors affecting ris2 for development of orofacial cleft
Risk of recurrence enetic factors (ie, genes participating in the etiolog# of n ons#ndromic orofacial clefts) are passed to the ne"t generation, thus creating an increased ris2 for such anomal# in offspring he ris2 of recurrence also differs with respect to proportion of genetic and nongenetic factors +n cleft lip with or without cleft palate, the h#pothetical 7'threshold model (see ;tiolog#) closel# corresponds with differences in the ris2 of recurrence 5rom a clinical point of view, * factors are most important when evaluating the ris2 of recurrence for cleft lip with or without cleft palate4 the se" of the individuals (ie, patient and individual at ris2) and the severit# of the affect in the patient (eg, unilateral vs bilateral) he lowest recurrence ris2 for cleft lip with or without cleft palate is for the subcategor# of male patients with unilateral cleft (see the first image below) and, within this categor#, for sisters of males with a unilateral cleft and for daughters of fathers with a unilateral cleft lip with or without cleft palate (see the second image below) he highest ris2 of recurrence of CL8P is for the subcategor# of female patients affected with a bilateral CL8P
Jecurrence ris2 in cleft lip with or without cleft palate
Aighest and lowest ris2 of recurrence of cleft lip with or without cleft palate he ris2 of recurrence for cleft palate seems to be influenced onl# b# se" he ris2 is highest for daughters of fathers affected with a cleft palate and lowest for sons of mothers affected with a cleft palate (see the image below)
Jecurrence ris2 in cleft palate
Etiology :ost orofacial clefts, li2e most common congenital anomalies, are caused b# the interaction between genetic and environmental factors (see the image below)
;tiolog# of cleft lip and palate anomalies
+n those instances, genetic factors create a susceptibilit# for clefts 1hen environmental factors (ie, triggers) interact with a geneticall# susceptible genot#pe, a cleft deve lops during an earl# stage of development he proportion of environmental and genetic factors varies with the se" of the individual affected with cleft +n cleft lip and cleft palate, it also varies with the severit# and the unilateralit# or bilateralit# of the cleft anomal#/ the highest proportion of genetic factors are in the subgroup of females with a bilateral cleft, and the smallest proportion is in the subgroup of males with a unilateral cleft hus, the classic multifactorial threshold (:5) model of liabilit# (see the first image below) can be applied to cleft lip with or without cleft palate as the multifactorial model of liabilit# with 7 different thresholds (see the second image below)
:ultifactorial threshold model for the distribution of liabilit# for
cleft lip and palate of the liabilit# for cleft lip and palate
5our'threshold multifactorial threshold model
his model can help to better understand differences in values of ris2 of recurrence as well as differences in prevention approaches between different subgroups of clefts[$*] heoreticall#, the subgroup of clefts closest to the population average should have the highest population prevalence, the lowest value of heritabilit#, and, thus, the lowest ris2 of recurrence his has been confirmed on a large, population'based stud# of whites with clefts (see the image below)[$*]
3ecreased occurrence of orofacial clefts he value of heritabilit# e"presses a ratio of genetic and nongenetic factors Aeritabilit# is equal to $ for conditions completel# controlled b# genetic factors and equal to & for conditions completel# controlled b# environmental factors ! higher proportion of environmental factors indicates a lower ris2 of recurrence and also gives a better chance to act in prevention, because the onl# etiological factors that can be changed are environmental factors hus, the subgroup whose average prevalence is closest to the population average represents males affected with a unilateral cleft lip with or without cleft palate his subgroup is most common among orofacial clefts/ the ris2 of recurrence for siblings and for offspring of an individual with cleft is the lowest, the value of h eritabilit# is the lowest, and efficac# of primar# prevention is the highest (see details for other subgroups in 5uture and Controversies) !s mentioned in the previous section, a cleft develops when embr#onic parts called processes (which are programmed to grow, move, and @oin with each other to form an individual part of the embr#o) do not reach each other in time and an open space (cleft) between them persists +n the normal situation, the processes grow into an open space b# means of cellular migration and multiplication, touch each other, and fuse together +n general, an# factor that could prevent the processes from reaching each other b# slowing down migration, multiplication, or both of neural crest cells b# stopping tissue growth and development for a time or b# 2illing some cells that are alread# in that location wou ld cause a persistence of a cleft !lso, the epithelium that covers the mesench#me ma# not undergo programmed cell death, so that fusion of processes cannot ta2e place[$$]
DNA studies Over the past decade, a considerable interest has developed in the identification of genes that contribute to the etiolog# of orofacial clefting !dvances in modern molecular biolog#, new methods of genome manipulation, and availabilit# of complete genome sequences led to an understanding of the roles of particular genes that are associated with embr#onic development of the orofacial comple" he first candidate gene was transforming growth factor'a (TGFA), which showed an association with nons#ndromic cleft lip and palate (CLP) in a white population[$7] Lidral et al investigated % different genes (TGFA, BCL3, DLX2, MSX1, TGFB3) in a largel# white population from +owa [$%, $<] he# found a significant lin2age disequilibrium between cleft lip with or without cleft
palate and both MSX1 and TGFB3 and between CP and MSX1 he TGFB3 gene was identified as a strong candidate for clefting in humans based on both the mouse model[$.] and the lin2age disequilibrium studies[$, $<, $6] Other candidate genes that show an association with nons#ndromic cleft lip and palate include D4S192, RARA, MTHFR, RFC1, GABRB3, PVRL1, and IRF6. MSX1 was found to be a strong candidate gene involved in orofacial clefts and dental anomalies Jecent anal#sis of the MSX1 sequence in a multiple" 3utch famil# showed that a nonsense
mutation (-er$&7stop) in e"on $ segregated with the phenot#pe of nons#ndromic cleft lip and palate[*&] -ome have proposed that cleft palate in MSX1 2noc2'out mice is due to insufficienc# of the palatal mesench#me[*$] Mucchero et al reported that variants of IRF6 ma# be responsible for $*F of nons#ndromic cleft lip and palate, suggesting that this gene would pla# a substantial role in the causation of orofacial clefts[**] ! meta'anal#sis of all'genome scans of sub@ects with nons#ndromic cleft lip and palate, including 5ilipino, Chinese, +ndian, and Colombian families, found a significant evidence of lin2age to the region that contains interferon regulator# factor < (+J5<) [*9] !lso, gene'gene interactions have been e"amined ! comple" interpla# of several genes, each ma2ing a small contribution to the overall ris2, ma# lead to formation of clefts Kugessur et al reported a strong effect of the TGFA variant among children homoB#gous for the MSX1 A4 allele (6 C! repeats)[*7] ;valuation of gene'environment interactions is still in a preliminar# stage -tudies of the role of smo2ing in TGFA and MSX1 as covariates suggested that these loci might be susceptible to detrimental effects of maternal smo2ing[$6, *%] 5olate'metaboliBing enB#mes such as meth#lenetetrah#drofolate reductase ( MTHFR), which is a 2e# pla#er in etiolog# of neural tube defects, and RFC1 are considered candidate genes based on data that suggest that folic acid supplementation can reduce incidence of nons#ndromic cleft lip and palate[*<] Jecentl#, more than 9& potential candidate loci and candidate genes throughout the human genome were identified as strong susceptibilit# genes for orofacial clefts he MSX1 (7p$<$), TGFA (*p$9), TGFB1 ($6q$9$), TGFB2 ($q7$), TGFB3 ($7q*7), RARA ($.q$*), and MTHFR ($p9<9) genes are among the strongest candidates[*9, *., *] he TGFB3 gene was identified as a strong candidate for clefting in humans based on a mouse model enerall#, palatogenesis in mice parallels that of humans and shows that comparable genes are involved[*6] Naartinen demonstrated that mice lac2ing the 5D9 peptide e"hibit cleft palate[$.] +n addition, the e"ogenous 5D9 peptide can induce palatal fusion in chic2en embr#os, although the cleft palate is a normal feature in chic2ens[9&] +n humans, association studies between the TGFB3 gene and nons#ndromic cleft lip with or without cleft palate have shown conflicting results Lidral reported failure to observe an association of a new allelic variant of TGFB3 with nons#ndromic cleft lip with or without cleft palate in a case'control stud# of the Philippines population[$%] !nother stud# b# anabe anal#Bed 3! samples from 79 Kapanese patients and compared results with those from .9 control
sub@ects with respect to 7 candidate genes, including TGFB3[9$] o significant differences in variants of TGFB3 between case and control populations were observed On the other hand, more recent case'control association studies, famil# based studies, and genome scans have supported a role of TGFB3 in cleft development Deat# e"amined mar2ers in % candidate genes in *<6 case'parent trios ascertained through a child with nons#ndromic orofacial clefts/[$6] %F of the probands in the stud# were white :ar2ers at * of the % candidate genes (TGFB3 and MSX1) showed consistent evidence of lin2age and disequilibrium due to lin2age -imilarl#, Iieira attempted to detect transmission distortion of MSX1 and TGFB3 in *$. -outh !merican children from their respective mothers[9*] ! @oint anal#sis of MSX1 and TGFB3 suggested a possible interaction between these * genes, increasing cleft susceptibilit# hese results suggest that MSX1 and TGFB3 mutations ma2e a contribution to clefts in -outh !merican populations +n a stud# of the Norean population, Nim reported that the allele at the -fa$ pol#morphism of TGFB3 is associated with an increased ris2 of nons#ndromic cleft lip with or without cleft palate he population stud# consisted of * patients with nons#ndromic cleft lip with or without cleft palate and 7$ health# controls[99] +n *&&7, :araBita performed a meta'anal#sis of $9 genome scans of 9 e"tended multiple" families with nons#ndromic cleft lip with or without cleft palate[*9] he families came from . diverse populations including *,%%$ genot#ped individuals he meta'anal#sis revealed multiple genes in < chromosomal regions including the region containing TGFB3 ($7q*7) +n the Kapanese population, blood samples from *& families with nons#ndromic cleft lip with or without cleft palate have been anal#Bed using TGFB3 C! repeat pol#morphic mar2er Dased on the results of the stud#, the investigators concluded that either the TGFB3 gene itself or an ad@acent 3! sequence ma# contribute to the development of cleft lip and palate[97] !nother stud# b# +chi2awa and colleagues, investigated the relationship between nons#ndromic cleft lip with or without cleft palate and . candidate genes (TGFB3, DLX3, PAX9, CLPTM1, TBX10, PVRL1, TBX22) in a Kapanese population[9%] he sample consisted of $$* patients with their parents and $6* controls Doth population based case'control anal#sis and famil# based transmission disequilibrium test (3) were used he results showed significant associations of single nucleotide pol#morphisms (-Ps) in TGFB3 and nons#ndromic cleft lip with or without cleft palate, especiall# +I-%9*$(rs*9&&<&.), with a P value of &&&$< !lthough +I-'$%.* (rs**<<*%) alone did not show a significant difference between cases and controls, the haplot#pe Q!8!Q for rs*9&&<&.' rs**<<*% showed significant association he author concluded that the results demonstrated positive association of TGFB3 with nons#ndromic cleft lip with or without cleft palate in Kapanese patients -everal micromanifestations of orofacial clefts have been studied,[9<, 9.] and additional candidate genes associated with these minimal, clinicall# less significant anomalies have been suggested[9<, 9]
!ssociations of specific candidate genes with nons#ndromic cleft lip and p alate have not been found consistent across different populations his ma# suggest that multiplicative effects of several candidate genes or gene'environmental interactions are noted in different populations he identification of factors that contribute to the etiolog# of nons#ndromic cleft lip and palate is important for prevention, treatment planning, and education 1ith an increasing number of couples who see2 genetic counseling as a part of their famil# planning, the 2nowledge of how specific genes contribute to formation of nons#ndromic cleft lip and palate has gained an increased importance
Indications Children who have an orofacial cleft require several surgical procedures and comple" medical treatments http://emedicine.medscape.com/article/995535-overview#showall
Medical !era"y Neonatal care 1hen a neonate with a cleft is born, a pediatrician has 9 ma@or concerns4 •
•
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Jis2 of aspiration because of communication between oral and nasal cavities !irwa# obstruction (in addition to sequelae of aspiration, especiall# in Job in sequence in which the cleft palate [CP] is combined with micrognathia and the tongue has a normal siBe) 3ifficulties with feeding of a child with a cleft and nasal regurgitation
hese 9 factors are influenced b# the presence of other ma@or or minor anomalies that ma#, in association with a cleft, represent $ of 9&& 2nown cleft s#ndromes[$$] herefore, a neonate with an orofacial cleft should be seen b# a medical geneticist as soon as possible !s with an# other medical condition, each case is different ! child with a severe cleft ma# do ver# well, whereas a child with a much less severe condition ma# e"perience man# problems !n individual approach is necessar#/ however, several ma@or rules appl# to ever# n eonate born with a cleft ! pediatrician8neonatologist is usuall# the first person to ta2e care of a neonate born with a cleft and the first to tal2 to the parents !s soon as possible, refer each bab# born with orofacial cleft to the cleft palate or craniofacial center, where each specialist evaluates the bab#, delineates the best management options and treatment plan, and continuousl# revises individual procedures and treatment during follow'up visits
Feeding an infant #it! a cleft he vast ma@orit# of children with cleft lip and palate (CLP) anomalies are born with a normal birth weight Aowever, because of feeding and other difficulties mentioned above, the most common problem the pediatrician has to deal with is insufficient weight gain One of the pediatrician?s main responsibilities is to closel# monitor the infant?s weight Pediatricians ma# supervise mothers themselves or ma# refer them to a nutritionist, feeding specialist, e"perienced nurse practitioner, or other specialist :ost children born with cleft lip and palate are unable to be breastfed hose with cleft palate cannot produce the negative pressure necessar# for suction :others of children with a unilateral cleft lip ma# succeed with breastfeeding when the child is positioned so that the cleft in the lip is obstructed b# the mother?s breast o single right or correct method of feeding has been identified Parents wor2ing together with the health care provider should choose the method that is best for their infant :ost infants can complete a feeding in $'9& minutes +f more than 7% minutes is required, the infant ma# be wor2ing too hard and ma# be burning calories that should be used for weight gain !n infant who nurses or bottle feeds ever# 9'7 hours tends to gain weight better than an infant who feeds frequentl# (R * h apart) for short periods Aelpful hints for a parent are as follows4 •
Dreastfeeding an infant with a cleft o
o
o
o
o
+n a case of an isolated cleft lip, the infant t#picall# does not e"perience feeding problems be#ond learning how to Qlatch onQ to the nipple at the beginning of the feeding +nfants with cleft palate must squeeBe the mil2 out of the nipple b# compressing the nipple between the tongue and whatever portion of the palate that remains :assaging the breast and appl#ing hot pac2s on the breast *& minutes before nursing usuall# helps he mother should appl# pressure to the areola with her fingers to help the engorged nipple protrude -he should hold the infant in a semi'upright, straddle, or football position -he should support the breast b# holding it between her thumb and middle finger, ma2ing sure that the infant?s lower lip is turned ou t and the tongue is under the nipple +f the infant cannot hold onto the nipple an# more, the mother can collect the remaining mil2 using an electrical or manual breast pump or b# squeeBing the breast with both hands and can finish the feeding with collected mil2 in a bottle he mother should increase her fluid inta2e (drin2 lots of water)
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5eeding breast mil2 with a bottle o
o
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he mother can use a breast pump (an electric pump ensures the highest level of success) hen, she can feed the bab# with a bottle (see below)
5eeding mil2 formula with a bottle o
o
o
o
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Particularl# for infants with bilateral cleft lip and palate, breastfeeding is not possible
he most appropriate mil2 formula should be selected b# a pediatrician or feeding specialist Iarious nipples and bottles are made specificall# for infants with clefts he goal is to find a nipple and bottle that ma2e feeding eas# for the infant and still allow ample opportunit# to suc2 ! soft nipple is generall# better than a hard nipple (some can be softened b# boiling) se a crosscut nipple to prevent cho2ing !n# nipple can be crosscut manuall# using a single'edged raBor blade he crosscut is on the tongue side
o
he bottle should be squeeBed and released, not continuall# squeeBed
o
he nipple is angled to a side of the mouth, awa# from the cleft
Other recommendations o
o
:ore upright or seated positions prevent the mil2 from lea2ing to the nose and causing the infant to cho2e !dvise the mother to stop feeding and allow the infant to cough or sneeBe for a few seconds when nasal regurgitation occurs ! palatal obturator ma# be used
aining weight and preventing aspiration and ear infections are the most important parts of caring for neonates with a cleft during their first da#s and wee2s of life
Multidisci"linary team :ost individuals with cleft lip, cleft palate, or both (and man # individuals with other craniofacial anomalies) require the coordinated care of providers in man# fields of medicine and dentistr#, as well as those in speech patholog#, otolar#ngolog#, audiolog#, genetics, nursing, mental health, and social medicine
reatment of cleft lip and palate anomalies requires #ears of specialiBed care and is costl# he average lifetime medical cost for treatment of one individual affected with a cleft lip and palate is 0$&&,&&&[$] !lthough successful treatment of the cosmetic and functional aspects of orofacial cleft anomalies is now possible, it is still challenging, length#, costl#, and dependent on the s2ills and e"perience of a medical team his especiall# applies to surgical, dental, and speech therapies Decause otitis media with effusion is ver# common among children with cleft palates, involvement of an otolar#ngologist in the multidisciplinar# treatment plan is ver# important he otolar#ngologist performs placement of ventilation tubes in con@unction with the cleft p alate repair [96] +f a concurrent cleft lip is present, the ventilation tubes are placed during that repair :an# of these children see otolar#ngologists well be#ond the time the# see man# of the other specialists because some children continue to have eustachian tube d#sfunction after their palates are closed ! team for the multidisciplinar# treatment of a child with an orofacial cleft includes the following specialists4 •
•
Pediatrician urse practitioner
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Plastic surgeon
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Pediatric dentist
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Otolar#ngologist
•
eneticist
•
enetic counselor
•
-peech pathologist
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Orthodontist
•
:a"illofacial surgeon
•
-ocial wor2er
•
Ps#chologist
o single treatment concept has been identified, especiall# for a cleft lip and palate he timing of the individual procedures varies in different centers and with different specialists
Delow is the most common treatment protocol presentl# used in most cleft treatment centers4 •
ewborn ' 3iagnostic e"amination, general counseling of parents, feeding instructions, palatal obturator (if necessar#)/ genetic evaluation and specification of diagnosis/ empiric ris2 of recurrence of cleft calculated/ recommendation of a protocol for the prevention of a cleft recurrence in the famil#
•
!ge 9 months ' Jepair of cleft lip (and placement of ventilation tubes)
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!ge < months ' Presurgical orthodontics, if necessar#/ first speech evaluation
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!ge 6 months ' -peech therap# begins
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!ge 6'$* months ' Jepair of cleft palate (placement of ventilation tubes if not done at the time of cleft lip repair)
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!ge $'. #ears ' Orthodontic treatment
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!ge .' #ears ' !lveolar bone graft
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Older than #ears ' Orthodontic treatment continues
Other surgical procedures can be performed in patients with severe c lefts as necessar# (see -urgical herap#)
$urgical !era"y ndoubtedl#, closure of the cleft lip is the first ma@or procedure that tremendousl# changes children?s future development and abilit# to thrive Iariations occur in timing of the first lip surger#/ however, the most usual time occurs at appro"imatel# age 9 months Pediatricians used to strictl# follow a rule of Qthree $&sQ as a necessar# requirement for identif#ing the child?s status as suitable for surger# (ie, $& lb, $& mg8L of hemoglobin, and age $& w2) !lthough pediatricians are presentl# much more fle"ible, and some surgeons ma# well @ustif# a neonatal lip closure, considering the rule of three $&s is still ver# useful !natomical differences predispose children with cleft lip and palate and with isolated cleft palate to ear infections herefore, ventilation tubes are placed to ven tilate the middle ear and prevent hearing loss secondar# to otitis media with effusion +n multidisciplinar# teams with significant participation of an otolar#ngologist, the tubes are placed at the initial surger# and at the second surger# routinel# he hearing is tested after the first placement when ears are clear with tubes +f no cleft surger# is planned earl#, placing the tubes b# age < months and monitoring hearing with repeated testing is recommended Complications include eardrum perforation and otorrhea, particularl# in patients with open secondar# palates in which closure is planned for later
5or preventive reasons, ear tubes are usuall# placed when the child is still under general anesthesia for cleft repair 3etailed surgical treatment is described elsewhere (see surgical articles Craniofacial, Dilateral Cleft Lip Jepair , Craniofacial, Dilateral Cleft asal Jepair , Craniofacial, nilateral Cleft asal Jepair , Craniofacial, nilateral Cleft Lip Jepair ) Pediatricians ma# find it useful to inform parents of the 2inds of procedures with a child with cleft ma# undergo he most common surgical procedures for a child with a cleft lip and palate anomal# are as follows4 •
Jepair of the cleft lip
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Jepair of the cleft palate
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Jevision of the cleft lip
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Closure and bone grafting of the alveolar cleft
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Closure of palatal fistulae
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Palatal lengthening
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Phar#ngeal flap
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Phar#ngoplast#
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Columellar lengthening
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Cleft lip rhinoplast# and septoplast#
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Lip scar revision
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Le5ort + ma"illar# osteotom#
+n addition, orthodontic treatment is ver# specialiBed and varies case b# case he * stages of orthodontic treatment of a child with cleft lip and palate are as follows4 •
-urger#'related orthodontics o
;arl# management (since birth until the time of surgical closure of the palate)
o
Orthodontics related to alveolar bone graft
o
•
Permanent dentition management
Cleft'related orthodontics (not related to surgical treatments)
Patient Education 5or e"cellent patient education resources, visit e:edicineAealth?s Children?s Aealth Center
Future and Contro%ersies !vailable research on the association between orofacial clefts and folic acid consumption highl# suggests that a certain proportion of these serious anomalies can be prevented b# periconceptional supplementation of folic acid and multivitamins he preventive approach is assumed to be especiall# successful in those situations in which env ironmental factors represent a substantial part of the etiological bac2ground Primar# prevention (ie, prevention of a birth defect before it develops in the embr#o or fetus) is attempted for prevention of recurrences in at'ris2 families in which a previous b ab# with the anomal# has been born/ it is also applicable in the general population for prevention of occurrences :ore than *& #ears after the first studies in e"perimental animals indicated that vitamin deficienc# in a mother could cause congenital malformations in the offspring,[7&, 7$, 7*] formiminoglutamic acid e"cretion testing for defective folate metabolism was found to be positive more often in women pregnant with a child with a neural tube defect (3) or other congenital abnormalit# than in control sub@ects[79] 5urthermore, periconceptional supplementation with multivitamins[77] or folic acid (Laurence, $6$)[7%] was found to have a role in the prevention of 3s onetheless, prevention of congenital anomalies seemed impossible to realiBe as the ultimate goal of teratolog#,[7<] until a randomiBed, controlled, double'blind, multicenter trial sponsored b# the Dritish :edical Jesearch Council (:JC) showed a .*F decrease in the recurrence of 3s when women ingested 7 mg8d of folic acid from the da# of randomiBation before conception and during $* wee2s thereafter [7., 7] Aowever, proph#lactic multivitamin therap#, including folic acid, was first used to prevent cleft lip (CL) and palate (CLP) anomal# in future offspring of women whose first child had cleft lip with or without cleft palate (CL8P)[76, %&, %$] Dased on the results of those studies, Durian (of the CBechoslova2 !cadem# of -ciences in Prague) initiated a stud# in which women who had given birth to a child with an orofacial cleft began ta2ing the multivitamin supplement preparation -pofavit (vitamins !, D'$, D'*, D'<, C, 3' 9, and ;/ nicotinamide/ and calcium pathothenicum) either immediatel# after a subsequent pregnanc# was confirmed or periconceptionall# when pregnanc# had been planned[%*] !lthough Durian?s observations were mainl# empirical, a prospective trial of periconceptional multivitamin
and high folic acid supplementation was conducted in women at ris2 of giving birth to a child with a cleft lip with or without cleft palate +n a nonrandomiBed interventional stud# completed in the CBech Jepublic, a dramatic reduction of cleft recurrences was found after periconceptional supplementation with multivitamins and a high dose of folic acid[%9, *<] +n this stud#, **$ pregnancies in women at ris2 for a child with a cleft lip and palate were prospectivel# evaluated he $&'step protocol included multivitamin supplementation with -pofavit and folic acid ($& mg8d), beginning at least * months before planned conception and continuing for at least 9 months thereafter ! comparison group comprised $6&$ women at ris2 of giving birth to a child with a cleft lip with or without cleft palate/ this group received no supplementation and gave birth within the same period as the stud# group +n the supplemented group, 9 of *$7 informative pregnancies resulted in neonates with cleft lip with or without cleft palate, a <%7F decrease from the e"pected value (see the image below) -ubset anal#sis b# proband se", severit# of cleft lip with or without cleft palate, and both variables showed the highest supplementation efficac# in probands with unilateral cleft (*
Jecurrence of clefts in supplemented and nonsupplemented groups o efficac# was observed for female probands with bilateral cleft lip with or without cleft palate enerall#, the efficac# was higher for subgroups with unilateral clefts than for those with bilateral clefts and for male than for female probands (see the image below)
Prevention of cleft lip and palate b# periconceptional vitamin (with particularl# high folic acid) supplementation -imilarl#, a large population'based case control stud# of fetuses and live'born infants in the $6.'$66 cohort of births in California reported that periconceptional use of multivitamins, which usuall# contain &7 mg or more of folic acid, reduced the occurrence of cleft lip with or without cleft palate b# appro"imatel# *.'%&F (see the image below)[%7] +n this stud#, .97
mothers with an infant with an orofacial cleft and .97 control mothers with an infant without a birth defect were evaluated
Jecurrence of clefts in supplemented and nonsupplemented groups, severit# of cleft +n contrast, the stud# completed b# Aa#es did not support a protective association between the periconceptional folic acid supplementation and the ris2 of oral cleft[%%] Aowever, the most interesting results that strongl# support using a high dose of folic acid in the prevention of nons#ndromic clefts are those of CBeiBel and his colleagues in the Aungarian Case' Control -urveillance of Congenital !nomalies[%<, %.] he Aungarian randomiBed double'blind, controlled trial of periconceptional supplementation with a multivitamin including a low Qph#siologicQ (as the authors call it) dose of folic acid (& mg8d) did not show an# preventive effect on the first occurrence of isolated cleft lip with or without cleft palate and cleft palate alone[%<, %.] Aowever, the general evaluation of congenital anomalies in this stud# indicated a reduction of nons#ndromic clefts after the use of high doses of folic acid (9'6 mg8d) in the earl# postconception period[%.] CBeiBel?s latest article discusses these * controversial findings and suggests a Qdose'dependent effectQ of folic acid in the prevention of orofacial clefts[%<]
