Undetected Anomalies in Foetuses with a Prenatal Diagnosis of Isolated Cleft, Int J Oral

Home , Van der Woude syndrome

YIJOM-4437; No of Pages 8

Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx

https://doi.org/10.1016/j.ijom.2020.05.005, available online at https://www.sciencedirect.com

Research Paper

Cleft Lip and Palate

1 1

M. Haj , M. J. Koudstaal ,

M. S. Ramcharan ,

Undetected anomalies in 3

A. J. M. Hoogeboom ,

2 3

M. P. H. Koster , M. I. Srebniak ,

T. E. Cohen-Overbeek

foetuses with a prenatal

Department of Maxillofacial Surgery,

Erasmus MC – Sophia Children’s Hospital,

University Medical Centre Rotterdam,

diagnosis of isolated cleft Rotterdam, The Netherlands; Department of

Obstetrics and Gynaecology, Division of

Obstetrics and Prenatal Medicine, Erasmus

MC – Sophia Children’s Hospital, University

M. Haj, M. J. Koudstaal, M. S. Ramcharan, A. J. M. Hoogeboom, M. P. H. Koster, M. Medical Centre Rotterdam, Rotterdam, The

I. Srebniak, T. E. Cohen-Overbeek: Undetected anomalies in foetuses with a prenatal Netherlands; Department of Clinical

Genetics, Erasmus MC – Sophia Children’s

diagnosis of isolated cleft. Int. J. Oral Maxillofac. Surg. 2019; xxx: xxx–xxx. ã 2020

Hospital, University Medical Centre

International Association of Oral and Maxillofacial Surgeons. Published by Elsevier

Rotterdam, Rotterdam, The Netherlands

Abstract. The aim of this study was to determine the rate of undetected additional

anomalies following a prenatal diagnosis of isolated oral cleft. Data of all infants

with a prenatal diagnosis of isolated oral cleft born between 2000 and 2015 were

studied retrospectively. Additional anomalies detected after birth were categorized

as minor or major and included structural and chromosomal anomalies. Isolated

clefts of the lip (CL), lip and alveolus (CLA) and lip, alveolus, and palate (CLAP)

were diagnosed prenatally in 176 live-born infants. The type of cleft was more

extensive after birth in 34/176 (19.3%) and less extensive in 16/176 (9.1%)

newborns. Additional anomalies were diagnosed in 24 infants (13.6%), of which 12

(6.8%) were categorized as major. The latter included two submicroscopic

chromosome anomalies and two gene mutations. Postnatal additional anomalies

occurred more frequently in CLA and CLAP than in CL, and more in bilateral than

in unilateral clefts. Major anomalies are still found in infants with a prenatal

Key words: genetic testing; prenatal diagnosis;

diagnosis of an isolated oral cleft. The prevalence of additional anomalies seems to cleft lip; cleft palate; prenatal ultrasonography.

be related to the type and bilaterality of the cleft, and this should be considered

during prenatal counselling. Accepted for publication 11 May 2020

Oral cleft (OC) is the most common challenging start to life and may have a The introduction of the routine prenatal

congenital craniofacial anomaly, with an substantial impact on the (psychosocial) anomaly scan in the Netherlands in 2007

1 4,5

incidence of 1:700 . The following phe- health of the child and parent . Prenatal has increased the prenatal detection rate of

notypes are distinguished: cleft lip (CL), assessment is important to determine the CL, CLA, and CLAP substantially, from

cleft lip and alveolus (CLA), cleft lip, type of OC and the presence of other 5% in the 1980s to over 86% in the past

11,12

alveolus, and palate (CLAP), and cleft anomalies in order predict the outcome. decade . Prenatal detection rates of

palate (CP) . The likelihood of the pres- Counselling may enable parents to process isolated CP are low and remain challeng-

ence of other structural anomalies and disappointment and prepare for adjusted ing. This could be explained by the ab-

chromosomal anomalies increases when care during the pregnancy and after birth, sence of obvious facial clues suggesting

2,3

an oral cleft is diagnosed . The presence rather than being confronted with difﬁcul- the presence of a CP when no other anom-

6–10 13

of additional anomalies may result in a ties when a child is born . alies are suspected .

Please cite this article in press as: Haj M, et al. Undetected anomalies in foetuses with a prenatal diagnosis of isolated cleft, Int J Oral

Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.05.005

YIJOM-4437; No of Pages 8

2 Haj et al.

Fig. 1. Overview of results: prenatal apparent isolated oral clefts and postnatal additional anomalies.

Cleft type: CL, cleft lip; CLA, cleft lip and alveolus; CLAP, cleft lip, alveolus, and palate; CLA(P), cleft lip, alveolus, and (probably) palate.

Invasive prenatal testing is offered in the recent literature (including 344 foe- Materials and methods

when an OC is diagnosed . In our labo- tuses), with this rate varying between 10%

17–19

ratory, foetal karyotyping was replaced by and 30% . These studies did not in- This was a retrospective cohort study of all

14,15

microarray analysis starting in 2011 . clude data on chromosomal anomalies consecutive pregnancies with foetuses di-

Despite advanced prenatal diagnostic detected by means of microarray analysis. agnosed with an isolated OC, live-born

methods, not all additional anomalies The aim of this study was to evaluate the between January 2000 and May 2015 in

may or can be detected before birth. In rate and severity of postnatally detected the South-West region of the Netherlands.

17 postnatal studies including 28,953 additional chromosomal aberrations and/ When an OC was suspected during the

infants with OC, the prevalence of addi- or structural anomalies in infants with a pregnancy, the prospective mother was

tional anomalies varied between 17% and prenatal diagnosis of isolated oral cleft in referred to Erasmus MC, a tertiary referral

60% . The rate of additional anomalies the South-West region of the Netherlands. hospital, for a prenatal expert ultrasound

following a prenatally diagnosed isolated The ultimate aim was to enable comprehen- examination, including two-dimensional

OC has been reported in only three studies sive prenatal counselling. and three-dimensional ultrasound. When

Table 1. Prenatal diagnosis and postnatal outcome of 12 cases with prenatal apparent isolated cleft and minor postnatal additional anomalies.

Prenatal Postnatal Prenatal genetic Postnatal structural Postnatal syndromic Postnatal genetic

Sex Birth year diagnosis diagnosis Side cleft investigation anomalies anomalies investigation Death

F 2014 CLAP CLAP L x Pre-auricular ﬁstula None x No

M 2014 CLAP CLAP B Normal ASD type II, mild None x No microarray peripheral

pulmonary stenosis,

syndactyly

M 2012 CLAP CLA B Normal None Van der Woude IRF6 gene No

microarray mutation (target mutation

analysis)

F 2012 CLA CLA L x Cleft earlobe None x No

F 2011 CLA(P) CLAP L x None Van der Woude x No

M 2010 CLAP CLAP B Normal Perimembranous None No CHD7 gene No

karyotype VSD, ASD type II mutation (target mutation

analysis), normal

microarray

M 2010 CLA(P) CLAP L x Accessory auricle None x No

F 2010 CLAP CLAP R Normal Syndactyly None x No

karyotype

M 2009 CLA(P) CLAP B Normal None Amniotic band x No

karyotype constriction left hand

M 2008 CLAP CLAP L x None Van der Woude x No

M 2003 CLA CLA L x Syndactyly None x No

F 2002 CLA(P) CLAP B x Congenital ectropion BCD CDH1 gene No

mutation (target mutation

analysis)

ASD, atrial septal defect; B, bilateral; BCD, blepharocheilodontic syndrome; CLA, cleft lip and alveolus; CLAP, cleft lip, alveolus, and palate;

CLA(P), cleft lip, alveolus, and (probably) palate; F, female; L, left; M, male; R, right; VSD, ventricular septal defect; ‘x’, not performed/not

available.

Please cite this article in press as: Haj M, et al. Undetected anomalies in foetuses with a prenatal diagnosis of isolated cleft, Int J Oral

Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.05.005

YIJOM-4437; No of Pages 8

Undetected anomalies in prenatal isolated cleft 3 Yes, at 4.5 months (infectious respiratory failure) No Yes, at 31 months (infectious respiratory failure) No No No Postnatal genetic investigation Death (c.1828dupG) (target mutation analysis) 3p21.31p14.1 (48,012,380- 64,294,973)x3 16.3 Mb 3p21 duplication (38,283-8,321,040) x1 8.3 Mb 4p deletion (41318438- 44676420)x1 3.4 Mb 6p21.1 deletion chromosome 3 der(3)del(3)(p25.3) inv dup(3) (p22.3p25.3) arr[hg18] 3p26.3p 25.3(48,603- 8,994,748) x1,3p25.3p22.3 (9021906- 36061113)x3 8.9 Mb 3p deletion 27 Mb 3p duplication mutation (target mutation analysis) on, genital abnormalities, and ear abnormalities; CL, M, male; R, right; VSD, ventricular septal defect; ‘x’, not Postnatal syndromic anomalies CHARGE CHD7 gene mutation NoneNone x arr[hg18] No None x No Wolf–Hirschhorn arr[hg18] 4p16 None Derivative BCD CTNND1 gene Goldenhar x No None x No VSD, laryngomalacia, malformation falx cerebri, deafness, Ebstein anomaly Microcephaly, hepatosplenomegaly, syndactyly, developmental delay pulmonary stenosis, developmental delay auditory canal atresia, accessory auricle Patent ductus arteriosus, ASDsevere type pulmonary II, stenosis, epilepsy, psychomotor retardation persisting cavum septi pellucidi, ASD type II (clinically insigniﬁcant), mild glandular hypospadias, psychomotor retardation, congenital dysplasia of the hip the intracranial space, congenital ﬁlamentous adhesion of thelower upper eyelids and Craniofacial microsomia, microtia, external auditory canal atresia, scoliosis Oesophageal atresia, hypertrophic pyloric stenosis Prenatal genetic investigation Postnatal structural anomalies microarray karyotype karyotype karyotype Postnatal diagnosis Side cleft Prenatal diagnosis . Prenatal diagnosis and postnatal outcome of 12 cases with prenatal apparent isolated cleft and major postnatal additional anomalies.

Table 2 Sex Birth year MM 2015 2014 CLAP CLAP CLAP CLAP L L x Normal Subglottic stenosis None x No M 2014 CLAP CLAP L x Choanal atresia, chorioretinal coloboma, FF 2013 2012 CL CLA CLAP CLAP L R x x Radioulnar synostosis Anterior ectopic anus, peripheral None x No F 2010 CLA(P) CLAP L Normal F 2012 CLAP CLAP L x Unilateral microtia/unilateral external M 2009 CLA(P)M CLAP 2008 R CLA(P) CLA x BF x 2008 Developmental delayM CLAP 2004 CLAP Ectopic posterior pituitary glands, CLA(P) B CLA None R x Normal arr[hg19] 6p21.1 Congenital nasal cyst with extension into M 2002 CLA(P) CLAP B Normal cleft lip; CLA, cleft lip andperformed/not alveolus; CLAP, available. cleft lip, alveolus, and palate; CLA(P), cleft lip, alveolus, and (probably) palate; F, female; L, left; ASD, atrial septal defect; B, bilateral; BCD, blepharocheilodontic syndrome; CHARGE, coloboma, heart defects, choanal atresia, growth retardati

Please cite this article in press as: Haj M, et al. Undetected anomalies in foetuses with a prenatal diagnosis of isolated cleft, Int J Oral

Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.05.005

YIJOM-4437; No of Pages 8

4 Haj et al.

the OC was conﬁrmed, invasive genetic Prenatal data CLAP: OR 8.32, 95% CI 1.02–67.9). Ad-

prenatal testing was offered to identify any ditional anomalies were diagnosed in 16/

During prenatal expert ultrasound exami-

chromosomal aberrations. From 2000 to 143 (11.2%) infants with a unilateral oral

nation, 32 (18.2%) foetuses were diag-

2011, conventional karyotyping was avail- cleft and in 8/33 (24.2%) infants with a

nosed with CL, 35 (19.9%) with CLA,

able as a routine diagnostic tool. In mid- bilateral oral cleft (OR 2.54, 95%

52 (29.5%) with CLAP, and 57 (32.4%)

2011, microarray genomic testing was CI 0.98–6.57). No statistical signiﬁcance

with CLA(P) (Fig. 1).

introduced as common practice. Prospec- was found.

tive parents were counselled by the ‘cleft All infants with additional anomalies

team’ on the prognosis and treatment categorized as major had multiple anoma-

20 Postnatal data

options prior to 24 weeks of gestation . lies. Eleven of the 12 infants with anoma-

Psychosocial support was available. Fol- Postnatal clinical assessment of the OC lies categorized as minor had a single

lowing birth, the infant was examined by conﬁrmed the ultrasound diagnosis in 126/ anomaly. Fig. 2 shows the distribution

a paediatric specialist. The type of cleft 176 (71.6%) infants, while 50 (28.4%) of the additional structural anomalies by

(CL/CLA/CLAP/CP) was conﬁrmed or diagnoses were revised (Fig. 1): 34 organ system. Chromosomal aberrations

revised. The extent of the oral cleft (19.3%) to a more extensive type and 16 and gene mutations associated with known

(unilateral/bilateral) was determined. If (9.1%) to a less extensive type of cleft. A syndromes were diagnosed in 8/176

dysmorphic features or an abnormal de- submucous cleft of the palate was deter- (4.5%) infants (one Van der Woude

velopment were suspected, the child was mined in two infants with a prenatal diag- syndrome, two blepharocheilodontic syn-

also examined by a clinical geneticist and nosis of CL and in two with CLA. (Bi) drome (BCD), one CHARGE syndrome,

if indicated, a targeted mutation analysis laterality was revised in 13/176 (7.4%) and four pathogenic chromosomal aberra-

was performed. infants; seven prenatally unilateral clefts tions, of which one was associated with

Data were extracted from the hospital’s were diagnosed as bilateral and six prena- Wolf–Hirschhorn syndrome). Syndromic

electronic health records (Elpado/Astraia). tally bilateral clefts were diagnosed as disorders were clinically diagnosed in 3/

Based on the ultrasound reports, the type unilateral after birth. A unilateral cleft 176 (1.7%) cases (two Van der Woude and

of cleft was categorized as CL, CLA, CLA was seen in 143 (81.3%) infants (15 CL, one Goldenhar syndrome). Two patients

(P), or CLAP. The CLA(P) type was 39 CLA, 89 CLAP) and a bilateral cleft in died due to respiratory failure as a result of

assigned when following the diagnosis 33 (18.8%) infants (1 CL, 6 CLA, 26 a viral pulmonary infection, one at 4.5

of CLA, the presence of a cleft palate CLAP). Ninety-seven of the unilateral months after birth and the other at 31

was noted as ‘probable but could not be clefts (67.8%) were left-sided and 46 months. Both had been diagnosed with a

ascertained on the sonographic images (32.2%) were right-sided. syndromic disorder (CHARGE syndrome

obtained’. Isolated cleft palates were not and Wolf–Hirschhorn syndrome).

detected prenatally and hence where not

included in this study. The postnatal data Postnatal assessment of associated

were reviewed by a clinical geneticist, structural and syndromic anomalies Chromosomal aberrations and prenatal

who categorized any additional anomalies cytogenetic diagnosis

Additional anomalies were found in 24/

into minor or major. This was based on the

176 (13.6%) infants with a prenatally ap- Invasive prenatal testing was performed in

clinical relevance; abnormalities resulting

parent isolated oral cleft; 12 (6.8%) were 87/176 (49.4%) pregnancies; 54/176

in any permanent functional impairment

categorized as minor (0 CL, 3 CLA, 9 (30.7%) by karyotyping and 33/176

were considered major. The cases with

CLAP) and 12 (6.8%) were categorized (18.7%) by microarray analysis. Eight of

chromosomal aberrations were re-evaluat-

as major (0 CL, 2 CLA, 10 CLAP) (Tables the 87 infants who had undergone amnio-

ed by a laboratory specialist. Terminated

1 and 2). A higher prevalence of additional centesis (9.2%) were diagnosed with ad-

pregnancies (n = 5) and premature

anomalies was noted with increasing se- ditional anomalies during the postnatal

deliveries (n = 1) were excluded because

verity of the type of cleft in reference to period, of which four were major. One

phenotypic data were lacking.

cleft lip only (CLA: odds ratio (OR) 2.91, infant with a prenatal normal karyotype

95% conﬁdence interval (CI) 0.29–29.45; was diagnosed postnatally with a submi-

CLA(P): OR 5.81, 95% CI 0.70–48.2; croscopic 4p deletion associated with

Statistical analysis

The statistical analysis was performed

using IBM SPSS Statistics version 21.0

software (IBM Corp., Armonk, NY,

USA). Associations between the prenatal

and postnatal type of OC and postnatal

additional anomalies were tested by logistic

regression analysis. Probabilities less than

0.05 were regarded as being signiﬁcant.

Results

The data of 176 live-born infants diag-

nosed prenatally with an isolated OC were

included. The postnatal follow-up period

ranged from 1.4 to 16.2 years (median 6

years). Fig. 2. Distribution of additional structural anomalies by organ system.

Please cite this article in press as: Haj M, et al. Undetected anomalies in foetuses with a prenatal diagnosis of isolated cleft, Int J Oral

Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.05.005

YIJOM-4437; No of Pages 8

Undetected anomalies in prenatal isolated cleft 5

Fig. 3. Three examples of the prenatal and postnatal diagnosis. (A–C) Prenatal diagnosis of cleft lip (CL), conﬁrmed after birth (CL). (D–F)

Prenatal diagnosis of cleft lip (CL), revised to cleft lip and alveolus (CLA) after birth. (G–I) Prenatal diagnosis of cleft lip (CL), revised to cleft lip,

alveolus, and palate (CLAP) after birth. Arrows indicate the cleft lip in the coronal ultrasound image. Arrowheads indicate the cleft lip and

apparent intact alveolus and palate.

Wolf–Hirschhorn syndrome identiﬁed by Amniocentesis was declined by 89 these women (3.4%), which were catego-

microarray analysis. Prenatal microarray (50.6%) pregnant women. Postnatal geno- rized as major: two microscopically visi-

analysis was not routinely available at the mic microarray revealed chromosomal ble (3p21 duplication and a derivative

time of pregnancy. aberrations in the offspring of three of chromosome 3) and one submicroscopic

Please cite this article in press as: Haj M, et al. Undetected anomalies in foetuses with a prenatal diagnosis of isolated cleft, Int J Oral

Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.05.005

YIJOM-4437; No of Pages 8

6 Haj et al.

aberration associated with developmental In the majority of cases, the prenatal BCD with intracranial extension). If pre-

delay and likely causal for CLAP (3.4 diagnosis was determined prior to 24 natal diagnosis using microarray and

21,22

Mb 6p21.1 deletion) . In two of these weeks of gestation. The additional struc- whole exome sequencing (WES) was per-

cases, additional structural anomalies tural anomalies not detected until after formed in all cases, the diagnosis of addi-

were found, and developmental delay birth were anomalies that may only be- tional genetic anomalies would have been

was detected in all three during follow- come evident late in gestation (microceph- possible before birth in an additional 4.5%

30,31

up. Furthermore, postnatal targeted muta- aly and severe pulmonary stenosis) or (8/176).

tion analysis identiﬁed two gene mutations anomalies known to be difﬁcult to diag- The strengths of this study are the large

in the major group (a CHD7 mutation nose due to the variable presentation of sample size, the subdivision of cleft types

associated with CHARGE syndrome and abnormal structures. Examples of the lat- (CL, CLA, CLAP) and extent (unilateral/

a CTNND1 mutation associated with BCD ter are Ebstein anomaly, ventricular septal bilateral), and the reporting on the addi-

syndrome) and two gene mutations in the defect, anterior ectopic anus, and oesopha- tional value of microarray analysis. A

31–34

minor group (an IRF6 mutation associated geal atresia . Similar anomalies were main limitation is the retrospective na-

with Van der Woude syndrome and not detected before birth in two recent ture. The shorter follow-up period of

a CDH1 mutation associated with BCD studies, indicating the limitations of ultra- infants born in the last 2 years of the

18,28

syndrome). sound in pregnancy . study might have resulted in an underes-

Two of the four patients with an aber- timation of the rate of associated anoma-

rant chromosome status carried a large lies (especially milder developmental

chromosomal aberration (3p duplication delay, speech disorders, and intellectual

Discussion

and derivative chromosome 3); the other disability revealed later in life). More-

Additional congenital structural anoma- two carried submicroscopic aberrations over, submicroscopic aberrations and

lies and/or constitutive chromosomal (6p21 deletion and 4p deletion). Novel gene mutations were not tested and ex-

aberrations were found in 13.6% of high-resolution genetic tests such as cluded in all of the cases during the

patients, half of which were considered microarray-based genomic analysis can follow-up period.

as major. The prenatal diagnosis of the detect all of these chromosomal aberra- In conclusion, additional anomalies

type of cleft was revised to a more exten- tions, in contrast to conventional karyo- were seen in almost one in every 7.5

sive type in 34 (19.3%) infants and to a typing, which has a limited resolution . infants diagnosed prenatally with an iso-

less extensive type in 16 (9.1%). The use of this technique reduces the rate lated OC. The introduction of microarray

No false-positive prenatal cleft diagno- of undetected chromosomal aberrations analysis has increased the diagnosis of

ses were noticed, conﬁrming earlier stud- associated with structural and syndromic chromosomal aberrations. Involvement

18,23,24 36

ies . The prenatal diagnosis of the malformations . Contrary to past opi- of the alveolus and the palate and a

15,37,38

type of cleft was revised in 28.4% of nions , we believe that invasive ge- bilateral cleft appear to be related to a

infants, which compares well with netic testing for all types of OC is higher risk of additional anomalies. The

the 30% and 35% found in previous justiﬁed in view of the occasional incon- diagnosis of only a CL during prenatal

12,18

studies . The revisions were most com- sistencies in the pre- and postnatal diag- screening does not rule out the presence

mon in the CL group. The prenatal diagnosis of the type of cleft in relation to the of associated anomalies postnatally, tak-

nosis of CL was revised in 19/32 (59.4%) prevalence of additional anomalies, the ing into account the revision rate of the

cases to a more extensive type (CLA or introduction of microarray analysis, and type of cleft after birth. Possible incon-

CLAP), and one infant with CLAP was the low additional risk of foetal loss sistencies with the ﬁnal postnatal diagno-

12,37,38

also revealed to have a radioulnar synos- following amniocentesis . Microar- sis of the type of cleft and the rate of

tosis. These revisions could be explained ray testing may reveal chromosomal undetected additional anomalies should

by the challenging detection of mild alve- aberrations associated with features that be discussed during prenatal parental

olar notches and (submucous) cleft palate, cannot be detected on ultrasound, such as counselling.

as reported previously by several authors developmental delay or hypotony, but

25–27

and shown in Fig. 3 . No additional which strongly inﬂuence the foetal prog-

structural anomalies or chromosomal nosis. Although microarray testing is of-

Patient consent

aberrations were found in infants with a fered in all pregnancies with anomalies

postnatal diagnosis of CL. detected on ultrasound, parents often de- Not required.

The type and extent of the OC is related cline genetic testing, as revealed in the

to the prevalence of additional anoma- present study and a previous Dutch

2,3,16,24 12

lies . The present study data conﬁrm study . Prior to the microarray era, the

Funding

these ﬁndings, as the frequency of addi- risk of an abnormal karyogram associated

tional anomalies increased with involve- with OC was low . This might have None.

ment of the alveolus and the palate. Only inﬂuenced counselling concerning inva-

this study and the study by Depla et al. sive procedures. Cultural attitudes in the

have reported the prenatal diagnoses of Netherlands, in addition to parental fear

Ethical approval

CL, CLA, and CLAP subdivisions, of miscarriage could also have played a

suggesting differences in the prevalence role, despite the low risk of pregnancy Data collection and protection took place

37,40

of additional anomalies. loss . according to the privacy regulations of the

Additional anomalies were diagnosed In addition to the chromosomal aberra- Erasmus MC. Approval was not required

more frequently in infants with a bilateral tions detected postnatally by microarray according to the judgement obtained from

cleft compared to a unilateral cleft, as analysis, gene mutations were identiﬁed the Ethics Review Board of the Erasmus

also reported by Hagberg et al. and using targeted mutation analysis, of which MC, Rotterdam, the Netherlands (MEC-

Fleurke-Rozema et al. . two were major anomalies (CHARGE and 2016-576).

Please cite this article in press as: Haj M, et al. Undetected anomalies in foetuses with a prenatal diagnosis of isolated cleft, Int J Oral

Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.05.005

YIJOM-4437; No of Pages 8

Undetected anomalies in prenatal isolated cleft 7

Competing interests 14. Srebniak M, Boter M, Oudesluijs G, Joosten Ultrasound Obstet Gynecol 2010; :495–

M, Govaerts L, Van Opstal D, Galjaard RJ. 502.

The authors have no conﬂicts of interest to

Application of SNP array for rapid prenatal 26. Maarse W, Pistorius LR, Van Eeten WK,

declare.

diagnosis: implementation, genetic counsel- Breugem CC, Kon M, Van den Boogaard

ling and diagnostic ﬂow. Eur J Hum Genet MJ, Mink van Der Molen AB. Prenatal

2011;19:1230–7. ultrasound screening for orofacial clefts.

15. Srebniak MI, Boter M, Oudesluijs GO, Ultrasound Obstet Gynecol 2011;38:434–9.

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Please cite this article in press as: Haj M, et al. Undetected anomalies in foetuses with a prenatal diagnosis of isolated cleft, Int J Oral

Maxillofac Surg (2020), https://doi.org/10.1016/j.ijom.2020.05.005