Syndromic and Non-Syndromic Orofacial Clefts

Literature and regulatory information updated: 6 October 2026.

Cleft lip with or without cleft palate and isolated cleft palate: non-syndromic forms with multifactorial inheritance, monogenic forms (IRF6-related van der Woude syndrome and popliteal pterygium syndrome, GRHL3-related van der Woude syndrome type 2, TBX22-related X-linked cleft palate with ankyloglossia, MSX1- and TP63-related forms), chromosomal forms (22q11.2 deletion) and teratogenic forms; Robin sequence, Stickler syndrome and 22q11.2 deletion enter the differential diagnosis

0. Initial Reference Table

1. Introduction

Clefts of the lip and palate constitute the most frequent group of craniofacial malformations and a classic model of complex aetiology, in which Mendelian, chromosomal and teratogenic forms coexist with a majority of isolated cases whose susceptibility results from the combined effects of genetic and environmental factors [1, 8]. Familial aggregation was recorded long before formal genetics, in descriptions by Trew (1757), Sproule (1863) and Darwin (1875), but the first systematic genetic study was undertaken by the Danish surgeon Poul Fogh-Andersen, who in 1942 documented increased cleft frequency among relatives of surgically treated patients [28]. Fogh-Andersen and, later, Fraser demonstrated that clefts involving the lip and primary palate are genetically and embryologically distinct from those affecting only the secondary palate, a division maintained to this day between cleft lip with or without cleft palate and isolated cleft palate [8]. The patient lists maintained by Fogh-Andersen between 1934 and 1986 became the basis of the Danish Facial Cleft Database, from which the most precise recurrence risks currently available were calculated [16].

In the mid-1960s, the observation that common malformations such as clefts, neural tube defects, clubfoot and hypertrophic pyloric stenosis clustered in families without following Mendelian proportions led to the formulation of the multifactorial threshold model, attributed to Falconer. In this model, susceptibility, continuously distributed in the population and determined by multiple genes and the environment, is expressed as a malformation only above a threshold [13, 29]. This model continues to underpin empirical counselling for isolated clefts, although segregation analyses suggest a small number of loci (between two and eight) with a multiplicative effect [13, 16].

Among monogenic forms, Anne van der Woude described in 1954 the association of congenital lower lip fistulae with cleft lip and palate and dominant transmission, after Demarquay had observed the condition in 1845 [4, 30]. In 2002, Kondo and colleagues identified IRF6 mutations in the affected monozygotic twin of a pair discordant for van der Woude syndrome and subsequently in 45 families with this syndrome and 13 families with popliteal pterygium syndrome, establishing the allelic relationship between the two entities [31]. This was followed by identification of TBX22 in X-linked cleft palate with ankyloglossia in 2001 and GRHL3 in families with van der Woude syndrome without an IRF6 mutation in 2014 [11, 32]. From 2009, genome-wide association studies identified risk loci for non-syndromic forms, such as the 8q24 region, VAX1, NOG, MAFB and ABCA4, and confirmed the role of common IRF6 variants [8, 28].

Care organisation evolved alongside these developments. The American Cleft Palate-Craniofacial Association (ACPA) codified ten principles of interdisciplinary care in 1991 and published assessment and treatment parameters in 1993, 2018 and 2024 [20]. In Europe, the Eurocleft study revealed marked differences in outcomes between centres and led, between 1996 and 2000, to a European Commission-funded project that produced clinical policy statements, minimum care recommendations and shared records; the survey conducted at that time found 194 different protocols for unilateral cleft alone among 201 registered centres [33]. In South America, the Latin American Collaborative Study of Congenital Malformations (ECLAMC) has monitored oral clefts since 1967 through a hospital network across all countries in the region [34]. In France, the reference centre network for clefts and facial malformations (MAFACE) has had a coordinating centre recognised by the Ministry of Health since 2005, and the Haute Autorité de Santé published in 2021 a Protocole National de Diagnostic et de Soins (PNDS; French National Diagnosis and Care Protocol) dedicated to cleft lip and/or palate [10].

This article addresses non-syndromic clefts together with the principal syndromic forms presenting with a cleft, with dedicated subsections on IRF6-related syndromes (van der Woude and popliteal pterygium), GRHL3, TBX22 and MSX1; Stickler syndrome, Robin sequence and 22q11.2 deletion enter the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. Embryology of the lip and palate

The face forms through cell migration and fusion of prominences: the upper lip is a mosaic structure composed of the frontonasal, maxillary and mandibular processes [1]. Around seven weeks of gestation, the maxillary prominences approach the already fused medial nasal prominences, forming labial grooves normally filled by mesenchyme; if filling fails, the groove persists and residual tissue in its floor ruptures, producing a complete unilateral cleft [1]. Smith places normal lip fusion at 35 days of intrauterine age and complete palatal shelf closure between the eighth and ninth weeks, explaining how failed lip fusion may secondarily compromise palate closure; hence the frequent association of cleft lip and cleft palate, dental anomalies in the cleft region and incomplete growth of the nasal ala on the affected side [7]. Cleft palate results from failure of approximation and fusion of the mesenchymal masses of the lateral palatal processes with each other, the nasal septum or the posterior margin of the median palatal process; in females, the palatal processes fuse approximately one week later than in males, and upper lip and palate formation is complete by 12 weeks [1]. The Dutch guideline emphasises that most complete lip clefts and alveolar process clefts arise in the first seven weeks after conception, whereas incomplete lip and alveolar process clefts and palatal clefts arise during or after palatal fusion (after seven to eight weeks), a period that, according to the authors, lies outside their country's recommended window for folic acid supplementation [18]. The French PNDS places cleft lip and cleft lip and alveolus between the 5th and 7th weeks of pregnancy, through failed fusion of the nasal and maxillary processes, and velopalatal cleft between the 7th and 10th weeks (up to the 12th, in another passage of the same document), through failed fusion of the palatal processes; because palatal fusion progresses from front to back, incomplete forms are posterior [10].

In Robin sequence, mandibular hypoplasia before nine weeks keeps the tongue between the vertical palatal shelves and prevents their horizontalisation and fusion, producing a posterior “U-shaped” cleft, distinct from the inverted “V-shaped” cleft of primary closure failure; fetal MRI showing the tongue interposed in the cleft supports this mechanical mechanism [27, 35].

2.2. Non-syndromic clefts: multifactorial architecture

The multifactorial threshold model makes predictions consistent with clinical observations: familial aggregation and variation in prevalence between populations; first-degree relative risk close to the square root of population risk; a marked fall in risk in second-degree relatives; increased risk with the number of affected relatives, consanguinity and the severity of the proband's malformation; and greater risk for relatives of the less frequently affected sex [13]. For cleft lip with or without cleft palate, Smith reports recurrence of 5.7% after a child with severe bilateral cleft lip and palate, compared with 2.5% when the defect is less severe [13]. Concordance of 40–60% in monozygotic twins versus 3–5% in dizygotic twins indicates a strong but non-exclusive genetic component [28]. Smith acknowledges that the model is probably not biologically exact, but that the empirical data underlying it remain the basis for counselling, and adds that low-penetrance copy number variants (1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.3) should be understood within this framework [13].

Genome-wide association studies confirmed IRF6 and identified the 8q24 region, a gene desert near MYC with a particularly strong signal in European populations, and the VAX1 (10q25) and NOG (17q22) loci; the GENEVA consortium added MAFB and ABCA4, with a stronger signal in Asian trios, suggesting that the relative contribution of each susceptibility gene varies between populations [8]. A 2012 meta-analysis increased to 12 the number of regions with genome-wide significance for non-syndromic lip clefts, whereas loci associated with isolated cleft palate show almost no overlap with these, reinforcing the historical separation of the two categories [28]. SGRT lists genome-wide significant polymorphisms in RAD54B, TMEM19, KRT18, WNT9B, GSC/DICER1, PTCH1, RPS26, OFCC1/TFAP2A, TAF1B, FGF10, MSX1, LINC00640, FGFR1 and SPRY1 [6]. The French PNDS lists as candidate genes for non-syndromic clefts IRF6, the 8q24 region, VAX1, MSX1, FOXE1, MYH9, MAFB, ABCA4, the 17q22 region, BMP4 and FGFR2, to which meta-analyses add TGFA, CRISPLD2, MTHFR, WNT3, RFC1 and the 20q12 region, and associates GRHL3, SMC2 and a locus at 1p33 with cleft palate in particular; the document stresses the low level of evidence and the sometimes contradictory results of these studies, some with an effect restricted to certain ethnic origins [10]. IRF6 variation accounts for approximately 12% of the genetic contribution to cleft lip with or without cleft palate and, in a study of 1,968 families from 10 populations, tripled recurrence risk in families with one affected child [36]. The mechanism was partly clarified by identification of rs642961, situated in an enhancer approximately 10 kb upstream of the IRF6 transcription start site, which disrupts an AP-2α binding site and is overtransmitted in isolated cleft lip [8, 37]. In 2025, a multiancestry meta-analysis with more than 14,000 individuals replicated 13 known loci and identified new associations at 1p36.32, 7q33 (CALD1), 16p13.3 (RBFOX1) and a second independent signal at 8q22.1 (ESRP1) [38].

2.3. Rare and de novo variants in apparently isolated clefts

The boundary between syndromic and non-syndromic forms is less distinct than the clinical classification suggests. Pathogenic IRF6 variants were found in 0.47% (18/3,811) of individuals with non-syndromic orofacial clefts [4]; MSX1 mutations were identified in approximately 2% of cleft cases and should be considered when there is dominant transmission or tooth agenesis segregating with the cleft [1, 39]; TBX22 mutations were described in approximately 5% of non-syndromic cleft palates in clinical series [19]. In a genome-wide association study of non-syndromic cleft palate, the missense variant GRHL3 p.Thr454Met (c.1361C>T; rs41268753, in the authors' designation) reached genome-wide significance, with an odds ratio of 8.3 in the discovery sample and 2.16 in replication, approximately one-third of normal protein transcriptional activity and altered periderm development in zebrafish [12]. Analysis of 818 cleft palate trios showed overall enrichment of protein-altering de novo variants (1.48-fold), greater in syndromic (1.70) than non-syndromic probands (1.31), with specific enrichment in SATB2, MEIS2, COL2A1, ZC4H2, EFTUD2, KAT6B and ANKRD11; IRF6 stood out in non-syndromic and ZC4H2 in syndromic cases [40]. A study of 2,497 trios, still a preprint without peer review, described enrichment of truncating and deleterious missense de novo variants (odds ratio 2.17 relative to 5,515 control trios) and proposed 39 risk genes with a false discovery rate below 5% [41]. The Dutch guideline reports, in a retrospective series of 212 patients tested with a cleft panel between 2015 and 2020, a genetic diagnosis in 11.3% through the panel and a further 3.8% through additional tests, with a warning that this population was biased towards cases with additional anomalies or a family history [18]. The French PNDS reports that, in the experience of the MAFACE reference centre, 11% of patients with non-syndromic cleft lip and palate had an IRF6 variant and 4% an MSX1 variant, without van der Woude syndrome; the document does not state the denominator, the method or the variant classification criteria, and these values from a reference centre series are far higher than the 0.47% given by GeneReviews for non-syndromic clefts, so they cannot serve as a population estimate [4, 10].

2.4. IRF6-related syndromes: van der Woude (VWS1) and popliteal pterygium

IRF6 (1q32.2; OMIM 607199) encodes interferon regulatory factor 6, a member of a transcription factor family sharing a highly conserved helix–turn–helix DNA-binding domain (amino acids 13–113 in IRF6, with a pentatryptophan motif) and a less conserved protein-binding domain (amino acids 226–394), the IRF association or SMIR domain [4]. IRF6 determines the transition between keratinocyte proliferation and differentiation and is required for oral periderm formation; Irf6-deficient mice show skin, limb and facial abnormalities, and heterozygous embryos exhibit oral epithelial adhesions that, in the absence of periderm, expose E-cadherin at the surface and prevent timely elevation and apposition of the palatal shelves [4, 8]. IRF6 is also a direct target of p63, which activates it through an enhancer, linking clefts in TP63 syndromes to the same pathway [8]. ClinGen assigns IRF6 a haploinsufficiency score of 3 (sufficient evidence), with no evidence of triplosensitivity (last assessment in 2012) [42].

Two mechanisms explain the clinical spectrum. In van der Woude syndrome, whole-gene deletions and almost all truncating variants indicate haploinsufficiency, and missense variants are distributed across the DNA-binding (exons 3 and 4) and protein-binding domains (exons 7 to 9) [4]. In popliteal pterygium syndrome, 78% of variants are missense and 72% are in exon 4, concentrated in residues directly contacting DNA (Trp60, Lys66, Gln82, Arg84, Lys89); by structural analogy with IRF1, these variants prevent DNA binding without affecting dimerisation, producing a dominant-negative effect [4]. Mice carrying the p.Arg84Cys allele have more extensive oral adhesions than null heterozygotes, supporting this effect [4]. Variants in exons 3, 4, 7 and 9 account for 80% of known VWS variants (307 families) [4, 43]. Sequence analysis should include the upstream regulatory region, particularly the MCS9.7 enhancer, situated 9.7 kb before the transcription start site, where substitutions and small duplications have been identified in VWS families [4].

The coordinate conversions in the table were confirmed in VariantValidator, which identifies NM_006147.4 as the MANE Select transcript; the Brazilian case was published using the previous version NM_006147.3, which produces the same c. and p. descriptions [44, 45].

2.5. GRHL3 (VWS2), TBX22, MSX1 and TP63

GRHL3 (1p36.11; MANE transcript NM_198173.3) encodes a transcription factor required for stratified epithelial differentiation, the epidermal barrier and oral periderm development [5, 44]. Coding GRHL3 mutations were found in 8 of 45 VWS families without an IRF6 mutation; in a zebrafish assay, these mutations abolished periderm development in a manner consistent with a dominant-negative effect, contrasting with haploinsufficiency in most IRF6 cases; all Grhl3-null mouse embryos had abnormal oral periderm and 17% developed cleft palate, and the absence of epistasis in Irf6/Grhl3 double heterozygotes suggests distinct but convergent pathways [32]. According to GeneReviews, GRHL3 accounts for 17% of patients with a VWS phenotype without an IRF6 variant and approximately 5% of all VWS cases, whereas Smith reports approximately 10% [4, 17].

TBX22 (Xq21.1; MANE transcript NM_001109878.2) is a T-box family transcription factor and a major determinant of human palatogenesis; X-linked cleft palate with ankyloglossia (CPX) results from nonsense, splice-site, frameshift and missense mutations indicating complete loss of function [11, 44]. A functional promoter haplotype reduces TBX22 activity by up to 50% and is associated with cleft palate, particularly with ankyloglossia, in patients without a coding mutation [19].

MSX1 (4p16.2; MANE transcript NM_002448.3) is a homeodomain transcriptional repressor required for palatal shelf development and fusion and for the tooth germ expression programme; the same variant may cause tooth agenesis, clefting or both in the same family, and ClinGen classifies the relationship with selective tooth agenesis as definitive and attribution of Witkop syndrome as disputed [5, 44]. TP63 (MANE transcript NM_003722.5) causes a spectrum of six overlapping phenotypes, including EEC and AEC syndromes, in which the cleft may affect the lip or palate within the same family [5, 44, 46].

2.6. Environmental factors and gene–environment interaction

Prenatal exposure to valproic acid, maternal smoking and alcohol, and mycophenolate mofetil have been identified as environmental factors associated with cleft lip with or without cleft palate [7]. Antiepileptic drugs overall increase congenital malformation risk two- to three-fold, more with polytherapy and high doses; valproate is particularly associated with cleft palate without cleft lip, and hydantoin and carbamazepine with oral clefts [25, 47]. Susceptibility to hydantoin teratogenesis appears to correlate with genetically determined epoxide hydrolase activity, and in mice cortisone produces cleft palate at very different frequencies depending on the strain, experimental examples showing that phenotype expression requires genetic susceptibility and exposure [13]. In humans, GSTT1 and NOS3 variants appear to modulate the risk associated with maternal smoking, and interactions between IRF6 variants, tobacco and multivitamins have been described [8]. The relationship with folic acid, alcohol and other nutrients is addressed in section 7.

3. Clinical Spectrum and Manifestations by System

3.1. Morphology and classification

Cleft lip with or without cleft palate is unilateral in 80% of cases, predominantly left-sided, and bilateral in 20%; boys tend to have more severe forms with alveolar and palatal involvement [1]. The spectrum ranges from a small notch lateral to the midline to a bilateral cleft extending into the nostrils, gums and palate; median cleft lip is rare and may form part of orofaciodigital syndrome, Ellis-van Creveld syndrome and holoprosencephaly [1]. In the series from the largest Portuguese referral centre (701 children treated in Lisbon between 1981 and 2012), 50% of lip clefts were left-sided, 25.9% right-sided and 24.1% bilateral; cleft lip and palate accounted for 40.9%, cleft palate 35.5% and isolated cleft lip 23.5% of cases [48]. In cleft palate, the spectrum progresses from bifid uvula to submucous cleft with velopharyngeal insufficiency (nasal milk regurgitation in infants and nasal speech in children), to soft palate cleft, a narrow “V-shaped” cleft and, finally, a wide “U-shaped” cleft involving the hard palate [1].

SGRT describes the classification most commonly used in Brazil, Spina's classification, based on the incisive foramen: group I, preforamen clefts (lip and lip–gum); group II, transforamen clefts (lip–palate); group III, postforamen clefts (palatal); group IV, rare facial clefts [6]. Clefts are also classified as unilateral or bilateral and complete or incomplete, and may be as subtle as a lip scar or bifid uvula [6].

The French PNDS adopts its own anatomoclinical classification, which it considers more appropriate than those in the literature: clefts of the palate (bifid uvula, velar cleft, velopalatal cleft and submucous velopalatal cleft); clefts of the lip without cleft palate (unilateral or bilateral cleft lip without alveolar cleft, unilateral or bilateral cleft lip and alveolus, and mixed bilateral lip/lip-and-alveolus forms); and clefts of the lip with cleft palate (complete or incomplete unilateral cleft lip and palate, and symmetrical or asymmetrical bilateral cleft lip and palate) [10]. In cleft lip and alveolus, the alveolar cleft lies in the axis of the upper lateral incisor, which may show anomalies of shape, size, number (duplication or agenesis) and position; nostril deformity ranges from mild ptosis to the characteristic “S-shaped” deformity [10]. Submucous velopalatal cleft combines muscular dehiscence of the velum, sometimes with a bony cleft, beneath intact oral and nasal mucosa, and is revealed by nasal reflux of milk from birth [10]. On average, cleft lip and cleft lip and alveolus account for 25% of the total, cleft lip and palate for 50% (80–90% unilateral and 10–20% bilateral) and velopalatal clefts for 25% [10].

Beyond obvious clefts, subclinical phenotypes are described in patients and “unaffected” relatives: microforms (congenitally healed cleft lip), orbicularis oris defects detectable by high-resolution ultrasound, dental anomalies (agenesis, microdontia, supernumerary teeth), lip print patterns, brain variations and, in the palate, bifid uvula, submucous cleft and possibly ankyloglossia [8, 28]. The Danish registry considers bifid uvula a microform of cleft palate [16].

3.2. Manifestations by system

3.3. Associated anomalies and proportion of syndromic forms

Isolated cleft palates are more frequently associated with other malformations and syndromes than lip clefts [1]. In Stoll's neonatal surveys, 37% of children with a cleft had another malformation (47% in cleft palate, 37% in cleft lip and palate and 13% in cleft lip), and in Milerad's surveys the figures were 22%, 28% and 8%, respectively [1]. Smith estimates that up to 15% of children with cleft lip with or without cleft palate and 42% of those with isolated cleft palate surviving the neonatal period have a broader pattern of altered morphogenesis [7].

These proportions are not directly comparable: the Portuguese series is hospital-based and tertiary, with 350 patients excluded because of incomplete records, whereas the EUROCAT and IPDTOC registries are population-based or broadly hospital-based [9, 14, 48]. The ECLAMC study emphasises that “isolated” and “associated” describe the presence of other anomalies, whereas “syndromic” and “non-syndromic” refer to aetiology: ten children without associated anomalies were diagnosed as syndromic solely through laboratory examinations or family history [49].

3.4. Van der Woude syndrome

VWS, or lip pit–cleft lip syndrome, is the multiple malformation syndrome most frequently associated with cleft lip with or without cleft palate [17]. The characteristic sign is congenital, usually bilateral and paramedian, fistulae of the lower lip, or small mounds with a sinus tract arising from a mucous gland; expression ranges from a single unilateral pit to conical elevations or swellings below the vermilion [4]. The pits correspond to small accessory salivary glands, or possibly ectopic parotid tissue, and may produce troublesome watery mucoid secretion [17].

The ratio of cleft lip with or without cleft palate to isolated cleft palate is approximately two to one, the same as in the general population, and the sex ratio is almost equal [4]. IRF6-related syndromes are among the few monogenic conditions in which, within the same family, one member has isolated cleft palate and another cleft lip and palate: 40% of families with at least three affected members have both forms and, of these, 75% have both among siblings [4]. In a small study, 8 of 17 patients with VWS (47%) had surgical wound complications after cleft repair, versus 13 of 68 (19%) with non-syndromic cleft lip and palate [4]. Intellectual disability should prompt testing for a larger chromosome 1 deletion including IRF6 or GRHL3 [17]; nevertheless, families with large deletions and normal intelligence have been described [4].

The French PNDS gives different frequencies for VWS: cleft lip and palate in 50%, lower lip pits in 88% and soft tissue and bone hypoplasia and hypodontia/oligodontia in 100%, with a frequency of 1/30,000 births, autosomal dominant transmission with high penetrance and variants in IRF6 and GRHL3 [10]. The document does not identify the source series for these figures; the difference from the 10–20% hypodontia and 37% cleft lip with or without cleft palate reported in GeneReviews may reflect recruitment by a surgical reference centre, and GeneReviews remains the reference for frequencies [4, 10]. According to the PNDS, the morphological and functional prognosis is less favourable than in isolated clefts, directly related to tissue hypoplasia and tooth agenesis, which justifies concentrating these patients in an experienced team [10].

3.5. Popliteal pterygium syndrome and the recessive Bartsocas-Papas form

Autosomal dominant popliteal pterygium syndrome (facio-genito-popliteal syndrome), described by Trélat in 1869, combines cleft palate with or without cleft lip (90%), lower lip pits (46%), an intraoral fibrous band between the maxillary and mandibular alveolar ridges (43%), popliteal pterygium extending, at its most extreme, from heel to ischium (90%), nail dysplasia and a pyramidal great toe skin fold (33%), toe syndactyly and genital anomalies (51%), such as hypoplastic labia majora, dysplastic scrotum and cryptorchidism [50]. GeneReviews reports clefting in 91–97% and syndactyly in 59%, and considers the pyramidal great toe fold almost pathognomonic [4]. Other occasional manifestations include skin webs between the eyelids (20%), intercrural pterygium (9%), vertebral, rib and patellar anomalies, renal agenesis and ambiguous genitalia [50]. Filiform synechiae between the jaws (syngnathia) or eyelids (ankyloblepharon) may occur in non-classic forms [4]. A dense fibrous cord is usually present in the posterior portion of the pterygium, and the peroneal nerve and popliteal artery frequently traverse the fibrous band; intelligence is normal and walking is generally good despite muscle deficits and multiple interventions [50]. The autosomal recessive form, or Bartsocas-Papas syndrome, is due in most cases to biallelic RIPK4 variants, is generally more severe and frequently fatal prenatally or neonatally, although cases of variable severity have been described [5, 50].

3.6. Van der Woude type 2 (GRHL3)

The presentation is almost identical to VWS1 [32]. Smith states that cleft palate is the most common phenotype in GRHL3 mutation carriers, whereas cleft lip with or without cleft palate is twice as frequent as cleft palate in IRF6 mutation carriers [17]. When present, pits tend to be located on the upper lip, and an undulating lower lip contour has been described [4]. Published VWS manifestation frequencies derive from IRF6 cohorts and should not be applied unreservedly to the GRHL3 form [5].

3.7. X-linked cleft palate with ankyloglossia (TBX22)

CPX combines complete, partial or submucous cleft palate and ankyloglossia, with an abnormal uvula (absent, bifid, shortened or deviated), a short lingual frenulum and dental anomalies such as crossbite and missing or malformed teeth; mild clinodactyly and syndactyly have been described [2]. Inheritance is semidominant: in the large Icelandic family that defined the disease, 26 members had cleft palate, 19 of them with ankyloglossia, and another 20 women and 1 man had ankyloglossia alone. Thus, the typical heterozygous female phenotype is isolated ankyloglossia, with clefting in a minority [5]. Heterozygous women should therefore not be regarded as asymptomatic carriers without direct examination of the palate and lingual frenulum [5].

3.8. MSX1

MSX1 variants produce a dental and craniofacial spectrum in which the same variant may cause selective tooth agenesis alone (characteristically involving premolars and second molars), clefting alone or both, sometimes within the same family [5, 39].

4. Clinical Recognition and Warning Signs

The purpose of the first genetics clinic visit is to exclude a syndrome as far as possible before counselling with empirical risks, because many syndromes may present with clefting and their other features may be subtle [1, 13]. The ACPA recommends that initial assessment take place in the first days or weeks of life and lists the patients most likely to benefit from a genetics consultation: those in whom it is unclear whether the cleft is isolated or syndromic, or sporadic or familial; those with prenatal or postnatal growth restriction, developmental delay, intellectual disability, autism spectrum disorder, sensorineural hearing loss or seizures; those with a family history; those with an existing genetic diagnosis; those first assessed at an older age; and families requesting it [20]. The Dutch guideline recommends discussing with every family the role of genetic factors and the possibility of genetics referral, expediting this in growth or feeding problems, associated anomalies, developmental delay or suspected syndrome or chromosomal aberration [18]. The French PNDS considers as indications for genetic investigation the association of the cleft with another sign, a positive family history, suspicion of a specific syndrome or an atypical cleft, and notes that additional signs may be subtle or appear only later [10].

Parental examination forms part of assessment: look for submucous cleft, bifid uvula and lip pits and, in nasal speech, exclude 22q11.2 deletion [1]. Offspring and siblings of patients with an IRF6-related syndrome should be examined for cleft palate, including submucous cleft, lip abnormalities and the great toe skin fold, given variable expressivity and incomplete penetrance [4]. Some syndromes become recognisable only later, such as the myopia of Stickler syndrome, justifying genetic reassessment throughout growth [18, 20].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Prenatal diagnosis

Cleft lip may be detected by ultrasound at approximately 20 weeks, but may escape routine obstetric examination, and a small cleft may not be seen even by experienced operators; cleft palate is difficult to detect even with three-dimensional ultrasound, and the small mandible of Robin sequence may be visualised during a specialised examination [1]. Oxford Desk Reference indicates ultrasound screening for cleft lip from 16 weeks and for very severe micrognathia from 12 to 14 weeks, while SGRT places prenatal diagnosis at approximately 18 weeks [6, 27, 55]. The Eurofetus study, in an unselected population, documented an overall ultrasound malformation detection rate of approximately 60%, and Smith emphasises that isolated cleft palate is not always detected [56]. In the Portuguese series, prenatal diagnosis was achieved in only 24% of cases, predominantly cleft lip [48]. For the ACPA, when cleft lip is visualised, families should be prepared for possible cleft palate, and GeneReviews notes that ultrasound is much less capable of detecting isolated cleft palate or VWS lip pits [4, 20].

The Dutch guideline considers it very likely that an ultrasound-suspected cleft is actually present, but severity cannot be predicted with complete reliability and palatal involvement cannot be excluded; it recommends three-dimensional ultrasound in prenatal diagnostic centres, referral to a specialised centre within one week (preferably before 22 weeks because of possible karyotyping), involvement of the cleft team and a geneticist, and counselling by two professionals, one with surgical knowledge and another with psychosocial expertise [18]. Regarding invasive genetic testing, the guideline considers it not indicated, but to be offered, in cleft lip without associated anomalies; recommends caution in cleft lip and palate without associated anomalies; considers testing for 22q11.2 deletion indicated when cleft palate is identified; and requires cytogenetic or molecular diagnosis and genetics consultation in median cleft, associated anomalies or mandibular hypoplasia; in median cleft, targeted ultrasound should look for hypertelorism, hypotelorism, microcephaly, holoprosencephaly, encephalocele and agenesis of the corpus callosum [18]. These statements are at expert opinion level because the guideline found no directly applicable studies [18].

In France, screening is based on the routine second-trimester ultrasound scan, between 20 and 24 weeks of gestation, whose report must validate the mandatory item “continuity of the upper lip” and include a frontal “nose–mouth” view among the 13 minimum images, according to the recommendations of the Comité National Technique de l'Échographie de Dépistage (2010), revised by the Conférence Nationale d'Échographie Obstétricale et Fœtale (2016); integrity of the secondary palate is not a mandatory item, because its reproducibility between sonographers is uncertain, which contributes to the low detection rate of cleft palate [10]. Screening sensitivity decreases with high maternal body mass index, oligohydramnios, unfavourable fetal position, advanced gestational age and operator inexperience; in the sagittal view, a fleshy or bony premaxillary bud suggests a bilateral cleft and retrognathia indirectly suggests cleft palate, but this view cannot be used to assess the secondary palate, because the base of the vomer may mimic a bony roof [10]. Detection requires a reference ultrasound scan in a multidisciplinary prenatal diagnosis centre (CPDPN), with serial views of the lip, nostrils, alveolus, maxillary arch, bony palate and, if possible, the velum, assessment of tongue and chin position and exclusion of an atypical facial cleft; the palate is accessible only in an upward-tilted transverse translingual plane, with the fetal head in extension, and a normal-looking uvula has a good negative predictive value; three-dimensional ultrasound does not eliminate bony artefacts but allows planes to be reconstructed from stored volumes [10]. In pregnant women at increased risk of recurrence, the PNDS allows the reference ultrasound scan from 15 weeks of gestation [10]. After discussion at the CPDPN, the geneticist examines the couple and may offer amniocentesis with targeted (FISH) and genome-wide (microarray) testing; fetal magnetic resonance imaging complements ultrasound in the presence of brain anomalies or technical limitations, computed tomography is reserved for bony anomalies, and a prenatal consultation with the surgeon who will treat the child helps parents anticipate the treatment plan [10]. The Dutch guideline sets referral within one week and preferably before 22 weeks, whereas the PNDS describes the CPDPN pathway and early ultrasound for at-risk pregnant women without setting a referral deadline [10, 18].

5.2. Postnatal diagnosis and clinical assessment

Cleft diagnosis is clinical, through inspection including palatal palpation to identify submucous clefts [6, 27]. Aetiological assessment includes a three-generation pedigree with targeted enquiry about clefts and missing teeth, pregnancy history (anticonvulsants, corticosteroids, oligohydramnios, maternal diabetes), vision, speech development and schooling, and examination of stature, skeleton, mouth (lip pits, frenula, ankyloglossia), face, chin, hands and feet, limbs, heart and genitalia, as well as the parents [1]. The Dutch guideline recommends notifying the regional team of every newborn with a cleft within the first 24 hours and assessment by a paediatrician or geneticist within the first two weeks, to identify or exclude additional anomalies, and including dysmorphological examination and clinical photographs in the genetics consultation [18]. The French PNDS adds that the newborn should be examined in the delivery room for signs of respiratory distress and by a complete examination (facies, head circumference, fontanelles, ears, extremities, genitalia) looking for associated malformations; examination of the mouth with a tongue depressor and palpation may reveal a submucous cleft, also suggested by nasal regurgitation of fluids, bifid uvula or a translucent central zone of the velum [10].

5.3. Genetic testing strategy

Oxford Desk Reference recommends genomic analysis (microarray, gene panel, exome or genome) when there are signs of a chromosomal or syndromic diagnosis, namely when clefting is accompanied by another anomaly, and targeted IRF6 testing in VWS, TP63 testing in EEC syndrome and TBX22 testing in X-linked cleft palate with ankyloglossia [1]. The ACPA lists chromosomal microarray, targeted testing, comprehensive panels, exome and genome sequencing as options, always with pre- and post-test counselling and informed consent [20]. SGRT, published in 2021, considers molecular tests not part of the aetiological diagnosis of multifactorial clefts, being used in research, and reserves karyotyping, microarray comparative genomic hybridisation, MLPA or exome sequencing for suspected syndromes [6]. The French PNDS, without setting a testing strategy, lists microarray, cleft gene panels and high-throughput sequencing, and provides for access to them under the Plan France Médecine Génomique 2025 [10]. The Dutch guideline, revised in 2021, takes a broader position and proposes a strategy by cleft type [18]:

The same guideline highlights a practical limitation: in trio exome analysis, autosomal dominant variants with reduced penetrance segregating within the family, such as CDH1, IRF6 or SIX3 variants, may be filtered out and not reported [18]. It also recommends discussing inconclusive results and incidental findings, storing DNA from cord blood or collected during surgery for future studies, reviewing variants of uncertain significance in a joint laboratory and clinical genetics meeting, and informing the laboratory of the final diagnosis [18].

GeneReviews estimates yield at approximately 72% in VWS, whereas Oxford Desk Reference reports a detection rate of approximately 50% and Smith 68% to 72%; differences reflect testing scope (coding exons, regulatory region, deletions) and the era of the data [1, 4, 17, 50]. These percentages are proportions of probands with a variant detected by the method, not the clinical sensitivity of a diagnosis itself partly defined by the molecular result; a negative test does not exclude the syndrome in an evident clinical presentation [4, 5]. The report should state the gene, transcript with version (NM_006147.4 for IRF6, MANE Select), HGVS nomenclature, zygosity, classification according to ACMG/AMP criteria and methodological limitations [4, 44]. When the variant is not found in either parent, de novo mutation and parental somatic and germline mosaicism, potentially undetectable in leucocyte analysis, should be considered; the designation “de novo” requires confirmation of biological maternity and paternity [4].

5.4. Other clinically directed examinations

Oxford Desk Reference proposes skull and/or skeletal radiographs when examination or pedigree warrants them, 7-dehydrocholesterol with signs of Smith-Lemli-Opitz, echocardiography if a murmur is present, renal ultrasound in orofaciodigital syndromes and ophthalmic assessment when Stickler syndrome is suspected [1]. The ACPA recommends audiological assessment of all newborns with a cleft or craniofacial difference (universal hearing screening in the United States, with complete diagnostic assessment by three months if the child fails screening), airway assessment with risk of obstruction or sleep apnoea, with polysomnography as the reference examination, and instrumental studies of velopharyngeal function, such as nasometry, pressure–flow studies, multiplanar videofluoroscopy, nasopharyngoscopy and MRI, when indicated [20]. The Dutch guideline permits diagnosis of velopharyngeal insufficiency after initial palatoplasty only following six months of specialised speech therapy without sufficient improvement, recommends nasendoscopy when the child cooperates (usually from three and a half years), videofluoroscopy as an alternative or adjunct, and advises against MRI as a routine examination [18].

6. Differential Diagnosis

In practice, the differential diagnosis is the aetiological diagnosis: more than 275 syndromes have clefting as a primary feature, and approximately 75% of them have a known genetic cause [28]. The table brings together the entities selected by Oxford Desk Reference because they are relatively common and may present with clefting, those considered by GeneReviews in the differential diagnosis of IRF6-related syndromes and those listed by the French PNDS among the most frequent. The PNDS cites 679, 2,280 and 1,749 OMIM entries for the searches “cleft lip and palate”, “cleft lip or palate” and “cleft palate”, numbers of search results that do not equate to distinct entities [10].

Voice hypernasality may occur in several oral malformations suggesting clefting, but the defect is usually visible on careful palatal examination [6]. Primary cleft palate is distinguished from clefting secondary to micrognathia by its shape (inverted “V” or “U”) and mandibular context, and deformation-related micrognathia, as in oligohydramnios, tends to normalise by two years, unlike syndromes with an intrinsic mandibular anomaly [27, 35].

7. Treatments and Risk Management Strategies

There is no pharmacological therapy targeting orofacial clefts or the monogenic syndromes causing them; treatment is surgical, dental, orthodontic, speech and language, audiological and psychosocial, extends from the neonatal period to adulthood and should be coordinated by a specialised team [4, 6, 20]. GeneReviews expressly states that no specific clinical practice guidelines exist for IRF6-related syndromes, whose treatment follows general cleft protocols [4].

7.1. Organisation of care: interdisciplinary teams

The ten ACPA principles establish that treatment is best provided by an interdisciplinary team with a sufficient caseload to maintain competence, initial assessment should occur in the first weeks of life and whenever possible in the first days, the family should be supported from first contact and participate in decisions, the plan is decided by the team but implemented locally whenever possible, with complex procedures concentrated in experienced centres, and outcomes should be assessed in the short and long term, including satisfaction and psychosocial wellbeing [20]. The March–April 2026 revision of the ACPA Standards for Approval reorganised voluntary team approval into seven components, adding “Transition and adult care” and “Social determinants of health” to the previous components; the core team must include, at minimum, a speech and language therapist, an orthodontist and a cleft-trained surgeon, a care coordinator and a leader, and should include or refer to nursing, anaesthesia, psychology, social work, audiology, genetics, general and paediatric dentistry, prosthodontics, maxillofacial surgery, ENT, plastic surgery and paediatrics, with designated leads for feeding and growth, airway and sleep health [21]. SGRT describes a Brazilian team of similar composition (social worker, paediatrician, ENT specialist, plastic surgeon, orthodontist, speech and language therapist, psychologist, geneticist, radiologist and prosthetist), aiming for morphological, functional and psychosocial rehabilitation [6]. In the Netherlands, teams have existed since the 1960s, decreased from 23 to 11, and have been federated since 1985 in the NVSCA association, which maintains a validated cleft registry [18]. In Europe, ERN CRANIO (European reference network for rare or complex craniofacial anomalies and ENT diseases, with 36 hospitals in 15 countries) has a dedicated cleft working group and has made the Dutch guideline available in English [18, 26].

In France, the 2021 PNDS, prepared by the MAFACE reference centre under the aegis of the TETECOU rare disease health network (filière), requires diagnosis, treatment and follow-up to take place in a centre of the MAFACE network (réseau), which comprises the coordinating reference centre at Necker-Enfants malades University Hospital (Paris), recognised since 2005, 22 competence centres and one specialised centre (Montpellier), with local and national multidisciplinary team meetings and registration in the Banque Nationale de Données Maladies Rares [10]. When the cleft forms part of a multiple malformation picture, these centres work with the other TETECOU networks (CRANIOST for craniosynostoses and craniofacial malformations, MALO for rare ear, nose and throat malformations, O-Rares for rare oral and dental diseases and SPRATON for Pierre Robin syndromes and congenital sucking-swallowing disorders); professionals from France, Belgium, Canada and Switzerland meet in the Association Francophone des Fentes Faciales and, at European level, belong to ERN CRANIO [10]. The attending physician maintains liaison with the centre coordinator, renews the care protocol, monitors growth (weight, height, body mass index) and psychomotor development and assesses the psychological, family and school impact [10]. Clefts are not on the list of 30 long-term conditions (ALD), but may be recognised as an off-list ALD (ALD 31) or through a combination of conditions (ALD 32), with an application completed by the surgeon from birth; recognition is decisive for orthodontics, which is subject to prior approval but without a limit on semesters or age (reimbursement of €215 per active semester, for costs of €600 to €1,200, according to the PNDS), whereas implants and prostheses for the missing lateral incisor are not reimbursed, except in oligodontia through off-list ALD; the PNDS recommends reimbursement of nasal conformers and, as an exceptional recourse, of implants prescribed by the centres [10]. An isolated cleft does not usually reach the disability rate above 50% required for the AEEH allowance from the Maisons Départementales des Personnes Handicapées, unlike some syndromic forms with hearing or developmental impairment; parents may use parental presence leave in the first year, which is marked by several consultations and two operations [10].

7.2. Neonatal period and feeding

Feeding is the neonatal priority [1]. Infants with cleft palate require specialised systems of two types: caregiver-assisted systems, in which the caregiver squeezes the bottle or teat, and infant-directed systems with a one-way valve; feeds should be reciprocal, last 30 minutes or less and allow pauses, and exclusive direct breastfeeding is extremely difficult, so mothers wishing to provide breast milk should be supported in expressing milk and using an appropriate bottle [20]. The initial goal is to regain birth weight by two weeks, with weekly assessment of intake and weight during the first month [4, 20]. The Dutch guideline recommends starting oral feeding after birth, not using tube feeding as the primary feeding method, using modified bottles in cleft palate, contacting the team's speech and language therapist with inadequate intake, feeds exceeding 30 minutes or pressure lesions on the palate or septum, and permits spoon introduction from 4 months [18]. The ACPA states that most children with clefts may follow the American Academy of Pediatrics complementary feeding schedule and that, in cleft palate, free-flow cups may be introduced at 6 months [20]. Nasal splints and premoulded palatal plates may be indicated by the team [6]. In Robin sequence with significant respiratory obstruction, nasogastric feeding may be necessary, with the tube also potentially acting as a tongue and airway splint for days or weeks [1]. The French PNDS recommends that, after prenatal diagnosis, a neonatologist or paediatrician be available at delivery, that parents contact a team member within the first 24–72 hours and that the first morphological and feeding assessment take place in the first days of life; bottles with a softened teat and adjustable flow are generally the most effective, and a palatal orthosis (obturator plate) is indicated in cleft palate for persistent feeding difficulty despite adapted teats and the advice given, or for painful ulceration of the vomer [10]. The team's nursing staff contact the family soon after birth, assess intake and weight weekly in the first month, maintain support by telephone or home visit, liaise with hospital-at-home services when necessary, reinforce airway care (positioning and, if there are associated anomalies, nasogastric tube, tracheostomy or cardiac and apnoea monitoring) and ensure newborn hearing screening [10].

7.3. Primary surgery: timing and differences between sources

The difference between the ACPA, which considers closure before 9 months controversial, and the TOPS trial, published in the year before the parameter revision, should be interpreted in light of the trial population: medically fit infants with non-syndromic isolated cleft palate, treated in adequately resourced centres [20, 22].

The French reference centre protocol, described by Talmant and applied for more than 30 years, repairs at a first stage the lip (modified Millard technique), the nose (rhinoseptoplasty to reposition the alar cartilage and the septum, which is always deviated to the side opposite the cleft) and the velum (Kriens intravelar veloplasty, modified by Sommerlad), without touching the vomer, whose integrity ensures the blood supply of the premaxilla in bilateral clefts; bilateral clefts are repaired in a single stage, with simultaneous columellar lengthening and a removable nasal conformer for 4–6 months [10]. The hard palate cleft, which narrows spontaneously after lip and velum closure, is closed at 12–18 months in two layers without areas of exposed bone; the PNDS advises against push-back techniques, the single-layer vomer flap and Veau-Wardill flaps, because of their negative impact on maxillary growth, and leaves the alveolar cleft intact until gingivoperiosteoplasty [10]. The document cites the study by Dissaux and colleagues, according to which two-stage palate repair with intravelar veloplasty combined less impact on maxillary growth with good speech, whereas early hard palate repair with alveolar closure at the same stage reduced fistulae at the expense of anteroposterior growth [10]. This scheme resembles the second option of the Dutch guideline (velum in the first year and hard palate later) and differs from the ACPA, which places palate closure between 9 and 14 months; the TOPS trial compared closure at 6 and 12 months and did not test a two-stage protocol [10, 18, 20, 22]. As for presurgical orthopaedics, the PNDS considers it controversial and cites a review showing no significant effect compared with other appliances or no treatment, a position close to Dutch caution and more restrictive than that of the ACPA [10, 18, 20]. Postoperatively, the PNDS dispenses with upper limb splints or immobilisation and positions the infant supine and head-up; it recommends an anaesthetist with paediatric experience for all procedures, pain prevention with possible use of locoregional anaesthesia, coordination of procedures to reduce the number of anaesthetics and hospital admissions, and annual peer-reviewed assessment of complications [10].

These trials have relevant limitations. In TOPS, the relative reduction of 41% corresponds to an absolute difference of approximately 6 percentage points, with a confidence interval whose upper limit approaches no effect, and the result applies only to non-syndromic isolated cleft palate; approximately 17% of recordings were not analysable [22]. In the Brazilian trial, comparison with the historical rate is not randomised and the small number of analysed births limits precision; the authors themselves consider a new trial necessary [64].

Regarding technique, the Dutch guideline recommends combining techniques the surgeon has mastered best to minimise complications and anatomically repositioning velar musculature for better speech outcomes [18]. The ACPA warns of acute airway obstruction and haemorrhage after palatoplasty, requiring surveillance protocols and capacity for immediate reintervention, and recommends that palatal surgery be performed only by surgeons whose experience ensures a low failure risk [20]. Presurgical orthopaedics (including lip taping and nasoalveolar moulding) may improve alveolar segment position or nasolabial outcomes in some patients according to the ACPA, whereas the Dutch guideline recommends caution with nasoalveolar moulding and preferably using it in clinical trials [18, 20]. In severe cleft lip, primary rhinoplasty with or without limited septoplasty should accompany cheiloplasty, and definitive septorhinoplasty should await skeletal maturity and, if indicated, orthognathic surgery [18, 20].

7.4. Secondary surgery, alveolar bone grafting and orthognathic surgery

Velopharyngeal insufficiency should be diagnosed by a multidisciplinary team (at least a surgeon, ENT specialist and speech and language therapist) [18]. The Dutch guideline recommends selecting technique based on speech assessment and nasendoscopy or videofluoroscopy, considering intravelar veloplasty with muscle repositioning before pharyngoplasty when the palate is already closed, using pharyngoplasty if insufficiency persists, preferring palatoplasty alone in submucous cleft, and using fat injection only in research [18]. The ACPA notes that velopharyngeal surgery does not correct compensatory articulation, such as glottal stops or nasal fricatives, requiring subsequent speech therapy, and that these operations may cause or worsen obstructive sleep apnoea [20]. Symptomatic palatal fistulae may be closed surgically or with a prosthetic obturator, recognising that success probability decreases with each attempt [20].

Alveolar bone grafting is generally performed before permanent teeth erupt in the cleft region; grafting after permanent canine eruption is associated with insufficient bone support and shorter survival of adjacent teeth [20]. The Dutch guideline prefers early secondary grafting, timed according to root formation of the canine on the cleft side (one-half to two-thirds) and lateral incisor eruption, decided with the orthodontist, using iliac crest or chin bone, potentially supplemented by a bone substitute; bone substitutes alone remain experimental [18]. For sagittal discrepancies not resolved by orthodontics, the guideline considers Le Fort I osteotomy, potentially with mandibular setback, and reserves distraction osteogenesis for large discrepancies; the ACPA notes that maxillary advancement may worsen velopharyngeal dysfunction and recommends speech assessment before and after [18, 20].

The French PNDS diverges from the American and Dutch guidelines on the timing of alveolar grafting: instead of secondary grafting guided by canine root formation, it performs gingivoperiosteoplasty with iliac cancellous bone graft at 4–6 years, in the primary dentition, after transverse expansion with a quad-helix or expander at 4.5–5 years (screw plates are not recommended), aiming for a maxillary intercanine distance 4 mm greater than the mandibular one (approximately 32–35 mm) and retention with a quad-helix for 6 months; in bilateral clefts, the two sides are operated on 6 months apart, to protect the blood supply of the premaxillary mucosa [10, 18, 20]. The document cites a series by Dissaux and colleagues with greater graft success at around 5 years than at around 10 years, considers that every patient with complete cleft lip and palate should receive an alveolar graft, accepts secondary grafting before permanent canine eruption and regards the results of bone substitutes (hydroxyapatite, demineralised bone matrix, β-tricalcium phosphate, calcium phosphate, rhBMP-2 and rhBMP-7) as divergent [10]. For maxillary surgery, the PNDS indicates interceptive maxillary distraction, with an internal bone- and tooth-anchored distractor, when the maxillomandibular discrepancy exceeds 10 mm, particularly in syndromic forms with a short, hypoplastic lip and multiple agenesis, such as VWS, at around 10–12 years, without dispensing with orthognathic surgery at the end of growth (Le Fort I osteotomy, possibly segmental) [10]. In velopharyngeal insufficiency, the decision on repeat veloplasty or pharyngoplasty should be made before entry to primary school; the choice between pedicled flap pharyngoplasty, sphincteroplasty and secondary veloplasty relies on nasendoscopy or videofluoroscopy, and the PNDS accepts autologous fat injection into the posterior pharyngeal wall in patients with good palatopharyngeal movement and small closure defects, whereas the Dutch guideline reserves it for research [10, 18]. Secondary corrections follow their own schedule: the lip scar may be revised after alveolar grafting (at around 5 years) or when the child asks for it, possibly with lipostructure or hyaluronic acid, the latter used in France outside its marketing authorisation; functional septal and alar correction may be performed from 5–6 years when breathing is not nasal at rest and at night, with a nasal conformer for 4 months; and definitive rhinoplasty awaits skeletal maturity (generally 15 years or older in females and 17 years or older in males) and correction of the bony bases, with particular caution over reoperations between 2 and 6 years [10].

7.5. Ears, hearing, speech, teeth and orthodontics

The ACPA recommends regular otological examination from the neonatal period, audiological assessment before and after ventilation tubes, monitoring of Eustachian tube function and cholesteatoma, and amplification for persistent hearing loss [20]. The Dutch guideline proposes periodic audiological assessments until 3–4 years, aligned with the surgical protocol, checking hearing at least once after ventilation tubes, and inserting tubes only when indicated by audiological and speech findings, rather than by otitis media with effusion alone [18]. The French PNDS defines otitis media with effusion as a retrotympanic effusion persisting for more than three months, reports a history of this otitis in approximately 90% of children with cleft palate (prevalence of 75% versus 19% without cleft between 1 and 5 years, in a prospective study), accepts ventilation tubes as the most widespread treatment, advises against adenoidectomy at the same operation, because of the risk of velopharyngeal incompetence, and notes that adherence to hearing aids in these children was only 52%; in the absence of French or European recommendations, it proposes annual otoscopy until adulthood and age-appropriate hearing testing every 6–12 months in the first years [10]. Speech therapy should be based on formal assessment; the ACPA emphasises that therapy does not correct structurally caused hypernasality, for which surgery or a prosthesis should be considered, and that blowing exercises and other non-speech oral motor exercises are ineffective and should not be used [20]. The French PNDS provides for speech therapy guidance sessions from 15 months, if the bony palate is already closed, and between 24 and 36 months, formal assessment at 3 years with nasometry and then annual follow-up, with continuation of the blowing exercises taught in the sessions or local speech therapy depending on the result; the reference to blowing exercises diverges from the ACPA [10, 20].

Oxford Desk Reference adds that children with an alveolar cleft frequently have missing teeth and that orthodontic treatment generally does not begin before the early mixed dentition, at 7–8 years [1]. The French PNDS, which starts orthodontic expansion earlier (4.5–5 years) to prepare for gingivoperiosteoplasty, adds that caries risk is higher than in controls, favoured by oral hygiene and salivary lactobacilli, and that, over 25 years of follow-up, patients with cleft lip, alveolus and palate had greater periodontal progression, bone loss and attachment loss of the teeth adjacent to the cleft, which justifies periodontal maintenance; definitive replacement of the missing lateral incisor (bonded bridge or implant) is performed only at the end of growth and orthodontic treatment, with provisional paediatric prostheses in the meantime, and cone-beam computed tomography helps locate supernumerary teeth in the cleft area [10]. Prosthetic rehabilitation may include fistula obturators, speech prostheses for non-surgical velopharyngeal dysfunction, and osseointegrated implants after growth is complete [20].

7.6. Specific measures for IRF6-related syndromes

Lip pits may be excised for aesthetic or functional reasons, particularly when connected to mucus-secreting glands [4, 17]. In popliteal pterygium syndrome, MRI has been used to locate the peroneal nerve and popliteal artery before pterygium correction, and treatment includes physiotherapy, orthopaedics and plastic surgery; syndactyly and genital anomalies, including cryptorchidism, may require surgery, and genital anomalies may cause infertility [4, 50]. Syngnathia frequently requires urgent release because of feeding and respiratory compromise and may require tracheotomy; ankyloblepharon may require excision [4]. The higher frequency of wound-healing complications after cleft repair in VWS (47% versus 19%) should be anticipated in surgical planning [4].

7.7. Anaesthesia, airway and sleep

The ACPA recommends an anaesthetist experienced in the paediatric craniofacial airway, airway assessment before any surgery and particular attention to Robin sequence, bilateral cleft lip, midface hypoplasia and micrognathia, and notes that difficult laryngoscopy is associated with age below 6 months, deformity type and severity, and micrognathia; patients with obstructive apnoea may require overnight monitoring with continuous oximetry [20]. Sleep-disordered breathing should be screened for (for example with BEARS or the Pediatric Sleep Questionnaire) and confirmed by polysomnography; adenoidectomy is relatively contraindicated in children at risk of velopharyngeal dysfunction, in whom medical treatment or partial adenoidectomy is preferred [20].

7.8. Psychosocial support and transition

The ACPA recommends psychosocial screening from childhood to early adulthood using validated instruments such as CLEFT-Q, the Psychosocial Assessment Tool Craniofacial Version, the Ages and Stages Questionnaire, PedsQL, PROMIS instruments and the Strengths and Difficulties Questionnaire [20]. The Dutch guideline specifies child and parent screening time points: after birth, at 2–3, 5, 10–11 and 17 years [18]. Adult needs include scars, nasal deformity, malocclusion, missing teeth, surgical or orthodontic relapse, hearing loss, persistent speech abnormalities and their own genetic counselling; many teams are based in paediatric hospitals, complicating transition [20].

The French PNDS organises psychological follow-up by age and lists warning signs: in the first year, relational withdrawal of the infant, feeding or oral disorders, maternal depression and massive parental disorganisation or distress; at 4–5 years, the first questions and teasing (the child should be helped to build a simple sentence explaining their difference), refusal of examinations or appliances and sleep disturbances after hospital admission; in primary school, school difficulties and social withdrawal, with standardised neuropsychological assessment if necessary; in adolescence, teasing or bullying, depressive problems, refusal of care or an imperative demand for surgery and school dropout [10]. Any child who is teased or bullied should be referred to a psychologist; the absence of prenatal diagnosis is identified as a factor of parental vulnerability before the first operation; and psychological consultation cannot be imposed, but the mere availability of a psychologist unknown to the family is not enough [10]. Therapeutic education covers the anatomy and origin of the malformation, the treatment schedule, preparation for procedures, feeding, oral hygiene, speech therapy guidance and self-image; in November 2021 an authorised programme existed in France at the Necker Hospital reference centre, and the programme “E…change de regard”, developed on the initiative of the ANNA association and the AnDDi-Rares network, addresses stigmatisation and the gaze of others [10]. Transition is prepared from adolescence, with consultations without the parents and joint paediatric and adult consultations, around five competencies (self-confidence, self-care, managing everyday demands, maintaining follow-up in the adult world and making choices); in adults considering further treatment, the PNDS recommends an analysis of benefits and risks, time to decide, consultation with the team psychologist, simulations and contact with other patients [10].

7.9. Primary prevention and modifiable exposures

For clefts as well, the Dutch guideline endorses the Health Council of the Netherlands recommendation of folic acid 0.4 mg/day from at least 4 weeks before to 8 weeks after conception, permits extension for another 4 weeks (without a maximum dose defined in the source) and recognises that the evidence is predominantly observational [18]. The US Preventive Services Task Force grade A recommendation (0.4–0.8 mg/day for all people planning or capable of pregnancy) targets neural tube defect prevention and does not constitute an approved indication for cleft prevention [68]. Oxford Desk Reference recommends folic acid 5 mg/day before conception in women taking anticonvulsants, a reference textbook recommendation rather than a label recommendation, without a maximum dose defined in the source [25]. The 4 mg/day doses in the Brazilian trial were used in a research setting [64]. The French PNDS considers the studies on the preventive effect of periconceptional folic acid supplementation to be discordant and does not set a dose for cleft prevention [10].

Table data come from US labels, official EMA referral procedure pages and Oxford Desk Reference [25, 62, 66, 69, 70]. For women with epilepsy, Oxford Desk Reference recommends reassessing the indication before conception, selecting the antiepileptic drug with the lowest teratogenic potential, preferring monotherapy at the lowest effective dose, not changing treatment once pregnancy is established, and offering prenatal diagnosis [25].

7.10. Ongoing trials and developments in the last 6–12 months

Between October 2025 and October 2026, the identified developments concerned organisation and genetic research rather than pharmacological therapy: the 2026 revision of the ACPA Standards for Approval (a scientific society's normative document) [21]; peer-reviewed publication of de novo variant analysis in 818 cleft palate trios (AJHG, November 2025) [40]; and the non-peer-reviewed preprint analysis of 2,497 orofacial cleft trios (May 2026) [41]. No approved medicinal product, application for authorisation or regulatory opinion for orofacial cleft prevention or treatment was identified in the consulted sources; this absence refers to the searches performed and does not prove that other studies do not exist.

8. Reproductive Options and Family Counselling

8.1. Principles

Only after careful examination confirms that the cleft is isolated can multifactorial inheritance be assumed and empirical risks used; in syndromic forms, and isolated clefts with an established genetic diagnosis, risk is that of the diagnosis concerned [1, 13]. Counselling should include factual information, relief of guilt, correction of misconceptions, discussion of reproductive decisions and support for adaptation [20]. The multifactorial model helps explain to parents that genetic factors come from both sides of the family [13]. The Dutch guideline recommends information about recurrence risk, prenatal diagnosis and preimplantation genetic testing, as well as the right to a second opinion and contact with patient associations [18].

8.2. Isolated clefts: empirical risks

The table reproduces Oxford Desk Reference Table 2.3, constructed from Grosen and colleagues' data; in Oxford Desk Reference, the middle column is labelled “CL/P”, but its values correspond in the original article to probands with cleft lip and cleft palate (for example, 3.9% for siblings) [1, 16]. In that study of 6,776 probands and 54,229 relatives, recurrence risk for first-, second- and third-degree relatives of probands with cleft lip and palate was 3.5%, 0.8% and 0.6%; relative risk for first-degree relatives was 17 times population risk; sibling risk for a proband with isolated bilateral cleft lip and palate was 4.6%, versus 2.5% for unilateral disease; clefts tend to recur as the same type, and cross-risk between cleft palate and cleft lip and palate was only slightly above population risk (0.2%); affected mothers transmit lip clefts more often and affected fathers cleft palate more often [16].

Smith provides general figures for cleft lip with or without cleft palate: 4% for future siblings when the parents are unaffected and one child is affected; 10% with two affected children; 4% for children of an affected parent; 14% when a parent and child are affected; and 2.7% in unilateral versus 5.4% in bilateral clefting [7]. Smith Table 2.1 gives 4–5% for cleft lip with or without cleft palate and 2–6% for isolated cleft palate after one affected child of unaffected parents [13]. Smith adds that with two affected children, risk for the next child is two to three times higher, approximately 10–15%, and risk for children of an affected person is similar to sibling risk [13]. SGRT summarises that, in multifactorial clefting, risk increases with greater severity of the index case's cleft, more affected relatives and closer relatedness; in syndromes it depends on the syndrome concerned; in environmental clefts it is negligible if the causal factor is removed [6]. IRF6 variation tripled recurrence risk in families already having an affected child, but susceptibility genotypes are not yet used in counselling practice [8, 36].

The French PNDS uses empirical recurrence risks, for a couple with an affected first child, of 2–3% for unilateral cleft lip, 4% for cleft lip and palate and 1.8% for cleft palate, to be weighted by the sex and ethnic origin of the affected child, after a Mendelian form has been excluded by the pedigree and clinical examination [10]. It also cites a Norwegian longitudinal study in which the relative risk of recurrence among first-degree relatives was 32 (95% CI 24.6–40.3) for any cleft lip and 56 (37.2–84.8) for isolated cleft palate, similar for children of affected mothers and affected fathers and for parent–child and sibling pairs, with a cross-risk between cleft lip and cleft palate of 3.0 (1.3–6.7) and no relation to the severity of the primary case [10]. This absence of a severity effect diverges from the Danish registry and Smith, in which the bilateral form is associated with higher recurrence (4.6% versus 2.5% for siblings), and the similarity between affected mothers and fathers contrasts with the sex-specific transmission differences described in the Danish cohort; for individual counselling, the Danish data remain the most useful, because they stratify by cleft type and degree of relationship [7, 10, 16].

8.3. Monogenic forms

In IRF6-related syndromes, inheritance is autosomal dominant and each child of a carrier has a 50% probability of inheriting the variant; most probands inherited it from a parent, with or without manifestations, and a de novo variant is possible [4]. Oxford Desk Reference reports that 30–50% of VWS cases represent new mutations and penetrance ranges from 89% to 99%; GeneReviews estimates that 92% of carriers have clinical signs and approximately 70% have a cleft requiring surgery [1, 4]. The risk of clefting is therefore lower than the genetic risk, and prenatal testing does not predict phenotype: lip pits alone, isolated cleft palate, cleft lip and palate or the complete popliteal pterygium presentation may coexist in one family [1, 4]. Parental testing is recommended for reliable counselling; if the variant is absent from both parents, de novo mutation or germline mosaicism should be considered, and siblings of clinically unaffected, untested parents remain at increased risk because reduced penetrance is possible [4]. No incomplete penetrance was observed in the approximately 40 reviewed popliteal pterygium pedigrees [4]. Once the familial variant is identified, prenatal diagnosis and preimplantation genetic testing are possible, and ideally these options should be discussed before pregnancy [4].

In X-linked cleft palate with ankyloglossia, a heterozygous mother transmits the variant in 50% of pregnancies; daughters inheriting it should be examined for ankyloglossia, abnormal uvula and submucous cleft; an affected man transmits it to all daughters and no sons [5]. Bartsocas-Papas syndrome is autosomal recessive [50]. In fetal anticonvulsant syndrome, sibling recurrence risk is high if the mother continues the same drug and dose (estimated at 39–55%) [25]. For 22q11.2 deletion and Stickler syndrome, counselling follows the rules of each entity.

8.4. Pregnancy and delivery

According to the Dutch guideline, pregnant women with known increased risk (a cleft in a parent or previous child) should undergo specialised ultrasound at a prenatal diagnostic centre [18]. Targeted level 2 ultrasound at an experienced centre is the most accurate method for prenatal cleft detection in families with IRF6-related syndromes [4]. The Dutch guideline recommends that, when termination of pregnancy is discussed, professionals remain neutral and the decision rests with the pregnant woman, factually informed; that delivery for prenatally diagnosed isolated cleft have no location restrictions; and that delivery occur in a tertiary centre when clefting forms part of more extensive congenital problems [18]. Prenatal preparation should include feeding information and prior acquisition of specialised systems and, for mothers wishing to provide breast milk, an expressing pump [20]. In France, when CPDPN assessment shows that the cleft forms part of a syndrome or genetic anomaly with a poor prognosis and no curative treatment and the informed couple requests termination of pregnancy, the CPDPN rules on the admissibility of the request; depending on the type of cleft, delivery may be organised in a level 3 maternity unit with paediatric maxillofacial surgery [10].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Geographical and ethnic variation

Cleft lip with or without cleft palate affects approximately 1 in 700 live births, with higher prevalences in Asian and Amerindian populations (up to 1/500), intermediate prevalences in those of European ancestry (approximately 1/1,000), and lower prevalences in those of African ancestry (approximately 1/2,500) [7, 8]. These differences suggest that each susceptibility gene's relative contribution varies between populations; for example, the 8q24 signal is stronger in European trios and IRF6, MAFB and ABCA4 signals in Asian trios [8]. Among non-syndromic clefts, cleft lip with or without cleft palate is approximately twice as frequent in males and isolated cleft palate approximately twice as frequent in females [6, 28]; in series including all cleft palates, female predominance is smaller (approximately 1:1.3 in Smith; male:female ratio 0.83 in the EUROCAT series) [13, 15]. The French PNDS, which relies on the literature rather than a national registry, estimates the incidence of all cleft lip and/or palate in France at 1/700 to 1/1,000 and states that cleft lip, cleft lip and alveolus and cleft lip and palate are twice as frequent in males and on the left side, and velopalatal cleft more frequent in females [10].

9.2. Critical interpretation of the numbers

The table values measure different things. The European cleft palate estimate for Portugal and the Netherlands is much lower than the Danish estimate, but the EUROCAT series itself acknowledges that inter-registry differences are only partly explained by methodological reasons [3, 15]. In Brazil, comparison between the population-based SINASC system and hospital-based ECLAMC showed a cleft lip and palate frequency of 1.7/10 000 in the former versus 10.4/10 000 in the latter, with only 33% of clefts classified as cleft lip and palate in SINASC versus 51% in ECLAMC; the authors attribute part of the discrepancy to ICD-10 coding, which has no severity modifiers or subtypes [77]. SGRT reports Brazilian notifications of 5–20/10 000 live births, with cleft lip and palate reported twice as often as other types [6]. Hospital series such as the Portuguese series of 701 children describe patients of a referral centre and do not allow population prevalences to be calculated; the authors cite an incidence of approximately 5.5/10 000 births in southern Portugal [48].

In ECLAMC, clusters with high cleft lip with or without cleft palate rates were associated with high altitude, Amerindian ancestry and low socioeconomic strata, and low-rate clusters with African ancestry; clefts in high-rate clusters were more severe; advanced maternal age, a recognised cleft palate risk factor, was associated with the sole cleft palate cluster [34]. In the Netherlands, the NVSCA registry documented a significant decrease in cleft lip with or without cleft palate prevalence between 1997 and 2007, for which two hypotheses were proposed: increased second-trimester pregnancy termination and increased folic acid use [18]. Pregnancy termination reduces birth prevalence in several European programmes, which should be considered when comparing with programmes where it is not recorded or not legal [75].

9.3. Monogenic forms and founder effects

The frequencies in this table apply to each syndrome, not to clefts overall or to the proportion of isolated clefts with an IRF6 variant (0.47%) [4, 5]. No founder effect for non-syndromic clefts was identified in the consulted sources; this absence reflects only the search scope. In populations of African ancestry, a whole-gene IRF6 microdeletion was described in a sub-Saharan African family with VWS [4].

10. Illustrative Clinical Case

Bossolani-Martins and colleagues described in 2025 a Brazilian girl assessed at the genetics clinic of the Faculdade de Medicina de São José do Rio Preto (São Paulo) at 9 years because of severe autistic behaviour [45]. She was the second daughter of non-consanguineous parents (mother aged 27 and father 26), born at term weighing 2,280 g and measuring 47.5 cm, without teratogenic exposure or pregnancy complications [45]. Examination showed short stature (3rd percentile), flat midface, narrow palpebral fissures, bilateral lower lip pits, submucous cleft palate, bifid uvula, absent right upper canine and congenital right upper limb anomalies suggesting amniotic band sequence (finger reductions and ring constrictions), alongside intellectual disability and autism spectrum disorder diagnosed at 3 years after developmental regression from approximately one year of age; brain MRI was normal [45]. Her father had only bilateral lower lip pits and normal development, and her sister had lower lip pits and sinus tracts and learning difficulties; all three received a clinical VWS1 diagnosis [45]. At 17 years, reassessment additionally showed a hip-swaying gait, cervical kyphosis and thoracolumbar scoliosis, with persistent short stature and severe cognitive impairment [45].

Karyotype was 46,XX and microarray comparative genomic hybridisation (4×180K) showed no clinically significant copy number variants [45]. IRF6 sequencing (coding exons 3 to 8 and part of 9, 5' untranslated region with exons 1 and 2, part of the 3' region, exon–intron junctions and 143 bp upstream) identified nine single-nucleotide variants, eight benign or likely benign and one novel, published as NM_006147.3:c.970T>C p.(Ser324Pro) (= NM_006147.4:c.970T>C p.(Ser324Pro), MANE Select), in exon 7 in the SMIR/IAD domain, absent from control databases including the Brazilian ABraOM database and classified as likely pathogenic using PM1, PM2, PP3, PP1 and PP4 criteria [45]. The father and sister were carriers and the mother was not [45]. The same variant is described as NM_006147.4:c.970T>C in the current MANE transcript, with GRCh38 coordinate NC_000001.11:g.209790585A>G [44]. Figure 1 of the article shows the patient (short stature, kyphoscoliosis, lip pits, hypodontia, right hand abnormalities) and her father's and sister's pits after excision (https://pmc.ncbi.nlm.nih.gov/articles/PMC11895807/figure/f1/), and Figure 2 shows IRF6 structure and the variant chromatogram (https://pmc.ncbi.nlm.nih.gov/articles/PMC11895807/figure/f2/) [45].

The case illustrates several points of this article: intrafamilial variability (isolated pits in the father, submucous cleft in the proband), the importance of examining parents' lips, the need to sequence non-coding IRF6 regions as well, and the value of updating nomenclature to the MANE transcript [4, 45]. Interpretation should be cautious: the authors classified the variant with an automated tool and relied, among other criteria, on segregation in only three carriers; severe intellectual disability and autism are not part of the usual VWS phenotype, in which growth and intelligence are normal, and association with amniotic bands is the authors' hypothesis rather than an established relationship [4, 45]. In intellectual disability within a VWS family, Smith recommends seeking a larger deletion including IRF6, which the microarray performed did not show [17, 45].

11. Prognosis and Long-Term Follow-up

The prognosis of isolated clefts is generally favourable and complete rehabilitation is possible, with better outcomes from earlier intervention; untreated clefts may leave sequelae such as hearing loss, speech disorders and nutritional deficiency [6]. In syndromic forms, prognosis depends on the underlying diagnosis [6, 7]. In the analysis of 22 ICBDSR programmes, overall survival of liveborn infants with cleft lip and palate was 91%: 97.7% in isolated forms, 77.1% with associated multiple congenital anomalies and 40.9% with associated genetic or chromosomal syndromes [75]. In VWS and popliteal pterygium syndrome, growth and intelligence are normal, and good walking is expected in most popliteal pterygium patients despite multiple corrections [4, 50]. In the long term, people born with clefts have been described as having higher overall mortality, mental health problems, increased cancer risk (particularly breast cancer) in affected individuals and relatives, and altered reproductive patterns, findings justifying viewing clefting as a lifelong condition [8]. Psychosocial problems and difficulty accessing adult teams influence education, employment and relationships [20]. The French PNDS stresses that the speech prognosis is clearly less favourable in syndromic forms, particularly 22q11.2 deletion, which more often requires additional surgical treatment, and that the functional outcome depends mainly on the quality of the primary repair: nasal obstruction left by the first operation tends to perpetuate mouth breathing even after appropriate nasal surgery [10].

12. Summary and Final Considerations

For embryological and genetic reasons, orofacial clefts are divided into cleft lip with or without cleft palate and isolated cleft palate; approximately 70% of the former and 50% of the latter are non-syndromic, and birth frequency is approximately 1/700 to 1/1 000 for cleft lip with or without cleft palate and 4/10 000 for cleft palate, with marked variation between populations and recording systems [1, 8, 9]. Isolated clefting follows a multifactorial threshold model supported by Danish recurrence studies and association studies identifying IRF6, 8q24, VAX1, NOG, MAFB, ABCA4 and, more recently, CALD1, ESRP1 and RBFOX1 [8, 16, 38]. Trio sequencing shows that rare and de novo variants, including in syndrome genes, also contribute to apparently isolated clefts [4, 40].

Van der Woude syndrome is the principal monogenic form: it should be sought in every family by examining the parents' lips, palate and teeth because it converts an empirical risk of 2–5% into a 50% risk of inheriting the variant, with high but incomplete penetrance and unpredictable expressivity [1, 4]. GRHL3, TBX22, MSX1 and TP63 complete the minimum panel, and 22q11.2 deletion should be considered particularly in cleft palate and velopharyngeal insufficiency [1, 4, 18]. Test selection depends on cleft type, associated anomalies and family history, and negative or uncertain-significance results require clinical integration [18].

Treatment is multidisciplinary and prolonged. The American (ACPA 2024) and Dutch guidelines agree on cheiloplasty in the first six months and palate closure in the first year or shortly afterwards, but differ on the lower limit, and TOPS favoured 6 months over 12 months in isolated cleft palate [18, 20, 22]. Possible primary prevention relies on periconceptional folic acid, with observational evidence for cleft lip, tobacco avoidance and preconception antiepileptic management, particularly valproate and topiramate, which are subject to European pregnancy prevention programmes [23, 24, 69, 70]. In France, the 2021 HAS PNDS entrusts the care pathway to the centres of the MAFACE network and proposes a three-stage surgical scheme, with gingivoperiosteoplasty and alveolar grafting at 4–6 years, which differs from the American and Dutch guidelines [10]. The European reference network is ERN CRANIO, and patient associations (CLAPA, ACPA, Children's Craniofacial Association, Face Equality International, Pierre Robin Network and the Dutch patient association, called “CLA/P Nederland” in the guideline translation) support families, as do, in France, the Association pour les Porteurs de Fentes Faciales et leurs Parents (APFFP) and associations dedicated to syndromic forms; no specific Portuguese or Brazilian associations were identified in the consulted sources [1, 4, 10, 18, 26, 27].

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