Craniofacial Microsomia and Oculo-Auriculo-Vertebral Spectrum (Goldenhar)

Congenital malformation of the structures derived from the first and second pharyngeal arches, usually asymmetrical, which brings together under the name craniofacial microsomia hemifacial microsomia, Goldenhar syndrome and the oculo-auriculo-vertebral spectrum; mostly sporadic, with monogenic (SF3B2, FOXI3), chromosomal and environmental causes identifiable in a minority.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition and scope

Craniofacial microsomia (CFM) designates a spectrum of malformations of the structures derived from the first and second pharyngeal (or branchial) arches: mandible, maxilla, external and middle ear, orbit, facial nerve and facial soft tissues. Facial asymmetry is its defining feature, present even when involvement is bilateral, and is associated with mandibular hypoplasia due to shortening of the ramus and condyle, preauricular and facial tags or pits, microtia or anotia, external auditory canal atresia and conductive, sensorineural or mixed hearing loss [1]. A variable proportion of patients also have epibulbar dermoids and vertebral, cardiac, renal and central nervous system (CNS) anomalies, which gives the spectrum the name oculo-auriculo-vertebral (OAVS) [3, 12].

The European guideline of the European Reference Network for rare and/or complex craniofacial anomalies and ear, nose and throat disorders (ERN CRANIO), published in 2020, recommends the exclusive use of the term craniofacial microsomia and the abandonment of Goldenhar syndrome, hemifacial microsomia and auriculo-oculo-vertebral spectrum [2]. The 2021 French PNDS, led by a member of the European working group, adopts the same recommendation and includes among the names to be abandoned facio-auriculo-vertebral syndrome and sequence and first and second branchial arch syndrome [26]. The rationale is empirical: in a retrospective multicentre study of 755 patients, principal component analysis showed correlation between the mandible, orbit and soft tissues, without distinct clusters, and the three components of the so-called Goldenhar triad (mandibular hypoplasia, epibulbar dermoids and vertebral anomalies) did not correlate with one another; in another cohort of 138 patients, 34% had vertebral anomalies, 17% epibulbar dermoids and 7.2% both, but 32% had a recorded diagnosis of "Goldenhar", assigned more often to bilateral and severe forms without an objective difference in facial severity on the OMENS classification (orbit, mandible, ear, facial nerve and soft tissues) [2]. The term craniofacial is preferred to hemifacial because slightly more than 10% of patients have bilateral involvement and because the more hypoplastic side also deforms the contralateral side [2]; GeneReviews adds that many patients classified as unilateral have subtle differences on the "unaffected" side [1]. In the genetics literature the names OAVS and Goldenhar syndrome remain in use, and OMIM and Orphanet adopt craniofacial microsomia as the main entity [18, 28].

In addition to typical CFM, the article groups three related entities: OAVS with radial defects (OMIM 141400; ORPHA:2549), in which the first and second arch anomalies are invariably accompanied by radial ray defects [4]; oculo-auriculo-frontonasal syndrome (OAFNS, OMIM 601452), which combines frontonasal dysplasia with OAVS features [1, 5]; and isolated microtia, considered by many authors to be the mild end of the same spectrum [1, 2]. Frontonasal dysplasia (ALX1, ALX3, ALX4), Treacher Collins syndrome, the branchio-oto-renal (BOR) spectrum, CHARGE syndrome, the 22q11.2 deletion and duplication syndromes, orofacial clefts and Robin sequence are included as differential diagnoses.

1.2. Historical milestones

In 1952, in Geneva, Maurice Goldenhar described the association of epibulbar dermoid, auricular tags and fistula auris congenita, discussing its relationship with mandibulofacial dysostosis [7, 29]. In 1963, Gorlin and colleagues introduced the name oculo-auriculo-vertebral dysplasia, recognising the frequency of vertebral anomalies [30]. In 1973, Poswillo proposed, on the basis of an animal model, that the defect resulted from focal haemorrhage in the territory of the stapedial artery during development of the arches, a vascular hypothesis that continues to guide aetiological research [3, 31]. In 1987, Rollnick and colleagues described the phenotypic features of 294 patients from a single clinic and showed that ipsilateral mandibular hypoplasia almost always accompanies microtia [32]. Gorlin later recommended the term oculo-auriculo-vertebral spectrum to emphasise the heterogeneity [33].

Clinical classifications evolved in parallel: the Pruzansky radiographic classification of the mandible, subdivided by Kaban into types I, IIA, IIB and III [2, 34]; the O.M.E.N.S. classification (Orbit, Mandible, Ear, Nerve, Soft tissue) of Vento, LaBrie and Mulliken, in 1991, based on 154 patients, which considered the mandibular deformity to be the cornerstone of the spectrum [35]; its pictographic version and OMENS-plus, which includes the extracraniofacial anomalies [2, 36]; and the severity score of Tasse and colleagues (2005), in 53 German patients [37].

1.3. From unknown cause to the first genes

Until the end of the 2010s, textbooks described the cause as unknown and stated that no responsible gene had been identified [3, 38]. GeneReviews withdrew the CFM review chapter on 2 April 2020 on the grounds that the condition is rarely genetic [1]. The subsequent molecular milestones were the association of MYT1 with OAVS in 2016, with evidence that has remained limited [9, 39]; the demonstration, in 2021, that haploinsufficiency of SF3B2, a spliceosome component, causes CFM, accounting for about 3% of sporadic cases and 25% of familial cases in a cohort of 146 families [6]; and the identification, in 2023, of FOXI3 variants in dominant forms with reduced penetrance and in recessive forms [7, 8]. OMIM designates these forms as craniofacial microsomia 1 (CFM1, #164210, SF3B2) and 2 (CFM2, #620444, FOXI3) [28]. Genome-wide association studies in China and Finland point to a polygenic component near ROBO1 [22, 40].

2. Molecular Genetics and Pathophysiology

2.1. Embryology of the pharyngeal arches

The head and neck form from six pharyngeal apparatuses, each consisting of a pouch, arch, groove and membrane. In the fourth week of gestation, neural crest cells migrate from the neural tube to form the ectomesenchyme of the arches; each arch has endoderm, mesenchyme (ectomesenchyme and mesoderm) and ectoderm, which give rise to muscle, artery, nerve and cartilage [1]. The structures most affected in CFM derive from the first arch (mandible, maxilla, masticatory muscles, orbit and facial soft tissues) and from the second (pinna, ossicles and facial nerve) [1]. This division explains the correlations observed in the cohort of 105 patients of Tuin and colleagues: orbit, mandible and soft tissues correlate with one another (first arch), as do ear and facial nerve (second arch) [2]. The pinna forms from six auricular hillocks around the first pharyngeal groove and ascends to eye level during embryonic life; preauricular tags correspond to accessory hillocks and, in OAVS, lie along the line from the tragus to the corner of the mouth, the line of fusion of the maxillary and mandibular processes [41].

The "developmental field" hypothesis proposes that the arches respond in a similar way to different insults — chromosomal anomaly, monogenic variant, vascular disruption or teratogen — and explains the existence of identical malformations in other vertebrate species [1]. The clinical overlap with the VACTERL association (vertebral, anal, cardiac, tracheo-oesophageal, renal and limb anomalies), CHARGE, MURCS and OEIS led to the hypothesis of an axial mesodermal dysplasia spectrum [1].

2.2. Vascular hypothesis and environmental factors

Three pathogenic models have been proposed — vascular anomalies with haemorrhage in the craniofacial region, injury to Meckel's cartilage and abnormal development of cephalic neural crest cells — which are interdependent and none of which is entirely consistent with the clinical variability [26]. Poswillo's model attributes the malformation to interference with the vascular supply and focal haemorrhage in the developing first and second arches, at the time when the blood supply of the arches shifts from the stapedial artery to the external carotid [3, 16, 31]. A 2026 systematic review (450 records, 8 included studies) found indirect and heterogeneous support for a vascular mechanism: exposure to vasoactive drugs, diabetes, multiple pregnancy, second-trimester haemorrhage, single umbilical artery, growth restriction and attenuation of the carotid artery, possibly interacting with neural crest migration [42]. The high discordance between monozygotic twins favours environmental factors: of 14 monozygotic pairs gathered by Connor and Fernandez, only 2 were concordant, and the 5 monozygotic pairs with placental information were discordant, including 2 dichorionic pairs, which contradicts the explanation by placental vascular anastomoses [1, 3, 16]. In severe non-syndromic microtia, by contrast, Artunduaga and colleagues found concordance for ear malformations of 61.5% in 13 monozygotic pairs and 4.5% in 22 dizygotic pairs (OR 33.4; p=0.003), figures cited again by Mao and colleagues [7, 15]. An analysis of 5260 newborns with multiple malformations from four registries identified 312 probable cases of OAV and found a relationship with the VATER and CHARGE patterns, but not with OEIS, which the authors attributed to a common disturbance of neural crest development [16].

The main risk factor studies are summarised in the following table. Case definitions differ between studies (isolated microtia, CFM with minimum criteria or registry OAVS), which limits comparison [1].

The divergence between Werler 2004 and Van Bennekom 2013 affects counselling: the former supports vascular disruption, while the latter, restricted to non-syndromic microtia, finds no association with vasoactives and interprets microtia as part of diabetic embryopathy [43, 44]. The 2014 GeneReviews recommended, on the basis of the first study, avoiding vasoactive drugs in subsequent pregnancies; that recommendation was not reproduced by the European guideline [1, 2]. The abstract of the Brazilian study does not specify the abortifacient methods used [48].

Known teratogens produce phenocopies. Isotretinoin in the first trimester causes an embryopathy with microtia or anotia, micrognathia, cleft palate, conotruncal and aortic arch heart disease, thymic hypoplasia, retinal and optic nerve anomalies and CNS malformations; in a series of 154 exposed pregnancies, the relative risk of selected major malformations was 25.6 (95% CI 11.4–57.5) [49]. Mycophenolate mofetil causes microtia, clefts, micrognathia and heart disease, being distinguished by hypoplasia of the toes and toenails, diaphragmatic hernia and tracheo-oesophageal fistula [1, 50]. Thalidomide embryopathy includes a Goldenhar syndrome picture with microtia, deafness, hemifacial microsomia, epibulbar dermoids and vertebral anomalies [51]. Alcohol and retinoic acid are among the exposures to ask about [33]. The French PNDS adds prenatal exposure to triazenes and type 2 maternal diabetes among the associations described, while still considering the cause unknown [26]. Neither of these two formulations matches the primary evidence. Triazene is an experimental teratogen: it was administered to pregnant mice in Poswillo's model to reproduce haemorrhage in the stapedial artery territory, with no documented human exposure [31]. The association with diabetes is not limited to type 2 either: in the Spanish ECEMC registry, the risk of OAVS increased with gestational diabetes (OR 2.28; 95% CI 1.03–4.82), and the estimate for pre-conceptional type 1 or 2 diabetes (OR 1.50; 95% CI 0.08–9.99) was not significant [46].

2.3. Genetic architecture

Most cases are simplex and without an identified cause [1]. About 1–2% of families show autosomal dominant (AD) inheritance and rare families autosomal recessive (AR) inheritance [1]; in EUROCAT, the family history was positive in 5.6% (11/196) and consanguinity was present in 1% [12], and in the Coimbra and Manchester cohort 31% (16/51) had a family history [52]. The largest segregation analysis, with clinical examination of 311 relatives of 74 probands, supported AD transmission with reduced penetrance [1]. Families with nine affected individuals over three generations and male-to-male transmission, which excludes X-linked inheritance, have been described [16]. AD families differ from simplex cases (Tasse 2007): bilateral involvement 71% vs 46%, hearing loss 26% vs 87%, aural atresia 41% vs 79%, and fewer mouth anomalies and epibulbar dermoids [1, 16]. The empirical recurrence risk of 2–3% in first-degree relatives, the higher frequency of twinning and ART and maternal exposures support a multifactorial model [1].

Estimates of the current yield: the known genes account for about 6% of patients according to Li and colleagues (2025), and a genetic diagnosis is established in fewer than 10% according to Sequeira and colleagues (2025) [53, 54]. These are authors' estimates, not results of systematic diagnostic yield studies. Timberlake and colleagues estimated that, in addition to SF3B2, about 5.6% more cases are due to de novo loss-of-function variants in other genes not yet identified [6].

2.4. SF3B2 (CFM1)

SF3B2 (11q13.1; MIM *605591; MANE Select transcript NM_006842.3) encodes a subunit of the SF3B subcomplex of the U2 snRNP, which takes part in branch point recognition during splicing and is also part of the minor spliceosome [55, 56]. The defining study sequenced the exome (n=42) or genome (n=104) of 146 families with CFM (138 sporadic trios and 8 multiplex families) recruited between 2009 and 2020 in a multinational consortium, excluding abnormal karyotype and known syndromes [6]. There was an excess of de novo loss-of-function (LoF) variants in cases (1.7-fold; p=0.01), two of them in SF3B2 (p=9.6×10⁻⁷), and the overall LoF burden in SF3B2 reached p=3.8×10⁻¹⁰ [6]. A total of 20 individuals from 7 families were identified, with de novo or transmitted variants, all absent from gnomAD, in a gene with a pLI of 1.00; no damaging missense variants or structural variants were found in the probands, but a DECIPHER child with a 1 Mb deletion including SF3B2 had microtia and a preauricular tag [6]. The authors' conclusion — SF3B2 accounts for about 3% of sporadic cases and 25% of familial cases — refers to that cohort [6].

The phenotype of the 8 probands included mild to moderate unilateral maxillomandibular hypoplasia, duplication or hypoplasia of the tragus, grade I microtia (bilateral in 3), external auditory canal atresia, preauricular or facial tags (7/8), macrostomia (3), epibulbar dermoid (1), upper eyelid coloboma (1), conductive hearing loss (3), C7 cervical ribs in the 3 with radiographs, scoliosis (1), bifid thumb (1), heart disease (2; one with absent left pulmonary artery, aberrant left subclavian artery and right aortic arch), submucous cleft palate (1) and special educational needs (3/8); renal ultrasound was normal in the 5 assessed [6]. In family 7, from Australia, with 12 affected individuals aged 6 to 63 years and previous linkage to 11q12-13 (lod 2.1), preauricular tags (11/12) and mild mandibular hypoplasia (9/12) predominated, with normal neurodevelopment; one individual considered unaffected at the first assessment had mandibular hypoplasia on reassessment in 2020, which reflects variable expressivity with high penetrance [6]. Two affected siblings with p.(Arg638Ter) and parents without the variant document gonadal mosaicism [6]. Compared with Nager syndrome (SF3B4), the SF3B2 form has ear anomalies limited to the tragus and canal, less severe malar and mandibular hypoplasia and rare limb involvement, and no proband required tracheostomy or early mandibular surgery for the airway [6].

Subsequent functional studies showed, in sf3b2-null zebrafish, a deficit of cartilage and bone progenitors due to mdm2/Tp53-dependent apoptosis and reduced neural crest proliferation; in heterozygous human induced pluripotent stem cells differentiated into neural crest there was more cell death, and tp53 inhibition reduced early death without correcting the cartilage [57]. Xia and colleagues (August 2026) described the p.(Gln60Ter) variant, with complete loss of the protein and a complete phenotype (mandibular hypoplasia, cleft palate, bilateral tragus anomalies, microtia, canal stenosis with hearing loss, epibulbar dermoid), and p.(Lys507Ter), with 15.5% residual truncated protein and a mild craniofacial phenotype with hearing loss and developmental delay; the sf3b2 knockout zebrafish had 25.33% malformed embryos, with shortened Meckel's cartilage and palatoquadrate [58]. The clinical spectrum extends beyond the face: a child with complex congenital heart disease and Hirschsprung disease, without craniofacial features, had the p.(Val316SerfsTer5) variant inherited from a parent with heart disease only [59], and a French patient with a de novo variant had otomandibular syndrome with progressive camptodactyly and very low maxillomandibular bone density, a finding that required adaptation of the bimaxillary osteotomy [60]. There is no biochemical assay; diagnosis is by sequencing [55].

2.5. FOXI3 (CFM2)

FOXI3 (2p11.2; MIM *612351; MANE NM_001135649.3) encodes a forkhead transcription factor that regulates the preplacodal ectoderm; Foxi3−/− mice lack the external and inner ear and show apoptosis of neural crest cells [8, 61]. Mao and colleagues studied 670 unrelated probands of European and Chinese ancestry and identified 18 likely pathogenic variants in 21 (3.1%): 5/124 Europeans (4.0%), 5 of 48 Chinese families (10.4%) and 10 of 498 sporadic Chinese cases (2.0%) [7]. Six variants lay in the forkhead domain, six in the nuclear localisation signal (residues Arg235, Arg236, Arg238 and Arg240, in CpG dinucleotides) and two in disordered regions; there was also a 2.06 Mb deletion including the gene, inherited from an asymptomatic father [7]. That deletion corresponds to the infant described by Tassano and colleagues in 2015, with left microtia and aural atresia, velopharyngeal insufficiency and ipsilateral agenesis of the internal carotid artery confirmed by MR angiography [17]. In a consanguineous Pakistani family, two siblings with bilateral grade III microtia and deafness were homozygous for p.(Phe234Leu), with parents and 4 of 6 siblings heterozygous and unaffected (AR inheritance); in a Chinese family, p.(Arg236Trp) co-segregated in an AD manner with a phenotype ranging from absence of the posterior crus of the antihelix to bilateral grade III microtia with micrognathia [7].

Quiat and colleagues, in the Gabriella Miller Kids First cohorts (USA and South America), found p.(Arg236Trp) in a five-generation Italian-American family (LOD 3.33, with modelled penetrance of 30%) and variants in 3 of 413 additional families, a total of 4/415 (about 1% of all cases and 13% of familial cases in that cohort) [8]. All had grade II or III microtia, 90% canal atresia and 80% bilateral microtia; only 27% had mandibular hypoplasia [8]. The proposed genotype–phenotype correlation separates the missense variants of the nuclear localisation signal, which alter nuclear localisation in vitro and are associated with isolated microtia with atresia, from LoF variants, associated with microtia with mandibular hypoplasia through dosage sensitivity [8, 61]. In France, a four-generation family with 6 affected individuals had a novel missense variant in the nuclear localisation signal with incomplete penetrance, and in another 3 of 251 patients there were variants of uncertain significance (VUS) [54]. A Chinese group published in 2025 the identification and functional characterisation of additional pathogenic FOXI3 variants in CFM [62].

Reduced penetrance is the rule: many variants are inherited from unaffected parents [7, 8]. Mao and colleagues described a 94.83 kb haplotype in trans (rs11686866–rs111497808), frequent in Europeans (12.9%) and East Asians (19.7%), present in 7 of 25 (28%) cases with grade II/III microtia; 16 carriers of a pathogenic variant without the haplotype did not have microtia (χ² p=2.8×10⁻⁵; transmission disequilibrium test p=0.0325), but the model does not explain all cases [7]. FOXI3 haploinsufficiency is also associated with low T-cell receptor excision circles (TREC) on newborn screening and with non-severe T lymphopenia, described in 2 individuals with truncating variants inherited from unaffected parents, without a craniofacial phenotype; ClinGen formally separated the two phenotypes [61, 63]. Sequeira and colleagues consider FOXI3 the most recurrent genetic cause, whereas Timberlake and Quiat place SF3B2 first; the difference reflects distinct cohorts and inclusion criteria [6, 8, 54].

2.6. MYT1 and other candidate genes

MYT1 (20q13.33; MIM *600379; MANE NM_004535.3) encodes myelin transcription factor 1 and was the first gene associated with OAVS: Lopez and colleagues (2016) described a de novo nonsense variant and a missense variant in 169 patients, and Berenguer and colleagues (2017) a de novo missense variant among 57 Brazilian patients [9, 16, 39, 64]. Lopez's nonsense variant was identified by exome sequencing in 5 sporadic patients from a French cohort of 169, and the missense variant p.(Ser105Leu) was inherited from a father with progressive sensorineural hearing loss since the age of 25 and scoliosis, without vertebral malformation [16]. Luquetti and colleagues sequenced 128 trios from 360 families recruited in the USA, Colombia and Peru and found two rare missense variants inherited from the mother, one of them in a mother who had only an earlobe cleft [9]. Of the five variants published up to then, only two were de novo and three inherited from unaffected parents; the gene is intolerant to LoF (o/e 0.18) but tolerant to missense (o/e 0.72), and the authors proposed a ClinGen classification of moderate evidence [9]. In a cohort of 73 Brazilian patients, sequencing of 10 candidate genes found no variants in MYT1 [65]; in the same cohort, a later study found the 3′ untranslated region variant c.*305G>T in 5 unrelated patients, all with microtia, mixed or sensorineural hearing loss and hemifacial microsomia with orbital asymmetry, inherited from an unaffected father in the 3 families with parental DNA (incomplete penetrance), and an enrichment of copy number variants (CNV) in the neighbouring topologically associating domain, compared with 455 Brazilian controls [66]. The proposed mechanism is disturbance of the retinoic acid pathway: in Berenguer's functional studies, overexpression of MYT1 reduced expression of the three retinoic acid receptor genes (RARA, RARB, RARG), with no effect on CYP26A1, which links the gene to retinoid embryopathy [9, 16]. OMIM treats MYT1, like TCOF1, BAPX1 (epigenetic dysregulation of allelic expression in 5 of 12 patients) and VWA1, as an association pending confirmation, without its own phenotype; ClinGen has no assertion and GenCC is discordant (limited in Gene2Phenotype; strong in PanelApp Australia for OAVS with radial defects) [10, 16]. GSC (14q32) was excluded by sequencing in 2 families and 120 sporadic cases, and EYA1 and SALL1 in 3 families with AD OAVS [16].

Other genes have evidence from a single family, from a cohort without replication or only experimental evidence. EYA3: missense p.(Asn358Ser) in two siblings and in an unrelated family among 122 patients, with incomplete penetrance and craniofacial anomalies in zebrafish; the authors considered it the second recurrent OAVS gene [67], and a Chinese letter proposed EYA3–EFTUD2 digenic inheritance in one family [68]. PAX1: heterozygous 4 bp duplication, NM_001257096.2:c.1154_1157dup p.(Tyr386Ter), in a three-generation New Zealand family with 5 affected individuals, complete penetrance and variable expressivity, without vertebral anomalies in the 3 studied by imaging; biallelic PAX1 variants cause otofaciocervical syndrome type 2 (OTFCS2, MIM 615560), sometimes with severe combined immunodeficiency due to thymic aplasia, an allelic disorder [56, 69]. SHROOM3 (4q21.1): burden of rare variants in 2009 Chinese patients (p=0.008), with 78% of carriers having "conchal"-type microtia and penetrance dependent on the combination in cis with common regulatory variants [53, 70]. GBX2: two heterozygous missense variants in 3 of 201 Chinese families, with AD co-segregation [71]. FGFR1: one frameshift variant in a patient, with in vitro studies in mesenchymal stem cells [72]. HOXA2: heterozygous NM_006735.4:c.703C>T p.(Gln235Ter) in a three-generation family with AD bilateral microtia and mixed hearing loss (the first known cause of AD non-syndromic microtia), and a homozygous missense variant in a consanguineous Iranian family with more severe AR microtia and partial cleft palate [1, 11, 56]. A Lebanese family with three affected individuals illustrates the interpretive difficulty: exome sequencing found a shared variant in MID1, p.(Ile593Phe), without sufficient evidence by the American College of Medical Genetics and Genomics (ACMG) criteria, a de novo variant in FBXW11 and a frameshift variant in NDUFAF8 [73].

2.7. Polygenic component

A Chinese genome-wide association study (GWAS) with 939 cases and 2012 controls, and replication in 443 and 1669, identified 8 significant loci (lead SNP rs13089920, p=2.15×10⁻¹²⁰) and 5 suggestive loci, with candidate genes (ROBO1, GATA3, GBX2, FGF3, NRP2, EDNRB, SHROOM3, SEMA7A, PLCD3, KLF12, EPAS1) enriched in neural crest development and vasculogenesis [40]. A second study with 6074 samples raised the total to 15 loci and showed that a polygenic risk score is associated with CFM (OR 3.15; 95% CI 2.74–3.63), with a 6.8-fold higher risk in the top 5% of scores relative to the 10th percentile and an interaction with paternal smoking; clinical use of this score has not been validated [74]. In the Finnish founder population (FinnGen), a GWAS with 82 cases and 500,104 controls confirmed the intergenic ROBO1/ROBO2 locus (rs62256696; p=2.27×10⁻⁸), in linkage disequilibrium with the Chinese signal, and showed a genetic correlation between CFM and developmental hearing phenotypes [22]. A cross-analysis in Asian populations suggested genetic correlations with lymphoma, thyroid cancer and chronic obstructive pulmonary disease, with no established clinical implication [75].

2.8. Chromosomal causes

The recurrent associations — del(5p), dup(14q23.1), anomalies of chromosomes 18 and 22 — may be causal; others are probably coincidental [1]. The following table reproduces the reported chromosomal anomalies compiled by GeneReviews.

Source: GeneReviews, table 4 [1].

Chromosome 22 is the most frequently involved [33, 76]. Digilio and colleagues described three patients with 22q11.2 deletion and an OAVS phenotype, all with hemifacial microsomia, unilateral microtia, hearing loss, heart disease or aortic arch anomalies and feeding difficulties [77]. Atypical 581 kb deletions in 22q11.21 [76], distal 22q11.2 deletions between LCR repeats D and E with candidate genes HIC2, YPEL1 and MAPK1 [78] and a combination of proximal duplication (cat eye syndrome region) with distal deletion [79] have been described. In the Coimbra and Manchester cohort, 10 of 22 probands studied by array comparative genomic hybridisation (array-CGH) had dosage changes in 22q11 [52]. Ballesta-Martínez and colleagues described a Spanish family with AD OAVS and a co-segregating 1.34 Mb 14q23.1 duplication including OTX2 [80]. In a complex rearrangement with dup 14q22.3-q23.3 (including SIX1, SIX6 and OTX2), the phenotype overlapped BOR and OAVS [81]. Rooryck and colleagues found, by high-density array-CGH in 86 French patients, 12 novel rearrangements in 11 patients (12.8%), without established pathogenicity for all of them [82]; GeneReviews rounds this figure to 14% [1]. In an Italian study of 19 patients with OAVS and heart disease, microarray found pathogenic CNVs in 2 (10.5%) and VUS in 7 (36.9%), including changes in DACH1, DACH2, DMBX1/OTX3 and HSD17B6, which implicate the PAX-SIX-EYA-DACH network and the retinoic acid pathway [83]. The French PNDS identifies the 22q11 region as a candidate locus, with the genes CLTCL1, GSC2, HIRA, MAPK1 and TBX1, mentions associated variants in OTX2, PLCD3 and MYT1 and accepts a contribution of epigenetic mechanisms and somatic variants, the latter supported by their demonstration in overgrowth disorders [26].

2.9. Variant nomenclature

The published variants were normalised according to Human Genome Variation Society (HGVS) nomenclature in VariantValidator (GRCh38, MANE Select transcripts) and cross-checked with ClinVar; the "X" and "fsX" nomenclature of the original articles is historical and was converted to "Ter" [56, 84].

Sources: [6, 7, 9, 11, 56, 59, 69, 84–87].

ClinVar also records, for CFM1, the SF3B2 variants c.180+2T>C and c.664C>T p.(Arg222Ter) as pathogenic, c.1107dup p.(Glu370Ter) and c.2101del as likely pathogenic, and c.2321C>T p.(Ala774Val) and c.181-48G>A as VUS [84]. The PUF60, FGFR1 and GBX2 variants described in the abstracts were not normalised because no transcript was given.

2.10. Monogenic phenocopies with overlap

TCOF1: a patient with typical OAVS (unilateral microtia, aural atresia, unilateral mandibular hypoplasia with absent zygomatic arch) had the missense variant p.Ala362Thr (historical numbering), and two with Goldenhar syndrome had silent variants absent from 150 controls; similar polymorphisms were found in controls and the association is not established [1, 86, 88]. EFTUD2: at least two people with mandibulofacial dysostosis with microcephaly (MFDM) had been diagnosed as having bilateral OAVS, and a patient with a de novo variant had an epibulbar dermoid [1, 89]. SALL1: at least three individuals with predominant CFM features had a SALL1 variant, all with an anteriorly placed anus or preaxial polydactyly [1, 24]. PUF60: a 12-month-old Brazilian boy with unilateral mandibular hypoplasia, microtia, canal anomalies and developmental delay had the de novo variant p.(Ser238Ter), overlapping with Verheij syndrome [90]. FGFR3: a patient with achondroplasia and hemifacial microsomia with the c.138G>A variant has been published, probably a coexistence [91].

3. Clinical Spectrum and System-Specific Manifestations

3.1. Variability and laterality

The spectrum ranges from subtle facial asymmetry with a small tag in front of a normal ear to bilateral involvement, usually asymmetrical, with microtia or anotia, canal atresia, microphthalmia and respiratory compromise due to severe mandibular hypoplasia [1]. About 70% of cases are unilateral according to Smith's [3]; the European guideline reports slightly more than 10% of bilateral forms in the strict sense [2], and the definition adopted explains the difference, because many "unilateral" patients have subtle contralateral changes [1]. The right side is more often affected, with a right:left ear involvement ratio of 3:2 [1, 33]. Facial asymmetry is severe in about 20% and evident to some degree in about 65% [1, 33].

In the classical series of Rollnick and colleagues (294 patients from a US clinic, 78% Caucasian, male:female ratio 191:103), microtia was unilateral in 193 and bilateral in 98 (symmetrical in 34 of these), ipsilateral mandibular hypoplasia accompanied microtia in 135 of 137 unilateral cases and in 55 of 62 bilateral cases, and 154 patients had no other anomalies, 51 had one and 89 had two or more [32]. In recent multicentre studies, the frequency of involvement by OMENS component was: mandible 91%, soft tissues 82%, ear 83% and orbit 45% (Caron, n=755), and ear 92%, mandible 88%, soft tissues 77%, facial nerve 39% and orbit 28% (Tuin, n=105); the facial nerve could be assessed in only 32% of the Caron cohort, of whom 34% had palsy [2].

In a case-control study of 142 patients and 316 healthy controls (Heike and colleagues), mild changes were also frequent in controls — orbital displacement in 40% vs 20%, mild mandibular hypoplasia in 25% vs 12%, mild ear malformation in 15% vs 5% and soft tissue asymmetry in 34% vs 5% — which led to setting minimum thresholds by component and defining four phenotypic groups: microtia only; microtia with mandibular hypoplasia; more than two features (epibulbar dermoid, tags, macrostomia, orbital deformity, facial palsy) without that combination; and atypical CFM [2]. In the North American longitudinal CLOCK cohort, 52% had microtia with mandibular hypoplasia, 30% microtia only and 18% other phenotypes [92].

3.2. Frequency of anomalies

The following table reproduces the GeneReviews compilation (adapted from Cousley and Calvert 1997, with more than 20 reports between 1983 and 2014 and exclusion of selected samples), to which the last column adds the data from the European EUROCAT registry for the 259 cases with a detailed description [1, 12].

In EUROCAT, 69.5% (180/259) had anomalies outside the skull, face and spine — one in 61.7%, two in 30% and three or more in 8.3% — and only conotruncal heart defects were more frequent than in the general population of the registries (p=0.02) [12]. In the Alberta registry, 65% of the 63 cases had anomalies outside the craniofacial and vertebral region, 33.3% heart disease and 12.7% single umbilical artery, and 9.5% overlapped with another recurrent constellation of embryonic malformations, such as VACTERL [21]. In the cohort of 51 patients from Coimbra and Manchester, ear anomalies affected 92%, hemifacial microsomia 90% (17 with facial palsy), hearing loss 85%, ocular anomalies 29%, vertebral 20%, limb 12% and brain and urogenital 10% each; bilateral forms were always asymmetrical [52]. The differences between series reflect inclusion criteria (EUROCAT requires microtia or an ear anomaly with at least one major anomaly and excludes isolated microtia), type of centre and access to imaging [1, 12].

The synthesis of the French PNDS, which draws on the compilations of the European guideline, gives the following frequencies: microtia 83–88%, mandibular hypoplasia 73–91%, soft tissue hypoplasia 82%, facial palsy 22–53%, cleft lip or palate 15–22%, ocular and adnexal anomalies 67%, dental 8–33% and vertebral 8–79%; among the functional consequences, respiratory difficulties in about 18%, feeding difficulties in 42–83% and articulation, speech and language difficulties in 38–74% [2, 26]. The 42–83% range for feeding difficulties is the synthesis of the literature made by the European guideline; in the multicentre cohort of 755 patients, these difficulties were recorded in 26% (199 patients), 60% of them diagnosed before 6 months of age [2]. Extracraniofacial anomalies are more prevalent in bilateral forms [26].

3.3. Face, mandible and oral cavity

The hypoplasia mainly affects the ramus, condyle and temporomandibular joint (TMJ), with malar and maxillary hypoplasia, hypoplasia of the facial muscles and of the depressor anguli oris, macrostomia due to lateral extension of the commissure (the most common facial cleft in CFM, usually unilateral), ankylosis with limited mouth opening and malocclusion [1, 3]. Cleft lip and palate may be of any type [1]. There is reduced or absent parotid secretion, tongue anomalies and soft palate dysfunction [3]; hypoplasia or aplasia of the parotid and submandibular glands is frequent and is associated with facial and trigeminal nerve anomalies, without symptoms of hyposalivation [2]. The Pruzansky-Kaban radiographic classification grades the mandible into types I, IIA, IIB and III; in Kaban's original series, types I and IIA were treated by mandibular lengthening and types IIB and III required construction of a new ramus and TMJ with a costochondral graft [2, 34].

In the dentition, tooth agenesis (excluding third molars) occurs in 8–33%, versus 1–11% in the general population, mainly of the first and second premolars, with no difference between the affected and unaffected sides; in types IIB and III, dental development on the affected side is delayed, and the mandibular molars and canines are smaller [2]. In addition there are smaller teeth (mainly first and second molars), morphological changes of the mandibular first molar, such as cusp asymmetry, delayed dental development and an increased risk of caries; these anomalies may cause occlusal problems with repercussions on oral health, feeding and speech articulation [26]. The authors of the PNDS note that, in their practice in France, they have not observed more agenesis than in the general population, a clinical observation that contrasts with the published data [26].

3.4. Ear and hearing

Microtia, graded from I to III up to anotia, is associated with canal atresia or stenosis, dysplastic or absent ossicles and malformations of the vestibule and semicircular canals [2]. The European guideline collates hearing loss prevalences of 50–82% (unspecified), 30–86% conductive, 1–20% sensorineural and 6–17% mixed; in unilateral CFM, 6–10% have bilateral or contralateral-only hearing loss [2]. In the Boston cohort (213 patients assessed between 1980 and 2023, at 4.6±4.8 years), 85.9% had hearing loss, conductive in 91.5% of cases; in unilateral CFM, 21.8% had bilateral hearing loss and 5.2% contralateral only, and the M3 mandibular and E3 ear forms were associated with the presence and severity of hearing loss [93]. The severity of microtia correlates with hearing loss; the total OMENS score correlates with inner ear malformation but not with the degree of hearing loss, and facial nerve dysfunction is associated with ipsilateral inner ear anomalies [2]. Tags may contain cartilage that grows with the child [1]. Eustachian tube dysfunction, which is particularly frequent, causes chronic otitis media with effusion, with an impact on hearing and a risk of tympano-ossicular complications; the hearing risk depends mainly on age and the severity of CFM [26].

3.5. Eye

Ocular anomalies include epibulbar dermoids and lipodermoids, colobomas of the upper eyelid and sometimes of the iris, blepharoptosis, microphthalmia and anophthalmia, strabismus, lacrimal anomalies and vertical orbital displacement [1, 2]. The European guideline collates epibulbar dermoids in 10–56%, lipodermoids in 4–61%, eyelid colobomas in 3–32%, blepharoptosis in 9–37%, microphthalmia in 5–71% and strabismus in 12–22%; in a single study there was astigmatism in 18%, amblyopia in 16%, anisometropia in 8% and visual loss in 8% (n=49) [2]. Colobomas frequently accompany dermoids, and bilateral forms have a significantly higher risk of ocular anomalies (n=755, p<0.001) [2]. The epibulbar dermoid is the most common congenital benign tumour of the eye (1–3/10,000 births in the general population) and is classified as grade I (superficial, smaller than 5 mm, at the limbus), II (covers most of the cornea and reaches the deep stroma without reaching Descemet's membrane) and III (covers the whole cornea and reaches the anterior chamber) [2]. Intellectual disability is more frequent when there is microphthalmia [3]. Anomalies of the lacrimal pathways or glands affect 5–11% [26]. Facial palsy adds two visual risks: brow ptosis, which may reduce acuity, and lagophthalmos, which exposes to keratitis, corneal ulcer, endophthalmitis and blindness [26].

3.6. Cranial nerves, speech and feeding

Facial palsy may be unilateral or bilateral and affect some or all branches of the VII nerve; sensorineural hearing loss, asymmetrical palatal elevation and abnormal eye movements also occur [1]. Speech difficulties affect 38–74% of patients, receptive or expressive language difficulties 33% (cohort of 24), dysphonia 24% and social communication difficulties, including autism spectrum disorder, 11% [2]. Velopharyngeal dysfunction without a cleft was 15% in a cohort of 48 and 35% in another, due to asymmetrical velopharyngeal closure [2]; a scoping review of 1253 patients reports velopharyngeal insufficiency with hypernasality in 12.5–55% and altered speech in 35–74% [55]. In two Los Angeles centres (1997–2019; 68 patients aged 13 years or older), velopharyngeal insufficiency affected 27.9%, diagnosed at a mean age of 7.2 years, in 19.6% of patients without a cleft and in all 7 with a cleft; none of the patients without a cleft underwent surgery and only 2 of 8 completed nasendoscopy [94]. Mouth breathing in patients with OSAS alters occlusion and, through that route, articulation; difficulties range from mild, delaying the onset of speech without affecting intelligibility, to severe, with unintelligible speech that may require alternative communication in early childhood [26].

Feeding difficulties range from 26% to 63% (sucking, swallowing, chewing, reflux, restricted mouth opening, growth delay); in the cohort of 755 patients, severity was mild in 46%, moderate in 13% and severe in 41%, and dysphagia affected 13.5% [2]. They are more frequent in bilateral forms, with cleft lip or palate, heart disease or gastrointestinal anomaly, obstructive sleep apnoea, Pruzansky-Kaban type III or orofacial hypotonia [2]. Other contributing factors are facial nerve weakness with lip incompetence, anomalies of the tongue, oropharynx and larynx, cardiac or gastrointestinal anomalies and paediatric feeding disorders secondary to repeated experiences of discomfort (nasogastric tube, hospital admissions, intraoral examinations); difficulties may arise at birth or become apparent at weaning, at the transition to lumpy food, and sensory oral disorders may persist and affect speech [26].

3.7. Airway and sleep

Obstructive sleep apnoea syndrome (OSAS) affects 7–24% of patients in studies with 38 to 124 participants, with a guideline estimate of about 18%; in the general paediatric population, the prevalence is 2–4% [2]. In the multicentre cohort of 755 patients from Rotterdam, Boston and London, 133 (17.6%) had OSAS, diagnosed at a median of 2.4 years (0–25.8); severity was mild in 25, moderate in 22, severe in 48 and unknown in 38, with greater frequency in bilateral cases and in types IIB and III, and 52% of type III patients with OSAS had the severe form [2, 95]. In a series of 62 unilateral patients, with polysomnography only if symptoms were present, OSAS occurred in 11.3%, always with a IIB or III mandible, and in 5 of the 6 type III patients; in a study of 124 patients and 349 controls, sleep-disordered breathing affected 23% vs 9% (OR 3.0; CI 1.5–5.1); in a series of 41 patients, 22% were tracheostomised [2]. The severity criteria used in children are an obstructive apnoea–hypopnoea index (oAHI) of 1–5 (mild), 5–24 (moderate) and more than 24 per hour (severe) [2]. Bilateral hearing loss and severe orbital deformity are additional risk factors [2]. Symptoms appear shortly after birth or during childhood. Untreated OSAS is associated with learning and behavioural difficulties (hyperactivity, aggressiveness, attention deficit hyperactivity disorder), morning headaches, excessive daytime sleepiness, feeding difficulties and upper respiratory tract infections and, in severe forms, with developmental delay, growth delay, pulmonary hypertension with right ventricular hypertrophy and sudden death [26].

3.8. Spine, limbs and other systems

Vertebral anomalies occur in 8–79% (guideline estimate about 28%), in all segments, mainly cervical and thoracic: block vertebrae, hemivertebrae, scoliosis and rib anomalies [2]. In 991 patients, 44% had symptoms (torticollis, neck or back pain, limited cervical mobility), and the risk is higher in bilateral forms, with high Pruzansky-Kaban grades or high O, N and S scores on OMENS; those with vertebral anomalies have more extracraniofacial anomalies in other systems [2]. Cervical vertebral fusion affects 20–35% [33, 41].

The most frequently cited heart defects, in decreasing order, are ventricular septal defect (VSD) and atrial septal defect (ASD), patent ductus arteriosus, tetralogy of Fallot, conotruncal defects and coarctation of the aorta, as well as transposition of the great arteries and aortic arch anomalies [1, 3]. Genitourinary anomalies include renal agenesis (unilateral in 4.6% in EUROCAT), renal ectopia or fusion, vesicoureteric reflux, pelviureteric junction obstruction, ureteral duplication, multicystic dysplastic kidney and hypospadias [3, 12]. Limb defects mainly affect the radial ray (duplication or deficiency of the thumb) [1, 33]. Other anomalies described are oesophageal atresia with tracheo-oesophageal fistula (2.7% in EUROCAT), anorectal anomalies, diaphragmatic hernia, Hirschsprung disease, pulmonary hypoplasia or aplasia, tracheomalacia due to vascular compression, cervical branchial cleft remnants, laryngeal anomalies, hypertrophic pyloric stenosis, hernias, clubfoot and a low hairline [3, 12, 38, 96]. Poland sequence has been described in association with Goldenhar syndrome [97]. The French PNDS emphasises that children with microtia have a substantial risk of congenital heart disease and that children with CFM, particularly bilateral or associated with microtia, have an increased risk of renal anomalies capable of progressing to chronic kidney disease [26].

In the CNS there may be hydrocephalus, Arnold-Chiari malformation, occipital encephalocele, agenesis or hypoplasia of the corpus callosum, callosal lipoma, intracranial dermoid cyst, falx calcification, polymicrogyria, microcephaly and holoprosencephaly [1, 3]. In a Brazilian series of 17 patients with neuroimaging (Porto Alegre), 8 (47%) had CNS changes — diffuse cerebral hypoplasia, ventriculomegaly, dysgenesis of the corpus callosum, frontal hypodensities — associated with ophthalmological anomalies (63% vs 11%) [98].

3.9. Growth, development and psychosocial aspects

Low birth weight is frequent: 29% of cases versus 5% of controls weighed less than 2500 g in the North American study by Werler, and in EUROCAT 20.8% of boys and 36.7% of girls [1, 12]. Most have normal intelligence; Smith's reports an intelligence quotient (IQ) below 85 in 13% [3]. In the CLOCK cohort (92 cases and 76 controls at 38 months), Bayley-III cognitive and motor scores were similar to those of controls, language was lower (effect size −0.58 to −0.20) and "delay" defined by any score more than 1 standard deviation below the mean affected 39% vs 15% (adjusted OR 1.73; p=0.21, not significant) [99]. In behaviour, composite scores were average, with more anxiety and depression, stress problems and autism spectrum scores (effect 0.34–0.41), the latter mainly reflecting concerns about speech [92]. The European guideline describes a higher risk of stigma, low self-esteem and bullying, slightly lower IQ and more learning difficulties than controls, and parental stress related to learning difficulties and not to appearance [2]. Tasse and colleagues associated higher severity scores and bilateral involvement with motor delay and brain anomalies [37]. Among patients with microtia, 30–100% report having been teased since early childhood; hearing, speech and visual difficulties may be associated with psychiatric, behavioural and social disorders, and the neurodevelopmental profile between 1 and 2 years does not differ from that of unaffected children [2, 26]. Parents describe a daily life of stress linked to multiple appointments, functional problems, teasing and learning difficulties [26].

3.10. Genetic forms and subtypes

SF3B2-associated CFM. Tragus and canal anomalies, preauricular and facial tags, mild to moderate mandibular hypoplasia and cervical ribs predominate; the spectrum extends from isolated tags to neonatal forms with airway obstruction, and there are carriers with heart disease only [6, 59, 85].

FOXI3-associated CFM. Most have isolated grade III microtia, unilateral or bilateral, with or without aural atresia; some have only minor defects of the external ear, and mandibular hypoplasia, micrognathia and dental anomalies are less frequent [8, 28].

OAVS with radial defects. Unilateral or bilateral craniofacial malformation of variable degree with constant radial defects — preaxial polydactyly, hypoplasia or agenesis of the thumb or radius, triphalangeal thumb —, low postnatal weight, short stature, vertebral defects, hearing loss, orofacial clefts and cardiac, pulmonary, renal and CNS involvement; about 40 cases or families have been described [4]. OMIM describes cases with a radial defect ipsilateral to the facial anomalies (8 Brazilian patients of van Bever and colleagues, 3 with radial ray anomalies), a mother-to-child transmission with duplicated triphalangeal thumbs (Moeschler and Clarren, 1982) and a patient with trisomy 7 mosaicism in fibroblasts from the unaffected arm [13]. In a series of 14 sporadic Brazilian patients (Vendramini and colleagues, 2007), 42.8% had bilateral radial involvement and 78.6% inner ear malformation, more frequent than in Goldenhar syndrome, with a tendency to sensorineural hearing loss, low weight and short stature; the authors consider it a subtype of OAVS [13]. In EUROCAT, 6 of the 355 cases were classified as this entity [12]. The presence of radial defects requires consideration of Duane-radial ray syndrome (SALL4) and Townes-Brocks syndrome (SALL1) [24].

Oculo-auriculo-frontonasal syndrome. It combines frontonasal dysplasia (hypertelorism, notched or bifid nasal tip) with microtia, auricular and facial tags, eyelid colobomas, epibulbar dermoids, mandibular hypoplasia, facial asymmetry, intracranial lipomas, falx calcification and callosal anomalies; the extracranial anomalies resemble those of CFM (cardiac 44%, renal 23%, vertebral segmentation 37%), and CT showed distinctive nasal ossification in 5 of 7 patients [1, 5]. Cognition is usually normal, most cases are simplex and the cause is unknown [1, 5]. In the review by Gabbett and colleagues (4 new cases and 25 published), sporadic occurrence was statistically more likely than AR inheritance, without excluding AD; epibulbar dermoids and upper eyelid colobomas were more frequent than in OAVS, and manifestations outside the craniofacial region less frequent (14% vs 50%), a figure that diverges from the GeneReviews percentages; the first patients described, two siblings, were children of a diabetic mother [14]. All published cases had microtia or auricular tags, and distinction from frontofacionasal dysplasia depends on the type of ocular defect and the shape of the nose [14]. There were no cases in EUROCAT [12].

Isolated microtia. The arguments for including it in the continuum are the similarity of the ear malformations and of the proposed causes, the frequent presence of mild CFM features in so-called isolated microtia and the much higher prevalence of microtia in relatives of patients with CFM than in the population [1, 2]. Intrafamilial variability in the SF3B2 and FOXI3 forms, in which relatives with the same variant have only microtia or full CFM, supports this model [6, 8]. In the 2023 survey of teams from 30 countries, 65% considered isolated microtia a mild form of CFM, although the ICHOM criteria exclude it [15, 100]. In the Italian malformation registry (1983–1992; 1,173,794 births), microtia-anotia occurred in 1.46/10,000, with anotia in 22.1%; 66.2% were isolated, 27.9% were part of multiple malformations and 5.8% of defined syndromes; bilaterality was 12% in non-syndromic cases and 50% in syndromic cases, and insulin-dependent maternal diabetes significantly increased the risk [15]. Microtia-anotia is also part of isotretinoin and thalidomide embryopathies and may be part of fetal alcohol syndrome and diabetic embryopathy [15].

3.11. Natural history and treated disease

Data on the prevalence of complications come, for the most part, from cohorts in tertiary centres with patients who have already undergone treatment, which overestimates severe forms and does not allow natural and treated course to be separated rigorously [2]. According to the European guideline and the French PNDS, mandibular and facial asymmetry is not progressive, but the deformities become harder to correct when no intervention is made during growth [2, 26]. In EUROCAT, 95.8% of cases were live births, 0.8% fetal deaths, 3.4% terminations of pregnancy for medical reasons and 1.5% of live births died in the neonatal period [12].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

In the newborn and infant, CFM should be considered in the presence of any combination of facial asymmetry, mandibular hypoplasia, preauricular or facial tags, microtia, macrostomia, epibulbar dermoids or upper eyelid coloboma [1]. Preauricular tags or pits occur in 0.5–1% of newborns; 20% of these have associated anomalies, so the pinna and the rest of the body are examined before considering them isolated, and 17% of infants with isolated tags or pits have conductive or sensorineural hearing loss [101]. Location helps: in OAVS the tags lie on the line between the tragus and the corner of the mouth, whereas preauricular pits suggest the BOR spectrum [33, 41]. In newborns, particularly preterm infants, a "crumpled" ear without a major anomaly should be reassessed weeks later [41].

Other contexts of suspicion are microphthalmia or anophthalmia with facial asymmetry, tags and ear anomalies [102], eyelid colobomas [103], micrognathia [104], oesophageal atresia with preauricular tags [96] and conotruncal heart disease or Hirschsprung disease with relatives carrying mild facial features, in which the SF3B2 form may have no craniofacial expression [59]. In the older child and the adult, mandibular asymmetry, malocclusion, unilateral conductive hearing loss or congenital facial palsy may be the first recognised manifestation of mild forms, and relatives with a variable phenotype are often classified as unaffected [6, 52].

4.2. Targeted history and examination

The history should include maternal diabetes, bleeding in pregnancy (particularly in the second trimester), multiple pregnancy, ART, vasoactive drugs, retinoic acid, mycophenolate and alcohol, as well as oligohydramnios, abnormal presentation and bicornuate uterus (which suggest deformation), progression of the asymmetry, developmental delay, visual or hearing problems and seizures; the three-generation pedigree looks for facial asymmetry, tags, pits, hearing loss, anal atresia, heart disease and thumb anomalies [1, 33].

The examination includes measurements and clinical photography, the overall shape of the face, distinction between the normal and affected side, the shape, size and symmetry of the ears and patency of the canals (removing hearing aids, whose tubing hides pits), malar flattening, mandibular asymmetry, intercanthal distance and exorbitism, epibulbar dermoid and microphthalmia (OAVS) in contrast with coloboma of the outer third of the lower eyelid (Treacher Collins), macrostomia, facial palsy (also frequent in CHARGE), fontanelles and sutures (craniosynostosis), facial clefts, the neck (torticollis, branchial cysts or fistulae, which suggest BOR), pigmentation and haemangiomas, heart murmurs and the hands (thumb duplication or deficiency in OAVS; triphalangeal or hypoplastic thumb in Townes-Brocks; mild syndactyly in Saethre-Chotzen) [33, 41]. Video documents asymmetrical facial movement [33].

4.3. Warning signs and urgent situations

Signs of upper airway obstruction — tachypnoea, stridor, stertor, glossoptosis, recession and apnoeas — require immediate referral to a craniofacial or ear, nose and throat (ENT) centre [1]. The risk of OSAS is higher in bilateral forms and with a IIB or III mandible, which justify polysomnography in the first year even without symptoms [2]. Difficulty sucking, nasal regurgitation, coughing or choking during feeds, pneumonias and weight gain below the 5th centile indicate specialist feeding assessment [1]. Neurological symptoms (paraesthesiae, numbness, weakness) or neck pain suggestive of neural injury require neurological assessment as early as possible, and the cervical spine should be considered in any general anaesthetic [2]. A difficult airway is the rule in the anaesthesia of these patients: in a systematic review of 28 cases, intubation was achieved at the first attempt in only half, and multiple attempts were associated with delayed extubation, haemodynamic instability and one perioperative death [105]. A dermoid that interferes with eyelid closure or vision and amblyopia are relative ophthalmological emergencies, because amblyopia treatment should take place before 6 years of age [2]. In an emergency, the health record and information on the diagnosis, associated malformations and ongoing treatments should accompany the patient; in France, the centres of the MAFACE network give patients at risk the TETECOU network emergency card "Malformations de la tête et du cou avec risque d'intubation difficile", to be shown to any team providing emergency care [26].

4.4. Prenatal diagnosis

Prenatal diagnosis is rarely reported and is generally restricted to severe forms (for example, unilateral microphthalmia) or those with multiple malformations; there are no studies on detection by two- or three-dimensional ultrasound, or by magnetic resonance imaging (MRI), of microtia, tags and asymmetrical mandibular hypoplasia [1]. In EUROCAT, anomalies were detected on prenatal ultrasound in 18.9% (58/307) of pregnancies (15.9% in 1990–1999 and 20.6% in 2000–2009, a non-significant difference), at a mean gestational age of 21.3±4.1 weeks (11–40), but the diagnosis of OAVS was established only at birth or later; 12 of the 58 detected cases (20.7%) were terminated at 22.1±4.8 weeks [12]. The detected cases had more CNS, cardiac, genitourinary and vertebral anomalies, and 14.8% (16/108) of cases with a major anomaly had a negative prenatal ultrasound [12]. The diagnosis was made at birth in 69.7%, in the first week in 3.9% and in the first year in 6.1% [12]. There is no specific newborn screening; low TRECs on newborn screening for severe combined immunodeficiency may reveal carriers of FOXI3 LoF variants, without this constituting screening for CFM [63].

The French PNDS describes the diagnosis as being made, in most cases, at the second-trimester scan, in the presence of auricular aplasia, microtia or asymmetry of the facial skeleton, a statement that diverges from the low sensitivity documented by EUROCAT [12, 26]. The recommended pathway includes a reference ultrasound in a multidisciplinary prenatal diagnosis centre (CPDPN), with fetal echocardiography and MRI to look for associated malformations and estimate the prognosis; an offer of amniocentesis to exclude a genomic imbalance, as for any malformation syndrome; information for the parents in successive consultations, with a referring doctor who synthesises the specialists' opinions; delivery in a level 3 maternity unit, ideally linked to a reference or competence centre; and confirmation of the diagnosis at birth [26]. Termination of pregnancy for medical reasons is discussed only in very severe syndromic forms (severe micrognathia and retrognathia, microphthalmia, severe heart disease, renal, vertebral and rib anomalies, clefts), because of the burden of care, and parents may decide to continue the pregnancy; the announcement, prenatal or postnatal, is made by an experienced doctor accompanied by another professional, to both parents whenever possible, with a systematic offer of an interview with a psychologist to both [26].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

The diagnosis of CFM is clinical. There is no biomarker and, until 2020, there were no consensus criteria, so CFM was often a diagnosis of exclusion, considered only in the absence of features specific to another condition [1, 38]. The historical minimum criteria required hemifacial microsomia with preauricular tags, or microtia with or without tags, and epidemiological studies used very different definitions, from isolated microtia to registry OAVS [1].

The European guideline adopts the criteria of the CFM working group of the International Consortium for Health Outcomes Measurement (ICHOM), with level of evidence 5 (consensus) [2]:

Source: ERN CRANIO European guideline, table 1 [2]. The French PNDS recommends the same criteria for postnatal diagnosis [26].

In a multicentre database of 730 patients, the FACIAL research criteria had a sensitivity of 99.6% and the ICHOM criteria 94.4%, with fair agreement (kappa 0.38); the patients who did not meet the FACIAL criteria had facial asymmetry only [106]. In the 2023 survey of 57 multidisciplinary teams from 30 countries (response rate of about 3%), 86% used the ICHOM criteria and 74% the OMENS classification, without consensus on the diagnostic criteria [100].

5.2. Severity classification

The OMENS classification scores each component from 0 to 3 (orbit, mandible, ear, facial nerve and soft tissues), and OMENS-plus adds extracraniofacial anomalies, clefts and the inclination of the occlusal plane [2, 35, 36]. The mandible is classified radiographically according to Pruzansky-Kaban (I, IIA, IIB, III) [2, 34]. Inter-observer reliability of the PAT-CFM tool (53 patients, 106 hemifaces, 3 clinicians) was high for the radiographic mandible (Krippendorff's α 0.904; 95% CI 0.860–0.948) and for the ear (0.958; 0.934–0.983), but limited for the orbit (0.682; 0.542–0.821), nerve (0.782; 0.666–0.900) and soft tissues [107]. Three-dimensional photography, in a cross-sectional study of 179 patients from the Netherlands and the United Kingdom, showed greater facial hypoplasia in patients with ocular anomalies, tags, clefts, inner ear anomalies, speech and language difficulties and visual problems, and identified two clusters; the authors propose it for selecting patients to be screened as a priority [108]. The Tasse score (2 points per main finding, 1 per associated finding) correlates with developmental prognosis [37].

The SAT classification (Skeletal, Auricle, soft Tissue) distinguishes five levels of skeletal deformity (S1–S5), four auricular (A0–A3) and three soft tissue (T1–T3), from S1A0T1 in the mildest form to S5A3T3 in the most severe [26]. In the Pruzansky-Kaban classification, type I corresponds to a small but normally shaped ramus and TMJ; in type II, the condyle and ramus are small and deformed, with a well-positioned TMJ and symmetrical mouth opening in IIA and a malpositioned TMJ in IIB; in type III, the ramus, condyle and TMJ are grossly deformed or absent [2, 26]. The distribution is 41% type I, 26% IIA, 14% IIB and 10% III; the higher the type, the greater the number of interventions and the complexity of treatment, and two studies with three-dimensional imaging showed great morphological variability within each type without calling the use of the classification into question [2, 26]. Maxillary severity does not necessarily follow the mandibular type [26].

5.3. Recommended initial assessment

The assessment at diagnosis, reconciling the European guideline, the French PNDS, the ACPA and the historical GeneReviews, includes [1, 2, 23, 26]:

Screening for vertebral anomalies has costs: data from idiopathic scoliosis indicate false positives of 0.8–21.5%, paediatric spinal CT has a mean dose 50% higher than conventional radiography, and a cervical CT at 12 months carries a lifetime risk of radiation-induced cancer mortality estimated at 0.07–0.18% [2]. GeneReviews recommended four-view cervical radiographs (anteroposterior, lateral, flexion and extension) at 3 years, when ossification allows, or earlier if there is torticollis, with referral to orthopaedics if anomalies are present; the Oxford Desk Reference recommends a cervical radiograph in all children with OAVS and considering imaging of the whole spine [1, 33]. The Alberta and EUROCAT authors recommend echocardiography, renal ultrasound and whole-spine radiography for all newborns with the diagnosis [12, 21]. In children of diabetic mothers, an immunodeficiency work-up is added if indicated, because of the overlap with DiGeorge sequence (10% in Wang's series) [46].

5.4. Genetic testing

No CFM-specific guideline addresses genetic testing; the European guideline describes the cause as unknown and associated with prenatal exposures and genetic anomalies [2]. The ACPA recommends, generically for craniofacial differences, assessment by a clinical geneticist with a genetic counsellor, a three-generation pedigree and tests according to the presentation — chromosomal microarray (CMA), targeted tests, panels, exome or genome — with pre- and post-test counselling and later genetic reassessment, because technologies evolve and some syndromes become evident only later [23]. Those who benefit in particular are patients in whom there is doubt between an isolated and a syndromic form or between sporadic and familial, those with growth or developmental delay, intellectual disability, autism spectrum disorder, sensorineural hearing loss or seizures, those with a positive family history, those seen for the first time at an older age and families who request it [23]. Of the teams surveyed in 2023, 81% supported genetic counselling [100]. The 2021 French PNDS states that no gene has been identified as a cause and that the geneticist sees patients within the research setting, expecting next-generation sequencing, under the France Genomic Medicine Plan 2025, to provide simpler access to genetic diagnosis; the text does not include SF3B2, published months earlier, nor FOXI3, published later, and is outdated on that point [6, 8, 26].

There is divergence regarding the karyotype: the Brazilian book recommends a karyotype in all cases, followed by array-CGH [38], whereas the Oxford Desk Reference considers a routine karyotype not indicated in the infant with normal development and facial asymmetry only, reserving genomic analysis for patients with signs of a chromosomal or syndromic aetiology [33]. The 2014 GeneReviews indicated array-CGH mainly in the presence of atypical extracranial malformations, developmental delay or AD inheritance (dup 14q23.1), and single-gene tests or panels in the presence of overlap with BOR (EYA1), CHARGE (CHD7), MFDM (EFTUD2), Townes-Brocks (SALL1) and Treacher Collins (TCOF1) [1]. Digilio and colleagues recommend targeted testing for the 22q11.2 deletion when hemifacial microsomia and microtia coexist with signs of that deletion; the three patients they described had heart disease or aortic arch anomalies and feeding difficulties, and some had neonatal hypocalcaemia [77]. Timberlake and colleagues recommend including SF3B2 in craniofacial panels, with greater usefulness when there is a family history, tragus malformations or preauricular and facial tags [6]; FOXI3 is the gene to prioritise in grade II or III microtia with atresia, familial or not [7, 8]. In practical terms, the strategy that follows from these sources is: CMA when there are extracraniofacial anomalies, delay or signs of del22q11; exome or genome (or a craniofacial panel including SF3B2, FOXI3, TCOF1, POLR1C, POLR1D, EFTUD2, SALL1, SALL4, EYA1, SIX1, CHD7, SF3B4, HOXA2 and PUF60) when there is a family history, features of a differential monogenic syndrome or a request from the family; and periodic reassessment of a negative result.

The expected yield is low: below 10% across all patients with OAVS, about 3% for SF3B2 in sporadic cases and 25% in familial cases, 1–3% for FOXI3 and about 13% of CNVs in array series (with uncertain pathogenicity in part) [6–8, 54, 82]. A karyotype was performed in 54.8% of EUROCAT cases and revealed only two anomalies, probably coincidental (47,XXY and 45,X/46,XY) [12].

5.5. Test limitations and interpretation

A negative result does not exclude a genetic cause. Most cases have no identifiable monogenic cause, and panels vary in genes, methods (sequencing, deletions and duplications) and sensitivity from laboratory to laboratory, with a risk of VUS [1, 23]. Exome sequencing does not cover deep intronic and regulatory regions, and small or low-level mosaic CNVs may escape CMA and sequencing. Mosaic chromosomal anomalies have been described in CFM (trisomies 7, 9 and 18), and the Oxford Desk Reference includes chromosomal mosaicism among the differential diagnoses of facial asymmetry, which may justify analysis of another tissue besides blood [1, 33]. The reduced penetrance of FOXI3, MYT1 and EYA3 and the variable expressivity of SF3B2 make family segregation difficult to interpret, because an "unaffected" parent may be a carrier without a phenotype or with minimal features [6, 7, 9, 67]. Therefore, before classifying an inherited variant as incidental, the carrier parent should be examined clinically (tragus, tags, mandibular asymmetry, hearing) [52, 55]. Splicing variants (such as SF3B2 c.777+1G>A) may be reclassified from VUS to likely pathogenic with minigene or RNA studies [85]. The FOXI3 signals in TREC screening and the SF3B2 carriers with isolated heart disease show that the same variant may have phenotypes without craniofacial expression [59, 63].

The report should state the gene, the versioned transcript (for example NM_006842.3 for SF3B2, NM_001135649.3 for FOXI3), the HGVS nomenclature of the variant at DNA and protein level, the zygosity, the classification according to the ACMG/AMP (Association for Molecular Pathology) criteria, the segregation evidence and, where applicable, the correspondence with the historical nomenclature [23, 56]. A VUS should not guide prenatal diagnosis or predictive testing in relatives.

5.6. Practical algorithm

1. Clinical suspicion (facial asymmetry, microtia, tags, macrostomia, dermoid) → apply the ICHOM criteria and document OMENS and Pruzansky-Kaban [2].
2. Immediate assessment of the airway and feeding; newborn hearing screening and diagnostic audiological assessment before 3 months [2, 23].
3. Search for associated anomalies: echocardiogram, renal ultrasound, clinical and radiological assessment of the spine, ophthalmology and, if indicated, neuroimaging [1, 12, 21].
4. Genetics clinic: gestational history and three-generation pedigree, examination of the parents, search for features of differential diagnoses (symmetry, thumb, anus, lower colobomas, cervical fistulae, microcephaly) [1, 23, 33].
5. Genetic tests according to the phenotype and family history (CMA; exome, genome or panel with SF3B2 and FOXI3) [6, 8, 23].
6. Referral to a multidisciplinary craniofacial team with a care coordinator [2].

6. Differential Diagnosis

6.1. General principle

Unlike CFM, most differential diagnoses have symmetrical facial malformations, and bilateral features help to separate them from OAVS [1, 33]. Vertebral anomalies point to CFM and not to mandibulofacial dysostosis with microcephaly [89], and isolated hemifacial microsomia does not suggest Townes-Brocks syndrome [24]. The French PNDS limits the differential diagnosis to clefts and Treacher Collins syndrome, which share the respiratory, feeding, speech and hearing difficulties, without the full picture being confused with CFM [26].

6.2. Comparative table

6.3. Main differential diagnoses

Treacher Collins syndrome shares with CFM malar and mandibular hypoplasia, microtia and conductive hearing loss (40–50%), but it is symmetrical, has a V-shaped lower eyelid coloboma at the junction of the medial two-thirds and lateral third and preauricular hair in a "sideburn", rarely has extracranial malformations and is associated with normal intelligence; TCOF1 accounts for 78–93% of cases and 60–70% are de novo [1, 41]. The TCOF1 variant p.Ala362Thr described in a patient with OAVS and the silent variants in two patients with Goldenhar syndrome did not establish a causal association [86, 88].

In the BOR spectrum, preauricular pits, branchial fistulae and renal malformations are the discriminating features, and the inner ear is also affected; mild facial asymmetry with mandibular hypoplasia or hemifacial microsomia has been described [33, 81]. The role of SIX5 has not been confirmed and the ClinGen hearing loss gene curation panel classified the association as disputed, so the 5% attributed to SIX5 in the 2014 GeneReviews is out of date [1, 81].

In Townes-Brocks syndrome, the auricular, renal and cardiac overlap with CFM is extensive and there are patients with SALL1 and predominant CFM features; all of these patients had an anteriorly placed anus or preaxial polydactyly [1, 24]. In a series of 165 individuals from 101 families, dysplastic ears occurred in 87%, thumb malformations in 76%, imperforate or stenotic anus in 70%, hearing loss in 62% and renal anomalies in 40%; renal failure may arise without a structural anomaly and requires lifelong monitoring, and the recurrent variant NM_002968.3:c.826C>T p.(Arg276Ter) is associated with heart disease in 50% [87]. Smith's describes in Townes-Brocks syndrome variable features of hemifacial microsomia, sometimes with microtia, epibulbar dermoids and mandibular hypoplasia, and estimates the prevalence at 1/250,000 [109]. The Oxford Desk Reference recommends considering SALL1 testing in patients with overlapping OAVS features [33]. If the radius is involved or there is a Duane anomaly, SALL4 is tested first [24].

Mandibulofacial dysostosis with microcephaly (EFTUD2) shares tags, microtia, aural atresia, hearing loss and facial asymmetry (about 65% in CFM and 58% in MFDM), but the cleft palate is typically median (in CFM it may be of any type, including macrostomia), microcephaly is almost universal in childhood and intellectual disability is prominent; at least two people with an EFTUD2 variant had been diagnosed as having bilateral OAV, and the term "otofacial syndrome" and Guion-Almeida-type acrofacial dysostosis correspond to this entity [33, 41, 89].

The 22q11.2 deletion syndromes and cat eye syndrome should be sought by CMA when CFM is accompanied by conotruncal heart disease or other extracraniofacial anomalies; the 22q11.2 deletion GeneReviews lists OAVS among the differential diagnoses with OMIM number 141400, which corresponds to OAVS with radial defects and not to CFM (164210), an inconsistency that should not be reproduced [28, 112]. In cat eye syndrome, hemifacial microsomia and stenotic auditory canals are occasional anomalies [110].

CHARGE syndrome frequently presents with ear and facial asymmetry and unilateral facial palsy; chorioretinal colobomas, choanal atresia and aplasia of the semicircular canals on temporal bone CT discriminate it, and a compatible CT justifies CHD7 testing [1, 33]. Moebius sequence shares the proposed vascular aetiology; in a series of 25 patients there were limb anomalies in 10, Poland sequence in 2, hypodontia in 7, microglossia in 6, cleft palate in 4, hearing loss in 5, external ear malformation in 1 and autism in 6 [33].

7. Treatments and Risk Management Strategies

7.1. Principles and organisation of care

There is no treatment directed at the cause and no authorised medicine for CFM; treatment is symptomatic, surgical and rehabilitative, age-dependent and organised in time windows [1, 2]. The 2020 ERN CRANIO European guideline, developed by an international working group with a conference in February 2019 and consultation of patients and parents, is the reference document; its conclusions rest mainly on retrospective descriptive studies (level 3) and expert opinion [2]. The survey of patients and parents (32 responses from Italy, Germany, the Netherlands and Sweden) identified as the main problems insufficient information on diagnosis and treatment, difficulty in being referred to an experienced centre and the absence of psychological care [2]. The American guideline of the American Cleft Palate-Craniofacial Association (ACPA), the 2024 Parameters of Care, is generic for clefts and craniofacial differences, but complements the European guideline on airway, hearing, sleep and genetics [23]. The 2021 French PNDS, coordinated by the MAFACE reference centre, adapts the European guideline to the French health system and adds details on orthodontics, ophthalmology, hearing, psychological support, therapeutic education and the follow-up schedule [26].

The European guideline recommends timely referral to a multidisciplinary CFM team following a clinical pathway, information in the patient's language and a care coordinator in each centre, with one specialised centre per 10 million inhabitants [2]. The team includes a maxillofacial surgeon, plastic surgeon, ENT and audiology, psychology, orthodontics, ophthalmology, paediatric anaesthesia, paediatrics, clinical genetics, paediatric intensive care, neurosurgery or spinal orthopaedics, paediatric radiology, social work, speech and language therapy, education, facial physiotherapy, prosthetics and a respiratory team, with access to 3D photography, CT, MRI, 3D surgical planning, a paediatric intensive care unit, a sleep laboratory, audiology and a dental laboratory [2]. GeneReviews added a nutritionist, nurse coordinator, paediatric dentist and genetic counsellor [1]. At all ages, surgical decisions are coordinated with one another (airway, mandible, ear, auricular reconstruction, facial nerve, soft tissues), because the incisions and grafts of one intervention constrain the following ones [2, 23]. The PNDS adds to the team a respiratory physician, orthoptist, dietitian, maxillofacial physiotherapist, prosthetist and team coordinator, and stipulates that CFM anomalies be treated only in reference or competence centres meeting the criteria, including volume criteria, defined by the MAFACE network [26].

7.2. Airway and obstructive sleep apnoea

The European guideline recommends that all patients complete the paediatric sleep questionnaire (PSQ, Paediatric Sleep Questionnaire, free and agreed in the ICHOM standard set) in clinic, "biannually", at least until 6 years of age; polysomnography is performed when the questionnaire raises suspicion and, in the first year of life, in all patients with a Pruzansky-Kaban IIB or III mandible or with bilateral involvement [2]. The text of the guideline does not define whether "biannual" means twice a year or every two years, and the recommendation rests on expert opinion [2]. The ACPA accepts BEARS or the respiratory subscale of the PSQ for screening, considers polysomnography the reference standard at any age (daytime studies are useful in infants) and reserves drug-induced sleep endoscopy or imaging for selected cases [23]. The French PNDS applies the frequency as twice a year, at least until 6 years, in the outpatient setting, and includes the French version of the PSQ as an appendix [26].

Treatment of OSAS is discussed by the team and depends on age, severity and the level of obstruction [2]. In infants and young children, non-surgical respiratory support is considered first (prone positioning, nasopharyngeal tube, oxygen, continuous positive airway pressure — CPAP); in older children with mild to severe OSAS and adenotonsillar hypertrophy, adenotonsillectomy may be the first choice, and most need no additional therapy; in severe OSAS, tracheostomy is considered at any age; mandibular distraction osteogenesis (MDO) is considered in severe OSAS already tracheostomised or to reduce the need for tracheostomy or respiratory support, and is frequently a secondary intervention for tongue base obstruction [2]. Patients should be informed of the uncertainty of the respiratory results of mandibular or maxillary surgery [2]. The French PNDS, drawing on the position of the European Respiratory Society (ERS) on the need to treat OSAS, acknowledges the lack of a standardised protocol and adds three points: non-invasive ventilation (NIV) should be considered in infants and young children; adenotonsillectomy in the older child may be combined with maxillary disjunction or transverse distraction, in the primary or mixed dentition, in the presence of a high-arched palate or maxillary endognathia; and, in severe OSAS, NIV is the priority at any age and tracheotomy is reserved for NIV failure, whereas the European guideline considers tracheostomy at any age [2, 26]. The PNDS decision tree separates mild to moderate OSAS (prone positioning, nasal spray, nasopharyngeal tube, CPAP or bilevel positive airway pressure — BiPAP —, tonsillectomy) from severe OSAS (nasopharyngeal tube, CPAP or BiPAP, tonsillectomy, intubation, tracheotomy); in the infant or young child with severe OSAS, MDO follows; if OSAS persists after 2 years, MDO in Pruzansky types IIA–IIB; without OSAS, mandibular reconstruction in type III in the mixed dentition; and orthognathic surgery at skeletal maturity [26]. Neonatal MDO is discussed in the severe bilateral form with respiratory obstruction, after CPAP has failed and when tracheotomy becomes necessary [26].

Efficacy data are limited. Bilateral MDO in children with micrognathia, respiratory distress and tracheostomy (mean ages 2 months to 5 years) allowed decannulation in 78–94% with the "tracheostomy first" strategy, and 5–11% required tracheostomy with the "MDO first" strategy; in unilateral CFM, the success of MDO for OSAS was 36.4%, and in a study of 62 patients (7 with CFM) decannulation after MDO was lower in CFM than in Robin sequence or Treacher Collins syndrome (OR 0.05; 95% CI 0.005–0.43) [2]. A systematic review of 36 studies with 405 patients with CFM and OSAS showed a reduction in the apnoea–hypopnoea index with CPAP and polysomnographic improvement with MDO and adenotonsillectomy, with an MDO efficacy rate of up to 60% [113]. In a Chinese retrospective series of 72 patients undergoing MDO for OSAS, overall efficacy was 47.2%, adenoid hypertrophy was present in 61.1% and the adenoid/nasopharynx ratio correlated with postoperative oAHI (r=0.261; p=0.027), whereas the Pruzansky-Kaban class was not associated with severity or outcome; the authors recommend assessing the adenoids before MDO [114]. In the cohort of 755 patients, 37 required more than one treatment [95].

7.3. Feeding and nutrition

The European guideline recommends a feeding questionnaire with the same "biannual" frequency until at least 6 years, regular monitoring of growth on World Health Organization (WHO) or national charts and involvement of the speech and language therapist when there is tube feeding; difficulties are treated by the team, with a strategy tailored to severity [2]. Treatment may be conservative (special bottles and teats, supplemented milk, anti-reflux measures, nasogastric tube) or surgical (gastrostomy, cleft closure, MDO) [1, 2]. GeneReviews mentioned Haberman-type bottles, Mead-Johnson squeeze bottles, the Pigeon teat and Dr. Brown's, and referral to a nutritionist if weight or length were below the 5th centile or growth was slow [1]. The French PNDS assigns screening, from birth until at least 6 years, to the paediatrician and a reference nurse of the team; speech and language therapy is the first intervention on oromotor behaviour and swallowing, conservative treatment includes adapted breastfeeding or bottle feeding, supplemented milk and anti-reflux medication, gastrostomy is decided with a paediatric gastroenterologist and, after discharge, the person responsible for monitoring growth and development should be designated [26].

7.4. Hearing

The European guideline recommends newborn hearing screening for all and, when indicated, a complete audiological assessment in an experienced centre before 3 months, reassessment at 24–30 months, regular otoscopy and audiometry by the ENT surgeon in patients with microtia or cleft palate, audiological intervention before 6 months in congenital hearing loss and treatment, surgical or otherwise, of moderate to severe hearing loss [2]. The French PNDS provides, after newborn screening by automated otoacoustic emissions or ABR, annual ENT and audiometric follow-up until 6 years, spaced out in the absence of otitis media with effusion and hearing loss at 3 years and brought closer if there is otological disease, with speech and language surveillance twice a year and fitting of hearing aids for bilateral hearing loss before 6 months [26]. The rehabilitation options, decided case by case according to contralateral hearing and anatomy, include softband bone conduction devices (BAHA®, Ponto™), air conduction aids and, from 5 years, semi-implantable bone conduction devices (BAHA®, Ponto™), an active bone conduction implant (Bonebridge™) or a middle ear implant (Vibrant Soundbridge®), whose timing is coordinated with auricular reconstruction and mandibular surgery [26]. The ACPA recommends a complete diagnostic assessment by 3 months if screening is failed, accepts it up to 9 months even with a normal screen, recommends repeating it in the first year and following up into adulthood as needed; in hearing loss with microtia and atresia, unilateral or bilateral, amplification should be "strongly considered", with bone conduction systems chosen according to degree, candidacy and preference, and with school support (preferential seating, frequency modulation system) [23]. GeneReviews recommended ear-specific auditory brainstem responses (ABR) or otoacoustic emissions in the first 2 months in one section and in the first 6 months in another, an internal divergence resolved by current guidelines in favour of 3 months [1, 2, 23].

In unilateral conductive hearing loss with a normal contralateral ear, many children do not need amplification, but require speech surveillance; unilateral atresia justifies serial hearing assessments and surveillance of the unaffected ear, and Eustachian tube dysfunction justifies a low threshold for tympanostomy tubes [1]. Before any ear surgery, CT of the middle and inner ear determines whether atresia repair may improve hearing (typically after 5 years) and may reveal cholesteatoma in a small proportion [1]. Hearing surgery is coordinated with auricular reconstruction and mandibular surgery, and the ACPA warns that osseointegrated implants, including those for amplification, may compromise future surgical reconstruction [2, 23]. Ototoxic drugs should be avoided [1].

7.5. Speech, language and communication

The European guideline recommends screening pre-verbal communication and babbling at 9 months and assessing receptive and expressive language at 2 years and then "biannually" until 8 years, with referral to community speech and language therapy if difficulties arise [2]. At each visit a structural and functional orofacial assessment is performed (facial symmetry, lips, occlusion, tongue mobility, dentition, hard palate, velar mobility during a sustained "ah") [2]. In children with cleft palate, the cleft team speech and language therapist performs annual screening from 2 to 5 years according to the local protocol, and velopharyngeal dysfunction is assessed from 2 years or when there is verbal output; in children without a cleft, screening for velopharyngeal dysfunction due to asymmetry is performed at 2 years and, if positive, follows the same pathway [2]. Tracheostomised children should be assessed for a speaking valve or augmentative and alternative communication (AAC), and social communication should be monitored [2].

The intervention includes early language stimulation from 9 months if babbling is delayed (modelling, imitation, repetition, expansion), articulation therapy from 3 years when there are cleft speech characteristics, low- or high-tech AAC (gestures, signs from the first year, symbols, boards, voice output devices) for non-verbal or unintelligible children, and social communication intervention [2]. Velopharyngeal insufficiency is treated with speech therapy and, if necessary, a pharyngeal flap or pharyngoplasty [55]. In the CLOCK cohort, the authors recommend early language monitoring, given the lower performance than controls at 3 years [99]. The French PNDS sets language assessment at 2 years and then at least once a year until 8 years, orofacial examination twice a year and surveillance of social communication twice a year from 9 months; it recommends the Glatzel mirror, with repetition of oral syllables and sentences, for screening velopharyngeal dysfunction at 2 years in children without a cleft, the same screening in children with microtia without speech complaints, closer surveillance when mandibular hypoplasia coexists with microtia or hearing loss, and distinguishing the speech difficulties specific to CFM from psychological symptoms [26]. In the intervention, it accepts articulation therapy as soon as the hospital therapist identifies cleft speech characteristics, with local parental guidance before 3 years, treatment before 3 years of oromyofunctional disorders (lip and tongue hypotonia, drooling, mouth breathing), systems such as MAKATON for AAC and regular surveillance of tracheotomised children with a speaking valve [26].

7.6. Eye

All patients should have at least one assessment by an orthoptist and ophthalmologist during visual development, before 5 years, with follow-up according to the result; refractive errors are corrected and amblyopia is treated before 6 years; surgery is discussed by the team, weighing the risks in a child with developing vision [2]. Ultrasound of the dermoid is performed when posterior or orbital extension is suspected, and imaging before resection avoids incomplete excision or perforation [2]. A grade I dermoid is resected if it causes irritation or recurrent conjunctivitis, growth, inadequate eyelid closure, corneal erosion, progressive dellen, refractory amblyopia, astigmatism or cosmetic concern, and is not resected if small and asymptomatic, because excision may leave a scar, epithelial defects and neovascularisation [2]. The proposed technique, with level of evidence 4, is simple excision in thin grade I; keratectomy with amniotic membrane and autologous limbal stem cell allograft, with or without a pericardial patch, or anterior or deep lamellar keratoplasty in grades II and deep I; and total reconstruction of the anterior segment in grade III; amniotic membrane allowed rapid epithelialisation in 29 of 31 eyes [2]. Grades II and III and dome-shaped dermoids cause astigmatism more often and resection is usually indicated [2]. The French PNDS brings forward the first orthoptic and ophthalmological examination to 3 years at the latest, or immediately if an anomaly obstructs the visual axis, and recommends high-resolution ultrasound biomicroscopy (UBM) of the dermoid and B-mode ultrasound when retro-orbital or orbital extension is suspected; surgery for the epibulbar dermoid is by lamellar keratectomy after the depth has been assessed, supplemented if necessary by keratoplasty, and surgery for the orbital dermolipoma is guided by B-mode ultrasound [26].

7.7. Teeth and orthodontics

Routine dental care and primary prevention are recommended, an orthodontist in the team from 5 years, screening by intraoral inspection and dental records, and orthodontic records at 6, 9, 12, 15 and 18 years [1, 2]. Dentofacial orthopaedics (functional appliances) has a place only in very mild cases, because in severe CFM the evidence does not support the activator and there are no conclusions on mandibular growth; orthodontics is coordinated with the decision on orthognathic surgery [2]. The ACPA recommends, generically for craniofacial differences, orthodontic assessment at least annually from birth [23]. The French PNDS brings orthodontics forward to 3 years, with visits at 3, 5, 9–10, 12, 15 and 17–18 years, orthopantomogram and frontal and lateral cephalometric radiographs at 5–6, 9–10, 12, 15 and 17–18 years and oral health-related quality of life questionnaires; the patient's own dentist performs the annual check, the first dental visit is recommended from 1 year and oral hygiene from the first tooth, because the primary teeth serve as anchorage for early orthodontics [26]. The orthodontic strategy depends on the condyle: in mild cases with a condyle, mandibular growth can be stimulated asymmetrically with an adjustable-rod activator, activating the affected side more, for a maximum of one year, preceded by removal of the dentoalveolar compensations (overbite, retroalveolism and maxillary endognathia, with expansion by Hyrax or quad-helix) for a maximum of 6 months; without a condyle, the activator is contraindicated and orthodontics is limited to alignment and palatal expansion, in the mixed dentition, to prepare for surgery [26]. In occlusal problems, mild asymmetry is treated with orthodontics alone (unlocking mandibular growth in the mixed dentition and correcting the malocclusion in the permanent dentition); in severe asymmetry, orthodontic preparation precedes MDO in the mixed dentition and, in the permanent dentition, pre-surgical orthodontics (levelling, alignment, decompensation, arch coordination) and post-surgical orthodontics frame orthognathic surgery, a combination considered indispensable for stability [26].

7.8. Spine

The European guideline recommends screening questions and targeted examination for cervical and back symptoms at the first visit and preoperatively, urgent referral to paediatric neurology in the presence of neurological symptoms, attention to the cervical spine in any general anaesthetic, limited use of CT, and surgical fusion or orthosis when necessary for stability and prevention of secondary injury, in a multidisciplinary approach [2]. Early-onset scoliosis surgery with growth-preserving techniques improved the curve, spinal height and hemithoracic dimensions in a series of 17 patients with CFM [2]. GeneReviews recommended a cervical radiograph at 3 years and annual examination for scoliosis with a radiograph if suspected, and advised against high-impact contact sports in patients with cervical anomalies or a single kidney [1]. The French PNDS recommends systematic radiological assessment looking for vertebral anomalies, in addition to inspection of the shoulders, scapulae and hips; for an unstable spine, orthopaedic bracing to prevent secondary spinal cord injury and fusion if bracing fails; before surgery, MRI, CT and CT angiography; intraoperative neuromonitoring is indispensable; and it cites growth modulation surgery as an effective technique in early-onset scoliosis, with an increase in the height of the convex hemithorax [26].

7.9. Psychological health

All patients should have access to clinical psychology with experience in CFM, with reviews at life transitions (birth, school entry, secondary school) and routine use of validated measures — CLEFT-Q, CFEQ, YP-CORE, HADS and the Distress Thermometer for Parents — at 2, 5, 8 and 22 years, with assessment and support in the presence of high scores [2]. Parents of newly diagnosed children should have access to specialised psychology and information on support groups at first contact and at reviews; specialised support covers low self-esteem, depression, anxiety, concerns about appearance or treatment and medical trauma, with liaison with schools, cognitive assessment if warranted and psychological follow-up before and after facial surgery [2]. Social work supports access to community resources, surgical decisions and adaptation to facial difference [1]. The French PNDS adds that psychology consultations, recommended at certain ages, cannot be imposed, but that the mere availability of a psychologist unknown to the family is not enough; it provides for psychosocial assessments at birth, at 3, at 10–12 and at 15 years and assessment of concerns about facial shape at 8, 12 and 22 years [26]. It highlights 4–5 years, the age of the first questions about the difference, at which the child should be helped to understand the malformation and to prepare a short sentence of explanation, entry into primary school and systematic referral to a psychologist of children who are victims of teasing or bullying; learning or behavioural difficulties detected in preschool require early multidisciplinary assessment and liaison with the school [26]. Parents of newly diagnosed children should have access to clinical psychology for parenting support and observation of attachment, with information on maternal and child protection services and support groups; social and family support and social integration skills are the predictive factors of good psychosocial outcome [26]. Therapeutic education, starting at the announcement with the parents and then with the patient, covers the malformation and its origin, the chronology of treatments, preparation for surgery, infant feeding, oral hygiene, speech and language therapy guidance and self-image; the "E…change de regard" programme, of the ANNA association and the AnDDi-Rares network, is intended for children with a rare disease who suffer from the way others look at them [26]. A study of posts in Facebook groups of families with microtia or CFM showed frequent exchange of health information, and the authors conclude that accessible, reliable and personalised education is needed [26].

7.10. Surgery of the mandible and maxilla

The indications are respiratory, feeding and occlusal, and psychosocial or aesthetic; about one-third of patients with CFM need mandibular surgery [2]. The European guideline recommends starting with non-surgical treatment (oxygen, CPAP) in mild to moderate OSAS in the infant; in infants with mandibular hypoplasia and severe OSAS without response, tracheostomy or MDO; elective MDO to end CPAP; mandibular reconstruction with a costochondral graft after 6 years; in severe occlusal problems, MDO in the mixed dentition with a mandatory combined orthodontic–orthognathic plan and secondary orthognathic surgery at skeletal maturity; and, for aesthetic reasons, postponing mandibular or maxillary surgery until skeletal maturity, discussing in the team early surgery for psychosocial reasons and the risk of reintervention, with psychological support and 3D planning [2]. GeneReviews indicated, without airway compromise, bone grafting or MDO between 5 and 7 years to lengthen the mandible or create a functional TMJ, and orthodontics with final orthognathic surgery when growth is almost complete (13–16 years) [1].

Results are more stable in types I and IIA, and the number of operations is greater when treatment starts early; early unilateral MDO (before 16 years) has poor long-term stability, with relapse of asymmetry and need for orthognathic surgery, and unpredictable results in types IIB and III [2]. In a single-surgeon series (1989–2010; 19 unilateral I/IIA patients, distraction at a mean of 68.2 months, follow-up up to 19.6 years), the result was satisfactory in 63.2% and unsatisfactory in 36.8%; the satisfactory ones were distracted earlier (56.4 vs 89.8 months; p=0.07) and with more overcorrection (41.7% vs 1.8%; p=0.003) [115]. A meta-analysis of 10 studies (175 patients up to 16 years, follow-up longer than 1 year) found relapse, measured by the ramus height ratio, of 67.8% before 6 years and 72.5% after, with no significant difference, and increasing relapse after 5 years of follow-up; the confidence intervals of the abstract are inconsistent and are not reproduced [116]. A Chinese prospective cohort of 24 children (11 operated on at 1–3 years and 13 at 4–6 years), followed for 5 years, showed sustained improvement in symmetry and compensatory maxillary growth in the younger group, with occlusal plane inclination of 4.40° before, 2.23° after surgery and 2.51° at 5 years [117]. Custom TMJ prostheses at maturity, after failure of autologous reconstruction, improved 10 patients (follow-up 6 months to 4 years) [2]. The osteotomy may require adaptation when bone density is very low, as in the French patient with an SF3B2 variant [60].

The French PNDS, based on the European guideline, details the techniques. MDO is performed mainly in moderate hypoplasia (types IIA to IIB, about 30% of cases) or with an occlusal impact (occlusal plane inclination, crossbite), preferably after 6 years, when the first permanent teeth allow surgery and orthodontics to be combined; unilateral MDO widens the oropharynx and nasopharynx and reduces airway resistance, the results of interceptive MDO in type IIB are temporary and bilateral MDO has high success in micrognathia with respiratory distress, avoiding tracheotomy or allowing decannulation [2, 26]. The internal distractor is preferable in most patients, owing to fewer relapses, complications, technical failures and scars (complications of 8–23% vs 22–33% with the external device, in micrognathia studies), despite requiring another anaesthetic for removal; the external device gives better vector control and may be preferred in severe hypoplasia in the first 2 years [2, 26]. The complications of MDO in CFM (24–37%) overlap with overall complications (20–34%): minor and temporary in 15–18% (hypoaesthesia, local infection, pin loosening, dehiscence, incorrect vector), moderate with invasive treatment in 4–12% (detachment of the distractor or pins, incomplete osteotomy) and major and permanent in 5–8% (dental injury, facial palsy, non-union or malunion, skeletal open bite) [2, 26]. A pilot study of a hybrid technique, combining MDO and a mandible-guided functional appliance, improved symmetry and occlusal balance compared with MDO alone [26]. Reconstruction with a non-vascularised rib graft is used in types IIB to III, with secondary surgery for residual or recurrent asymmetry in 18–23% and complications in 0–33% (infection, hypoaesthesia, ankylosis, malposition); at the end of growth, the vascularised free fibula flap is an option when there is no other [26]. Orthognathic surgery is a primary treatment in mild hypoplasia and secondary in severe or bilateral hypoplasia, at skeletal maturity, with 3D planning, computer-aided design and manufacture, surgical navigation, cutting guides and custom plates, and may be combined with distraction in the same procedure; in chin asymmetry without an occlusal problem, genioplasty [26]. A TMJ prosthesis may be implanted before or after skeletal maturity, after failure of reconstruction or ankylosis of the graft, with promising results in two small single-centre studies [26]. Whenever possible, the decision waits until the child is mature enough to take part in an informed way [26].

7.11. Facial nerve

All patients with facial palsy should have psychosocial support; lagophthalmos is assessed by an ophthalmologist, and eyelid surgery is considered in the presence of loss of function of the upper branches, failure of conservative treatment or corneal ulcer [2]. For lagophthalmos, a gold weight or platinum chain (preferred; revision in up to 19% for extrusion, migration, persistent lagophthalmos or ptosis), muscle or tendon transfers or a cross-facial nerve graft are used; tarsorrhaphy is advised against [2]. For asymmetrical lip depression, the guideline recommends starting with botulinum toxin in the depressor labii inferioris muscle on the unaffected side, considering myectomy of that muscle if the toxin result is satisfactory and dynamic techniques (digastric transfer, with prior imaging because agenesis of the anterior belly is frequent) if it is not [2]. For spontaneous animation, a cross-facial nerve graft with free flap and functional muscle transfer from 4 years; the masseteric nerve is reserved for cases without a favourable cross-facial graft, bilateral cases or as a "babysitter", and regional muscle transfers are an alternative [2]. Reanimation is performed after microtia reconstruction and major craniofacial or orthognathic surgery; free flaps have a failure rate of 1–2% and 91% required revisions [2]. Facial movement is assessed with the CLEFT-Q at 8, 12 and 22 years and the facial physiotherapist is part of the team [2]. The French PNDS specifies the lip sequence: repeat the botulinum toxin every 4–6 months while the result is satisfactory and consider myectomy after 2 to 3 satisfactory injections; it attributes to the anterior belly of the digastric an agenesis rate of 55%, a figure that the European guideline restricts to patients with palsy of the marginal mandibular branch (40% in CFM overall) [2, 26]. It adds intraoral transposition of the temporalis muscle, minimally invasive when the temporalis is functional; preference for the gracilis in free transfers (low donor site morbidity, reinnervation potential, reliability); functional transfer from 4 or 5 years; later commissural excursion with cross-facial graft and gracilis than with myoplasty, but comparable at 3 months; greater displacement and speed with the masseteric nerve, at the cost of spontaneous movement; and collection of clinician- and patient-reported outcomes before and after treatment [26]. In the facial palsy decision tree, brow ptosis with visual loss leads to static surgical correction; insufficient eyelid closure is treated with lubricants and then by lowering the upper eyelid (botulinum toxin, gold weight or platinum chain, levator correction) or reducing the palpebral fissure (muscle transfers, tendon slings, cross-facial graft); the mid and lower face moves from non-surgical treatment (toxin in the contralateral depressor, facial therapy) to surgical treatment (contralateral myectomy, digastric transfer, cross-facial graft with free flap), always with psychological support [26].

7.12. Soft tissues

The indication is mainly aesthetic; fat grafting can be performed from childhood, the free flap only in very severe deficiency, alloplastic implants ideally at skeletal maturity, and pedicled flaps are advised against [2]. Comparison between free flap and fat grafting showed complications in 27% vs 4% (p<0.001) and greater symmetry with fat; serial fat grafting raised symmetry from 75–86% to 95–99% (p<0.003), with retention of 68–82%, stabilised at 3 months and greater in children [2]. Facial tags and macrostomia are frequently corrected in the first year, and so is the cleft palate, unless respiratory compromise requires postponement [1]. The French PNDS specifies that serial fat grafting, first line in most patients and in all children and adolescents, significantly improves symmetry in more than three-quarters of patients, with complications in 4–5% (infection, irregular contours); that alloplastic implants, useful mainly at the mandibular angle, are postponed until 18 years or later, and fat grafting should follow their placement; and that pedicled flaps are strongly advised against [26]. In the decision tree, mild deficiency is treated with fat grafting, and moderate or severe deficiency, at skeletal maturity, with implants or free flaps, respectively, or with fat grafting [26].

7.13. Microtia and auricular reconstruction

The indication is aesthetic and psychosocial, with psychological support and the EAR-Q questionnaire before and after surgery [2]. There are four options: no intervention; adhesive or osseointegrated prosthesis; staged reconstruction with autologous costal cartilage; and a synthetic porous polyethylene framework [1, 2]. The European guideline recommends costal cartilage as the first choice from 8 years, does not recommend reconstruction before that age (if desired, an adhesive silicone prosthesis), accepts porous polyethylene (Medpor®) from 6 years and osseointegrated implants as a salvage option, and bases the choice on the patient's preferences [2]. Rib reconstruction is durable, grows similarly to the normal ear and is usually performed at 8–10 years, with 16% overall complications (unsatisfactory result 9%, hypertrophic scar 6%, asymmetry 2%, wire extrusion 2%, venous congestion 2%, resorption 1%, facial nerve injury 1%) and donor site morbidity (pain, atelectasis, pleural tear, chest deformity, thoracic scoliosis, scar) [2]. Porous polyethylene (6–18 years) improved quality of life in 73%, with extrusion or fracture in up to 13–15%, better size and worse definition and colour than rib [2]. The osseointegrated prosthesis had frequent satisfaction but skin reactions in 32–100%, in non-CFM populations [2]. Reconstruction did not change psychosocial functioning in a series of 68 patients [2].

The sources diverge on age: GeneReviews indicated reconstruction or prosthesis generally after 6 years, because adult ear height is reached at 6–8 years; the Brazilian book indicates surgery preferably after 10 years; the ACPA sets neither an age nor a first choice and emphasises that the sequence of operations should avoid ear incisions that compromise later mandibular or hearing surgery [1, 23, 38]. The French PNDS sets reconstruction with costal cartilage (Nagata technique) from 10 years, sometimes later if the microsomia is marked, noting that cartilage calcifies with age (80% above 18 years vs 11% below); it accepts porous polyethylene from 5–6 years, an age at which the motivation is mainly parental, with a greater risk of trauma up to 7–8 years; it considers the adhesive epithesis exceptional (risk of detachment and skin reactions in 32–100%), reserved for severe psychological distress in a young child, and the prosthesis on osseointegrated implants a salvage option, exceptional in children [26]. The PNDS age tree orders the options: adhesive silicone prosthesis from 0 to 5 years, porous polyethylene from 5, costal cartilage from 10 and prosthesis on osseointegrated implants above 18 [26]. In a recent series, reconstruction with autologous cartilage required, in addition to the two planned stages, 2.2 additional procedures on average; a technique with a scalp flap without a skin graft, combined with intense pulsed light during expansion, satisfied patients with unilateral CFM and a very low hairline (mean age 10.2 years), without serious complications [26]. An interview with a psychologist is systematic before reconstruction, to obtain the child's informed consent and assess the expectations of the child and parents, and follow-up continues after surgery [26].

7.14. Kidneys, heart and other anomalies

Cardiac anomalies are followed by paediatric cardiology and renal anomalies by nephrology [1]. Oesophageal atresia, anorectal anomalies and CNS malformations follow the management of those conditions, with difficult airway planning for anaesthesia [105].

7.15. Anaesthesia and the perioperative period

The ACPA recommends sequential airway assessments (flexible or rigid endoscopy, CT or MRI, polysomnography), airway assessment before any surgery, preoperative polysomnography in selected conditions, an anaesthetist experienced in the paediatric airway, difficult airway equipment (videolaryngoscope, supraglottic device, fibreoptic scope) with its own algorithm and age-appropriate overnight postoperative monitoring, because anaesthesia and analgesia worsen OSAS [23]. In a systematic review of 28 cases of Goldenhar syndrome (search up to January 2026), the first attempt was most successful with a Macintosh-type curved-blade videolaryngoscope and then with a Miller-type straight blade; failures with direct laryngoscopy required invasive rescue (retrograde intubation, tracheostomy), and sevoflurane was the most used agent; the evidence comes from case reports with publication bias [105]. The cervical spine should be considered in positioning and intubation [2]. The French PNDS points out that intubation may be difficult and that the cervical spine requires attention in any general anaesthetic, and provides for the TETECOU network difficult intubation emergency card to be given to patients at risk [26].

7.16. Drugs and regulatory status

No drugs are indicated for CFM. The only specific pharmacological intervention mentioned in the European guideline and the French PNDS is botulinum toxin type A in the depressor labii inferioris on the unaffected side, repeated every 4–6 months if the result is satisfactory, without a specified dose [2, 26]. In the absence of a published dose for CFM, the closest reference is congenital unilateral lower lip palsy (asymmetric crying facies), in which 11 patients received 10 units of botulinum toxin type A into the contralateral depressor labii inferioris, with reduced concern about asymmetry when smiling and speaking and no loss of oral competence; this is an extrapolation from an analogous condition, and the abstract does not identify the product [118]. The FDA label for onabotulinumtoxinA (Botox®) does not include this indication, sets in the paediatric age group a cumulative maximum, over 3 months, equal to the lower of 10 units/kg and 340 units, and emphasises that the units of different products are not interchangeable [119]. The other medicines mentioned are supportive: ocular lubricants in lagophthalmos and anti-reflux medication in feeding difficulties [26]. The search of ClinicalTrials.gov and the literature did not identify medicines in development, orphan designations or procedures at the Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for CFM; the orphan designation databases were not searched in a targeted way [120].

Sources: [2, 26, 118–120].

7.17. Intervention studies and registered trials

No completed study is randomised, and the only registered randomised trial (NCT07802639) is recruiting; the surgical series are small, single-centre and with selected patients, outcomes and ages at intervention differ between studies, and indirect comparisons between techniques are not possible. Of the 14 studies registered on ClinicalTrials.gov, none is phase 3 and none has results posted in the registry; the observational studies (CLOCK, NCT02224677, 417 participants; NCT04351893, 935; the candidate gene study NCT04056858; and the National Institutes of Health (NIH) natural history study of craniofacial anomalies, NCT02639312, recruiting until 2046) feed genetic and developmental research [120].

7.18. Developments in the last twelve months

Between October 2025 and October 2026 the following were published: the prospective MDO cohort with 5 years of follow-up (non-randomised cohort) [117]; the cross-sectional 3D photography study in 179 patients proposing phenotypic clusters (observational study) [108]; the case and zebrafish models of truncating SF3B2 variants (human and preclinical study) [58]; the Finnish GWAS confirming the ROBO1 locus (association study) [22]; the description of GBX2 as a CFM gene in Chinese families (family study and mouse model) [71]; the systematic review on the vascular mechanism [42]; the systematic review on airway and anaesthesia [105]; the narrative review on gene–environment interaction [121]; and the functional study of FGFR1 in mesenchymal stem cells from a patient (preclinical) [72]. Two new studies were registered (NCT07654647 and NCT07802639) [120]. The sources consulted did not identify regulatory announcements, opinions or authorisations relating to CFM in that period.

7.19. Agents and circumstances to avoid

Ototoxic drugs should be avoided in hearing loss, and high-impact contact sports in cervical spine anomalies or with a single kidney [1]. In anaesthesia, repeated attempts at direct laryngoscopy are avoided and the difficult airway is planned for [23, 105]. Pedicled flaps for the soft tissues and tarsorrhaphy for lagophthalmos are advised against [2]. Spinal CT should be limited to situations in which it changes management [2].

7.20. Pregnancy, transition and adulthood

The sources consulted do not describe specific management of pregnancy or lactation in women with CFM; the recommendations on difficult airway planning and attention to the cervical spine apply to any anaesthetic, including obstetric anaesthesia, and genetic counselling before pregnancy allows prenatal diagnosis to be discussed when the cause is known [1, 2, 23]. The 2014 recommendation to avoid vasoactive drugs (pseudoephedrine, phenylpropanolamine, ibuprofen, acetylsalicylic acid) in subsequent pregnancies of a woman with a child with CFM was based on Werler 2004 and was not confirmed in the later microtia study; good control of diabetes before and during pregnancy is supported by several studies [1, 43–45]. Transition to adult care coincides with orthognathic surgery at skeletal maturity, the psychological assessment at 22 years and discussion of the risk to offspring, and the ACPA recommends that young adults have the opportunity to revisit genetic counselling [2, 23]. The French PNDS places transition at the end of adolescence: by 18 years the primary and secondary operations have usually been performed, but further procedures may be needed or wanted, particularly at the patient's request; preparation begins in adolescence (autonomy, information on health structures, rights and educational and professional pathway), with consultations without the parents and joint consultations between paediatric and adult doctors, to avoid loss to follow-up [26].

7.21. Divergences between guidelines and sources

Sources: [1, 2, 12, 21, 23, 26, 33, 38, 44].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by scenario

In most families the cause is unknown and counselling is based on empirical risks [1]. For siblings of a proband without a family history, the estimated recurrence risk is 2–3%, and about 2% for first-degree relatives, figures possibly underestimated owing to reduced penetrance and the difficulty of recognising subtle features such as preauricular tags [1, 3, 12]. Clinical examination of the parents precedes application of the empirical risk, because there are dominant families with variable expression and mildly affected relatives are often classified as unaffected [33, 52].

In the EUROCAT families with AD inheritance there was no phenotypic difference from sporadic cases, whereas in Tasse's series the AD families had more bilaterality and less hearing loss and atresia [1, 12]. In a European registry, all multiple pregnancies with OAVS had only one affected twin [12].

8.2. Cascade testing and interpretation in relatives

When a pathogenic variant is identified, testing the parents clarifies whether it is de novo or inherited; in the presence of an inherited SF3B2 or FOXI3 variant, the carrier parent should be examined with attention to minimal features (tragus, tags, mandibular asymmetry, hearing, heart disease), and testing of apparently unaffected relatives may be justified [6, 55, 59]. For MYT1, EYA3 and SHROOM3, the gene–disease evidence is limited and penetrance incomplete, so segregation should be interpreted with caution and the variant should not be used on its own for reproductive decisions [9, 67, 70]. Carriers of FOXI3 LoF variants or deletions may have low TRECs and T lymphopenia; immunological surveillance is a consideration of the authors and not a guideline recommendation [63].

8.3. Prenatal and preimplantation diagnosis

When there is a known pathogenic or likely pathogenic variant in the family (SF3B2, FOXI3) or a causal CNV, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible; variable expressivity and reduced penetrance prevent prediction of severity from the genotype [6, 8, 33]. The 2014 GeneReviews considered prenatal molecular diagnosis impossible because no genes had been identified, a statement superseded in families with a known cause [1]. Without a genetic cause, ultrasound is the only tool and has low sensitivity: in EUROCAT, anomalies were detected in 18.9% of pregnancies, but the diagnosis of OAVS was made only at delivery or later; severe forms may be recognised from 11 weeks [12]. Ultrasound better detects other symmetrical craniofacial syndromes, such as Treacher Collins [1]. In pregnancy, the Brazilian book mentions fetal genetic study with karyotype, without expecting a chromosomal change [38]. When CFM is detected on ultrasound, the French PNDS recommends offering amniocentesis to exclude a genomic imbalance, as for any malformation syndrome, and discussing termination of pregnancy for medical reasons only in very severe syndromic forms [26].

8.4. Prevention and content of counselling

Counselling should ideally take place before pregnancy and be offered to affected young adults, with the option of DNA banking [1, 23]. The topics to be addressed are the heterogeneous and mostly sporadic nature, the meaning of a negative test, variable expressivity within families, the empirical risk, control of diabetes before and during pregnancy, the conflicting evidence on vasoactive drugs, the association with multiple pregnancy and ART and targeted ultrasound in subsequent pregnancies [1, 43–45, 47]. Women who may become pregnant should avoid isotretinoin and mycophenolate without effective contraception [49, 50]. In Siebold's study, intake of vitamin A or liver was associated with a 70% lower risk, an observational result that does not justify supplementation [45]. In asymptomatic minors, testing for a familial variant is justified when it may guide surveillance (hearing, heart disease, TREC screening) and should be accompanied by counselling.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

Frequency estimates vary more than tenfold, because they depend on the case definition (whether isolated microtia and mild forms are included), the age at ascertainment and the source (congenital anomaly registry, tertiary clinic or review estimate) [1, 12].

The figure of 1:3000–1:5000 comes from estimates that include mild forms and is the most cited in reviews, with no population study supporting it in the sources consulted; the EUROCAT figure is a minimum [2, 12]. The European guideline considers CFM the second most frequent congenital facial anomaly, after cleft lip and palate, a statement it attributes to a 2012 review [2]. The French PNDS repeats the incidence of 1:3000–1:5000 and the same frequency ranking [26].

9.2. Sex, ethnicity and geography

Male predominance is about 3:2 in textbook estimates and 1.4:1 in EUROCAT (205:148) [1, 3, 12]. In the USA, the risk is higher in Native American and Hispanic children, a pattern consistent with that of isolated microtia, including in South America (data from the Latin American Collaborative Study of Congenital Malformations, ECLAMC) [1]. The association signal near ROBO1/ROBO2 has been described in Amerindian populations for microtia, in Chinese individuals for CFM and in the Finnish founder population [7, 22, 40]. In the genetic cohorts, FOXI3 accounted for 4.0% of Europeans, 10.4% of Chinese families and 2.0% of sporadic Chinese cases [7]. Rollnick's cohort was 78% Caucasian and the CLOCK cohort 47% Latino [32, 92].

9.3. Europe, Portugal and Brazil

In Europe, EUROCAT gathered 355 cases from 34 registries in 16 countries between 1990 and 2009, and Portugal is among the data providers to the network [12]. The cohort of 51 patients from Coimbra (Portugal) and Manchester (United Kingdom), published by Beleza-Meireles and colleagues, is one of the European series with molecular study, with a 31% positive family history and 22q11 dosage changes in 10 of 22 probands studied by array-CGH; it is a clinical cohort and does not measure national prevalence [52, 122]. The sources consulted do not provide the prevalence of CFM in Portugal.

In Brazil, the sources consulted include cohorts and reports from São Paulo (Federal University of São Paulo, UNIFESP; 73 patients studied for candidate genes and MYT1) [65, 66], Berenguer's Franco-Brazilian cohort [64], 22q11 deletions in Brazilian patients, including a distal deletion described in Campinas (State University of Campinas, UNICAMP) [76, 78], the patient with PUF60 from the Hospital for Rehabilitation of Craniofacial Anomalies in Bauru [90], the neuroimaging series and the case-control study from Porto Alegre [48, 98] and families with AD inheritance described by Vendramini-Pittoli and Kokitsu-Nakata, cited by GeneReviews [1]. The Brazilian book on genetic syndromes devotes a chapter to Goldenhar syndrome [38]. The sources consulted do not provide the Brazilian national prevalence.

9.4. Special populations

Children of diabetic mothers with OAVS have more associated anomalies: in Wang's series, 50% had hemifacial microsomia, 46.7% hearing loss, 33.3% facial palsy and vertebral anomalies, 36.7% cardiovascular anomalies (conotruncal in 45% of these), 26.7% renal anomalies, 13.3% radial hypoplasia and 10% DiGeorge sequence [46]. Children conceived by ART and twins have an increased risk, usually with only one twin affected [12, 47]. Patients with bilateral forms or Pruzansky-Kaban type III concentrate the risk of OSAS, feeding difficulties and ocular and vertebral anomalies [2]. Tracheostomised children require assessment of communication and of alternatives for voicing [2].

9.5. European network and patient associations

ERN CRANIO is the European reference network for rare craniofacial anomalies and ENT disorders and is the author of the European guideline and of its version for patients and families [25, 27]. The patient associations identified are Face Equality International, Microtia UK, Changing Faces (United Kingdom), AboutFace (Canada) and the Children's Craniofacial Association (USA); GeneReviews also listed Faces of Children, AmeriFace and FACES [1]. The sources consulted did not identify CFM-specific associations in Portugal or Brazil.

In France, the 2021 PNDS was prepared by the coordinating reference centre Fentes et malformations faciales (MAFACE), at the Necker-Enfants malades University Hospital (Assistance Publique-Hôpitaux de Paris), which coordinates a network with 22 competence centres and one expert centre, integrated into the TETECOU rare disease health network (malformations of the head, neck and teeth) and, at European level, into ERN CRANIO [26]. CFM is recognised as an off-list long-term condition, with 100% coverage by the Assurance Maladie, except for consultations with psychologists in private practice and the excess fees of private orthodontists; the authors propose a specific orthodontic coding without a limit on semesters and highlight the waiting lists of public child mental health centres [26]. Families should be informed early about parental presence leave (up to 1 year, shareable between the parents and part-time, with a partial allowance and a guarantee of return to employment), the departmental commission that recognises the child's disability from 0 to 20 years and grants the education allowance, the medical certificate for the departmental house for people with disabilities (MDPH) and local services (maternal and child protection, early medico-social action centres, medico-psychological centres) [26]. The French associations listed are Coline (CFM and Treacher Collins syndrome), which supports families morally and financially, APFFP (people with facial clefts), Le Trèfle (Écully cleft team) and ANNA (congenital bodily difference and the way others look); the therapeutic education programmes for malformations of the head, neck and teeth are described on the TETECOU network website [26]. Microtia–atresia, isolated or part of the spectrum, also has its own HAS PNDS (major aplasia of the ear, 2021), prepared by the reference centre for rare ENT malformations (MALO) of the same network.

10. Illustrative Clinical Case

In 2023, Zhang and colleagues described a Chinese newborn girl, the first child of non-consanguineous parents, born by caesarean section at 38 weeks and 2 days because of intrauterine growth restriction and polyhydramnios, weighing 2620 g, with Apgar scores of 7 and 10; the placenta was battledore and praevia [85]. She was admitted to the neonatal intensive care unit on the fourth day because of intermittent cyanosis [85].

Examination showed a right transverse facial cleft (macrostomia, with the right commissure open horizontally into the cheek and a hard granular mass at the corner), cleft palate from the uvula to the junction of the soft and hard palate (about 1.5 cm), a short and deviated mandible, glossoptosis, low-set ears with bilateral accessory auricles and dysplasia of the pinna and canal, a respiratory rate of 66 breaths per minute, recession and a grade II/6 systolic murmur [85]. Blood gases revealed type 2 respiratory failure due to airway obstruction (partial pressure of CO2 of 51.7 mmHg and of O2 of 74.9 mmHg on oxygen). CT showed glossoptosis, a narrow oropharynx and a short mandible, with the left side shorter than the right on 3D reconstruction; chest and spinal CT showed no abnormalities [85]. Photographs of the phenotype of the patient, her father and her grandmother are in figure 1 and the CT in figure 2 of the article.

In the family history, the father had an asymmetrical face, a malformed left pinna with an inaccessible auditory canal and a right auricular tag (with a surgical scar on the right cheek), and the paternal grandmother had bilateral auricular tags and right canal atresia [85]. Trio exome sequencing identified the SF3B2 variant NM_006842.3:c.777+1G>A in the heterozygous state, inherited from the father and absent from the mother and from gnomAD, initially classified as a VUS by the ACMG criteria; the pedigree and Sanger confirmation are in figure 3 [85]. The minigene assay showed two aberrant transcripts, both with a premature termination codon: skipping of exon 7, c.668_777del p.(Val223AspfsTer3), and the same skipping with a 67 bp insertion from intron 6, p.(Val223GlyfsTer15) [56, 85]. The article does not describe long-term management or outcome.

The case illustrates the variable expressivity of SF3B2-associated CFM over three generations — from the grandmother's auricular tags with canal atresia and the father's facial asymmetry to the neonatal form with airway obstruction — and shows that relatives with minimal features may be carriers, which changes the recurrence risk from empirical (2–3%) to 50% [1, 85]. It also shows the value of functional studies for reclassifying a canonical splice-site variant and the need for immediate assessment of the airway, feeding and hearing in the newborn with asymmetrical micrognathia, in line with the recommendations of the European guideline [2]. The founding series of Timberlake and colleagues documents, with photographs and 3D CT, the same spectrum in probands with LoF variants and in a family of 12 affected individuals with the initiation variant p.(Met1?) (figure 2) [6].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

The vital prognosis is generally good and depends on the complications and associated malformations [38]. In EUROCAT, 95.8% of cases were live births and 1.5% of these died in the neonatal period; cases with prenatal detection had more multiple major anomalies [12]. Most patients have normal intelligence; IQ below 85 in 13% and intellectual disability are more frequent when there is microphthalmia, bilateral involvement, brain anomalies or a high severity score [3, 37]. At 3 years, cognitive and motor development is similar to that of controls, with a disadvantage in language [99]. Long-term morbidity is concentrated in hearing (hearing loss in 85.9% of the Boston cohort), speech, occlusion and the need for multiple operations, with high relapse of asymmetry after MDO at all ages [2, 93, 116]. The factors associated with worse outcome are bilateral involvement, Pruzansky-Kaban type III, high O, N and S scores on OMENS and the presence of extracraniofacial anomalies [2, 37]. The psychosocial risk (stigma, low self-esteem, bullying, anxiety) is greater in childhood, and children aged 8 to 10 years have more anxiety and low mood than those aged 11 to 17 [2]. Quality of life increases after treatment of peripheral facial palsy (p<0.001; level 1) [2]. In the SF3B2 form, neurodevelopment was normal in the multigenerational family, but 3 of 8 sporadic probands required an individual education programme [6].

11.2. Surveillance

The "biannual" frequency in the European guideline is not defined in the original text; the French PNDS, led by a member of the European group, applies it as twice a year to OSAS screening and orofacial examination and sets language assessment at least once a year [2, 26]. Immunological surveillance in FOXI3 carriers is a consideration of the authors, not a guideline recommendation [63]. The recommendation of echocardiography and renal ultrasound in all at diagnosis follows the population registries and the ACPA, and not the European guideline, which does not address it [2, 12, 21, 23].

11.3. Follow-up in adulthood

In adulthood, hearing surveillance, orthodontics and orthognathic surgery at skeletal maturity, TMJ prostheses if autologous reconstruction fails, the psychological assessment at 22 years and revisiting genetic counselling before reproduction continue [2, 23]. Osseointegrated ear prostheses, used mainly in adults (mean age 37–44 years in the series), require skin surveillance [2]. OSAS in adults is poorly described (5 adults among the 133 patients with OSAS in the cohort of 755) and is classified with adult criteria (apnoea–hypopnoea index of 5–15, 15–30 and more than 30 per hour) [2].

12. Summary and Final Considerations

Craniofacial microsomia is the recommended name for a continuous spectrum of malformations of the first and second pharyngeal arches that includes hemifacial microsomia, Goldenhar syndrome and the oculo-auriculo-vertebral spectrum, and that extends from isolated microtia to bilateral forms with vertebral, cardiac, renal and central nervous system anomalies [1, 2]. The minimum prevalence measured in European registries is 3.8 per 100,000 births, and estimates that include mild forms reach 1 in 3000–5000 [2, 12]. Asymmetry is the defining feature, and the diagnosis is clinical, supported by the ICHOM criteria and documented by the OMENS and Pruzansky-Kaban classifications [2].

The cause is heterogeneous. Most cases are sporadic and multifactorial, with contributions from maternal diabetes, multiple pregnancy, ART, gestational bleeding and teratogens, and with conflicting evidence for vasoactive drugs [12, 43, 44]. Identifiable genetic causes account for fewer than 10% of patients: SF3B2 haploinsufficiency (CFM1), particularly in families with vertical transmission and tragus anomalies, FOXI3 variants (CFM2), particularly in grade III microtia with atresia and with reduced penetrance, CNVs, notably 22q11.2 and 14q23.1, and a set of genes with limited evidence (MYT1, EYA3, PAX1, SHROOM3, GBX2) [6–8, 54]. Variable expressivity makes it necessary to examine the parents before applying the empirical risk of 2–3%, and identification of a familial variant turns that risk into 50% transmission with unpredictable severity [1, 6, 85].

Treatment is multidisciplinary and staged: airway and feeding in the neonatal period, hearing before 3 months, language from 9 months to 8 years, eyes by 3 years, orthodontics from 3, auricular reconstruction with costal cartilage from 8–10 years, mandibular surgery guided by respiratory, occlusal or psychosocial indications, with frequent relapse after early distraction, and psychological support at defined ages [2]. There are no specific drugs or drug trials; recent research focuses on genetics, 3D phenotyping and surgical techniques [108, 120]. The main gaps are the absence of specific genetic recommendations, the ambiguous screening frequency in the European guideline, which the French PNDS makes concrete as six-monthly, the scarce data on adulthood and pregnancy and the lack of prevalence estimates for Portugal and Brazil in the sources consulted.

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