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Craniofacial Microsomia Overview

, MD, MS, , MD, PhD, and , MD.

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Initial Posting: ; Last Update: October 9, 2014.

Estimated reading time: 34 minutes


Clinical characteristics.

Craniofacial microsomia (CFM) includes a spectrum of malformations primarily involving structures derived from the first and second branchial arches. Characteristic findings include facial asymmetry resulting from maxillary and/or mandibular hypoplasia; preauricular or facial tags; ear malformations that can include microtia (hypoplasia of the external ear), anotia (absence of the external ear), or aural atresia (absence of the external ear canal); and hearing loss. Severity can range from subtle facial asymmetry with a small skin tag in front of an otherwise normal-appearing ear to bilateral involvement (typically asymmetric), microtia/anotia with atresia of the ear canals, microphthalmia, and respiratory compromise from severe mandibular hypoplasia. Other craniofacial malformations including cleft lip and/or palate can be seen. Non-craniofacial malformations, especially vertebral, renal, cardiac, and limb, can be seen.


The diagnosis of CFM is based on clinical findings.

Genetic counseling.

CFM most frequently occurs as a simplex case (i.e., occurrence in a single individual in a family) with unknown etiology; recurrence risks are empiric. If an individual with CFM is found to have an inherited or de novo chromosome abnormality, genetic counseling for that condition is indicated. Occasional autosomal dominant or autosomal recessive inheritance is observed. If a proband has CFM and no reported family history of CFM, the risk to sibs is 2%-3%, although this may be an underestimate because of low penetrance and the difficulty of obtaining an accurate family history for some of the subtle features of CFM.


Treatment of manifestations: For optimal outcome children with CFM require timely and coordinated assessments and interventions. Ideally, children should be managed by an experienced multidisciplinary craniofacial team. The goals of treatment for CFM are to assure adequate respiratory support and feeding in infants with severe facial malformations, maximize hearing and communication, improve facial symmetry, and optimize dental occlusion. Treatment is age-dependent, with time-sensitive interventions at appropriate stages of craniofacial growth and development.

GeneReview Scope

Craniofacial Microsomia Overview: Included Phenotypes
  • Hemifacial microsomia
  • Oculo-auriculo-vertebral spectrum
  • Goldenhar syndrome
  • First and second branchial arch syndrome
  • Otomandibular dysostosis
  • Facio-auriculo-vertebral syndrome
  • Lateral facial dysplasia


Craniofacial microsomia (CFM) includes a spectrum of malformations primarily involving structures derived from the first and second branchial arches.

Characteristic findings (Figure 1, Figure 2, and Figure 3):

Figure 1.

Figure 1.

Examples of the variability of the skeletal malformations associated with craniofacial microsomia

Figure 2.

Figure 2.

Grades of auricular malformations described by Marx [1926]

Figure 3. . (A) Frontal and (B) lateral views of a boy with right-sided microtia, preauricular tag, macrostomia, and mandibular hypoplasia with soft tissue deficiency.

Figure 3.

(A) Frontal and (B) lateral views of a boy with right-sided microtia, preauricular tag, macrostomia, and mandibular hypoplasia with soft tissue deficiency. Illustrations by Bridget Rafferty.

  • Facial asymmetry, a hallmark of this condition; common even when individuals demonstrate bilateral features
  • Mandibular hypoplasia, also called micrognathia (see Figure 2 and Figure 3); usually the result of shortening of the ramus and often asymmetric
  • Preauricular or facial tags and/or pits. Tags are common, variable in size, and generally distributed along the skin overlying the mandibular ramus. These branchial remnants can be simple skin tags, but may also contain cartilaginous structures that grow over time.
  • Microtia (hypoplasia of the external ear) (see Figure 2)
  • Anotia (absence of the external ear)
  • Aural atresia (absence of the external ear canal and associated middle ear anomalies)
  • Conductive, sensorineural, or mixed hearing loss

No diagnostic criteria have been established; thus, CFM is often a diagnosis of exclusion (see Differential Diagnosis).

Proposed minimal diagnostic criteria [Grabb 1965, Melnick et al 1979, Rollnick & Kaye 1983, Teconi & Hall 1983, Bennun et al 1985, Tasse et al 2007]:

  • Hemifacial microsomia (asymmetric hypoplasia of facial structures) with preauricular tags
  • Microtia (with or without preauricular skin tags)

The following evidence supports the notion that isolated microtia (i.e., microtia with no other malformations) may be a part of the continuum of CFM [Grabb 1965, Melnick et al 1979, Rollnick & Kaye 1983, Teconi & Hall 1983, Bennun et al 1985, Tasse et al 2007]:

Several systems have been designed to define the spectrum of anomalies seen in CFM [Grabb 1965, Teconi & Hall 1983, David et al 1987, Rollnick 1988, Vento et al 1991, Cousley 1993, Gougoutas et al 2007].

Note: Individuals with features of CFM have been classified under a number of different diagnoses. It has not yet been established whether these diagnoses are distinct entities or represent the phenotypic continuum of CFM. In this GeneReview, the term CFM includes all of the following terms (listed from most common to least common):

  • Hemifacial microsomia (asymmetric hypoplasia of facial structures)
    Note: The term CFM is more inclusive than the term “hemifacial microsomia” because the term CFM includes the large percent of individuals with bilateral involvement, including those diagnosed with hemifacial microsomia who have subtle differences in the “non-affected” side.
  • Oculo-auriculo-vertebral spectrum
  • Goldenhar syndrome
  • First and second branchial arch syndrome
  • Otomandibular dysostosis
  • Facio-auriculo-vertebral syndrome
  • Lateral facial dysplasia


The head and neck originate from six embryonic structures called the pharyngeal apparati (see Figure 4A), which resemble the branchial apparatus in fish [Moore & Persaud 2003]. Each pharyngeal apparatus comprises a pouch, an arch, a groove, and a membrane. In the fourth week of gestation neural crest cells migrate from the neural tube to begin the development of the pharyngeal arch ectomesenchyme (see Figure 4B). Each arch has three layers (endoderm, mesenchyme from ectomesenchyme and mesoderm, and ectoderm), which produce the four primordial components: muscle, artery, nerve, and cartilage. The craniofacial structures most commonly affected in CFM develop from the first and second pharyngeal (branchial) arches (see Figure 4, Figure 5, Figure 6, and Figure 7).

Figure 4. A.

Figure 4

A. Lateral view of the six embryonic pharyngeal arches (I-VI) B. Coronal view through the first pharyngeal arch showing the migration of cells from the neural tube to the neural crest where they will develop into the head, neck, and body

Figure 5.

Figure 5.

Origin of the external ear structures from the first and second pharyngeal arches Adapted from Sze et al [2002], published with permission from AJR Am J Roentgenol

Figure 6.

Figure 6.

Bones (A) and muscles (B) derived from the first pharyngeal arch Adapted from Sze et al [2002], published with permission from AJR Am J Roentgenol

Figure 7.

Figure 7.

Bones (A) and muscles (B) derived from the second pharyngeal arch Adapted from Sze et al [2002], published with permission from AJR Am J Roentgenol

The spectrum of anomalies involved in CFM may result from an embryonic “developmental field” functioning as a unit that responds in a similar manner to different insults such as chromosome abnormalities, mutation in a single gene, vascular disruption, and teratogens [Opitz 1985, Opitz & Lewin 1987, Cousley & Wilson 1992]. In support of this theory, CFM is causally heterogeneous (see Causes). In addition, malformations identical to CFM are observed in different vertebrate species, suggesting a developmental commonality.

The clinical findings in individuals with craniofacial microsomia can overlap with those observed in syndromes, developmental anomaly associations, and sequences. Examples include:

  • VATER (expanded to VACTERL: vertebral anomalies, anal atresia, cardiac anomalies, tracheoesophageal atresia, renal anomalies, and limb anomalies);
  • CHARGE (coloboma, heart, atresia choanae, retardation of growth and development, and genitourinary and ear anomalies);
  • MURCS (variable developmental anomalies of the müllerian ducts, unilateral renal, cervicothoracic, and somite structures or their derivatives); and
  • OEIS (omphalocele, exstrophy of the cloaca, imperforate anus, and spinal anomalies).

This overlap has led investigators to hypothesize that these conditions may represent developmental abnormalities which result in anomalies that may be a part of a broad spectrum, such as the axial mesodermal dysplasia spectrum [Hartsfield 2007].

Clinical Manifestations of CFM

Phenotypic variability is common in CFM. Whereas some individuals have subtle facial asymmetry with a small skin tag in front of an otherwise typical-appearing ear, others have bilateral involvement (commonly asymmetric), microtia/anotia with atresia of the ear canals, microphthalmia, and possibly respiratory compromise from severe mandibular hypoplasia (see Table 1).

In addition to the features that define CFM, the following are commonly observed in affected individuals:


  • Midface hypoplasia (underdevelopment of the midface, usually asymmetric)
  • Ankylosis (limited opening of the mouth)
  • Malocclusion


Oral region

  • Macrostomia (lateral oral clefting). Unilateral macrostomia is the most common form of facial clefting associated with CFM, though all types of clefts can be observed.
  • Cleft lip and/or palate

Skeleton. Vertebral anomalies [Stueckle et al 2014]:

  • Malformed and/or fused cervical vertebrae are common, though anomalies can be noted throughout the spine.
  • Hemivertebrae are also common.

Cranial nerves

  • Facial palsy (unilateral or bilateral involvement of either part or all branches of cranial nerve VII)
  • Sensorineural hearing loss
  • Asymmetric palatal elevation
  • Impairment of extraocular movements

An estimated 65% of individuals with CFM have some degree of facial asymmetry [Cohen et al 1989]. Individuals with facial asymmetry associated with CFM are more likely to have malformations that involve the right side of the face than the left side of the face. The ratio of affected individuals with right-sided to left-sided ear involvement is 3:2 [Gorlin et al 2001].

Of those individuals with bilateral facial involvement (e.g., left microtia and a right preauricular tag), most demonstrate asymmetric involvement [Grabb 1965, Burck 1983, Rollnick et al 1987].

Less common additional malformations:

Table 1.

Prevalence of Selected Anomalies in Craniofacial Microsomia

AnomaliesPrevalence 1
PrincipalMandibleMandibular hypoplasia49%-100%
Malformed glenoid fossa24%-27%
Preauricular tags34%-61%
Conductive hearing loss50%-66%
OcularOrbital dystopia15%-43%
Epibulbar dermoids4%-35%
NerveVII nerve palsy10%-45%
Soft tissueMasticatory muscle hypoplasia85%-95%
Velopharyngeal insufficiency35%-55%
Palatal deviation39%-50%
Cranial skull base abnormalities9%-30%
Cleft lip and/or palate15%-22%
Coloboma of the upper eyelid4%-25%
Hypodontia/dental hypoplasia8%-25%
Lacrimal duct atresia/stenosis11%-14%
Frontal plagiocephaly10%-12%
Sensorineural hearing loss6%-16%
Preauricular sinus6%-9%
Cervical spine21%-42%
Central nervous system5%-18%

Prevalence rates from more than 20 reports published between 1983 and 2014 are summarized. Studies based on selected samples were omitted to minimize selection bias.

Establishing the Diagnosis of CFM

The diagnosis of CFM can be established based on clinical examination alone.

Differential Diagnosis of CFM

As discussed in Embryology, the clinical features observed in individuals with CFM can also be associated with syndromes, developmental anomaly associations, and sequences. In this review, the diagnosis of CFM is only considered for those individuals who do not have features unique to these other conditions. Unlike CFM, individuals with the diagnoses listed below (in alphabetical order) typically have symmetric facial malformations. The similarities among the conditions are also illustrated in Table 2.

Auriculocondylar syndrome (OMIM 602483) is typically an autosomal dominant condition with variable mandibular hypoplasia frequently with temporomandibular joint ankylosis, cleft palate, and distinctive question mark appearance of the ears due to separation of the lobule from the external ear. Although findings are typically bilateral and symmetric, the occasional presence of preauricular tags and mandibular hypoplasia can overlap with CFM. Additional features include hearing loss, prominent cheeks, and microstomia. Heterozygous pathogenic variants have been noted in two genes in the endothelin receptor pathway, PLCB4 and GNAI3 [Rieder et al 2012].

Bixler syndrome (hypertelorism-microtia-clefting) (OMIM 239800) is a rare condition with presumed autosomal recessive inheritance based on recurrences in sibs and parental consanguinity. Clinical features include: hypertelorism, cleft lip and palate, broad nasal tip, and microtia. Etiology is not known [Amiel et al 2001].

Branchiootorenal (BOR) syndrome is characterized by malformations of the outer, middle, and inner ear associated with conductive, sensorineural, or mixed hearing impairment, branchial fistulae and cysts, and renal malformations. The diagnosis is based on clinical findings. A heterozygous pathogenic variant in any one of three genes is known to cause BOR: EYA1 (locus name: BOR1) (approximately 40% of affected individuals), SIX5 (locus name: BOR2) in 5%, and SIX1 in 4%. Inheritance is autosomal dominant.

CHARGE syndrome is a mnemonic for coloboma, heart defects, choanal atresia, retarded growth and development, genital abnormalities, and ear anomalies. CHARGE syndrome typically involves unilateral or bilateral coloboma of the iris, retina-choroid, and/or disc, with or without microphthalmos; unilateral or bilateral choanal atresia or stenosis; cranial nerve dysfunction; abnormal ears (including abnormal external ear shape, middle ear anatomy, and inner ear findings including Mondini defect of the cochlea, and absent or hypoplastic semicircular canals); cryptorchidism in males and hypogonadotropic hypogonadism in males and females; developmental delay; cardiovascular malformation; and growth deficiency. Orofacial clefts and tracheoesophageal fistula are seen in a subset of individuals. A heterozygous pathogenic variant in CHD7 is identified in 65%-70% of individuals with CHARGE syndrome. For those with a CHD7 pathogenic variant, inheritance is autosomal dominant.

Hemifacial myohyperplasia sequence (OMIM 606773) is a rare craniofacial condition characterized by unilateral hypertrophy of the facial muscles and ipsilateral hypoplasia of the facial bones of unknown cause. The facial asymmetry is progressive after birth [Pereira-Perdomo et al 2010].

Mandibulofacial dysostosis with microcephaly is characterized by malar and mandibular hypoplasia; congenital- or postnatal-onset microcephaly; malformations of the outer ear, auditory canal, and/or middle ear (ossicles and semi-circular canals) with hearing loss; and facial features that include: prominent glabella, broad nasal bridge, bulbous nasal tip, and everted lower lip. Individuals may also have cleft palate, choanal atresia, and facial asymmetry. Intellectual disability is a prominent feature. Extracranial malformations include: esophageal atresia, congenital heart disease, and thumb abnormalities. Presence of a heterozygous pathogenic variant in EFTUD2 is causative. Inheritance is autosomal dominant [Lines et al 2012, Lehalle et al 2014]. In one patient with a de novo heterozygous pathogenic variant in EFTUD2, clinical features included a unilateral epibulbar dermoid similar to findings seen in CFM [Luquetti et al 2013].

Miller syndrome (postaxial acrofacial dysostosis) (OMIM 263750) is characterized by postaxial limb deficiency (hypoplasia, syndactyly, absence of postaxial digits [the 5th digits and in some cases the 4th and 3rd digits], and ulnar hypoplasia that causes shortening of the forearms) and distinctive facial features (malar hypoplasia, micrognathia, cleft palate, rarely cleft lip, small "cup-shaped" ears, and colobomas and/or ectropion [drooping] of the lower eyelids). Miller syndrome is rare. Biallelic pathogenic variants in DHODH are causative. Inheritance is autosomal recessive [Chrzanowska & Fryns 1993].

Nager syndrome (preaxial acrofacial dysostosis) (OMIM 154400) is characterized by preaxial limb anomalies (hypoplasia or absence of radius, hypoplasia/absence of the thumbs, triphalangeal thumbs, radioulnar synostosis) and facial anomalies (malar hypoplasia with downward slanting palpebral fissures, lower eyelid coloboma, severe micrognathia). Nager syndrome is rare, most cases are simplex (i.e., a single occurrence in a family); however, families with autosomal dominant and autosomal recessive inheritance have been reported [Hecht et al 1987, Bonthron et al 1993]. Heterozygous pathogenic variants in SF3B4 have been reported in 58%-64% of individuals with clinical features of Nager syndrome [Bernier et al 2012, Czeschik et al 2013, Petit et al 2014].

Oculoauriculofrontonasal syndrome (OAFNS) (OMIM 601452) is a rare craniofacial condition with features of both frontonasal dysplasia and oculo-auriculo-vertebral spectrum [Gabbett et al 2008]. Characteristic findings include: ocular hypertelorism, notched or bifid nasal tip, microtia, ear and facial skin tags, eyelid colobomas, epibulbar dermoids, mandibular hypoplasia, and facial asymmetry. Extracranial findings are similar to those noted in individuals with CFM and include: cardiac (44%), renal (23%), and vertebral segmentation (37%). Cranial CT imaging showed distinctive nasal ossification in five of seven individuals studied [Evans et al 2013]. Most cases are simplex (i.e., a single occurrence in a family) and genetic cause is not known.

Parry Romberg syndrome (progressive hemifacial atrophy) (OMIM 141300) is characterized by slowly progressive unilateral atrophy of the skin and soft tissues of the face [Grippaudo et al 2004]. It is more common in females than in males. Initial facial changes usually involve the tissues above the maxilla or near the nasolabial fold and later progress to involve the areas around the eye, lower face, and neck. The tongue and gums may also atrophy. The skin overlying affected areas may become darkly pigmented. Neurologic abnormalities include seizures and trigeminal neuralgia. In Parry-Romberg syndrome atrophy typically begins between ages five and 15 years, whereas in CFM the facial malformations are congenital (i.e., present at birth).

Townes-Brocks syndrome (TBS) is characterized by a triad of clinical findings: imperforate anus, dysplastic ears (overfolded superior helices andpreauricular tags) frequently associated with sensorineural and/or conductive hearing impairment, and thumb malformations (triphalangeal thumbs, duplication of the thumb, and rarely hypoplasia of the thumbs). Associated findings include: renal impairment, including end-stage renal disease, may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoureteral reflux), congenital heart disease, foot malformations, and genitourinary malformations. Intellectual disability occurs in approximately 10% of individuals. Most individuals with CFM do not have thumb and/or anal malformations; however, the overlap of the ear, renal, and cardiac findings in CFM and TBS is significant. Presence of a heterozygous pathogenic variant in SALL1 is causative. Inheritance is autosomal dominant.

At least three individuals with predominant features of CFM had mutation of SALL1 [Kohlhase et al 1999, Keegan et al 2001, Kosaki et al 2007]; however, each also had anterior displacement of the anus and/or preaxial polydactyly.

Treacher Collins syndrome (TCS) is characterized by malar (zygoma) and mandibular hypoplasia, external ear abnormalities (microtia), coloboma of the lower eyelid with deficient eyelashes, and a distribution of the scalp hair in the preauricular region (i.e., sideburn). An estimated 40%-50% of individuals with TCS have conductive hearing loss resulting from abnormalities/hypoplasia of middle ear structures. Extracranial malformations are rare and intellect is typically normal. Mutation in one of three genes – TCOF1 (78%-93%); POLR1C and POLR1D (8%) – is causative. Inheritance is most often autosomal dominant (TCOF1 and POLR1D) with rare reports of autosomal recessive inheritance as a result of biallelic pathogenic variants in POLR1C or POLR1D [Schaefer et al 2014].

Of note, one individual with a diagnosis of oculo-auriculo-vertebral spectrum (unilateral microtia, aural atresia, and unilateral mandibular hypoplasia with an absent zygomatic arch) had a TCOF1 missense variant (1084G>A) resulting in the substitution Ala362Thr [Su et al 2007].

In another study, two individuals diagnosed with Goldenhar syndrome had silent (Glu621Glu; Gln54Gln) TCOF1 sequence variants not noted in 150 controls [Splendore et al 2002].

Table 2.

Comparison of Phenotypic Characteristics Among Conditions in the Differential Diagnosis of CFM

ConditionGene(s)Phenotypic Characteristics
/ ear
Auriculocondylar syndrome 1PLCB4, GNAI3XXX
Axial mesodermal dysplasia complex 2UnknownXXXXXXX
Bixler (hypertelorism -microtia-clefting) syndrome 3UnknownX
Branchiootorenal spectrum disordersEYA1, SIX1, SIX5XXXXX
Cat-eye syndrome 4Chromosome 22 markerXXXXXXX
Hemifacial myohyperplasia 5UnknownXX
Mandibulofacial dysostosis with microcephaly 6EFTUD2XXXXXX
Miller syndrome 7DHODHXX
Nager syndrome 8SF3B4XXXXX
Parry Romberg syndrome 9UnknownXX
Townes-Brocks syndromeSALL1 (SALL4)XXXXXXX
Treacher Collins syndromeTCOF1, POLR1C, POLR1DXX
VACTERL association 10UnknownXXX

Prevalence of CFM

CFM has an estimated prevalence of between 1:5600 and 1:26,550 live births – possibly an underestimate because of varying criteria used to define the disorder and underdiagnosis of milder cases.

The male to female ratio is 3:2 [Gorlin et al 2001].

Causes of CFM

The causes of craniofacial microsomia (CFM) can be divided into environmental, heritable, multifactorial, and unknown (the largest category).

Environmental (Acquired) Causes

Several studies have assessed the maternal environmental risk factors that may be associated with CFM in offspring. Because each study used different inclusion criteria, the authors have summarized the patient characteristics for each study in Table 3.


Minimal Diagnostic Criteria Used in Select Studies Assessing Risk Factors for CFM

StudyMinimal Inclusion Criteria for Participants
Grabb [1965], Rollnick & Kaye [1983], Lawson et al [2002], Wieczorek et al [2007]Microtia
Taysi et al [1983]Skin tags and a family history of features of hemifacial microsomia
Rollnick [1988]Microtia and/or preauricular tags
Kaye et al [1992]Microtia and mandibular hypoplasia
Araneta et al [1997](1) Microtia, anotia, or preauricular tags AND (2) hypoplasia of the mandible or select physical features of Goldenhar syndrome
Maris et al [1999]Hemifacial microsomia, followed at a dental clinic affiliated with a craniofacial center
Kelberman et al [2001]Skin tags and a family history of features of hemifacial microsomia
Wang et al [2002]Any ear anomaly or at least 2 features of oculoauricular-vertebral spectrum
Werler et al [2004a]Hemifacial microsomia, facial asymmetry, Goldenhar syndrome, oculoauricular-vertebral syndrome as diagnosed by a craniofacial geneticist or surgeon
Werler et al [2004b]Hemifacial microsomia, facial asymmetry, Goldenhar syndrome, or unilateral anotia/microtia as diagnosed by a craniofacial geneticist or surgeon
Tasse et al [2005], Tasse et al [2007]Microtia or hemifacial microsomia with preauricular tags
Van Bennekom et al [2013]Microtia
Barisic et al [2014]ICD9/BPA, ICD10/BPA and OMIM codes assigned to OAVS, Goldenhar syndrome, and hemifacial microsomia

Reported risk factors include:

  • Maternal use of vasoactive drugs
  • Maternal second trimester bleeding
  • Maternal diabetes mellitus
  • Multiple gestation
  • Maternal use of assisted reproductive technology (ART)

Use of the vasoactive drugs pseudoephedrine, aspirin, or ibuprofen during pregnancy has been associated with a 1.5- to 2-fold increase in the risk for CFM [Werler et al 2004a]. However, a subsequent study of the National Birth Defects Prevention Study on nonsyndromic microtia found no association for any vasoactive mediations or smoking; either in isolated microtia or microtia associated with other birth defects [Van Bennekom et al 2013].

In general, greater concordance in monozygotic (MZ) twins compared to dizygotic (DZ) twins supports the influence of genetic factors. Conversely, the high levels of discordance for CFM in MZ twins argues in favor of the role of environmental factors [Grabb 1965, Burck 1983, Araneta et al 1997, Gorlin et al 2001, Lawson et al 2002, Wang et al 2002].

In an epidemiologic study of 239 individuals with CFM and 854 controls, risk factors identified for CFM included the following [Werler et al 2004b]:

  • Lower birth weight. 29% of babies with CFM weighed less than 2500 g compared to 5% of the control group. The risk for CFM to infants with a birth weight below 3000 g was two to six times the risk to infants with a birth weight between 3000 and 3499 g. This was confirmed in a population-based study in Europe with 355 cases for which 21% of males and 37% of females weighed less than 2500 g [Barisic et al 2014].
  • Lower family income. The average family income was lower in the case group compared with controls. For infants with a family income below $25K, the risk for CFM was twofold that of controls.
  • Very low maternal body-mass index (BMI) (defined as weight in kg/height in meters squared). The risk for CFM was twofold greater for infants born to mothers with a BMI lower than 18 than women with a BMI between 19 and 23.9.
  • Native American or Hispanic race/ethnicity [Werler et al 2004b]. This ethnic heterogeneity is consistent with that also reported for isolated microtia [Harris et al 1996, Lopez-Camelo & Orioli 1996, Shaw et al 2004].

Maternal ingestion of Accutane® during the first trimester of pregnancy can result in malformations associated with abnormal migration of neural crest cells, some of which overlap with those of CFM, including: microtia/anotia, mandibular hypoplasia, cleft palate, and cardiac defects (conotruncal and aortic arch). Additional findings include: central nervous system malformations, retinal or optic-nerve abnormalities, and thymus hypoplasia [Lammer 1991].

Maternal ingestion of the immunosuppressive medication mycophenolate mofetil during pregnancy can also lead to malformations (microtia, cleft lip/palate, micrognathia, cardiac malformations) that overlap with CFM. Additional findings distinct from CFM observed in infants exposed in utero to mycophenolate mofetil include hypoplastic fingers and toenails, diaphragmatic hernia, and tracheoesophageal fistula [Koren 2008, Parisi et al 2009].

Heritable Causes

Chromosomal Causes

Craniofacial microsomia has been observed in a number of chromosome disorders (Table 4).

Single-Gene Causes

Approximately 1%-2% of families demonstrate autosomal dominant inheritance and rare families demonstrate autosomal recessive inheritance of CFM or isolated microtia [Burck 1983, Schmid et al 1985, Kaye et al 1992, Bestelmeyer et al 1996, Llano-Rivas et al 1999, Tasse et al 2005, Tasse et al 2007, Vendramini-Pittoli & Kokitsu-Nakata 2009, Farra et al 2011, Barisic et al 2014]. Table 5 compares oculo-auriculo-vertebral spectrum findings in families with autosomal dominant inheritance with findings in simplex cases (i.e., a single occurrence in a family) [Tasse et al 2007].

Table 5.

Oculo-Auriculo-Vertebral Spectrum Findings in Families with Autosomal Dominant Inheritance vs Findings in Simplex Cases

FindingFamilialSimplex 1
Bilateral facial involvement71%46%
Hearing loss26%87%
Aural atresia41%79%

Simplex= a single occurrence in a family

To date, the largest segregation analysis included clinical examination of 311 members of the families of 74 probands with CFM. The study provided evidence for genetic transmission, and more specifically, an autosomal dominant mode of inheritance with reduced penetrance [Taysi et al 1983, Kaye et al 1992].

To the authors’ knowledge, two linkage studies have been performed in families with features of CFM [Kelberman et al 2001, Huang et al 2010a].

Recently, a study reported on a HOXA2 nonsense pathogenic variant (c.703C>T) in a three-generation family of European ancestry with bilateral nonsyndromic microtia and mixed hearing loss segregating as an autosomal dominant trait [Brown et al 2013]. Individuals from this family presented with middle ear abnormalities of the ossicular chain; the external auditory canals of all affected individuals had normal anatomy.

A missense variant in HOXA2 had been previously associated with autosomal recessive bilateral microtia in a consanguineous Iranian family. Although the external and middle ear features of both families were similar, affected individuals in the Iranian family had more severe microtia and abnormalities of the ear canal, profound mixed hearing impairment, and partial cleft palate [Alasti et al 2008]. The more severe phenotype in this family is probably secondary to the presence of the pathogenic variant in both alleles.

As discussed in Differential Diagnosis, mutation of TCOF1, (Treacher Collins syndrome) EFTUD2 (mandibulofacial dysostosis with microcephaly), and SALL1 (Townes-Brocks syndrome) has also been identified in individuals with features that overlap with CFM.

Multifactorial Inheritance

Although most cases of CFM appear to be simplex (i.e., a single occurrence in a family), multifactorial inheritance is suggested by the following:

Unknown Cause

Whereas some individuals have subtle facial asymmetry with a small skin tag in front of an otherwise normal-appearing ear, others have bilateral involvement (typically asymmetric), microtia/anotia with atresia of the ear canals, microphthalmia, and possibly respiratory compromise from severe mandibular hypoplasia.

Possible explanations for those with CFM of unknown cause include:

  • Mutation of a yet-to-be-identified gene or regulatory region of gene
  • Pathogenic variants or benign variants in multiple genes involved in craniofacial development (polygenic inheritance)
  • Effects of both gene and environmental interactions (multifactorial inheritance)

Evaluation Strategy

A diagnosis of CFM should be considered in individuals with variable combinations of facial asymmetry, mandibular hypoplasia, preauricular tags, microtia, epibulbar dermoids, and/or upper-eyelid coloboma.

Once a diagnosis of CFM has been considered, the following approach can be used to exclude other conditions and to assist with discussions of prognosis and recurrence risk counseling.

The following information should be obtained from pregnancy and family history, physical examination, hearing and ophthalmologic evaluation, imaging studies, and genetic testing.

Pregnancy history. A history of maternal diabetes mellitus, second trimester bleeding, multiple gestation, assisted reproductive technology (ART), or exposure to teratogenic agents such as: vasoactive drugs or retinoic acid (Accutane®), and mycophenolate mofetil should be obtained.

Family history. A three-generation family history with attention to other relatives with facial asymmetry, ear tags, ear pits, hearing loss, anal atresia, cardiac malformations, and/or thumb abnormalities should be pursued.

Physical examination. A complete physical examination should be performed by a medical geneticist or physician who specializes in craniofacial disorders.

  • Facial asymmetry should be noted as well as severity of mandibular hypoplasia.
  • Ear findings should be noted, including presence of ear pits and/or tags and patency of the external auditory canal.
  • Eyes should be examined for upper- and lower-eyelid colobomata and epibulbar dermoids. Ophthalmologic consultant should evaluate for chorioretinal colobomas (seen in CHARGE syndrome).
  • The neck should be inspected for branchial sinuses or cysts and torticollis or impaired mobility.
  • The heart; spine, and limbs should be evaluated.


  • Audiologic diagnostic testing (ear-specific and frequency-specific) in all individuals
  • Additional imaging studies. X-rays of the cervical spine, echocardiogram, and renal ultrasound examination
  • CT scan of the temporal bone (commonly after age five years). Those with significant hearing impairment, aural atresia, and/or features of CHARGE syndrome. If temporal bone CT findings are consistent with CHARGE syndrome, testing for CHD7 is recommended.
  • Consideration of array comparative genomic hybridization, particularly if there are atypical extracranial malformations, delays in development, or possible autosomal dominant inheritance (which can be caused by chromosome 14q23.1 duplication).

Molecular genetic testing. No specific molecular genetic testing is indicated for individuals with features characteristic of CFM.

One approach is single-gene testing. Molecular genetic testing should be considered for those whose clinical findings overlap with the following disorders:

Alternative approaches include:

  • Use of a multigene panel that includes the five genes and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Comprehensive genomic testing such as exome sequencing, which has been shown to be effective in defining the genetic basis of CFM [Luquetti et al 2013]. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Craniofacial microsomia (CFM) most frequently occurs as a simplex case (i.e., occurrence in a single individual in a family) with unknown etiology; recurrence risks are empiric.

If an individual with CFM has an inherited or de novo chromosome abnormality, genetic counseling for that condition is indicated.

Occasional autosomal dominant or autosomal recessive inheritance is observed.

Empiric Risks to Family Members

Sibs of a proband. If a proband has CFM and no reported family history of CFM, the risk to sibs is 2% to 3%. This may be an underestimate because of the difficulty of obtaining an accurate family history for some of the subtle features of CFM, such as preauricular tags [Rollnick & Kaye 1983, Rollnick et al 1987, Rollnick 1988].

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis of simplex cases has been reported rarely, and typically in those with severe (unilateral microphthalmia) or multiple malformations [Martinelli et al 2004, Hattori et al 2005, Castori et al 2006].

Molecular genetic testing. Because the gene(s) in which pathogenic variant(s) are responsible for craniofacial microsomia have not been identified, prenatal diagnosis using molecular genetic testing is not possible.

Fetal ultrasound examination. Recurrences in families are infrequent, and no reports in the literature have evaluated the ability of fetal imaging (2D or 3D ultrasound or MRI) to detect microtia, preauricular tags, and/or asymmetric mandibular hypoplasia. Prenatal ultrasound examination can be used to detect other craniofacial malformation syndromes, such as Treacher Collins syndrome [Rotten et al 2002]. In a European population-based study of oculo-auriculo-vertebral spectrum, prenatal anomalies were detected in 18.9% of pregnancies; however, the diagnosis of oculo-auriculo-vertebral spectrum was not established until delivery or later [Barisic et al 2014].


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Foundation for Faces of Children
    258 Harvard Street
    Brookline MA 02446-2904
    Phone: 617-355-8299
  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
  • AmeriFace: The Cleft/Craniofacial Advocates
    PO Box 751112
    Las Vegas NV 89136
    Phone: 888-486-1209 (toll-free 24 hours); 702-769-9264
    Fax: 702-341-5351
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free)
  • FACES: The National Craniofacial Association
    PO Box 11082
    Chattanooga TN 37401
    Phone: 800-332-2373 (toll-free)
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791


Evaluations Following Initial Diagnosis

To establish the extent of involvement in an individual diagnosed with craniofacial microsomia (CFM), the authors recommend the following evaluations.

Upper airway obstruction. Evaluate all individuals with CFM for clinical findings of upper-airway obstruction with physical examination to assess for tachypnea, stridor, stertor, glossoptosis (e.g., tongue-based upper airway obstruction) increased work of breathing with visible retractions, and/or episodic upper-airway obstruction with apnea.

Children with findings of upper-airway obstruction should be referred to a craniofacial center and/or otolaryngologist.

For those without obvious findings of upper-airway obstruction, a sleep history should be obtained from caretakers to screen for airway obstruction during sleep, and a sleep study and/or sleep medicine consultation should be pursued in those with concerning reports.

Clinical feeding and nutrition evaluation. Assess the nutritional status of the infant/child as part of the general physical examination with weight and height plotted on standard growth charts.

If the child demonstrates both normal parameters for age and normal rate of growth, no further studies are needed.

If the child’s rate of growth and/or current measurements is below the fifth percentile, consultation with a clinical dietitian/nutritionist should be considered. Caretakers should be queried regarding feeding history with particular attention to inadequate suction with breast/bottle feeding, nasal regurgitation, coughing or choking during meals, or recurrent pneumonia. If any of these findings are reported, evaluation by a clinical feeding specialist (often occupational therapist or speech pathologist) and/or videofluoroscopic swallowing study is indicated.

Hearing evaluation. An ear-specific diagnostic hearing evaluation (with either brain stem auditory evoked response or otoacoustic air emissions) in the first two months of life is recommended (see Deafness and Hereditary Hearing Loss). Timing of subsequent hearing evaluations should be determined by the patient’s results and medical history.

Cervical spine films. Perform screening cervical spine imaging at age three years, or earlier if there are concerns (e.g., torticollis). If there are abnormalities on the radiographs, referral to an orthopedist is indicated.

Children should be screened for scoliosis at diagnosis and yearly thereafter with annual physical examination. Radiographs should be obtained for children with evidence of scoliosis.

Echocardiogram. If there are concerns based on history or physical examination, obtain an echocardiogram.

Renal ultrasound examination. A screening renal ultrasound examination should be obtained at the time of diagnosis.

Treatment of Manifestations

For optimal outcome children with CFM require timely and coordinated assessments and interventions. Ideally, children should be managed by an experienced multidisciplinary craniofacial team that includes the following (in alphabetical order):

  • Audiologist
  • Dietitian
  • Clinical geneticist and genetic counselor
  • Nurse coordinator
  • Ophthalmologist
  • Oral and maxillofacial surgeon
  • Orthodontist
  • Orthopedist
  • Otolaryngologist
  • Pediatric dentist
  • Pediatrician
  • Plastic and reconstructive surgeon
  • Psychosocial professionals (psychologist, social worker)
  • Speech pathologist

The goals of treatment for CFM are to assure adequate respiratory support and nutritional status, maximize hearing and communication, optimize development, improve facial symmetry, and treat dental malocclusion. Treatment is age dependent, with time-sensitive interventions at appropriate stages of craniofacial growth and development. Treatment plans should be individually tailored to ensure the best results.

The phenotype in CFM is quite variable (see Table 1 for associated anomalies). Details of common surgical interventions have been reviewed elsewhere [Birgfeld & Heike 2012]. The following medical issues may need to be addressed in an individual with CFM:

Feeding. Infants with significant micrognathia, macrostomia, or a cleft palate may have difficulty with feeding and may require specialized bottles designed for infants with cleft palate and/or dysphagia (e.g., Habermann feeder, Mead-Johnson Squeeze bottle, Pigeon nipple, Dr. Brown nipples), supplemental nasogastric (NG) feedings, and gastrostomy tube placement. Consultation with an infant feeding specialist and/or dietitian should be considered.


  • Infants with severe mandibular hypoplasia may have significant upper-airway compromise and require tracheostomy placement and/or early mandibular advancement. Referral to a craniofacial center or otolaryngologist is recommended.
  • Those children with moderate mandibular hypoplasia may develop obstructive sleep apnea and require either medical (CPAP) or surgical (tonsillectomy and adenoidectomy or mandibular surgery) intervention.

Face. Surgical repair is often recommended for facial tags and macrostomia within the first year. Surgery for palatal clefts typically occurs within the first year although this may be deferred for children with respiratory compromise.

Jaw and teeth

  • Good oral hygiene is especially important for children with CFM. Children should have consistent primary preventative dental care.
  • Orthodontic evaluations are important to assess for missing teeth, dental crowding, jaw growth, and dental malocclusion. Some children may need one or more dental appliances or braces to optimize facial growth, dental appearance, and function.
  • Children with mandibular hypoplasia may require a bone graft and/or mandibular distraction osteogenesis to lengthen the mandible and/or create a functional TMJ. In a child without airway compromise, these options may be considered when the child is between ages five and seven years.
  • The use of functional dental appliances to try and influence facial growth, vertical alveolar growth, and dental eruption in the younger patient may be considered, depending on the patient. When facial and jaw growth is nearly complete (age 13 to 16 years), most children with CFM require orthodontics, and many benefit from a final orthognathic surgery to create skeletal symmetry.


  • All infants with CFM should have a diagnostic hearing evaluation (brain stem auditory evoked response [BAER]) within the first six months of life (regardless of whether the child passed the newborn hearing screen). Timing and type of additional testing depend on results from this initial evaluation and the child’s medical history. Early referral to an otolaryngologist is recommended. Early intervention for infants with hearing loss is important to optimize speech and language outcome.
  • Children with hearing impairment should receive guidance regarding recommendations for hearing aids, appropriate academic accommodations, and avoidance of ototoxic medications to prevent further hearing loss.
  • Conductive hearing loss, related to aural atresia in which the ossicles may be poorly formed or absent, may be treated with hearing aids. Children with unilateral conductive hearing loss and normal hearing in the contralateral ear are frequently not treated with amplification; however, their speech and language should be monitored closely.
  • Prior to planning external ear surgery, the authors recommend obtaining a CT scan to assess the middle- and inner-ear structures to help determine if atresia repair is likely to improve hearing. This surgery typically occurs after age five years. The CT may also reveal cholesteatomas, which occur in a small proportion of children with aural atresia.
  • Children with unilateral aural atresia should have serial screening (with hearing evaluations and tympanoscopy) to ensure maximal hearing of the unaffected ear.
  • Individuals with eustachian tube dysfunction should continue to have hearing and otologic status monitored, with a low threshold for placing tympanostomy tube(s).

Speech. Children with CFM may have cranial nerve palsies, clefts of the palate, malocclusion, and muscular deficiencies that can contribute to abnormal speech patterns (including velopharyngeal insufficiency). The authors recommend a speech evaluation prior to age two years, and ongoing monitoring by a speech and language pathologist.

Ears. Surgical options for treating ear malformations include auricular reconstruction or creation of a prosthetic ear. Options for management of microtia include the following:

  • No action
  • Prosthetic management, either adhesive or implant-retained
  • Staged surgical reconstruction, using autogenous rib or a synthetic framework

Because adult ear height is achieved by age six to eight years, surgical reconstruction or prosthetic management is often considered after age six years. Ear reconstruction should be coordinated with jaw surgeries for optimal long-term outcomes.

Eyes. Individuals with congenital or acquired epibulbar dermoids (pinkish-white growth on the sclerae) should be referred to the ophthalmologist. Large epibulbar dermoids and those that interfere with vision may require excision.

Cardiac. Children with physical examination findings suggestive of a cardiac anomaly should receive a timely referral to a pediatric cardiologist.

Renal. Individuals with renal anomalies should be referred to a nephrologist.


  • Children should undergo screening with four-view cervical spine radiographs (i.e., AP, lateral, flexion, and extension) at age three years when the bones are ossified. Those with anomalies should be referred to an orthopedic surgeon.
  • Children should be screened for scoliosis at diagnosis with annual physical examination. The authors recommend obtaining radiographs for children with evidence of scoliosis.

Family and social support. Children with CFM may be at increased risk for psychosocial difficulties [Maris et al 1999]. Social workers can provide support and guidance to children and their families, such as accessing community resources, making decisions about surgery, and adjusting to having facial differences.


Click here (pdf) for an overview of the common medical and surgical management recommendations for children with craniofacial microsomia (Adapted from Birgfeld & Heike [2012], published with permission from Semin Plast Surg).

Agents/Circumstances to Avoid

Individuals with any degree of hearing loss. Avoid exposure to ototoxic drugs.

Individuals with cervical spine anomalies. Follow guidelines outlined by the appropriate subspecialists (which likely include avoiding high-impact contact sports).

Individuals with a single kidney. Follow guidelines outlined by the appropriate subspecialists (which likely include avoiding high-impact contact sports).

For subsequent pregnancies of a woman who has had a child with CFM

  • Avoid vasoactive medications (pseudoephedrine, phenylpropanolamine, ibuprofen, and aspirin);
  • Manage diabetes mellitus to maintain good control and avoid hyperglycemia.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.


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Chapter Notes


We thank the following Seattle Children’s Craniofacial Center members for their valuable contributions to this article: Dr Michael Cunningham, Dr Kathleen Sie, Dr Craig Birgfeld, Dr Mark Egbert, Dr Jacqueline Starr, Marsha Ose, and Cassandra Aspinall.

Revision History

  • 9 October 2014 (me) Comprehensive update posted live
  • 19 March 2009 (cg) Review posted live
  • 29 August 2008 (clh) Original submission
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