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Congenital Craniofacial Abnormalities

By Simeon A. Boyadjiev Boyd, MD, Professor of Pediatrics and Genetics, Section of Genetics, Department of Genetics, University of California, Davis

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Congenital craniofacial abnormalities are a group of defects caused by abnormal growth and/or development of the head and facial bones.

Various craniofacial abnormalities (CFA) result from maldevelopment of the 1st and 2nd visceral arches, which form the facial bones and ears during the 2nd month of gestation. Causes include several thousand genetic syndromes as well as prenatal environmental factors (eg, use of vitamin A, valproic acid).

Each of the specific congenital anomalies discussed here typically can be associated with many different genetic syndromes, some of which are named (eg, Treacher Collins syndrome). Because of the large number of syndromes, the discussions focus on the different structural manifestations. Detailed information on many of the specific syndromes is available from the Online Mendelian Inheritance in Man® (OMIM®) catalog of genetic disorders.

In general, children with CFA should be evaluated for other associated physical anomalies and developmental delays that may require treatment and/or help identify specific syndromes and causes. Identification of the underlying syndrome is important for prognosis and family counseling; a clinical geneticist, when available, can help guide the evaluation.


Macrocephaly (megacephaly) is a head circumference > 3 standard deviations above the mean for age. There are two types.

In disproportionate macrocephaly, the head is larger than appropriate for the child's size; affected children are at risk of autism spectrum disorders, developmental disability, and seizures.

In proportionate macrocephaly, the head appears appropriately sized for the body (ie, the large head is associated with a large stature), and an overgrowth syndrome (eg, growth hormone excess) should be considered.

Evaluation should include a 3-generation family history, developmental and neurologic assessment, examination for limb asymmetry and cutaneous lesions, and brain MRI. Sometimes disproportionate macrocephaly is familial and not associated with other anomalies, complications, or developmental delays; this form is transmitted in an autosomal dominant pattern, so at least one parent has a large head circumference. The diagnoses to be considered include neurofibromatosis type I, Fragile X syndrome, Sotos syndrome, and lysosomal storage disorders.


Microcephaly is a head circumference < 2 standard deviations below the mean for age. In microcephaly, the head is disproportionately small in relation to the rest of the body. Microcephaly has many chromosomal or environmental causes, including prenatal drug, alcohol, or radiation exposure, prenatal infections (eg, TORCH [toxoplasmosis, other pathogens, rubella, cytomegalovirus, and herpes simplex] and possibly Zika virus), and poorly controlled maternal phenylketonuria. Microcephaly also is a feature of > 400 genetic syndromes. The consequences of microcephaly itself include neurologic and developmental disorders (eg, seizure disorders, intellectual disability, spasticity).

Evaluation should include detailed prenatal history to identify risk factors, developmental and neurologic assessment, and brain MRI. Primary autosomal recessive microcephaly may involve a defect in one or more of at least four genes.

Among the genetic syndromes to be considered are Seckel syndrome, Smith-Lemli-Opitz syndrome, syndromes due to defective DNA repair (eg, Fanconi and Cockayne syndromes), and Angelman syndrome. For parents of an affected child, risk of the disorder appearing in subsequent offspring may be as high as 25%, depending on which syndrome is present, and thus clinical genetic assessment is necessary.


Craniosynostosis is premature fusion of one or more calvarial sutures, which causes a characteristic skull deformity due to decreased growth in a direction perpendicular to the closed suture. It occurs in 1 of 2500 live births. There are several types, depending on which suture is fused.

Sagittal craniosynostosis is the most common type and causes a narrow and long skull (dolichocephaly). Most cases are isolated and sporadic, with risk of transmission to offspring < 3%. Learning disability may be present in up to 40 to 50% of patients.

Coronal craniosynostosis is the second most common type and can be bilateral, causing a short and broad skull (brachycephaly), or unilateral, causing a diagonal skull deformity (plagiocephaly). True plagiocephaly (ie, caused by craniosynostosis) often results in asymmetric orbits and is to be differentiated from positional plagiocephaly, which is due to torticollis or positioning the infant predominantly on one side and does not result in asymmetric orbits. In positional plagiocephaly, the back of the skull is flattened on one side, there is frontal bossing on the same side, and the ear on the flattened side may be pushed forward, but the orbits remain symmetrical. About 25% of coronal craniosynostosis cases are syndromic and due to single-gene mutations or chromosomal defects. Coronal craniosynostosis is commonly associated with facial and extracranial anomalies within the context of Crouzon, Muenke, Pfeiffer, Saethre-Chotzen, Carpenter, or Apert syndromes.

Eye anomalies

Hypertelorism is widely spaced eyes, as determined by increased interpupillary distance, and can occur in several congenital syndromes, including frontonasal dysplasia (with midline facial cleft, and brain abnormalities), craniofrontonasal dysplasia (with craniosynostosis), and Aarskog syndrome (with limb and genital anomalies).

Hypotelorism is closely spaced eyes, as determined by decreased interpupillary distance. This anomaly should raise suspicion of holoprosencephaly (a midline brain abnormality).

Coloboma is a gap in the structure of the eye that may affect the eyelid, iris, retina, or optic nerve of one or both eyes. Coloboma of the eyelid is frequently associated with epibulbar dermoid cysts and is common in Treacher Collins syndrome, Nager syndrome, and Goldenhar syndrome. Coloboma of the iris raises the possibility of CHARGE association (coloboma, heart defects, atresia of the choanae, retardation of mental and/or physical development, genital hypoplasia, and ear abnormalities), cat eye syndrome, Kabuki syndrome, or Aicardi syndrome.

Microphthalmia is a small eye globe, which may be unilateral or bilateral. Even when unilateral, mild abnormalities (eg, microcornea, colobomas, congenital cataract) of the other eye are frequently present. It causes sight-threatening complications such as angle-closure glaucoma, chorioretinal pathology (eg, uveal effusion), strabismus, and amblyopia. Causes include prenatal exposure to teratogens, alcohol, and infections (TORCH), and numerous chromosomal or genetic disorders, some of which are suggested by other clinical features. Growth and developmental delays are frequently present in microphthalmia that is caused by a chromosomal disorder. Facial asymmetry suggests Goldenhar syndrome or Treacher Collins syndrome; hand abnormalities suggest trisomy 13, oculo-dental-digital syndrome, or fetal alcohol syndrome; and genital abnormalities may suggest chromosomal defects, Fraser syndrome, or CHARGE association.

Anophthalmia is complete absence of the eye globe and occurs in > 50 genetic syndromes caused by chromosomal anomalies or mutations in one of several genes (eg, SOX2, OTX2, BMP4). When skin covers the orbit, the anomaly is called cryptophthalmos, which suggests Fraser syndrome, Nager syndrome, or ophthalmia-mental retardation.

Cleft palate and cleft lip

Cleft lip, cleft lip and palate, and isolated cleft palate, are collectively termed oral clefts (OCs). OCs are the most common congenital anomalies of the head and the neck with a total prevalence of 2.1 per 1000 live births. Both environmental and genetic factors have been implicated as causes. Prenatal maternal use of tobacco and alcohol may increase risk. Having one affected child increases risk of having a second affected child. Folate, taken just before becoming pregnant and through the 1st trimester, decreases the risk.

Oral clefts are divided into 2 groups:

  • Syndromic (30%)

  • Nonsyndromic (70%)

Syndromic OCs are those present in patients with recognized congenital syndromes or with multiple congenital anomalies. These OCs are typically caused by chromosome abnormalities and defined monogenic syndromes.

Nonsyndromic (isolated) OCs are those present in patients without associated anomalies or developmental delays. A number of different gene mutations can cause the phenotype, including mutations of some of the genes that are involved with syndromic OCs, which suggests there is significant overlap between syndromic and nonsyndromic OCs.

The cleft may vary from involvement of only the soft palate to a complete fissure of the soft and hard palates, the alveolar process of the maxilla, and the lip. The mildest form is a bifid uvula. An isolated cleft lip can occur.

A cleft palate interferes with feeding and speech development and increases the risk of ear infections. Goals of treatment are to ensure normal feeding, speech, and maxillofacial growth and to avoid formation of fistulas.

Early treatment, pending surgical repair, depends on the specific abnormality but may include specially designed bottle nipples (to facilitate flow), dental appliances (to occlude the cleft so suckling can occur), a feeder that can be squeezed to deliver formula, taping, and an artificial palate molded to the child’s own palate. The frequent episodes of acute otitis media must be recognized and treated.

Ultimate treatment is surgical closure; however, timing of surgery, which may interfere with growth centers around the premaxilla, is somewhat controversial. For a cleft palate, a 2-stage procedure is often done. The cleft lip, nose, and soft palate are repaired during infancy (at age 3 to 6 mo). Then, the residual hard palate cleft is repaired at age 15 to 18 mo. Surgery can result in significant improvement, but if deformities are severe or treatment is inadequate, patients may be left with a nasal voice, compromised appearance, and a tendency to regurgitate. Dental and orthodontic treatment, speech therapy, and counseling may be required.

Micrognathia (small mandible)

Micrognathia may occur in > 700 genetic syndromes.

Pierre Robin sequence is a common manifestation of micrognathia characterized by a U-shaped cleft soft palate and upper airway obstruction caused by glossoptosis (a tongue that falls to the back of the throat); conductive hearing loss may also be present. Feeding can be difficult, and sometimes cyanosis develops because the tongue is posterior and may obstruct the pharynx. Prone positioning during feeding may help, but uncoordinated swallowing may require nasogastric gavage feedings or a gastrostomy tube. If cyanosis or respiratory problems persist, tracheostomy or surgery to affix the tongue in a forward position (eg, sewing it to the inner lower lip) may be required. Otologic evaluation is indicated.

About one third of patients with micrognathia have associated anomalies that suggest an underlying chromosomal defect or genetic syndrome. When other anomalies are present, a clinical geneticist can help guide the evaluation because identification of the underlying syndrome is important for prognosis and family counseling. Some of the diagnoses to be considered include Treacher Collins syndrome (associated with downward slant of the eyes, coloboma of the eyelid, malformed pinna [microtia], and hearing loss), Nager syndrome, Goldenhar (oculoauriculovertebral) syndrome, and cerebrocostomandibular syndrome.

Surgical extension of the mandible can improve appearance and function. In the typical procedure, called distraction osteogenesis, an osteotomy is done and a distraction (separator) device is attached to both pieces. Over time, the distance between the two pieces is widened, and new bone grows in between to enlarge the mandible.


Congenital absence of the condyloid process (and sometimes the coronoid process, the ramus, and parts of the mandibular body) is a severe malformation. The mandible deviates to the affected side, resulting in severe malocclusion; the unaffected side is elongated and flattened. Abnormalities of the external, middle, and inner ears, temporal bone, parotid gland, masticatory muscles, and facial nerve often coexist. Syndromes to be considered include agnathia-holoprosencephaly, otocephaly, a severe form of cerebrocostomandibular syndrome, and Ivemark syndrome.

X-rays or facial CT of the mandible and temporomandibular joint show the degree of underdevelopment and distinguish agenesis from other conditions that result in similar facial deformities but do not involve severe structural loss. Facial CT is usually done before surgery.

Treatment consists of prompt reconstruction with autogenous bone grafting (costochondral graft) to limit progression of facial deformity. Often, mentoplasty, onlay grafts of bone and cartilage, and soft-tissue flaps and grafts further improve facial symmetry. Distraction osteogenesis (see Micrognathia (small mandible)) is being increasingly used. Orthodontic treatment in early adolescence helps correct malocclusion.

Congenital ear malformations

Microtia and external auditory canal atresia (which causes conductive hearing loss) involve the external ear. These malformations, which frequently coexist, are often identified at or soon after birth. Occasionally, school-based screening tests identify a partially occluded external auditory canal in children with a normal pinna.

Hearing tests (see Hearing Loss : Physical examination) and CT of the temporal bone are necessary to evaluate possible additional bony malformations.

Treatment can include surgery and a bone-conduction hearing aid, depending on whether the malformation is unilateral or bilateral; whether it affects hearing, learning, and social development; and whether complications (eg, facial nerve involvement, cholesteatoma, otitis media) are present. Surgery may include pinna reconstruction and the creation of an external auditory canal, tympanic membrane, and ossicles.

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