Embryology

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 Figures 4, 5, 6, 7).

Figure

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
Adapted (more...)

Figure

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

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

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, 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 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 (see Table 1).

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

Face

• 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

Jaw

• Ankylosis (limited opening of the mouth)

• Asymmetric mandible (usually the result of shortening of the ramus)

• Midface hypoplasia (underdevelopment of the midface, usually asymmetric)

• Malocclusion

Eye

• Epibulbar dermoid

• Asymmetric shortening of the palpebral fissure

• Microphthalmia/anophthalmia (rare)

• Coloboma of the upper eye lid

• Vertical displacement of the orbit

Skeleton. Vertebral anomalies. 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

• Trigeminal anesthesia

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 include:

• Cardiac. Tetralogy of Fallot, ventricular septal defects, transposition of the great vessels, and aortic arch anomalies [Gorlin et al 2001]

• Renal. Absent kidney, double ureter, crossed renal ectopia, hydronephrosis, hydroureter [Gorlin et al 2001]

• Limb. Radial or ulnar ray anomalies

• Central nervous system. Brain malformation, microcephaly, encephalocele, hydrocephaly, hypoplasia of the corpus callosum, Arnold-Chiari malformation, holoprosencephaly [Cohen et al 1989]

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 described below typically have symmetric facial malformations.

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). Forty to fifty percent 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. Mutations in TCOF1 are causative. Inheritance is autosomal dominant.

• 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 mutation (1084G>A) resulting in the substitution Ala362Thr [Su et al 2007].

• Two individuals diagnosed with Goldenhar syndrome had silent (Glu621Glu; Gln54Gln) sequence alterations not noted in 150 controls [Splendore et al 2002].

Nager syndrome (preaxial acrofacial dysostosis) 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; its cause is not known. 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].

Miller syndrome (postaxial acrofacial dysostosis) is characterized by postaxial limb deficiency [hypoplasia, syndactyly, absence of postaxial digits (e.g., the fifth digits and, in some cases, the fourth and third digits); ulnar hypoplasia that causes shortening of the forearms]; 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; the causative gene is known. Inheritance is autosomal recessive [Chrzanowska & Fryns 1993].

Townes-Brocks syndrome (TBS) is characterized by a triad of clinical findings: imperforate anus, dysplastic ears with/without preauricular 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 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. Mutations in SALL1 are causative. Inheritance is autosomal dominant.

At least three individuals with predominant features of CFM had mutations in 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.

CHARGE syndrome was first described as an association of clinical features using the mnemonic (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, and/or optic nerve, with or without microphthalmos; unilateral or bilateral choanal atresia; 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 hypogonadotrophic hypogonadism in males and females; cardiovascular malformation; growth deficiency; and variable developmental delay. Orofacial clefts and tracheoesophageal fistula are seen in a subset of individuals. Mutations in CHD7 are identified in 60%-65% of individuals with CHARGE syndrome. For those with CHD7 mutations, inheritance is autosomal dominant.

Branchiootorenal (BOR) syndrome is characterized by branchial cleft anomalies; malformation of the outer-, middle-, and inner-ear structures associated with conductive, sensorineural, or mixed hearing impairment; and renal malformations. The diagnosis is based on clinical findings. Three causative genes are known: EYA1 (locus name: BOR1) mutations are identified in approximately 40% of individuals, SIX5 (locus name: BOR2) in 5.2%, and SIX1 in fewer than one percent. Inheritance is autosomal dominant.

Parry Romberg syndrome (progressive hemifacial atrophy) 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 5 and 15 years, whereas in CFM the facial malformations are congenital (i.e., present at birth).

Prevalence of CFM

CFM has an estimated prevalence 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].

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 2.

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 twofold increase in the risk for CFM [Werler et al 2004a].

CFM risk was also positively associated with other potential correlates of vascular activity, including the following [Werler et al 2004b]:

• Second trimester bleeding (odds ratio [OR] 13.2, 95% confidence interval [CI] 2.3, 76)

• Maternal diabetes mellitus (OR 6.0, 95% CI 2.5, 14)

• Multiple gestation (OR 9.4, 95% CI 4.3, 21)
  
  Note: Among the potential risk factors examined in these investigations, the only ones examined in other epidemiologic studies are multiple gestation and maternal diabetes mellitus, both of which have consistently displayed associations with occurrence of CFM.

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].

Individuals with CFM appear to have an increased prevalence of twinning [Lawson et al 2002] and use of maternal ART [Wieczorek et al 2007].

In an epidemiologic study of 239 individuals with CFM and 854 controls, risk factors identified for CFM included the following:

• Lower birth weight. 29% of babies with CFM weighed less than 2500 g compared to five percent of the control group. The risk of CFM for infants with a birth weight below 3000 g was two to six times the risk for infants with a birth weight between 3000 and 3499 g.

• 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 kilograms/height in meters squared). The risk of 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, cardiac defects (conotruncal and aortic arch). Additional findings include: central nervous system malformations, retinal or optic-nerve abnormalities, and thymus hypoplasia [Lammer 1991].

Heritable Causes

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:

• Small genomic microdeletion/microduplication not detected on chromosome analysis

• Mutation in a yet-to-be-identified gene

• Mutations or polymorphisms in multiple genes involved in craniofacial development (polygenic inheritance)

• Effects of both gene and environmental interactions (multifactorial inheritance)

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 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.

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 two to three percent. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

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) and mutation(s) responsible for craniofacial microsomia have not been identified, prenatal diagnosis using molecular genetic testing is not available.

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].

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, 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 infant’s/child’s nutritional status 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 are 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 (see Management).

Cervical spine films. Perform cervical spine imaging between ages two and three years. 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

• Medical geneticist and genetic counselor

• Ophthalmologist

• Oral and maxillofacial surgeon

• Orthodontist

• Orthopedist

• Otolaryngologist

• Pediatric dentist

• Pediatrician/nurse coordinator

• Plastic and reconstructive surgeon

• Psychosocial professionals (psychologist, social worker)

• Speech pathologist

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. Treatment plans should be individually tailored to ensure the best results.

The phenotype in CFM is quite variable (see Table 1 for associated anomalies). The following medical issues may need to be addressed in an individual with CFM:

Feeding. Infants with significant micrognathia 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, and Dr. Brown nipples), supplemental nasogastric (NG) feedings, gastrostomy tube placement, and/or consultation with a dietitian.

Respiratory

• 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 good dental care.

• Orthodontic evaluations are important to assess for missing teeth, dental crowding, jaw growth, and dental occlusion. 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.

Hearing

• 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 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.

• At age five years, 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. 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).

• Individuals with eustachian tube dysfunction should continue to have hearing and otologic status monitored.

Speech. Children with CFM may have cranial nerve palsies, clefts of the palate, and muscular deficiencies that can contribute to abnormal speech patterns (including velopharyngeal insufficiency [VPI]). 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:

• No action;

• Prosthetic management, either adhesive or implant-retained; or

• 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 are considered after age six years.

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.

Skeletal

• 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.

Surveillance

See management guidelines for children with CFM ages 0-4 years and ages 5-21 years (pdf).

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.

Testing of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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Author Notes

Web site: craniofacial.seattlechildrens.org

Acknowledgments

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

• 19 March 2009 (cg) Review posted live

• 29 August 2008 (clh) Original submission