Syndromes with craniofacial abnormalities

INTRODUCTION — Interruption of normal embryologic growth and differentiation of the face and skull results in a wide variety of craniofacial abnormalities [1]. Craniofacial surgery, which consists of reconstruction of the cranial vault and/or facial skeleton with or without simultaneous soft tissue reconstruction, can be performed when these deformities interfere with physical and/or mental well-being.

Specific syndromes in which craniofacial abnormalities are the primary feature will be reviewed here. The pathogenesis, diagnosis, and surgical management of craniosynostosis (a subset of craniofacial anomalies) and syndromes in which craniosynostosis is a primary abnormality, are discussed separately. (See "Overview of craniosynostosis" and "Craniosynostosis syndromes".)

CRANIOFACIAL MICROSOMIA — Craniofacial microsomia (CFM), also referred to as hemifacial microsomia, oculo-auriculo-vertebral spectrum, or first and second branchial arch syndrome, is a sporadically acquired association of anomalies that results from a defect in development of the first and second branchial arches (figure 1 and figure 2) [2-4]. It is sometimes associated with vertebral and/or ocular anomalies. Goldenhar syndrome appears to be part of this spectrum (MIM #164210) [5,6]. The disorder occurs in approximately 1 in 5500 live births [7]. It is typically sporadic [8], but autosomal-dominant inheritance has been reported [9,10].

The mechanism underlying CFM is uncertain. A vascular insult to the developing branchial arches is the most widely accepted explanation. In an animal model, hemorrhage induced in the region of the first and second branchial arches produced the characteristic facial features. The degree of abnormality was proportional to the size of the hematoma [11].

Clinical features of CFM — The stigmata of this disorder are indicated by the acronym OMENS, for orbit, mandible, ear, facial nerve, soft tissue, although extracranial features also occur [12,13]. Orbital distortion is typically present, as is mandibular hypoplasia. Ear anomalies include microtia, accessory preauricular tags and/or pits, and middle ear defects with hearing impairment (picture 1) [3]. Facial nerve involvement leads to hypoplasia of the facial muscles. Soft tissue deficiency, such as profound hypoplasia or absence of the parotid gland and masticatory muscles (temporalis, masseter), may be present.

The defects are unilateral in 85 to 90 percent of cases. In these cases, the right side predominates [3]. The abnormalities occur in variable combinations and range in extent from imperceptible to severe.

The mandibular abnormalities are described using the Pruzansky classification (figure 3 and figure 4) [14]:

●Type 1 is characterized by mild hypoplasia of the ramus with little abnormality of the mandibular body.

●In type 2, the mandible has a small condylar head and ramus. The condyle is flat, the glenoid fossa is poorly developed or absent, and the infratemporal surface assumes a flat contour.

●In type 3, the temporomandibular joint (TMJ) fails to form, and the ramus may exist as a thin bony lamina or may be completely absent. The increasing degree of mandibular hypoplasia is associated with increased difficulty with endotracheal intubation for anesthesia and surgery [15].

Bony abnormalities include a decreased maxillary height on the affected side and an occlusal cant, which is defined as rotation of the occlusal plane (a plane passing through the biting surface of the teeth) in the sagittal view [16]. As a general guide, each degree of rotation of the occlusal plane results in a 0.5 mm change in the dental occlusal relationship. This rotation occurs in all types of CFM, with increasing severity from type 1 to type 3. Occlusal cant can be demonstrated clinically by having the child bite down on a tongue depressor to identify any angulation (figure 5).

The zygomatic arch is frequently hypoplastic, and the distance between the lateral orbit and the tragus of the ear is decreased. Cleft palate occurs in 25 percent of cases [17].

Auricular abnormalities are described using the OMENS+ classification [18]:

●Grade 1 describes an external ear that is small but contains all of its components. The auditory canal is not affected.

●A grade 2 abnormality is characterized by a vertical auricular remnant and complete atresia of the external auditory canal.

●The most severe deformity is grade 3, in which there is a limited remnant of the ear lobe. Hearing does not correlate with the extent of external ear abnormality.

One study reviewed the clinical features of 121 patients with CFM [17]. Extracraniofacial anomalies occurred in 55 percent and ranged from one anomaly (13 percent) to multiple affected organ systems (42 percent). No gender or side predominance was detected. Central nervous system, cardiac, and skeletal anomalies each occurred in more than 10 percent of cases. Pulmonary, gastrointestinal, and renal deformities were less common. The majority of the heart defects involved the outflow tract or septum. The increased frequency of cardiac anomalies in this condition suggests that abnormal development of neural crest may result in both CFM and conotruncal defects.

Surgery for CFM — The majority of patients with CFM do not require surgical correction. This is usually reserved for severe cases. Surgical correction of CFM is usually performed in stages [19]. Preauricular skin tags are typically excised before the child is two years old. This is often comforting to the parents, who see steps being taken to remedy their child's problem. Cranial remodeling may be required at approximately 8 to 12 months of age if the craniofacial abnormality is severe and orbital dystopia (malalignment of the orbits) is present. Surgical reconstruction of the oral commissure is performed before two years of age in patients with CFM.

Distraction osteogenesis of the mandible can be used to correct severe mandibular hypoplasia with airway compromise [20,21]. Children with a Pruzansky type 1 mandibular deformity are followed clinically from two to six years of age. Type 2 abnormalities respond favorably to distraction osteogenesis [22]. The more severe type 3 deformities require reconstruction with a costochondral rib graft. There is still significant debate regarding the optimal timing to perform distraction osteogenesis. It has been postulated that by normalizing dimensions at a younger age, the maxilla and overlying soft tissue may have a longer time to develop with a balanced "functional matrix," thereby improving long-term facial symmetry [21]. However, this hypothesis has yet to be confirmed by prospective outcome studies.

The data on recurrence of the facial deformity after surgery over time are inconsistent as well. One study, for example, found that facial asymmetry improved significantly after distraction (surgical separation) [23]. Despite mild relapse observed during the first year, surgical correction was stable in the later years of follow-up. However, another study found that the facial proportions gradually returned to their original asymmetry after the growth of the patient in those treated with mandibular distraction osteogenesis in early childhood, and this growth was similar to the outcomes in an untreated group of patients [24]. While early surgery may have aesthetic and psychologic advantages, some of these patients may require a second procedure once their growth has completed.

Orthodontic treatment is started at anywhere from 6 to 14 years of age [25], and ear reconstruction is performed at approximately eight years. Ears can be fashioned from rib cartilage and placed under the mastoid skin. Alternatively, an osseointegrated post can be surgically implanted in the mastoid area, allowing a prosthetic ear to be firmly attached. The ear is displaced in a downward and anterior direction to accommodate future growth, and calvarial bone grafts may be needed to reconstruct the appropriate topography [26].

Craniofacial growth is completed at approximately 14 to 15 years of age [27]. Further surgical intervention is initiated at that time. Maxillary repositioning (Le Fort 1), mandibular advancement [28], and soft tissue augmentation in the form of microsurgical flap transfers and fat grafting are used to improve both form and function [29].

TREACHER COLLINS SYNDROME — Treacher Collins syndrome (TCS), also called mandibulofacial dysostosis, is an autosomal-dominant disorder of craniofacial development with a variable degree of penetrance. It occurs with a frequency of 1 in 25,000 to 1 in 50,000 live births [30].

Genetics and pathogenesis — In the majority of cases, abnormal bilateral first and second branchial arch development is due to mutations in the gene TCOF1 (Treacher Collins-Franceschetti syndrome 1 [TCS1], MIM #154500), located on chromosome 5 (5q31.3-q33.3) [31-35]. This gene encodes the protein treacle that plays an essential role in ribosomal ribonucleic acid (rRNA) transcription [36] and ribosome biogenesis [37] and shows peak expression in the neural crest cells of the branchial arches [33,38]. Missense mutations in the POLR1D (polymerase I, RNA, subunit D) gene located at 13q12.2 cause TCS2 (MIM #613717). TCS type 1 and 2 are autosomal dominant. A third type, TCS3 is autosomal recessive and caused by compound heterozygous mutations in the POLR1C (polymerase I, RNA, subunit C) gene located at 6p22.3 (MIM #248390), which encode subunits of RNA polymerases I and III and have been detected in individuals with TCS who are negative for TCOF1 mutations [39]. The underlying genetic defect is still unknown in approximately 10 percent of patients with TCS.

Macroscopically, craniofacial tissues such as cartilage, bone, and connective tissues fail to develop correctly as a direct result of neural crest cell dysfunction [40]. One hypothesis posits that significant craniofacial malformations largely arise through defects in the formation, migration, or differentiation of this particular cell population [41].

According to Tessier's classification of clefts, this syndrome consists of a cleft between the 6 through 8 positions [42]. TCS may result from insufficient mesodermal penetration affecting soft tissue thickness and leading to aplasia or hypoplasia of maxilla and zygoma. (See "Overview of craniofacial clefts and holoprosencephaly", section on 'Classification of clefts'.)

Clinical features of TCS — Affected patients have malar hypoplasia and a cleft in the zygoma [30,43]. The eyes have an antimongoloid slant with colobomas (eyelid notch) along the lateral one-third of the lower lid. Lashes are absent from the medial two-thirds of the lower eyelid. The face has a convex profile with a retrusive chin and jaw, which is associated with a class 2 malocclusion (overbite).

External ear abnormalities are common. Profound conductive hearing loss is common in severe cases, and children must be fitted early with bone-conducting hearing aids to facilitate development of normal speech. Cleft lip and palate and choanal atresia may occur. (See "Hearing loss in children: Treatment", section on 'Bone conduction hearing devices' and "Etiology, prenatal diagnosis, obstetric management, and recurrence of cleft lip and/or palate" and "Congenital anomalies of the nose", section on 'Choanal atresia'.)

The craniofacial abnormalities can result in airway narrowing and respiratory compromise. As a result, affected patients may require prone positioning or surgery to maintain a patent airway. Weak, uncoordinated swallowing may necessitate gavage feedings or placement of a gastrostomy tube. (See 'Surgery for TCS' below.)

Surgery for TCS — Patients with airway and feeding difficulties may require surgery during the first couple of years of life [44-46]. These procedures may include tongue-lip adhesion (glossopexy), distraction osteogenesis of the mandible, tracheostomy, correction of cleft lip and/or palate and choanal atresia, and gastrostomy tube placement.

Surgical correction of the facial abnormalities in patients with severe TCS is initiated at approximately seven years of age when a significant degree of facial growth has occurred. The zygomatic contour is improved using split calvarial bone grafts or iliac crest grafts [45,47-49]. Lower eyelid colobomas are treated with a layered approach to reconstruction, using mucosal grafts to replace missing lining in conjunction with a lateral canthopexy.

Surgical correction of the mandible is undertaken at 13 to 16 years of age as the jaw reaches dental and skeletal maturity. In the presence of a functioning temporomandibular joint (TMJ), the preferred treatment is ramus osteotomies and orthodontic manipulation. If the TMJ is absent, a costochondral graft is placed at 6 to 10 years of age and followed up with orthognathic surgery in adolescence. Bilateral distraction osteogenesis of the mandible is also used in an attempt to correct the mandibular hypoplasia [44]. Finally, the contour of the facial soft tissues generally requires correction at a later stage when the patient has achieved facial skeletal maturity. The use of microsurgical free flap transfer has improved correction of facial soft tissue contours [50].

Improvement in facial appearance has positive psychosocial and social influences. In one report, 20 patients with TCS (mean age 12.2 years) were studied before and at intervals up to four years after craniofacial reconstruction [51]. Although intellectual ability was unchanged, appearance, self-esteem, and adaptive function improved. The improvement peaked at the one year postoperative assessment and subsequently leveled off.

PIERRE ROBIN SEQUENCE — Pierre Robin sequence, also known as Pierre Robin syndrome, is a condition with multiple causes [52,53]. Most cases are thought to result from hypoplasia of the mandible that occurs before the ninth week of development. Prior to the eighth week, the tongue is interposed between the developing palatal shelves. In the normal course of development, the tongue is drawn down during the 10^th and 11^th weeks, allowing fusion of the palatal shelves. In the Pierre Robin sequence, hypoplasia of the mandible results in posterior displacement of the tongue, preventing palatal closure and producing a cleft palate. The etiology of Pierre Robin sequence is uncertain. Possible mechanisms include genetic disorders, oligohydramnios (which may limit chin growth), myotonia, or connective tissue disease.

Pierre Robin sequence often is an isolated abnormality. However, some cases (37 percent in one series of 74 patients) occur as part of a syndrome with multiple malformations [54]. One-third of the patients with associated malformations had Stickler syndrome or velocardiofacial syndrome (VCFS). Some cases of Pierre Robin sequence may thus result from developmental misexpression of SOX9 (sex-reversed Y chromosome [SRY]-box 9, a transcription factor essential for sex and skeletal development) due to disruption of very long range cis regulatory elements [55]. Ophthalmologic examination and fluorescence in situ hybridization (FISH) study for chromosome 22 deletion should be performed on patients with Pierre Robin sequence because of the association with Stickler syndrome and VCFS. (See 'Stickler and Marshall syndromes' below and 'Velocardiofacial (Shprintzen) syndrome' below.)

Clinical features of Pierre Robin sequence — The clinical features of Pierre Robin sequence are micrognathia, glossoptosis, and cleft palate (picture 2). The tongue tends to prolapse backward, leading to airway obstruction that can be life threatening. Respiratory compromise can lead to hypoxia, cardiopulmonary arrest, pulmonary hypertension, and failure to thrive. Feeding problems are common [54].

The rapid facial growth that occurs from 3 to 12 months of age leads to resolution of airway problems in a majority of cases. The mortality associated with Pierre Robin sequence is generally related to airway compromise and is higher when associated with prematurity. Mortality rates in term infants with Pierre Robin sequences range from 1.7 to 11.3 percent [53,56]. However, the reported mortality rate increases to 26 percent when other anomalies are present [53].

Management of Pierre Robin sequence — The two primary issues in patients with Pierre Robin sequence are upper airway obstruction and feeding difficulties [53,57]. Affected patients should be monitored to detect apnea and airway obstruction. Prone positioning is indicated, especially during feeding, to minimize airway obstruction. A rubber tube placed through the nose (nasopharyngeal trumpet) may protect the airway while awaiting compensatory growth. More invasive temporizing procedures are needed if respiratory obstruction is unresponsive to conservative measures.

Nonsurgical options for treatment of upper airway obstruction include noninvasive respiratory support (NRS) and a nasopharyngeal airway (NPA). Surgical options include mandibular distraction osteogenesis and glossopexy. Cases of airway obstruction that are refractory to these measures may require a tracheostomy [54]. (See "Tracheostomy: Rationale, indications, and contraindications".)

●NRS uses continuous positive airway pressure or noninvasive positive pressure ventilation to correct the airway obstruction. In a series of 81 patients over 10 years, 63 percent were treated with positioning and medical treatment, 12 percent required temporary intubation and positioning, 16 percent required tracheotomy, and 9 percent were treated with NRS [58]. NRS was shown to improve breathing patterns, respiratory efforts, and transcutaneous carbon dioxide pressures in infants with severe upper airway obstruction due to Pierre Robin sequence. None of the seven infants treated with NRS required tracheostomy, and six out of seven were able to discontinue nutritional support.

●A second nonsurgical option to relieve airway obstruction is placement of a NPA [59-61]. Improved oxygen saturation and weight gain have been documented with this method.

●Distraction of the mandible, in which osteotomy or fracture of the mandible is performed and an external fixator is used to open the oral passage, is the most commonly used surgical procedure [62-64]. Distraction has the benefit of affecting permanent change in mandibular size creating adequate space for the tongue. It has allowed many patients to avoid tracheostomy.

●Historically, glossopexy or tongue-lip adhesion, where the tongue is sutured to the lip to prevent retrusion, was the surgical method of choice. The use of glossopexy has decreased in popularity; however, it is associated with decreased morbidity and normalized weight gain and remains a valid alternative [65,66].

NAGER SYNDROME — Nager syndrome, also known as Nager acrofacial dysostosis syndrome, is a rare disorder [67,68]. Most cases are sporadic, although both autosomal-recessive and autosomal-dominant inheritance have been reported [69]. Mutations in SF3B4 (splicing factor 3B, subunit 4) leading to haploinsufficiency were identified in 61 percent of affected individuals in one cohort [70]. SF3B4 encodes spliceosome-associated protein 49 kD (SAP49), a subunit of the pre-messenger ribonucleic acid (mRNA) spliceosome complex.

The craniofacial features of Nager syndrome are similar to those of Treacher Collins syndrome (TCS). Nager syndrome is distinguished from TCS by the absence of eyelid colobomas. Severe cleft palate is always present. The palatal defect is unique in that the cleft is wide, but the hard and soft palates are shortened in the anterior-posterior dimension. Characteristic limb anomalies include preaxial deformities such as hypoplasia or agenesis of the radius and thumb [71]. Affected children have short stature. Intelligence is normal, although delays in speech and language development may occur secondary to hearing impairment [67,72].

Infants with Nager syndrome frequently have respiratory and feeding problems that may require gavage feeding or gastrostomy tube placement. The high perinatal mortality rate (approximately 11 percent) is related to respiratory compromise [73].

Management is similar to that for the Pierre Robin sequence as described above [74]. (See 'Pierre Robin sequence' above.)

BINDER SYNDROME — Binder syndrome, also known as maxillonasal dysplasia, is a very rare disorder of unknown etiology [75]. It is hypothesized that Binder syndrome is the mildest form of chondrodysplasia punctata [76]. Binder syndrome is characterized by a shortened nose with an acute nasolabial angle and a convex upper lip (picture 3). Class III malocclusion may be present. An underdeveloped frontal sinus and cervicospinal abnormalities occur in 40 to 50 percent of cases [77].

The treatment consists of nasal and maxillary correction, followed by orthodontic rehabilitation [78,79]. Depending on the involvement of the malformation, surgical treatment can be limited to reconstruction of the nasal dorsum and apex only or extend to include maxillary advancement. Grafting to the nasal osteochondral scaffold can be performed in early adolescence; however, osteotomy with maxillary advancement should be reserved until the late teenage years [80]. Surgeons have reported the use of bone and cartilage grafts, and a comparison between the two demonstrated that either option is adequate for creating a normal nasolabial angle and tip projection [81,82].

VELOCARDIOFACIAL (SHPRINTZEN) SYNDROME — Velocardiofacial syndrome (VCFS), also known as Shprintzen syndrome, is an autosomal-dominant disorder caused by a deletion in chromosome 22q11 [83,84]. This deletion has also been identified in the majority of patients with DiGeorge sequence and conotruncal anomaly face syndrome, suggesting that these are phenotypic variants of the same disorder [84]. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis".)

The deletion occurs in approximately 1 in 4000 live births [84] and can be detected by fluorescence in situ hybridization (FISH), multiple ligation-dependent probe amplification (MLPA), and array comparative genomic hybridization (aCGH). The deletion occurs "de novo" in the majority of cases, but approximately 15 percent are inherited from an affected parent. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Detecting cytogenetic abnormalities' and "Genomic disorders: An overview", section on 'Detection of genomic disorders'.)

Clinical features of VCFS — Affected patients have retrognathia, a long face with a prominent nose [85]. Velopharyngeal incompetence (weak pharyngeal musculature) producing speech abnormalities such as hypernasal speech is very common. Submucous or overt clefts of the secondary palate can occur. Chronic otitis media is present in 75 percent of cases. Transient neonatal hypocalcemia occurs in 20 percent. (See "Neonatal hypocalcemia".)

Congenital heart defects occur in 85 percent of cases [85]. The most common are ventricular septal defect (62 percent), right-sided aortic arch (52 percent), and tetralogy of Fallot (21 percent). The carotid arteries frequently follow an anomalous course that may complicate the performance of pharyngeal surgical procedures. (See "Isolated ventricular septal defects (VSDs) in infants and children: Anatomy, clinical features, and diagnosis" and "Vascular rings and slings" and "Tetralogy of Fallot (TOF): Pathophysiology, clinical features, and diagnosis" and "Diagnosis and initial management of cyanotic heart disease in the newborn".)

Learning disabilities are frequent, and mild intellectual impairment occurs in approximately 40 percent of patients. (See "Specific learning disorders in children: Clinical features", section on 'Risk factors'.)

Psychiatric disorders, primarily schizophrenia and paranoid delusions, develop in 10 to 30 percent of cases [86,87]. Magnetic resonance imaging studies comparing patients with VCFS and controls have demonstrated structural changes in the temporal lobe, left hippocampal, frontal, and caudate areas that are similar to the alterations of these regions that are seen in patients with schizophrenia [88,89].

Management of VCFS — Pharyngeal surgery (pharyngoplasty) is frequently required to treat the nasal air escape that causes abnormal speech [90,91]. High inset of the pharyngeal flap is indicated because of severe, refractory velopharyngeal incompetence. This is technically difficult because of visualization issues. Some authors report success with through and through dissection of the soft palate to allow direct visualization of flap placement [92].

Removal of the tonsils and adenoids is contraindicated because they aid in velopharyngeal closure [93].

STICKLER AND MARSHALL SYNDROMES — Stickler (also known as hereditary arthroophthalmopathy) and Marshall syndromes are related disorders of connective tissue with overlapping characteristics [94-96]. It is unclear whether they are distinct entities or different clinical manifestations of a single syndrome. Most patients have autosomal-dominant inheritance, although autosomal-recessive forms of Stickler syndrome occur.

Mutations of the gene for the alpha-1 chain of type II collagen (COL2A1), located on chromosome 12q13.11-q13.2, cause Stickler syndrome type I (MIM #108300) [97]. These mutations result in the abnormal production and assembly of type II collagen, which is a major component of cartilage, vitreous, and nucleus pulposus. Mutations in the COL11A1 gene, located at 1p21, that encodes the alpha-1 chain of type XI collagen have been found in patients with Stickler syndrome type II (MIM #604841) or Marshall syndrome (MIM #154780) or with overlapping phenotypes of both [98]. Stickler syndrome type III (MIM #184840) is caused by mutation in the COL11A2 gene, located at 6p21.3 [99]. Rare autosomal-recessive forms of Stickler syndrome are caused by biallelic mutations in any of the three genes encoding collagen IX (ie, COL9A1, COL9A2, and COL9A3) [100,101].

Clinical features — The clinical features of Stickler syndrome include characteristic orofacial and ophthalmologic abnormalities, deafness, and arthritis [95,96,98]. Affected patients typically have a flat midface with a depressed nasal bridge, short nose, anteverted nares, and micrognathia. Cleft of the soft palate can occur and is associated with Pierre Robin sequence. Abnormal architecture of the vitreous gel is pathognomonic of this disorder and is usually associated with high myopia. Retinal detachment (also called ablatio retinae) occurs frequently and is considered a medical emergency [102]. Joint hypermobility is present in infancy and decreases with age. Patients typically develop osteoarthritis in the third or fourth decade. Some patients have sensorineural deafness. Mitral valve prolapse may occur. (See 'Pierre Robin sequence' above and "Retinal detachment".)

Marshall syndrome has clinical features similar to Stickler syndrome. These include a craniofacial appearance characterized by a flat midface, depressed nasal bridge, short nose, and anteverted nares. Patients have ocular abnormalities (eg, cataracts, myopia), sensorineural hearing loss, and spondyloepiphyseal abnormalities [103]. Hypohidrotic ectodermal dysplasia may occur [104]. (See "Cataract in children", section on 'Clinical features' and "Ectodermal dysplasias".)

Early ophthalmologic examination is indicated, and follow-up is essential given the difficulty in slit-lamp examination of infants and young children. Treatment of Pierre Robin sequence is discussed above (see 'Management of Pierre Robin sequence' above). Cleft palate, if present, should be repaired prior to speech production. Surgery is performed earlier in infancy if the airway is unstable. Further surgery for speech competence is often indicated because of the increased incidence of velopharyngeal insufficiency in these patients. Otolaryngologists should be consulted for auditory concerns. Orthopedic surgery and physical therapy are often involved in patient care for early onset of arthritis, which is most commonly treated with over-the-counter anti-inflammatories.

VAN DER WOUDE SYNDROME — Van der Woude syndrome is an autosomal-dominant disorder with a high degree of penetration. It is characterized by pits and/or sinuses in the lower lip and cleft lip and/or cleft palate [105]. This condition represents 1 percent of cleft lip and palate cases and should be suspected when lower lip pits are present (picture 4). Identification of this syndrome is important for genetic counseling because of the 50 percent risk of occurrence in the offspring of an affected individual. The syndrome is usually caused by mutations in the IRF6 (interferon regulatory factor 6) gene, located on chromosome 1q32-41, but another locus has been identified at 1p34 where the candidate gene WDR65 (Tryptophan-Aspartic acid [W-D] dipeptide repeat-containing protein 65) resides [105-108].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Syndromes with craniofacial anomalies".)

SUMMARY AND RECOMMENDATIONS

●Specific syndromes with craniofacial abnormalities – Interruption of normal embryologic growth and differentiation of the face and skull results in a wide variety of craniofacial abnormalities (figure 1 and figure 2). There are several syndromes in which craniofacial abnormalities are the primary feature (see 'Introduction' above):

•Craniofacial microsomia – The defects in craniofacial microsomia involve the orbit, mandible, ear, facial nerve, and soft tissue and are typically unilateral (picture 1). (See 'Craniofacial microsomia' above.)

•Treacher-Collins syndrome (TCS) – Patients with TCS have jaw defects, a notch in the lower eyelid at the junction of the inner two-thirds and outer one-third (eyelid colobomas), partially absent lashes on the lower eyelids, and sensorineural hearing loss. Cleft lip and palate and choanal atresia may occur. The craniofacial abnormalities can result in respiratory compromise and feeding difficulties. (See 'Treacher Collins syndrome' above.)

•Pierre Robin sequence – Pierre Robin sequence, also known as Pierre Robin syndrome, is a condition with multiple causes. Most cases are thought to result from hypoplasia of the mandible that occurs before the ninth week of development (picture 2). Some cases occur as part of a syndrome with multiple malformations (eg, Stickler syndrome or velocardiofacial syndrome [VCFS]). (See 'Pierre Robin sequence' above.)

•Nager syndrome – The craniofacial features of Nager syndrome are similar to those of TCS. Nager syndrome is distinguished from TCS by the absence of eyelid colobomas. Severe cleft palate is always present. (See 'Nager syndrome' above.)

•Binder syndrome – Binder syndrome is characterized by a shortened nose with an acute nasolabial angle and a convex upper lip. (See 'Binder syndrome' above.)

•Velocardiofacial syndrome (VCFS) – VCFS, also known as Shprintzen syndrome, is an autosomal-dominant disorder caused by a deletion in chromosome 22q11. This deletion has also been identified in the majority of patients with DiGeorge sequence and conotruncal anomaly face syndrome. Common clinical features include cleft palate, velopharyngeal incompetence (weak pharyngeal musculature) producing speech abnormalities, chronic otitis media, hypotonia, and congenital heart defects. (See 'Velocardiofacial (Shprintzen) syndrome' above.)

•Stickler syndrome and Marshall syndrome – Stickler and Marshall syndromes have similar clinical features, including a craniofacial appearance characterized by a flat midface, depressed nasal bridge, short nose, and anteverted nares. Stickler syndrome is also characterized by abnormal architecture of the vitreous gel and osteoarthritis. However, there is limited information to distinguish the two syndromes aside from clinical manifestations. (See 'Stickler and Marshall syndromes' above.)

•Van der Woude syndrome – Van der Woude syndrome is characterized by pits and/or sinuses in the lower lip and cleft lip and/or cleft palate (picture 4). (See 'Van der Woude syndrome' above.)

●Management – Patients with airway and feeding difficulties may require surgery during the first couple years of life. The most common surgical procedure used to correct mandibular hypoplasia is that distraction osteogenesis of the mandible. Other surgeries may be performed during early and later childhood for functional reasons, as well as for aesthetic and psychologic reasons. (See 'Surgery for CFM' above and 'Surgery for TCS' above and 'Management of Pierre Robin sequence' above and 'Management of VCFS' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Patrick Cole, MD and Larry H Hollier, Jr, MD, who contributed to earlier versions of this topic review.