Syndromes of the First and Second Branchial Arches, Part 2: Syndromes

PRS: OMIM 261800

The original account of PRS in 1923, by a French physician,² described neonates with unusually small mandibles (micrognathia), posterior displacement or retraction of the tongue (glossoptosis), and upper airway obstruction. Because incomplete closure of the roof of the mouth (CP) is present in most patients, Robin later added CP deformity as an associated feature.^3–7 Studies have documented that there is also associated bimaxillary retrognathia, with reduced sagittal length of not only the mandible but also the maxilla.⁸ Although the possibility that the mandible may grow forward and partially or fully catch up during the first years of life has been discussed in the literature, recent studies have suggested that no significant catch-up growth of the mandible in PRS occurs in the first 22 months of life. The differential growth shown in these studies does not improve the size of the pharyngeal airway but does improve the relative size of the oropharynx, which can have a positive effect on breathing difficulties.^5,8,9

Glossoptosis may be detected on a lateral radiograph of the soft tissues of the neck by identifying encroachment of soft tissues on the pharyngeal airway.¹⁰ The obstructing mechanism of the tongue is a combination of the backward displacement of the mandibular symphysis causing passive dorsal pressure on the tongue and the backward placement of the genioglossi muscles, the principal means of drawing the tongue forward. The problems seen with glossoptosis are compounded by the lack of adequate skeletal support for the pharyngeal soft tissues seen in isolated micrognathia. Radiographic evaluation typically reveals relatively symmetric hypoplasia of the mandible. There may be associated condylar and coronoid hypoplasia. The tongue may appear prominent in relation to the relative size of the oropharynx. Additionally, various severities of CP are seen, which may involve both the primary and secondary palates, leading to open communication between the nasal and oral cavities.

Stickler syndrome and VCFS are present in as many as one- third of patients with PRS. The sequence can also be seen in ACS, Goldenhar syndrome, and TCS.

HFM: OMIM 164210

HFM is a common facial birth defect involving the first and second BA structures and ranks second in prevalence only behind facial clefting.¹¹ Males are affected more frequently than females. About 45% of patients have affected relatives, and 5%–10% have affected siblings.¹² The phenotype is highly variable. There may be cardiac, vertebral, and central nervous system defects, in addition to craniofacial anomalies. Ear deformities occur along a spectrum from the size and shape of the external auricle to anotia.

When epibulbar dermoids and vertebral anomalies are seen along with other findings of HFM, the syndrome is called Goldenhar syndrome.¹³ Goldenhar¹⁴ first described the triad of epibulbar choristomas, preauricular skin appendages, and pretragal blind-ending fistulas in association with mandibular facial dysplasia. Later patients with associated vertebral anomalies were given the classification of OAV dysplasia.¹³ The combination of OAV features and microtia is termed the “OAV complex.”¹² When the features of the OAV complex are predominantly unilateral and lack vertebral anomalies and epibulbar dermoids, the condition has been called HFM. This pattern is thought to represent a variant of the expanded OAV complex.¹⁵

A variety of terms have been proposed that serve to indicate the spectrum of anomalies associated with the OAV complex. Additional names of these variants include Goldenhar-Gorlin syndrome, first arch syndrome, first and second BA syndrome, lateral facial dysplasia, unilateral craniofacial microsomia, otomandibular dysostosis, unilateral mandibulofacial dysostosis, unilateral intrauterine facial necrosis, auriculobranchiogenic dysplasia, and facioauriculovertebral malformation complex. The terms and systems of classification have been reviewed multiples times.^16–20

Radiographic evaluation of HFM reveals asymmetric hypoplasia of the maxilla and mandible. One side of the face may be normally developed (Fig 1). There are variable degrees of malformation involving the TMJ, including hypoplasia of the condyle and coronoid. A large variation in the TMJ has been observed on the more affected side; however, the degree of TMJ disk dysplasia does not appear to correlate with the degree of mandibular dysplasia.²¹ There is often a unilateral deformity of the external ear. A coloboma of the upper eyelid is frequently encountered and may be seen radiographically on soft-tissue windows. Ear deformities range from isolated preauricular tags to atresia of the EAC. A detailed examination of the temporal bone should be performed to evaluate associated, though uncommon, malformations of the middle ear and an aberrant course of the facial nerve. The OMENS (orbit, mandible, ear, cranial nerve, and soft tissues) system has been proposed to classify the severity of each of the major craniofacial manifestations of HFM.²⁰

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Fig 1.

Young adult with hemifacial microstomia. A−C, 3D bone reconstruction shows right mandibular and maxillary hypoplasia compared with the normal-appearing left condyle. D, A 3-year-old boy with hemifacial microstomia. 3D bone reconstruction shows a more dramatic appearance of asymmetric hypoplasia of the mandible.

ACS: OMIM 602483

The ACS, first described by Uuspää in 1978, is now recognized as a distinct autosomal dominant disorder. The features seen in ACS have previously been ascribed the names “Cosman ear” and the “question mark ear.”^22,23 Prominent malformed ears, with auricular clefts, mandibular condyle aplasia or hypoplasia, and a number of other auricular and oral abnormalities characterize ACS. In its most severe form, there are severe micrognathia and a characteristically round facial appearance with prominent cheeks. Inter- and intrafamilial variability is marked, and some obligate carriers are nonpenetrant.^24–26 A genome-wide search of 2 families with ACS revealed evidence of linkage to 1p21.1-q23.3 in 1 of the families and nonlinkage in the other. These findings suggest evidence for genetic heterogeneity and the existence of at least 2 loci responsible for this syndrome.²⁷

A characteristic auricular cleft malformation is seen in ACS, which consists of a protuberant cupped pinna with a cleft or notching between the lobule and the helix. The cleft may be subtle or severe enough to detach the lobule from the helix. The anomalies can be unilateral or bilateral and are typically asymmetric. Some individuals have low-set and posteriorly rotated ears. Pre- and postauricular tags may be present. Hearing and middle ear functions are generally normal; however, sensorineural hearing loss has been reported.²⁸

Complete mandibular condyle agenesis, hypoplasia, or more subtle clinical and radiographic anomalies may be present. These findings include micrognathia, short mandibular rami, small coronoid processes, poorly formed TMJs, small condylar necks with anterior placement of the condylar articulations, and increased distances between the EACs and the posterior glenoid fossa (Fig 2).²⁹ In some first-degree relatives of patients with ACS, the auricular malformations may be seen associated with macrognathia (type III malocclusion). Additional anomalies, somewhat specific to ACS, include a prominent bony ridge along the lateral aspect of the mandible (Fig 3). Reconstructive surgical techniques specific to ACS focus on functional improvement in mandibular excursion and the cosmetic appearance of the auricle.³⁰

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Fig 2.

A 5-year-old boy with ACS. A−C, 3D bony reconstructions show an absent condylar processes, asymmetric micrognathia, and hypoplastic condyles. D, Axial CT scan shows bilateral abnormal TMJs (arrows) with dysplastic condylar processes.

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Fig 3.

An 18-year-old man with ACS. A, 3D bony reconstruction shows micrognathia with overprotrusion of the mandible in relation to the maxilla. The lateral mandibular cleft is a feature commonly seen in ACS (see also Fig 2). B, Axial CT scan also shows the asymmetry of the dysplastic protruding mandible.

TCS: OMIM 154500

TCS is a rare congenital disorder of craniofacial development that arises as the result of mutations in the TCOF1 gene, which encodes a nucleolar phosphoprotein known as “Treacle.”³¹ The condition appears to have been first described by Thompson in 1846³²; however, TCS was given its eponym after E. Treacher Collins, who described the essential components of the condition in 1900.³³ The first extensive review of the condition was published by Franceschetti and Klein in 1949,³⁴ who first used the term “mandibulofacial dysostosis” and also identified its hereditary nature.

TCS is inherited in an autosomal dominant fashion with variable penetrance and phenotypic expression. It occurs in approximately 1 in 50,000 births. Forty percent of patients with TCS have a family history of the disease, and 60% of cases are seen sporadically.³⁵ Anomalous development in TCS is characterized by a combination of findings isolated to the head and neck. Facial bone hypoplasia, involving the mandible and zygomatic complex in >75% of patients, is an extremely common feature of TCS. The maxilla may also be hypoplastic but sometimes can be seen as overprojecting. Other characteristic abnormalities include downward slanting of the palpebral fissures with notching of the lower eyelids and a scarceness of lid lashes medial to the defect.³⁵ The nose may be broad or protruding. Auricular anomalies include absent EAC, middle ear malformations, and pinna deformities. Craniofacial radiologic abnormalities include hypoplastic or aplastic zygomatic arches, choanal shortening, micrognathia and maxillary narrowing, or overprojection. CP is a common co-occurrence and may be severe. Craniofacial defects in TCS are often bilateral and relatively symmetric (Fig 4). Limb anomalies do not occur in TCS, which helps differentiate it from other syndromes that manifest with similar facial features.^24,35–38

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Fig 4.

A 4-year-old girl with TCS. A−C, 3D bone reconstructions show bilateral and asymmetric abnormalities of the mandibular condyle and coronoid process as well as maxillary hypoplasia and micrognathia. The EACs are absent bilaterally. D, Axial CT image shows bilateral hypoplastic zygomatic arches, maxillary bone dysplasia, and temporal bone abnormalities.

Facial deformaties are prioritized and addressed based on function and the basis for proper development. Surgical techniques have been described to address most of the anomalous development in TCS. Surgical correction of the zygoma, orbit, and mandible are usually not performed until the patient is 4–10 years of age. Auricular repair is often delayed until after 6 years of age to allow time for adequate costal cartilage development, which is harvested and used for successful reconstruction.^39,40

Stickler Syndrome: OMIM 108300

Stickler et al⁴¹ first described this autosomal dominant syndrome, also called hereditary progressive arthro-ophthalmopathy, characterized by ocular and orofacial changes, arthritic changes, and deafness.⁴² The clinical picture is highly variable and sometimes confusing, with phenotypic features varying from dwarfism/marfanoid habitus to phenotypically healthy individuals. This variability can lead to diagnostic difficulties.^42–44 Phenotypic variation can, in part, be explained by genetic heterogeneity, because the syndrome is often broken into 3 types based on mutations in different genes (type 1, COL2A1; type 2, COL11A1; and type 3, COL11A2). Despite the genotypic heterogeneity, the systemic features are similar for the different types. Diagnostic criteria have been proposed for type 1, comprising most patients with Stickler syndrome, which include molecular or family history data and characteristic ocular, orofacial, auditory, and musculoskeletal findings.⁴⁵

The most serious manifestations of the syndrome are ocular, including retinal detachment, high nonprogressive myopia, and vitreoretinal degeneration. These features may lead to eventual blindness.⁴⁶ Less common ophthalmologic features include perivascular pigmented lattice degeneration and cataracts.⁴² Nonocular features show high variability in expression. Enlarged joints, epiphyseal changes, and mild platyspondyly are typical of the disorder. Mild ligamentous laxity is seen early in life that occasionally leads to generalized ligamentous stiffness. Osteoarthritis typically develops in the third or fourth decade. Mild spondyloepiphyseal dysplasia is often apparent radiologically. Occasional findings include slender extremities and long fingers.^43,45

Patients with Stickler syndrome may have congenital sensorineural, congenital conductive, or acquired conductive hearing loss. The association with CP and a high arched palate leads to an increased incidence of serous otitis media, which may lead to conductive hearing loss. Defects of the auditory ossicles can be seen with associated congenital conductive hearing loss. Forty percent of patients show some evidence of sensorineural hearing loss, which in many patients may be clinically occult.^42,44,47

Radiographic evaluation of children with Stickler syndrome may reveal a flat midface with a depressed nasal bridge, short nose, anteverted nares, and micrognathia (Figs 5 and 6). These features can become less pronounced with age. Facial clefting is often seen and may range in severity from a cleft of the soft palate to a full PRS. Temporal bone evaluation can reveal ossicular chain abnormalities.⁴⁴ Prenatal detection of polyhydramnios and micrognathia with a family history of Stickler syndrome should be considered diagnostic of the syndrome and appropriate anticipatory care can be given before delivery.⁴⁸

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Fig 5.

A 47-year-old woman with Stickler syndrome. A−C, 3D bony reconstructions show a flat midface with a depressed nasal bridge, short nose, anteverted nares, and zygomatic hypoplasia. Reconstructive and cosmetic hardware and implants are present. D, Axial CT scan shows incomplete fusion of the palatal bones with a posterior submucosal cleft (arrow).

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Fig 6.

A 6-year-old boy with Stickler syndrome. 3D bony reconstructions show the characteristic flat midface with a depressed nasal bridge. The degree of zygomatic hypoplasia is more subtle. There is mild micrognathia. An endotracheal tube is present. Courtesy of Michael Cunningham.

VCFS: OMIM 192430

DiGeorge⁴⁹ first reported the association of the absence of the thymus with aplasia of the parathyroid glands. These observations were appreciated with variable anomalies of the cardiovascular system and craniofacial syndromes.¹⁶ Although there has been debate about the distinct etiologic nature of DiGeorge syndrome and VCFS, there is considerable phenotypic and genotypic overlap. A 1.5- to 3.0-Mb hemizygous deletion of chromosome 22q11.2 causes VCFS.⁵⁰ This monoallelic microdeletion is considered the most common human deletion syndrome.⁵¹ DiGeorge syndrome has been shown to share a genetic defect with VCFS in 45%- 85% of cases in different series.^16,52

VCFS consists of CP, cardiac anomalies, typical facies, and learning disabilities. In a recent study, cortical areas of reduced gyration were observed, further substantiating the pattern of cerebral alterations presented with the syndrome.⁵³ Almost all individuals with 22q11 deletion syndrome have behavior and/or learning problems, with >40% meeting the criteria for either autism spectrum disorder, attention deficit/hyperactivity disorder, or both. More than half of patients, in some series, meet the criteria for mental retardation.⁵⁴ Less frequent features include microcephaly, short stature, slender hands and digits, minor auricular anomalies, and inguinal hernia. Skeletal anomalies are not uncommon.⁵⁵ VCFS is the most frequent clefting syndrome, accounting for approximately 8.1% of children with palatal clefts seen in some centers.⁵⁶ Cardiac anomalies have been described in 82% of patients, including isolated ventricular septal defect and tetralogy of Fallot.⁵⁷

Two emergent clinical situations may arise in children with VCFS on the basis of the variable associated defects of the third and fourth BAs. The first is tetany, which can be sudden and fatal, due to hypocalcemia relating to aplasia of the parathyroids.⁵⁸ Although the absence of parathyroid gland function is rare, parathyroid dysfunction is present in approximately half of patients with VCFS.⁵⁹ The second emergent situation is related to infections from deficiencies with the T-cell−mediated response of the immune system due to an absent or hypoplastic thymus. Immunologic evaluation is critical in affected children to identify those that may require either lymphocyte or thymus transplantation.⁶⁰ Both of these situations require special care of patients who may require cardiac surgery.⁵⁸

Radiographic evaluation of a patient with suspected VCFS is multifaceted because the radiologist may be called on to evaluate the central nervous system, craniofacial structures, cardiothoracic contents, or the musculoskeletal system. Focus on the craniofacial system should include an evaluation for PRS, EAC stenosis, prominent nose, thin upper lip, and asymmetric facies (Fig 7). The adenoids are typically hypoplastic, and middle ear anomalies are also sometimes seen. An aberrant course of the internal carotid arteries is often seen, and contrast-enhanced CT is often requested for surgical planning involving the head and neck.

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Fig 7.

A 6-year-old boy with VCFS. A−C, 3D bone reconstructions show mild micrognathia with normal condyle and coronoid process morphology. D, Axial CT angiogram shows relatively symmetric micrognathia and areas of malocclusion (arrows).