Mandibulofacial Dysostosis

Etiology

Treacher Collins syndrome is genetically and phenotypically heterogeneous.[4] TCS has autosomal dominant and, less commonly, autosomal recessive inheritance patterns, though most cases are sporadic.[2] It has been linked to human chromosome 5q32 locus.[8] Up to 60% of TCS cases have no family history and are a result of de novo mutation. With autosomal dominant TCS, each offspring of an individual with TCS has a 50% likelihood of inheriting the TCOF1 or POLR1D pathogenic variant. With autosomal recessive TCS, the parents of an affected child are heterozygotes (carriers of one POLR1C or POLR1D pathogenic variant). Each sibling of a person with autosomal recessive TCS has a 25% chance of also having TCS, a 50% chance of asymptomatically carrying, and a 25% chance of being neither affected nor a carrier.[2] 

Inter- and intrafamilial clinical variability is quite common in TCS.[2] Some individuals may go undiagnosed because of their mild presentation, while others will have life-threatening airway compromise due to their severe facial involvement. 

Once a pathogenic variant has been identified in an affected family member, it is possible to offer prenatal and preimplantation genetic testing.[2] Affected individuals and their families are highly encouraged to seek genetic counseling.[8]

Epidemiology

The incidence of Treacher Collins syndrome is estimated between 1 in 25,000 to 1 in 70,000 live births (most commonly cited as 1 in 50,000).[3][7] There is no gender or racial preference. The degree of malformation present at birth is relatively stable and nonprogressive.[7]

History and Physical

The most common clinical manifestations are downward-slanting palpebral fissures (89%-100%), malar hypoplasia or hypoplasia of the zygomatic complex (81% to 97%), mandibular hypoplasia or micrognathia (a small lower jaw) (78% to 91%), auricular pinna malformations (77%), lower eyelid colobomas (54% to 69%), and dental anomalies (60%; most commonly hypoplastic, but also heterotopic or hyperplastic).[2][3][4][9] 

Eye manifestations of Treacher Collins syndrome include downward-slanting palpebral fissures, colobomas, and hypoplasia of the lower lids and lateral canthi, hypertelorism (a large distance between the eyes), and partial absence of eyelid cilia (or eyelashes).[8] The lateral aspects of the orbits are also commonly hypoplastic, and in severe cases, there is a palpable notch corresponding to a Tessier 6 cleft. Visual disability of some kind is found in up to a third of TCS individuals.[5] 

Facial bone malformation manifestations include malar and mandibular hypoplasia. The malar and mandibular hypoplasia can lead to respiratory distress via obstructive sleep apnea (46%).[5][10] There can be variable soft-tissue abnormalities, sometimes including a Tessier 7 cleft (macrostomia). Severe mandibular hypoplasia can cause obstruction at the level of the hypopharynx because the base of the tongue is retropositioned into the posterior pharyngeal airway.[11] The associated micrognathia and retrognathia (posterior positioning of the jaw) can have variable effects on the jaw muscles and temporomandibular joints and may cause an anterior open bite, a class II or III malocclusion, or a steep occlusal plane.[2][8] 

Ear manifestations of Treacher Collins syndrome most commonly involve abnormalities of the auricular pinna (or microtia) and are variably (though often) associated with atresia of the external auditory canals (EAC) and anomalies of the middle ear ossicles. Bilateral conductive hearing loss is a common result (83% to 96%).[2][4][5][6] Many patients with Treacher Collins will fail their newborn hearing screening as a result. Most of the hearing loss in individuals with Treacher Collins syndrome is due to their malformed middle ears.[7] Preauricular hair displacement, where the hair extends in front of the ear further to the lateral cheekbones, is also seen with TCS.[2]

There are other less common manifestations of Treacher Collins syndrome as well. Salivary gland abnormalities and subsequent dry mucosa can be seen in up 48% of patients with TCS.[5] Cleft palate with or without cleft lip (21% to 33%) and unilateral or bilateral choanal stenosis or atresia (13%-25%) are also described.[2][4] Nasal deformities and a high-arched palate have also been reported in patients with TCS.[8] Cardiac malformations have also been rarely described (11%).[2] Intellect is typically normal, and disability or delayed motor development has been rarely reported, though it is important to remember (1.7% to 10%).[2]

Evaluation

Every case of Treacher Collins syndrome is unique and needs unique, individual assessment ideally by an interprofessional team.[8] Areas of specific focus include:

• Visual examination: eyelid as well as visual acuity exams
• Comprehensive hearing testing, as conductive hearing loss is very prevalent, and early intervention can facilitate normal language development and auditory rehabilitation.
• Upper airway examination, as micro and retrognathia, can predispose to obstructive sleep apnea.

Postnatal diagnosis is usually made via a blood sample for DNA isolation from the individual and family members based upon either family history or characteristic facies. Once a pathogenic variant has been identified in an affected individual, it is possible to offer prenatal and preimplantation genetic testing.[2] Prenatal diagnosis requires the same blood sample from family members and a specimen from amniocentesis or chorionic villous sampling and is typically only performed in children of affected individuals.[7] A tentative diagnosis can be made prenatally by the presence of micrognathia and microtia on the ultrasound examination.[9] 

The diagnosis of TCS in about 96% of patients is made through molecular genetic testing and detection of a heterozygous (in an autosomal dominant pattern of inheritance) pathogenic variant in TCOF1 or POLR1D or biallelic (in an autosomal recessive pattern of inheritance) pathogenic variants in POLR1C or POLR1D.[2] 4% of patients are diagnosed by clinical findings when molecular genetic testing has not been done, or no pathogenic variants are identified.[2] 

A full craniofacial computed tomography (CT) scan is usually conducted during the first six months of life to determine the extent of dysmorphology. Hypoplasia or aplasia of the zygomatic arch can be detected by a waters’ view radiograph, and mandibular retrognathia can be seen on an orthopantomogram, though in the era of widespread CT availability, these plain-film X-rays are rarely relied upon.[2] 

If there is a concern for obstructive sleep apnea, polysomnography, and a thorough ear, nose, and throat examination are in order to decipher the level of upper airway obstruction.[5]

Treatment / Management

There is no cure for Treacher Collins syndrome, and treatment is aimed at meeting the specific manifestations and needs of each individual patient.[8] An interprofessional team approach is the most beneficial. Correction of the different deformities associated with TCS is usually staged and is linked to facial growth patterns, functionality, and psychosocial needs, and many may not require any surgical correction.[7] (B3)

Obstructive Sleep Apnea

At birth, the airway may be compromised secondary to maxillary hypoplasia (which can narrow the nasal passages into choanal stenosis or atresia) or, more commonly, due to mandibular hypoplasia with secondary retro-positioned tongue and obstruction of hypopharyngeal spaces.[7] The goal of early interprofessional treatment should be timely recognition of obstructive sleep apnea via polysomnography and a thorough ear, nose, and throat examination in order to decipher the level of upper airway obstruction.[5] Neonates with airway concerns may require special positioning, such as proning (or, much more commonly, preferential lateral sleeping - alternating sides nightly), supplemental oxygen, continuous or bilevel positive airway pressure, intubation, or a tracheostomy (12 to 41%).[2][5][11] Some patients remain with a tracheostomy for several years, awaiting lower jaw growth or mandibular reconstruction or distraction, though neonatal mandibular distraction has beecome much more common.[7] Tracheostomies can interfere with speech and can result in subglottic scar tissue and subsequent stenosis, and the aim of more conservative measures, as well as adjuvant surgical measures such as neonatal mandibular distraction, is to avoid tracheostomy in these patients.[7] It is proposed that a patient with TCS with a cleft palate has a decreased probability of requiring a tracheostomy.[5] Reevaluation for respiratory distress should be done every three to six months.[5] (A1)

Feeding Difficulties

Feeding support via a gastric tube may be necessary for patients with mandibular hypoplasia (because of persistent airway obstruction and frequent hypoxic episodes) or choanal atresia.[4][11] Dental occlusal discrepancies can result from mandibular hypoplasia, which can cause dietary limitations and create difficulties with dental hygiene.[11] (B3)

Speech Delay or Impairment

Tracheostomies can interfere with speech and can result in subglottic scar tissue and subsequent stenosis.[7] Mandibular size and occlusal discrepancies may also affect speech development (most specifically articulation).[11] Hypernasality secondary to palatopharyngeal incompetence, and hyponasality secondary to restricted nasal cavities or choanal atresia can likewise impede speech development and quality.[5] Special attention should be given to the restoration of hearing and speech at the earliest stage so that treatment with speech therapy can begin as soon as possible (see below).[5] (A1)

Ear Malformations and Hearing Impairment

Early evaluation by a pediatric otolaryngologist and formal audiological testing coupled with the early fitting of hearing aids will help in the acquisition of communication skills.[7] Bone conduction amplification and speech therapy are used for hearing impairment.[2] Bone-anchored hearing aids (BAHA) offer better hearing improvement when compared to conventional bone-conduction hearing aids and should be considered after 3 years of age.[5] Before the age of 3, a banded hearing aid is a good option.[5] External ear reconstruction is usually accomplished through a staged approach around six to nine years of age when there is adequate rib cartilage to assist in the repair, but the results are aesthetic and not related to hearing.[5][7] External auditory canal and middle ear reconstruction are still usually left with residual hearing loss requiring some form of amplification.[7] Significant hearing improvement is only seen in a minority of patients.[5] (A1)

Not all patients with TCS receive middle ear reconstruction for this reason and are therefore individually selected based on their specific presentation and personal motivation.[7] BAHA remains the mainstay of hearing rehabilitation in this patient population, independent of whether they elect to undergo pinna reconstruction (with or without EAC drill-out for external auditory canal re-creation) for aesthetic reasons.(B3)

Eye Anomalies and Visual Impairment

Orbital dystopia correction and lateral canthopexies are rarely required and are rarely aesthetically normalizing and have low patient satisfaction. The overall appearance of the eye position is a function of the craniofacial skeleton and is usually asymptomatic. Despite the malposition, the visual function is usually normal or near-normal.[5][7] Because of the potential threat to vision via corneal drying, colobomas need attention from birth onward, and in the rare cases where there is incomplete eyelid coverage of the globes, lid-lengthening procedures are occasionally indicated in these severe cases.[5] (A1)

Malar and Mandibular Hypoplasia

Craniofacial reconstruction is occasionally required, and the age of maxillomandibular reconstruction is dictated by severity, but the most aesthetic results are seen in patients who receive these surgeries near the time of early skeletal maturity (15-17 years old in females and 17 to 21 years old in males).[7] This is the most challenging aspect of treatment for patients with TCS, given that there is a lack of sufficient evidence to dictate a full treatment protocol.[5] Zygomatic and orbital reconstruction is commonly completed around age five to seven years old [2]. Orthognathic therapies are typically completed before 16 years of age.[2] Nasal reconstruction (septorhinoplasty), if deemed necessary, is usually postponed until after the orthognathic procedures, usually after the age of 17.[5][7] Skeletal repositioning and remodeling procedures come with significant morbidity and mortality and are indicated in only the most severe cases. There are other aesthetic options to correct and/or camouflage the micro- and retrognathia and midface hypoplasia if there are no physiologic symptoms or ill-effects.[12](A1)

Cleft Palate

Cleft palate repair occurs around one year of age.[2] A sleep study should be done with imitated closure prior to closure of a cleft palate to avoid potential severe respiratory distress status post-closure.[5] (A1)

Psychological Concerns

It is important to pay attention to the psychological needs of the patient with TCS in order for them to build confidence and lead a normal life.[8] Counseling and creating realistic expectations seem essential.[5] A psychologist or psychiatrist is an essential part of the interprofessional team.[5](A1)

Differential Diagnosis

There exist a few conditions that may be on the differential diagnosis list with Treacher Collins syndrome. The hearing loss in Treacher Collins syndrome is often symmetric and bilateral, which can help differentiate it from some other syndromes, again emphasizing the importance of comprehensive audiological evaluation in any patient undergoing a syndromic workup.

Goldenhar syndrome (vertebral oculo-auricular dysplasia) shares some craniofacial abnormalities with Treacher Collins syndrome.[3] While Goldenhar syndrome and TCS share some facial anomalies, Goldenhar syndrome is usually unilateral and asymmetrical, while TCS is usually bilateral and symmetrical. Individuals with Goldenhar syndrome also commonly have vertebral anomalies and epibulbar dermoids, whereas patients with TCS do not.[6][8]

Nager syndrome (acrofacial dysostosis) also shares facial features with Treacher Collins syndrome.[3] While the two syndromes may have similar facial features, in Nager syndrome, the limb defects are preaxial while there are no limb anomalies associated with Treacher Collins syndrome.[6]

Miller syndrome again shares similar facial features with Treacher Collins syndrome, but in Miller syndrome, the limb defects are postaxial, whereas Treacher Collins syndrome has no associated limb anomalies.[3][6] 

Nonsyndromic congenital mandibular hypoplasia is a rare subgroup of all patients with mandibular hypoplasia at large.[11] As the name implies, these patients are not associated with any syndrome. These patients’ mandibles tend to remodel to preoperative form status post bilateral mandibular distraction, whereas the mandibles of the patients with Treacher Collins syndrome tend to maintain their post-distraction angle.[13]

Prognosis

With proper management, individuals with Treacher Collins syndrome have a normal life expectancy.[2] Psychological functionality should be an early concern. Lack of fear of negative appearance evaluation, patients’ satisfaction with facial appearance, and self-esteem are positive predictors for lasting psychological functionality.[5] The objective severity of the deformity is not a positive predictor, but the early restoration of hearing is, as this allows integration into peer-aged schooling and social environments in these patients who are often otherwise intellectually on par with their peers. Congenital craniofacial individuals are less likely to have a partner or children and tend towards internalizing behavior problems.[5]

Complications

There are multiple medical complications possible in patients with Treacher Collins syndrome, including but not limited to obstructive sleep apnea, speech delay, hearing impairment, feeding difficulties, visual impairment, and psychological sequelae.[5] Surgical complications can also result in morbidity and mortality.