Multisystemic Manifestation in Treacher Collins Syndrome

1. Introduction

Treacher Collins syndrome (TCS), also known as mandibulofacial dysostosis, is an autosomal dominant congenital disorder characterized by craniofacial deformities arising from underdevelopment of the facial bones during embryonic development [1]. The estimated incidence is 1 in 50,000 live births [2]. TCS results from mutations in the TCOF1 gene which encodes for the treacle protein, an important factor in craniofacial development [3]. Abnormalities include hypoplasia of the facial bones especially the mandible and zygomatic complex, antimongoloid slant of palpebral fissures, coloboma of the lower eyelids, microtia, and conductive hearing loss [4]. In addition to the physical characteristics, TCS also includes neurological disorders resulting from craniofacial defects and abnormal brain development. This essay will provide an overview of TCS with a focus on the neurological abnormalities particularly facial nerve paralysis, neurodevelopmental delay, intellectual disability, and autism spectrum disorder. The pathophysiology, diagnosis, and management of the neurological disorders will be reviewed.

2. Facial Nerve Paralysis

One of the most common neurological manifestations of TCS is facial nerve paralysis which can be unilateral or bilateral [5]. The facial nerve emerges from the brainstem and enters the internal auditory canal before branching out to supply the muscles involved in facial expression. The facial nerve nuclei in the brainstem receive input from the cerebral cortex for voluntary control of facial movements [6] In TCS, the underdevelopment of the craniofacial bones places pressure on the developing facial nerve leading to hypoplasia. The resulting facial nerve paralysis leads to an inability to control facial muscles and a lack of facial expressions.

The diagnosis of facial nerve paralysis can be made clinically by physical examination. The facial expressions and ability to raise eyebrows, close eyes tightly, smile, and bare teeth should be inspected. Strabismus or misalignment of the eyes may be present if the nearby cranial nerve that controls extraocular movements is also affected. Imaging studies like CT or MRI can confirm facial nerve hypoplasia [7]. Electromyography can help evaluate the degree of nerve damage. Once diagnosed, facial rehabilitation therapy focusing on mime therapy helps patients regain some control over specific facial muscles. Surgical interventions like nerve grafting have limited benefit [8].

The facial nerve originates from the pons region of the brainstem, where it has a motor nucleus that contains lower motor neurons innervating the muscles of facial expression. The nerve travels through the posterior cranial fossa within the cerebellopontine angle cistern, enters the internal auditory canal, travels through the temporal bone, exits via the stylomastoid foramen, and divides into five major branches supplying the forehead, eyelids, nose, lips, and chin. Bilateral facial nerve paralysis is rare since the nuclei and proximal nerves have dual blood supply, but can occur with brainstem strokes, infection, trauma or malignancy. Unilateral palsy is more common.

In TCS, underdeveloped craniofacial bones place mechanical compression on the developing facial nerve, leading to hypoplasia and reduced numbers of motor axons. The facial muscles then do not receive sufficient innervation to allow full voluntary control of expression. Staining of facial nerve tissue from TCS patients shows loss of large myelinated motor fibers. There may also be aberrant branching, fibrosis, and misdirected regeneration further impairing function.

Clinically, facial nerve palsy manifests as paralysis of muscles involved in facial expression. Patients are unable to wrinkle their forehead, close their eyes tightly, show teeth when smiling, whistle or pucker lips. Food and liquids can fall out of the paralyzed side of mouth when eating or drinking. Eye closure may be incomplete on the affected side causing exposure keratitis. Asymmetry is apparent at rest and with animated expressions. Physical exam assesses facial resting tone, motion, and synkinesis which is involuntary movement with voluntary facial gestures.

The degree of nerve damage can be quantified using the House-Brackmann scale which grades palsy as I (normal) to VI (total paralysis). Imaging like CT and MRI visualizes facial nerve anatomy and confirms hypoplasia. Nerve conduction studies check integrity of the nerve’s motor and sensory fibers. Electromyography evaluates activity in facial muscles and is useful for monitoring progression and recovery.

Mime therapy is first line treatment, teaching patients to consciously perform facial expressions using accessory muscles not innervated by the facial nerve, like the tongue or jaw muscles. This takes advantage of crosstalk between adjacent muscle groups controlled by different nerves. With time and repetition, some independent motion of paralyzed facial muscles can return through cortical neuroplasticity developing new engram connections. Surgical options have limited benefit but may include nerve grafting, nerve transfers from adjacent healthy branches, or muscle transfers for severe cases unresponsive to conservative measures. The prognosis depends on the degree and chronicity of nerve damage. Mild to moderate palsy often improves over months as collateral sprouting regenerates axonal connections to denervated fibers. Severe paralysis carries a poorer prognosis. Multidisciplinary management optimizes functional and psychosocial outcomes.

3. Neurodevelopmental Delay

Neurodevelopmental Delay in Treacher Collins Syndrome (TCS) encompasses a range of challenges that extend beyond the physical manifestations commonly associated with the condition. In addition to the distinctive facial anomalies, infants diagnosed with TCS often face hurdles in meeting early motor and language milestones, achieving these milestones later than their typically developing peers. This aspect of TCS warrants a closer examination, as it has profound implications for the developmental trajectory of affected children.

Research findings have illuminated the prevalence of neurodevelopmental delays in TCS. A notable study observed gross motor delays in virtually all infants with TCS who were less than 12 months old. These delays extend to fine motor skills, such as grasping objects, which are also frequently impaired in these young individuals. Moreover, the majority of young TCS patients experience delays in both receptive and expressive language development. These findings underline the intricate nature of neurodevelopmental challenges associated with TCS [9].

The underlying factors contributing to neurodevelopmental delays in TCS are multifaceted and encompass a variety of aspects. Hearing loss is a prominent factor, as individuals with TCS often contend with auditory deficits that can impede language acquisition and overall cognitive development. Additionally, facial paralysis may affect oral motor control and, in turn, impact speech and feeding skills. Feeding difficulties, often arising from craniofacial anomalies, can lead to suboptimal nutrition, further exacerbating developmental concerns. Recurrent infections can also take a toll on a child’s overall health and development [10].

Further complicating the picture, neuroimaging studies have revealed structural brain abnormalities in individuals with TCS. These abnormalities, such as white matter hypoplasia and diffuse cortical atrophy, shed light on the complex neurological aspects of the syndrome.

To address these neurodevelopmental challenges, it is crucial for healthcare providers to closely monitor the development of infants with TCS during well-child visits. Early identification of developmental delays is key to ensuring timely intervention. Pediatricians should refer infants suspected of delay to early intervention services, where a multidisciplinary approach can be employed [11].

Developmental therapists play a vital role in providing targeted exercises aimed at improving motor skills such as rolling over, sitting, crawling, and walking. Speech therapists offer interventions that facilitate the development of communication skills, while feeding therapy helps establish proper oral motor control, ensuring adequate nutrition and fostering independence in feeding [12].

In conclusion, while Treacher Collins Syndrome presents distinctive physical characteristics, it is essential to recognize the significant neurodevelopmental challenges that individuals with TCS may face. Through early intervention, access to a range of therapeutic services, and a holistic approach to care, children with TCS can work toward reaching their full developmental potential, overcoming the multifaceted barriers they encounter on their journey toward growth and independence.

4. Intellectual Disability

Intellectual Disability in the context of Treacher Collins Syndrome (TCS) is a multifaceted aspect of the condition that warrants a comprehensive examination. While TCS is known for its distinct facial features and physical anomalies, it is important to recognize that many individuals with TCS also contend with challenges related to intellectual functioning [13].

Numerous studies have shed light on the prevalence of below-average IQ scores and intellectual disability among individuals with TCS. One notable meta-analysis revealed that nearly one third of individuals diagnosed with TCS exhibit an IQ score below the threshold of 70, indicative of intellectual disability. These findings underscore the significance of understanding the cognitive dimensions of TCS and the potential impact on an individual’s life [14].

Neurocognitive testing has provided further insights into the specific areas of cognitive functioning that may be affected in individuals with TCS. Notable deficits are often observed in domains such as verbal reasoning, working memory, vocabulary, and perceptual reasoning. These cognitive challenges can have far-reaching implications for an individual’s educational attainment, daily functioning, and overall quality of life.

The etiology of intellectual disability in TCS is complex and likely multifactorial. Various factors contribute to these cognitive challenges, including hearing loss, which can hinder language development and communication skills. Facial dysmorphisms may also play a role, as they can impact self-esteem and social interactions. Structural brain abnormalities are another facet of the condition, with dilated ventricles, cortical atrophy, white matter hypoplasia, cerebellar hypoplasia, and reduced grey matter volume being commonly observed in TCS. These neurological factors further underscore the intricate interplay between physical and cognitive aspects of the syndrome [15].

Effective management of intellectual disability in individuals with TCS requires a tailored approach that addresses their unique needs and abilities. This includes the provision of special education services designed to accommodate their cognitive profile. Speech therapy can be invaluable in improving communication skills, and physical therapy can help individuals maximize their physical potential.

Social skills training is another critical component of intervention, as it equips individuals with TCS with the tools they need to navigate social interactions and build meaningful relationships. In cases where speech is severely affected, assistive communication devices can supplement verbal communication, providing alternative means of expression.

In some instances, psychopharmacological medications may be considered, especially when individuals with TCS present with comorbid conditions such as attentional disorders that can further impede learning and adaptive functioning. However, the use of such medications should be judicious and guided by a thorough assessment of the individual’s needs.

With early and ongoing supportive interventions and therapies, many individuals with TCS and below-average cognitive abilities can make significant strides in their development. These interventions not only foster cognitive growth but also help individuals with TCS integrate socially and gain valuable skills that can open doors to employment opportunities tailored to their intellectual disability, promoting independence and enhancing their overall quality of life.

Autism Spectrum Disorder

Multiple studies have shown an increased prevalence of autism spectrum disorder (ASD) among patients with TCS, ranging from 10-33% compared to about 1% in the general population [16]. ASD is a neurodevelopmental disorder characterized by persistent deficits in social communication and social interaction as well as restricted repetitive behaviors, interests, or activities [17]. The underlying reasons for increased ASD prevalence in TCS remains speculative but likely involves hearing loss during critical language development periods, facial dysmorphisms limiting nonverbal communication and social reciprocity, and potential structural brain changes affecting socio-emotional processing [18].

The diagnosis of ASD is made clinically based on history and observation of behavioral criteria. There are no laboratory or imaging tests to confirm the diagnosis. Early screening around 18 to 24 months using ASD screening tools like the M-CHAT questionnaire can identify children at risk who should undergo formal diagnostic evaluation by psychologists, psychiatrists, and behavioral specialists. Early intensive behavioral and communication therapies are the mainstay of treatment [19]. Medications may be used to treat comorbid symptoms like irritability, aggression, anxiety, hyperactivity, and obsessive behaviors which interfere with daily function and socialization. With early therapy, some children on the high functioning end of the autism spectrum can gain adequate communication and social skills to attend mainstream schools and participate meaningfully in the community, however ASD is a lifelong disorder.

5. Respiratory Manifestations

Individuals with TCS often have respiratory complications resulting from their craniofacial abnormalities. Micrognathia or hypoplasia of the mandible leads to glossoptosis or posterior displacement of the tongue which can obstruct the airway [20]. Laryngomalacia due to floppy laryngeal structures is also more common. These upper airway anomalies predispose to obstructive sleep apnea which is reported in over 60% of pediatric TCS cases in some studies [21]. The obstructions can lead to oxygen desaturations, increased work of breathing, and pulmonary hypertension over time if not addressed. Children may present with symptoms like snoring, apneas, restless sleep, and daytime somnolence. Polysomnography is used to confirm the diagnosis of obstructive sleep apnea. First line treatment is adenotonsillectomy if large tonsils and adenoids are present [22]. For severe cases, tracheostomy or mandibular distraction osteogenesis helps pull the tongue base forward and relieve the obstruction. Continuous positive airway pressure (CPAP) may be needed if other measures fail.

6. Cardiac Manifestations

Congenital heart defects have been reported in around 11% of TCS patients [23]. The most common abnormalities are atrial and ventricular septal defects leading to intracardiac shunts [24]. Echocardiography readily diagnoses septal defects which may spontaneously close over time or require surgical repair for hemodynamically significant defects. Another cardiovascular issue in TCS is pulmonary hypertension which can arise secondary to obstructive sleep apnea or upper airway obstruction. Annual screening echocardiograms are recommended to monitor for pulmonary hypertension which if severe may need treatment with pulmonary vasodilators and oxygen therapy.

7. Skeletal Manifestations

In addition to craniofacial bone hypoplasia, patients with TCS can present with chest wall deformities including pectus excavatum and carinatum which are depressed or protruding sternums respectively [25]. These anomalies result from unbalanced growth of the ribs and sternum likely due to a genetic predisposition in TCS. Pectus excavatum can impair cardiac and respiratory function if severe. The diagnosis is made clinically on examination and both conditions can be treated surgically if symptomatic. Orthopedic manifestations are also seen more often such as scoliosis, kyphosis, lower limb asymmetry, and joint hyperextensibility [26]. Physical therapy focuses on postural control and strengthening while severe spinal curvature may necessitate bracing or surgery.

8. Renal and Genitourinary Issues

An association between TCS and structural renal abnormalities has been reported in several studies. Ultrasound screening has revealed a high prevalence of unilateral renal agenesis in TCS, occurring in up to 30% of patients [27]. Other defects like duplicated ureters, horseshoe kidney, and small or enlarged kidneys have also been documented. The etiology may relate to gene mutations disrupting embryologic development of both the craniofacial complex and kidneys. Most renal anomalies are asymptomatic but can lead to problems like recurrent infections, renal failure, or hypertension thereby requiring monitoring of kidney function and blood pressure. Cryptorchidism or undescended testes have also been reported more frequently in TCS males [28]. Hormonal therapy or orchidopexy surgery can be done to move undescended testes into the scrotum.

9. Ophthalmologic Issues

Common eye abnormalities in TCS include strabismus, amblyopia, refractive errors, and colobomas of the lower eyelids which appear as notches [29]. Vision loss can occur from exposure if the lid defects cause incomplete eye closure during blinking and sleep. Aggressive ophthalmologic management is required to prevent corneal scarring and ulcers which can lead to blindness. Strabismus or misaligned eyes requires patching therapy in children to force use of the weaker eye and may eventually need corrective surgery. Nystagmus or abnormal eye movements are also seen due to poor binocular vision from strabismus. Retinal and optic nerve hypoplasia have been documented in severe TCS cases resulting in visual impairment [30]. Regular eye exams allow for early detection and treatment optimization to prevent vision loss.

10. Hearing Loss

Conductive hearing loss is almost universally present in TCS due to external and middle ear malformations [31]. The microtia or underdeveloped pinna leads to obstructed or absent ear canals. Middle ear bones including the malleus, incus and stapes can also be malformed, fused, or absent. Recurrent otitis media with effusion is common, exacerbating the conductive loss. Hearing aids should be fitted early to maximize language development. Bone conduction devices that transmit sound via bone vibration bypass the external and middle ear impediments. For severe bilateral microtia, reconstruction of the ear canal and pinna can improve hearing. Cochlear implantation may be an option for those who do not benefit sufficiently from amplification. Monitoring for hearing loss should continue through adulthood.

11. Dental Manifestations

Dental anomalies are present in over 90% of patients with TCS [32]. The most common issues are malocclusion due to mandibular hypoplasia, tooth agenesis, delayed dental development, and enamel defects making the teeth prone to cavities. Orthodontic treatment with palatal expanders can help correct crowding and malocclusion. Missing teeth may need prosthetic replacement. Dental surgeons often manage TCS cases starting from childhood since early intervention improves outcomes. Other oral complications include cleft palate, high arched palate, bifid uvula, and tongue anomalies which can affect feeding, speech and oral hygiene [33]. Multidisciplinary management by pediatric dentists, orthodontists, oral surgeons, and speech therapists is key.

The underlying craniofacial bone hypoplasia in TCS alters the morphology and position of tooth buds and alveolar processes during development. This affects tooth eruption patterns, spacing, occlusion and jaw relationships resulting in malocclusion which requires orthodontic correction. Tooth agenesis or missing teeth occurs frequently, especially premolars and sometimes incisors, due to the abnormal developmental environment. Oligodontia with multiple missing teeth may require dental prosthetics [34].

Enamel defects like hypocalcification and hypoplasia increase caries risk. The enamel may have a mottled opaque appearance, be thin, soft, and lack normal mineralization and protective properties, making the teeth more susceptible to cavities and wear. Preventive measures include fluoride treatment, sealants, dietary counseling, more frequent dental cleanings, and early restorative work.

Dental development is often delayed, with late eruption of both primary and permanent teeth, which can affect nutrition, speech, and occlusion. Serial panoramic radiographs from an early age help assess development and eruption status. Monitoring for impacted or ectopic teeth is also important as surgical exposure or repositioning may be needed. Some patients have anterior open bites and other occlusal problems requiring orthodontic therapy to correct.

High arched and narrow palates are common and lead to crowding. Palatal expanders can mechanically widen the upper jaw to alleviate crowding and posterior crossbites. Cleft palate and bifid uvula occur in a subset of TCS patients and may necessitate speech therapy and surgical repair. Tongue reduction surgery is sometimes done for macroglossia causing airway obstruction and poor oral alignment.

A multidisciplinary team including pediatric dentists, orthodontists, prosthodontists, oral surgeons, and speech pathologists optimizes dental management starting early in childhood. Regular dental visits every 3-6 months for cleaning, fluoride application, sealants, and home care instruction help maintain oral health and prevent problems. Ongoing care throughout development and into adulthood addresses the complex dental issues associated with TCS to improve function and esthetics.

12. Psychosocial Functioning

Psychosocial Functioning in Treacher Collins Syndrome (TCS) is profoundly influenced by the distinctive facial features and multisystemic manifestations characteristic of this condition. These unique physical traits predispose individuals to a range of psychosocial challenges, encompassing issues such as poor self-image, social isolation, anxiety, depression, and peer victimization. This complex interplay between the physical and emotional aspects of TCS can significantly impact daily life and overall well-being [35].

Children affected by TCS often grapple with self-consciousness regarding their dental anomalies, hearing aids, facial paralysis, or other visible irregularities. These concerns can create barriers to social interactions, potentially leading to feelings of isolation and reduced self-esteem. Adolescents and adults living with TCS may face ongoing struggles with self-acceptance, contributing to lower quality of life measures when compared to the general population. This underscores the importance of comprehensive support and intervention strategies tailored to the unique needs of individuals with TCS.

Fortunately, a multifaceted approach to support exists. Social skills training equips individuals with practical tools and strategies to navigate social situations with confidence and ease. Behavioral therapy offers valuable techniques for managing anxiety and improving emotional well-being. Support groups provide a vital sense of community and understanding, allowing individuals to share experiences and coping mechanisms. Additionally, advocacy organizations play a crucial role in raising awareness, providing resources, and fostering a sense of belonging for those affected by TCS [36].

Vocational counseling represents another pivotal aspect of psychosocial support for individuals with TCS. By identifying their unique strengths and talents, individuals can develop adaptive coping strategies to effectively address challenges in educational and employment settings. This empowers them to pursue their aspirations and goals with confidence.

A robust family support system serves as an anchor for individuals with TCS. The unwavering support, understanding, and encouragement provided by family members can be transformative in bolstering self-esteem and resilience. Furthermore, positive environmental reinforcement, such as inclusive communities and workplaces, plays a critical role in creating an atmosphere of acceptance and belonging.

In conclusion, addressing the psychosocial aspects of TCS requires a holistic approach that acknowledges the intricate interplay between physical and emotional well-being. Through a combination of tailored interventions, support networks, and positive environmental influences, individuals with TCS can build self-confidence, resilience, and ultimately, lead fulfilling lives.

13. Genetics and Prenatal Diagnosis

Treacher Collins syndrome follows an autosomal dominant pattern of inheritance with most cases resulting from a mutation in the TCOF1 gene on chromosome 5q32. Single gene sequencing identifies over 90% of pathogenic variants. If neither parent has TCS, the mutation likely occurred de novo in the affected child. Prenatal diagnosis by chorionic villus sampling or amniocentesis allows for molecular testing of the fetus if the family specific mutation is known. Ultrasound can also detect craniofacial anomalies prenatally but definitive diagnosis requires genetic analysis. Due to variable expression, the severity may be hard to predict prenatally simply based on ultrasound findings. Genetic counseling provides information on recurrence risks and reproductive options but decisions are highly personal. Some families opt for preimplantation genetic diagnosis with in vitro fertilization to prevent transmission. Continued research aims to elucidate genotype-phenotype correlations and the contribution of potential modifier genes.

14. Surgical Management

The crux of treatment for TCS is coordinated surgical management from early childhood into adulthood focusing on both reconstructive and functional outcomes. Initial procedures often aim to optimize airway patency and breathing. Tracheostomy may be done as an emergency measure for severe upper airway obstruction. Distraction osteogenesis techniques can lengthen and advance the mandible using an external device to allow gradual bone growth. This opens the airway while also improving facial symmetry and occlusion. Orthognathic surgery on the maxilla, zygomatic complex and mandibular body is commonly done during adolescence once growth nears completion. Rhinoplasty refines nasal structure. Ear reconstruction for microtia is ideally performed in stages using cartilage grafts to fashion new ear framework. Implanted prostheses remain an option if surgery is declined. Blepharoplasty on the lower lids can reduce notching defects. Laser resurfacing of zygomatic scars gives a smoother facial appearance. While the operations are extensive, staged reconstruction from childhood into adulthood offers significant functional and esthetic improvements.

15. Multidisciplinary Care

The optimal management of Treacher Collins requires early evaluation and longitudinal follow-up by a craniofacial team encompassing primary care pediatricians, otolaryngologists, audiologists, ophthalmologists, dentists, orthodontists, speech therapists, psychologists, genetic counselors and surgeons across orthopedics, plastic surgery, oral maxillofacial, and oculoplastic subspecialties. Care coordination is essential to align treatment timelines and minimize conflicts between different interventions. Open communication ensures all providers are up to date on the treatment plan. Centralized care at a craniofacial center with all specialists present in one location offers immense benefits for patients and families who otherwise must attend numerous separate appointments. A holistic approach also considers developmental, educational and psychosocial needs in addition to surgical and medical aspects. Support groups and family networks offer camaraderie and resources that augment clinical management. Ongoing research continues to advance diagnostics and therapeutics. The future looks brighter for individuals with Treacher Collins syndrome as multidisciplinary care improves quality of life.

16. Research Directions

While much progress has been made in understanding Treacher Collins syndrome, significant knowledge gaps remain with ample opportunities for impactful research. Elucidating the intricate molecular pathways regulated by TCOF1 and downstream effects of pathogenic mutations can reveal new treatment targets to prevent craniofacial anomalies. Developing genetic therapies to replace or correct the abnormal gene and restore normal protein expression may be possible. Further characterizing genotype-phenotype correlations can improve genetic counseling prognostic capabilities. Better delineating neurodevelopmental and neuroanatomical anomalies is needed to optimize therapies for delays and intellectual disability. Identifying objective biomarkers for autism diagnosis and monitoring response to interventions would be invaluable. Enhancing reconstructive surgical techniques through tissue engineering and 3D planning can continually improve functional and cosmetic outcomes. Reducing psychosocial challenges requires research on building resilience and optimizing behavioral interventions. Creating animal models that accurately recapitulate the human syndrome will accelerate translational research. Multicenter collaborative efforts with data sharing and patient registries can power big data analytics to uncover new insights. With sustained innovative research, the promise of precision prevention and personalized medicine can transform the prognosis for Treacher Collins syndrome.

17. Conclusions

Treacher Collins syndrome has highly variable phenotypic expression but commonly involves numerous craniofacial anomalies and secondary effects on respiratory, cardiac, renal, visual, auditory, dental, and psychological function. The multisystemic manifestations pose significant healthcare challenges for patients across their lifespan. Multidisciplinary care coordination is indispensable to ensure various specialties work synergistically. Continued research on the pathophysiology and clinical spectrum of TCS helps delineate monitoring and treatment guidelines. Genetic counseling is also integral for family planning. While TCS presents daunting disabilities, forward-thinking comprehensive management enables individuals with this condition to enjoy fulfilling lives by cultivating their capabilities. With compassionate support and ongoing research advances, the prognosis continues to improve for this complex disorder.