NORD gratefully acknowledges Joseph Lee, NORD Editorial Intern from the University of Notre Dame, Dr. Paul Trainor, Stowers Institute for Medical Research, Dr. Pedro A. Sanchez-Lara, Children's Hospital Los Angeles, Dr. Michael Dixon, Univ. of Manchester, UK, and Ethylin Wang Jabs, MD, Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, for assistance in the preparation of this report.
SummaryTreacher Collins syndrome (TCS) is a rare genetic disorder characterized by distinctive abnormalities of the head and face. Craniofacial abnormalities tend to involve underdevelopment of the zygomatic complex, cheekbones, jaws, palate and oral cavity (mouth) which can lead to breathing (respiratory) and feeding difficulties. In addition, affected individuals may also have malformations of the eyes (ocular) including a downward slant of the opening between the upper and lower eyelids (palpebral fissures), and anomalies of external and middle ear structures, which may result in hearing loss. Brain and behavioral anomalies such as microcephaly and psychomotor delay have also been occasionally reported as part of the condition. The specific symptoms and physical characteristics associated with TCS can vary greatly from one individual to another. Some individuals may be so mildly affected as to go undiagnosed, while others may develop serious, life-threatening complications. TCS is caused by a mutation in the TCOF1, POLR1C or POLR1D genes. In the case of TCOF1 the mode of inheritance is autosomal dominant, while for POLR1C it is autosomal recessive. In contrast, both autosomal dominant and recessive mutations in POLR1D have been reported in association with TCS.
IntroductionTCS is named after Edward Treacher Collins, a London ophthalmologist who first described the disorder in the medical literature in 1900. TCS is also known as mandibulofacial dysostosis or Treacher Collins-Franceschetti syndrome.
The symptoms and severity of TCS can vary dramatically from one person to another, even among members of the same family. Some individuals may be so mildly affected that they can go undiagnosed; others may have significant abnormalities and the potential for life-threatening respiratory complications. It is important to note that affected individuals will not have all of the symptoms discussed below.
The major characteristic features of TCS encompass certain bones of the face, ears and soft tissues around the eyes. Affected individuals present with distinctive facial features and potentially develop hearing and vision problems. The abnormalities of TCS are typically symmetric (almost identical on both sides of the face) and are present at birth (congenital). Speech and language development can be compromised by hearing loss, cleft palate or jaw and airway problems. Intelligence is usually unaffected but brain and behavioral anomalies such as microcephaly and cognitive delay have been reported infrequently as part of the condition.
Infants with TCS exhibit underdeveloped (hypoplastic) or absent cheekbones (malars), causing this area of the face to appear flat or sunken. The bone of the lower jaw (mandible) is incompletely developed (mandibular hypoplasia), causing the chin and the lower jaw to appear abnormally small (micrognathia). Certain bony structures (e.g., coronoid and condyloid processes) that anchor portions of the lower jaw bone to muscle can be unusually flat or absent. Affected infants may also exhibit underdevelopment of the throat (pharyngeal hypoplasia). Pharyngeal hypoplasia with underdevelopment of the lower jaw (mandibular hypoplasia) and/or abnormal smallness of the jaw (micrognathia) may contribute to feeding problems and/or breathing difficulties (respiratory insufficiency) during early infancy. Children may experience obstructive sleep apnea which is characterized by repeated short interruptions of normal breathing and air movement during sleep. In some severely-affected individuals, life-threatening respiratory difficulties may develop. (For more information on this condition, choose “Infantile Apnea” as your search term in the Rare Disease Database.)
Additional abnormalities that may contribute to respiratory or feeding difficulties include narrowing or obstruction of the nasal airways (choanal stenosis or atresia). Some children may be described as having features of “Pierre Robin Sequence” which include severe micrognathia, a tongue that is displaced farther back in the mouth than normal (glossoptosis) with or without incomplete closure of the roof of the mouth (cleft palate). In addition, malformations of the mouth and the jaw may result in dental abnormalities, such as teeth that are underdeveloped (hypoplastic) and/or misaligned (malocclusion). Additional dental abnormalities have also been reported including missing teeth (tooth agenesis), clouding or discoloration of the enamel of teeth (enamel opacity), and improper (ectopic) eruption of certain upper teeth (maxillary molars)Individuals with TCS may develop hearing loss due to the failure of sound waves to be conducted through the middle ear (conductive hearing loss). Conductive hearing loss usually results from abnormalities affecting structures within the middle ear and individuals with TCS may also have malformed or absent ossicles, the three small bones through which sound waves are transmitted in the middle ear (i.e., incus, malleus, and stapes). In addition, the external ear structures are often absent, small or malformed (microtia), with narrowing (stenosis) or blockage (atresia) of the external ear canals. The outer ears may be crumpled or rotated. In contrast, the inner ear is usually unaffected, although malformation of the bony spiral organ in the inner ear (cochlea) and the structures within the inner ear that play a role in balance (vestibular apparatus) have been reported. Additional symptoms may include the presence of small growths of skin or pits just in front of the external ear (preauricular tags) and an abnormal passage that is closed on one end (blind fistula) that normally drains the ears to the nose.
Many infants with TCS have abnormalities of the tissue surrounding the eyes. These eye differences can give affected individuals a saddened facial appearance. The most common ocular symptom is a downward slant to the opening between the upper and lower eyelids (palpebral fissures). Additional symptoms include a lower eyelid notch or cleft of missing lid tissue (lid coloboma), partial absence of eyelashes on the lower eyelid, crossed eyes (strabismus) and narrowed tear ducts (dacrostenosis). Occasionally malformations of the globe are seen and can include notch or cleft of missing tissue of the iris or abnormally small eyes (microphthalmia). Vision loss may occur in some patients. The degree of visual impairment varies depending upon the severity and combination of ocular abnormalities. Lower eyelid abnormalities can cause the eyes to dry out, which increases the risk of chronic irritation and eye infections.
Some individuals with TCS exhibit additional physical abnormalities such as an widely spaced eyes, notching of the upper eyelid, nasal deformity, an abnormally wide mouth (macrostomia), a highly-arched roof of the mouth (palate), unusual growth of the scalp hair toward the cheeks, and/or congenital heart defect.
Approximately 5% of individuals with TCS display development deficits or neurological problems such as psychomotor delay. However, intelligence is generally unaffected with normal language development. Nonetheless, issues with speech development can occur because of hearing loss, cleft palate or difficulties producing sounds because of structural distortion.
TCS is caused by mutation of the TCOF1, POLR1C or POLR1D genes. In the case of TCOF1 the mode of inheritance is autosomal dominant, while for POLR1C it is autosomal recessive and for POLR1D, it can be autosomal dominant or autosomal recessive.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. For TCOF1, and POLR1D, the abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. In approximately 60% of TCS cases, the mutation is a new mutation that occurs randomly without a previous family history of the disorder (de novo mutation). However, a parent may be mildly affected and unaware that they have the disorder. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child or whether previous pregnancies have resulted in affected, or indeed unaffected, children.
Recessive genetic disorders (e.g. TCS caused by POLR1C or POLR1D mutations) occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically unaffected for that particular trait is 25%.
Investigators have determined that mutations of the TCOF1 gene, located on the long arm of chromosome 5 (5q32), cause most (approximately 80%) cases of TCS. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 5q32” refers to band 32 on the long arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
TCOF1 carries instructions that encode (create) a protein known as treacle. The precise role that treacle plays in the development of TCS is not fully understood. Researchers have determined that treacle plays a role in the creation of certain small structures found within cells that assemble proteins (ribosomes). This is particularly important for the formation of a group of cells called neural crest cells which form very early during embryonic development and give rise to most of the bone and cartilage underlying the face. Conditions that arise from defects in the formation (biogenesis) of ribosomes are termed ribosomopathies. POLR1C and POLR1D encode subunits of RNA polymerases I and III, are also essential for ribosome biogenesis. It seems likely that mutations in TCOF1, POLR1C and POLR1D cause insufficient protein assembly and do not allow cells to meet their proliferation and growth needs of neural crest cells during the development of the embryo. Because TCS is highly variable, researchers speculate that additional genetic and possibly environmental factors may also play a role in the variable severity of the disorder. In support of this concept, recent experimental data has indicated that treacle plays a critical role in protection against oxidative stress induced DNA damage in neural cells, as well as in spindle orientation during neural cell division, both of which subsequently affects head and facial development.
Some individuals (approximately 10-15%) with the features and physical findings of TCS do not have mutations in any of the three abovementioned genes, suggesting that additional as yet unidentified genes may also cause TCS in some cases.
TCS affects males and females in equal numbers. The prevalence is estimated to be between 1 in 10,000-50,000 individuals in the general population. Some mildly affected individuals may go undiagnosed, making it difficult to determine the disorder’s true frequency in the general population.
A diagnosis of TCS is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic physical findings. Many associated abnormalities such as malformation or absence of the external ear are present at birth (congenital).
Clinical Testing and Work-Up
Specialized X-ray studies will confirm the presence and/or extent of certain observed craniofacial abnormalities. For example, such imaging tests show the abnormal smallness of the jaw (micrognathia) due to underdevelopment of the lower jaw bone (mandibular hypoplasia), the presence and/or extent of hypoplasia affecting certain parts of the skull, and/or the presence of additional malformations of the ear that cannot be seen during clinical evaluation.
In addition, in those affected individuals who exhibit few signs, a thorough clinical examination and X-ray imaging of the craniofacial area can demonstrate the subtle presence of certain characteristic features (e.g., hypoplasia of zygomatic arches) associated with TCS. Because TCS shares several physical features that may occur in other craniofacial syndromes, many researchers recommend that diagnostic confirmation be made through molecular genetic testing and/or, in some cases, a careful, detailed family history.
Molecular genetic testing to confirm a diagnosis is available through commercial and academic research laboratories to detect mutations in the TCOF1, POLR1C and POLR1D genes. Approximately 90-95% of individuals have an identifiable mutation of the TCOF1 gene. Furthermore, genetic confirmation of a TCOF1, POLR1C, or POLR1D mutation can be detected before birth (prenatally) by amniocentesis and chorionic villus sampling if a mutation has been identified in an affected family member. In certain cases, fetal ultrasonography, which uses reflected sound waves to create an image of the developing fetus, can reveal characteristic findings suggestive of TCS. Relatives, especially parents and siblings, of an individual diagnosed with TCS should be carefully examined because mild cases often go unrecognized and undiagnosed.
There is no cure for TCS. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric ear, nose and throat specialists (pediatric otolaryngologists), pediatric dentist, pediatric nurse, plastic surgeon, speech pathologists, audiologists, ophthalmologists, psychologists, geneticists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
Physicians regularly monitor individuals with TCS to detect certain abnormalities that may be associated with the disorder. For example, an affected individual’s hearing should be carefully monitored to detect any onset of hearing loss. Assessment of an infant’s hearing is critical. A full assessment should be done early during life, even before one year of age and then yearly, in order to ensure proper speech development.
An instrument (ophthalmoscope) is used to visualize the interior of the eye to detect any possibility of visual impairment. This examination is important to ensure appropriate preventive steps and/or prompt treatment for those who exhibit abnormalities of the eyes in association with TCS (e.g., colobomas, strabismus, microphthalmia). Affected individuals should also be monitored for jaw and dental abnormalities.
Early intervention is important to ensure that affected children reach their potential. Special services that may be beneficial may include speech therapy, special social support, and other medical, social, and/or vocational services. Genetic counseling will be of benefit for affected individuals and their families.
In some patients, surgical reconstruction of craniofacial malformations may be necessary. Surgery may be performed to repair cleft palate, to reconstruct the jaw, or to repair other bones in the skull (e.g., malar bones, zygomatic complex). The specific surgical procedures used and the age when surgery is performed depends upon the severity of the malformations, overall health and personal preference.
For example, different abnormalities may be treated at different ages. Cleft palate is often corrected around 1-2 years of age. Zygomatic and orbital reconstruction usually occurs around 5-7 years of age. External and inner ear reconstruction usually occurs around 6 years of age. Jawbone lengthening or reconstruction can range from newborn to teenager years depending upon the extent and severity of the condition.
Obstructive airways can be a serious problem not always obvious to parents or clinicians. A sleep or nap study may be used to help determine the severity of the obstruction and may influence the treatment plan. In severe affected individuals, a tube may be surgically inserted into the windpipe (trachea) to maintain an effective airway, a procedure called a tracheostomy. A procedure known as mandibular distraction, which is used to increase the length of the jawbone, may be necessary. A tube may be surgically implanted into the stomach to assure that affected infants experiencing feeding difficulties receive a sufficient amount of calories (gastrostomy).
Multiple surgeries may be required to treat the various craniofacial abnormalities that are potentially associated with TCS. Despite the number of surgeries, results vary from one person to another and the end result is rarely fully corrective.
In some individuals, an operation may be performed to help correct middle ear malformations and associated conductive hearing loss. However, specialized hearing aids such as bone-anchored hearing aids (BAHA) may suffice rather than surgery in most patients. Bone-anchored hearing aids transmit sound directly through bone into the inner ear, bypassing the external ear canal and the middle ear (both of which are often affected in individuals with TCS. Reconstructive surgery may be performed to help correct outer ear malformations for functional and cosmetic reasons. Generally, reconstruction of the external ear should be performed first.
In individuals with TCS who exhibit eye abnormalities and associated visual impairment, corrective glasses, contact lenses, surgery, and/or other supportive techniques may be used to help improve vision in some cases. Artificial teeth (dentures), dental implants, braces, dental surgery, and/or other corrective procedures may be used to correct dental abnormalities.
Structural airway problems associated with TCS can make it difficult for anesthesiologists to manage and maintain an airway during surgery. Proper evaluation including a comprehensive preoperative assessment and complete clinical history should be performed to best plan an anesthetic strategy.
In Tcof1, Polr1c and Polr1d animal models of TCS, p53 protein, which helps the body to kill off damaged, sick or unwanted cells, is abnormally activated, leading to the loss of cranial neural crest cells and consequently the craniofacial bone and cartilage features characteristic of TCS. Researchers are exploring ways to inhibit p53 function or block the mechanisms that lead to p53 activation as possible therapeutic treatments to prevent the development of TCS. Recent advances in studies of animal models which mimic TCS in humans, indicate that dietary antioxidant supplementation may protect neural cells against damage during embryogenesis and facilitate normal craniofacial development. More research is necessary to determine the long-term safety and effectiveness of such approaches and what role they may play in the prevention of TCS or the treatment of individuals with TCS.
Some researchers are studying the use of stems cells found in fat tissue (adipose-derived stem cells) as an adjunct therapy for improved surgery outcomes in individuals with craniofacial disorders such as TCS. Initial results have shown that surgical outcomes may be improved using these stem cells to help stimulate regrowth of the affected areas. However, this therapy is experimental and controversial, and requires more research to determine its viability as a potential therapy.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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