Information on the following diseases can be found in the Related Disorders section of this report:

• Mandibulofacial Dysostosis, Treacher Collins Type, Autosomal Recessive
• Nager Syndrome (Acrofacial Dysostosis, Treacher Collins Type, with Limb Anomalies)
• Miller Syndrome
• Hemifacial Microsomia
• Goldenhar Syndrome
• Oculoauriculovertebral (OAV) Spectrum
• Maxillofacial Dysostosis
• .
• NORD wishes to thank John Mulliken, M.D., of Harvard Medical School and The Children's Hospital in Boston, for assistance in updating this report during the fall of 1999.

The symptoms and severity of Treacher Collins syndrome vary dramatically from case to case. Some individuals may have a very mild form that goes undiagnosed; others may have significant abnormalities and the potential for life-threatening respiratory complications.

The major features of Treacher Collins syndrome are distinctive abnormalities of the craniofacial region, eye abnormalities, structural abnormalities of the ears, and hearing loss. The abnormalities of Treacher Collins syndrome are symmetric (almost identical on both sides of the face). Symptoms are present at birth (congenital). Intelligence is usually unaffected.

Infants with Treacher Collins syndrome exhibit underdeveloped (hypoplastic) or absent cheekbones (malars), causing this area of the face to appear sunken or depressed. 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). In some infants with Treacher Collins syndrome, this 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 (neonatal period). Older infants and young children may experience repeated interruptions of normal breathing rhythm during sleep (obstructive sleep apnea). 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 may occur that contribute to respiratory or feeding difficulties including narrowing or obstruction of the nasal airways (choanal stenosis or atresia) or an abnormally large tongue (glossoptosis). Affected infants may also have an abnormally large mouth (macrostomia), incomplete close of the roof of the mouth (cleft palate), and an abnormally short, absent or immobile soft palate. The soft palate, the flap of fibrous tissue and muscle that leads into the throat, normally presses against the rear portion of the throat during swallowing, preventing food from entering the nose. As a result, abnormalities of the palate may cause feeding problems in some children with Treacher Collins syndrome. In addition, malformations of the palate and the jaw may result in dental abnormalities in many cases, such as teeth that are widely spaced, 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 Treacher Collins syndrome may develop hearing loss due to 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. Affected infants often 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 some cases, the entire middle ear cavity may be absent and may be replaced by connective tissue.

Most affected infants have abnormalities of external ear structures as well. Affected infants may have absent, small or malformed ears (microtia), with narrowing (stenosis) or blockage (atresia) of the external ear canals. The outer ears may be crumpled or rotated. Structures of the inner ear are 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 connects the external ears and the mouth.

Many infants with Treacher Collins syndrome have abnormalities of the eyes. The most common ocular symptom is an abnormal downward slant to the opening between the upper and lower eyelids (palpebral fissures). Additional symptoms include widely spaced eyes (hypertelorism), a notch or cleft of missing tissue (coloboma) on the lower eyelid, partial absence of eyelashes on the lower eyelid, a notch or cleft of missing tissue of the iris, abnormally small eyes (microphthalmia), and crossed eyes (strabismus). Vision loss may occur in some case. The degree of visual impairment varies depending upon the severity and combination of ocular abnormalities.

Some individuals with Treacher Collins syndrome exhibit additional physical abnormalities such as an unusually narrow face; narrow nostrils and a raised nasal bridge; a highly-arched roof of the mouth (palate), an abnormal groove in the upper lip (cleft lip), and/or unusual growth of the scalp hair toward the cheeks.

In approximately 60 percent of cases, no positive family history of Treacher Collins syndrome can be identified. These cases most likely represent a new genetic change (mutation) that occurs randomly, for no apparent reason (sporadically).

The Treacher Collins syndrome mutation is inherited as an autosomal dominant trait. 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. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. 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.

Investigators have determined that the mutations of the treacle (TCOF1) gene, located on the long arm of chromosome 5 (5q32-q33.1), cause Treacher Collins syndrome. 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-q33.1" refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

TCOF1 is the only gene to have been identified that causes Treacher Collins syndrome. It carries instructions to create (encode) a protein known as treacle. Treacle plays a role in the formation and accumulation (proliferation) of neural crest cells in the body. Neural crest cells may develop into a wide variety of different cell types during vertebrate development. In the head, neural crests cells develop into cartilage and bone and are extremely important for proper craniofacial formation. Researchers believe that defects in the formation, accumulation, spread and development into other cell types (differentiation) of neural crest cells cause craniofacial abnormalities. Mutation of the TCOF1 gene results in deficiency or defective development of treacle, which researches believe results in problems with the formation or accumulation of neural crest cells. (For more information see the investigational therapies section below.)

In most cases, an individual with the defective TCOF1 gene will exhibit the classic physical malformations of Treacher Collins syndrome (high penetrance). However, the physical findings that develop may vary greatly in severity from case to case (variable expressivity).

Treacher Collins syndrome affects males and females in equal numbers. More than 400 cases have been reported in the medical literature, including some affected individuals within several large, multigenerational families (kindreds). The prevalence is estimated to be between 1-10,000 and 1 in 50,000. Some mildly affected individuals may go undiagnosed, making it difficult to determine the disorder’s true frequency in the general population.

Symptoms of the following disorders can be similar to those of Treacher-Collins syndrome. Comparisons may be useful for a differential diagnosis.

Nager syndrome (also known as acrofacial dysostosis, Treacher Collins type with limb anomalies) is a rare inherited disorder characterized by craniofacial malformations similar to those in Treacher Collins syndrome occurring in association with abnormalities of the arms, hands, and/or feet. Craniofacial malformations include underdevelopment of the cheekbones (malar hypoplasia); incomplete development of the lower jaw (mandibular hypoplasia), causing the jaw to appear abnormally small (micrognathia); hypoplastic and/or malformed (dysplastic) external ears (pinnae) and blind ending or absent external ear canals (microtia), resulting in hearing impairment (conductive hearing loss); and/or downwardly slanted palpebral fissures, lack or absence of the lower eyelashes, and/or drooping upper eyelids (ptosis). Limb abnormalities include underdevelopment or absence of the thumbs, absence of one of the bones in the forearms (radius), abnormal fusion of bones in the forearms (radioulnar synostotis), permanent flexion of certain fingers (camptodactyly), and/or webbing of the toes (syndactyly). In most cases, Nager syndrome appears to occur randomly, for no apparent reason (sporadic). In other cases, researchers suggest that the disorder may be inherited as an autosomal dominant or recessive trait. (For more information on this disorder, choose "Nager" as your search term in the Rare Disease Database.)

Miller syndrome (also known as postaxial acrofacial dysostosis) is a rare inherited disorder characterized by craniofacial malformations occurring in association with abnormalities of the arms, hands, and/or feet. Craniofacial malformations include underdevelopment of the cheekbones (malar hypoplasia); an abnormally small lower jaw (micrognathia); incomplete closure of the roof of the mouth (cleft palate); small, protruding, "cup-shaped" ears; and/or absence of tissue (colobomas) from the lower eyelids. Limb abnormalities may include incomplete development (hypoplasia), webbing (syndactyly), and/or absence of certain fingers and/or toes; improper positioning of certain toes; and/or improper development and/or abnormal fusion of bones in the forearms (radioulnar synostosis), causing the forearms to appear unusually short. Additional physical abnormalities can occur in some cases. Miller syndrome is thought to be inherited as an autosomal recessive trait. (For more information on this disorder, choose "Miller" as your search term in the Rare Disease Database.)

Hemifacial microsomia is a rare disorder characterized by craniofacial abnormalities involving the jaws, mouth, and ears in addition to extra cranial anomalies of the cardiac, skeletal, renal systems, and extremities (HFM with expanded spectrum). Many researchers consider Goldenhar syndrome a variant and subgroup of hemifacial microsomia. In the medical literature, hemifacial microsomia and Goldenhar syndrome are often grouped together under the term "Oculoauriculovertebral (OAV) Spectrum." Most cases occur randomly, with no apparent cause (sporadic). In other cases, there has been a positive family history that, according to some researchers, appears to suggest autosomal dominant inheritance. The physical features associated with hemifacial microsomia OAV Spectrum vary dramatically from case to case. Such features tend to involve one side of the body (unilateral) and may represent varying combinations of certain abnormalities. These include underdevelopment of the cheekbones, the upper jaw, and the lower jaw (malar, maxillary, and mandibular hypoplasia); underdevelopment of certain muscles in the face; abnormalities of the tongue, incomplete closure of the roof of the mouth (cleft palate), and/or an abnormal groove in the lip (cleft lip); malformed external ears (pinnae) with blind ending or absent external ear canals (microtia), resulting in hearing impairment (conductive hearing loss); abnormal outgrowths of skin on the ears (skin tags); and/or incomplete development of certain bones in the spinal column (vertebral hypoplasia). Additional abnormalities include partial or total absence of tissue (coloboma) from the upper eyelids, crossed eyes (strabismus), and/or abnormally small eyes (microphthalmia); heart (cardiac) defects; kidney (renal) abnormalities; and/or additional physical abnormalities. The two keys in differentiating TCS from HRM are: 1)Treacher Collins syndrome is symmetrical; and 2)Treacher Collins syndrome does not affect the nerve. (For more information on this disorder, choose "OAV Spectrum" as your search term in the Rare Disease Database.)

A diagnosis of Treacher Collins syndrome 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). 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.

Treacher Collins syndrome can be detected before birth (prenatally) by ultrasonography. In fetal ultrasonography, reflected sound waves create an image of the developing fetus, revealing characteristic findings suggestive of Treacher Collins syndrome.

In addition, in those affected individuals who exhibit few signs, a thorough clinical examination and x-ray imaging tests of the craniofacial area can demonstrate the subtle expression of certain characteristic features (e.g., hypoplasia of zygomatic arches) associated with Treacher Collins Syndrome. Because Treacher Collins Syndrome shares several physical features that may occur in other craniofacial syndromes, many researchers suggest that stronger diagnostic confirmation be made through molecular genetic testing and/or, in some cases, a careful, detailed family history. (For more information concerning genetic testing, see the Investigational Therapies section below.)

Treatment
The treatment of Treacher Collins syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, head and neck surgeons, dental specialists, speech pathologists, specialists who asses and treat hearing problems (audiologists), specialists who asses and treat hearing problems (ophthalmologists) eye specialists, ear, nose and throat specialists (otolaryngologists) and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.

In some cases, 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.

Surgery may also be necessary to correct respiratory difficulties. A tube may be surgically inserted into the windpipe (trachea) to maintain an effective airway, a procedure called a tracheostomy. A tube may be surgically implanted into the stomach to assure that affected infants experiencing feeding difficulties receive a sufficient amount of calories (gastrostomy).

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 may suffice rather than surgery in most cases. 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 Treacher Collins syndrome. Reconstructive surgery may be performed to help correct outer ear malformations. However, artificial devices (prostheses) may be preferred some affected individuals.

In individuals with Treacher Collins syndrome 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.

Physicians regularly monitor individuals with Treacher Collins syndrome 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. Early recognition of potential hearing loss may play an essential role in ensuring prompt intervention and appropriate, early correction or supportive treatment.

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 Treacher Collins syndrome (e.g., colobomas strabismus, microphthalmia). Affected individuals should also be monitored for 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 addition, thorough clinical evaluation is important in other family members of diagnosed individuals to detect any signs or physical characteristics that may be potentially associated with Treacher Collins syndrome.

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.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

Researchers at the Stowers Institute for Medical Research in Kansas City, Missouri, collaborated with colleagues at the University of Manchester Dental School in the United Kingdom (UK) on a study identifying the cellular origins for craniofacial abnormalities that occur in Treacher Collins syndrome. In September 2006, the lab team of Paul Trainor, PhD, with colleagues in the U.K., published a paper in the Proceedings of the National Academy of Sciences. They concluded that the head and facial characteristics associated with a mouse model of Treacher Collins syndrome arose as a result of a high degree of cell death, leading to a failure to produce sufficient neural crest cells. These are the cells that ultimately form most of the bone, cartilage and connective tissue in the head and face. If translated to human development, these findings may indicate that findings associated with Treacher Collins syndrome occur as a result of a period of extensive cell death early in pregnancy (during the first three to eight weeks) that results in failure to produce enough neural crest cells. This research is continuing in the hope that it will lead to increased understanding of how this syndrome occurs and, ultimately, how it may be prevented.

Due to the discovery and characterization of the faulty gene responsible for Treacher Collins syndrome, researchers are able to work on developing tests that will aid in more accurate prenatal and postnatal diagnosis of affected individuals. This includes diagnosis of individuals with even minor signs of the disorder that may not be apparent during clinical and radiological evaluation. However, it is important to note that, to date, the specific genetic mutation of the faulty gene for Treacher Collins syndrome has been different in every affected family. Therefore, although more accurate diagnosis will be possible in those cases where the specific genetic mutation has been identified, identification is more difficult in families affected by unidentified mutations. Researchers within the team that identified the faulty gene (the Treacher Collins Syndrome Collaborative Group) are continuing their work to characterize additional mutations responsible for Treacher Collins syndrome.

TEXTBOOKS
Wulfsburgh EA. Treacher Collins Syndrome. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:262-3.

Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Syndromes of the Head and Neck. 4th ed. Oxford University Press, New York, NY; 2001:649-51.

Jones KL, Smith's Recognizable Patterns of Human Malformation, 5th ed. Philadelphia, PA: W. B. Saunders Company; 1988:250, 642-45.

JOURNAL ARTTICLES
Dixon J, Jones NC, Sandell LL, et al., TCOF1/Treacle is required for neural crest cell formation and proliferation deficiencies that cause craniofacial abnormalities. Proc Natl Acad Sci. 2006;103:13403-8.

Kobus K, Wojcicki P. Surgical treatment of Treacher Collins syndrome. Ann Plast Surg. 2006;56:549-54.

Teber OA, Gillessen-Kaesbach G, Fischer S, et al., Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation. Eur J Med Genet. 2004;12:879-90.

Marszalk B Wojcicki P, Kobus K, Trzeciak WH. Clinical features, treatment and genetic background of Treacher Collins syndrome. J Appl Genet. 2004;43:223-33.

Dixon J, Ellis I, Bottani A, Temple K, Dixon MJ. Identification of mutations in TCOF1: use of molecular analysis in the pre- and postnatal diagnosis of Treacher Collins syndrome. Am J Med Genet A. 2004;127:244-8.

Toriello HV. Treacher Collins syndrome. Ear Nose Throat J. 1999;78:752

Marsh KL, Dixon J, Dixon MJ. Mutations in the Treacher Collins syndrome gene lead to mislocalization of the nucleolar protein treacle. Hum Mol Genet. 1998;112:1795-800.

Dixon MJ. Treacher Collins syndrome: from linkage to prenatal testing. J Laryngol Otol. 1998;112:705-09.

The Treacher Collins Syndrome Collaborative Group. Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome. Nat Genet. 1996;12:130-36.

ON THE INTERNET
Katsanis SH, Cutting GR. Updated:10/27/2006. Treacher Collins Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:154500; Last Update:05/05/2005. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=154500 Accessed on: June 19, 2007.