About treacher collins syndrome

What is treacher collins syndrome?

Treacher Collins syndrome (TCS) is a rare genetic disorder characterized by distinctive abnormalities of the head and face area resulting from underdevelopment (hypoplasia) of certain facial structures including the jaw, cheekbones and nearby structures (zygomatic complex). Craniofacial abnormalities tend to involve the cheekbones, jaws, mouth, ears, and/or eyes. In addition to the various facial abnormalities, affected individuals may have malformations of the external ears and middle ear structures and eye (ocular) abnormalities including an abnormal downward slant to the opening between the upper and lower eyelids (palpebral fissures). Affected individuals may develop hearing loss and breathing (respiratory) difficulties. Furthermore, 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 have mild symptoms and go undiagnosed, while others may develop serious, life-threatening respiratory complications. TCS is caused by a mutation in the TCOF1, POLR1C or POLR1D genes. In the case of TCOF1 or POLR1D, the mode of inheritance is autosomal dominant, while in the case of POLR1C it is autosomal recessive.

TCS 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.

What are the symptoms for treacher collins 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. 

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). Even in patients where the palate fuses, it may remain high arched which can still affect feeding and respiration. 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.

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. Some individuals with TCS exhibit additional Physical abnormalities such as widely spaced eyes, notching of the upper eyelid, nasal deformity, an abnormally wide mouth (macrostomia), unusual growth of the scalp hair toward the cheeks, congenital Heart defects and/or gastrointestinal malformation.

What are the causes for treacher collins syndrome?

TCS is caused by mutation of the TCOF1, POLR1B, POLR1C or POLR1D genes. In the case of TCOF1 the mode of inheritance is autosomal dominant, although very rare cases of autosomal recessive mutations have been observed. Mutations in POLR1B are autosomal dominant, whereas in POLR1C they are autosomal recessive, and for POLR1D, 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, POLR1B and POLR1D, the abnormal gene can be inherited from either parent, or can be the result of a new mutation (spontaneous gene change) in the affected individual. In approximately 60% of TCS patients, the mutation is a new mutation that occurs randomly (spontaneously) 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. The risk is the same for male and female children. Irrespective of whether the mutation is inherited from the mother or father, it appears to have no bearing on severity of the TCS condition in their 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%.

Mutations of the TCOF1 gene cause most (approximately 80%) cases of TCS. 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. POLR1B encodes a subunit of RNA polymerase 1, whereas POLR1C and POLR1D encode subunits of RNA polymerases I and III, each of which are also essential for ribosome biogenesis. It seems likely that mutations in TCOF1, POLR1B, POLR1C and POLR1D cause insufficient protein assembly and do not allow specific neural and neural crest cells to meet their proliferation and growth needs 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.

What are the treatments for treacher collins syndrome?

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 and a full assessment should be done early during life, even before one year of age and then yearly, 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 include speech therapy, special social support, and other medical, social, and/or vocational services.

Genetic counseling is recommended for affected individuals and their families.

Surgery 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 sufficient calories (gastrostomy).

Multiple surgeries may be required to treat the various craniofacial abnormalities that are 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.

Additional Therapies 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.

Anesthesia Considerations 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.

What are the risk factors for treacher collins syndrome?

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. It is therefore highly recommended, that the parents and perhaps siblings of a child affected with TCS in association with a mutation in TCOF1, POLR1B, POLR1C or POLR1D, be tested even if they appear unaffected. This is important for future family planning. It should not be assumed that the mutation in an affected child occurred spontaneously, just because each parent exhibits no facial differences. However, it should be noted that some individuals (approximately 10-15%) with the features and physical findings of TCS do not have mutations in any of the four above mentioned genes, suggesting that additional as yet unidentified genes may also cause TCS.

Is there a cure/medications for treacher collins syndrome?

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.

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