Treacher-Collins syndrome: what is it, symptoms, treatment, prognosis

What is Treacher-Collins Syndrome?

Treacher-Collins Syndrome (abbr. STK, maxillofacial dysostosis) Is a rare genetic disorder characterized by distinctive anomalies of the head and face. Craniofacial abnormalities tend to cause underdevelopment of the malar complex, cheekbones, jaws, palate and mouth, which can lead to breathing and feeding difficulties. In addition, patients may have malformations of the eyes, including downward-sloping holes between the upper and lower eyelids (palpebral fissures) and abnormalities in the structures of the outer and middle ear, which can lead to loss of hearing.

Brain and behavioral abnormalities such as microcephaly and psychomotor delay are also sometimes seen in the syndrome. The specific symptoms and physical signs associated with STK can vary greatly. Some people may be so mildly affected that their condition may go undiagnosed, while others may develop serious, life-threatening complications.

Although STK primarily results from a change (mutation) in the gene TCOF1it is also associated with mutations in genes POLR1B, POLR1C or POLR1D. When TCOF1 and POLR1B the type of inheritance is autosomal dominant (a type of inheritance in which a genetically determined disease manifests itself if a person has at least one corresponding "defective" gene, and this gene is not contained in the sex (X and Y) chromosomes), while POLR1C inherited in an autosomal recessive manner (a type of inheritance in which a genetically determined disease manifests itself in both only if the "defective" gene was inherited from both parents and is not contained in the sex (X and Y) chromosomes). On the contrary, a mutation in a gene POLR1D, can be both autosomal dominant and autosomal recessive.

The syndrome is named after Edward-Treacher-Collins, a London ophthalmologist who first described the disorder in the medical literature in 1900. STK is also known as maxillofacial dysostosis or Treacher-Collins-Franceschetti syndrome.

Signs and symptoms

The symptoms and severity of Treacher-Collins syndrome can vary greatly from one person to another, even among members of the same family. In some people, symptoms may be mild, others may be severely impaired and potentially life-threatening respiratory complications. It is important to note that affected individuals will not have all of the symptoms discussed below.

The main characteristic features of STCs encompass certain bones of the face, ears, and soft tissue around the eyes. Affected people have distinctive facial features and could potentially have hearing and vision problems. STK abnormalities are usually symmetrical (nearly identical on both sides of the face) and present at birth (congenital). Speech and language development can be impaired by hearing loss, cleft palate or jaw and airway problems. They usually do not affect intelligence, but brain and behavioral abnormalities such as microcephaly and cognitive delay are common.

Children with the syndrome have underdevelopment or lack of cheekbonescausing this area of ​​the face to appear flat or sunken. The bone of the lower jaw does not develop completely (hypoplasia of the lower jaw), as a result of which the chin and lower jaw look abnormally small (micrognathia). Some bony structures (such as coronal and condyloid processes) that connect portions of the mandibular bone to muscle may be unusually flat or absent. Affected children may also experience underdeveloped throat (hypoplasia of the pharynx). Pharyngeal hypoplasia with underdevelopment of the lower jaw (hypoplasia of the lower jaw) and / or abnormal smallness of the jaw (micrognathia) can contribute to eating problems and / or breathing difficulties (respiratory distress) in early childhood. Children may experience obstructive sleep apnea, which is characterized by repeated short-term disturbances in normal breathing and air movement during sleep. Some people with severe injuries may have life-threatening breathing problems.

Additional disorders that can contribute to breathing or feeding difficulties include narrowing or obstruction of the nasal airways. Some children may have signs of "Pierre Robin sequence"which include severe micrognathia, a tongue that is displaced further back in the mouth than usual (glossoptosis), with or without incomplete closure of the roof of the mouth (cleft palate). Even in patients where the palate is fused, it can remain bulging, which can affect nutrition and breathing. In addition, malformations of the mouth and jaw can lead to dental abnormalitiessuch as malocclusion. Additional dental abnormalities have also been reported, including missing teeth.

People with STK may develop hearing loss due to the inability of sound waves to pass through the middle ear (conductive hearing loss). Conductive hearing loss usually occurs due to abnormalities affecting structures in the middle ear, and people with STC may also have malformed or missing bones, three small bones through which sound waves are transmitted to the middle ear. In addition, the outer ear structures are often missing. The outer ears can be crumpled or twisted. In contrast, the inner ear is usually unaffected, although malformation of the bony spiral organ has been reported during inner ear (cochlea) and structures in the inner ear that play a role in balance (vestibular apparatus). Additional symptoms may include the presence of small skin bumps or pits just in front of the outer ear (preauricular marks) and an abnormal passage that is closed at one end (blind fistula), which is usually pulls the ears to the nose.

Many children with STK have abnormalities of the tissues surrounding the eyes. These differences in eyes can give affected patients a sad facial appearance. The most common eye symptom is tilting downward toward the opening between the upper and lower eyelids (palpebral fissures). Additional symptoms include a notch of the lower eyelid or a cleft of missing eyelid tissue (eyelid coloboma), partial absence of eyelashes on the lower eyelid, strabismus and narrowed tear ducts (dacrostenosis). Malformations of the eyeball are sometimes observed, which may include an incision or cleft in missing tissue in the iris or abnormally small eyes (microphthalmia). Some patients may experience loss of vision. The degree of visual impairment varies with the severity and combination of ocular abnormalities. Breach of the lower eyelid can lead to dry eyes, which increases the risk of chronic irritation and eye infections.

Approximately 5% of people with STK have developmental deficits or neurological problemssuch as psychomotor delay. However, intelligence usually does not affect the normal development of the language. However, speech development problems can arise from hearing loss, cleft palate, or difficulty making sounds due to structural distortion. Some patients with STK have additional physical deviationssuch as wide-set eyes, upper eyelid notch, deformity of the nose, abnormally wide mouth (macrostomy), unusual hair growth on the head towards the cheeks, congenital heart defects and / or gastrointestinal developmental defects.

Causes

STK is caused by a gene mutation TCOF1, POLR1B, POLR1C or POLR1D. In case of gene mutation TCOF1 the mode of inheritance is autosomal dominant, although very rare cases of autosomal recessive mutations have been observed. Mutations POLR1B are autosomal dominant, while POLR1C they are autosomal recessive and mutations POLR1D may be autosomal dominant or autosomal recessive.

Genetic diseases are defined by a combination of genes for a specific trait, which are found on chromosomes received from the father and mother. Dominant genetic disorders occur when only one copy of an abnormal gene is needed for a disease to appear. For TCOF1, POLR1B and POLR1D the abnormal gene can be inherited from either parent, or it can be the result of a new mutation (spontaneous gene change) in the affected person. In about 60% of patients with Treacher-Collins syndrome, the mutation is new, which occurs accidentally (spontaneously) without a previous family history of the disease (de novo mutation). However, parents may also be mildly affected and unaware that they have the disorder. The risk of passing the abnormal gene from the affected parent to the offspring is 50% with every pregnancy. The risk is the same for both male and female children. Regardless of whether the mutation is inherited from the mother or father, it does not appear to be relevant to the severity of the STK condition in their children.

Recessive genetic disorders (for example, STK caused by mutations POLR1C or POLR1D) occur when a person inherits the same abnormal gene for the same trait from each parent. If a person receives one normal gene and one gene for the disease, the person will carry the disease but usually show no symptoms. The risk for two carrier parents to pass on both defective genes and therefore give birth to a sick child is 25% with each pregnancy. The risk of conceiving a child who will be a carrier, like a parent, is 50% with every pregnancy. The chance for a child to receive normal genes from both parents and be genetically unaffected for this particular disease is 25%.

Gene mutations TCOF1 cause the majority (approximately 80%) of Treacher-Collins syndrome cases. TCOF1 contains instructions that encode (create) a protein known as treacle. The exact role that protein plays treacle in the development of STK is not fully understood. Researchers have determined that treacle plays a role in creating certain small structures in cells that collect proteins (ribosomes). This is especially important for the formation of a group of cells called neural crest cells, which are formed very early during embryonic development and give rise to most of the bone and cartilage underlying under the face.

Conditions that arise due to defects in the formation (biogenesis) of ribosomes are called ribosomopathies. POLR1B encodes a subunit of RNA polymerase 1, while POLR1C and POLR1D encode subunits of RNA polymerase I and III, each of which is also important for ribosome biogenesis. It is likely that mutations in TCOF1, POLR1B, POLR1C and POLR1D cause insufficient protein assembly and prevent certain cells of the nervous system and neural crest from meeting their needs for proliferation and growth during embryo development. Because STKs vary widely, researchers suggest that additional genetic and possibly environmental factors may also play a role in the varying severity of the disease. In support of this concept, recent experimental data have shown that protein treacle plays a critical role in protecting against oxidative stress-induced DNA damage in nerve cells, and also in the orientation of the ridge during the division of nerve cells, which subsequently affect the development of the head and faces.

Affected populations

Treacher-Collins syndrome affects both men and women in equal numbers. The estimated prevalence is between 1 in 10,000-50,000 in the general population. Some people with mild disease may not be diagnosed, making it difficult to determine the true frequency of the disorder in the general population. Therefore, it is strongly recommended that the parents of the child and possibly the siblings of the child suffering from STK due to a mutation in the genes TCOF1, POLR1B, POLR1C or POLR1Dhave been tested even if they seem healthy. This is important for future family planning. It should not be assumed that the mutation in a sick child occurred spontaneously, simply because the parents do not have facial differences. However, it should be noted that some people (approximately 10-15%) with the features and physical signs of STK do not have mutations in either one of the four aforementioned genes, suggesting that additional, not yet identified genes may also cause STK.

Diagnostics

Diagnosis of STK is based on careful clinical evaluation, detailed patient history, and identification of characteristic physical signs. Many associated abnormalities are present at birth, such as malformations or the absence of the outer ear.

- Clinical testing and examination.

Specialized X-ray examinations will confirm the presence and / or extent of certain observable craniofacial abnormalities. For example, such visual studies show an abnormal smallness of the jaw (micrognathia) due to underdevelopment of the bone of the lower jaw (hypoplasia of the lower jaw), the presence of and / or the degree of hypoplasia affecting certain parts of the skull and / or the presence of additional ear malformations that cannot be seen during clinical evaluation.

In addition, in those with few signs, a thorough clinical examination and radiography of the craniofacial area may demonstrate the subtle presence of certain characteristic features (eg, hypoplasia of the zygomatic arch) associated with syndrome. Because Treacher-Collins syndrome has several physical features that can occur with other craniofacial syndromes, many researchers recommend that diagnostic confirmation be done through molecular genetic testing and / or, in some cases, thorough, detailed family history.

Molecular genetic testing to confirm the diagnosis is available in commercial and academic research laboratories to detect mutations in genes TCOF1, POLR1B, POLR1C and POLR1D. Approximately 80% of people have an identifiable gene mutation TCOF1. In addition, genetic confirmation TCOF1, POLR1B, POLR1C or POLR1D mutations can be detected before birth (prenatally) by amniocentesis and chorionic villus sampling if the mutation has been identified in an affected family member. In some cases, fetal ultrasound, which uses reflected sound waves to imaging a developing fetus may reveal characteristic features that indicate the presence of STC in child. Relatives, especially parents and siblings, of individuals diagnosed with STK should be carefully evaluated, as mild cases often go unrecognized and undiagnosed.

Standard treatments

There is no cure for Treacher-Collins syndrome. Treatment focuses on the specific symptoms that each person experiences. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, ear, nose and throat specialists (pediatric otolaryngologists), pediatric dentists, nurses, plastic surgeons, speech therapists, audiologists, ophthalmologists, psychologists, geneticists and other healthcare professionals may need to systematically and comprehensively plan treatment for a child affected by disease.

Doctors routinely monitor individuals with STS for specific abnormalities that may be associated with the disorder. For example, a patient with STK should be closely monitored for any signs of hearing loss. An infant's hearing assessment is critical and a full assessment should be done at an early age, even before one year of age, and then annually thereafter to ensure proper speech development.

An instrument (ophthalmoscope) is used to visualize the inside of the eye to detect any possible visual impairment. This examination is important to ensure appropriate preventive measures and / or prompt treatment for patients in whom there are abnormalities in the eyes due to Treacher-Collins syndrome (for example, colobomas, strabismus, microphthalmia). Affected people should also be monitored for jaw and dental abnormalities.

Early intervention is essential to ensure that affected children reach their potential. Special services that may be helpful include speech therapy, special social support, and other medical, social, and / or professional services.

Forecast

Typically, people with Treacher-Collins syndrome become full-fledged adults with normal intelligence. With proper handling and treatment of a child, life expectancy is about the same as that of the general population. In some cases, the prognosis depends on the specific symptoms and the severity of the patient. For example, very severe cases of STK can cause perinatal death due to respiratory failure.