Treacher Collins syndrome is a genetic (sometimes hereditary) disease accompanied by deformities of the bones and soft tissues of the face. The symptoms include gross defects in the structure of the face: anti-mongoloid eye incision, eyelid tissue clippings (colobomas), reduced jaw and cheekbones, hypoplasia and anomalies of ear structures, cleft or arched palate, enlarged mouth slit and tongue, underdeveloped facial bones. The diagnosis is established according to clinical examination, biogenetic test and family history. Treatment is symptomatic, aimed at improving hearing, eliminating life-threatening deformities and cosmetic defects surgically.
Q75.4 Maxillofacial dysostosis
Treacher Collins syndrome has several synonyms: maxillofacial dysostosis, Treacher Collins-Franceschetti syndrome, mandibulofacial dysostosis. The pathology was first described by an ophthalmologist from the UK, Edward Treacher Collins, in 1900, so the most common name corresponding to his name. An extensive review of the disease was made in 1949 by European researchers E. Franceschetti and D. Klein. Currently, the concept of “Treacher Collins syndrome” is more common in the UK and the USA, and the term “Franceschetti-Klein syndrome” is more commonly used in European countries. The epidemiology of the disease is 1:50,000. The incidence is the same among boys and girls.
The development of the syndrome in 78-93% of cases is caused by mutations of the TCOF1 gene located on the fifth chromosome in the 5q32 region. This gene encodes the production of the nuclear phosphoprotein Treacle. In 7-9% of patients, the cause of the disease is a defect in the POLR1C gene localized on the sixth chromosome, or the POLR1D gene located on the thirteenth chromosome. They are responsible for the synthesis of RNA polymerase I and III.
With mutations in the TCOF1 gene, the type of inheritance of the syndrome is autosomal dominant with a penetration rate of 90%. This means that with a mutation in one chromosome from a pair, the probability of the disease is very high. A sick parent has a 50% risk of having a child with Treacher Collins syndrome. Hereditary transmission of the defect and sporadic genetic changes (new mutations) are possible. The expressiveness of the mutation is variable – within one family, both weakening and strengthening of the symptoms of the disease in subsequent generations is likely. With defects in the POLR1C and POLR1D genes, inheritance occurs according to an autosomal recessive type. In couples where the parent has the syndrome, the probability of having a sick baby is 25%.
The fifth chromosome is responsible for the correct formation of the skeleton during intrauterine development. The TCOF1 gene localized in it encodes the structure and synthesis of the nuclear transport protein Treacle. This protein is expressed in most body tissues in the embryonic and postembryonic period, participates in the transfer of genetic information from DNA to RNA.
The syndrome is most often based on a nonsense mutation that leads to the formation of a premature termination codon and the development of haplon-sufficiency – a protein deficiency necessary for the normal formation of the facial part of the skull. A healthy gene provides the body with Treacle protein by half, but this amount is not enough for the proper development of facial structures. With changes in the POLR1D and POLR1C genes, the DNA transcription process is disrupted due to the insufficiency of the DNA-dependent RNA polymerase catalyst enzyme. The clinical manifestations of the syndrome are the same as with primary Treacle protein deficiency.
Patients have anomalies in the structure of the face. A common sign occurring in 80% of cases is bilateral symmetrical hypoplasia of the zygomatic bones, the infraorbital margin and the mandible. Externally, this is manifested by a kind of flattened shapeless face, on which the nose stands out, and the rest of the parts are “drowned” in soft tissues. Deformity of the jaw causes malocclusion, the formation of orthognathia (constantly open mouth). 89% of patients have a limited possibility of opening the mouth and an anti-mongoloid type of eye incision with a noticeable omission of the outer corner. These features are partly due to the pathological structure of the temporomandibular joint.
In 69% of patients, a coloboma of the iris and lower eyelids is determined in the interval between the middle and outer third, more often it has a triangular shape. There are no eyelashes on the outer edge of the lower eyelid. The palate is arch-shaped, sometimes a cleft is formed (in 28% of patients). Anomalies of the outer ear are represented by underdevelopment or complete absence of the auricle (microtia, anotia), atresia of the external auditory canal and deformation of the auditory ossicles. Often patients have conductive hearing loss. In rare cases, enchondroma, precancerous fistulas, abnormal structure of the heart and spine are diagnosed.
Micrognathia and stenosis of the upper respiratory tract in the first years of life can provoke problems with eating and breathing difficulties up to suffocation. Timely diagnosis of the disease allows you to predict these complications and take measures to prevent them. As a rule, patients do not have congenital intellectual disorders, but in the absence of correction of hearing disorders, it becomes impossible to correctly form speech and learn under normal conditions. Children begin to lag behind their peers in mental development, have mental retardation of varying degrees of severity. Due to the presence of defects in appearance and the negative attitude of others, patients of all ages belong to the risk group for depression, hypochondria, anxiety and other neurotic disorders.
The diagnosis can be made during pregnancy or immediately after birth. The examination is indicated for women at risk and children with congenital facial deformities. Geneticists and pediatricians take part in the diagnostic process. Treacher-Collins syndrome needs to be differentiated from other genetic diseases in which there is a deformation of the facial part of the skull, for example, with Nager syndrome and Goldenhar syndrome. The following methods are used:
- Examination, anamnesis collection. Characteristic craniofacial anomalies are determined: underdevelopment of the bones of the cheekbones and jaw, deformation and hypoplasia of the auricles, antimongoloid type of eye slits, hearing disorders and a defect of the upper palate. Sometimes one of the parents has a confirmed diagnosis of the syndrome.
- Biogenetic test. The antenatal study includes a molecular analysis of a sample of chorionic villi at 10-11 weeks of pregnancy, fetoscopy and blood analysis from placental vessels at 18-20 weeks. After delivery, blood is taken from the child’s vein. In both cases, the TCOF1 gene is being investigated. The disease is confirmed if there is a mutation of any type in it.
- Prenatal ultrasound. From 20-24 weeks of pregnancy, ultrasound examination of the fetus is able to detect typical facial changes. The most clearly visible bilateral anomaly of the ears, hypoplasia of the cheekbones and jaw.
Additionally, examinations are prescribed to detect life-threatening conditions in a timely manner, to assess the degree of deformation of the skull bones. The effectiveness of feeding the child, the level of hemoglobin saturation with oxygen, the rhythm and depth of breathing are determined. To diagnose the preservation of hearing on the 5th-6th day of life, audiological testing is carried out. Instrumental diagnostics includes skull x-ray, CT and MRI of the brain.
There is no specific therapy. Treatment is aimed at eliminating the symptoms and consequences of the disease, involves surgical operations and rehabilitation measures. The scope of procedures and the timing of their implementation are set individually, taking into account the presence of a threat to the patient’s life, contraindications and risks associated with surgical intervention. The general treatment regimen includes:
- Restoration of swallowing and breathing. With the development of respiratory distress syndrome, tracheostomy, distraction of the movable jaw, non-invasive ventilation of the lungs is performed. If it is impossible to consume food, a gastrostomy is installed.
- Hearing restoration. Deformity of the outer and middle ear is eliminated surgically, but hearing loss is more often caused by damage to the auditory small bones, therefore surgical interventions to eliminate hearing loss are ineffective. Rehabilitation with hearing aids is preferable.
- Elimination of external defects. Deformities are corrected by plastic and mandibular surgery. Liposculpture, surgical bone distraction, graft placement and surgical palate restoration are used.
Prognosis and prevention
Comprehensive treatment and rehabilitation significantly improve the quality of life of patients. With mild and moderate severity of the syndrome, the prognosis is favorable. Prevention is difficult because the disease is genetic, and mutations can occur spontaneously. Married couples in which one parent is ill need medical and genetic counseling and perinatal diagnosis of the syndrome in the early stages of pregnancy. To reduce the risk of carrying a sick child, an in vitro fertilization procedure with pre-selection of genetically healthy embryos is recommended.