Apert syndrome is a genetic disease characterized by disorders of the processes of ossification of the skull and related secondary disorders, as well as numerous malformations of the skeleton and limbs. Symptoms of this condition are dwarfism, the tower shape of the skull, an enlarged bridge of the nose, non-infection of the hard palate, syndactyly on the hands and feet. Diagnosis is made according to the characteristic clinical picture of the pathology, based on radiological data and molecular genetic studies. There is no specific treatment for the disease, supportive therapy is used, palliative surgical interventions are performed.
Apert syndrome (acrocephalosyndactyly type 1) is a genetic pathology caused by a violation of the formation of certain types of connective tissue, mainly bone. For the first time this condition was described in 1906 by the French pediatrician E. Apert, further studies confirmed the genetic nature of this disease. The etiology and molecular genetic mechanisms of the development of the Apert syndrome were determined much later – only in 1995. This pathology can be inherited by an autosomal dominant mechanism, but in the vast majority of cases it is caused by spontaneous mutations in the germ cells of the parents (so-called germinative mutations).
Apert syndrome affects both boys and girls with the same frequency, its occurrence is on average 1 case per 160,000-200,000 newborns. Geneticists currently attribute the Apert syndrome to a special group of hereditary diseases – acrocephalosyndactyly, characterized by simultaneous damage to the bones of the skull and limbs. The peculiarity of this pathology is its importance as an early diagnosis, since palliative measures at an early age can significantly affect the further intellectual development of the patient.
According to the latest scientific data, the Apert syndrome is caused by mutations of the FGFR2 gene located on chromosome 10. It encodes a protein-fibroblast growth factor receptor-2, which has a significant effect on the development of connective tissue cells, including bone. The significant size (20 exons) and the specific location of the gene make it vulnerable to various kinds of damage, which are then phenotypically manifested by hereditary diseases. In addition to the Apert syndrome, FGFR2 gene defects lead to the development of pathologies such as Beer-Stevenson syndrome, Pfeiffer syndrome, Setre-Chotzen syndrome, craniofacial-skeletal-dermatological dysplasia and a number of others. Therefore, studies of this gene are quite common in modern genetics.
As studies from 1995-2000 have shown, mutations in the region of exon 7 of the FGFR2 gene most often (in 96% of cases) lead to the development of the Apert syndrome. At the same time, the S252W mutation accounts for about 74-76% of all cases of the disease, and approximately 21-23% are caused by the P253R defect. Thus, the cause of the vast majority of cases of Apert syndrome are only two types of mutations, which simplifies the molecular genetic diagnosis of this condition. Since these defects relate to missense mutations, the receptor for fibroblast growth factor resulting from the translation of such a gene has a broken structure and is unable to perform its functions. This leads to a violation of the processes of ossification of the skull, in particular – to premature overgrowth of the sutures and stopping the normal growth of the skull. Receptor defect in Apert syndrome also causes malformations of other structures involving fibroblasts (large-caliber vessel walls, heart, facial skull bones, trachea). This condition is inherited by an autosomal dominant mechanism, but spontaneous mutations most often occur.
In addition, with Apert syndrome, there is an abnormal expression of the KGFR gene, also located on chromosome 10. It encodes the sequence of a protein that is a receptor for the keratocyte growth factor. No mutations or other disorders in the structure of KGFR in Apert syndrome were detected, only its excessive activity, leading to an increase in the number of receptors encoded by it. Perhaps this phenomenon is explained by complex gene relationships, or the receptor for fibroblast growth factor 2 has a suppressive effect on the KGFR gene. The result of abnormal expression of this gene are phenotypic disorders of limb formation – various forms of syndactyly, always found in the Apert syndrome, sometimes polydactyly.
Some manifestations of the Apert syndrome are noticeable from birth – for example, syndactyly, which can be complete or in the form of membranes. As a rule, 2, 3 and 4 fingers on the hands grow together, sometimes a similar defect occurs on the toes. Among neonatologists, the symptom is sometimes called the “middle finger” – in severe cases, these three fingers are firmly fused together and have one common nail. Another constant symptom of the Apert syndrome, which is found immediately after birth or in the first months of life, is the early development of synostosis of the skull bones. Most often, the fusion of the coronal or arrow-shaped suture occurs, which, as the brain grows, leads to deformation of the skull according to the “tower” type. Due to cranial synostosis, patients with Apert syndrome have a chronic increase in intracranial pressure, which causes mental retardation, headaches, nausea and vomiting.
In addition to the deformation of the skull, the presence of the Apert syndrome is evidenced by the characteristic appearance of patients. They usually have a flat or convex forehead, hypertelorism and exophthalmos, strabismus may develop. Deformities also affect the bones of the facial skull – the bridge of the nose is dilated, the jaws are often underdeveloped, there is a malocclusion. Of the other symptoms of the Apert syndrome, respiratory disorders are sometimes recorded (due to underdevelopment of the upper jaw, narrowing of the choan or trachea), non-infection of the hard palate, congenital heart defects, abnormalities of the vertebrae, kidneys, rectum.
In adults suffering from Aper syndrome, atrophy of the optic nerves may occur up to complete blindness. The intellectual development of patients often lags behind the age norm, but it is not known for certain whether this is due to genetic disorders or secondary factors (chronic intracranial hypertension). Dwarfism is almost always observed with Apert syndrome. With appropriate palliative treatment and care, patients can live to an advanced age, but the risk of sudden death due to lesions of the respiratory, nervous and cardiovascular systems is much higher than in the population.
Diagnosis of the Apert syndrome is made on the basis of examination and examination of the patient’s current status, X-ray studies, molecular genetic analyses. Upon examination, the patient reveals syndactyly (in older people, traces of its surgical correction may be found), a deformity of the skull – a tower skull or brachycephaly, a characteristic appearance of the face.
With age, patients with Apert syndrome may develop signs of respiratory disorders, with EchoCG, heart and vascular defects are often detected – stenosis of the pulmonary trunk or aorta, defects of the interventricular septum. Sometimes, against this background, signs of heart failure are revealed. It is also possible to have other malformations – vertebral anomalies, deafness, blindness (due to cataract, retinitis pigmentosa, optic nerve atrophy), kidney and pancreatic pathologies. Due to such a wide range of possible disorders, patients with Apert syndrome need a thorough and comprehensive medical examination.
X-ray techniques can already detect synostosis of the skull bones in the area of the coronal or arrow-shaped suture in young children. In the future, with the help of radiography, it is possible to determine the deformation of the cranial box characteristic of the Apera syndrome, malformations of the bones of the facial skull, vertebral anomalies and other disorders.
The most reliable diagnostic method for this condition is molecular genetic analysis. As a rule, to detect the Aper syndrome, the 7 exon of the FGFR2 gene is sequenced, sometimes less expensive techniques are used, focused only on finding the most common mutations (S252W and P253R) that lead to this disease. Such techniques are cheaper and faster to perform, have an accuracy of 95%, and can be used as a prenatal diagnosis of this condition. Such an analysis is especially relevant if, through preventive ultrasound, fetal disorders are detected, presumably associated with the Apert syndrome – malformations of the skull, heart, upper or lower extremities.
There is no specific treatment for Apert syndrome today, but palliative and symptomatic measures can significantly alleviate the patient’s condition and improve his quality of life. It is especially important to diagnose this disease as early as possible for the reason that timely surgical correction of cranial synostosis will avoid a significant increase in intracranial pressure. According to numerous data, after such operations performed in early childhood, the signs of mental disability in patients with Aper syndrome were much weaker, sometimes normal intelligence was preserved. Therefore, the fight against intracranial hypertension plays a central role in the palliative treatment of this condition. If patients have mental retardation, then its severity is reduced by psychocorrective work.
Another frequently performed palliative surgery for Apert syndrome is an intervention to separate fused fingers and toes. This is a relatively simple procedure for the webbed type of fusion, but with more severe forms of the defect, the operation becomes much more complicated. Apert syndrome may also require the help of surgeons in the case of heart defects, narrowing of the choan or trachea, disorders of the formation of the rectum and other manifestations of this genetic disease. Patients need regular medical examinations by specialists of various profiles.
Prognosis and prevention
The prognosis of Apert syndrome is uncertain due to a very wide range of manifestations and a significant range of their severity. The prognosis is also influenced by factors such as the timeliness of diagnosis of the disease, the volume of palliative and symptomatic treatment. With relatively mild cases of Aper syndrome or proper therapy of this condition, patients can live to an advanced age. At the same time, it is possible to reduce intelligence and disorders of new organs and systems that appear with age, which negatively affects the quality of life of patients. In severe cases, there is a fatal outcome in early childhood due to congenital heart defects or multiple organ failure.
Prevention of Apert syndrome is possible only as a prenatal diagnosis, which can be performed both by ultrasound techniques and by molecular genetic analysis. Usually, manifestations of pathology are first detected on preventive ultrasound, and then the diagnosis is confirmed by a geneticist. If this condition can be detected in the early stages of pregnancy, then the question of its termination is raised.