Crouzon syndrome is a rare genetic disease accompanied by progressive deformities of the facial and cerebral part of the skull and craniosynostosis with the development of concomitant disorders. Symptoms of this condition are a change in the shape of the head (brachycephaly, scaphocephaly, trigonocephaly), a hooked nose, hypoplasia of the middle third of the face, visual and hearing impairments. Diagnosis of Crouzon syndrome is carried out on the basis of external manifestations of the disease, radiological data, as well as molecular genetic analyses. There is no specific treatment for this pathology, palliative and symptomatic measures, including surgical ones, are used.
General information
Crouzon syndrome (craniofascial dysostosis type 1) is a genetic disease characterized by a violation of the processes of ossification and development of elements of the skeleton of the facial and cerebral skull. For the first time this condition was described in 1912 by the French pediatrician O. Cruzon, since then the syndrome has been named after him. The mechanism of inheritance of Crouzon syndrome is autosomal dominant, but the disease is often caused by spontaneous mutations. Pathology is quite rare – about 1.6 cases per 100,000 newborns, while this syndrome is caused by almost 5% of all malformations accompanied by cranial dysostosis. For a long time it was believed that this condition has two varieties – common and accompanied by skin disorders (hyperkeratosis, acanthosis), but taking into account modern data, experts in the field of genetics have established that Crouzon syndrome with black acanthosis is a separate hereditary disease. At the same time, the pathogenesis of its development is similar to the classical form of the disease, which explains the significant similarity of symptoms. The condition is equally likely to affect both boys and girls.
Causes
The classic variant of Crouzon syndrome is caused by mutations of the FGFR2 gene located on chromosome 10 – it encodes the amino acid sequence of the receptor for fibroblast growth factor 2. This gene has a significant size and a large number of exons, which reduces its stability – defects often develop in it, leading to numerous genetic diseases, mainly affecting skeletal elements. So, in addition to Crouzon syndrome, FGFR2 mutations can cause the syndromes of Apert, Setre-Chotzen, Beer-Stevenson, Pfeiffer syndrome and many other pathologies. Genetic studies have shown that craniofascial dysostosis type 1 can cause more than 35 mutations of the above gene, mainly they are localized in the region of 7 and 9 exons.
Almost all defects of the FGFR2 gene are related to missense mutations, that is, they provoke a change in the structure of the encoded protein. A change in the conformation of the receptor for fibroblast growth factor 2 disrupts intercellular interactions in the connective tissues of the skull, mainly bone and cartilage. This leads first to the accumulation of fibroblasts in the area of the interosseous sutures, and then to the activation of ossification processes, which is the cause of the leading manifestation of Crouzon syndrome – cranial synostosis. Some researchers believe that these genetic defects also affect the embryonic development of the structures of the first gill arch – they include the jaws and partly elements of the middle third of the face. This explains the hypoplasia of the jaws, especially the lower one, in Crouzon syndrome.
The causes of Crouzon syndrome with black acanthosis are somewhat different – it is caused by mutations of the FGFR3 gene localized on chromosome 4. The product of its expression is also a receptor for fibroblast growth factor, only type 3 (as opposed to type 2, which is a product of the FGFR2 gene). It was found out that only one mutation of this gene causes Cruson syndrome with characteristic skin manifestations – Ala391Glu. This is also a missense mutation that changes the structure of the receptor protein. The pathogenesis of the disease practically does not differ from the classical version. Changes in the face and skull with Crouzon syndrome with black acanthosis are similar to the previous type, but they are joined by hyperkeratosis of various skin areas and acanthosis, numerous moles are often observed.
Symptoms
Manifestations of Crouzon syndrome can be noticed already at the birth of a child, but they become most pronounced during the first 3-4 years of life. The most characteristic symptom of the disease is craniosynostosis, which can develop on a coronal or arrow-shaped (much less often) suture, firmly connecting the bones and stopping the normal growth of the head. Immediately after birth, the first signs of synostosis may be erased, but there is always hypertelorism, prognathia of the lower jaw, a change in the shape of the nose like a “parrot’s beak”, minor exophthalmos due to the reduced size of the eye sockets, low location of the external auditory canal. Sometimes with Crouzon syndrome, finger syndactyly is detected, in this case it is necessary to make a differential diagnosis with Aper syndrome. Some patients have choan atresia, which makes breathing difficult, as well as hydrocephalus, which further complicates the course of the disease due to a sharp increase in intracranial pressure.
A feature of Crouzon syndrome is the inevitable progression of the disease, especially with regard to the shape of the skull. Due to the formation of a strong synostosis and the continued growth of the size of the brain, the shape of the head changes, brachycephaly or a “tower skull” occurs – depending on which seam the fusion occurred. With Crouzon syndrome, exostoses can also form in the area of the fused bones of the skull. This deformation also leads to damage to the organs of vision – first there is a divergent strabismus, then exophthalmos progresses strongly until the eyeballs fall out of the orbit. Often, Crouzon syndrome is accompanied by hearing disorders due to a violation of the structure of the pyramid of the temporal bone – its cavities are reduced in size, some of them may be absent, often this leads to complete deafness. Changes are also observed on the part of the nervous system, there are increasing signs of mental retardation (in the absence of palliative measures), symptoms of increased intracranial pressure (headaches, vomiting), convulsive seizures.
Crouzon syndrome with black acanthosis is characterized by similar changes in the face and skull. At the same time, some researchers note that this form of the disease is generally more severe and is characterized by an increased frequency of complications. Thus, hoan atresia, which rarely develops in the classical type of craniofascial dysostosis type 1, in the case of Crouzon syndrome with black acanthosis, is registered in almost half of patients. In addition, patients have severe skin disorders – hyperkeratosis (wart growth, hypertrophy of the skin), increased pigmentation. The main localization of skin manifestations in Crouzon syndrome with black acanthosis is the areas of the knee and elbow bends, neck, abdomen, nasolabial folds, the area around the eyes. Also, this disease is characterized by the presence of a large number of nevi (moles), hypertrophic weakly pigmented scars and scars often develop.
Diagnostics
Detection of Crouzon syndrome is possible at the stage of prenatal development, immediately after birth or in the first years of the patient’s life. For this purpose, X-ray techniques, general examination, molecular genetic analyses are used. Methods such as ophthalmological examination, hearing examination, assessment of intellectual and mental development play an auxiliary role in the diagnosis of Crouzon syndrome. When examining young children, low-set ears, hypoplasia of the middle third of the face, exophthalmos are determined. In older patients with Crouzon syndrome, these manifestations are joined by divergent strabismus, hearing loss up to complete deafness, and a change in the shape of the skull. On the X-ray of the skull, synostosis is recorded in the area of the coronal, arrow-shaped or lambdoid sutures, it is possible to detect exostoses and a flattened shape of the eye sockets.
Tomography of the pyramid of the temporal bone in Crouzon syndrome reveals a violation of the formation of the external auditory canal (atresia or stenosis) and other cavities, sometimes there is no tympanic cavity. The Turkish saddle is somewhat expanded, additional small paranasal sinuses may form. Molecular genetic diagnosis of Cruson syndrome is performed by a geneticist and in the classical form of the disease is reduced to automatic sequencing of 7 and 9 exons of the FGFR2 gene in order to detect mutations. In the presence of skin manifestations (hyperkeratosis, warts, multiple moles), it makes sense to search for the mutation Ala391Glu in the FGFR3 gene. Prenatal genetic diagnosis is possible for both forms of Crouzon syndrome, while ultrasound techniques are usually ineffective.
Treatment
There is no specific treatment for Crouzon syndrome at the moment, only palliative measures are used. These include surgical interventions to remodel the shape of the skull and eliminate synostoses – such procedures should be started as early as possible and then performed several more times as the head grows. This reduces the level of intracranial pressure, which has a positive effect on the mental development of patients with Crouzon syndrome and reduces the likelihood of neurological disorders. Also, with the help of surgical techniques, artificial blepharophimosis is created to reduce the degree of exophthalmos and prevent dislocation of the eyeball. With hoan atresia, their expansion is performed surgically to facilitate breathing. The techniques of radical complex operations aimed at eliminating the majority of facial disorders in Crouzon syndrome are described. In case of skin changes to reduce their severity, external use of retinoid-based products is recommended, sometimes corticosteroids are prescribed.
Prognosis and prevention
The prognosis of Crouzon syndrome is usually uncertain, many experts assess it as unfavorable. This is due to the fact that even with all symptomatic and palliative measures, divergent strabismus still increases in patients, deafness almost always develops over time, hypoplasia of the middle third of the face becomes more pronounced with age. Nevertheless, many patients with appropriate treatment and care can live to an advanced age. Due to severe visual and hearing impairment, patients are almost always disabled, and mental retardation can also be the cause of disability. Prevention of Crouzon syndrome has not been developed, only prenatal determination of pathology by molecular genetic methods is possible.