Aarskog-Scott syndrome is a genetic disease characterized by numerous anomalies in the development of the face, limbs (especially fingers), and genitourinary system. Symptoms of this condition are wide lips, hypertelorism, underdevelopment of the upper jaw, strabismus, brachydactyly, genital anomalies, mental and physical development delay. Diagnosis of Aarskog-Scott syndrome is made on the basis of the data of the patient’s current status, radiological and molecular genetic studies. There is no specific treatment for this disease, the manifestations are eliminated by symptomatic and palliative therapeutic measures, including surgical ones.
Aarskog-Scott syndrome (faciogenital or faciodigitogenital dysplasia) is a hereditary disease characterized mainly by a recessive X–linked transmission mechanism and manifested by numerous malformations. For the first time this condition was described in 1970 by the Norwegian pediatrician D. Aarskog and almost simultaneously with him (in 1971) by the American doctor P. Scott, since then this pathology bears their name. The mechanism of inheritance of Aarskog-Scott syndrome leads to the fact that men predominate among the patients. In some cases, a smoothed course of pathology in women is possible. This allowed some researchers to assume the dominant nature of genetic disorders with incomplete penetrance. In addition, cases of Aarskog-Scott syndrome with all signs of autosomal dominant and autosomal recessive inheritance have been described. After the discovery of this pathology, specialists described about a hundred proven clinical cases, but this was not enough to accurately determine its occurrence. According to geneticists, the frequency of Aarskog-Scott syndrome can be one case per 25,000-100,000 newborns.
The main cause of disorders in Aarskog-Scott syndrome is a genetic mutation in the FGD1 gene located on the X chromosome. It encodes the sequence of a protein that regulates the exchange of guanine nucleotides GTP/GDP and is part of an extensive group of protein-binding proteins. This protein is responsible for the transport of proteins from the Golgi complex to the cell membrane. In Aarskog-Scott syndrome, a missense mutation occurs in the FGD1 gene, as a result of which the protein expressed by it turns out to be defective. The process of transporting proteins and lipids to the cell surface is disrupted, the process of tissue differentiation is hindered, which causes numerous embryonic malformations.
It is assumed that the mechanism of inheritance of Aarskog-Scott syndrome is X–linked recessive, however, there are data on cases of similar symptoms in women who were heterozygous for this allele. In addition, the study of the family history of some patients suggests the presence of autosomal varieties of this disease. To date, the presence of extremely rare autosomal dominant and autosomal recessive variants of Aarskog-Scott syndrome is not in doubt, however, the key genes whose mutations cause this condition have not yet been identified. The transmission of the classic variant of the disease can occur both from a phenotypically healthy female carrier and from a sick father – with this pathology, fertility is preserved in many cases.
Currently, the molecular mechanism of the pathogenesis of Aarskog-Scott syndrome has not been studied enough – in particular, it is unclear why the face, genitals and partly limbs are affected in this disease. Several types of FGD1 gene defect have been identified, most of them belong to the type of missense mutations, but cases of sufficiently extended deletions have also been described. In addition, many researchers believe that other disorders in the above gene may be the cause of conditions such as attention deficit hyperactivity disorder (ADHD) and some forms of hereditary mental retardation.
Aarskog-Scott syndrome is characterized by multiple malformations, many of which can be identified immediately after the birth of a child. First of all, typical facial changes are noticeable – a wide nose and bridge of the nose, often inverted nostrils, underdevelopment of the upper jaw, hypertelorism and a thickened upper lip. Among other frequent changes in Aarskog-Scott syndrome, softening of the cartilage of the auricles, an antimongoloid incision of the eyes are distinguished, sometimes it is possible to develop a cleft of the hard palate and upper lip. Brachydactyly is often found on the upper extremities. Characteristic of the Aarskog-Scott syndrome are malformations of the genital organs in boys – cryptorchidism, scrotum in the form of a “shawl”, inguinal hernias.
As a child suffering from Aarskog-Scott syndrome grows, additional manifestations of the disease arise. Numerous violations of the dental system are found – anomalies of the dentition, enamel hypoplasia, a high tendency to caries development. On the part of the nervous system, there may be a moderate degree of mental retardation or manifestations of attention deficit hyperactivity disorder. In many cases of Aarskog-Scott syndrome, intelligence is maintained at a sufficient level – at the same time, timely diagnosis of the condition and psychological assistance in raising a child plays an important role.
In patients with Aarskog-Scott syndrome, growth retardation is detected due to both endocrine causes (decreased secretion of growth hormone) and bone formation disorders. However, this disease has one feature – many of its manifestations weaken sharply during puberty and become less pronounced in adults than in children. The only exceptions are severe facial defects (cleft upper lip and hard palate, strabismus), inguinal hernias, mental retardation, dental anomalies. The diagnostic sign of this pathology is normal height and weight at birth, a lag in physical development before puberty and a sharp intensification of growth during puberty. In adult patients with Aarskog-Scott syndrome, growth is often below average, but dwarfism is extremely rare.
Determination of the Aarskog-Scott syndrome is carried out on the basis of data from the general examination of the patient, the study of hormonal background, neuropsychiatric studies, molecular genetic analyses. The examination is carried out by specialists of different profiles, a pediatrician or therapist can detect facial changes characteristic of the disease, which allows pre-diagnosing this pathology in the first weeks of a child’s life. Also, patients with Aarskog-Scott syndrome have various malformations of the reproductive system – cryptorchidism, scrotum in the form of a “shawl”, phimosis, inguinal hernias. When examined by an ophthalmologist, nystagmus, strabismus, corneal abnormalities can be established. Dental examination reveals hypoplasia of the upper jaw and numerous defects in the formation of teeth. In women carrying the pathological form of the FGD1 gene, only hypertelorism and a change in the hairline on the forehead (the so-called “widow’s cape”) can be observed.
The determination of the level of the main hormones in the blood in Aarskog-Scott syndrome confirms the lack of somatotropin, often the amount of other hormones is also violated. Sometimes an X-ray examination is performed, which reveals a violation of the process of ossification of the metaphyses of the bones of the extremities, expansion of the interphalangeal joints without signs of arthrosis. Neuropsychiatric examination for Aarskog-Scott syndrome is not proven in early childhood – with a delay in mental development at the age of 3-8 years after puberty, the patient may have normal intelligence. Molecular genetic diagnosis of the disease is performed by sequencing the FGD1 gene and can be performed in both male and female patients to determine the carrier.
There is no specific treatment for Aarskog-Scott syndrome, but it is important to make a timely diagnosis of this condition, since symptomatic measures can greatly affect the prognosis. So, according to most psychologists, a timely psychological and pedagogical correction can prevent the development of mental retardation and attention deficit disorder. A number of disorders with Aarskog-Scott syndrome are eliminated surgically, operations are performed with splitting of the upper lip and palate, cryptorchidism, phimosis, inguinal hernias. When violations of the endocrine system are detected, hormonal background is corrected according to laboratory tests.
Violation of the formation of teeth often requires the intervention of a dentist and an orthodontist, often carious teeth lead to the development of other diseases. Vision correction in Aarskog-Scott syndrome is performed by selecting glasses or contact lenses, sometimes surgery is required to eliminate corneal abnormalities. Physiotherapy procedures and therapeutic gymnastics in childhood can reduce the severity of lag in physical development and, according to psychologists, reduce the likelihood of attention deficit disorder. In addition, with Aarskog-Scott syndrome, nootropic drugs, vitamin preparations can be prescribed according to indications, in the presence of mental abnormalities, tranquilizers and other similar medications.
Prognosis and prevention
The prognosis of Aarskog-Scott syndrome, especially with full-fledged therapeutic measures, is usually favorable. Malformations in this disease practically do not affect vital systems and organs, and after adolescence, the symptoms of pathology become much less pronounced. The main danger in Aarskog-Scott syndrome is the lack of treatment by correctional teachers (prevention of mental retardation and ADHD) and pediatric surgeons. Untreated cryptorchidism can further lead to malignant degeneration of testicular tissues, serious complications are threatened by ignoring inguinal hernias and phimosis. Preventive measures regarding Aarskog-Scott syndrome have not been developed to date, with a burdened hereditary history, it is recommended to perform medical and genetic counseling before conceiving a child or resort to methods of genetic prenatal diagnosis.