Robinow syndrome is an orphan hereditary disease characterized by growth retardation with multiple phenotypic abnormalities. Pathology occurs with autosomal recessive and autosomal dominant inheritance of mutations. The disease is characterized by mesomelic dwarfism, pathognomonic congenital malformations of the facial structure, lag in development. For diagnostic purposes, special molecular genetic studies are carried out, various imaging methods are used. In case of Robinow syndrome, only symptomatic treatment is possible: surgical correction of developmental abnormalities, neuropsychological rehabilitation program for patients.
Q87.1 Syndromes of congenital anomalies, manifested mainly by dwarfism
Mesomelic dwarfism was described in 1969 by the American geneticist M. Robinow in collaboration with doctors F. Silverman and H. Smith, therefore in some medical sources the disease is called the Robinow-Silverman-Smith syndrome. Pathology is extremely rare — 1 case per 500 thousand newborns. The largest database of such patients has been collected in the USA thanks to the Robinow Syndrome Foundation, which is engaged in statistical work and provides support to people who have encountered this disease.
Thanks to the achievements of modern genetics in 2000, the exact genetic prerequisites of the Robinow syndrome were established. The disease can be inherited by an autosomal dominant type (when one of the parents is sick), by an autosomal recessive type (if both parents are carriers of a mutant gene). The development of mesomelic dwarfism is caused by the following gene defects:
- Mutations of WNT5A, DVL1, DVL3. All three variants of genetic defects are transmitted in an autosomal dominant way. This type of Robinow syndrome is characterized by less pronounced developmental anomalies, has a favorable prognosis for patients.
- ROR2 mutations. The pathology of this gene is inherited in an autosomal recessive way, causes gross intrauterine defects and, in addition, is usually combined with intellectual disorders.
The main predisposing factor for the development of Robinow syndrome are closely related marriages, in which a large number of mutations accumulate in the population, and the risk of an unfavorable combination of the genetic material of the parents sharply increases. Therefore, the maximum spread of the disease is observed in Turkey and Oman, where marriages between relatives are still quite common. The influence of teratogenic factors in the embryonic period of pregnancy is not excluded, but there is no exact scientific data on this issue yet.
The characteristic clinical manifestations of Robinow syndrome are caused by disorders of the maturation processes and differentiation of tissues that occur during the embryonic development of a child. In the autosomal dominant type of syndrome, during embryogenesis, there is a deficiency of proteins from the WNT group, which are necessary for the proper formation of connective tissue and the formation of the skeleton.
The autosomal recessive variant of the disease is characterized by mutations of the gene responsible for the tyrosine kinase receptor, which is located on the surface of all types of cells of the embryo’s body. With ROR2 deficiency, gross violations of cell growth and reproduction occur, and the biochemical reactions of cellular metabolism change. As a result of such mutations, bone and cartilage tissue, as well as tissues of internal organs, suffer.
Signs of pathology are clearly visible immediately after childbirth. Features of the craniofacial structure include a large head size (macrocephaly), large bulging eyes, a short upturned nose with dilated nostrils and a depressed bridge of the nose. Also, the child has a large mouth (macrostomy), exposed front teeth in a calm state, an underdeveloped lower jaw (micrognathia). Often there is a convex high forehead, low-lying ears.
Typical disorders of the body structure are mesomelia — underdevelopment of the middle areas of the upper and lower extremities (forearms, lower legs). Anomalies of skeletal development are complemented by brachydactyly (short-fingered), congenital scoliosis, which is caused by malformations of the structure of the thoracic and cervical vertebrae. As the child grows older, growth retardation, overweight becomes a substitute.
Robinow syndrome, as a rule, is accompanied by disorders of sexual development: girls have underdevelopment of the clitoris and labia majora, boys have severe penile hypoplasia. If the disease is associated with an autosomal dominant type of mutation, the clinical symptoms are not as pronounced, there is no pathological completeness, and sexual development is within normal limits.
Robinow syndrome is often accompanied by somatic diseases caused by disorders of intrauterine development. Typical complications include hydronephrosis with subsequent organ atrophy, anomalies in the shape, size or position of the kidneys. Congenital inguinal or umbilical hernias are often diagnosed. 10% of patients develop congenital heart defects and large vessels.
About 20% of patients with Robinow syndrome have mental development disorders of the type of mild or moderate mental retardation. In combination with pronounced skeletal abnormalities, this disrupts the socialization of children, provokes serious psychological problems. Due to skeletal abnormalities, such patients are incapable of most types of work, therefore they need medical and social assistance.
Often, the phenotypic signs of Robinow syndrome are determined even in the period of intrauterine development with routine ultrasound screening. However, the study does not give a 100% probability of diagnosis, so the examination continues after the birth of the child. To establish mesomelic dwarfism, the doctor requires a complete physical examination of the patient and the following instrumental and laboratory methods:
- Radiography of the skeleton. X-ray examination demonstrates a characteristic mesomelic shortening of the limbs, various anomalies of the facial skull and other deviations from the physiological norm.
- Ultrasound of the heart. Given the high frequency of heart defects in patients with Robinow syndrome, ultrasound scanning and consultation with a cardiologist (if necessary) are an important stage of diagnosis.
- Abdominal ultrasound. Instrumental visualization is used to assess the structural and functional features of the kidneys, urinary tract, and confirm the diagnosis when anterior abdominal wall hernias are detected.
- Genetic testing. Molecular genetic analysis by automatic sequencing is carried out to diagnose Robinow disease, to clarify its clinical variant, which is important for assessing the prognosis of the disease.
There are no specific methods of therapy. Drug therapy for this disease is ineffective, but it can be used with concomitant somatic abnormalities to stabilize the patient’s condition. The main role in the treatment of such patients is played by the help of plastic and maxillofacial surgeons to eliminate skeletal abnormalities as much as possible. It is advisable to carry out the following types of operations:
- extracranial or intracranial correction of hypertelorism;
- correction of the position of the lower jaw with its fixation plates and the installation of implants to add the missing volume;
- dental operations to restore a normal bite;
- correction of limb length using surgical reconstruction.
Operations are performed starting from the early age of the child, and each type of intervention has its own time frame and indications. To eliminate the shortcomings of appearance as completely as possible, patients require complex multi-stage interventions. In the presence of life-threatening defects, surgical treatment is recommended to begin at an early date in order to restore the functioning of the body.
If the Robinow syndrome is accompanied by intellectual disabilities, patients need the help of teachers-defectologists. With a mild degree of disorders, children are successfully trained in special programs, and they remain functional. With moderate severity of disorders, speech and mental development are significantly reduced, therefore, the essence of rehabilitation is to instill self-service skills in the patient.
Prognosis and prevention
Robinow syndrome does not significantly affect life expectancy, but significantly worsens its quality, especially in case of untimely plastic surgery to correct skeletal abnormalities. With multi-stage surgical care, it is possible to achieve a natural appearance, improve the functionality of the skeleton. In patients suffering from mesomelic dwarfism and concomitant somatic defects, the prognosis is unfavorable.
If there have been cases of diagnosed Robinow syndrome or dwarfism in the family, probably related to genetic pathologies, a geneticist’s consultation is necessary before planning a child. When examining both partners, an analysis is carried out for typical mutations, based on the results of which the risk of giving birth to a sick child is determined. In the future, such couples are subject to genetic counseling during pregnancy.