Holt-Oram syndrome is a rare hereditary pathology characterized by morphological abnormalities of the upper extremities, various congenital heart defects. It occurs due to a gene mutation TBX5, inherited by autosomal dominant type. To diagnose Holt-Oram syndrome, an X-ray examination of the hand, echocardiography and electrocardiography are prescribed, the presence of the mutation is confirmed by genetic testing. Treatment includes surgical operations to eliminate heart defects, the help of orthopedic traumatologists with severe deformities of the musculoskeletal system.
ICD 10
Q87.2 Syndromes of congenital anomalies involving mainly limbs
General information
Holt-Oram syndrome has additional names in the medical literature: hand-heart syndrome, atrial-finger dysplasia. Typical clinical manifestations of pathology were first described in 1960 by British cardiologists Mary Holt and Samuel Oram, after whom the disease is named. The exact genetic causes of skeletal and cardiac abnormalities were established in 1997. Holt-Oram disease belongs to orphan pathologies, occurs with a frequency of 1 case per 100 thousand population, has no sex differences.
Causes
The disease is caused by mutations in the TBX5 gene, which is located on the long arm of the 12th chromosome at the 12q24.21 locus. The pathology has an autosomal dominant type of inheritance, however, cases of spontaneous mutation in a child who has absolutely healthy parents are not uncommon. The gene mutation has a different degree of expressiveness, which causes the variability of the clinical picture of the syndrome.
Pathogenesis
Typical morphological changes in Holt-Oram disease are associated with the absence or insufficient synthesis of transcription factor Tbx5, belonging to the T-box family. It regulates many processes of connective tissue formation during intrauterine development, including the development of atrial and interventricular septa, the conduction system of the heart, muscles and tendons.
With an insufficient level of Tbx5 protein, the structure of the septum of the heart and the aortic valve is usually disrupted, it is in these zones that up to 95% of all congenital malformations occur in patients with Holt-Oram syndrome. Also, the presence of a transcription factor is a prerequisite for the differentiation of cardiomyocytes of the conducting system of the heart, so pathology is often accompanied by a rhythm disturbance.
Symptoms
The main sign of Holt-Oram syndrome are anomalies of the structure of the upper limb, which are detected in 100% of patients. They are mainly manifested by isolated hypoplasia of the tenar — palmar elevation at the base of the thumb, the appearance of the third phalanx on the thumb, left-right asymmetry. In severe cases of the syndrome, gross disabling malformations occur — phocomelia (seal-like limbs).
The second most common symptom, which is observed in 85% of patients, is congenital heart defects. Most often, patients have a defect of the atrial septum (44.4%), a defect of the interventricular septum (29.4%). Gross cardiac anomalies are much less common — tetrad of Fallot, hypoplasia syndrome of the left heart, coarctation of the aorta.
The third most common manifestation of Holt-Oram syndrome is rhythm and conduction disorders, which are recorded in 40% of cases. They are represented by sinus bradycardia, blockage of the right leg of the Gis bundle, atrioventricular dissociation or sinus node weakness syndrome. In rare cases, the stigmas of embryogenesis are determined: hypertelorism, cleft palate, absence of a large pectoral muscle.
Complications
Patients with Holt-Oram syndrome often lag behind in growth and physical development from early childhood, while mental development occurs according to age. If cardiac surgery is not performed, circulatory disorders are observed against the background of heart defects, up to severe heart failure. With the long-term existence of the syndrome, cellular immunity decreases, due to frequent acute respiratory infections, pneumonia, otitis and sinusitis.
Diagnostics
Since the first signs of the syndrome are noticeable already in early childhood, a pediatrician is engaged in the examination of the child, according to the indications, a pediatric cardiac surgeon, a geneticist, an orthopedic traumatologist are involved in the diagnosis. It is possible to suspect the diagnosis by the presence of specific deformities of the upper extremities. To confirm the Holt-Oram syndrome, the following diagnostic methods are prescribed:
- Radiography of the hand. On the X-ray image, hypoplasia of the tenar is determined, the appearance of the third phalanx at the thumb of one or both hands, insufficient opposition of the thumb. Occasionally, more severe deformities of the arm bones are detected with the involvement of the upper extremity belt in the process.
- Echocardiography. Ultrasound examination of the heart is the leading method of diagnosing congenital anomalies characteristic of the syndrome. During the examination, it is possible to visualize the structural changes of the organ, to assess its functional capabilities. To clarify the diagnosis, chest x-ray is used.
- Electrocardiography. The method allows you to detect signs of periodic and aperiodic sinus arrhythmias, sinoatrial blockades, sinus tachycardia, atrial extrasystole, and other typical rhythm disturbances in time. In some cases, daily ECG monitoring is recommended for more accurate diagnosis.
- Genetic testing. The search for a specific mutation by exon sequencing is the main method of confirming the diagnosis, which is used in doubtful cases, within the framework of scientific research. In routine practice, as a rule, standard clinical and instrumental methods are sufficient.
Treatment
Therapeutic measures are selected taking into account the nature and degree of clinical manifestations of the syndrome. The basis of treatment is the help of cardiac surgeons for the elimination of congenital heart defects, which allows to eliminate circulatory disorders, to provide patients with a high duration and standard of living. Depending on the type of defect, surgical intervention is performed at different ages:
- With a defect of the interventricular septum, the optimal age of correction is from 1 to 2-2.5 years, which allows avoiding severe complications, ensuring normal physical development of the child.
- In case of atrial septal defect, the best correction results are achieved when performing surgery at preschool age (3-6 years).
- In severe defects (for example, tetrad Fallot), cardiac surgery is performed at 4-6 months, and in the presence of dyspnea-cyanotic seizures — even earlier.
- In case of life-threatening arrhythmias, implantation of an electrocardiostimulator is indicated if medical treatment methods do not give effect.
In addition to cardiac surgery, the patient may need reconstructive surgery to reduce the degree of defect of the upper extremities, increase its functionality. Throughout his life, a patient with Holt-Oram disease stays under the dispensary supervision of a cardiologist, orthopedist, geneticist.
Prognosis and prevention
The prognosis is determined by the severity of the heart lesion: non-rough defects can be completely eliminated during cardiac surgery, but occasionally there are severe heart abnormalities with a high risk of death. Given the spontaneous nature of the mutation, measures for the primary prevention of the syndrome have not been developed. Secondary prevention includes timely diagnosis, cardiac surgery in full.
