According to abbreviationfinder, Holt-Oram syndrome is a malformation syndrome that is mainly associated with heart defects and anomalies of the thumb and is caused by a mutation. In most cases, the causative mutation occurs sporadically and thus corresponds to a new mutation. The surgical correction of the heart defect is the focus of the therapy.
The congenital malformation syndromes with predominant involvement of the extremities are a group of diseases that include various malformations of the arms and legs. One of them is Holt-Oram syndrome, also known as heart-hand syndrome. The syndrome is associated with the atriodigital dysplasia group, which includes congenital disorders with malformations of the upper extremities and the heart.
In addition to the Holt-Oram syndrome, the heart-hand syndrome type 2, the heart-hand syndrome type 3 and the heart-hand syndrome of the Slovenian type are in this group of diseases. The Holt-Oram syndrome was first described in 1960. The British pediatrician Holt and the cardiologist Samuel Oram are considered to be the first to describe the disease. Holt-Oram syndrome This is a comparatively rare disease and is associated with an average prevalence of one in 100,000 people affected.
The cause of the malformations of the hands and heart in Holt-Oram syndrome lies in genetics. The symptoms of the syndrome are as varied as its suspected causes. The malformations in the disease are concentrated in the heart and thumb.
Although the Holt-Oram syndrome is a genetic and congenital disease, familial frequency can hardly be observed in the cases documented to date. Although the syndrome seems to be inherited in an autosomal dominant manner in individual cases, most of the case documentation suggests sporadic occurrence. Around 85 percent of the documented cases appear to be due to a new mutation.
The primary cause of Holt-Oram syndrome lies in genetic mutations at the gene locus 12q23-24.1 This gene locus contains the so-called TBX5 gene, which is located on chromosome 12 and codes for a protein involved in limb and muscle function heart development encoded. The exact functions of the protein have not yet been clarified. It is also not clear whether external factors such as exposure to toxins or malnutrition in the mother during pregnancy favor the mutation of the TBX5 gene.
Mutations in the gene can be detected in at least up to 70 people out of 100 patients with Holt-Oram syndrome. However, science assumes that abnormalities in other genes can also cause the symptoms of the syndrome. For example, malformation syndrome is associated with tripartite thumb polysyndactyly.
Symptoms, Ailments & Signs
Patients with Holt-Osram syndrome suffer from a complex of malformations that primarily affect the thumbs and heart. Although the location of the patient’s malformations is common, different types of malformations on the heart and thumb can be considered. The clinical picture is therefore extremely varied.
The cardiac defects can manifest themselves, for example, in the form of a ventricular septal defect, an atrial septal defect, a cardiac arrhythmia or a conduction disorder. The skeletal anomalies can correspond to reduction malformations of the thumb, but anomalies such as the non-formation of the radius also occur.
Many patients with the syndrome also have radioulnar synostoses and anomalies of the ribs, scapula, or clavicle. In addition, Holt-Oram syndrome is associated with pectus carinatum and scoliosis. A large proportion of those affected also suffer from syndactyly of the fingers or toes. In isolated cases, these symptoms are associated with hypertelorism.
Diagnosis & disease progression
Holt-Oram syndrome is often misdiagnosed. In the differential diagnosis, the physician must delimit the symptom complex of Okihiro syndrome according to gene mutations in the SALL4 gene on chromosome 20, which is associated with the same arm malformations and heart defects. What is particularly relevant in the differential diagnosis is that patients with Okihiro syndrome usually have a Duane anomaly.
They squint, are often affected by kidney malformations and have hearing disorders, foot anomalies or ear malformations. The thrombocytopenia absent radius syndrome must also be differentiated from the Holt-Oram syndrome, which is mainly possible with laboratory diagnostics. Other diseases with a clinically similar picture are Fanconi anemia and Pallister-Hall syndrome.
The life expectancy of patients with Holt-Oram syndrome is not below average. Only in severe cases is there a heart defect that can hardly be treated, which makes the prognosis unfavorable.
Holt-Oram syndrome causes a number of different malformations and deformities in the patient, which can make life and everyday life more difficult. The heart is particularly affected by the malformations, so that the patient suffers from a heart defect. It also comes to a cardiac arrhythmia, from which the affected person can die in the worst case.
Likewise, anomalies occur in the thumbs, so that certain movements or processes in everyday life are also made more difficult. It is not uncommon for the deformities on the body to lead to teasing and bullying of other children, which can lead to psychological problems and depression in many patients. It is not uncommon for kidney disorders to occur, which in the worst case can lead to kidney failure.
Furthermore, those affected also suffer from visual impairment and hearing impairment. As a rule, life expectancy is not affected by Holt-Oram syndrome unless there is a heart defect that leads to death. A causal treatment of the Holt-Oram syndrome is usually not possible, so that only the symptoms can be treated. In many cases, psychological support is also necessary.
When should you go to the doctor?
Holt-Oram syndrome is usually diagnosed shortly after birth. Depending on how severe the malformations are, the affected child requires further medical examinations. Basically, the cardiac defects must be treated promptly in order to reduce the risk of serious complications. If complications such as cardiac arrhythmia or signs of an atrial septal defect occur, medical advice is required. A medical professional must also be consulted with skeletal abnormalities of the thumbs.
Parents of affected children should consult their doctor closely and inform them of any unusual symptoms. Since Holt-Oram syndrome is a hereditary disease, no causal treatment is possible. Patients may need lifelong treatment, depending on what malformations occur and what the condition of the patient is. Since this often causes psychological problems as well, psychological support is indicated as an accompaniment. Children who suffer from bullying or teasing should seek therapeutic advice together with their parents.
Treatment & Therapy
No causal treatments are available for patients with Holt-Oram syndrome. There is hope for future causal treatability, since gene therapy is currently the subject of medical research. However, as long as this type of therapy does not reach the clinical phase, Holt-Oram syndrome remains an incurable disease.
Currently, only symptomatic therapy options are available for the treatment of patients. The therapy depends on the symptoms in the individual case. The early correction of the heart defect is of particular relevance. This correction is carried out operationally. In the case of a vestibular septal defect, for example, the surgical intervention aims to close the respective defect. The same applies to a ventricular septal defect.
Corrections of the malformations on the extremities are initially of secondary importance. After successfully correcting the heart defect, reconstructive surgical procedures can restore missing spokes and separate syndactylies. An existing scoliosis is usually treated in physiotherapeutic care. In particularly severe cases, surgical intervention to implant a titanium rib prosthesis may be necessary.
No intervention is usually necessary for the pectus carinatum. For psychological reasons, however, the thorax can be surgically reshaped, for example following the method according to Nuss.
Outlook & Forecast
The prognosis of Holt-Oram syndrome is favorable. Although there is a genetic defect, it can be adequately treated with current medical options. The life expectancy of a patient with the syndrome is in most cases not below average. A severe malformation can lead to a significant loss of life expectancy. The prognosis in these patients is significantly worse. Heart activity is limited and can lead to premature death.
However, the majority of patients can be treated well and successfully. Although no cure can occur due to the genetic defect present, there are good prospects for various correction options. Heart activity is regulated and, if possible, completely corrected in a surgical procedure. Although there may be a permanent impairment in lifestyle compared to healthy people, a good quality of life is achieved as a result of the treatment.
Physical abnormalities or malformations are changed in a further step. In most cases, a necessary or desired correction of the existing malformations is initiated after the child’s growth phase is complete. If the disturbances within the development process lead to significant impairments, corrective measures are taken in childhood to alleviate the symptoms. The optical changes can lead to psychological consequences for the patient. This worsens the overall prognosis.
So far, the Holt-Oram syndrome cannot be prevented because the external influencing factors have not been finally clarified.
Since Holt-Oram syndrome is a congenital disease, it cannot be completely cured. Therefore, the measures or the options for aftercare are very limited, so that the person concerned is primarily dependent on early detection and subsequent treatment. If the patient or the parents wish to have children, genetic counseling is given to prevent the syndrome from reoccurring.
The treatment of Holt-Oram syndrome is primarily aimed at treating the heart defect. This is corrected by a surgical procedure, whereby the patient must recover and rest after the procedure in any case. Efforts or physical activities should be avoided. It is not uncommon for physiotherapeutic treatment to be carried out, although many of the exercises can also be carried out at home.
Those affected are sometimes dependent on the help and support of their own family and friends. This can also prevent mental upsets or depression. Furthermore, a healthy lifestyle with a healthy diet has a very positive effect on the course of Holt-Oram syndrome.
You can do that yourself
The Holt-Oram syndrome cannot be prevented and also cannot be treated with self-help methods. With this syndrome, those affected are always dependent on a surgical procedure that treats the heart defects in order to extend the life expectancy of the patient. The earlier the syndrome is detected, the higher the chances of a positive course of the disease. The other malformations on the body must also be corrected surgically.
Since many of those affected also suffer from psychological complaints or from inferiority complexes with this syndrome, they are dependent on psychological treatment. However, talking to other patients, their own parents or friends can also strengthen the patient’s self-confidence and thus alleviate the psychological symptoms. Furthermore, some patients are dependent on the help of their fellow human beings in their everyday life, with warm care having a very positive effect on the course of the Holt-Oram syndrome.
Since the disease can also affect the internal organs, patients are dependent on regular examinations and checks by different doctors. This can prevent kidney problems, for example. Affected children should be informed about the consequences and complications of the disease.