Holt-Oram syndrome is a malformation syndrome associated primarily with heart defects and abnormalities of the thumbs that results from a mutation. In most cases, the causative mutation occurs sporadically and thus corresponds to a new mutation. Surgical correction of the cardiac defect is the focus of therapy.
Holt-Oram syndrome?
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 these is Holt-Oram syndrome, also known as heart-hand syndrome. The syndrome is associated with the group of atriodigital dysplasias, which includes congenital disorders with malformations of the upper extremities and heart. In addition to Holt-Oram syndrome, heart-hand syndrome type 2, heart-hand syndrome type 3, and heart-hand syndrome of the Slovenian type are in this group of diseases. Holt-Oram syndrome was first described in 1960, and the British pediatrician Holt and the cardiologist Samuel Oram are considered the first describers of the condition. Holt-Oram syndrome Das is a comparatively rare disorder and is associated with an average prevalence of one affected person in every 100,000 people. In Holt-Oram syndrome, the cause of the malformations of the hands and heart is genetics. The symptoms of the syndrome are as varied as its suspected causes. The malformations are concentrated in the heart and thumb in this disorder.
Causes
Although Holt-Oram syndrome is a genetic and congenital disorder, little familial frequency can be observed in the cases documented to date. Although the syndrome appears to be inherited in an autosomal dominant inheritance in individual cases, much of the case documentation suggests sporadic occurrence. Approximately 85 percent of documented cases appear to be due to a new mutation. The primary cause of Holt-Oram syndrome is genetic mutations at gene locus 12q23-24.1 At this gene locus is the so-called TBX5 gene, which is located on chromosome 12 and codes for a protein involved in limb and heart development. The exact functions of the protein have not yet been clarified. Nor is it yet clear whether external factors such as exposure to toxins or maternal malnutrition during pregnancy promote mutation of the TBX5 gene. Mutations in the gene can be detected in at least up to 70 people out of 100 Holt-Oram syndrome patients. However, scientists believe that abnormalities in other genes can also cause the symptoms of the syndrome. For example, the malformation syndrome is associated with three-limb thumb polysyndactyly.
Symptoms, complaints, and signs
Patients with Holt-Osram syndrome suffer from a complex on malformations that preferentially affect the thumbs and heart. Although the localization of the patient’s malformations is common, different types of malformation of the heart and thumbs may be involved. The clinical picture is therefore extremely varied. For example, the cardiac defects may manifest as a ventricular septal defect, atrial septal defect, arrhythmia, or conduction disturbance. The skeletal anomalies may correspond to reduction malformations of the thumbs, but anomalies such as nonunion of the radius also occur. Many patients of the syndrome also suffer from 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 affected individuals also suffer from syndactyly of the fingers or phalanges. In isolated cases, these symptoms are associated with hypertelorism.
Diagnosis and course of the disease
Holt-Oram syndrome is often misdiagnosed. Differentially, the physician must differentiate the symptom complex from Okihiro syndrome according to gene mutations in the SALL4 gene on chromosome 20, which is associated with the same arm malformations and heart defects. Most relevant to the differential diagnosis is that patients with Okihiro syndrome usually have a Duane anomaly. They have strabismus, are often affected by renal malformations, and have hearing disorders, foot anomalies, or ear malformations. In addition, the thrombocytopenia-absent radius syndrome must be differentiated from the Holt-Oram syndrome, which is mainly achieved by laboratory diagnostics.Other syndromes 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 severe cases present with a barely treatable cardiac defect that makes the prognosis unfavorable.
Complications
Holt-Oram syndrome causes the patient to develop a number of different malformations and deformities that can complicate life and daily living. The heart in particular is affected by the malformations, so the patient suffers from a heart defect. This also leads to a cardiac arrhythmia, which in the worst case can cause the death of the patient. 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 malformations on the body to lead to teasing and bullying of other children, which can lead to psychological complaints and depression in many patients. It is not uncommon for kidney disorders to occur, and in the worst cases, kidney failure can result. Furthermore, those affected also suffer from impaired vision and hearing. As a rule, life expectancy remains unchanged by Holt-Oram syndrome, as long as there is no heart defect leading to death. Causal treatment of Holt-Oram syndrome is usually not possible, so only the symptoms can be treated. In many cases, psychological care is also necessary.
When should you see a doctor?
Holt-Oram syndrome is usually diagnosed shortly after birth. Depending on how pronounced the malformations are, the affected child requires further medical examinations. In principle, the cardiac defects must be treated promptly to reduce the risk of serious sequelae. If complications such as cardiac arrhythmias or signs of an atrial septal defect develop, medical advice is required. A medical professional must also be consulted with skeletal abnormalities of the thumbs. Parents of affected children should consult closely with the appropriate physician and inform him or her of any unusual symptoms. Because Holt-Oram syndrome is a hereditary disease, no causative treatment is available. Patients may therefore have to be treated for the rest of their lives, depending on which malformations occur and the constitution of the sufferer. Since this often also causes psychological complaints, accompanying psychological care is indicated. Children who suffer from bullying or teasing should seek therapeutic counseling together with their parents.
Treatment and therapy
No causal treatments are available for patients with Holt-Oram syndrome. There is some hope for causal treatability in the future, as gene therapy is currently the subject of medical research. However, until this type of therapy reaches the clinical phase, Holt-Oram syndrome will remain an incurable disease. Thus, only symptomatic therapeutic options are currently available to treat patients. Thus, the therapy depends on the symptoms in the individual case. Particularly relevant is the early correction of the heart defect. This correction is performed surgically. In the case of a Vohof septal defect, for example, the surgical intervention aims to close the defect in question. The same is true for a ventricular septal defect. Corrections of the malformations of the extremities are secondary at first. After successful correction of the cardiac defect, reconstructive surgical procedures can restore missing spokes and separate syndactyls. Existing scoliosis is usually addressed with physical therapy. In particularly severe cases, surgical intervention to implant a titanium rib prosthesis may be required. For the pectus carinatum, surgery is usually not required. However, for psychological reasons, surgical reshaping of the thorax may be performed, following the Nuss procedure, for example.
Outlook and prognosis
The prognosis of Holt-Oram syndrome is favorable. Although a genetic defect is present, it can be adequately treated with current medical options. In most cases, the life expectancy of a sufferer with the syndrome is not below average. In the case of a severe malformation, life expectancy can be considerably reduced. The prognosis is significantly worse in these patients.Cardiac activity is restricted and can lead to a premature end of life. 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 corrective options. The cardiac activity is regulated and, if possible, completely corrected in a surgical procedure. Although there may be a permanent impairment in the way of life compared to healthy people, a good quality of life is achieved due to the treatment. Physical abnormalities or malformations are modified in a further step. In most cases, a necessary or desired correction of the existing malformations is initiated after the child’s growth phase has been completed. If the disorders lead to significant impairments within the developmental process, corrective measures are taken in childhood to alleviate the symptoms. Due to the visual changes, the patient may experience psychological sequelae. This worsens the overall prognosis.
Prevention
To date, Holt-Oram syndrome cannot be prevented because the external influencing factors have not been conclusively clarified.
Follow-up
Since Holt-Oram syndrome is a congenital disease, it cannot be completely cured. Therefore, the measures or options for follow-up care are also very limited, so the affected person is primarily dependent on early detection with subsequent treatment. If the patient or parents wish to have children, genetic counseling should be provided to prevent the recurrence of this syndrome. The treatment of Holt-Oram syndrome is mainly focused on the treatment of the heart defect. The heart defect is corrected by surgery, and the patient must recover and rest after the procedure. In doing so, the patient must refrain from exertion or physical activities. It is not uncommon for physiotherapeutic treatment to be required, although many of the exercises can also be performed in the patient’s own home. Sufferers are sometimes dependent on the help and support of their own family and friends. This can also prevent psychological upsets or depression. Furthermore, a healthy lifestyle with a healthy diet has a very positive effect on the course of Holt-Oram syndrome.
What you can do yourself
Holt-Oram syndrome cannot be prevented and likewise cannot be treated by self-help means. Sufferers of this syndrome are always dependent on surgical intervention to treat the heart defects in order to prolong the patient’s life expectancy. 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 inferiority complexes with this syndrome, they are dependent on psychological treatment. However, conversations with other patients, one’s own parents or friends can strengthen the patient’s self-confidence and thus alleviate the psychological complaints. Furthermore, some patients are dependent on the help of their fellow human beings in their everyday life, whereby cordial care has a very positive effect on the course of Holt-Oram syndrome. Since the disease can also affect the internal organs, patients are dependent on regular examinations and check-ups with various doctors. This can prevent kidney problems, for example. Affected children should be educated about the consequences and complications of the disease.
