Holt-Oram syndrome: Description, Causes and Risk Factors:
Holt-Oram syndrome is a developmental disorder characterized by distinctive malformations of the bones of the thumbs and upper limbs and abnormalities of the heart. The syndrome shows a marked variability in phenotype, with radial ray defects ranging from minor thumb abnormality through to severe reduction defect or phocomelia. The cardiac manifestations of Holt-Oram syndrome are similarly varied, and patients can present with a variety of structural heart abnormalities, atrial septal defects and ventricular septal defects being the most common, or conduction defects evident on ECG profiles. The syndrome is estimated to occur in about 1 out of every 100,000 births. 60% of affected individuals have an affected parent. In about 40 percent of cases, the disorder is the result of a spontaneous genetic change.
Holt-Oram syndrome is a genetic disorder that is autosomal dominant and highly penetrant. Initial linkage studies demonstrate that the gene defect resides on the long arm of chromosome 12. Molecular genetic studies reveal that the disease is caused by mutations that inactivate the transcription factor TBX5. Sporadic disease may represent a de novo germline mutation in TBX5. Recognizing that individuals who present with sporadic disease may transmit the disease to offspring is important. The identification of the role of TBX5 in Holt-Oram syndrome suggests an important but as yet undefined role for TBX5 in human cardiac septation, isomerization, and upper limb development.
The TBX5 gene encodes a protein of 518 amino acids that belongs to the family of the T box transcriptional factors, and is expressed in embryonic heart and limb tissues, consistent with its involvement in development of the heart and skeletal structures. TBX5 contains a highly conserved DNA binding domain, the T box domain. TBX5 can bind to DNA and activate transcription of its target genes.
About 75 percent of individuals with Holt-Oram syndrome have heart problems. The most common problem is a defect in the muscular wall, or septum, that separates the right and left sides of the heart. Atrial septal defects (ASD) are caused by a hole in the septum between the left and right upper chambers of the heart (atria), and ventricular septal defects (VSD) are caused by a hole in the septum between the left and right lower chambers of the heart (ventricles). Sometimes people with Holt-Oram syndrome have cardiac conduction disease, which is caused by abnormalities in the electrical system that coordinates contractions of the heart chambers. Cardiac conduction disease can lead to problems such as a slow heart rate (bradycardia) or a rapid and ineffective contraction of the heart muscles (fibrillation). Cardiac conduction disease can occur along with other heart defects (such as septal defects) or as the only heart problem in people with Holt-Oram syndrome.
Holt-Oram syndrome is estimated to affect 1 in 100,000 individuals.
All people with this disorder have at least one limb abnormality that affects bones in the wrist (carpal bones). Often, these wrist bone abnormalities can be detected only by X-ray. Affected individuals may have additional bone abnormalities that can include a hypoplastic thumb or a thumb that looks like a finger, partial or complete absence of bones in the forearm, an underdeveloped bone of the upper arm, and abnormalities
that affect the collar bone and shoulder blades
. Bone abnormalities may affect each arm differently, and the left side can be affected more than the right side. In some cases, only one arm and/or hand is affected.
Diagnosis may include imaging studies, which may include:
- Chest radiography.
Mutational analysis of TBX5 is not available on a routine clinical basis and remains a research tool. TBX5 mutations are detected in about 75% of individuals meeting strict clinical criteria for Holt-Oram syndrome. On a case-by-case basis, specifics regarding genotype-phenotype correlations are not available. The ability to identify the disease causing mutation in a family may allow for expanded reproductive options such as preimplantation genetic diagnosis for couples at 50% risk of having an affected child.
Evaluation can usually be performed in an outpatient setting, but inpatient studies and surgical treatment may be necessary. Patients with advanced heart block may require a permanent pacemaker. Surgical therapy can be used to correct cardiac defects or to possibly improve limb function.
Most cardiac lesions such as ASD and VSD are amenable to complete surgical correction if pulmonary hypertension or ventricular failure has not developed. Several percutaneous transcatheter devices that can be placed to occlude the septum are in US Food and Drug Administration-approved clinical trials and may be nonsurgical options in the future.
Septal defects without hemodynamically significant shunts do not require correction.\
Children with severe limb anomalies can be referred to orthopedic surgeons for consideration of procedures such as pollicization of the fifth digit (to improve upper limb function). Children with severe limb shortening may benefit from prostheses.
NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.