Holt–Oram syndrome (also called atrio-digital syndrome, atriodigital dysplasia, cardiac-limb syndrome, heart-hand syndrome type 1, HOS, ventriculo-radial syndrome) is an

autosomal dominant disorder In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

that affects

bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...

s in the

arm In human anatomy, the arm refers to the upper limb in common usage, although academically the term specifically means the upper arm between the glenohumeral joint (shoulder joint) and the elbow joint. The distal part of the upper limb between th ...

s and hands (the upper limbs) and often causes

heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...

problems. The syndrome may include an absent radial bone in the forearm, an

atrial septal defect Atrial septal defect (ASD) is a congenital heart defect in which blood flows between the atria (upper chambers) of the heart. Some flow is a normal condition both pre-birth and immediately post-birth via the foramen ovale; however, when this d ...

in the heart, or heart block. It affects approximately 1 in 100,000 people.

Presentation

All people with Holt-Oram syndrome have, at least one, abnormal wrist bone, which can often only be detected by

X-ray An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 picometers to 10 nanometers, corresponding to frequencies in the range 30&nb ...

. Other bone abnormalities are associated with the syndrome. These vary widely in severity, and include a missing thumb, a thumb that looks like a finger, upper arm bones of unequal length or underdeveloped, partial or complete absence of bones in the forearm, and abnormalities in the

collar bone The clavicle, or collarbone, is a slender, S-shaped long bone approximately 6 inches (15 cm) long that serves as a strut between the shoulder blade and the sternum (breastbone). There are two clavicles, one on the left and one on the righ ...

or shoulder blade. Bone abnormalities may affect only one side of the body or both sides; if both sides are affected differently, the left side is usually affected more severely. About 75 percent of individuals with Holt–Oram syndrome also have congenital heart problems, with the most common being defects in the tissue wall between the upper chambers of the heart (

) or the lower chambers of the heart (

ventricular septal defect A ventricular septal defect (VSD) is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart. The extent of the opening may vary from pin size to complete absence of the ventricular septum, creating one ...

). People with Holt–Oram syndrome may also have

cardiac conduction disease The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...

, or abnormalities in the electrical system that coordinates contractions of the heart chambers. Cardiac conduction disease can lead to slow heart rate ( bradycardia); rapid, ineffective contraction of the heart muscles (

fibrillation Fibrillation is the rapid, irregular, and unsynchronized contraction of muscle fibers. An important occurrence is with regard to the heart. Cardiology There are two major classes of cardiac fibrillation: atrial fibrillation and ventricular fib ...

); and

heart block Heart block (HB) is a disorder in the heart's rhythm due to a fault in the natural pacemaker. This is caused by an obstruction – a block – in the electrical conduction system of the heart. Sometimes a disorder can be inherited. Despite the se ...

. People with Holt-Oram syndrome may have only congenital heart defects, only cardiac conduction disease, both or neither.

Genetics

Mutations in the ''

TBX5 T-box transcription factor TBX5, (T-box protein 5) is a protein that in humans is encoded by the ''TBX5'' gene. This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes ...

'' gene cause Holt–Oram syndrome. The ''TBX5'' gene produces a protein that is critical for the proper development of the heart and upper limbs before birth. Holt–Oram syndrome has an autosomal dominant pattern of inheritance, meaning one abnormal copy of the gene is sufficient to cause disease, which each child has a 50% chance of inheriting from an affected parent. However, in 85 percent of cases, the gene mutation isn't inherited, but a new

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...

Diagnosis

Diagnosis may be made on physical features alone, if a person has an arm or hand bone abnormality and a personal or family history of heart problems. If the symptoms aren't enough to diagnose, a person may undergo genetic testing for the mutations associated with the syndrome.

Treatment

A person with Holt-Oram syndrome may need various treatments, depending on how the syndrome manifests. Surgery, prosthetics and physical or occupational therapy can help people with bone abnormalities. Heart defects may call for surgery, medication, pacemakers or close monitoring. Pregnant women with Holt-Oram syndrome and heart abnormalities should be followed by a cardiologist during pregnancy.

History

It is named for Mary Holt and Samuel Oram, who published a paper on it in 1960.

References

External links

{{DEFAULTSORT:Holt-Oram syndrome Syndromes affecting the heart Autosomal dominant disorders Transcription factor deficiencies Congenital disorders Syndromes with dysmelia Rare syndromes