Holt-Oram Syndrome

Definition

Holt-Oram syndrome (HOS) is one of several hereditary conditions characterized by abnormalities of the heart and hands at birth.

Description

HOS involves variable abnormalities of the heart and the hands, or hands and arms. The heart abnormalities may range from disturbances in the electrical conduction pattern of the heart to severe structural defects requiring surgical intervention for survival. The abnormalities of the upper limbs are usually bilateral (occurring on both sides) and asymmetric (not identical from side to side). The severity of the upper limb changes may range from minor signs, such as clinodactyly (inward curvature of the fingers) to disabling defects, such as small or missing bones resulting in very short arms.

Some individuals with HOS are so mildly affected, they do not require any special care or treatment. Other individuals are severely affected and may have significant disability resulting from abnormalities of the arms, or may have limited life spans due to serious heart abnormalities. The signs of HOS are usually limited to the heart and skeleton. HOS does not cause mental retardation.

Some references may use the alternative name of hand-heart syndrome. However, Holt-Oram syndrome is one of many hereditary hand-heart syndromes, so the two names are not truly interchangeable.

Genetic profile

HOS is inherited as an autosomal dominant condition, with variable expressivity (meaning that different individuals with HOS may have very different signs of the condition) and complete penetrance (meaning that every individual that has the genetic change causing the condition has some physical symptoms). An autosomal dominant condition only requires the presence of one abnormal gene on a non-sex-linked chromosome for the disorder to occur. Some researchers have observed families with incomplete penetrance (meaning that not every individual with the gene abnormality shows symptoms) as well.

In some individuals and families, HOS is caused by mutations in the TBX5 gene located on the long arm of chromosome 12. The TBX5 gene encodes a transcription factor that helps regulate DNA expression. Other families with HOS do not show mutations in the TBX5 gene, indicating that mutations in other genes can also cause HOS. HOS families that have TBX5 mutations do not appear to differ significantly from those which do not.

Some patients with HOS have inherited it from an affected parent, whereas others have it as the result of a new change in a gene. The proportion of patients with HOS resulting from new mutations ranges from 8% to 85%. Regardless of where the gene came from, an affected individual has a 50% chance of passing on the gene and the condition to each child. It is difficult to predetermine the severity of symptoms a child may have.

Demographics

Since HOS was first described in 1960, more than 200 cases have been reported in individuals of diverse ethnicity. The incidence of the condition has been estimated as one in 100,000 live births.

Signs and symptoms

All individuals with HOS have some degree of upper limb abnormality, and most (approximately 95% in familial cases) have defects or dysfunction of the heart. Other body parts and systems are usually not significantly affected by HOS.

Defects of the upper limbs

The limb abnormalities in HOS primarily affect the radial side (the inner or thumb side of the arm/hand). Involvement of the ulnar side (the outer side of the arm/hand, opposite the thumb) may also occur to a lesser degree. In some individuals, the abnormality of the upper limb may be very mild, such as hypoplasia (underdevelopment) of the muscle at the base of the thumb, limited rotation of the arm, or narrow, sloping shoulders. Rarely, severe abnormalities of the upper limbs may be present, resulting in extremely short, "flipper-like" arms. Abnormalities of the upper limb are always bilateral and usually asymmetric. In 90% of patients, the left side is more severely affected.

The thumb is the most commonly affected part of the upper limb in HOS, and is affected in some way in 84% of patients. Some individuals have three phalanges (or bones) in the thumb, resulting in a thumb that can bend in three places, like a finger. In other cases, the thumb may be hypoplastic (underdeveloped). Syndactyly (or skin webbing) may occur between the thumb and index finger.

Abnormalities of the fingers may include hypoplasia, underdevelopment, or absence of one or more fingers. Clinodactyly (inward curvature) of the fifth or "pinky" finger is also common. In some patients, polydactyly (extra fingers) has been reported.

The bones of the arms may also be affected by HOS. The radius (the inner bone of the forearm, adjacent to the thumb) may be hypoplastic or even missing. Such patients may have a lesser degree of hypoplasia of the ulna (outer bone of the forearm, opposite the thumb). The upper arm may be short. In rare cases, as noted above, the bones of the arm are dramatically shortened, resulting in a tiny arm.

Individuals with HOS often appear to have narrow, sloping shoulders. This likely results from some degree of hypoplasia of the clavicles (collarbones), as well as decreased musculature which occurs secondarily to bone hypoplasia.

Defects and dysfunction of the heart

The vast majority (95%) of individuals with HOS who have inherited it from an affected parent have heart involvement. Most have a defect in the structure of the heart. In some patients, there is no structural defect in the heart, but abnormalities are present in the pattern of electrical conduction in the heart.

The most common heart abnormalities in people with HOS are septal defects, or holes in the heart. A hole may occur in the wall separating the atria of the heart (atrioseptal defect or ASD), or the wall separating the ventricles of the heart (ventriculoseptal defect or VSD). In rare cases, more severe and complex heart defects may occur, such as hypoplastic left heart (in which the chambers of the left side of the heart are too small to function normally) or tetralogy of fallot (a specific combination of four heart defects). In the case of severe defects, surgical correction is necessary for survival. However, most persons with HOS do not require surgical intervention.

Some individuals with HOS have a cardiac conduction defect, or an abnormal electrical pattern in the heart. The complex motion of the heart requires a system of electrical impulses for coordinated contraction of the muscle fibers. In people with cardiac conduction defects, these electrical impulses may not occur in the normal pattern, resulting in an abnormal heartbeat. In rare cases, this can result in sudden death.

Other defects

Additional skeletal abnormalities occasionally reported in patients with HOS include scoliosis, vertebral abnormalities, and minor deformities of the rib cage. Some patients may have abnormalities unrelated to the cardiac or skeletal systems, such as minor eye defects and various birthmarks. It is not clear whether these additional findings are coincidental or part of HOS.

Diagnosis

The diagnosis of HOS is made on the basis of the clinical judgement by a specialist physician, usually a geneticist, following physical examination and review of pertinent tests or studies. Diagnostic criteria may be employed to guide this decision. One commonly used set of criteria for the diagnosis of HOS require that there be 1) defect(s) of the radial side of the hand/arm, as well as 2) septal defect(s) or conduction abnormality of the heart, within one individual or family.

X rays may be necessary to determine involvement of the bones of the upper limb. Diagnosis of structural defects of the heart requires echocardiography, or ultrasound visualization of the heart. Conduction defects of the heart are identified via electrocardiography (EKG). This test involves measuring the electrical activity of the heart and charting the electrical impulses associated with each heartbeat.

Testing to identify changes in the TBX5 gene may be offered, but is not necessary for a diagnosis of HOS. Identification of a change or alteration in the TBX5 gene could provide confirmation of the clinical diagnosis, prenatal diagnosis, or assist in the diagnosis of at risk family members who are minimally affected. Prenatal screening in a pregnancy at-risk for HOS may also be attempted by fetal ultrasonography targeted toward the fetal arms and heart. However, a normal ultrasound examination does not eliminate the possibility of HOS in the unborn baby.

Treatment and management

There is no specific treatment for HOS. Surgery or other treatment may be recommended for cardiac abnormalities. Referral for genetic counseling should be considered for families in which HOS has been diagnosed.

Some patients with HOS have life-threatening heart defects that require surgical correction for survival. The most complex heart defects may require multiple surgeries. However, many individuals have asymptomatic or no heart abnormalities. When life-threatening irregularities are present in the heartbeat, a pacemaker device is inserted. These devices correct the abnormal electrical patterns which cause the irregularities and stimulate the heart to beat normally.

Because eye abnormalities have been occasionally reported in HOS, an eye examination may be recommended at the time of diagnosis.

Prognosis

The prognosis for individuals with HOS depends on the severity of associated birth defects, which varies considerably. Positive correlation has been reported between the severity of upper limb and heart defects. In other words, individuals who have more severe hand or arm involvement may be more likely to have a symptomatic heart defect. People who have HOS resulting from new mutations are more likely to have severe defects than those who have inherited it from a parent.

In some cases, HOS may lead to death in early infancy due to multiple septal defects or other complex structural abnormalities of the heart. Severe and unrecognized disturbances of the cardiac conduction system can lead to sudden death. In other cases, heart involvement is limited to asymptomatic irregular heartbeat requiring no treatment.

Several unusual findings have been described with respect to the severity of HOS in families. Affected women have been reported to have a higher chance of having a severely affected child than do affected men. The severity of defects associated with HOS has also been reported to increase with successive generations. The possible explanations for these observations are not known.

BOOKS

Jones, Kenneth L. Smith's Recognizable Patterns of Human Malformation. Philadelphia, PA: W.B. Saunders Company, 1997.

PERIODICALS

Newbury, R. A., R. Leanage, J. A. Raeburn, and I. D. Young. "Holt-Oram Syndrome: A clinical genetic study." Journal of Medical Genetics (April 1996): 300-307.

Jennifer A. Roggenbuck, MS, CGC