Holt-Oram Syndrome (HOS)

At a glance

Genetically transmitted malformation syndrome characterized by congenital anomalies of the upper extremity malformations involving radial, thenar (hypoplasia or triphalangeal thumb), or carpal bones associated with heart disease (ventricular and atrial septal defect as well as conduction problems). This medical condition can also affect other part of the skeletal structure. It is reported that approximately 75% of individuals with Holt-Oram Syndrome have severe heart problems.

Synonyms

Atriodigital Dysplasia; Cardiac-Limb Syndrome; HOS; Heart-Hand Syndrome, Holt-Oram Type; Atrio-Digital Syndrome; Ventriculo-Radial Syndrome.

History

Congenital disorder of digital and/or radial dysostosis associated with congenital heart disease. First described in 1960 by Mary Holt and Samuel Oram in a four-generation family with atrial septal defects and thumb abnormalities.

Incidence

Prevalence estimated at 1:100,000 live births. More than 50% of cases are caused by new mutations (no parental inheritance).

Genetic inheritance

Autosomal dominant, variable expression but strong penetrance (90-100%). Mutation of the long arm of chromosome 12 (12q24.1) has been associated to the disease. No sex predilection.

Pathophysiology

Holt-Oram Syndrome is caused by mutations in the transcription factor TBX5, which is critical for development of the heart and upper limbs. No contributory environmental factors are known. A number of syndromes phenotypically resemble Holt-Oram Syndrome but arise from different mutations.

Diagnosis

Absent, bifid, hypoplastic, or triphalangeal thumb associated with cardiac septation defects, classically atrial septal defect (often with conduction defects), but also ventricular septal defect.

Clinical aspects

As well as dysostosis of the thumb, the Holt-Oram Syndrome may be associated with radial dysgenesis. Clinical presentation depends on the severity of cardiac disease (atrial septal defect in 70% of cases) but may include severe endocardial cushion defects, mitral valve prolapse, and hypoplastic left heart syndrome. The presence of severe bradycardia is also reported.

Precautions before anesthesia

An anesthesiology consultation is recommended before elective surgery. Obtain a history and examine for signs and symptoms suggestive of ventricular failure and cyanosis. The presence of major visceral anomalies must be determined. Perform an electrocardiogram (ECG) and echocardiography to define cardiac anatomy and conductivity problems. Almost every type of arrhythmia has been reported in these patients ranging from sinus node dysfunction, sinus arrest, atrioventricular node block, atrial fibrillation, wandering pacemaker, and Wolff–Parkinson–White Syndrome. In one study done in 55 patients, 3 presented a complete heart block that required permanent pacemaker and 1 patient had sinus arrest. Cardiomyopathy, end-stage renal disease, stroke, difficult intubation, and ventilation have also been reported. Cardiac catheterization may be indicated for complex lesions. Finally, special attention must be given to the possibility of an association between malignant hyperthermia (MH)-like symptoms in a 2-year-old child ...