Holt-Oram syndrome

Holt-Oram syndrome

Holt-Oram syndrome was described by Mary Holt and Samuel Oram as ‘Familial heart disease with skeletal malformations’ [1]. The initial description was of familial atrial septal defects and abnormalities of the thumb and radial aspect of the upper limb. Simian thumb, in which the thumb lies in the same plane as the other fingers is a characteristic description. Terminal phalanx was curved and pointed inwards. The thumb can also be triphalangeal and finger like, with inability to oppose. Most severe form of upper limb dysplasia resembling phocomelia has also been reported.  Atriodigital dysplasia was another name suggested for the Holt-Oram syndrome. The original family described had also cardiac conduction disturbances and arrhythmias.

Holt-Oram syndrome is inherited in an autosomal dominant pattern and the mutation is in the transcription factor TBX5. The mutation was described by Li et al, in 1997 [2]. Though the most common cardiac anomaly is atrial septal defect of the secundum variety, other defects like ventricular septal defect have been described. Ventricular septal defect is of the muscular or trabecular variety. Cardiac malformations are seen in 75% of the affected family members. Carpal bone abnormalities are seen in all affected individuals, though it may be clinically silent and evident only radiologically.

As it has an autosomal dominant mode of transmission, offspring have a 50% chance of being affected. But about 85% of cases of Holt-Oram syndrome have de novo mutations. Mutations in TBX5 account for upto 70% of cases of Holt-Oram syndrome.

References

1. M Holt, S Oram. Familial heart disease with skeletal malformations. Br Heart J. 1960 Apr;22(2):236-42.
2. Q Y Li, R A Newbury-Ecob, J A Terrett, D I Wilson, A R Curtis, C H Yi, T Gebuhr, P J Bullen, S C Robson, T Strachan, D Bonnet, S Lyonnet, I D Young, J A Raeburn, A J Buckler, D J Law, J D Brook. Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet. 1997 Jan;15(1):21-9.