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Holt-Oram syndrome (HOS) is an autosomal dominant condition characterised by the association of congenital heart defect (CHD), with or without rhythm disturbances and radial defects, due to TBX5 variants.

https://doi.org/10.1038/s41431-018-0303-3

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• It is also known as "heart-hand syndrome type 1".

Mnemonic: “HOLT” = Hand & Heart

• H: Heart (ASD, VSD, heart block)
• O: Often inherited (Autosomal Dominant, TBX5)
• L: Limb anomalies (radial ray defects)
• T: Thumb abnormalities

🔬 Etiology

• Gene involved: TBX5 gene mutation (chromosome 12q24.1)
• Inheritance pattern: Autosomal dominant with variable expressivity and incomplete penetrance
• The TBX5 gene plays a key role in the development of both the heart and upper limbs during embryogenesis.

Clinical Features

1. Skeletal Abnormalities (in ~100%)

• Most commonly affect the radial ray of the upper limbs
• Can be unilateral or bilateral, asymmetric
• Examples:
  • Absent or hypoplastic thumbs
  • Radial aplasia or hypoplasia
  • Shortened humerus or phocomelia
  • Carpal bone abnormalities
  • Clavicle and shoulder girdle anomalies (less common)

![Clinical and radiological phenotypes in HOS patients. a Left triphalangeal thumb, I–II syndactyly, elbow mobility defect; b Right thumb hypoplasia; c Left thumb hypoplasia; d Left triphalangeal thumb; e Left thumb agenesis in a foetus: f Left digitalised thumb, I–II syndactyly, radial hypoplasia; g Radial and ulnar hypoplasia, I–II phalangeal syndactyly; h Right thumb hypoplasia

Vanlerberghe, C., Jourdain, AS., Ghoumid, J. et al. Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants. Eur J Hum Genet 27, 360–368 (2019). https://doi.org/10.1038/s41431-018-0303-3](attachment:53ad5ddc-88c9-4559-8180-1635029628c0:41431_2018_303_Fig1_HTML.png)

Clinical and radiological phenotypes in HOS patients. a Left triphalangeal thumb, I–II syndactyly, elbow mobility defect; b Right thumb hypoplasia; c Left thumb hypoplasia; d Left triphalangeal thumb; e Left thumb agenesis in a foetus: f Left digitalised thumb, I–II syndactyly, radial hypoplasia; g Radial and ulnar hypoplasia, I–II phalangeal syndactyly; h Right thumb hypoplasia

Vanlerberghe, C., Jourdain, AS., Ghoumid, J. et al. Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants. Eur J Hum Genet 27, 360–368 (2019). https://doi.org/10.1038/s41431-018-0303-3

2. Cardiac Abnormalities (in ~75%)