49 Holt-Oram Syndrome
HOS, heart-hand syndrome type 1,
cardiac-limb syndrome, atriodigital dysplasia
Upper limb anomalies, cardiac defects, narrow shoul- ders
Frequency: Rather rare (over 200 cases described)
Genetics
Autosomal dominant (OMIM 142900) with complete penetrance, variably expressed, evidence for antici- pation; one locus, TBX5, mapped to 12q24.1; SALL4 gene, mapped to 20q13, mutated in some patients.
Clinical Features
• Congenital heart defect (95% of familial cases), atrial septal defect (34%), ventricular septal defect (25%), cardiac conduction disease (39%)
• Radial ray defects, highly variable expression and asymmetric involvement, thenar abnormalities, absent or altered thumb, upper limb anomalies, phocomelia (10%)
Differential Diagnosis
• Other heart-hand syndromes
• Thrombocytopenia-absent radius syndrome
• Fanconi anemia
• VATER association
Radiographic Features Extremities
• Thumb abnormalities (absent/hypoplastic, tri- phalangeal finger-like, bifid, abnormally placed, absent/hypoplastic first metacarpal)
• Carpal bone abnormalities (absent/hypoplastic, irregularly shaped, fused, supernumerary, late- appearing)
• Varying degrees of radial deficiency
Other limb abnormalities
• Hypoplastic/absent, deformed humerus
• Hypoplastic/absent ulna
• Radioulnar or humeroulnar synostosis Chest
• Hypoplastic or broadened clavicle
• Clavicles with lateral hooks
• Rotated, small scapula with hypoplastic glenoid fossa
• Sprengel deformity
• Pectus excavatum/carinatum
• Hypoplastic/absent ribs
• Supernumerary ribs Spine
• Scoliosis
• Fused vertebrae, hemivertebrae
Holt-Oram Syndrome 724
Fig. 49.1. Patient 1, age 2 months. Upper limb anomalies, with severe hypoplasia of both forearms and absent thumbs
Bibliography
Basson CT, Cowley GS, Solomon SD, Weissman B, Poznanski AK, Traill TA, Seidman JG, Seidman CE. The clinical and ge- netic spectrum of the Holt-Oram syndrome (heart-hand syndrome). N Engl J Med 1994; 330: 885–91
Gall JC, Stem AM, Cohen MM, Adams MS, Davidson RT. Holt- Oram syndrome: clinical and genetic study of a large fami- ly. Am J Hum Genet 1966; 18: 187–200
Hurst JA, Hall CM, Baraitser M. The Holt-Oram syndrome.
J Med Genet 1991; 28: 406–10
Kohlhase J, Schubert L, Liebers M, Rauch A, Becker K, Mo- hammed SN, Newbury-Ecob R, Reardon W. Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syn- drome, and patients previously reported to represent thalidomide embryopathy. J Med Genet 2003; 40: 473–8 Newbury-Ecob RA, Leanage R, Raeburn JA, Young ID. Holt-
Oram syndrome: a clinical genetic study. J Med Genet 1996;
33: 300–7
Terrett JA, Newbury-Ecob RA, Cross GS, Fenton I, Raeburn JA, Young ID, Brook JD. Holt-Oram syndrome is a genetically heterogeneous disease with one locus mapping to human chromosome 12q. Nature Genet 1994; 6: 401–4
Wilson GN. Correlated heart/limb anomalies in mendelian syndromes provide evidence for a cardiomelic develop- mental field. Am J Med Genet 1998; 76: 297–305
Holt-Oram Syndrome 725
H
Fig. 49.2. Patient 2, age 7 years and 6 months. Note small, broad clavicles with lateral hooks. Glenoid fossae are hypo- plastic
Fig. 49.3 a, b. Patient 3, age 17 years. Vertebral segmentation defects in cervical spine, lumbar scoliosis, and lack of normal widening of interpediculate distance from upper to lower lumbar spine
a b
Holt-Oram Syndrome 726
Fig. 49.4 a–c. Different degrees of thumb defects. a Patient 2, age 7 years and 6 months. Thumb and radial carpal bones are absent. b Patient 3, at 6 years of age.
Left thumb is markedly hypoplastic and is distally placed, with almost complete absence of metacarpal (floating thumb); right thumb is also hypoplastic, albeit to a lesser extent. Note hypoplasia/aplasia of the radially placed carpal bones (scaphoid, trapezium, and trapezoid). c Patient 4, adult. A finger-like thumb is seen, made up of three instead of the normal two phalanges. Note metacarpal and scaphoid hypoplasia and synostosis between triquetrum and lunate
a
c
b
