Holt-Oram Syndrome

A number sign (#) is used with this entry because of evidence that Holt-Oram syndrome (HOS) is caused by heterozygous mutation in the TBX5 gene (601620) on chromosome 12q24.

Description

Holt-Oram syndrome is an autosomal dominant disorder characterized by abnormalities of the upper limbs and shoulder girdle, associated with a congenital heart lesion. The typical combination is considered to be a triphalangeal thumb with a secundum atrial septal defect (ASD), but there is a great range in the severity of both the heart and skeletal lesions (summary by Hurst et al., 1991).

Clinical Features

Although the abnormality of the upper extremities is more extensive in some cases, the characteristic findings in the Holt-Oram syndrome are thumb anomaly and atrial septal defect. The thumb may be absent or may be a triphalangeal, nonopposable, finger-like digit. The thumb metacarpal has both a proximal and a distal epiphyseal ossification center (Temtamy and McKusick, 1978).

This syndrome was first clearly described by Holt and Oram (1960), who observed atrial septal defect in members of 4 generations of a family, associated with 'a congenital anomaly of the thumbs which lay in the same plane as the fingers, their terminal phalanges being curved inwards.' McKusick (1961) reported mother and daughter with atrial septal defect and absent or triphalangeal, fingerlike thumb. In 1966 the daughter gave birth to a male infant with upper extremity phocomelia and ventricular septal defect (VSD). The involvement of the arm was more extensive and the cardiovascular involvement more varied in the families described by Lewis et al. (1965) and Harris and Osborne (1966) than in the family of Holt and Oram (1960). However, it is not certain that these represented a separate mutation (McKusick, 1966). The family reported by Kuhn et al. (1963) may be an example of the Lewis type of heart-hand syndrome.

Lenz (1968) noted that the involvement of the arms in the Holt-Oram syndrome can be sufficiently severe to simulate thalidomide embryopathy.

Boehme and Shotar (1989) described a Jordanian family of normal intelligence in which members of 3 generations had complex malformations of the arms combined with variably expressed congenital heart disease. Because of the pedigree pattern, which included 1 instance of male-to-male transmission, they suggested autosomal dominant inheritance, but concluded that the disorder was distinct from HOS.

Poznanski et al. (1970) pointed out that carpal abnormalities, e.g., extra carpal bones, are more specific for the Holt-Oram syndrome than are changes in the thumb. Posteriorly and laterally, protuberant medial epicondyles of the humerus were seen in several patients. The left side was more severely affected in 27 of 39 cases (Smith et al., 1979). Cardiac involvement may be absent in patients with limb defects; 5 of 39 had normal clinical and EKG findings despite typical limb defects (Smith et al., 1979). Although a secundum atrial septal defect is most common, a wide variety of other cardiac defects occur, including ventricular septal defects and mitral valve prolapse. Patients with only limb defects may bear offspring with the complete syndrome.

Glauser et al. (1989) described a family in which the father had atrial septal defect and a hypoplastic thumb, and a son had triphalangeal thumb and syndactyly of digits 1 and 2 on the left with aplasia of the right thumb, and hypoplastic left heart syndrome with large atrial septal defect, coarctation of the aorta, patent ductus arteriosus (PDA), severe aortic stenosis, small left ventricle, and pulmonary hypertension. An older sister of this son had atrial septal defect but no clinically or radiologically apparent abnormalities of the upper limbs.

Moens et al. (1993) reported a 4-generation family with HOS. In addition to the typical changes in the thumb and atrial septal defect, there was postaxial/central polydactyly in some family members.

Basson et al. (1994) reported 2 extensively affected kindreds with HOS showing linkage to chromosome 12. The first family was previously reported by Gall et al. (1966). Of 49 at-risk family members in 5 generations, 26 (11 male and 15 female) were affected. Each affected member was the offspring of an affected parent, thereby confirming the high penetrance of the disease gene. All affected members had some skeletal abnormalities, although many of these were subtle and detected only by radiography. Skeletal deformities generally manifested as deformities of the thenar and carpal bones, occasionally in association with mildly hypoplastic clavicles and shortened radii. Thenar abnormalities included distal displacement of the thenar eminence in the presence or absence of a triphalangeal digit. Only one subject had an aplastic thumb on one side; the contralateral thumb was triphalangeal. None of the subjects had phocomelia or severe ectromelia. All affected members had cardiovascular disease. Septal defects were present in 15 of the surviving family members; 4 had atrial septal defects, 9 had ventricular septal defects, and 2 had both. The atrial septal defects were all of the ostium secundum type, except for one which involved an ostium primum defect. Four had required surgical correction of hemodynamically significant defects. One member of the family died of complications related to a complete atrioventricular canal defect. Eisenmenger syndrome, resulting from an uncorrected ventricular septal defect, was present in 1. Cardiac conduction disease, including bradycardia, atrioventricular block, atrial fibrillation, and sinus node dysfunction, was present in 11 of the surviving affected family members, and 6 required permanent pacemakers. The second family studied by Basson et al. (1994) had 18 affected members (10 male and 8 female) surviving with HOS. All had skeletal abnormalities, which were typically more severe than those found in the first family. Bilateral frank phocomelia or severe ectromelia characterized by hypoplastic humeri, radii, and clavicles, with thenar aplasia and carpal and digital deformities, was present in 7. On the other hand, congenital cardiovascular disease was milder and less frequent in the second family in which 6 had cardiac disease, all consisting of atrial septal defect of the ostium secundum type. Surgery for the septal defect had been required in 3 of these. Only one member of the family had conduction disease (incomplete right bundle branch block), and none had patent ductus arteriosus or superior vena cava anomaly, which were present in members of the first kindred. Since the 2 families showed the same linkage relationship to markers on 12q, the disorders are probably due to different mutations in the same gene, which is important to the development of both the limbs and the cardiovascular system.

Newbury-Ecob et al. (1996) reported a detailed study of a large cohort of patients that included 44 familial and 11 sporadic cases. Association of cardiac and radial abnormalities was a criterion for inclusion of familial cases. Limb defects were found in all affected persons. The thumb was the most commonly affected structure, although in 7 of 44 cases, the thumbs were normal. In most cases, the thumb defects (absence in 19/44, hypoplasia in 17/44, triphalangeal thumbs in 8/44) were associated with hypoplastic thenar or limited supination of the forearm. Radial hypoplasia (18/44) was more frequent than absence of radius (10/44). Ulnar hypoplasia occurred only in patients with radial defects. Most patients had narrow, sloping shoulders. Limb defects were always bilateral and often asymmetrical, the left side being more severely affected. Cardiac involvement was found in 95% of familial cases; secundum atrial septal defect (15) and ventricular septal defect (11) were the most common defects. In 17 of the familial cases, only ECG abnormalities were found. Both cardiac and limb abnormalities were more severe in the sporadic group. Newbury-Ecob et al. (1996) found a significant positive correlation (r = 0.49) between severity of the limb and cardiac defects. The patients with atrial septal defects had more severe limb abnormalities. Correlation between sibs was greater than that between parent and offspring.

Sletten and Pierpont (1996) described a family in which the proband had hypoplastic left thumb, hypoplastic left ventricle and endocardial cushion defect. His mother, aunt, uncle, grandfather and some other relatives had less pronounced manifestations of HOS. Analysis of the literature showed that single cardiovascular malformations (CVM) such as ASD, VSD, or PDA were reported in 125 of 189 cases (66%), and 33 patients (17.5%) had more complex cardiac defects (hypoplastic left heart, total anomalous pulmonary venous return, truncus arteriosus). Sletten and Pierpont (1996) emphasized that the proportion of severe CVM in patients with HOS has been underestimated and should be considered in counseling families with the disorder.

Kantaputra et al. (2002) described a Thai family in which the mother and 3 offspring were affected with a dominantly inherited malformation syndrome with short stature, upper limb anomaly, and minor craniofacial anomalies suggestive of HOS; however, molecular studies did not reveal any mutations in the TBX5 gene. One of the offspring, a 23-year-old man, was cardiologically asymptomatic, although echocardiography revealed he had a quadricuspid aortic valve associated with mild aortic regurgitation.

Tseng et al. (2007) reported a Taiwanese male infant with genetically confirmed HOS and right lung agenesis. He presented at birth with severe respiratory distress, sloping shoulder, and absence of bilateral thumbs and radii. Cardiac ultrasound showed atrial and ventricular septal defects, patent ductus arteriosus, and dextroposition of the heart. Chest CT scan showed absence of the right lung and bronchial tree. He also had absence of the right pulmonary artery and vein. Tseng et al. (2007) noted that pulmonary anomalies are uncommon in HOS, but may expand the phenotypic abnormalities associated with the disorder.

Diagnosis

Brons et al. (1988) discussed the prenatal diagnosis of HOS in 2 pregnancies. More severe forms of the disorder were excluded early in gestation. In the first fetus, ventricular septal defect, atrial septal defect, and a minor skeletal defect were found at 22 weeks. In a second fetus in the same sibship, no structural abnormalities were discovered until the thirtieth week, when a small atrial septal defect was detected.

Cytogenetics

Rybak et al. (1971) described many cases in 4 generations of a Polish family and concluded that partial deletion of the long arm of a B-group chromosome was related to the abnormality. They suggested that the single case of Ockey et al. (1967) had the Holt-Oram syndrome; a similar deletion of the long arm of a group B chromosome was present. Rybak (1981) reported that the family refused to be restudied with banding techniques.

Turleau et al. (1984) described de novo deletion of the q23-q24.2 region of chromosome 14 in a boy with arm and cardiac abnormalities possibly consistent with the Holt-Oram syndrome. In addition, he had mental retardation, synophrys, strabismus, thin upper lip, bilateral pretragian skin tags, and cryptorchidism. Using linkage studies, Ruiz et al. (1994) excluded the 14q23-q24 region as the site of the HOS gene in a Belgian family with several affected persons in 4 generations.

Kristoffersson et al. (1987) found normal high-resolution karyotypes in 3 patients: a mother, her daughter, and an unrelated woman. Yang et al. (1990) described a sporadic case of HOS associated with a de novo pericentric inversion of chromosome 20. The breakpoints in chromosome 20 were at p13 and q13.2. They suggested that the HOS mutation is located at the site of one of these breakpoints.

Basson et al. (1999) described a child with a chromosome 5;12 translocation that caused severe skeletal and composite cardiac malformations. The affected child had left arm phocomelia, right radial hypoplasia, and right thumb aplasia. Cardiac angiography demonstrated a common atrium and a complete atrioventricular canal defect.

Mapping

Terrett et al. (1994) studied linkage between microsatellite DNA markers and HOS in 7 families. In 5, linkage between HOS and markers on 12q was found, whereas the 2 remaining families, phenotypically indistinguishable from the others, did not show this linkage. Analysis of the family data with the computer program HOMOG indicated that HOS is a heterogeneous disorder. In the five 12q-linked families, Terrett et al. (1994) narrowed the assignment to a 21-cM interval in the distal region.

In each of 2 extensively affected kindreds, Basson et al. (1994) demonstrated linkage of HOS to markers in the 12q2 region; combined multipoint lod score = 16.8. Judging by the location of the markers used, HOS probably is in the q21.3-q22 region.

Fryns et al. (1996) reported a family in which linkage to 12q was excluded, thus demonstrating genetic heterogeneity in the Holt-Oram syndrome.

Inheritance

The Holt-Oram syndrome is inherited as an autosomal dominant trait (Hurst et al., 1991).

Braulke et al. (1991) reported a probable instance of germinal mosaicism: an unaffected man fathered 4 offspring with HOS by 3 different women.

Molecular Genetics

Li et al. (1997) and Basson et al. (1997) demonstrated mutations in the TBX5 gene as the basis of Holt-Oram syndrome (see, e.g., 601620.0001-601620.0005). The dominant phenotype of HOS appears to result from haploinsufficiency of TBX5. The glu69-to-ter mutation (601620.0002) identified by Basson et al. (1997) in affected members of one kindred was predicted to encode a markedly truncated TBX5 protein that lacked most T-box residues.

Basson et al. (1999) showed that TBX5 mutations predicted to create null alleles caused substantial abnormalities in both limb and heart. In contrast, missense mutations of the TBX5 gene produced distinct phenotypes: gly80 to arg (601620.0004) caused significant cardiac malformations but only minor skeletal abnormalities, whereas 2 mutations of codon 237, arg237 to gln (601620.0003) and arg237 to trp (601620.0005), caused extensive upper limb malformations but less significant cardiac abnormalities. They noted that residue 80 is highly conserved within T-box sequences that interact with the major groove of target DNA, whereas residue 237 is located in the T-box domain that selectively binds to the minor groove of DNA.

Yang et al. (2000) analyzed 11 Chinese patients with Holt-Oram syndrome using SSCP analysis of TBX5. The authors identified 3 novel mutations, including a frameshift mutation caused by a deletion of 1 basepair (601620.0006), and 2 missense mutations (601620.0007 and 601620.0008). The patients with the frameshift mutation had more severe upper limb anomalies, including aplasia/hypoplasia of the arm and thumbs, while those with missense mutations had milder anomalies, such as absent or hypoplastic thumbs, without arm abnormalities.

In 2 unrelated families with HOS, Gruenauer-Kloevekorn and Froster (2003) found the same truncation mutation in all affected members (601620.0009). The phenotype was similar in both families and included ASD, hypoplastic deltoid muscles, and hypoplastic or absent thumbs extending to radial defects in 1 patient.

Borozdin et al. (2006) reported a Czech mother and 2 daughters who were diagnosed with Holt-Oram syndrome, in whom they identified a 2.19 to 2.27-Mb contiguous deletion encompassing the TBX5 and TBX3 (601621) genes. Clinical reexamination confirmed the presence of features of ulnar-mammary syndrome (UMS; 181450) that were previously unrecognized. Borozdin et al. (2006) noted that the contiguous deletion also included the RBM19 gene (616444), but commented that it was unlikely to contribute to or modify the phenotype since all the anomalies present in the affected individuals could be explained by either TBX5 or TBX3 haploinsufficiency.

In affected members of a 5-generation family segregating an atypical form of HOS, consisting predominantly of nonseptal cardiac defects and mild limb anomalies, Patel et al. (2012) identified a 48-kb duplication encompassing exons 2 through 9 of the TBX5 gene. The duplication, which was identified by array CGH and multiplex ligation-dependent probe amplification, segregated with the disorder in the family.

Nomenclature

McKusick (1961) suggested the alternative designations atriodigital dysplasia and Holt-Oram syndrome; the latter 'caught on.'

History

An obituary of Samuel Oram (1913-1991) was provided by Davies (1992).