Holt-Oram syndrome (HOS)

Qu'est-ce que Holt-Oram syndrome (HOS)?

This rare disease is a genetic syndrome that occurs in 1 in every 100,000 live births.

Symptoms of the syndrome may vary widely, even amongst family members with the same diagnosis. But common features include abnormalities in the upper limb bones, congenital heart defects (over 75% of patients diagnosed with this syndrome will also be diagnosed with a congenital heart defect) and/or coartic conduction defect which affects how muscle contractions in the heart are managed.

This syndrome is also known as:
Atriodigital Dysplasia Heart-hand Syndrome Hos1 Upper limb - cardiovascular syndrome - type - 1

Quelles sont les causes des changements génétiques Holt-Oram syndrome (HOS)?

Une mutation du gène TBX5 provoque le syndrome. Dans environ 74% des cas héréditaires, ce gène en est la cause.
Lorsqu'il est hérité, il est hérité selon un modèle autosomique dominant.

Dans le cas de l'hérédité autosomique dominante, un seul parent est porteur de la mutation génique, et ils ont 50% de chances de la transmettre à chacun de leurs enfants. Les les syndromes hérités d'une transmission autosomique dominante sont causés par une seule copie de la mutation génique.

Quels sont les principaux symptômes de Holt-Oram syndrome (HOS)?

1. Upper limb abnormalities: these might include very long thumbs that actually look like fingers (triphalangy), absent thumb bones or absent thumbs in some cases. Symptoms related to the upper limbs might also include absence of the bones in the forearm or their underdevelopment, the fusing together or under development of bones in the wrist and thumb. The thumb, forearm and shoulder may all be affected in terms of their positioning. Severe cases might include a feature known as phocomelia, where the hands are attached to a shoulder due to absent or very short arms. In less severe cases the only presenting syndrome is an abnormal wrist bone.

2. Congenital heart defect: the most common defects are atrial septal defect (ASD) and ventral septal defect (VSD). Symptoms of both of these congenital heart defects may vary between individuals.

3. Cardiac conduction defects: this might present with or without other congenital heart defects. This usually results in what is known as a heart block and an interruption in the flow of electrical impulses through the heart. Individuals may be affected by this defect in different ways, with some showing no symptoms and others showing more severe symptoms including breathless, blacking out, chest pains or in some cases life-threatening symptoms affecting the heart.

Possible clinical traits/features:
Arrhythmia, Pectus excavatum, Scoliosis, Thoracic scoliosis, Radioulnar synostosis, Ventricular septal defect, Aplasia/Hypoplasia of the radius, Aplasia of the pectoralis major muscle, Aplasia/Hypoplasia of the thumb, Abnormality of the humerus, Abnormality of the carpal bones, Abnormality of the metacarpal bones, Abnormal aortic morphology, Atrial septal defect, Abnormality of the ribs, Abnormality of the sternum, Abnormality of the shoulder, Abnormality of the wrist, Abnormal vertebral morphology, Anomalous pulmonary venous return, Triphalangeal thumb, Absent thumb, Sprengel anomaly, Complete atrioventricular canal defect, Finger syndactyly, Partial duplication of thumb phalanx, Patent ductus arteriosus, Autosomal dominant inheritance, Phocomelia, Hypoplasia of the radius, Hypoplastic left heart

Comment quelqu'un se fait-il tester pour Holt-Oram syndrome (HOS)?

Le test initial du syndrome de Holt-Oram peut commencer par un dépistage par analyse faciale, via la plate-forme télégénétique FDNA Telehealth, qui peut identifier les marqueurs clés du syndrome et souligner la nécessité de tests supplémentaires. Une consultation avec un conseiller en génétique puis un généticien suivra.

Sur la base de cette consultation clinique avec un généticien, les différentes options de tests génétiques seront partagées et le consentement sera recherché pour d'autres tests.

Informations médicales sur Holt-Oram syndrome (HOS)

This condition is variable, but can be categorized by upper limb abnormalities and congenital heart defects.

The limb abnormalities in this condition are variable. The thumbs are most commonly involved and they might be digitalized, absent, hypoplastic, triphalangeal or, rarely, bifid. The other fingers might be absent, or have clinodactyly or syndactyly.
The radiographic abnormalities in the hand are well reviewed by Poznanski et al., (1970).
In an excellent study by Smith et al., (1979) the radius was involved in 22 out of 39 cases, whereas the ulna was involved in 15. More proximally, the humerus was hypoplastic in nearly a half of cases and the clavicle was sometimes anomalous.
Turleau et al., (1984) reported two patients with an interstitial 14q deletion.
Moens et al., (1993) reported an unusual family where some affected individuals had postaxial or mesoaxial polydactyly. Fryns et al., (1996) showed that this family did not map to 12q (see below).
Scaphoid abnormalities are common and include hypoplasia and bipartite ossification (supposedly due to delayed fusion of the os centrale). The other carpals may be hypoplastic, enlarged, irregular or fused. The first metacarpal may have both proximal and distal epiphyses. Occasional cases have been reported with Duane anomaly.
Ruiz et al., (1994) excluded linkage to this region in a four generation family.
Heart lesions are predominantly an ASD, or more rarely a VSD, but other lesions have also occurred (Sletten and Pierpont, 1996). In definite familial cases, 85% of affected individuals have heart defects. In those cases with no structural heart defect, ECG abnormalities are common (Newbury-Ecob et al, 1996). Despite expression being variable, if wrist X-rays are taken, and the heart carefully assessed, penetrance is probably close to 100%.
Yang et al., (1990) reported a sporadic case with an inversion of chromosome 20 (p13:q13.2). Interestingly, bone morphogenetic protein-4 (BMP4) has been mapped to 14q and BMP2 to 20p (Tabas et al., 1993).
Terrett et al., (1994), Bonnet et al., (1994) and Basson et al., (1994) demonstrated linkage to markers on 12q, however two families studied by Terrett et al., (1994) did not show this linkage. There were no clinical differences between the families and linkage heterogeneity was formally demonstrated.
Newbury-Ecob et al., (1996) provide an excellent review.
Spranger et al., (1997) demonstrated that specific muscles were hypoplastic in this condition.
Li et al., (1997) and Basson et al., (1997) demonstrated mutations in the TBX5 gene located at 12q21. This is a member of the brachyury (T) family. Mutations were expected to cause haploinsufficiency.
Basson et al., (1999) provided some genotype/phenotype correlation. They suggest that null alleles cause substantial abnormalities in both limb and heart whereas the Gly80Arg mutation causes significant cardiac malformations with only minor skeletal abnormalities, but Arg237Gln and Arg237Trp cause extensive upper limb malformations but less significant cardiac malformations. Further mutations in the TBX5 gene were reported by Yang et al., (2000).
Cross et al., (2000) studied 47 cases and found mutations in the TBX5 gene in 30%. Interestingly, 46% of sporadic cases had mutations compared to 24% of familial cases.
The effects of various mutations of the TBX5 binding site were investigated by Ghosh et al., (2001). Akrami et al., (2001) reported a family with a large TBX5 deletion. Bruneau et al., (2001) report a mouse model.
Kantaputra et al., (2002) reported a Thai family with clinical features of Holt-Oram syndrome together with short stature, quadricuspid aortic valve and minor craniofacial anomalies. No TBX5 mutation could be detected.
Forty two patients were screened by Heinritz et al., (2005) and nine mutations were found.
Kolhase et al., (2003) reported cases with mutations in the SALL4 gene. In two families the clinical diagnosis had been Holt-Oram syndrome. Brassington et al., (2003) screened 55 probands with clinical features of Holt-Oram syndrome and found 17 mutations. They also found two Sall4 mutations.
Preimplantation diagnosis has been achieved.
Packham et al., (2003) provide a good review of the role of T-box genes in developmental disorders.
Dreßen et al. (2016) identified a novel missense de novo mutation in the TBX5 gene leading to a severe phenotype. The 15-month-old male patient’s left upper arm was dramatically shortened and the thumb on this side was completely missing. The right forelimb showed an aplasia of the radius and a deformed, shortened thumb. In addition, the mobility of both hands was reduced due to a radial flexion.
Koçak Ekera et al. (2016) described a patient with a novel c.481A>C mutation in the TBX5 gene. The clinical features included capillary hemangiomas on the forehead, nose and upper lip, narrow and sloping shoulders, bilateral deep skin folds on the arms, bilateral radial deviation of the hands, cutaneous syndactyly between the left thumb and the index finger, long right triphalangeal thumb, and left long biphalangeal thumb. Echocardiography showed secundum atrial septal defect, ventricular septal defect, and patent ductus arteriosus. X-rays revealed bilateral glenoid hypoplasia, hooked clavicles, high scapulae, hypoplastic humeri and radii, triphalangeal thumb with a long first phalanx on the right, and hypoplastic, malformed first metacarpal on the left.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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