Holt–Oram syndrome

(Redirected from Holt-Oram Syndrome) Genetic disorder causing malformation of the heart and upper limb bones Medical condition

Holt-Oram syndrome
Other names	Heart-hand syndrome, Atrio-digital syndrome, Atriodigital dysplasia

Holt-Oram syndrome has an autosomal dominant pattern of inheritance
Specialty	Medical genetics
Causes	Mutations in the TBX5 gene

Holt–Oram syndrome (also called atrio-digital syndrome, atriodigital dysplasia, cardiac-limb syndrome, heart-hand syndrome type 1, HOS, ventriculo-radial syndrome) is an autosomal dominant disorder that affects bones in the arms and hands (the upper limbs) and often causes heart problems. The syndrome may include an absent radial bone in the forearm, an atrial septal defect in the heart, or heart block. It affects approximately 1 in 100,000 people.

Presentation

All people with Holt-Oram syndrome have at least one abnormal wrist bone, which can often only be detected by X-ray. Other bone abnormalities are associated with the syndrome. These vary widely in severity, and include a missing thumb, a thumb that looks like a finger, upper arm bones of unequal length or underdeveloped, partial or complete absence of bones in the forearm, and abnormalities in the collar bone or shoulder blade. Bone abnormalities may affect only one side of the body or both sides; if both sides are affected differently, the left side is usually affected more severely.

About 75 percent of individuals with Holt–Oram syndrome also have congenital heart problems, with the most common being defects in the tissue wall between the upper chambers of the heart (atrial septal defect) or the lower chambers of the heart (ventricular septal defect). People with Holt–Oram syndrome may also have abnormalities in the electrical system that coordinates contractions of the heart chambers. Cardiac conduction disease can lead to slow heart rate (bradycardia); rapid, ineffective contraction of the heart muscles (fibrillation); and heart block. People with Holt-Oram syndrome may have only congenital heart defects, only cardiac conduction disease, both or neither.

Genetics

Mutations in the TBX5 gene cause Holt–Oram syndrome. The TBX5 gene produces a protein that is critical for the proper development of the heart and upper limbs before birth.

Holt–Oram syndrome has an autosomal dominant pattern of inheritance, meaning one abnormal copy of the gene is sufficient to cause disease, which each child has a 50% chance of inheriting from an affected parent. However, in 85 percent of cases, the gene mutation isn't inherited, but a new mutation.

Diagnosis

Diagnosis may be made on physical features alone, if a person has an arm or hand bone abnormality and a personal or family history of heart problems. If the symptoms aren't enough to diagnose, a person may undergo genetic testing for the mutations associated with the syndrome.

Treatment

A person with Holt-Oram syndrome may need various treatments, depending on how the syndrome manifests. Surgery, prosthetics and physical or occupational therapy can help people with bone abnormalities. Heart defects may call for surgery, medication, pacemakers or close monitoring. Pregnant women with Holt-Oram syndrome and heart abnormalities should be followed by a cardiologist during pregnancy.

History

It is named for Mary Holt and Samuel Oram, who published a paper on it in 1960.

References

^ "Holt-Oram syndrome". Genetics Home Reference. U.S. National Library of Medicine. June 2014. Retrieved 18 April 2018.
^ McDermott, Deborah A.; Fong, Jamie C.; Basson, Craig T. (2015-10-08) . Adam, MP; Ardinger, HH; Pagon, RA; et al. (eds.). "Holt-Oram Syndrome". GeneReviews. Seattle, WA: University of Washington. PMID 20301290. Retrieved 2018-01-01 – via NCBI Bookshelf.
Bossert, T; Walther, T; Gummert, J; Hubald, R; Kostelka, M; Mohr, FW (October 2002). "Cardiac malformations associated with the Holt-Oram syndrome—report on a family and review of the literature". The Thoracic and Cardiovascular Surgeon. 50 (5): 312–4. doi:10.1055/s-2002-34573. PMID 12375192. S2CID 19665997.
Virdis, G.; Dessole, M.; Dessole, S.; Ambrosini, G.; Cosmi, E.; Cherchil, P. L.; Capobianco, G. (2016-01-01). "Holt Oram syndrome: a case report and review of the literature". Clinical and Experimental Obstetrics & Gynecology. 43 (1): 137–139. doi:10.12891/ceog3060.2016. ISSN 0390-6663. PMID 27048037. S2CID 11803484.
Holt, Mary; Oram, Samuel (1960-04-01). "Familial Heart Disease with Skeletal Malformations". British Heart Journal. 22 (2): 236–242. doi:10.1136/hrt.22.2.236. ISSN 0007-0769. PMC 1017650. PMID 14402857.

External links

Classification	D ICD-10: Q87.2 OMIM: 142900 MeSH: C535326 C535326, C535326 DiseasesDB: 5988 SNOMED CT: 205814003
External resources	eMedicine: med/2940 ped/1021 GeneReviews: Holt-Oram Syndrome Orphanet: 392

v t e Congenital abnormality syndromes
Craniofacial	Acrocephalosyndactyly Apert syndrome Carpenter syndrome Pfeiffer syndrome Saethre–Chotzen syndrome Sakati–Nyhan–Tisdale syndrome Bonnet–Dechaume–Blanc syndrome Other Baller–Gerold syndrome Cyclopia Goldenhar syndrome Moebius syndrome Pierre Robin sequence
Short stature	1q21.1 deletion syndrome Aarskog–Scott syndrome Cockayne syndrome Cornelia de Lange syndrome Dubowitz syndrome Noonan syndrome Robinow syndrome Silver–Russell syndrome Seckel syndrome Smith–Lemli–Opitz syndrome Snyder–Robinson syndrome Turner syndrome
Limbs	Adducted thumb syndrome Holt–Oram syndrome Klippel–Trénaunay syndrome Nail–patella syndrome Rubinstein–Taybi syndrome Gastrulation/mesoderm: Caudal regression syndrome Ectromelia Sirenomelia VACTERL association
Overgrowth syndromes	Bannayan–Riley–Ruvalcaba syndrome Beckwith–Wiedemann syndrome Benign symmetric lipomatosis Klippel–Trénaunay syndrome Neurofibromatosis type I Perlman syndrome Proteus syndrome Sotos syndrome Tatton-Brown–Rahman syndrome Weaver syndrome
Laurence–Moon–Bardet–Biedl	Bardet–Biedl syndrome Laurence–Moon syndrome
Combined/other, known locus	2 (Feingold syndrome) 3 (Zimmermann–Laband syndrome) 4/13 (Fraser syndrome) 8 (Branchio-oto-renal syndrome, CHARGE syndrome) 12 (Keutel syndrome, Timothy syndrome) 15 (Marfan syndrome) 19 (Donohue syndrome) Multiple Fryns syndrome

Genetic disorders relating to deficiencies of transcription factor or coregulators

(1) Basic domains

1.2	Feingold syndrome Saethre–Chotzen syndrome
1.3	Tietz syndrome

(2) Zinc finger
DNA-binding domains

2.1	(Intracellular receptor): Thyroid hormone resistance Androgen insensitivity syndrome PAIS MAIS CAIS Kennedy's disease PHA1AD pseudohypoaldosteronism Estrogen insensitivity syndrome X-linked adrenal hypoplasia congenita MODY 1 Familial partial lipodystrophy 3 SF1 XY gonadal dysgenesis
2.2	Barakat syndrome Tricho–rhino–phalangeal syndrome
2.3	Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome Denys–Drash syndrome Duane-radial ray syndrome MODY 7 MRX 89 Townes–Brocks syndrome Acrocallosal syndrome Myotonic dystrophy 2
2.5	Autoimmune polyendocrine syndrome type 1

(3) Helix-turn-helix domains

3.1	ARX Ohtahara syndrome Lissencephaly X2 MNX1 Currarino syndrome HOXD13 SPD1 synpolydactyly PDX1 MODY 4 LMX1B Nail–patella syndrome MSX1 Tooth and nail syndrome OFC5 PITX2 Axenfeld syndrome 1 POU4F3 DFNA15 POU3F4 DFNX2 ZEB1 Posterior polymorphous corneal dystrophy Fuchs' dystrophy 3 ZEB2 Mowat–Wilson syndrome
3.2	PAX2 Papillorenal syndrome PAX3 Waardenburg syndrome 1&3 PAX4 MODY 9 PAX6 Gillespie syndrome Coloboma of optic nerve PAX8 Congenital hypothyroidism 2 PAX9 STHAG3
3.3	FOXC1 Axenfeld syndrome 3 Iridogoniodysgenesis, dominant type FOXC2 Lymphedema–distichiasis syndrome FOXE1 Bamforth–Lazarus syndrome FOXE3 Anterior segment mesenchymal dysgenesis FOXF1 ACD/MPV FOXI1 Enlarged vestibular aqueduct FOXL2 Premature ovarian failure 3 FOXP3 IPEX
3.5	IRF6 Van der Woude syndrome Popliteal pterygium syndrome

(4) β-Scaffold factors
with minor groove contacts

4.2	Hyperimmunoglobulin E syndrome
4.3	Holt–Oram syndrome Li–Fraumeni syndrome Ulnar–mammary syndrome
4.7	Campomelic dysplasia MODY 3 MODY 5 SF1 SRY XY gonadal dysgenesis Premature ovarian failure 7 SOX10 Waardenburg syndrome 4c Yemenite deaf-blind hypopigmentation syndrome
4.11	Cleidocranial dysostosis

(0) Other transcription factors

0.6	Kabuki syndrome

Ungrouped

Transcription coregulators

Coactivator:	CREBBP Rubinstein–Taybi syndrome
Corepressor:	HR (Atrichia with papular lesions)

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