0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Special Feature |

Picture of the Month—Diagnosis FREE

[+] Author Affiliations

Section Editor: Albert C Yan, MD
Assistant Section Editor: Samir S. Shah, MD

More Author Information
Arch Pediatr Adolesc Med. 2007;161(7):712. doi:10.1001/archpedi.161.7.712.
Text Size: A A A
Published online

Holt-Oram syndrome, also known as heart-hand syndrome I or atriodigital dysplasia, is characterized by forelimb deformities and congenital heart defects (Online Mendelian Inheritance in Man #142900).1 Holt-Oram syndrome is inherited in an autosomal dominant manner with high penetrance. Mutations in the TBX5 gene located on chromosome 12q24.1 that encodes a transcription factor have been implicated as the cause of this syndrome, and up to 37 mutations have been identified.2 Increasing severity occurs in succeeding generations. The prevalence is 1 in 100 000 patients, with 85% of new cases attributed to new mutations. Up to 50% of sporadic cases and 25% of familial cases represent new mutations.2

This syndrome was first described by Holt and Oram in 1960, who had 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.”3(p238) More than 300 case reports have subsequently been published.

CLINICAL FEATURES

All patients have upper limb anomaly and about 85% to 95% have cardiac malformation.3,4 Other occasional defects include hypertelorism, absence of pectoralis major muscle, thoracic scoliosis, vertebral anomalies, Sprengel deformity, lung hypoplasia, and polydactyl and refractive errors.

Upper Limb Involvement

Upper limbs are always involved. Abnormalities may be unilateral or bilateral and asymmetric and may involve the radial, carpal, and thenar bones. Left-sided defects are often more severe than those on the right. The most prevalent findings are malformations or fusions of the carpal bones. Thumbs are commonly affected and can be triphalangeal, hypoplastic, or completely absent. Abnormalities range from minor (clinodactyly of the fingers, limited supination of the forearms, and sloping shoulders) to severe (reduction deformities, including phocomelia [10%] and ectromelia). Other defects observed include posteriorly and laterally protuberant medial epicondyles of the humerus, hypoplastic clavicles, shortened radii, and ulnar hypoplasia. In this case, the bifid thumb with duplication of the distal phalanx on the right hand is an unusual finding.

The differential diagnosis includes conditions with limb and heart anomalies.2 Fanconi anemia is characterized by malformations of thumbs, forearms, and heart with progressive marrow failure. Thrombocytopenia–absent radius syndrome has thrombocytopenia with bilateral absence of radii but thumbs are always present. Heart-hand syndrome II (Tabatznik syndrome) shows brachydactyly of the thumb with supraventricular tachycardia. Heart-hand syndrome III will have shortening of the middle phalanges along with sick sinus syndrome. Okihiro syndrome has upper limb reduction defects, cardiac malformations, and Duane syndrome. Long thumb brachydactyly syndrome has elongation of the distal thumb with index finger brachydactyly and heart conduction defects. VACTERL anomalies show association of vertebral, anal, cardiac, tracheal, esophageal, renal, radial, and limb abnormalities.

Cardiac Defects

Secundum atrial septal defect and ventricular septal defect are the most common heart defects. About one-third of patients have other types of congenital heart defects. These vary from asymptomatic conduction disturbances like bradycardia and first-degree heart block to more serious multiple structural defects of the heart. Conduction defects tend to progress with aging.

DIAGNOSIS

The diagnosis is made on clinical grounds. Genetic testing is usually reserved for research purposes. There is no distinctive facial dysmorphism to aid diagnosis.5 Radiography, electrocardiography, and echocardiography are usually needed to evaluate the extent of defects. Occasionally, cardiac catheterization and 24-hour Holter monitor may also be necessary to evaluate severe structural or conduction defects.

Prenatal diagnosis of Holt-Oram syndrome has been made when upper limb abnormalities and cardiac defects were noted during prenatal sonography.6 Detailed family history is needed to ascertain if the disease is a new mutation or a familial syndrome.

TREATMENT

Treatment depends on the degree of upper limb and cardiac involvement. Surgical therapy is used to correct hemodynamically significant cardiac defects. Orthopedic surgery consultation is advised to improve limb function in those with severe limb anomalies with or without prostheses. Advanced heart block may require a permanent pacemaker.

Correspondence: Nirav Shastri, MD, Department of Pediatrics, University of Kansas Medical Center, 2006 HCM, Mail Stop 4004, 3901 Rainbow Blvd, Kansas City, KS 66160 (nshastri@kumc.edu).

Accepted for Publication: October 24, 2006.

Financial Disclosure: None reported.

 #142900 Holt-Oram syndrome. Online Mendelian Inheritance in Man Web site http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=142900Accessed May 25, 2006
Huang  T Current advances in Holt-Oram syndrome. Curr Opin Pediatr 2002;14 (6) 691- 695
PubMed
Holt  MOram  S Familial heart disease with skeletal malformations. Br Heart J 1960;22236- 242
PubMed
Basson  CTCowley  GSSolomon  SD  et al.  The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome) N Engl J Med 1994;330 (13) 885- 891
PubMed
Allanson  JENewbury-Ecob  RA Holt-Oram syndrome: is there a “face”? Am J Med Genet A 2003;118 (4) 314- 318
PubMed
Tongsong  TChanprapaph  P Prenatal sonographic diagnosis of Holt-Oram syndrome. J Clin Ultrasound 2000;28 (2) 98- 100
PubMed

Figures

Tables

References

 #142900 Holt-Oram syndrome. Online Mendelian Inheritance in Man Web site http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=142900Accessed May 25, 2006
Huang  T Current advances in Holt-Oram syndrome. Curr Opin Pediatr 2002;14 (6) 691- 695
PubMed
Holt  MOram  S Familial heart disease with skeletal malformations. Br Heart J 1960;22236- 242
PubMed
Basson  CTCowley  GSSolomon  SD  et al.  The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome) N Engl J Med 1994;330 (13) 885- 891
PubMed
Allanson  JENewbury-Ecob  RA Holt-Oram syndrome: is there a “face”? Am J Med Genet A 2003;118 (4) 314- 318
PubMed
Tongsong  TChanprapaph  P Prenatal sonographic diagnosis of Holt-Oram syndrome. J Clin Ultrasound 2000;28 (2) 98- 100
PubMed

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles
Holt-Oram syndrome. Rom J Morphol Embryol 2007;48(1):67-70.