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Picture of the Month—Diagnosis
Arch Pediatr Adolesc Med. 2007;161(7):712.
Denouement and Comment: Holt-Oram Syndrome
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.
AUTHOR INFORMATION
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{at}kumc.edu).
Accepted for Publication: October 24, 2006.
Financial Disclosure: None reported.
REFERENCES
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1. #142900 Holt-Oram syndrome. Online Mendelian Inheritance in Man Web site. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=142900. Accessed May 25, 2006.
2. Huang T. Current advances in Holt-Oram syndrome. Curr Opin Pediatr. 2002;14(6):691-695.
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3. Holt M, Oram S. Familial heart disease with skeletal malformations. Br Heart J. 1960;22:236-242.
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4. Basson CT, Cowley GS, Solomon 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.
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5. Allanson JE, Newbury-Ecob RA. Holt-Oram syndrome: is there a "face"? Am J Med Genet A. 2003;118(4):314-318.
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6. Tongsong T, Chanprapaph P. Prenatal sonographic diagnosis of Holt-Oram syndrome. J Clin Ultrasound. 2000;28(2):98-100.
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SECTION EDITOR: ALBERT C. YAN, MD; ASSISTANT SECTION EDITOR: SAMIR S. SHAH, MD
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