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Current Advances in Holt-Oram Syndrome Taosheng Huang, MD, Phd

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Current Advances in Holt-Oram Syndrome Taosheng Huang, MD, Phd Current advances in Holt-Oram syndrome Taosheng Huang, MD, PhD Holt-Oram syndrome is an autosomal-dominant condition Clinical features characterized by congenital cardiac and forelimb anomalies. It Holt and Oram first described this syndrome when they is caused by mutations of the TBX5 gene, a member of the reported on a family with atrial septal defects and con- T-box family that encodes a transcription factor. Molecular genital anomalies of the thumbs [1]. Since then, about studies have demonstrated that mutations predicted to create 200 clinical papers have been published that further de- null alleles cause substantial abnormalities in both the limbs lineate the clinical features of Holt-Oram syndrome and heart, and that missense mutations of TBX5 can produce (HOS). The prevalence of HOS is 1 of 100,000 live distinct phenotypes. One class of missense mutations causes births, and it occurs with wide ethnic and geographic significant cardiac malformations but only minor skeletal distribution. Its clinical manifestations have proved to be abnormalities; others might cause extensive upper limb variable [2,3•,4•], but with complete penetrance. All pa- malformations but less significant cardiac abnormalities. tients with HOS have upper limb anomaly and about Intrafamilial variations of the malformations strongly suggest 85% to 95% have cardiac malformation. On the basis of that genetic background or modifier genes play an important these findings, the criteria for diagnosis include either role in the phenotypic expression of HOS. Efforts to the presence of cardiac malformations, conduction de- understand the intracellular pathway of TBX5 would provide a fects and radial ray abnormalities (or both) in an indi- unique window onto the molecular basis of common vidual, or the presence of radial ray abnormalities with or congenital heart diseases and limb malformations. Curr Opin without cardiac malformations or conduction defects in Pediatr 2002, 14:691–695 © 2002 Lippincott Williams & Wilkins, Inc. individuals with a family history of HOS [5••]. The fam- ily history should be consistent with autosomal-dominant inheritance. Cardiac defects Division of Human Genetics, Department of Pediatrics, University of California, Secundum-type atrial septal defect (ASD) and ventricu- Irvine, California, USA. lar septal defect (VSD) are the most common heart de- Correspondence to Taosheng Huang, MD, PhD, Division of Genetics, Department fects. Other cardiac defects range from asymptomatic of Pediatrics, Med-Sci, C202, University California, College of Medicine, Irvine, CA 92697, USA; e-mail: [email protected] conduction disturbances (first-degree heart block) to multiple structural defects. Almost every type of cardiac Current Opinion in Pediatrics 2002, 14:691–695 anomaly has been reported, either singly or as part of a Abbreviations group of multiple defects [6–8]. Sudden death from heart ASD atrial septal defect block has been reported. Bruneau et al. summarize the HOS Holt-Oram syndrome VSD ventricular septal defect defects in 240 patients [9••]. Among these patients, 58% had ASD, and 28% have VSD. Less common anomalies, ISSN 1040–8703 © 2002 Lippincott Williams & Wilkins, Inc. such as conduction defect, truncus arteriosus, mitral valve defect, patent ductus arteriosus, and tetralogy of Fallot, occur in 18%, 8%, 4%, 4%, and 3%, respectively. In an earlier series of studies [3•], heart defects in 189 patients were classified by severity. Among these patients, 66% had single abnormalities, including iso- lated conduction defects; 16% had “mild” combinations consisting of two or three malformations (eg, ASD, VSD); 11% had “moderate” combinations that required more complicated surgical repair (eg, tetralogy of Fallot and endocardial cushion defect); and 6% had “severe” com- binations with life-threatening defects, including hypo- plastic left heart, total anomalous pulmonary venous re- turn, and truncus arteriosus. Diagnosis of heart defects requires electrocardiography and two-dimensional echocardiography with doppler. 691 692 Genetics Cardiac catheterization may be required to fully define a with hypoplasia or absence of the thumb [4]. Phoco- defect. melia occasionally occurs. The lower limbs can be involved, including club foot and instability of the Upper limb anomalies knee. Thrombocytopenia, present in infancy, gener- Skeletal abnormalities affect the upper limbs exclu- ally improves with time. Heart defects can be sively; lower limb abnormalities have not been reported. present. The abnormalities are always bilateral and often asym- • Heart-hand syndrome II (Tabatznik): type D brachy- metric, predominantly involving the radial ray. The dactyly (shortening of the distal phalanx of the thumb thumb is the most commonly affected structure and can with or without shortening of the fourth and fifth be triphalangeal, hypoplastic, or completely absent. Ab- metacarpals), sloping shoulders, short upper limbs, normalities range from minor (clinodactyly of the fingers, bowing of the distal radii, and absence of the styloid limited supination of the forearms, and sloping shoul- process of the ulna with supraventricular tachycardia. ders) to severe (reduction deformities, including phoco- Patients can also have mild facial dysmorphism and melia and ectromelia). Clinical recognition of subtle limb mild mental retardation [22]. anomalies in patients with HOS can require both physi- • Heart-hand syndrome III: type C brachydactyly cal examination and radiographs of the upper extremities. (shortening of the middle phalanges) with an acces- sory wedged-shaped ossicle on the proximal phalanx Poznanski et al. demonstrated that carpal abnormalities of the index fingers with sick sinus syndrome [23]. are more specific for HOS than are changes in the thumb • Okihiro syndrome: Duane syndrome (a congenital [10]. Other radiographic abnormalities include posteri- eye-movement disorder resulting from abnormal de- orly and laterally protuberant medial epicondyles of the velopment of cranial nerve VI and characterized by humerus, hypoplastic clavicles, shortened radii, and absence of abduction of the globe and narrowing of ulnar hypoplasia (occurring only in patients with radial the palpebral fissure on adduction of the globe), up- defects). per extremity reduction defects, and cardiac malfor- mation [24]. Overlapping conditions and differential diagnosis • Long thumb brachydactyly syndrome: elongation of Other congenital malformations reported with cardiac the thumb distal to the proximal interphalangeal malformation and upper limb anomalies, include lung joint, often associated with index finger brachydac- hypoplasia and cardiomyopathy, postaxial or central tyly, clinodactyly, narrow shoulders, secondary short polydactyly, arachnodactyly, thoracic scoliosis, hemiatro- clavicles, and pectus excavatum. Occasionally, rhizo- phy of the body, high myopia, Hirschsprung disease, melic limb shortening occurs. The cardiac abnormal- malformations of the urinary system, the Rokitansky- ity is often a conductive defect [25]. Kuster-Hauser syndrome, cryptorchidism, malformations • Vertebral, anal, cardiac, tracheal, esophageal, renal, of renal and cerebral arteries, hypoplastic peripheral up- and limb (VACTERL) anomalies association: radial per extremity vasculature, hypoplasia of the left radial defects are usually unilateral and accompanied by artery, pulmonary hypertension, multiple strokes and characteristic other malformations (ie, imperforate end-stage renal failure, and malignant tumors [11–21]. anus, tracheoesophageal [TE] fistula). These reports probably reflect fortuitous occurrences or represent different conditions. To date, no mutations in TBX5 have been found in individuals with “atypical” Genetic counseling and management phenotypes (Huang et al., unpublished data). Genetic counseling should be provided to all patients with HOS. Of probands, 60% to 70% have an affected The following autosomal-dominant conditions need to parent, and 30% to 40% have a de novo mutation. Evalu- be considered for differential diagnosis: ation of both parents is recommended, including physi- cal examination and radiographs of the upper extremities • Fanconi anemia syndrome is characterized by con- to detect subtle changes of the thumb and carpal bones, genital abnormalities. These abnormalities include and examination of the heart, including electrocardio- malformations of the thumbs, forearms, and heart; gram and echocardiogram are recommended. progressive bone marrow failure with pancytopenia, typically in the first decade; and increased risk for myelodysplasia or acute myelogenous leukemia. The Risk to siblings depends on the genetic status of the diagnosis of Fanconi anemia syndrome relies on de- parents. If one of the parents is affected, the siblings of tection of chromosomal breakage or rearrangements a proband have a 50% risk of inheriting the disease- in the presence of diepoxybutane or mitomycin C. causing mutation. When the parents are clinically unaf- • Thrombocytopenia-absent radius: both radii are al- fected, the risk to the siblings of a proband appears to be ways absent; the thumbs are always present. By con- low. Each individual with HOS has a 50% chance of trast, radial aplasia in HOS is invariably associated inheriting the disease-causing mutation. Current advances in Holt-Oram syndrome Huang 693 For individuals with conduction defects, regular electro- Figure 1. Three-dimensional structure of T-box and the cardiograms are recommended, as conduction defects missense
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