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Holt-Oram Syndrome

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Holt-Oram Syndrome Holt-Oram Syndrome In 1960, Holt and Oram described a family in which nine b. Unilateral or bilateral members in four generations were affected by skeletal abnor- c. Symmetric or asymmetric (left side more affected malities of the upper limbs, cardiac malformations, and than the right side) arrhythmias. The prevalence is about 1 in 100,000 live births. d. Severe (phocomelia) to mild phenotype due to aplasia, About 40 to 85% of cases are due to fresh mutation. hypoplasia, fusion, or anomalous development of involved bones e. Thumbs GENETICS/BASIC DEFECTS i. Aplasia 1. An autosomal dominant disorder ii. Hypoplasia a. Complete penetrance iii. Triphalangeal b. Widely variable expression iv. Syndactyly 2. Holt-Oram syndrome frequently linked to the gene TBX5, v. Long which is mapped to 12q24.1 vi. Normal 3. Caused by mutations in the TBX5 gene, a member of the f. Fingers T-box family that encodes a transcription factor i. Clinodactyly a. Mutations predicted to create null alleles cause sub- ii. Brachydactyly stantial abnormalities in both the limb and heart iii. Hypoplasia b. Nonsense mutations of TBX5 produce distinct pheno- iv. Absent types v. Syndactyly i. One class of missense mutations: causes signifi- vi. Normal cant cardiac malformations but only minor g. Radial bones skeletal abnormalities i. Hypoplasia ii. Other class of nonsense mutations: causes exten- ii. Aplasia sive upper limb malformations but less signifi- h. Ulnar cant cardiac abnormalities i. Hypoplasia 4. Intrafamilial variations of the malformations: suggest that ii. Aplasia genetic background or modifier genes plays an important i. Carpal bones role in the phenotypic expression of Holt-Oram syndrome i. Deformed 5. Hand-heart syndromes (syndromes with frequent associa- ii. Extra tion of congenital cardiac and upper-limb malforma- j. Thenar bones: hypoplastic thenar eminence tions): genetically heterogeneous k. Humerus a. Holt-Oram syndrome: the most common form i. Hypoplasia b. Heart-hand syndrome type II (Tabatznik syndrome) ii. Abnormal head i. Hypoplastic deltoids iii. Aplasia ii. Skeletal anomalies in the humeri, radii, ulnae, iv. Normal and thenar bones l. Clavicles iii. Brachydactyly type D i. Hypoplasia iv. Congenital cardiac arrhythmias (junctional ii. Prominent acromioclavicular joint rhythms and atrial fibrillation) iii. Normal c. Heart-hand syndrome type III m. Thorax i. Cardiac conduction defects (intraventricular i. Pectus excavatum delays and sick sinus syndrome) ii. Hypoplasia pectoralis major ii. Skeletal malformations limited to the hands and n. Limited supination feet (Brachydactyly type C) o. Limited extension of the elbow d. Autosomal dominant “partial phenocopy” conditions 2. Cardiac anomaly (75% of cases) i. Familial atrial septal defects with conduction a. Structural defects disease occurring without limb deformities i. Atrial septal defect (most common type, usually ii. Familial limb malformations occurring without of secundum variety) cardiac defects ii. Ventricular septal defect iii. Pulmonary stenosis (including peripheral arterial) iv. Mitral valve prolapse CLINICAL FEATURES v. Complex cardiac malformations (tetralogy of 1. Preaxial radial ray abnormalities of the upper limb(s) Fallot, hypoplastic left heart, endocardial cush- a. Almost always present ion defects, truncus arteriosus) 502 HOLT-ORAM SYNDROME 503 b. Cardiac conduction defects a) A congenital eye-movement disorder result- i. Paroxysmal tachycardia ing from abnormal development of cranial ii. Prolonged PR interval (ECG) nerve VI iii. Wandering atrial pacemaker b) Absence of abduction of the globe iv. Atrial ectopics c) Narrowing of the palpebral fissure on adduc- v. Sinus bradycardia tion of the globe vi. Syncope ii. Upper extremity reduction defects vii. Sinus arrest iii. Cardiac malformations viii. Atrioventricular block f. Long thumb brachydactyly syndrome ix. Atrial fibrillation i. Elongation of the thumb distal to the proximal 3. Mild to no symptoms in children and young adult interphalangeal joint a. Recurrent respiratory infections ii. Often associated with index finger brachydactyly, b. Failure to thrive and clinodactyly 4. Older adults iii. Narrow shoulders a. Congestive heart failure iv. Secondary short clavicles b. Supraventricular arrhythmia, especially atrial fibrilla- v. Pectus excavatum tion vi. Occasional rhizomelic limb shortening 5. Differential diagnosis vii. Frequent with cardiac conductive defect a. Fanconi anemia syndrome g. VACTERL anomalies association i. Multiple congenital anomalies consisting of mal- i. Radial defect usually unilateral formations of the thumbs, forearms, and heart ii. Accompanied by other malformations such as ii. Progressive bone marrow failure with pancy- imperforate anus and tracheoesophageal fistula, topenia, typically in the first decade and congenital heart defect iii. An increased risk for myelodysplasia or acute myelogenous leukemia DIAGNOSTIC INVESTIGATIONS iv. Diagnosis based on detection of chromosomal breakage or rearrangement in the presence of 1. Radiography diepoxybutane or Mitomycin C a. Phocomelia of the upper limbs b. Thrombocytopenia-absent radius b. Shortened humeri i. Both radii always absent c. Shortened forearms ii. Thumbs always present i. Aplasia/hypoplasia of the radius iii. Occasional phocomelia ii. Hypoplastic ulna iv. Possible involvement of lower limbs iii. Radio-ulnar synostosis a) Club foot iv. Humeral-ulnar synostosis b) Knee instability d. Thumbs v. Thrombocytopenia i. Absent thumbs a) Present in infancy ii. Triphalangeal thumbs b) Generally improves with time iii. Clinodactyly vi. Heart defect can be present iv. Syndactyly c. Heart-hand syndrome II (Tabatznik) v. Absent first metacarpals i. Type D brachydactyly (shortening of the distal vi. Hypoplastic thenar eminences phalanx of the thumb with or without shortening e. First metacarpals of the 4th and 5th metacarpals) i. Absent ii. Sloping shoulders ii. Hypoplastic iii. Short upper limbs f. Fifth fingers iv. Bowing of the distal radii i. Short middle phalanx v. Absence of the styloid process of the ulna ii. Clinodactyly vi. Supraventricular tachycardia g. Carpal bones vii. Possible mild mental retardation and mild facial i. Deformed dysmorphism ii. Extra carpals d. Heart-hand syndrome III iii. Fused i. Type C brachydactyly (shortening of the middle iv. Irregular phalanges) v. Delayed formation ii. An accessory wedged-shaped ossicles on the h. Shoulders proximal phalanx of the index fingers i. Deformed scapula and/or clavicle iii. Sick sinus syndrome ii. Deformed head of the humerus e. Okihiro syndrome iii. Accessory bones i. Duane syndrome i. Deformed sternum 504 HOLT-ORAM SYNDROME 2. Echocardiography for structural cardiac defects Bossert T, Walther T, Gummert J, et al.: Cardiac malformations associated with 3. Electrocardiography for cardiac conduction defects the Holt-Oram syndrome—Report on a family and review of the litera- ture. Thorac Cardiov Surg 50:312–314, 2002. a. Sinus arrest Brons JTJ, Van Geijn HP, Wladimiroff JW, et al.: Prenatal ultrasound diagno- b. Various degrees of atrioventricular block sis of the Holt-Oram syndrome. Prenat Diagn 8:175–181, 1988. c. Right bundle branch block Bruneau BG, Logan M, Davis N, et al.: Chamber-specific cardiac expression of d. Sinus node dysfunction Tbx5 and heart defects in Holt-Oram syndrome. Dev Biol 211:100–108, e. Wandering pacemaker 1999. Fan C, Duhagon MA, Oberti C, et al.: Novel TBX5 mutations and molecular f. Bradycardia mechanism for Holt-Oram syndrome. J Med Genet 40:e29, 2003. g. Atrial fibrillation/flutter Gall JC Jr, Stern AM, Cohen MM, et al.: Holt-Oram syndrome: clinical h. Supraventricular tachycardia and WPW syndrome and genetic study of a large family. Am J Hum Genet 18:187–200, i. Premature ventricular complexes 1966. 4. Molecualr genetic testing of TBX5 by sequencing of entire Gladstone I, Sybert VP: Holt-Oram syndrome: penetrance of the gene and lack of maternal effect. Clin Genet 21:98–103, 1982. coding region or mutation scanning Ghosh TK, Packham EA, Bonser AJ, et al.: Characterization of the TBX5 bind- ing site and analysis of mutations that cause Holt-Oram syndrome. Hum GENETIC COUNSELING Mol Genet 10:1983–1994, 2001. 1. Recurrence risk Holmes LB: Congenital heart disease and upper-extremity deformities. A report of two families. N Engl J Med 272:437–444, 1965. a. Probands Holt M, Oram S: Familial heart disease with skeletal malformations. Br Heart i. 60–70% have an affected parent J 22:236–242, 1960. ii. 30–40% have a de novo mutation Horb ME, Thomsen GH: Tbx5 is essential for heart development. Development b. Patient’s sib: not increased unless a parent is affected 126:1739–1751, 1999. in which case, there is 50% recurrence risk Huang T: Current advances in Holt-Oram syndrome. Curr Opin Pediatr 14:691–695, 2002. c. Patient’s offspring: 50% Hurst JA, Hall CM, Baraitser M: The Holt-Oram syndrome. J Med Genet 2. Prenatal diagnosis 28:406–410, 1991. a. Ultrasonography of Holt-Oram syndrome for fetuses Kaufman RL, Rimoin DL, McAlister WH, et al.: Variable expression of the at risk involving severe anomalies by demonstrating Holt-Oram syndrome. Am J Dis Child 127:21–25, 1974. Letts RM, Chudley AE, Cumming G, et al.: The upper limb-cardiovascular cardiac defect associated with upper limb defects, syndrome (Holt-Oram syndrome). Clin Orthop Rel Res 116:149–154, especially the radial ray defects 1976. b. Molecular genetic testing of TBX5 of fetal DNA Li QY, Newbury-Ecob RA, Terrett JA, et al.: Holt-Oram syndrome is caused by obtained from amniocentesis or CVS, provided the dis- mutations in TBX5, a member of the Brachyury (T) gene. Nat Genet ease-causing mutation has been identified in the family 15:21–29, 1997. Massumi RA, Nutter DO: The syndrome of familial defects of heart and upper 3. Management extremities (Holt-Oram syndrome). Circulation 34:65–76, 1966. a. A permanent pacemaker for advanced heart block Newbury-Ecob R, Leanage R, Raeburn JA, et al.: The Holt-Oram syndrome: a b. Surgery for severe cardiac defect clinical genetic study. J Med Genet 33:300–307, 1996. c. Prostheses for children with severe limb shortening Packham EA, Brook JD: T-box genes in human disorders. Hum Mol Genet d. Orthopedic management of severe limb defects 12:R37–R44, 2003.
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