HAND SYNDROMES
HolteOram Syndrome Charles A. Goldfarb, MD, Lindley B. Wall, MD
H
(Online Mendelian Inheritance in Man no. 142900) is a combination of a cardiac septal defect or conduction defect and an upper extremity anomaly often affecting the thumb. Alternative, less specific terminology includes heartehand syndrome, atriodigital dysplasia, and cardiac limb syndrome. The syndrome carries the name of Holt and Oram,1 who reported in 1960 on the familial occurrence of an atrial septal defect and thumb anomaly in family members over 4 generations. The estimated incidence is 1 in 100,000 live births. In a recent evaluation of medical conditions in 138 patients with radial longitudinal deficiency (RLD),2 7 patients had HolteOram syndrome, making it the fourth most common syndrome or association in patients with RLD. OLTeORAM
SYNDROME
ETIOLOGY Transcription factor TBX5, a key factor in limb and cardiac development,3 with a gene locus at 12q24.1, has been linked to HolteOram syndrome. More than 70 mutations in the TBX5 gene (Online Mendelian Inheritance in Man no. 601620) resulting in a haploinsufficiency have been associated with HolteOram syndrome. However, only 35% of cases of HolteOram syndrome can be linked to such mutations.4 In addition, neither the genotype nor the location of the mutation determines the phenotype in HolteOram syndrome.5 Although the presentation may be spontaneous, more commonly there is an autosomal dominant transmission with 100% penetrance and variable expressivity. PRESENTATION Patient presentation to the hand surgeon varies, typically depending on the presence or absence of a family From the Shriners Hospital for Children and St. Louis Children’s Hospital; and the Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO. Received for publication January 14, 2014; accepted in revised form February 15, 2014. No benefits in any form have been received or will be received related directly or indirectly to the subject of this article. Corresponding author: Charles A. Goldfarb, MD, Washington University Orthopedics, 660 South Euclid Avenue, Campus Box 8233, St. Louis, MO 63110; e-mail: addisonk@ wudosis.wustl.edu. 0363-5023/14/---0001$36.00/0 http://dx.doi.org/10.1016/j.jhsa.2014.02.015
history. In families with a parent with HolteOram syndrome, the diagnosis may have been suggested by prenatal ultrasound6 and confirmed after birth, before presentation to the hand surgeon. However, when HolteOram syndrome presents spontaneously, patients often come to the hand surgeon with an apparent upper extremity birth anomaly. This may seem to be isolated to the limb(s) because intelligence is normal and overall development is typical. In such patients, like others with RLD, we send the patient for an echocardiogram as part of a comprehensive evaluation. If a cardiac septal defect is identified, we refer the patient to a pediatric geneticist for confirmation of the diagnosis of HolteOram syndrome. CLINICAL PHENOTYPES Upper limb The clinical presentation of limb deficiency in HolteOram syndrome is variable, but most patients are on the spectrum of RLD. The thumb is often involved although not universally. When affected, the thumb is typically either absent or hypoplastic, but may be different from other hypoplastic thumbs and often is not classifiable by traditional grading systems. The thumb may be triphalangeal, syndactylized to the index ray, or have a finger-like appearance (5-finger hand), resting in the plane of the fingers. Other upper extremity anomalies are even more variable. The forearm is often involved, the most common finding of which is a deficient or completely absent radius (Figs. 1, 2); radioulnar synostosis may also be encountered. Abnormalities within the carpus, such as the presence of additional carpals, have also been reported.7 There may be brachydactyly,8 polydactyly,9 or clinodactyly (Fig. 2, small finger). Often, but not always, the upper extremity deficiencies are bilateral.10 Both the RLD and the thumb anomaly in HolteOram syndrome may be more severe than nonsyndromic forms. Lower limb Lower limb anomalies in HolteOram syndrome are infrequently reported. In 1 report, a single patient was described with bilateral findings of a bifid distal
Ó 2014 ASSH
r
Published by Elsevier, Inc. All rights reserved.
r
1
2
HOLTeORAM SYNDROME
FIGURE 1: A Clinical photograph of left radial longitudinal deficiency. Note the partial syndactyly between the index and middle fingers. B Radiograph of the same patient’s left hand. The index ray is hypoplastic.
phalanx of the third toe, an absent distal phalanx of the fourth toe, and hypoplasia of the second, third, and fourth toe phalanges.8 Cardiac Atrial septal defects and ventricular septal defects are the most common cardiac abnormalities in HolteOram syndrome. There is a correlation between the severity of the limb and the cardiac defects.10 In addition to the cardiac septal defects, some patients have cardiac conduction deficits or other assorted anomalies, including mitral valve prolapse, hypoplastic left heart syndrome, and coarctation of the aorta. REFERENCES 1. Holt M, Oram S. Familial heart disease with skeletal malformations. Br Heart J. 1960;22:236e242. 2. Goldfarb CA, Wall L, Manske PR. Radial longitudinal deficiency: the incidence of associated medical and musculoskeletal conditions. J Hand Surg Am. 2006;31(7):1176e1182. 3. Basson CT, Bachinsky DR, Lin RC, et al. Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet. 1997;15(1):30e35. 4. de Graaff E, Kozin SH. Genetics of radial deficiencies. J Bone Joint Surg Am. 2009;91(suppl 4):81e86. 5. Brassington AM, Sung SS, Toydemir RM, et al. Expressivity of HoltOram syndrome is not predicted by TBX5 genotype. Am J Hum Genet. 2003;73(1):74e85. 6. Gray BL, Calfee RP, Dicke JM, Steffen J, Goldfarb CA. The utility of prenatal ultrasound as a screening tool for upper
FIGURE 2: Radiograph of severe radial longitudinal deficiency (absent radius) with complete syndactyly of the thumb and index finger. The thumb is notably hypoplastic. There is a clinodactyly of the little finger, an atypical finding in HolteOram syndrome.
J Hand Surg Am.
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HOLTeORAM SYNDROME
extremity congenital anomalies. J Hand Surg Am. 2013;38(11): 2106e2111. 7. Poznanski AK, Gall JC Jr, Stern AM. Skeletal manifestations of the Holt-Oram syndrome. Radiology. 1970;94(1):45e53. 8. Garavelli L, De Brasi D, Verri R, et al. Holt-Oram syndrome associated with anomalies of the feet. Am J Med Genet A. 2008;146(9):1185e1189.
J Hand Surg Am.
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9. Moens P, De Smet L, Fabry G, Fryns JP. Holt-Oram syndrome: postaxial and central polydactyly as variable manifestations in a four generations family. Genet Couns. 1993;4(4):277e280. 10. Newbury-Ecob RA, Leanage R, Raeburn JA, Young ID. Holt-Oram syndrome: a clinical genetic study. J Med Genet. 1996;33(4): 300e307.
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Vol. -, - 2014
HolteOram Syndrome Charles A. Goldfarb, MD, Lindley B. Wall, MD
H
(Online Mendelian Inheritance in Man no. 142900) is a combination of a cardiac septal defect or conduction defect and an upper extremity anomaly often affecting the thumb. Alternative, less specific terminology includes heartehand syndrome, atriodigital dysplasia, and cardiac limb syndrome. The syndrome carries the name of Holt and Oram,1 who reported in 1960 on the familial occurrence of an atrial septal defect and thumb anomaly in family members over 4 generations. The estimated incidence is 1 in 100,000 live births. In a recent evaluation of medical conditions in 138 patients with radial longitudinal deficiency (RLD),2 7 patients had HolteOram syndrome, making it the fourth most common syndrome or association in patients with RLD. OLTeORAM
SYNDROME
ETIOLOGY Transcription factor TBX5, a key factor in limb and cardiac development,3 with a gene locus at 12q24.1, has been linked to HolteOram syndrome. More than 70 mutations in the TBX5 gene (Online Mendelian Inheritance in Man no. 601620) resulting in a haploinsufficiency have been associated with HolteOram syndrome. However, only 35% of cases of HolteOram syndrome can be linked to such mutations.4 In addition, neither the genotype nor the location of the mutation determines the phenotype in HolteOram syndrome.5 Although the presentation may be spontaneous, more commonly there is an autosomal dominant transmission with 100% penetrance and variable expressivity. PRESENTATION Patient presentation to the hand surgeon varies, typically depending on the presence or absence of a family From the Shriners Hospital for Children and St. Louis Children’s Hospital; and the Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO. Received for publication January 14, 2014; accepted in revised form February 15, 2014. No benefits in any form have been received or will be received related directly or indirectly to the subject of this article. Corresponding author: Charles A. Goldfarb, MD, Washington University Orthopedics, 660 South Euclid Avenue, Campus Box 8233, St. Louis, MO 63110; e-mail: addisonk@ wudosis.wustl.edu. 0363-5023/14/---0001$36.00/0 http://dx.doi.org/10.1016/j.jhsa.2014.02.015
history. In families with a parent with HolteOram syndrome, the diagnosis may have been suggested by prenatal ultrasound6 and confirmed after birth, before presentation to the hand surgeon. However, when HolteOram syndrome presents spontaneously, patients often come to the hand surgeon with an apparent upper extremity birth anomaly. This may seem to be isolated to the limb(s) because intelligence is normal and overall development is typical. In such patients, like others with RLD, we send the patient for an echocardiogram as part of a comprehensive evaluation. If a cardiac septal defect is identified, we refer the patient to a pediatric geneticist for confirmation of the diagnosis of HolteOram syndrome. CLINICAL PHENOTYPES Upper limb The clinical presentation of limb deficiency in HolteOram syndrome is variable, but most patients are on the spectrum of RLD. The thumb is often involved although not universally. When affected, the thumb is typically either absent or hypoplastic, but may be different from other hypoplastic thumbs and often is not classifiable by traditional grading systems. The thumb may be triphalangeal, syndactylized to the index ray, or have a finger-like appearance (5-finger hand), resting in the plane of the fingers. Other upper extremity anomalies are even more variable. The forearm is often involved, the most common finding of which is a deficient or completely absent radius (Figs. 1, 2); radioulnar synostosis may also be encountered. Abnormalities within the carpus, such as the presence of additional carpals, have also been reported.7 There may be brachydactyly,8 polydactyly,9 or clinodactyly (Fig. 2, small finger). Often, but not always, the upper extremity deficiencies are bilateral.10 Both the RLD and the thumb anomaly in HolteOram syndrome may be more severe than nonsyndromic forms. Lower limb Lower limb anomalies in HolteOram syndrome are infrequently reported. In 1 report, a single patient was described with bilateral findings of a bifid distal
Ó 2014 ASSH
r
Published by Elsevier, Inc. All rights reserved.
r
1
2
HOLTeORAM SYNDROME
FIGURE 1: A Clinical photograph of left radial longitudinal deficiency. Note the partial syndactyly between the index and middle fingers. B Radiograph of the same patient’s left hand. The index ray is hypoplastic.
phalanx of the third toe, an absent distal phalanx of the fourth toe, and hypoplasia of the second, third, and fourth toe phalanges.8 Cardiac Atrial septal defects and ventricular septal defects are the most common cardiac abnormalities in HolteOram syndrome. There is a correlation between the severity of the limb and the cardiac defects.10 In addition to the cardiac septal defects, some patients have cardiac conduction deficits or other assorted anomalies, including mitral valve prolapse, hypoplastic left heart syndrome, and coarctation of the aorta. REFERENCES 1. Holt M, Oram S. Familial heart disease with skeletal malformations. Br Heart J. 1960;22:236e242. 2. Goldfarb CA, Wall L, Manske PR. Radial longitudinal deficiency: the incidence of associated medical and musculoskeletal conditions. J Hand Surg Am. 2006;31(7):1176e1182. 3. Basson CT, Bachinsky DR, Lin RC, et al. Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet. 1997;15(1):30e35. 4. de Graaff E, Kozin SH. Genetics of radial deficiencies. J Bone Joint Surg Am. 2009;91(suppl 4):81e86. 5. Brassington AM, Sung SS, Toydemir RM, et al. Expressivity of HoltOram syndrome is not predicted by TBX5 genotype. Am J Hum Genet. 2003;73(1):74e85. 6. Gray BL, Calfee RP, Dicke JM, Steffen J, Goldfarb CA. The utility of prenatal ultrasound as a screening tool for upper
FIGURE 2: Radiograph of severe radial longitudinal deficiency (absent radius) with complete syndactyly of the thumb and index finger. The thumb is notably hypoplastic. There is a clinodactyly of the little finger, an atypical finding in HolteOram syndrome.
J Hand Surg Am.
r
Vol. -, - 2014
HOLTeORAM SYNDROME
extremity congenital anomalies. J Hand Surg Am. 2013;38(11): 2106e2111. 7. Poznanski AK, Gall JC Jr, Stern AM. Skeletal manifestations of the Holt-Oram syndrome. Radiology. 1970;94(1):45e53. 8. Garavelli L, De Brasi D, Verri R, et al. Holt-Oram syndrome associated with anomalies of the feet. Am J Med Genet A. 2008;146(9):1185e1189.
J Hand Surg Am.
3
9. Moens P, De Smet L, Fabry G, Fryns JP. Holt-Oram syndrome: postaxial and central polydactyly as variable manifestations in a four generations family. Genet Couns. 1993;4(4):277e280. 10. Newbury-Ecob RA, Leanage R, Raeburn JA, Young ID. Holt-Oram syndrome: a clinical genetic study. J Med Genet. 1996;33(4): 300e307.
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