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Liebenberg Syndrome: Case Report and Insight Into Molecular Basis
SCIENTIFIC ARTICLE
Liebenberg Syndrome: Case Report and Insight Into Molecular Basis Hisham Abdel-Ghani, MD, Ayman Mansour, MD, Mostafa Mahmoud, MD, Magdy Ez-Elarab, MD We report a case of Liebenberg syndrome in a 6-year-old girl, including the clinical, radiological, angiographic, and operative findings. We note that the forearm and hand malformations have similarities to leg and foot anatomy. Our observations may help provide insight into the etiology of this unusual condition. (J Hand Surg 2013;38A:459–465. Copyright © 2013 by the American Society for Surgery of the Hand. All rights reserved.) Key words Liebenberg syndrome, homeotic transformation.
IEBENBERG SYNDROME IS a rare condition characterized by dysplasia of the bony components of elbow, forearm, and hand. Most previous reports described different affected families and pedigrees and shared the same clinical and radiological description of dysplasia of the elbow and forearm, abnormally shaped carpals, and brachydactyly.1–3 Spielmann et al4 men-
L
tioned that the upper extremities undergo partial homeotic transformation and acquire features of the lower limbs in this syndrome. In this report, we describe a case of Liebenberg syndrome, including detailed clinical, radiographic, angiographic, and intraoperative findings that demonstrate a series of anomalies resembling lower extremity features in the elbow, wrist, and hand.
FIGURE 1: General appearance of the patient with Liebenberg syndrome, with deformities limited to elbows, forearms, and hands. From the Departments of Pediatric Orthopedics and Radiodiagnosis, Faculty of Medicine, Cairo University, Cairo, Egypt. Received for publication September 26, 2012; accepted in revised form December 11, 2012. No benefits in any form have been received or will be received related directly or indirectly to the subject of this article. Correspondingauthor:HishamAbdel-Ghani,MD,DepartmentofPediatricOrthopedics,Faculty of Medicine, Cairo University, 10 Mourad Street, Giza Square, 12511 Giza, Egypt; e-mail: [email protected] and [email protected]. 0363-5023/13/38A03-0005$36.00/0 http://dx.doi.org/10.1016/j.jhsa.2012.12.015
FIGURE 2: The wrist is fixed in radial deviation. A A volar bony prominence (arrow) is visible at the level of the wrist, with the tendon attached to it. B Clawing of the ulnar digits described in previous reports as camptodactyly or brachydactyly.1–3
© ASSH 䉬 Published by Elsevier, Inc. All rights reserved. 䉬 459
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FIGURE 3: A X-ray and 3-dimensional computed tomography of the elbow. The long arrow points to the bony prominence of the radius resembling the tibial tuberosity. The short arrow points to the proximal end of the ulna. B X-ray of normal knee and elbow. The long arrow points to the tibia and its counterpart in the upper limb (the radius). The short arrow points to the fibula and its counterpart in the upper limb (the ulna). This reflects the similarities between the forearm bones in A and the leg bones rather than the normal forearm bones in B.
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FIGURE 4: A Posteroanterior x-ray of the wrist. T, triquetrum; H, hamate; L, lunate; P, capitate; S, elongated radial styloid. The triquetrum and hamate are enlarged. The lunate occupies a position similar to the talus in the ankle. The scaphoid is absent, and the long styloid process of the radius (similar to the medial malleolus) replaces the scaphoid and articulates with the radial side of the lunate. B Oblique view of the patient’s wrist. C Corresponding view of a clubfoot, for comparison. There are strong similarities between the shapes and arrangement of the carpals and tarsals.
FIGURE 5: A Lateral view x-ray of a foot with equinus deformity. The arrow points to the calcaneal tuberosity. B Threedimensional computed tomography of the wrist. The arrow points to the enlarged pisiform fused to the triquetrum, which is the counterpart of the calcaneal tuberosity in the foot.
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FIGURE 6: A The fleshy muscle originating on the dorsum of the wrist. This is similar to the extensor digitorum brevis on the dorsum of the foot B.
FIGURE 7: A Volar aspect of the wrist. The unlabeled arrow points to the thick tendon inserted into the enlarged pisiform. B Cut section of the carpals at the osteotomy level showing shallow carpal tunnel.
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FIGURE 8: Arrows point to the terminal medial and lateral branches of the volar vessels that are similar to the medial and lateral plantar vessels.
CASE REPORT A 6-year-old girl presented with bilateral symmetric isolated malformations of the elbows, forearms, and hands (Fig. 1). She had bilateral 30° flexion deformity of the elbows and was able to flex to 110°. The forearms were fixed in midposition. The wrists were fixed in 30° radial deviation and 20° flexion. A bony prominence was evident at the level of the volar wrist crease (Fig. 2A). The ulnar border of the hands appeared curved. The ulnar 2 digits were not only short, as described before,1 but actually resembled toes, appearing dysplastic and clawed (Fig. 2). The patient had incomplete opposition of the thumbs. Active finger flexion and extension and single hand grasp were maintained. X-rays and computed tomography showed abnormalities of the distal end of the humerus resembling the distal end of the femur (Fig. 3). The proximal end of the radius and ulna were similar to the proximal tibia and fibula, respectively. The proximal end of the radius was flattened, with a bony prominence resembling the tibial tuberosity (Fig. 3). The proximal end of the ulna did not resemble a normal ulna, but rather was similar to the proximal end of fibula. It had a rounded small end lacking an olecranon process (Fig. 3). The distal end of the radius had a long radial styloid process similar in shape to the medial malleolus (Fig. 4). The triquetrum and hamate were enlarged, and the lunate occupied a position similar to the talus in the ankle mortise (Fig. 4). The radial-side carpals were smaller in size without a visible scaphoid (Fig. 4). The radiological appearance of the carpals was similar to that of a clubfoot (Fig. 4B, C). The pisiform was enlarged and fused to the triquetrum, producing the prominence on the volar aspect
463
FIGURE 9: Postoperative radiological and clinical appearance of the hand.
of the wrist. This pisiform provided a volar extension of the triquetrum akin to the calcaneal tuberosity (Fig. 5). Computed tomographic angiography revealed that instead of bifurcating into radial and ulnar branches, the brachial artery bifurcated at the level of the proximal forearm into volar and dorsal branches similar to the popliteal artery. The dorsal branch further bifurcated, 1 volar and 1 dorsal to the interosseous membrane. At the level of the wrist, the volar branch further bifurcated, 1 ulnar and the other radial, similar to the medial and lateral plantar vessels in the lower limb. This vascular pattern carried great similarities to that of the lower limb.5 There was no history of consanguinity or similar conditions in the family. History of drug intake during pregnancy was unavailable. We planned surgery to correct radial deviation and flexion deformity of the wrist by performing a dorsoulnar-based closing wedge carpectomy. We limited surgical exploration to the needed operative procedure without overdissection or anatomical exploration. We approached the wrist through an S-shaped incision along the ulnar side of the wrist and carried deeper dissection into the dorsal and volar aspects of it. On the dorsum, we found thick fleshy muscle deep to the extensor retinaculum. Tensioning this muscle produced extension of the metacarpophalangeal joint of the fingers and thumb. This muscle carried strong similarities to the extensor digitorum brevis muscle in the foot (Fig. 6). On the volar aspect, the thick, clinically visible tendon was inserted into the pisiform and did not extend beyond it to the base of the fifth metacarpal (the normal insertion of the flexor carpi ulnaris) (Fig. 7). The coalition of the pisiform to the triquetrum and its position in the middle of the wrist were similar to the calcaneal
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FIGURE 10: Diagram showing the role of different T-box genes in limb development and the effect of misexpression of these genes in the upper and lower limb buds.
tuberosity in the foot, and the thick tendon attached to it was similar to the Achilles tendon (Figs. 5, 7). The flexor retinaculum was not as thick as the normal flexor retinaculum and was located on the radial side of the centrally positioned pisiform. Deep to the flexor retinaculum, there were 2 terminal neurovascular bundles similar to the medial and lateral planter neurovascular bundles in the foot (Fig. 8). Deeper dissection on the radial aspect revealed a flexor digitorum muscle, but we could not distinguish 2 distinct muscle groups. A thick tendon surrounded by synovial sheath similar to the tibialis posterior tendon was deepest on the radial side. After retracting the volar and dorsal structures, we performed wedge carpectomy and fixed it with K-wires. The cross-section of the bones at the level of the osteotomy showed a shallow carpal tunnel (Fig. 7B). A below-elbow cast was applied for 6 weeks. We corrected the alignment of the wrist; clawing of the ulnar 2 digits improved after correction of the wrist flexion deformity. Preoperative hand function was maintained postoperatively and throughout 1 year of follow-up (Fig. 9).
DISCUSSION Liebenberg syndrome is a rare condition characterized by dysplasia of bony components of the elbow joint, abnormalities in the dimension and shape of carpals, and brachydactyly.1 There have been only a few case reports of this syndrome; most have included only limited clinical descriptions.1–3 These descriptions have been consistent with the original findings of Liebenberg,1 and the presence of affected pedigrees and twins suggests that this is a familial condition.1–3 The current study and recent work by Spielmann et al4 differ in describing strong similarities between the anatomy of the upper limb in Liebenberg syndrome and that of the leg and foot. This suggests that the genetic abnormality underlying this condition may be related to the genes determining limb bud identity. Studies on a range of vertebrate limb models have identified 3 genes that appear to program a limb to develop along either a forelimb or hind limb pathway. Tbx5 and Tbx4 are T-box family transcription factors expressed in the forelimb and hind limb, respectively. PITX1, another transcription factor, is expressed in the
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developing hind limb but not the forelimb. The temporal and spatial expression patterns of Tbx5, Tbx4, and PITX1 suggest they have an important role in programming the identity of the developing limb.6 Misexpression experiments in chicks have provided further evidence for the role of these genes. When ectopically expressed in the hind limb, Tbx5 can alter the morphology of the developing limb to a more winglike structure. Tbx4 and PITX1 can change forelimb morphology into hind limb morphology if misexpressed in the developing forelimb. T-Box genes may alter the morphology of the limb by selectively inducing or repressing genes or markers that are specific to either the forelimb or hind limb (Fig. 10). For instance, ectopically expressed Tbx5 can induce expression of the forelimb marker Hoxd9 and repress the hind limb marker Hoxc9.7 Recently, Spielmann et al4 hypothesized that the arm-to-leg transformation observed in affected subjects from families segregating Liebenberg syndrome results from misexpression of PITX1 in the upper extremities. The associated mutations they identified are likely to remove active PITX1 forelimb suppressor and/or insulator elements, and thereby move active enhancer elements in the vicinity of the PITX1 regulatory landscape. The authors generated transgenic mice in
465
which PITX1 was misexpressed under the control of a nearby enhancer and were able to recapitulate the Liebenberg phenotype. Our description may help in understanding the corresponding anatomical structures of the hand and foot, the underlying embryologic disturbances, and the genes responsible for determining limb identity in humans. REFERENCES 1. Liebenberg F. A pedigree with unusual anomalies of the elbows, wrists and hands in five generations. S Afr Med J. 1973;47(17):745– 748. 2. Tiberio G, Diglio MC, Graziani M, Testa F, Giannotti A. Liebenberg syndrome: brachydactyly with joint dysplasia (MIM 186550): a second family. J Med Genet. 2000;37(7):548 –551. 3. Di Gennaro G, Gilardi R, Landi A, Ferrari P, Sartini S. Liebenberg syndrome: first case of monovular twins. Plast Reconstr Surg. 2010; 125(1):25e–27e. 4. Spielmann M, Brancati F, Krawitz PM, et al. Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus. Am J Hum Genet. 2012;91(4):1–7. 5. Williams P, Warwick R. Gray’s Anatomy. Edinburgh: Churchill Livingstone; 1980:702–735. 6. Barham G, Clarke NM. Genetic regulation of embryological limb development with relation to congenital limb deformity in humans. J Child Orthop. 2008;2(1):1–9. 7. Rodriguez-Esteban C, Tsukui T, Yonei S, Magallon J, Tamura K, Izpisua Belmonte JC. The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity. Nature. 1999;398(6730):814 – 818.
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Liebenberg Syndrome: Case Report and Insight Into Molecular Basis Hisham Abdel-Ghani, MD, Ayman Mansour, MD, Mostafa Mahmoud, MD, Magdy Ez-Elarab, MD We report a case of Liebenberg syndrome in a 6-year-old girl, including the clinical, radiological, angiographic, and operative findings. We note that the forearm and hand malformations have similarities to leg and foot anatomy. Our observations may help provide insight into the etiology of this unusual condition. (J Hand Surg 2013;38A:459–465. Copyright © 2013 by the American Society for Surgery of the Hand. All rights reserved.) Key words Liebenberg syndrome, homeotic transformation.
IEBENBERG SYNDROME IS a rare condition characterized by dysplasia of the bony components of elbow, forearm, and hand. Most previous reports described different affected families and pedigrees and shared the same clinical and radiological description of dysplasia of the elbow and forearm, abnormally shaped carpals, and brachydactyly.1–3 Spielmann et al4 men-
L
tioned that the upper extremities undergo partial homeotic transformation and acquire features of the lower limbs in this syndrome. In this report, we describe a case of Liebenberg syndrome, including detailed clinical, radiographic, angiographic, and intraoperative findings that demonstrate a series of anomalies resembling lower extremity features in the elbow, wrist, and hand.
FIGURE 1: General appearance of the patient with Liebenberg syndrome, with deformities limited to elbows, forearms, and hands. From the Departments of Pediatric Orthopedics and Radiodiagnosis, Faculty of Medicine, Cairo University, Cairo, Egypt. Received for publication September 26, 2012; accepted in revised form December 11, 2012. No benefits in any form have been received or will be received related directly or indirectly to the subject of this article. Correspondingauthor:HishamAbdel-Ghani,MD,DepartmentofPediatricOrthopedics,Faculty of Medicine, Cairo University, 10 Mourad Street, Giza Square, 12511 Giza, Egypt; e-mail: [email protected] and [email protected]. 0363-5023/13/38A03-0005$36.00/0 http://dx.doi.org/10.1016/j.jhsa.2012.12.015
FIGURE 2: The wrist is fixed in radial deviation. A A volar bony prominence (arrow) is visible at the level of the wrist, with the tendon attached to it. B Clawing of the ulnar digits described in previous reports as camptodactyly or brachydactyly.1–3
© ASSH 䉬 Published by Elsevier, Inc. All rights reserved. 䉬 459
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FIGURE 3: A X-ray and 3-dimensional computed tomography of the elbow. The long arrow points to the bony prominence of the radius resembling the tibial tuberosity. The short arrow points to the proximal end of the ulna. B X-ray of normal knee and elbow. The long arrow points to the tibia and its counterpart in the upper limb (the radius). The short arrow points to the fibula and its counterpart in the upper limb (the ulna). This reflects the similarities between the forearm bones in A and the leg bones rather than the normal forearm bones in B.
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FIGURE 4: A Posteroanterior x-ray of the wrist. T, triquetrum; H, hamate; L, lunate; P, capitate; S, elongated radial styloid. The triquetrum and hamate are enlarged. The lunate occupies a position similar to the talus in the ankle. The scaphoid is absent, and the long styloid process of the radius (similar to the medial malleolus) replaces the scaphoid and articulates with the radial side of the lunate. B Oblique view of the patient’s wrist. C Corresponding view of a clubfoot, for comparison. There are strong similarities between the shapes and arrangement of the carpals and tarsals.
FIGURE 5: A Lateral view x-ray of a foot with equinus deformity. The arrow points to the calcaneal tuberosity. B Threedimensional computed tomography of the wrist. The arrow points to the enlarged pisiform fused to the triquetrum, which is the counterpart of the calcaneal tuberosity in the foot.
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FIGURE 6: A The fleshy muscle originating on the dorsum of the wrist. This is similar to the extensor digitorum brevis on the dorsum of the foot B.
FIGURE 7: A Volar aspect of the wrist. The unlabeled arrow points to the thick tendon inserted into the enlarged pisiform. B Cut section of the carpals at the osteotomy level showing shallow carpal tunnel.
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FIGURE 8: Arrows point to the terminal medial and lateral branches of the volar vessels that are similar to the medial and lateral plantar vessels.
CASE REPORT A 6-year-old girl presented with bilateral symmetric isolated malformations of the elbows, forearms, and hands (Fig. 1). She had bilateral 30° flexion deformity of the elbows and was able to flex to 110°. The forearms were fixed in midposition. The wrists were fixed in 30° radial deviation and 20° flexion. A bony prominence was evident at the level of the volar wrist crease (Fig. 2A). The ulnar border of the hands appeared curved. The ulnar 2 digits were not only short, as described before,1 but actually resembled toes, appearing dysplastic and clawed (Fig. 2). The patient had incomplete opposition of the thumbs. Active finger flexion and extension and single hand grasp were maintained. X-rays and computed tomography showed abnormalities of the distal end of the humerus resembling the distal end of the femur (Fig. 3). The proximal end of the radius and ulna were similar to the proximal tibia and fibula, respectively. The proximal end of the radius was flattened, with a bony prominence resembling the tibial tuberosity (Fig. 3). The proximal end of the ulna did not resemble a normal ulna, but rather was similar to the proximal end of fibula. It had a rounded small end lacking an olecranon process (Fig. 3). The distal end of the radius had a long radial styloid process similar in shape to the medial malleolus (Fig. 4). The triquetrum and hamate were enlarged, and the lunate occupied a position similar to the talus in the ankle mortise (Fig. 4). The radial-side carpals were smaller in size without a visible scaphoid (Fig. 4). The radiological appearance of the carpals was similar to that of a clubfoot (Fig. 4B, C). The pisiform was enlarged and fused to the triquetrum, producing the prominence on the volar aspect
463
FIGURE 9: Postoperative radiological and clinical appearance of the hand.
of the wrist. This pisiform provided a volar extension of the triquetrum akin to the calcaneal tuberosity (Fig. 5). Computed tomographic angiography revealed that instead of bifurcating into radial and ulnar branches, the brachial artery bifurcated at the level of the proximal forearm into volar and dorsal branches similar to the popliteal artery. The dorsal branch further bifurcated, 1 volar and 1 dorsal to the interosseous membrane. At the level of the wrist, the volar branch further bifurcated, 1 ulnar and the other radial, similar to the medial and lateral plantar vessels in the lower limb. This vascular pattern carried great similarities to that of the lower limb.5 There was no history of consanguinity or similar conditions in the family. History of drug intake during pregnancy was unavailable. We planned surgery to correct radial deviation and flexion deformity of the wrist by performing a dorsoulnar-based closing wedge carpectomy. We limited surgical exploration to the needed operative procedure without overdissection or anatomical exploration. We approached the wrist through an S-shaped incision along the ulnar side of the wrist and carried deeper dissection into the dorsal and volar aspects of it. On the dorsum, we found thick fleshy muscle deep to the extensor retinaculum. Tensioning this muscle produced extension of the metacarpophalangeal joint of the fingers and thumb. This muscle carried strong similarities to the extensor digitorum brevis muscle in the foot (Fig. 6). On the volar aspect, the thick, clinically visible tendon was inserted into the pisiform and did not extend beyond it to the base of the fifth metacarpal (the normal insertion of the flexor carpi ulnaris) (Fig. 7). The coalition of the pisiform to the triquetrum and its position in the middle of the wrist were similar to the calcaneal
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FIGURE 10: Diagram showing the role of different T-box genes in limb development and the effect of misexpression of these genes in the upper and lower limb buds.
tuberosity in the foot, and the thick tendon attached to it was similar to the Achilles tendon (Figs. 5, 7). The flexor retinaculum was not as thick as the normal flexor retinaculum and was located on the radial side of the centrally positioned pisiform. Deep to the flexor retinaculum, there were 2 terminal neurovascular bundles similar to the medial and lateral planter neurovascular bundles in the foot (Fig. 8). Deeper dissection on the radial aspect revealed a flexor digitorum muscle, but we could not distinguish 2 distinct muscle groups. A thick tendon surrounded by synovial sheath similar to the tibialis posterior tendon was deepest on the radial side. After retracting the volar and dorsal structures, we performed wedge carpectomy and fixed it with K-wires. The cross-section of the bones at the level of the osteotomy showed a shallow carpal tunnel (Fig. 7B). A below-elbow cast was applied for 6 weeks. We corrected the alignment of the wrist; clawing of the ulnar 2 digits improved after correction of the wrist flexion deformity. Preoperative hand function was maintained postoperatively and throughout 1 year of follow-up (Fig. 9).
DISCUSSION Liebenberg syndrome is a rare condition characterized by dysplasia of bony components of the elbow joint, abnormalities in the dimension and shape of carpals, and brachydactyly.1 There have been only a few case reports of this syndrome; most have included only limited clinical descriptions.1–3 These descriptions have been consistent with the original findings of Liebenberg,1 and the presence of affected pedigrees and twins suggests that this is a familial condition.1–3 The current study and recent work by Spielmann et al4 differ in describing strong similarities between the anatomy of the upper limb in Liebenberg syndrome and that of the leg and foot. This suggests that the genetic abnormality underlying this condition may be related to the genes determining limb bud identity. Studies on a range of vertebrate limb models have identified 3 genes that appear to program a limb to develop along either a forelimb or hind limb pathway. Tbx5 and Tbx4 are T-box family transcription factors expressed in the forelimb and hind limb, respectively. PITX1, another transcription factor, is expressed in the
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developing hind limb but not the forelimb. The temporal and spatial expression patterns of Tbx5, Tbx4, and PITX1 suggest they have an important role in programming the identity of the developing limb.6 Misexpression experiments in chicks have provided further evidence for the role of these genes. When ectopically expressed in the hind limb, Tbx5 can alter the morphology of the developing limb to a more winglike structure. Tbx4 and PITX1 can change forelimb morphology into hind limb morphology if misexpressed in the developing forelimb. T-Box genes may alter the morphology of the limb by selectively inducing or repressing genes or markers that are specific to either the forelimb or hind limb (Fig. 10). For instance, ectopically expressed Tbx5 can induce expression of the forelimb marker Hoxd9 and repress the hind limb marker Hoxc9.7 Recently, Spielmann et al4 hypothesized that the arm-to-leg transformation observed in affected subjects from families segregating Liebenberg syndrome results from misexpression of PITX1 in the upper extremities. The associated mutations they identified are likely to remove active PITX1 forelimb suppressor and/or insulator elements, and thereby move active enhancer elements in the vicinity of the PITX1 regulatory landscape. The authors generated transgenic mice in
465
which PITX1 was misexpressed under the control of a nearby enhancer and were able to recapitulate the Liebenberg phenotype. Our description may help in understanding the corresponding anatomical structures of the hand and foot, the underlying embryologic disturbances, and the genes responsible for determining limb identity in humans. REFERENCES 1. Liebenberg F. A pedigree with unusual anomalies of the elbows, wrists and hands in five generations. S Afr Med J. 1973;47(17):745– 748. 2. Tiberio G, Diglio MC, Graziani M, Testa F, Giannotti A. Liebenberg syndrome: brachydactyly with joint dysplasia (MIM 186550): a second family. J Med Genet. 2000;37(7):548 –551. 3. Di Gennaro G, Gilardi R, Landi A, Ferrari P, Sartini S. Liebenberg syndrome: first case of monovular twins. Plast Reconstr Surg. 2010; 125(1):25e–27e. 4. Spielmann M, Brancati F, Krawitz PM, et al. Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus. Am J Hum Genet. 2012;91(4):1–7. 5. Williams P, Warwick R. Gray’s Anatomy. Edinburgh: Churchill Livingstone; 1980:702–735. 6. Barham G, Clarke NM. Genetic regulation of embryological limb development with relation to congenital limb deformity in humans. J Child Orthop. 2008;2(1):1–9. 7. Rodriguez-Esteban C, Tsukui T, Yonei S, Magallon J, Tamura K, Izpisua Belmonte JC. The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity. Nature. 1999;398(6730):814 – 818.
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