American Journal of Medical Genetics 44:730-737 (1992)
Dominant Mesomelic Dysplasia, Ankle, Carpal, and Tarsal Synostosis Type: A New Autosomal Dominant Bone Disorder Piranit N. Kantaputra, Robert J. Gorlin, and Leonard 0. Langer, Jr. Department of Pediatric Dentistry, School of Dentistry, Chiangmai University, Chiang Mai, Thailand (P.N.K.); Department of Oral Sciences, School of Dentistry (P.N.K., R.J.G.) and Department of Radiology, School of Medicine (L.O.L.), University of Minnesota, Minneapolis
A new type of mesomelic dysplasia was in 3 generations of a large Thai family. It is characterized by bilateral symmetrical marked shortening of the ulnae and shortening and bowing of the radii. The proximal fibula is usually short and synostoses are present between the tibia and fibula and the small malformed calcaneus and talus. The prominent calcanei on the ventral surfaces of the distal fibulae are a characteristic feature of the new type. Carpal and tarsal synostoses are present in some affected people. All affected individuals walk on the tips of their toes with the dorsal foot deviated laterally. The deformities of the radius a n d ulna somewhat resemble those of mesomelic dysplasia, Langer type, but otherwise the condition is distinctly different. This new mesomelic dysplasia is an autosoma1 dominant trait with complete penetrance and variable expressivity over 3 generations. 0 1992 Wiley-Liss, Inc.
KEY WORDS: skeletal dysplasia, radial dysplasia, ulnar dysplasia, hypoplastic fibula, tibia-fibula synostosis INTRODUCTION The mesomelic dysplasias comprise a group of bone disorders characterized by disproportionate shortness of the middle segment of the limbs which may be accompanied by other anomalies involving the proximal or distal parts of the limbs. Affected individuals have nor-
ma1 intelligence. The International Nomenclature of Constitutional Disease of Bone classified mesomelic dysplasia into 5 groups: Nievergelt, Langer, Robinow, Reinhardt-Pfeiffer, and other types [Milgram, 19901.We would like to describe a new type of mesomelic dysplasia and to review briefly the literature regarding the previously described types of mesomelic dysplasia. CLINICAL REPORTS This disorder was transmitted from male identical twins to their sons, daughters, and 3 grandsons. Their clinical and radiographic appearances are distinctly different from previously described types of mesomelic dysplasia. The affected are of Thai origin, born to unrelated parents. Figure 1 shows the pedigree obtained from an affected individual (11-91. Fifteen individuals were affected, of which 10 are males. Clinical Findings Affected individuals share a common clinical appearance (Fig. 2). They are of normal intelligence. Craniofacial structures are unremarkable. Panoramic films show normal dental development. The forearms are severely short, radially bowed, and the hands deviate ulnarly (Fig. 3). There is mildly short stature as the legs are somewhat short. The ankle joints are absent. The long axes of the shanks, hind, and mid foot are essentially parallel. The affected stand on the tips of their toes with the dorsal foot deviated laterally. The soles face upwards. The feet appear of normal length (Figs. 2, 4). The dorsum of the feet in the weight bearing areas appears hyperkeratotic. The average height and weight of affected male adults were 152.0 * 3.5 cm and 56.4 * 7.7 kg, respectively. An affected adult female was 135 cm tall and weighed 40 kg.
Radiographic Findings All affected individuals share common radiographic Received for publication October 10, 1991; revision received appearances with some variation. The identical twin brothers (11-9 and 11-10) have almost identical radioMay 13, 1992. Address reprint requests t o Piranit N. Kantaputra, D.D.S., M.S., graphic appearances. The radiographic findings of the Department of Pediatric Dentistry, School of Dentistry, Chiang- youngest affected individual (IV-1)are somewhat differmai University, Chiang Mai 50002, Thailand. ent from those in the rest of the family. The findings 0 1992 Wiley-Liss, Inc.
Mesomelic Dysplasia, Ankle, Carpal, and Tarsal Synostosis Qpe
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Fig. 1. Family pedigree.
Fig. 4. Angle between the leg and foot is absent. The feet have normal length.
presented here are separated into 2 groups according to similarities: adults (11-9, 11-10, 111-1, 111-15, 111-18, and 111-23) and a grandson (IV-1). Fig. 2. Patient 11-9.Normal craniofacial development. The forearms are severely short and radially bowed. The hands deviate ulnarly. The legs are somewhat short. He stands on the tips ofhis toes with the dorsum of his left foot deviated laterally.
Adults (6 Cases) Upper limbs. The radii and ulnae are very short. The ulna is very broad and disproportionately shorter than the radius. The radius is markedly bowed radially and broad, but less so than the ulna. The changes in the radius and ulna are bilateral and symmetrical. The distal radius articulates with the scaphoid, often articulates with the lunate, and sometimes with the triquetrum. The distal ulna articulates with the triquetrum. The distal radius and ulna do not articulate as the triangular-shaped proximal carpal row with the lunate at the apex lies between them. The pisiform is absent (Fig. 5). Carpal synostoses are present in some individuals. Scaphoid-trapezium fusion is the commonest, but capitate-trapezoid, capitate-lunate, and in one trapezium-scaphoid-trapezoid-capitateindividual, lunate fusion is present. This same individual (111-1) also has a fusion between the fibulo-calcaneal complex and the tibio-talar complex and fusions in the feet. The hand is deviated ulnarlv due to the disDroDortionateiv short ulna. The metaca&ls and phalanges are (Fig. 5). I
Fig. 3. Forearms are severely short and plump. Hands deviate ulnarly.
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Fig. 5. AP forearm and hand of 111-1.The radius is markedly short and bowed radially. The ulna is shorter than the radius. The radius articulates with scaphoid and lunate. The ulna articulates with the triquetrurn. Seaphoid-trapezium and capitate-trapezoid fusions are present. The pisiform is absent. The metacarpals and phalanges are normal.
Lower limbs. The tibiae and fibulae are short in relation to the femora. The proximal end of the fibula is shorter than usual in relation to the tibia. A separate calcaneus and talus are not present. The long axis of the tarsals and metatarsals is in the same plane as that of the tibia and fibula (Figs. 6-8). There is deformity of the distal part of the fibula which, because of the prominent angular protrusion on the ventral surface and the distal articulation with the cuboid, appears to represent synostosis between the distal fibula and calcaneus. This will be referred to as the fibulo-calcaneal complex. No transverse lines residual from this fusion are seen in any of the individuals (Figs. 6,7).No lateral malleolus is present (Figs. 6, 8). The distal end of the tibia is fused to a small talus which articulates with the laterally placed navicular. This will be referred to as the tibio-talar complex (Figs. 6,8). There is a more or less conspicuous narrow lucency between parallel dense lines in the expected region of a tibio-talar synostosis (Fig. 6). This represents incipient, incomplete, or residual changes related to the fusion. It is present in all adult individuals. It is least apparent in the oldest individuals, the twin brothers. The medial malleolus is present. In the one individual who shows extensive carpal bone synostosis (111-1),there is fusion between the tibio-talar and fibulo-calcaneal complexes on the right (Fig. 8). In
Fig. 6. The proximal fibula is short. The malformed calcaneus protruded from the medial aspect of ventral surface of the distal fibulocalcaneal complex. The distal fibulo-calcaneal complex articulates with the cuboid. The arrowheads indicate exostosis off the medial aspect of the fibulo-calcaneal complex just below the proximal part of the calcaneus (see Fig.8). At the distal tibio-talar complex there is a lucent line between pararallel dense lines. These represent the fusion line between the tibia and talus. The navicular which articulates with the tibio-talar complex proximally is fused with the first cuneiform distally. The long axes of the tibia, fibula, and those of tarsals, and metatarsals are almost parallel.
another patient there is possible fusion here. In some patients a small exostosis off the medial aspect of the distal fibulo-calcaneal complex is seen. This is at the level of the above described fusion and may be related to it (Figs. 6, 8). In one case there is fusion between the talar portion of the tibio-talar complex and the fibulocalcaneal complex. The navicular is laterally placed. The tarsals and metatarsals appear everted. Synostosis between the navicular and first cuneiform is present in several individuals (Figs. 6, 8).
8-Year-Old Male Upper limbs. The radius is very short and broad and is markedly bowed radially. Only very small ossified proximal and distal radial epiphyses are present. The ulna is disproportionately shorter than the radius. No distal ulnar epiphysis is seen. The distal radius and ulna do not articulate. The lunate, scaphoid, trapezium, and trapezoid are small. The hand deviates ulnarly due to the disproportionately short ulna. The metacarpals and phalanges are normal (Fig. 9). Lowerlimbs. The tibia and fibula are short in relation to the femur. The proximal end of the fibula is
Mesomelic Dysplasia, Ankle, Carpal, and Tarsal Synostosis Q p e
Fig. 7. The prominent angular protrusion on the ventral surface of the fibulo-calcaneal complex represents the malformed proximal portion of the calcaneus. There is no fusion line between the fibula and calcaneus. The normal angle between the leg and foot is absent.
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Fig. 8. The knee is seen in lateral projection, the distal shank bones in oblique projection. The distal fibulo-calcaneal complex is larger than the proximal fibula. A separate talus and calcaneus are not present. The fibulo-calcaneal complex articulates with the cuboid. On the right, there is fusion between the fibulo-calcaneal and tibio-talar complexes. The arrowheads indicate a small exostosis off the medial aspect of the fibulo-calcaneal complex on the left. This is a t the same level as the fusion on the right. The lateral malleolus is not present. The navicular is laterally placed.
disproportionately short. In both limbs the distal fibulocalcaneal complexes articulate with the cuboid bones. On the right, the small malformed talus is separate from the tibia and is fused to the distal fibulo-calcaneal complex. Distally the talus articulates with the navicular which is irregularly ossified (Fig. 10). On the left, the talus is separate from both the distal tibia and the fibulo-calcaneal complex. It lies lateral to the tibia and medial to the fibulo-calcaneal complex in frontal projection and somewhat dorsal to the shank bones in lateral projection. It articulates distally with the navicular. The navicular lies more lateral than usual in relation to the cuboid. The tarsals and metatarsals appear everted in frontal projection. No tarsal synostoses are present (Fig. 10).
DISCUSSION The previously described types of mesomelic dysplasia have been described [Kaitila et al., 19761. The schematic presentation of characteristic radiographic changes of each type is presented in Figure lla,b. Although this new autosomal dominantly inherited mesomelic dysplasia appears distinctly different from those previously described, there are some similarities to mesomelic dysplasia, Langer type in the upper limbs. In both disorders, there are short and bowed radii, short ulna, ulnar deviation of hands, and hvwdasia of fibulae. The shortening of the humerus, tibii, and fibula
Fig. 9. AP forearms and hands of the 8-year-old boy (IV-1). The radius is very short and broad and is markedly bowed radially. Very small ossified proximal and distal radial epiphyses are present. The ulna is disproportionately shorter than the radius. The distal ulnar epiphysis is not present. The hand deviates ulnarly. The metacarpals and Dhalanees are normal.
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Fig. 10. The proximal fibula is disproportionately shorter than the tibia. The distal fibulo-calcaneal complex articulates with the cuboid. The right talus is separate from the tibia and fused with the fibulocalcaneal complex. The left talus articulates with the tibia proximally and with laterally placed navicular distally.
is greater in the Langer type [Langer, 19671. The malformations of the talus and calcaneus, the presence of tibio-talar and fibulo-calcaneal complexes, and synostoses of tibia and fibula and carpal and tarsal bones make this new type of mesomelic dysplasia distinctly different from the Langer type (Fig. 12). This new type clearly represents the heterozygous state of a different autosomal dominant gene. Carpal synostosis in this new disorder appears to be a variable and inconsistent finding. Bilateral fusion of the scaphoid-trapezium-trapezoid, found in one patient, is very rare in the general population. Fusion of carpal bones may occur as an isolated anomaly or as part of a generalized bone disorder. Fusion of carpal bones in the same row is generally an isolated anomaly. Garn et al. [1971] reported that no cases of fusion from proximal to distal rows were found in more than 25,000 hand radiographs. Carpal fusion across rows is usually associated with congenital malformation syndromes and appears to be progressive [Poznanski and Holt, 1971; Cope, 19741. Carpal fusion has been reported in association with Madelung deformity [Alexander and Johnson, 19411,diastrophic dysplasia [Poznanski and Holt, 19711, and dyschondrosteosis [Langer, 19651.Capitate-hamate fusion appears to be a constant finding in Ellis-van Creveld syndrome [Caffey, 19521. Carpal fusion may be associated with nonskeletal disorders such as UllrichTurner syndrome [Preger et al., 19681. The incidence of
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Fig. 11. a: A schematic presentation of characteristic radiographic features ofvarious forms of mesomelic skeletal dysplasia. The drawings are from original case reports. Patients were of different ages and therefore present different developmental stages for each dysplasia. Right forearm and hand the radius is shadowed. Normal, adult; dyschondrosteosis, adult; Langer type, 4 years; Nievergelt type, 2% years; Werner type, adult; Ellis-van Creveld type, 6 years; Campailla-Martinelli type, adult; Reinhardt-Pfeiffer type, 9 years; Robinow type, 5’/z years. b: Right leg; fibula has been shadowed. Normal, adult; dyschondrosteosis, adult; Langer type, 2% years; Nievergelt type, 2 years; Werner type, 10 months; Ellis-van Creveld type, 6 years; Maroteaux type, 13 years; Campailla-Martinelli type, adult; Reinhardt-Peiffer type, 14years; Robinow type, 5% years. (Reproduced from Kaitila et al., 1976, with permission of the publisher.)
Mesomelic Dysplasia, Ankle, Carpal, and Tarsal Synostosis w p e
Antero-Posterior View
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Fig. 12. The schematic presentation of the mesomelic dysplasia, carpal, and tarsal synostosis type.
ankle,
carpal synostosis varies with sex and race [Garn et al., 19711. It is more common in Nigerians with an incidence up to 8%[Cockshott, 19631.Fusion of 2 carpal bones was found in only 7 of 1,000 English schoolchildren [Hughes and Tanner, 19661. Triquetral-lunate fusion is the most common form of carpal fusion [Poznanski and Holt, 19711. Garn et al. [19711 reported triquetral-lunate fusion in 0.1% of 11,663 white Americans and 1.6% of 7,543 black Americans. It was found twice as common in females as in males [Garn et al., 19711. Giedion et al. 119753 report a case of Robinow syndrome with severe vertebral segmental defects and triquetral-lunate fusion. Fusion of multiple carpals is very rare in the general population [Hughes and Tanner, 1966;Thijn, 19861. Autosomal dominant inheritance of congenital mitral insufficiency, conductive deafness, short stature, and carpal and tarsal fusions has been described [Forney et al., 19661. The incidence of carpal fusion in the Thai population has never been reported. Radial and ulnar dysplasia in our patients is not associated with congenitally absent carpal bones. Our patients do not have a pisiform bone, but the absence of a pisiform bone is not uncommon. Congenitally missing carpal bones are usually associated with radial and ulnar dhypoplasia [ORahilly, 19511. Radial defects associated with carpal hypoplasia occur as an isolated finding or in association with Fanconi anemia [Juhl et al., 19671, Juberg-Hayward syndrome [Temtamy and McKusick, 1978;Poznanski, 19841,and Holt-Oram syndrome [Chang, 1967; Poznanski et al., 19701.
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According t o the Archipterygial theory, the upper limb develops from one main stem and 4 accessory rays. The main stem accounts for the humerus, ulna, 5th metacarpal, and phalanges of the 5th finger. The first accessory ray accounts for the radius, scaphoid, trapezium, first metacarpal, and its phalanges. The 2nd, 3rd, and 4th rays give rise to the 2nd, 3rd, and 4th fingers [Gegenbaur, 18761. Radial ahypoplasia commonly leads to defects of the radial ray which include hypoplasia or absence of scaphoid, trapezium, first metacarpal and its phalanges [O’Rahilly, 19511. When the radius is ahypoplastic, the ulna is usually curved, short, and thick [Skerik and Flatt, 19691. Ulnar ahypoplasia commonly leads to defects of the ulnar ray. When the ulna is absent or hypoplastic, the 4th and 5th fingers and corresponding carpal bones usually are involved. The pisiform is always absent, which is supported by our findings, and the hamate frequently [Pardini, 1967; Poznanski and Holt, 1971; Schinzel et al., 19741. A fibrous or fibrocartilaginous band extending from the hypoplastic ulna to the distal end of the radius or carpal bones, or both has been described. This band tends to make the hand deviate ulnarly [Ogden et al., 19761. When the radius is hypoplastic or aplastic, the ulna is usually curved and the distal ulnar epiphysis tends to have delayed onset of appearance [Heikel, 19591. In cases with radial and ulnar hypoplasia or aplasia, it is somewhat speculative to identify which is the primary or secondary defect. The association of radial and ulnar hypoplasia is seen in Brachmannde Lange syndrome, faciocardiomelic dysplasia, femurfibula-ulna dysplasia, Ives-Houston syndrome, Roberts syndrome, and WT syndrome [Poznanski, 19841. The radius appears to have hypoplastic epiphyses. It is important t o note that most of our patients do not have carpal synostosis or defects of metacarpals or phalanges. It has been reported that limbs are developed in proximodistal, postaxial, and preaxial directions, with distal part anomalies usually being dependent upon the abnormalities of the proximal ones [Saunders, 1948; Tschumi, 1957; Kwasigroch and Kochhar, 19801. Our cases and the absence of the radius with persistence of the thumb in TAR syndrome do not seem to follow the Archipterygial theory and Tschumi’s concept. The missing part of the fibula similar to that of the ulna is frequently replaced by a strong band of connective tissue which appears to inhibit longitudinal growth of the tibia [Silverman, 19851. Lewin and Opitz [19861 pointed out that individual anatomic structure was not developmentally autonomous but interrelated with that of contiguous and frequently more remotely located structures. We postulate that the presence of the fibrous tissue might have been caused by the ectopic migration of contiguous or remotely located mesenchyme. If limbs develop in proximodistal direction as mentioned earlier, one would think that undifferentiated mesenchymal cells migrated into the area but instead of differentiating into cartilage cells, differentiated into fibrous connective tissue. Due to the malformation of the talus and calcaneus, there is no angulation between the foot and leg of our patients which appears to be the characteristic of an
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embryo of 43 days gestation [Viladot et al., 19841. The distal part of the fibulae lacks lateral malleoli. Poorly developed lateral malleoli have been noted in patients with congenital shortening of the lower limb with a ball and socket ankle joint [Lamb, 19581. With regard to the fibulo-calcaneal complex, we have described the prominent angular protrusion on the ventral surface of the fibula as a calcaneus because of its morphology and distal articulation with the cuboid. However, we cannot prove that it really is the calcaneus because we did not see fusion lines in all the patients including the grandson (IV-1). It is interesting to note that normally the fibula does not articulate with the calcaneus. In our cases the fibula does articulate with the calcaneus. Thus, dysmorphogenesisof the fibulo-calcaneal complex remains an enigma. In 11-9and 11-10,the fibulae appear to be affected to a lesser degree than the rest. The fibular developmental field includes the pubic portion of the pelvis, proximal femur, patella, anterior cruciate ligament, and lateral and/or axial foot rays [Lewin and Opitz, 19861. Fibular hypoplasia is often present with oligodactyly, almost never associated with polydactyly [ORahilly, 19851,and never involves the hallux [Lewin and Opitz, 19861. Fibular malformation is always associated with other abnormalities of the limbs. It has never been found as a solitary defect [Pappas et al., 19721. Fibular h y p o plasia is often associated with talo-calcaneal fusion which sometimes involves the cuboid and other tarsal bones [Coventry and Johnson, 19521. Tarsal synostosis is more common in cases with complete absence of the fibula [Achterman and Kalamchi, 19791. Anthropologically, it has been suggested that tarsal synostosis is an ancient genetic anomaly of man [Heiple and Lovejoy, 1969; Garn et al., 19761.The incidence of tarsal synostosis in the general population is less than 1%. Tarsal synostoses have autosomal dominant inheritance [Leonard, 19741. The most common form is calcaneo-navicular synostosis (53%), followed by talo-calcaneal synostosis (37%) [Conway and Cowell, 1969; Stormont and Peterson, 1983; Percy and Mann, 19881. Naviculo-cuneiform synostosis found in our cases is extremely rare in the general population. To our knowledge, less than 10 cases of naviculo-cuneiformsynostosis have been reported in the literature. Most have described synostosis of the navicular with one cuneiform bone [Lusby, 1959; Gregersen, 1977; Miki et al., 1985; Wiles et al., 1988; Sato and Sugiura, 19901. Mesomelic dysplasia, Nievergelt type is the only previously described type which has carpal and tarsal synostoses as consistent findings [Pearlman et al., 1964; Dubois, 1970; Hess et al., 19781. However, the other features appear to be distinctly different from those of our cases. It has been proposed that carpal and tarsal synostoses are caused by failure of segmentation [O’Rahilly, 1953; Poznanski, 19841 or differentiation of mesenchyme LMcCredie, 19751. Carpal and tarsal synostoses have been found in embryos and fetuses. It has also been postulated that fusion arises in the cartilaginous carpus or tarsus of the embryo, later failure of separation between the two elements being subsequently “radiographically visible” [O’Rahilly, 1957;
Garn et al., 19761. This postulation is supported by the findings in our patient IV-1. He did not have either carpal or tarsal synostosis. It is possible that IV-1 will have carpal and tarsal synostoses when he matures. In our patients the ulna and fibula are more severely affected than the radius and tibia, respectively. This seems to support that ulna and fibula, radius and tibia are homologs [Sandrow et al., 1970; Lewin and Opitz, 19861. It is interesting to note that, even though ulna and fibula are homologs, hypoplasia almost always takes place at the distal ulna but the proximal fibula. Fibular hypoplasia, tibio-talar, and fibulo-calcaneal complexes,and fusions of navicular and cuneiform bones have never been reported in the literature. O’Rahilly [1951]found no involvement of the calcaneus, navicular, and cuneiform bones in fibular hemimelia. In our cases we question to which field the calcaneus, navicular, and cuneiform bones belong.
ACKNOWLEDGMENTS The authors wish to acknowledge and express our appreciation to the following: our patients, for their cooperation; Dr. and Mrs. Montri Kantaputra, for their generous help with contacting the patients and arrangements; Dr. Robert Vickers, Head of The Division of Oral Pathology, University of Minnesota, for his support throughout the project; Ms. Elizabeth Dempsey,medical illustrator at the Department of Biomedical Graphics, University of Minnesota, for her excellent illustration (Fig. 12).
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Pearlman HS, Edkin RE, Warren RF (1964): Familial tarsal and carpal synostosis with radial-head subluxation (Nievergelt’s syndrome). J Bone Joint Surg 46A:585-592. Percy EC, Mann DL (1988): Tarsal coalition: A review of the literature and presentation of 13 cases. Foot Ankle 9:40-44. Poznanski AK (1984): “The Hand in Radiologic Diagnosis.” Philadelphia: Saunders. Poznanski AK, Gall J C Jr, Stern AM (1970): Skeletal manifestations of the Holt-Oram syndrome. Radiology 94:45-53. Poznanski AK, Holt JF (1971): The carpals in congenital malformation syndromes. Am J Roentgenol 112:443-459. Preger L, Steinbach HL, Moskowitz P, Scully AL, Goldberg MB (1968): Roentgenographic abnormalities in phynotypic females with gonadal dysgenesis; comparison of chromatin positive patients and chromatin negative patients. Am J Roentgenol Radium Ther Nucl Med 104:899-910.
Sandrow RE, Sullivan PD, Steel HH (1970): Hereditary ulnar and fibular dimelia with peculiar facies. J Bone Joint Surg 5 2 A 367-370.
Sat0 K, Sugiura S (1990): Naviculo-cuneiform coalition-report of three cases. Nippon Seikeigeka Gakkai Zasshi 64:l-6. Saunders J W (1948): The proximo-distal sequence of origin of the parts of the chick wing and the role of the ectoderm. J Exp Zoo1 108363-403.
Schinzel A, Zellweger H, Grella A, Prader A (1974): Fetal face syndrome with acral dysostosis. Helv Paediatr Acta 29:55-60. Silverman F (1985): Aplasia and hypoplasia of fibula. In Silverman F (ed):“Caffey’s Pediatric X-ray Diagnosis.” Chicago: Yearbook Medical Publishers, p 500. Skerik SK, Flatt AE (1969): The anatomy of congenital radial dysplasia. Its surgical and functional implications. Clin Orthop 66: 125-143.
Stormont DM, Peterson HA (1983): The relative incidence of tarsal coalition. Clin Orthop 181:28-36. Temtamy SA, McKusick VA (1978): Juberg-Hayward syndrome. In Bergsma D (ed): “The Genetics of Hand Malformations.”New York: Alan R. Liss, Inc., for the National Foundation-March of Dimes. BD:OAS XIV (3):95-97. Thijn CJP (1986): “Radiology of the Hand.” Berlin: Springer-Verlag, p 81. Tschumi PA (1957): The growth of the hindlimb bud of Xempus h u i s and its dependence upon the epidermis. J Anat 91:149-173. Viladot A, Lorenzo JC, Salazar J, Rodriguez A (1984): The subtalar joint: Embryology and morphology. Foot Ankle 554-66. Wiles S, Palladino SJ, Stavosky J W (1988): Naviculocuneiform coalition. J Am Podiatr Med Assoc 78:355-360.
Dominant Mesomelic Dysplasia, Ankle, Carpal, and Tarsal Synostosis Type: A New Autosomal Dominant Bone Disorder Piranit N. Kantaputra, Robert J. Gorlin, and Leonard 0. Langer, Jr. Department of Pediatric Dentistry, School of Dentistry, Chiangmai University, Chiang Mai, Thailand (P.N.K.); Department of Oral Sciences, School of Dentistry (P.N.K., R.J.G.) and Department of Radiology, School of Medicine (L.O.L.), University of Minnesota, Minneapolis
A new type of mesomelic dysplasia was in 3 generations of a large Thai family. It is characterized by bilateral symmetrical marked shortening of the ulnae and shortening and bowing of the radii. The proximal fibula is usually short and synostoses are present between the tibia and fibula and the small malformed calcaneus and talus. The prominent calcanei on the ventral surfaces of the distal fibulae are a characteristic feature of the new type. Carpal and tarsal synostoses are present in some affected people. All affected individuals walk on the tips of their toes with the dorsal foot deviated laterally. The deformities of the radius a n d ulna somewhat resemble those of mesomelic dysplasia, Langer type, but otherwise the condition is distinctly different. This new mesomelic dysplasia is an autosoma1 dominant trait with complete penetrance and variable expressivity over 3 generations. 0 1992 Wiley-Liss, Inc.
KEY WORDS: skeletal dysplasia, radial dysplasia, ulnar dysplasia, hypoplastic fibula, tibia-fibula synostosis INTRODUCTION The mesomelic dysplasias comprise a group of bone disorders characterized by disproportionate shortness of the middle segment of the limbs which may be accompanied by other anomalies involving the proximal or distal parts of the limbs. Affected individuals have nor-
ma1 intelligence. The International Nomenclature of Constitutional Disease of Bone classified mesomelic dysplasia into 5 groups: Nievergelt, Langer, Robinow, Reinhardt-Pfeiffer, and other types [Milgram, 19901.We would like to describe a new type of mesomelic dysplasia and to review briefly the literature regarding the previously described types of mesomelic dysplasia. CLINICAL REPORTS This disorder was transmitted from male identical twins to their sons, daughters, and 3 grandsons. Their clinical and radiographic appearances are distinctly different from previously described types of mesomelic dysplasia. The affected are of Thai origin, born to unrelated parents. Figure 1 shows the pedigree obtained from an affected individual (11-91. Fifteen individuals were affected, of which 10 are males. Clinical Findings Affected individuals share a common clinical appearance (Fig. 2). They are of normal intelligence. Craniofacial structures are unremarkable. Panoramic films show normal dental development. The forearms are severely short, radially bowed, and the hands deviate ulnarly (Fig. 3). There is mildly short stature as the legs are somewhat short. The ankle joints are absent. The long axes of the shanks, hind, and mid foot are essentially parallel. The affected stand on the tips of their toes with the dorsal foot deviated laterally. The soles face upwards. The feet appear of normal length (Figs. 2, 4). The dorsum of the feet in the weight bearing areas appears hyperkeratotic. The average height and weight of affected male adults were 152.0 * 3.5 cm and 56.4 * 7.7 kg, respectively. An affected adult female was 135 cm tall and weighed 40 kg.
Radiographic Findings All affected individuals share common radiographic Received for publication October 10, 1991; revision received appearances with some variation. The identical twin brothers (11-9 and 11-10) have almost identical radioMay 13, 1992. Address reprint requests t o Piranit N. Kantaputra, D.D.S., M.S., graphic appearances. The radiographic findings of the Department of Pediatric Dentistry, School of Dentistry, Chiang- youngest affected individual (IV-1)are somewhat differmai University, Chiang Mai 50002, Thailand. ent from those in the rest of the family. The findings 0 1992 Wiley-Liss, Inc.
Mesomelic Dysplasia, Ankle, Carpal, and Tarsal Synostosis Qpe
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Fig. 1. Family pedigree.
Fig. 4. Angle between the leg and foot is absent. The feet have normal length.
presented here are separated into 2 groups according to similarities: adults (11-9, 11-10, 111-1, 111-15, 111-18, and 111-23) and a grandson (IV-1). Fig. 2. Patient 11-9.Normal craniofacial development. The forearms are severely short and radially bowed. The hands deviate ulnarly. The legs are somewhat short. He stands on the tips ofhis toes with the dorsum of his left foot deviated laterally.
Adults (6 Cases) Upper limbs. The radii and ulnae are very short. The ulna is very broad and disproportionately shorter than the radius. The radius is markedly bowed radially and broad, but less so than the ulna. The changes in the radius and ulna are bilateral and symmetrical. The distal radius articulates with the scaphoid, often articulates with the lunate, and sometimes with the triquetrum. The distal ulna articulates with the triquetrum. The distal radius and ulna do not articulate as the triangular-shaped proximal carpal row with the lunate at the apex lies between them. The pisiform is absent (Fig. 5). Carpal synostoses are present in some individuals. Scaphoid-trapezium fusion is the commonest, but capitate-trapezoid, capitate-lunate, and in one trapezium-scaphoid-trapezoid-capitateindividual, lunate fusion is present. This same individual (111-1) also has a fusion between the fibulo-calcaneal complex and the tibio-talar complex and fusions in the feet. The hand is deviated ulnarlv due to the disDroDortionateiv short ulna. The metaca&ls and phalanges are (Fig. 5). I
Fig. 3. Forearms are severely short and plump. Hands deviate ulnarly.
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Fig. 5. AP forearm and hand of 111-1.The radius is markedly short and bowed radially. The ulna is shorter than the radius. The radius articulates with scaphoid and lunate. The ulna articulates with the triquetrurn. Seaphoid-trapezium and capitate-trapezoid fusions are present. The pisiform is absent. The metacarpals and phalanges are normal.
Lower limbs. The tibiae and fibulae are short in relation to the femora. The proximal end of the fibula is shorter than usual in relation to the tibia. A separate calcaneus and talus are not present. The long axis of the tarsals and metatarsals is in the same plane as that of the tibia and fibula (Figs. 6-8). There is deformity of the distal part of the fibula which, because of the prominent angular protrusion on the ventral surface and the distal articulation with the cuboid, appears to represent synostosis between the distal fibula and calcaneus. This will be referred to as the fibulo-calcaneal complex. No transverse lines residual from this fusion are seen in any of the individuals (Figs. 6,7).No lateral malleolus is present (Figs. 6, 8). The distal end of the tibia is fused to a small talus which articulates with the laterally placed navicular. This will be referred to as the tibio-talar complex (Figs. 6,8). There is a more or less conspicuous narrow lucency between parallel dense lines in the expected region of a tibio-talar synostosis (Fig. 6). This represents incipient, incomplete, or residual changes related to the fusion. It is present in all adult individuals. It is least apparent in the oldest individuals, the twin brothers. The medial malleolus is present. In the one individual who shows extensive carpal bone synostosis (111-1),there is fusion between the tibio-talar and fibulo-calcaneal complexes on the right (Fig. 8). In
Fig. 6. The proximal fibula is short. The malformed calcaneus protruded from the medial aspect of ventral surface of the distal fibulocalcaneal complex. The distal fibulo-calcaneal complex articulates with the cuboid. The arrowheads indicate exostosis off the medial aspect of the fibulo-calcaneal complex just below the proximal part of the calcaneus (see Fig.8). At the distal tibio-talar complex there is a lucent line between pararallel dense lines. These represent the fusion line between the tibia and talus. The navicular which articulates with the tibio-talar complex proximally is fused with the first cuneiform distally. The long axes of the tibia, fibula, and those of tarsals, and metatarsals are almost parallel.
another patient there is possible fusion here. In some patients a small exostosis off the medial aspect of the distal fibulo-calcaneal complex is seen. This is at the level of the above described fusion and may be related to it (Figs. 6, 8). In one case there is fusion between the talar portion of the tibio-talar complex and the fibulocalcaneal complex. The navicular is laterally placed. The tarsals and metatarsals appear everted. Synostosis between the navicular and first cuneiform is present in several individuals (Figs. 6, 8).
8-Year-Old Male Upper limbs. The radius is very short and broad and is markedly bowed radially. Only very small ossified proximal and distal radial epiphyses are present. The ulna is disproportionately shorter than the radius. No distal ulnar epiphysis is seen. The distal radius and ulna do not articulate. The lunate, scaphoid, trapezium, and trapezoid are small. The hand deviates ulnarly due to the disproportionately short ulna. The metacarpals and phalanges are normal (Fig. 9). Lowerlimbs. The tibia and fibula are short in relation to the femur. The proximal end of the fibula is
Mesomelic Dysplasia, Ankle, Carpal, and Tarsal Synostosis Q p e
Fig. 7. The prominent angular protrusion on the ventral surface of the fibulo-calcaneal complex represents the malformed proximal portion of the calcaneus. There is no fusion line between the fibula and calcaneus. The normal angle between the leg and foot is absent.
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Fig. 8. The knee is seen in lateral projection, the distal shank bones in oblique projection. The distal fibulo-calcaneal complex is larger than the proximal fibula. A separate talus and calcaneus are not present. The fibulo-calcaneal complex articulates with the cuboid. On the right, there is fusion between the fibulo-calcaneal and tibio-talar complexes. The arrowheads indicate a small exostosis off the medial aspect of the fibulo-calcaneal complex on the left. This is a t the same level as the fusion on the right. The lateral malleolus is not present. The navicular is laterally placed.
disproportionately short. In both limbs the distal fibulocalcaneal complexes articulate with the cuboid bones. On the right, the small malformed talus is separate from the tibia and is fused to the distal fibulo-calcaneal complex. Distally the talus articulates with the navicular which is irregularly ossified (Fig. 10). On the left, the talus is separate from both the distal tibia and the fibulo-calcaneal complex. It lies lateral to the tibia and medial to the fibulo-calcaneal complex in frontal projection and somewhat dorsal to the shank bones in lateral projection. It articulates distally with the navicular. The navicular lies more lateral than usual in relation to the cuboid. The tarsals and metatarsals appear everted in frontal projection. No tarsal synostoses are present (Fig. 10).
DISCUSSION The previously described types of mesomelic dysplasia have been described [Kaitila et al., 19761. The schematic presentation of characteristic radiographic changes of each type is presented in Figure lla,b. Although this new autosomal dominantly inherited mesomelic dysplasia appears distinctly different from those previously described, there are some similarities to mesomelic dysplasia, Langer type in the upper limbs. In both disorders, there are short and bowed radii, short ulna, ulnar deviation of hands, and hvwdasia of fibulae. The shortening of the humerus, tibii, and fibula
Fig. 9. AP forearms and hands of the 8-year-old boy (IV-1). The radius is very short and broad and is markedly bowed radially. Very small ossified proximal and distal radial epiphyses are present. The ulna is disproportionately shorter than the radius. The distal ulnar epiphysis is not present. The hand deviates ulnarly. The metacarpals and Dhalanees are normal.
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Fig. 10. The proximal fibula is disproportionately shorter than the tibia. The distal fibulo-calcaneal complex articulates with the cuboid. The right talus is separate from the tibia and fused with the fibulocalcaneal complex. The left talus articulates with the tibia proximally and with laterally placed navicular distally.
is greater in the Langer type [Langer, 19671. The malformations of the talus and calcaneus, the presence of tibio-talar and fibulo-calcaneal complexes, and synostoses of tibia and fibula and carpal and tarsal bones make this new type of mesomelic dysplasia distinctly different from the Langer type (Fig. 12). This new type clearly represents the heterozygous state of a different autosomal dominant gene. Carpal synostosis in this new disorder appears to be a variable and inconsistent finding. Bilateral fusion of the scaphoid-trapezium-trapezoid, found in one patient, is very rare in the general population. Fusion of carpal bones may occur as an isolated anomaly or as part of a generalized bone disorder. Fusion of carpal bones in the same row is generally an isolated anomaly. Garn et al. [1971] reported that no cases of fusion from proximal to distal rows were found in more than 25,000 hand radiographs. Carpal fusion across rows is usually associated with congenital malformation syndromes and appears to be progressive [Poznanski and Holt, 1971; Cope, 19741. Carpal fusion has been reported in association with Madelung deformity [Alexander and Johnson, 19411,diastrophic dysplasia [Poznanski and Holt, 19711, and dyschondrosteosis [Langer, 19651.Capitate-hamate fusion appears to be a constant finding in Ellis-van Creveld syndrome [Caffey, 19521. Carpal fusion may be associated with nonskeletal disorders such as UllrichTurner syndrome [Preger et al., 19681. The incidence of
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Fig. 11. a: A schematic presentation of characteristic radiographic features ofvarious forms of mesomelic skeletal dysplasia. The drawings are from original case reports. Patients were of different ages and therefore present different developmental stages for each dysplasia. Right forearm and hand the radius is shadowed. Normal, adult; dyschondrosteosis, adult; Langer type, 4 years; Nievergelt type, 2% years; Werner type, adult; Ellis-van Creveld type, 6 years; Campailla-Martinelli type, adult; Reinhardt-Pfeiffer type, 9 years; Robinow type, 5’/z years. b: Right leg; fibula has been shadowed. Normal, adult; dyschondrosteosis, adult; Langer type, 2% years; Nievergelt type, 2 years; Werner type, 10 months; Ellis-van Creveld type, 6 years; Maroteaux type, 13 years; Campailla-Martinelli type, adult; Reinhardt-Peiffer type, 14years; Robinow type, 5% years. (Reproduced from Kaitila et al., 1976, with permission of the publisher.)
Mesomelic Dysplasia, Ankle, Carpal, and Tarsal Synostosis w p e
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Fig. 12. The schematic presentation of the mesomelic dysplasia, carpal, and tarsal synostosis type.
ankle,
carpal synostosis varies with sex and race [Garn et al., 19711. It is more common in Nigerians with an incidence up to 8%[Cockshott, 19631.Fusion of 2 carpal bones was found in only 7 of 1,000 English schoolchildren [Hughes and Tanner, 19661. Triquetral-lunate fusion is the most common form of carpal fusion [Poznanski and Holt, 19711. Garn et al. [19711 reported triquetral-lunate fusion in 0.1% of 11,663 white Americans and 1.6% of 7,543 black Americans. It was found twice as common in females as in males [Garn et al., 19711. Giedion et al. 119753 report a case of Robinow syndrome with severe vertebral segmental defects and triquetral-lunate fusion. Fusion of multiple carpals is very rare in the general population [Hughes and Tanner, 1966;Thijn, 19861. Autosomal dominant inheritance of congenital mitral insufficiency, conductive deafness, short stature, and carpal and tarsal fusions has been described [Forney et al., 19661. The incidence of carpal fusion in the Thai population has never been reported. Radial and ulnar dysplasia in our patients is not associated with congenitally absent carpal bones. Our patients do not have a pisiform bone, but the absence of a pisiform bone is not uncommon. Congenitally missing carpal bones are usually associated with radial and ulnar dhypoplasia [ORahilly, 19511. Radial defects associated with carpal hypoplasia occur as an isolated finding or in association with Fanconi anemia [Juhl et al., 19671, Juberg-Hayward syndrome [Temtamy and McKusick, 1978;Poznanski, 19841,and Holt-Oram syndrome [Chang, 1967; Poznanski et al., 19701.
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According t o the Archipterygial theory, the upper limb develops from one main stem and 4 accessory rays. The main stem accounts for the humerus, ulna, 5th metacarpal, and phalanges of the 5th finger. The first accessory ray accounts for the radius, scaphoid, trapezium, first metacarpal, and its phalanges. The 2nd, 3rd, and 4th rays give rise to the 2nd, 3rd, and 4th fingers [Gegenbaur, 18761. Radial ahypoplasia commonly leads to defects of the radial ray which include hypoplasia or absence of scaphoid, trapezium, first metacarpal and its phalanges [O’Rahilly, 19511. When the radius is ahypoplastic, the ulna is usually curved, short, and thick [Skerik and Flatt, 19691. Ulnar ahypoplasia commonly leads to defects of the ulnar ray. When the ulna is absent or hypoplastic, the 4th and 5th fingers and corresponding carpal bones usually are involved. The pisiform is always absent, which is supported by our findings, and the hamate frequently [Pardini, 1967; Poznanski and Holt, 1971; Schinzel et al., 19741. A fibrous or fibrocartilaginous band extending from the hypoplastic ulna to the distal end of the radius or carpal bones, or both has been described. This band tends to make the hand deviate ulnarly [Ogden et al., 19761. When the radius is hypoplastic or aplastic, the ulna is usually curved and the distal ulnar epiphysis tends to have delayed onset of appearance [Heikel, 19591. In cases with radial and ulnar hypoplasia or aplasia, it is somewhat speculative to identify which is the primary or secondary defect. The association of radial and ulnar hypoplasia is seen in Brachmannde Lange syndrome, faciocardiomelic dysplasia, femurfibula-ulna dysplasia, Ives-Houston syndrome, Roberts syndrome, and WT syndrome [Poznanski, 19841. The radius appears to have hypoplastic epiphyses. It is important t o note that most of our patients do not have carpal synostosis or defects of metacarpals or phalanges. It has been reported that limbs are developed in proximodistal, postaxial, and preaxial directions, with distal part anomalies usually being dependent upon the abnormalities of the proximal ones [Saunders, 1948; Tschumi, 1957; Kwasigroch and Kochhar, 19801. Our cases and the absence of the radius with persistence of the thumb in TAR syndrome do not seem to follow the Archipterygial theory and Tschumi’s concept. The missing part of the fibula similar to that of the ulna is frequently replaced by a strong band of connective tissue which appears to inhibit longitudinal growth of the tibia [Silverman, 19851. Lewin and Opitz [19861 pointed out that individual anatomic structure was not developmentally autonomous but interrelated with that of contiguous and frequently more remotely located structures. We postulate that the presence of the fibrous tissue might have been caused by the ectopic migration of contiguous or remotely located mesenchyme. If limbs develop in proximodistal direction as mentioned earlier, one would think that undifferentiated mesenchymal cells migrated into the area but instead of differentiating into cartilage cells, differentiated into fibrous connective tissue. Due to the malformation of the talus and calcaneus, there is no angulation between the foot and leg of our patients which appears to be the characteristic of an
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embryo of 43 days gestation [Viladot et al., 19841. The distal part of the fibulae lacks lateral malleoli. Poorly developed lateral malleoli have been noted in patients with congenital shortening of the lower limb with a ball and socket ankle joint [Lamb, 19581. With regard to the fibulo-calcaneal complex, we have described the prominent angular protrusion on the ventral surface of the fibula as a calcaneus because of its morphology and distal articulation with the cuboid. However, we cannot prove that it really is the calcaneus because we did not see fusion lines in all the patients including the grandson (IV-1). It is interesting to note that normally the fibula does not articulate with the calcaneus. In our cases the fibula does articulate with the calcaneus. Thus, dysmorphogenesisof the fibulo-calcaneal complex remains an enigma. In 11-9and 11-10,the fibulae appear to be affected to a lesser degree than the rest. The fibular developmental field includes the pubic portion of the pelvis, proximal femur, patella, anterior cruciate ligament, and lateral and/or axial foot rays [Lewin and Opitz, 19861. Fibular hypoplasia is often present with oligodactyly, almost never associated with polydactyly [ORahilly, 19851,and never involves the hallux [Lewin and Opitz, 19861. Fibular malformation is always associated with other abnormalities of the limbs. It has never been found as a solitary defect [Pappas et al., 19721. Fibular h y p o plasia is often associated with talo-calcaneal fusion which sometimes involves the cuboid and other tarsal bones [Coventry and Johnson, 19521. Tarsal synostosis is more common in cases with complete absence of the fibula [Achterman and Kalamchi, 19791. Anthropologically, it has been suggested that tarsal synostosis is an ancient genetic anomaly of man [Heiple and Lovejoy, 1969; Garn et al., 19761.The incidence of tarsal synostosis in the general population is less than 1%. Tarsal synostoses have autosomal dominant inheritance [Leonard, 19741. The most common form is calcaneo-navicular synostosis (53%), followed by talo-calcaneal synostosis (37%) [Conway and Cowell, 1969; Stormont and Peterson, 1983; Percy and Mann, 19881. Naviculo-cuneiform synostosis found in our cases is extremely rare in the general population. To our knowledge, less than 10 cases of naviculo-cuneiformsynostosis have been reported in the literature. Most have described synostosis of the navicular with one cuneiform bone [Lusby, 1959; Gregersen, 1977; Miki et al., 1985; Wiles et al., 1988; Sato and Sugiura, 19901. Mesomelic dysplasia, Nievergelt type is the only previously described type which has carpal and tarsal synostoses as consistent findings [Pearlman et al., 1964; Dubois, 1970; Hess et al., 19781. However, the other features appear to be distinctly different from those of our cases. It has been proposed that carpal and tarsal synostoses are caused by failure of segmentation [O’Rahilly, 1953; Poznanski, 19841 or differentiation of mesenchyme LMcCredie, 19751. Carpal and tarsal synostoses have been found in embryos and fetuses. It has also been postulated that fusion arises in the cartilaginous carpus or tarsus of the embryo, later failure of separation between the two elements being subsequently “radiographically visible” [O’Rahilly, 1957;
Garn et al., 19761. This postulation is supported by the findings in our patient IV-1. He did not have either carpal or tarsal synostosis. It is possible that IV-1 will have carpal and tarsal synostoses when he matures. In our patients the ulna and fibula are more severely affected than the radius and tibia, respectively. This seems to support that ulna and fibula, radius and tibia are homologs [Sandrow et al., 1970; Lewin and Opitz, 19861. It is interesting to note that, even though ulna and fibula are homologs, hypoplasia almost always takes place at the distal ulna but the proximal fibula. Fibular hypoplasia, tibio-talar, and fibulo-calcaneal complexes,and fusions of navicular and cuneiform bones have never been reported in the literature. O’Rahilly [1951]found no involvement of the calcaneus, navicular, and cuneiform bones in fibular hemimelia. In our cases we question to which field the calcaneus, navicular, and cuneiform bones belong.
ACKNOWLEDGMENTS The authors wish to acknowledge and express our appreciation to the following: our patients, for their cooperation; Dr. and Mrs. Montri Kantaputra, for their generous help with contacting the patients and arrangements; Dr. Robert Vickers, Head of The Division of Oral Pathology, University of Minnesota, for his support throughout the project; Ms. Elizabeth Dempsey,medical illustrator at the Department of Biomedical Graphics, University of Minnesota, for her excellent illustration (Fig. 12).
REFERENCES Achterman CA, Kalamchi A (1979):Congenital deficiency of the fibula. J Bone Joint Surg 61B:133-137. Alexander HH, Johnson GH (1941):Madelung’s deformity with fusion of semilunar and triangular bones. Am J Surg 53:349-351. Caffey J (1952): Chondroectodermal dysplasia (Ellis-van Creveld disease). Report of three cases. Am J Roentgenol 682375-886. Chang CH (1967): Holt-Oram syndrome. Radiology 88:479-483. Cockshott WP (1963):Carpal fusions. Am J Roentgenol 89:1260-1271. Conway JJ, Cowell HR (1969): Tarsal coalition: Clinical significance and roentgenographic demonstration. Radiology 92:799-811. Cope J R (1974): Carpal coalition. Clin Radio1 25261-266. Coventry MB, Johnson EW Jr (1952): Congenital absence of fibula. J Bone Joint Surg 34A:941-955. Dubois HJ (1970): Nievergelt-Pearlman syndrome. Synostosis in feet and hands with dysplasia of elbows. J Bone Joint Surg 52B: 325-329. Forney WR,Robinson SJ,Pascoe DE (1966):Congenital heart disease, conductivedeafness, and skeletal malformations. A new syndrome? J Pediatr 6814-26. Garn SM, Burdi AR, Babler WJ (1976): Prenatal origins of carpal fusions. Am J Phys Anthropol45:203-208. Garn SM, Frisancho AR, Poznanski AZ, Schweitzer J, McCann MB (1971): Analysis of triquetral-lunate fusion. Am J Phys Anthropol 34431-433. Gegenbaur C (1876): Zur Morphologie der Gliedmassen de Wirbelthiere. Morphol Jahrb 2:396-420. Giedion A, Battaglia GF, Bellini F,Fanconi G (1975):The radiological diagnosis of the fetal-face ( = Robinow)syndrome (mesomelic dwarfism and small genitalia).Report of three cases. Helv Paediatr Acta 30:409-423. Gregersen HN (1977):Naviculocuneiform coalition. J Bone Joint Surg 59A:128-130.
Mesomelic DysplasiaL, Ankle, Carpal, and Tarsal Synostosis e p e Heikel HVA (1959): Aplasia and hypoplasia ofthe radius. Acta Orthop Scand 39:l-155. Heiple KG, Lovejoy CO (1969): The antiquity of tarsal coalition. J Bone Joint Surg 51A979-983. Hess OM. Goebel NH. Streuli R (1978): Familiarer mesomeler Kleinwuchs (Nievergelt-Syndrom). Schweiz Med Wochenschr 108: 1202-1206.
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