American Journal of Medical Genetics 128A:6 –11 (2004)
Kantaputra Mesomelic Dysplasia: A Second Reported Family Deborah J. Shears,1 Amaka Offiah,2 Paul Rutland,1 Tony Sirimanna,3 Maria Bitner-Glindzicz,1* and Christine Hall2 1
Clinical and Molecular Genetics Unit, Institute of Child Health, London, United Kingdom Department of Radiology, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom 3 Department of Audiological Medicine, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom 2
We present the clinical and radiographic findings in a mother and son with a dominantly inherited mesomelic skeletal dysplasia almost identical to that described in a large Thai family by Kantaputra et al., in which ankle, carpal and tarsal synostoses were noted. The proband in the family is a 48-year-old woman with mesomelic limb shortening, most pronounced in the upper limbs. Her parents were of normal stature and build. Her 15-year-old son has similar mesomelic limb shortening, and in addition talipes equinovarus. Radiological examination showed severe shortening of the radius and ulna with bowing of the radius and dislocation of the radial head. Multiple carpal and tarsal synostoses were present and in addition, the talus and calcaneum were fused. In the original Thai family, linkage to chromosome 2q24-q32, which contains the HOXD cluster has been reported, and it is postulated that the phenotype may result from a disturbance of regulation of the HOXD cluster. Although linkage analysis was not possible in our family, molecular analysis was undertaken and HOXD11 was sequenced, however, no mutations were detected. This is only the second reported family affected with Kantaputra mesomelic dysplasia (MIM 156232), a distinct mesomelic skeletal dysplasia. ß 2004 Wiley-Liss, Inc.
Deborah J. Shears’s present address is Department of Clinical Genetics, 7th Floor, New Guy’s House, Guy’s Hospital, St. Thomas Street, London, SE1 9RT, UK. *Correspondence to: Dr. Maria Bitner-Glindzicz, Clinical and Molecular Genetics Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. E-mail:
[email protected] Received 29 April 2003; Accepted 30 August 2003 DOI 10.1002/ajmg.a.20640
ß 2004 Wiley-Liss, Inc.
KEY WORDS: Kantaputra mesomelic dysplasia; carpal and tarsal synostoses; HOXD cluster regulation INTRODUCTION The mesomelic dysplasias comprise a heterogeneous group of skeletal disorders in which there is disproportionate shortening of the middle segment of the limbs, which may be associated with anomalies of the proximal or distal segments of the limbs. Twelve different forms are recognized by the most recent International Nosology and Classification of Constitutional Disorders of Bone [Hall, 2002]. We present the clinical and radiological findings in a mother and son with mesomelic limb shortening which most closely resembles Kantaputra type mesomelic dysplasia in which ankle, carpal and tarsal synostoses are described. As far as we are aware, this is only the second reported family affected by this distinct type of mesomelic dysplasia. CLINICAL REPORTS The patients are a 48-year-old Danish woman and her 15-year-old son, both affected with mesomelic limb shortening without specific diagnosis (Fig. 1). There was no other family history of mesomelic limb shortening or short stature and both were of normal intelligence. The proband (II:1) was the only child of parents of normal stature with no limb abnormalities. Her mother (I:6) was epileptic and had taken the anticonvulsant drug trimethadione throughout the pregnancy. At birth, severe shortening of the forearms and plantar flexion of the feet were noted in II:1, and originally attributed to in utero exposure to trimethadione. As a child she underwent several operations to rearrange her tarsal bones and to lengthen her Achilles tendons. She did not require surgery to her upper limbs, but the position of her hands was improved with splints. During the first pregnancy of II:1, ultrasound scans revealed that the fetus had short limbs. The pregnancy continued and her son (III:1) was born at full term.
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ulna being relatively shorter and hypoplastic distally. The radius was bowed, with dislocation of the radial head. In II:1, there was fusion of the scaphoid and lunate bones, both of which articulated with the radius. In III:1, the carpal bones were small, the triquetral appeared to be absent and the scaphoid was elongated. In both individuals, the metacarpals and proximal phalanges were significantly long. In the lower limbs, the tibia and fibula were mildly short, and the metatarsals were long. Multiple tarsal synostoses were present, and several tarsal bones were absent. In II:1, the talus and calcaneum were fused and the distal end of the fibula was wide and showed a triangular extension posteriorly. III:1 had a mild scoliosis, but otherwise bone modeling was entirely normal. The radiological appearances of the mother and son were felt to be consistent with a diagnosis of mesomelic dysplasia Kantaputra type. METHODS Fig. 1. Pedigree drawing. Affected individuals II:1 and III:1 are shown as shaded symbols. The shaded small diamond indicates the affected second pregnancy of II:1.
Severe shortening of the forearms identical to that of his mother was immediately noted in him. Bilateral talipes equinovarus was also present and treated with splinting followed by surgery. At 3 years of age, III:1 was noted to have severe left-sided sensorineural hearing loss. Aetiological investigations including a CT of the petrous temporal bones were all normal, and his mother’s hearing (II:1) was normal. During the second pregnancy of II:1, an ultrasound scan at 12 weeks’ gestation showed that the fetus had short limbs and markedly plantar flexed feet described as ‘ballerina-like’ in appearance. This pregnancy did not, however, proceed to term. On examination of the mother (II:1), her height was 156 cm (10th centile) and there were no facial dysmorphic features. In the upper limb, the rhizomelic segment appeared to be of normal length, but extreme shortening and bowing of the mesomelic segment of the arm were present (Fig. 2). The hands appeared to be of normal size, but the fourth and fifth fingers bilaterally were rather hypoplastic with camptodactyly, and limited flexion and extension. In addition, there was hypoplasia of the hypothenar eminence and absence of skin creases over the interphalangeal joints. In the lower limbs, relatively mild mesomelia was apparent, with wasting of the calf muscles. The feet were long and narrow, with pes planus with hallux valgus. The son (III:1) also had no facial dysmorphic features and the clinical findings in his upper and lower limbs were almost identical to those in his mother (Fig. 3), however, he had marked pes cavus on the right, and the possibility of further surgery to lengthen the Achilles tendon on this side was being considered. His height was 158 cm (10th centile). RADIOGRAPHIC FINDINGS Radiographs of the mother and son both showed similar features (Fig. 4). In the upper limbs, severe shortening of the radius and ulna was present, with the
Chromosome preparations for karyotype analysis were made from PHA-stimulated lymphocytes prepared from whole blood following standard procedures and analyzed using standard cytogenetic techniques. DNA was obtained from whole blood using the salting out method. Both exons of HOXD11 were amplified using fluorescent PCR primers. The sequences of PCR primers used to amplify overlapping products of exon 1 have been previously published [Kosaki et al., 2002]. The sequence of primers used to amplify exon 2 was as follows: 50 ggcagagaacgtccccaacggggc-30 and 50 -gggaaggaatcgtgaagttca-30 . All primer sets were amplified in the presence of 10% DMSO with an annealing temperature of 578C. PCR products were sequenced using ABI Big Dye version 1.1 (Perkin Elmer Applied Biosystems, Warrington, UK). RESULTS II:1 had a normal female karyotype with no evidence of a rearrangement involving the 2q24-32 region. The coding sequence of HOXD11 was sequenced in II:1 but no mutation was detected. DISCUSSION The mesomelic skeletal dysplasias are a heterogeneous group and the differential diagnosis in this is aided by the pattern of bony involvement and by extra skeletal manifestations. Disorders in this group include Leri–Weill dyschondrosteosis characterized by the Madelung deformity and the more severe homozygous form Langer mesomelic dysplasia. The group also comprises Nievergelt type, which is characterized by a rhomboid-shaped tibia, Werner type, in which there is extreme hypoplasia or aplasia of the tibia associated with pre-axial polydactyly, and Robinow type where there are dysmorphic facial features and brachydactyly (recessive and dominant forms). Rarer types with just one or two case reports in the literature include Verloes type, Kozlowski–Reardon type, Savarirayan type, and Kantaputra type. The limb abnormalities in our proband II:1 were originally attributed to maternal trimethadione in-
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Fig. 2. Clinical photographs of the mother (II:1). a: Anterior full-length view. b: Posterior view. c: Lateral view. d: View of forearm in extension. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
gestion. This is an anticonvulsant which is related structurally to phenytoin and is known to be teratogenic, with exposure in utero being associated with a specific phenotype including developmental delay, low set ears, minor facial dysmorphic features, congenital cardiac anomalies, and palatal abnormalities. Occasionally intrauterine growth retardation, short stature, microcephaly, ocular anomalies, and hypospadias have also been described [Zackai et al., 1975; Feldman et al., 1977]. Skeletal abnormalities including congenital dislocation of the hip, lumbar scoliosis, and clinodactyly have been described in a small number of cases and in one case polydactyly, oligodactyly, and club foot deformity was reported [Feldman et al., 1977]. The proband II:1 in the present case, however, had normal intellectual function and no dysmorphic features. Once she
went on to have a child with the same features as herself it became apparent that the exposure to trimethadione was coincidental. Kantaputra et al. [1992] described a three-generation Thai pedigree with a novel phenotype in which marked shortening of the ulna and shortening and bowing of the radius were inherited as an autosomal dominant trait. In addition, there were synostoses between the tibia and fibula, a small malformed calcaneus and talus, and carpal and tarsal synostoses in some affected family members. The radial and ulnar deformities show similarities to those seen in Langer mesomelic dysplasia, which is caused by homozygous mutation or deletion of the SHOX gene, but otherwise the two conditions appear clinically distinct. The clinical and radiological features in our proband and her son were almost identical to
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Fig. 3. Clinical photographs of the son (III:1). a: Anterior view. b: Posterior view. c: Lateral view. d: Anterior arm. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
those described by Kantaputra et al., particularly the extreme shortening and bowing of the radius associated with carpal and tarsal synostoses. The affected individuals in the original Thai family all walked on the tips of their toes, but the individuals in the family reported here had the benefit of surgery to correct the positional deformity of the foot. The phenotype in the family described by Kantaputra has been mapped to chromosome 2q24-32, a region that
contains the HOXD cluster [Fujimoto et al., 1998], although no mutations have been identified in HOXD genes to date. Interestingly a family in which similar mesomelic limb shortening associated with vertebral abnormalities segregated with an apparently balanced reciprocal translocation 2;8(q32;p13) has been described [Ventruto et al., 1983]. Recently the breakpoints of this translocation have been analyzed and the chromosome 2 breakpoint was shown to lie approximately 60 kb from
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Fig. 4. Radiographic appearances of (a) the mother (II:1) and (b) her son (III:1). a: (i) Left arm and (ii) right arm of II:1 showing severe shortening of the radius and ulna, the ulna being relatively shorter and hypoplastic distally. The radius is bowed, with dislocation of the radial head. There is fusion of the scaphoid and lunate, both of which articulate with the radius. The metacarpals and proximal phalanges are significantly long. iii, iv: Lower limb and foot of II:1. The tibia and fibula are mildly short and the
metatarsals are long. There are multiple tarsal synostoses. The talus and calcaneum are fused and the distal end of the fibula is wide, showing a triangular extension posteriorly. b: (i) Left forearm of III:1. The same appearance of the radius and ulna is seen with bowed radius and hypoplastic distal ulna. The carpal bones are small, the triquetral is absent and the scaphoid is elongated. ii: Right foot and ankle of II:1. Multiple tarsal synostoses are present and several tarsal bones are absent.
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Fig. 4.
the HOXD cluster, although it did not disrupt any genes [Spitz et al., 2002; Sugawara et al., 2002]. It was therefore proposed that the balanced translocation led to the phenotype by modifying the regulation of the HOXD cluster. The similarity of these phenotypes suggests that Kantaputra mesomelic dysplasia may also be caused by a disruption of regulation of the HOXD cluster. Information from murine models also provides evidence to support the hypothesis that genes in the human HOXD cluster may be implicated in causing the phenotype of Kantaputra mesomelic dysplasia. Hoxa11/ Hoxd11 double knockout mice have a complete absence of the radius and ulna, with less severe defects of the tibia and fibula [Davis et al., 1995]. In addition, the ulnaless mouse which is linked to the murine Hoxd cluster has striking mesomelic shortening, more severe in the forelimbs than the hindlimbs [Peichel et al., 1996]. In view of this, HOXD11 was sequenced in II:1 from this family but no mutation was detected. We intend to continue to search for mutations or rearrangements in the regulatory region of the HOXD cluster in this family, the second reported family with the distinct Kantaputra type mesomelic dysplasia. REFERENCES Davis AP, Witte DP, Hsieh-Li HM, Potter SS, Capecchi MR. 1995. Absence of radius and ulna in mice lacking hoxa-11 and hoxd-11. Nature 375: 791–795.
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Feldman GL, Weaver DD, Lovrien EW. 1977. The fetal trimethadione syndrome; Report of an additional family and further delineation of this syndrome. Am J Dis Child 131:1389–1392. Fujimoto M, Kantaputra PN, Ikegawa S, Fukushima Y, Sonta S, Matsuo M, Ishida T, Matsumoto T, Kondo S, Tomita H, Deng H-X, D’urso M, Rinaldi M, Ventuto V, Tagaki T, Nakamura Y, Niikawa N. 1998. The gene for mesomelic dysplasia Kantaputra type is mapped to chromosome 2q24q32. J Hum Genet 43:32–36. Hall CM. 2002. International nosology and classification of constitutional disorders of bone. Am J Med Genet 113:65–77. Kantaputra PN, Gorlin RJ, Langer LO. 1992. Dominant mesomelic dysplasia, ankle, carpal, and tarsal synostosis type: A new autosomal dominant bone disorder. Am J Med Genet 16:589–594. Kosaki K, Kosaki R, Suzuki T, Yoshihashi H, Takahashi T, Sasaki K, Tomita M, McGinnis W, Matsuo N. 2002. Complete mutation analysis panel of the 39 human HOX genes. Teratology 65:50–62. Peichel CL, Abbott CM, Vogt TF. 1996. Genetic and physical mapping of the mouse ulnaless locus. Genetics 144:1757–1767. Spitz F, Montavon T, Monso-Hinard C, Morris M, Ventruto M, Antonarakis S, Ventruto V, Duboule D. 2002. A t(2;8) balanced translocation with breakpoints near the human HOXD complex causes mesomelic dysplasia with vertebral defects. Genomics 79:493–498. Sugawara H, Egashira M, Harada N, Jakobs TC, Yshiura K, Kishino T, Ohta T, Niikawa N, Matsumoto N. 2002. Breakpoint analysis of a familial balanced translocation t(2;8)(q31;p21) associated with mesomelic dysplasia. J Med Genet 39:e34. Ventruto V, Pisciotta R, Renda S, Festa B, Rinaldi MM, Stabile M, Cavaliere ML, Esposito M. 1983. Multiple skeletal familial abnormalities associated with a balanced reciprocal translocation 2;8(q32;p13). Am J Med Genet 16:589–594. Zackai EH, Mellman WJ, Neiderer B, Hanson JW. 1975. The fetal trimethadione syndrome. J Pediatr 87:280–284.
