Letters to the Editor

Abstract

Nagai et al. reported a 5-year-old Japanese boy who had, among other skeletal abnormalities, a brachydac-tyly remarkably similar to that exhibited by our affected Turkish family members (Nagai et al. 1995). The child's blood pressure was 110/74 mm Hg. This value is borderline high for age; however, it is lower than the blood pressures of similarly aged affected children from the Turkish family. A de novo chromosomal deletion (12)(pll.21p12.2) was identified in the Japanese child. The deleted segment overlaps the segment to which we mapped the gene(s) responsible for hypertension and brachydactyly. We now report a comparison of the brachydactyly described by Nagai et al. (1995) and that exhibited by our Turkish family, and we propose the hypothesis that a single gene locus is responsible for the brachydactyly in both the Turkish kindred and the Japanese boy. Our hypothesis allows for a more precise location of this gene locus. The children described in this report were identified and examined as described elsewhere (Nagai et al. 1995; Schuster et al. 1996). Roentgenograms of the hands were obtained by conventional techniques and were interpreted by a pediatric radiologist (Dr. Inna Nitz) familiar with brachydactyly syndromes. Measurements of meta-carpal, proximal, middle, and distal phalangeal bone length (in millimeters), as a mean pattern profile for the 5.5-year-old Japanese boy and a 6-year-old affected Turkish boy, were done according to standard procedures (Garn et al. 1972; Poznanski et al. 1972). Geno-typing was performed by use of the ABI PRISM Geno-typing System (Applied Biosystems). Genomic DNA from the patient and his parents was prepared from whole blood by standard methods. Fluorescence-labeled microsatellite markers were amplified by PCR, with use of 50 ng genomic DNA, 200 mM dNTPs, 5 pmol each of forward and reverse primers, 10 mM Tris-HCl pH 8.3,50 mM KCl, different concentrations (1.5-3.5 mM) of MgCl2, and 0.6 units Ampli-Taq-Polymerase (Perkin-Elmer) in a total volume of 15 gl. Primer sequences were available from Genome Data Base (GDB). Samples were run on a 6% denaturing polyacrylamide (19:1) gel. Al-lele sizes were automatically calculated by Genescan 1.2 software and were analyzed by Genotyper 1.1 software (Ziegler 1992). A deletion was scored if no allele from one parent was seen in the proband and if parental al-leles could be separated unambiguously. Band intensities were not scored for gene dosage. The Japanese child has been described in detail elsewhere (Nagai et al. 1995). In addition to brachydactyly with cone-shaped epiphyses, the child has thoracic dys-trophy, chondroectodermal dysplasia, mild mental retardation , short stature, hypoplastic hair and skin, and oligodontia. He has a de novo chromosomal deletion; his two brothers are completely healthy. Our affected family members, in contrast, do not have thoracic dys-trophy, hair or skin changes, or oligodontia, and they .AU DEL(1 2)(pll .21 pl2.2) (5 1/2 YEARS OLD) Figure 1 Left-hand roentgenograms of the two boys. The cone-shaped epiphyses are evident, particularly in the proximal interphalan-geal joints of the second and fifth digits (see text). are not mentally retarded. As adults, they average 10 cm less in height, compared with nonaffected family members. We have looked for deletions on chromosome 12p in the Turkish family and have found none (Schuster et al. 1996). In figure 1 are shown left-hand roentgenograms of the two boys. The cone-shaped epiphyses are evident, particularly in the proximal interphalangeal joints of the 2d and 5th digits. Both hands show a brachyphalangy of digits 2 through 4 and brachymetacarpalia of digits 4 and 5. The Japanese child shows brachymesophalangy and cone-shaped epiphyses in digits 2-5. The Turkish child shows brachymesophalangy and cone-shaped epiphyses in digits 2 and 5. Giedion (1965, 1967) described cone-shaped epiphy-ses of the hands, as well as their diagnostic value. According to Giedion's classification system, the Japanese child's phenotype corresponds to type 16 cone-shaped epiphyses (Giedion 1965, 1967; Poznanski 1984, pp. 155-160). The Turkish child has the features of type 16 as well. These very similar (if not identical) brachy-dactylies are both related to genetic defects on chromosome 12p. The brachydactyly features among the affected Turkish family members were heterogeneous. The syndromes do, of course, differ. The Turkish individuals do not feature the additional skeletal abnormalities described in the Japanese boy, and they are not retarded. We cannot state for certain whether the Japanese boy may exhibit hypertension at a later date; however, his blood pressure currently is decidedly lower than that of the 6-year-old Turkish boy. The cosegregating segment for hypertension and brachydactyly in the Turkish family overlaps the deleted segment in the Japanese boy shown in figure 2. Both traits-hypertension and brachydactyly-in the Turk-ish family follow an autosomal dominant mode of inheritance. The molecular mechanisms of genetic dominance 733