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Inheritance of Multiple Epiphyseal Dysplasia, Tarda

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Inheritance of Multiple Epiphyseal Dysplasia, Tarda Inheritance of Multiple Epiphyseal Dysplasia, Tarda RICHARD C. JUBERG1 AND JOHN F. HOLT2 Multiple epiphyseal dysplasia, tarda, a modeling error of the epiphyses, is charac- terized by shortness of stature and micromelia, particularly stubby hands (Rubin, 1964). A patient with this trait generally shows satisfactory development, adequate muscle mass, and normal intelligence. As a rule, there are few complaints of joint discomfort during childhood. Eventually, however, problems arise from joint motion, which lead to difficulty in walking because of pain in the hips, knees, or ankles. De- formities may result. On the other hand, the defect may not be recognized until the patient presents manifestations of degenerative arthritis at an unusually early age. The classification of epiphyseal modeling errors by Rubin (1964) contains six different entities. Spondyloepiphyseal dysplasia, congenita (Morquio's disease) is characterized by irregularity of epiphyses and vertebrae. It is an abnormality of mucopolysaccharide metabolism, and it is transmitted as an autosomal recessive. Multiple epiphyseal dysplasia, congenita (stippled epiphyses) is characterized by stippled or punctate epiphyses, and it too is transmitted as an autosomal recessive. Epiphyseal retardation, which occurs in cretinism (hypothyroidism), may result from any of several different metabolic errors which appear to be transmitted as autosomal recessives (Stanbury, 1966). Diastrophic dwarfism results in delayed appearance of epiphyses and joint luxations, and this, too, apparently is transmitted as an autosomal recessive. Multiple epiphyseal dysplasia, tarda, which is also known in the literature as epi- physeal dysplasia multiplex, must be differentiated from spondyloepiphyseal dys- plasia, tarda. As the name implies, one difference is in the extent and severity of spinal involvement as well as in the changes in the epiphyses of the long tubular bones. In spondyloepiphyseal dysplasia, tarda, platyspondyly is universal with the most promi- nent defects in the dorsolumbar spine; while in multiple epiphyseal dysplasia, tarda, spinal involvement is more variable in distribution and is manifest by defects of the anterior, superior, and inferior angles of the vertebrae (Rubin, 1964). Many epiphyses may be involved in both conditions, but the pathological changes frequently are more prevalent and more severe in multiple epiphyseal dysplasia, tarda, where they often Received March 15, 1968. This study was supported in part by a training grant from the Children's Bureau, Department of Health, Education, and Welfare, to the Department of Pediatrics, University of Michigan (R. C. J.), and in part by an institutional grant to the University of Michigan from the U.S. Public Health Serv- ice (R. C. J. and J. F. H.). I Department of Human Genetics and Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan 48104. Present address: Department of Pediatrics, West Virginia University, Morgantown, West Virginia 26506. 2 Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan 48104. 549 550 JUBERG AND HOLT are associated with mild stunting and metaphyseal flaring. While spondyloepiphyseal dysplasia, tarda has been reported as X-linked and as autosomal dominant, multiple epiphyseal dysplasia, tarda has generally been considered to be transmitted as an autosomal dominant. This report has three objectives. The first is to describe a patient with multiple epiphyseal dysplasia, tarda and her three similarly affected sibs who occurred in a sibship of 15 and whose parents were normal. The second is to review the literature concerning the heredity of the trait, and the third is to suggest the presence of a recessive form of the disease. 54 52 33 3228 26 4 220 1 15 513 12 I9 68 69 566d' 7d' 7d' 65" 6461"6d 58" 5d52" C female C" height in inches 65 male 3 stillbirth multiple epiphyseal proposita * dysplasia, tarda d. deceased 53 W1 age in years FIG. 1. Pedigree of the M. family compiled 12 years after ascertainment CASE HISTORY V. L. M. (UMH-067048), a white female, was first admitted to the University of Michigan Hospital at the age of 9' years for evaluation of her complaints of discom- fort in the hips and knees and the resulting limitation of joint motion, particularly in ambulation. She was born August 13, 1954, the fourteenth in a sibship of 15 (Fig. 1). Her parents were not consanguineous, although her father's ancestry could be traced only for one generation and her mother's for two. She had always experienced difficulty in walking and, therefore, had never been able to run well. Her discomfort had been noted mostly at the extremes of joint motion. She had progressed to the fourth grade satisfactorily. Her height was 50- inches, less than the third percentile for her age, and her weight was 72 pounds, between the fiftieth and seventy-fifth percentiles (Figs. 2 and 3). Her gait was characterized by short steps, waddling, and lordosis of the lumbo- sacral spine. Her head was normal in circumference, although it appeared large for MIULTI PLE, EPI1HYSEAL I)YSPLASIA, TARI)A 551 her body-. Her anterior chest appeared slightly as!mnmet rical, with the left side more prominent than the right. A slight, systolic, cardiac murmur was heard at the apex and at the left sternal border, but the heart was not enlarged. The long bones were unusually broad for her size, and their ends and the joints were prominent. All of her fingers were short, and she had bilateral ulnar deviation of the second and third digits. Both thumbs were abnornmally positioned with flexion at the metacarpal-phalangeal articulation and extension at the interphalangeal articulation (Fig. 4). She had bilateral cubitus varus and incomplete elbow extension, lacking 100 on each side. The range of motion of her hips was markedly limited, on the left to 40° of flexion, 170° of extension, no internal rotation, 50 of external rotation, 20) of abduction, but normal _ _ _3 __ FIG. 2.-Proposita at 1tO years. Height of 504 inches is less than the third percentile. FIG. 3.-Proposita at 1tO years. Her usual posture included pelvic flexion. 552 JUBERG AND HOLT adduction, and on the right to 700 of flexion, 1750 of extension, 100 of internal rotation, 300 of external rotation, 350 of abduction, but normal adduction. There was mild dorsal scoliosis with left convexity. A roentgenographic skeletal survey showed several significant abnormalities. All epiphyses of the tubular bones were flattened to some degree, with the most pro- nounced changes being evident in the metacarpals, metatarsals, phalanges, proximal femora, and distal radii. In addition to flattening and irregularity of the epiphyses of the metacarpals, metatarsals, and phalanges, all of these bones were strikingly short and broad (Fig. 5). In contrast, the diaphyses and metaphyses of the long tubular bones appeared rela- tively normal. There was slight irregularity of the carpal and tarsal bones. The capital femoral epiphyses were not only flattened but were also partially frag- FIG. 4.-Hands of proposita at 10O years. Short digits are characteristic of multiple epiphysea dysplasia, tarda. FIG. 5.-Roentgenogram of hands of proposita at 1O' years. The unfused epiphyses are flattened and irregular, and all bones are abnormally short and broad. The disproportionate shortening of each fourth metacarpal probably is not significant MULTIPLE EPIPHYSEAL DYSPLASIA, TARDA 553 mented and considerably increased in density. Secondary degenerative arthritis of the hip joints was evident, and the femoral necks were relatively short and broad (Fig. 6). The general configuration of the pelvis was normal. Considerable distortion of each elbow was evident, the sigmoid notch of the ulna being shallow and V-shaped, with a false joint being present between the distal hu- merus and the radial head. Conversely, the knees appeared relatively normal, except that a double-layered patella was seen bilaterally (Fig. 7). FIG. 6.-Pelvis and hips of proposita at 10- years. Flat, sclerotic femoral heads and short, broad femoral necks are associated with degenerative arthritis despite patient's age. The spine showed only minimal abnormalities, with all of the vertebral bodies being slightly decreased in vertical height (Fig. 8). Only in the cervical region was there evidence of minimal anterior wedging. The over-all appearance certainly did not suggest the typical platyspondyly of Morquio's disease. The skull and thoracic cage appeared normal in all respects. Laboratory studies disclosed normal values for the following: hemoglobin, hema- tocrit, total leukocytes, leukocyte differential, rate of erythrocyte sedimentation, fasting blood sugar, blood urea nitrogen, serum calcium, serum phosphorus, serum alkaline phosphatase, total serum protein, serum protein fractionation by electro- phoresis, bromsulphalein retention, serum protein bound iodine, urinalysis, urinary amino acid excretion by chromatography, and electrocardiogram. Cytogenetic analysis showed 46 chromosomes, and all appeared to be normal. Histological exam- ination of the synovium from the capsule of the left hip showed slight, chronic, non- specific synovitis. Because of flexion contracture of 600 of the left hip, surgery for the release of soft FIG. 7.-Right knee of proposita at 10t years. The proximal epiphyses of the tibia and fibula are only slightly flattened, and there is a coronal cleft in the patella. The left knee had a similar appear- ance. FIG. 8. Dorsolumbar spine of proposita at 9 - y-ears.
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