American Journal of Medical Genetics 22:791-809 (1985)
An Autosomal Dominant Syndrome of Short Stature With Mesomelic Shortness of Limbs, Abnormal Carpal and Tarsal Bones, Hypoplastic Middle Phalanges, and Bipartite Calcanei
William R. Osebold, David J. Remondini, Edward L. Lester, Jurgen W. Spranger, and John M. Opitz
Spokane Shriners Hospital for Crippled Children, Spokane, Washington (w. R. O., E. L. L.); Genetics Study Section, Division of Research Grants, National Institutes of Health, Bethesda, Maryland (D. J. R.); Universitats-Kinderklinik, Mainz, West Germany (J. W S.); and Department of Medical Genetics, Shodair Childrens Hospital, Helena, Montana (J. M. 0.)
This paper describes seven persons in a family affected with an autosomal domi- nant syndrome of short stature with mesomelic shortness of upper and lower limbs, abnormal carpal and tarsal bones, hypoplastic or absent middle phalanges of hands and feet, and delayed coalescence of bipartite calcanei. All affected relatives are of normal intelligence, are free of eye problems, and have a normal skull, spine, shoulders, and hips. The digits of the hands and feet are short, broad, and angulated. The hypoplastic or absent middle phalanges effectively result in one interphalangeal joint for each digit, with decreased mobility. The bones of the carpus and tarsus coalesce with increasing age. None of the previously described syndromes or brachydactylies encompasses the findings noted in this kindred.
Key words: autosomal dominant inheritance, shortness of stature, short limbs, brachydactyly, dysostosis condition, failure of phalangeal segmentation, hypoplastic, absent pha- langes, bipartite calcaneus ossification center
Failure of segmentation of the capitate and hamate with short broad digits, cutaneous syndactylies, hypoplastic middle phalanges, and bipartite calcaneal ossifi-
Received for publication December 24, 1984; revision reccived February 19, 1985
Address reprint requests to Dr. William R. Osebold, Shriners Hospital for Crippled Children, N. 820 Summit Boulevard, Spokane, Washington 99201-1598.
0 1985 Alan R. Liss, Inc.
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1 1 1
1 , 2 3 - 5 6
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Fig. 1. Pedigree. S indicates syndactyly of toes 2 and 3
Fig. 2 . 12 yr.
(A) JB at 12 yr. Note rnesornelic shortness of limbs. (B) Feet of JB at 12 yr. (C) Hands of JB at
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Fig. 3. (A), (B) SE at 9 yr. (C) Hands of SE at 9 yr.
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cation center have been described in the oto-palato-digital (OPD) syndrome. How- ever, OPD syndrome patients have a characteristic facial appearance with palatal malformation, mental retardation, and vertebral involvement [Langer, 1967a; Gall et al, 1972; Spranger et al, 1974; Smith, 19761. Here, we describe seven relatives with a syndrome of normal intelligence and a characteristic constellation of skeletal anom- alies including coalescence of carpal and tarsal bones, absent or severely abnormal and hypoplastic middle phalanges of digits of hands and feet, delayed coalescence of calcaneal ossification centers, and short tibiae and radii with short stature and auto- soma1 dominant inheritance. None of the previously described brachydactylies encom- passes the findings noted in this kindred.
JE (11-7, Fig. l), the first affected person in this kindred, has 11 normal sibs. His parents were normal, and none of his sibs have had affected children. By his first wife he had five children, the second (LE) and the fourth (EE) being affected. The three unaffected sons have a total of five unaffected offspring. LE and her normal husband have one child, JB (IV-3) who is affected. EE and his normal wife have three children, one of whom is normal. JLE (IV-5) is affected. Recently EE and his wife had a stillborn daughter SB (IV-7), who was affected and whose cause of death is unknown despite an autopsy [Opitz and Gilbert, 19851. By his second wife, JE has had two children, one of whom, SE (111-7) is affected.
At age 65, JE denies pain due to his hand and foot changes. He was engaged in heavy labor in the lumber trade and suffered several disabling back and leg injuries. He feels that over the years he has lost much of the motion at his hand and wrist joints, and that this is progressive and related to arthritis. On examination, he has shortness of stature (height: 160 cm), mesomelic shortness of limbs with short, broad digits of hands and feet, and decreased range of motion at the distal joints of upper and lower limbs, with sparing of the proximal limb joints and trunk (Appendix I). The clinical and radiographic changes present in JE closely resemble those of his fourth child, EE and of his grandson, JB. The findings of LE, SE, and JLE are similar.
Fig. 4. (A) Radiographs of JLE at 8 wk show shortness of the forearm relative to the humerus. (B) JB at 12 yr. The forearms show short radii and longer ulnae with dyplastic distal epiphyses and radial deviation of the hands. There is a distal radial-ulnar diastasis. ( C ) LE at 5 yr shows symmetric hand changes. The proximal phalanx of the thumb is delta shaped due to lateral fusion of the epiphysis to the metaphysis. The proximal phalanges of the 2nd to 5th fingers and all the metacarpals have proximal and distal growth plates. The middle phalanges are hypoplastic, that of the index finger is an ulnar ossicle leading to radial deviation and that of the middle finger is fused to the shaft of the proximal phalanx. Hamate and capitate are conjoint with a separate h a t e and triquetrum. Radius and ulna are short. The distal end of the radius and the proximal end of the ulna are wide; both bones have a club-like appearance. (D) Radiograph of right arm of JE at 65 yr. The middle phalanx of both index fingers is absent, while that of the long, ring, and little fingers is hypoplastic and block shaped. The distal phalanges of the index fingers are short and broad. Each carpus shows a triangular configuration with the lunate at the apex. On the left is coalescence of the lunate, triquetrum, and hamate. On the right, the abnormally shaped capitate and hamate abut on each other, and the naviculars are oblong. The radii and ulnae are short and abnormally modeled.
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Fig. 6. (A) JB, age 12 yr. The femora show proximal metaphyseal striations with 157" of valgus bilaterally and some uncovering of the femoral heads. (B) JE at age 65 yr. The lower portions of the ilia are somewhat wide, but otherwise there are no abnormalities.
Fig. 5 . (A) EE at 2 yr showed separate carpal bones. There are also proximal and distal plates for the 2nd to 4th metacarpals. The middle phalanges are hypoplastic or absent. (B) JB at 2 yr already exhibits coalescencc of the capitate and hamate bilaterally. (C) LE at 8 yr. The lunates and triquetra have coalesced, and the proximal metacarpal plates 2 through 5 are closing. (D) JB at 12 yr. A block-shaped trapezium abuts on the coalesced trapezoid, capitate and hamate. The proximal carpal row is almost a solid mass with a midline symphysis. Unlike his mother's thumbs, JB's thumbs are abnormal due to a long, phalanx-like metacarpal with two epiphyses; the middle phalanges are hypoplastic.
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Fig. 7. (A) At age 5 yr, the shortness of the tibiae of LE relative to the femora is apparent. The lateral portion of the proximal tibia1 epiphyses is flattened. (B) Like his father, JLE at 7 yr has flatness of the femoral condyles and his tibiae and fibulae are short. (C) At age 9 yr the tibiae and fibulae of SE are relatively short. (D) The tibiae and fibulae of JE at age 65 yr are short. JE has had previous internal fixation of the tibia with ankle fusion for trauma. The right ankle tends toward a ball and socket configuration.
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LE, the 38-year-old daughter of JE, finds that her finger abnormalities require use of both hands for most tasks, such as opening car doors and unscrewing jar lids. For many years her knees, right ankle, and low back hurt with activities such as running. She notes numbness and a dysesthesia resembling electrical shocks in the radial aspects of her distal forearms. She has a chronic, partial, uncharacterized hearing loss affecting only the right ear. Slit lamp examination of LE and JB showed no corneal or lens opacities, and their vision is 20/20. LE has bilateral partial syndactyly of toes 2 and 3 and a mild cavus deformity of both feet.
JB, the 12-year-old son of LE (Fig. 2A-C), also has broad, short hands and fingers but does not have radial deviation of the distal thumb phalanx. Instead, he has radial deviation of the distal phalanx of digits 2 and 3 (2.5" both index fingers, 15" at the middle fingers). He complains of a diffuse ache in his right hand (but not in the wrist) when he writes. He had a bilateral club foot deformity treated with a series of casts, followed by nighttime splinting. His feet ache with prolonged weight bearing,
Fig. 8. (A) LE at 8 yr. The 2nd to 5th proximal phalanges and the metatarsals of all toes show proximal and distal plates. There are no middle phalanges. (B) In JE's tarsus at age 65 yr, the bones have remained separate even in adulthood. The middle phalanges are either absent or, in the 2nd toe, are hypoplastic laterally placed ossicles.
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and he has a prominent right hallux varus. Unlike his affected mother, he has no syndactyly .
EE, the 32-year-old son of JE, has bilateral partial c