American J o u r n a l of Medical Genetics 39:91-96 (1991)
Familial Congenital Micromelic Dysplasia With Dislocation of Radius and Distinct Face: A New Skeletal Dysplasia Syndrome Zvi Borochowitz, Mila Barak, and Silvia Hershkowitz T h e Genetics Institute, Bnai-Zion Medical Center, Technion-Faculty of Medicine, Haifa (Z.B.), and Department of Neonatology, Malben Hospital, Naharia (M.B., S.H.), Israel
Recently Maroteaux et al. [Am J Med Genet 32:371-3751 described omodysplasia as a new distinct congenital bone disorder in 3 cases; autosomal dominant inheritance was suggested. In this same report, 2 other cases (patients 4 and 5) presented with the same facial and upper limb anomalies, but were also noted to have severe shortness of lower limbs. The authors considered all 5 cases to represent variable expressivity of the same disorder, namely, omodysplasia. Here we report 4 patients (3 survivors), offspring of consanguineous Arabic-Moslem couples. All presented at birth with severe short limb dwarfism and facial and radiologic appearance quite distinct from the first 3 patients of Maroteaux et al. 119891 with so-called omodysplasia. Thus, we suggest that our 4 cases and patients 4 and 5 of Maroteaux et al. [1989] represent a distinct, previously unpublished bone dysplasia. KEY WORDS: chondrodysplasia, humeral dysplasia, femoral dysplasia, autosomal recessive inheritance, consanguinity, nosology
variable expressivity of the same disorder, namely, omodysplasia. Here we report on 4 cases, 2 pairs of sibs, offspring of consanguineous couples from a large ArabicMoslem kindred (Fig. 1).All presented a t birth with severe short limb dwarfism and distinct facial and radiologic appearance, similar to that of patients 4 and 5 of Maroteaux et al. and quite distinct from their first 3 cases with so-called omodysplasia.
CLINICAL REPORTS Patients 1 and 2 Patients 1 and 2 (Fig. 1, IV-2,3) were monozygotic twin boys born to healthy consanguineous young Arabic-Moslem parents, after a n uneventful 39 weeks of gestation. The placenta was monochorionic-diamniotic. Both had a birth length of 40.5 cm (4 SD below the mean). Birth weights were 2,460 and 2,510 g, respectively (3-10th centile). Head circumferences were 36 and 35.5 cm, respectively (75-90th centile). Chest circumferences were 29 cm ( ~ 3 r centile). d The twins had a n identical facial appearance and skeletal changes (Fig. 2A). Neonatally, both had a round face, high forehead with frontal bossing, and a midline capillary nevus flammeus covering forehead and nose. Depressed nasal bridge, very short nose with anteverted nostrils, and slight epicanthal folds were noted. A striking finding was the
INTRODUCTION In 1989, Maroteaux et al. described omodysplasia as a new apparently autosomal dominant congenital bone disorder in 3 cases. In their report, the authors also described 2 other cases (patients 4 and 5) with the same facial and upper limbs anomalies but with severe micromelic dwarfism due to shortness of both femora. Nevertheless, the authors considered all 5 cases to represent Received for publication April 11, 1990; revision received June 25, 1990. Address reprint request to Z. Borochowitz, MD, Director, The Genetics Institute, Bnai-Zion Medical Center, P.O. Box 4940, Haifa 31048, Israel.
0 1991 Wiley-Liss, Inc
Fig. 1. Family pedigree.
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Fig. 2. A: Patient 1.Note peculiar face, prominent maxilla, severely short upper and lower limbs with normal upper body segment length, hands, and feet. B: Patient 2. Note frontal bossing, retrognathia, protruding peculiar philtrum, and short nose.
protrusion of the anterior inferior portion of the maxilla. The philtrum was long and the lips thick. The mandible was short. Both infants had highly arched palates. The ears were narrow and posteriorly angulated, with a pointed upper helix. All limbs were severely short; there was limited extention at the elbows. The arms were short; however, both hands had a normal appearance and length. Bilateral simian line and clinodactyly of the fifth fingers
were noted. Lower limbs were malformed in the same manner as the upper ones. The thighs were severely short, whereas the length of the forefeet was only mildly affected. Extension a t the knees and abduction of the thighs were limited. Length, shape, and positioning of feet were normal. Penis length was normal, but both infants had bilateral cryptorchidism (Figs. 2A,B). Both infants had normal chromosomes. HLA typing results were identical a t loci A, B, and C. Radiologic evaluation a t this age showed a normal skull and normal configuration of spine and vertebral bodies (Figs. 3A,B), sternum, clavicles and scapulae; the ribs (13 pairs in number) were normal in shape and configuration (Fig. 3A). The major skeletal anomalies seemed to be confined primarily to the limbs. Severe shortness was noted in the humeri, with mild distal hypoplasia. The radii were dislocated, and the ulnae appeared to be abnormally placed as well. There was considerable shortness of mesomelic segments. Two carpal centers were identified, and the hands appeared normal (Fig. 4). The lower limbs had similar abnormalities, with short femora. Mild metaphyseal widening was appreciated in its proximal end without evidence of cupping or splaying. Distally, the femora were somewhat hypoplastic. The tibiae were mildly short. The fibulae showed no gross anomaly. Distal femoral ossification was retarded, whereas the proximal tibia looked normal. Talus and calcaneus were well ossified, as were the other centers in the foot. The pelvis showed minor hypoplasia of the iliac
Fig. 3. A: AP radiograph of normal spine. Note normal ribs. B: Lateral radiograph of the spine. Note normal vertebral bodies.
Fig. 4. Patient 1 a t birth. AP radiograph of an upper limb in pronation and supination. The humerus is short, with distal hypoplasia. The radius is dislocated with hypoplasia of its proximal head. The ulna is abnormally placed. Both are severely short. Note two precocious ossified carpal centers. The hands appear normal
wings with a normal acetabulum. The sacrosciatic notch was mildly narrowed. Ischium and pubic bones were normal (Fig. 5). On follow-upexamination at 12 months, no changes in the clinical appearance of the twins were appreciated. The lengths were 58 and 55 cm, respectively (5 SD below the mean). They weighed 5,950 and 5,000 g, respectively (4-5 SD below the mean), whereas their head circumferences were 47 and 46.5 cm (50th centile). No teeth had erupted. However, motor development was grossly retarded with normal mental development for age. Results of vision and hearing tests were normal. A new series of roentgenograms a t this age showed normal size of skull with some midface hypoplasia. The spine showed a normal configuration and normal vertebral bodies once again, with no interpedicular abnormalities.
The ribs were also normal. Clavicles and scapulae were normal. Mild glenoid fossa hypoplasia was present bilaterally. The upper limbs showed marked rhizomelic shortness. The humeral shafts were twisted, with hypoplastic and everted lateral condyles. Mesomelic shortness with proximal dislocation of the radius was also noted. The ulnae were mildly short (Fig. 6). The hands showed normal configuration. Iliac wings and acetabular roofs were normal. Pubic bones were normal. The lower limbs showed hypoplasia of the distal ends of the femora, with some widening at both ends. There was persistent lack of ossification of the distal femoral epiphyses (Fig. 7). A recent follow-up examination a t 3.5 years showed gross motor delay. Both infants had only started to cruise lately. Hearing and vision were normal, and so was their mental status. Height and weight were 4 SD
Fig. 5. Patient 1 a t birth. AP radiograph of lower limbs and iliae. Femora are short, with mild proximal metaphyseal widening and mild hypoplasiaof the distal ends. The tibiae are short. Fibulae are not affected. Note ossification of proximal tibia1 epiphysis only. Iliac bones are mildly hypoplastic, with normal acetabulum. Mild narrowness of the sacrosciatic notches is noted Sacrum, ischium, and pubis are normal.
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Fig. 6. Patient 1 at age 1 year. The humeri, radii, and, ulnae are short. There are proximal radial dislocations and proximal radioulnar diastases bilaterally. The ribs, clavicles, and scapulae are normal. Fig. 8. Patients 1 (left) and 2. Age 3.5 years. Micromelic dwarfism with facial anomalies. Note normal hands.
below the mean whereas the head circumference was a t the 50th centile. Facial appearance, shortness of all limbs, elbow dislocation, and limited extention were present in the same degree as in previous examinations (Fig. 8). Both had undergone bilateral orchidopexy.
Patient 4 Nine years after the birth of the female infant described above, a brother was born after 36 weeks of gestation (Fig. 1, IV-16). During this 9 year period, 3 Patient 3 other normal sibs were born to this family. The present This female infant (Fig. 1,IV-121, was born after 40 infant weighed 2,600 g (25th centile), his length was 40 weeks of uneventful gestation to a 20-year-old, healthy, cm (4 SD below the mean), and his head circumference Arab woman and her 25-year-old first cousin. He was was 35 cm (50th centile). His gross appearance was the uncle of patients 1and 2, the brother of their mother strikingly similar to that of his affected sister (patient 3) (Fig. 1, 111-15). This was their second pregnancy; they as well as to that of his twin cousins (patients 1 and 21, already had a normal boy. Birth weight was 2,140 g (3 with extreme shortness of limbs; limited extention a t SD below the mean). She measured 39 cm in length ( - 4 the elbows, knees, and hips; and bilateral simian line. SD), and head circumference was 33 cm (25th centile). The head and face showed the same minor anomalies as At delivery, extreme shortness of her limbs were noted, described in cases 1and 2. Bilateral cryptorchidism was with round face, midline frontal nevus flammeus, pro- noted. Roentgenograms from the neonatal period documented the same radiographic changes as in the other 3 truding maxilla, and upper lip with long philtrum. Mild respiratory distress was noted during the first day of life, which improved with no specific treatment. She died rather suddenly a t age 5 weeks. Postmortem examination was not preformed. Radiographs showed changes identical to those of her twin cousins except that the tibiae were relatively shorter (Fig. 9).
Fig. 7. Patient 1 at age 1 year. Short femora with hypoplasia of the distal ends and lack of ossification of the distal femoral epiphysis. Note widening of metphyseal areas. Acetabular roof is flat. Pubis, ischium, and sacrum are normal.
Fig. 9. Patient 3 at birth. AP total body radiograph. Note changes identical to those of his twin cousins except for the relatively shorter tibiae and fibulae. Severe micromelia is well appreciated, including hypoplasia of the distal ends of humerus and femora and dislocation of elbows. Talus and calcaneus are ossified. Note lack ofossification ofthe epiphyses a t the knees.
Familial Micromelic Dysplasia
Fig. 10. Patient 4 at birth. AP total body radiograph. Note severe micromelia, dislocated elbows, mild hypoplasia of iliac bones, and narrow sacrosciatic notches. The tibiae and fibulae are relatively longer than in the other patients.
cases, except that both the tibiae and fibulae were relatively longer (Fig. 10). At age 10 months he weighed 5,000 g ( - 4 SD), his length was 55 cm ( - 4 SD), and his head circumference was 45 cm (50th centile). He had no teeth. As with his cousins, his motor development was retarded. Chromosome study showed a normal 46,XY constitution.
DISCUSSION These 4 patients had a similar skeletal disorder manifested predominantly with short humeri and in particular a deficiency in the distal end; complex deformity of the elbows, including “twisted” humeri, hypoplasia, and lateral eversion of the humeral condyle; dislocated radial head anteriorly and laterally; and diastasis of proximal radii and ulnae. Femora were short, with growth deficiency of the distal end. The tibiae and fibulae were variably affected, with less relative shortening than is present in the femora and the long bones of the upper limb. Hands and feet had a normal appearance and normal length. A distinctive facial appearance was noted in this disorder. It was round with a median port wine large frontal hemangiomata. A short nose with depressed nasal bridge was present. The philtrum had a peculiar protruded long appearance with prominent vermilion. Mental development was not affected; however, some gross motor delay was noted, and this was attributed to the severe micromelia. The patients reported herein are second cousins, all born to consanguinous healthy parents from a large Arabic-Moslem kindred, indicating autosomal recessive inheritance. Striking differences were appreciated by Maroteaux et al. [1989] between their first 3 patients and their last 2 patients, in particular, ear shape, severe short first metacarpals, and normal lower limbs which were found exclusively in the first ones. The main findings of their
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patients 4 & 5 were severe short upper as well as lower limbs. The radiographic changes were also different in these 2 groups. Nevertheless, the authors claim that all 5 patients represent variable expressivity of the same disorder. It seems that their first 3 patients do represent a distinct new syndrome, which they call omodysplasia. However, it is quite distinct in all aspects from their patients 4 and 5 and those reported herein. In 1987, Viljoen et al. reported 2 patients with “familial rhizomelic dysplasia.” Their patient 1 had clinical and radiologic manifestations similar to our patient. He had symmetrical shortness of the arms, dislocated radial heads, and abnormally angulated radiocarpal joints. His femora were short, with flat capital epiphyses. Shortness of the tibiae and fibulae was evident but to a relatively lesser extent than th a t of the proximal limb bones. Vertebrae, skull, thorax, and bones of the hands and feet were normal. Autosomal recessive inheritance was also suggested by these authors. Patient 2 in this same report, a first cousin of the propositus’ father, born from a consanguinouse union, presented with skeletal anomalies localized to the lower limbs, appears very different from the propositus. The relationship between these 2 cases is questionable due to the possibility that a chance familial association of 2 extremely rare, but similar, skeletal dysplasias was encountered. The distinct manifestations noted among our 4 patients, similar to those found in Maroteaux et al.’s [19891 2 patients and Viljoen et al.’s [1987] first case, makes this view the most appropriate. Thus these 7 cases represent a new bone dysplasia with a n autosomal recessive mode of inheritance. It is therefore clinically, radiographically, and genetically distinct from omodysplasia or other previously published bone dysplasia. Most patients with gross humeral shortness reported in the literature differ from the patients described here [Davis, 1956; Kozlowski et al., 1974; Patterson and Lowry, 1975; Yang and Lenz, 1976; Urbach et al., 19861. Investigation of more cases and in particular morphologic studies of cartilage and bone might shed more insight to the nature of this peculiar disorder. Early lethal outcome should be considered when counselling at-risk families, and, in view of the severe congenitally short humeri and femora, early intrauterine detection is probably possible and thus should be offered.
ACKNOWLEDGMENTS The authors are grateful to Drs. David Rimoin and Ralph Lachman from the International Bone Dysplasia Registry, Cedars-SinaiMedical Center, Los Angeles, for their comments. REFERENCES Davis AGM (1956):Bilateral humerus varus with report of a case. Br J Radio1 29:295-296. Kozlowski KS, Celermajer JM, Tink AR (1974):Humero-spinal dysostosis with congenital heart disease. Am J Dis Child 127:407-410. Maroteaux P, Sauvegrain J, Chrispin A, Farriaux JP (1989): Omodysplasia. Am J Med Genet 32:371-375.
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Patterson C, Lowry RB (1975):A new dwarfing syndrome with extreme shortening of humeri and severe coxa vara. Radiology 114:341-342. Urbach D, Hertz M, Shine M, Goodman RM (1986): A new skeletal dysplasia syndrome with rhizomelia of the humeri and other malformations. Clin Genet 29:83-87.
Viljoen D, Goldblatt J , Wallis C, Beighton P (1987):Familial rhizomelic dysplasia: Phenotypic variation or heterogeneity. Am J Med Genet 26:941-947. Yang TS, Lenz W (1976):Uber symmetrische Verkdrzung der Humeri. Padiatr Padol 11:12-16.
Familial Congenital Micromelic Dysplasia With Dislocation of Radius and Distinct Face: A New Skeletal Dysplasia Syndrome Zvi Borochowitz, Mila Barak, and Silvia Hershkowitz T h e Genetics Institute, Bnai-Zion Medical Center, Technion-Faculty of Medicine, Haifa (Z.B.), and Department of Neonatology, Malben Hospital, Naharia (M.B., S.H.), Israel
Recently Maroteaux et al. [Am J Med Genet 32:371-3751 described omodysplasia as a new distinct congenital bone disorder in 3 cases; autosomal dominant inheritance was suggested. In this same report, 2 other cases (patients 4 and 5) presented with the same facial and upper limb anomalies, but were also noted to have severe shortness of lower limbs. The authors considered all 5 cases to represent variable expressivity of the same disorder, namely, omodysplasia. Here we report 4 patients (3 survivors), offspring of consanguineous Arabic-Moslem couples. All presented at birth with severe short limb dwarfism and facial and radiologic appearance quite distinct from the first 3 patients of Maroteaux et al. 119891 with so-called omodysplasia. Thus, we suggest that our 4 cases and patients 4 and 5 of Maroteaux et al. [1989] represent a distinct, previously unpublished bone dysplasia. KEY WORDS: chondrodysplasia, humeral dysplasia, femoral dysplasia, autosomal recessive inheritance, consanguinity, nosology
variable expressivity of the same disorder, namely, omodysplasia. Here we report on 4 cases, 2 pairs of sibs, offspring of consanguineous couples from a large ArabicMoslem kindred (Fig. 1).All presented a t birth with severe short limb dwarfism and distinct facial and radiologic appearance, similar to that of patients 4 and 5 of Maroteaux et al. and quite distinct from their first 3 cases with so-called omodysplasia.
CLINICAL REPORTS Patients 1 and 2 Patients 1 and 2 (Fig. 1, IV-2,3) were monozygotic twin boys born to healthy consanguineous young Arabic-Moslem parents, after a n uneventful 39 weeks of gestation. The placenta was monochorionic-diamniotic. Both had a birth length of 40.5 cm (4 SD below the mean). Birth weights were 2,460 and 2,510 g, respectively (3-10th centile). Head circumferences were 36 and 35.5 cm, respectively (75-90th centile). Chest circumferences were 29 cm ( ~ 3 r centile). d The twins had a n identical facial appearance and skeletal changes (Fig. 2A). Neonatally, both had a round face, high forehead with frontal bossing, and a midline capillary nevus flammeus covering forehead and nose. Depressed nasal bridge, very short nose with anteverted nostrils, and slight epicanthal folds were noted. A striking finding was the
INTRODUCTION In 1989, Maroteaux et al. described omodysplasia as a new apparently autosomal dominant congenital bone disorder in 3 cases. In their report, the authors also described 2 other cases (patients 4 and 5) with the same facial and upper limbs anomalies but with severe micromelic dwarfism due to shortness of both femora. Nevertheless, the authors considered all 5 cases to represent Received for publication April 11, 1990; revision received June 25, 1990. Address reprint request to Z. Borochowitz, MD, Director, The Genetics Institute, Bnai-Zion Medical Center, P.O. Box 4940, Haifa 31048, Israel.
0 1991 Wiley-Liss, Inc
Fig. 1. Family pedigree.
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Fig. 2. A: Patient 1.Note peculiar face, prominent maxilla, severely short upper and lower limbs with normal upper body segment length, hands, and feet. B: Patient 2. Note frontal bossing, retrognathia, protruding peculiar philtrum, and short nose.
protrusion of the anterior inferior portion of the maxilla. The philtrum was long and the lips thick. The mandible was short. Both infants had highly arched palates. The ears were narrow and posteriorly angulated, with a pointed upper helix. All limbs were severely short; there was limited extention at the elbows. The arms were short; however, both hands had a normal appearance and length. Bilateral simian line and clinodactyly of the fifth fingers
were noted. Lower limbs were malformed in the same manner as the upper ones. The thighs were severely short, whereas the length of the forefeet was only mildly affected. Extension a t the knees and abduction of the thighs were limited. Length, shape, and positioning of feet were normal. Penis length was normal, but both infants had bilateral cryptorchidism (Figs. 2A,B). Both infants had normal chromosomes. HLA typing results were identical a t loci A, B, and C. Radiologic evaluation a t this age showed a normal skull and normal configuration of spine and vertebral bodies (Figs. 3A,B), sternum, clavicles and scapulae; the ribs (13 pairs in number) were normal in shape and configuration (Fig. 3A). The major skeletal anomalies seemed to be confined primarily to the limbs. Severe shortness was noted in the humeri, with mild distal hypoplasia. The radii were dislocated, and the ulnae appeared to be abnormally placed as well. There was considerable shortness of mesomelic segments. Two carpal centers were identified, and the hands appeared normal (Fig. 4). The lower limbs had similar abnormalities, with short femora. Mild metaphyseal widening was appreciated in its proximal end without evidence of cupping or splaying. Distally, the femora were somewhat hypoplastic. The tibiae were mildly short. The fibulae showed no gross anomaly. Distal femoral ossification was retarded, whereas the proximal tibia looked normal. Talus and calcaneus were well ossified, as were the other centers in the foot. The pelvis showed minor hypoplasia of the iliac
Fig. 3. A: AP radiograph of normal spine. Note normal ribs. B: Lateral radiograph of the spine. Note normal vertebral bodies.
Fig. 4. Patient 1 a t birth. AP radiograph of an upper limb in pronation and supination. The humerus is short, with distal hypoplasia. The radius is dislocated with hypoplasia of its proximal head. The ulna is abnormally placed. Both are severely short. Note two precocious ossified carpal centers. The hands appear normal
wings with a normal acetabulum. The sacrosciatic notch was mildly narrowed. Ischium and pubic bones were normal (Fig. 5). On follow-upexamination at 12 months, no changes in the clinical appearance of the twins were appreciated. The lengths were 58 and 55 cm, respectively (5 SD below the mean). They weighed 5,950 and 5,000 g, respectively (4-5 SD below the mean), whereas their head circumferences were 47 and 46.5 cm (50th centile). No teeth had erupted. However, motor development was grossly retarded with normal mental development for age. Results of vision and hearing tests were normal. A new series of roentgenograms a t this age showed normal size of skull with some midface hypoplasia. The spine showed a normal configuration and normal vertebral bodies once again, with no interpedicular abnormalities.
The ribs were also normal. Clavicles and scapulae were normal. Mild glenoid fossa hypoplasia was present bilaterally. The upper limbs showed marked rhizomelic shortness. The humeral shafts were twisted, with hypoplastic and everted lateral condyles. Mesomelic shortness with proximal dislocation of the radius was also noted. The ulnae were mildly short (Fig. 6). The hands showed normal configuration. Iliac wings and acetabular roofs were normal. Pubic bones were normal. The lower limbs showed hypoplasia of the distal ends of the femora, with some widening at both ends. There was persistent lack of ossification of the distal femoral epiphyses (Fig. 7). A recent follow-up examination a t 3.5 years showed gross motor delay. Both infants had only started to cruise lately. Hearing and vision were normal, and so was their mental status. Height and weight were 4 SD
Fig. 5. Patient 1 a t birth. AP radiograph of lower limbs and iliae. Femora are short, with mild proximal metaphyseal widening and mild hypoplasiaof the distal ends. The tibiae are short. Fibulae are not affected. Note ossification of proximal tibia1 epiphysis only. Iliac bones are mildly hypoplastic, with normal acetabulum. Mild narrowness of the sacrosciatic notches is noted Sacrum, ischium, and pubis are normal.
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Fig. 6. Patient 1 at age 1 year. The humeri, radii, and, ulnae are short. There are proximal radial dislocations and proximal radioulnar diastases bilaterally. The ribs, clavicles, and scapulae are normal. Fig. 8. Patients 1 (left) and 2. Age 3.5 years. Micromelic dwarfism with facial anomalies. Note normal hands.
below the mean whereas the head circumference was a t the 50th centile. Facial appearance, shortness of all limbs, elbow dislocation, and limited extention were present in the same degree as in previous examinations (Fig. 8). Both had undergone bilateral orchidopexy.
Patient 4 Nine years after the birth of the female infant described above, a brother was born after 36 weeks of gestation (Fig. 1, IV-16). During this 9 year period, 3 Patient 3 other normal sibs were born to this family. The present This female infant (Fig. 1,IV-121, was born after 40 infant weighed 2,600 g (25th centile), his length was 40 weeks of uneventful gestation to a 20-year-old, healthy, cm (4 SD below the mean), and his head circumference Arab woman and her 25-year-old first cousin. He was was 35 cm (50th centile). His gross appearance was the uncle of patients 1and 2, the brother of their mother strikingly similar to that of his affected sister (patient 3) (Fig. 1, 111-15). This was their second pregnancy; they as well as to that of his twin cousins (patients 1 and 21, already had a normal boy. Birth weight was 2,140 g (3 with extreme shortness of limbs; limited extention a t SD below the mean). She measured 39 cm in length ( - 4 the elbows, knees, and hips; and bilateral simian line. SD), and head circumference was 33 cm (25th centile). The head and face showed the same minor anomalies as At delivery, extreme shortness of her limbs were noted, described in cases 1and 2. Bilateral cryptorchidism was with round face, midline frontal nevus flammeus, pro- noted. Roentgenograms from the neonatal period documented the same radiographic changes as in the other 3 truding maxilla, and upper lip with long philtrum. Mild respiratory distress was noted during the first day of life, which improved with no specific treatment. She died rather suddenly a t age 5 weeks. Postmortem examination was not preformed. Radiographs showed changes identical to those of her twin cousins except that the tibiae were relatively shorter (Fig. 9).
Fig. 7. Patient 1 at age 1 year. Short femora with hypoplasia of the distal ends and lack of ossification of the distal femoral epiphysis. Note widening of metphyseal areas. Acetabular roof is flat. Pubis, ischium, and sacrum are normal.
Fig. 9. Patient 3 at birth. AP total body radiograph. Note changes identical to those of his twin cousins except for the relatively shorter tibiae and fibulae. Severe micromelia is well appreciated, including hypoplasia of the distal ends of humerus and femora and dislocation of elbows. Talus and calcaneus are ossified. Note lack ofossification ofthe epiphyses a t the knees.
Familial Micromelic Dysplasia
Fig. 10. Patient 4 at birth. AP total body radiograph. Note severe micromelia, dislocated elbows, mild hypoplasia of iliac bones, and narrow sacrosciatic notches. The tibiae and fibulae are relatively longer than in the other patients.
cases, except that both the tibiae and fibulae were relatively longer (Fig. 10). At age 10 months he weighed 5,000 g ( - 4 SD), his length was 55 cm ( - 4 SD), and his head circumference was 45 cm (50th centile). He had no teeth. As with his cousins, his motor development was retarded. Chromosome study showed a normal 46,XY constitution.
DISCUSSION These 4 patients had a similar skeletal disorder manifested predominantly with short humeri and in particular a deficiency in the distal end; complex deformity of the elbows, including “twisted” humeri, hypoplasia, and lateral eversion of the humeral condyle; dislocated radial head anteriorly and laterally; and diastasis of proximal radii and ulnae. Femora were short, with growth deficiency of the distal end. The tibiae and fibulae were variably affected, with less relative shortening than is present in the femora and the long bones of the upper limb. Hands and feet had a normal appearance and normal length. A distinctive facial appearance was noted in this disorder. It was round with a median port wine large frontal hemangiomata. A short nose with depressed nasal bridge was present. The philtrum had a peculiar protruded long appearance with prominent vermilion. Mental development was not affected; however, some gross motor delay was noted, and this was attributed to the severe micromelia. The patients reported herein are second cousins, all born to consanguinous healthy parents from a large Arabic-Moslem kindred, indicating autosomal recessive inheritance. Striking differences were appreciated by Maroteaux et al. [1989] between their first 3 patients and their last 2 patients, in particular, ear shape, severe short first metacarpals, and normal lower limbs which were found exclusively in the first ones. The main findings of their
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patients 4 & 5 were severe short upper as well as lower limbs. The radiographic changes were also different in these 2 groups. Nevertheless, the authors claim that all 5 patients represent variable expressivity of the same disorder. It seems that their first 3 patients do represent a distinct new syndrome, which they call omodysplasia. However, it is quite distinct in all aspects from their patients 4 and 5 and those reported herein. In 1987, Viljoen et al. reported 2 patients with “familial rhizomelic dysplasia.” Their patient 1 had clinical and radiologic manifestations similar to our patient. He had symmetrical shortness of the arms, dislocated radial heads, and abnormally angulated radiocarpal joints. His femora were short, with flat capital epiphyses. Shortness of the tibiae and fibulae was evident but to a relatively lesser extent than th a t of the proximal limb bones. Vertebrae, skull, thorax, and bones of the hands and feet were normal. Autosomal recessive inheritance was also suggested by these authors. Patient 2 in this same report, a first cousin of the propositus’ father, born from a consanguinouse union, presented with skeletal anomalies localized to the lower limbs, appears very different from the propositus. The relationship between these 2 cases is questionable due to the possibility that a chance familial association of 2 extremely rare, but similar, skeletal dysplasias was encountered. The distinct manifestations noted among our 4 patients, similar to those found in Maroteaux et al.’s [19891 2 patients and Viljoen et al.’s [1987] first case, makes this view the most appropriate. Thus these 7 cases represent a new bone dysplasia with a n autosomal recessive mode of inheritance. It is therefore clinically, radiographically, and genetically distinct from omodysplasia or other previously published bone dysplasia. Most patients with gross humeral shortness reported in the literature differ from the patients described here [Davis, 1956; Kozlowski et al., 1974; Patterson and Lowry, 1975; Yang and Lenz, 1976; Urbach et al., 19861. Investigation of more cases and in particular morphologic studies of cartilage and bone might shed more insight to the nature of this peculiar disorder. Early lethal outcome should be considered when counselling at-risk families, and, in view of the severe congenitally short humeri and femora, early intrauterine detection is probably possible and thus should be offered.
ACKNOWLEDGMENTS The authors are grateful to Drs. David Rimoin and Ralph Lachman from the International Bone Dysplasia Registry, Cedars-SinaiMedical Center, Los Angeles, for their comments. REFERENCES Davis AGM (1956):Bilateral humerus varus with report of a case. Br J Radio1 29:295-296. Kozlowski KS, Celermajer JM, Tink AR (1974):Humero-spinal dysostosis with congenital heart disease. Am J Dis Child 127:407-410. Maroteaux P, Sauvegrain J, Chrispin A, Farriaux JP (1989): Omodysplasia. Am J Med Genet 32:371-375.
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Patterson C, Lowry RB (1975):A new dwarfing syndrome with extreme shortening of humeri and severe coxa vara. Radiology 114:341-342. Urbach D, Hertz M, Shine M, Goodman RM (1986): A new skeletal dysplasia syndrome with rhizomelia of the humeri and other malformations. Clin Genet 29:83-87.
Viljoen D, Goldblatt J , Wallis C, Beighton P (1987):Familial rhizomelic dysplasia: Phenotypic variation or heterogeneity. Am J Med Genet 26:941-947. Yang TS, Lenz W (1976):Uber symmetrische Verkdrzung der Humeri. Padiatr Padol 11:12-16.
