The Dyggve-Melchior-Clausen Syndrome

Transcription

1 The Dyggve-Melchior-Clausen Syndrome S. SCHORR, C. LEGUM,2 M. OCHSHORN,3 M. HIRSCH,4 S. MOSES,5 E. E. LASCH,6 AND M. EL-MASRI Two families with Dyggve-Melchior-Clausen syndrome are reported. In the first family, Jews from Morocco, six of 10 siblings are affected. In the second family, a consanguineous marriage of Arabs from Gaza, two of three children are affected. A description of the skeletal changes in patients ranging in age from 4 to 25 years is presented. The radiologic signs of generalized platyspondyly with double humped end plates and the lacelike appearance of thickened iliac crests are pathognomonic and distinctive of the syndrome. The diagnostic features of the disease are compared to those of Morquio s disease, spondyloepiphyseal dysplasia tarda, and spondylometaphyseal dysplasia. Introduction In 1962, Dyggve, Melchior, and Clausen [1] described a family in Greenland in which three of eight children of an uncle-niece marriage suffered from a condition somewhat resembling Morquio-Ullnich disease. The children had a severe generalized bone dysplasia with universal platyspondyly. Urinary mucopolysaccharide excretion was initially considered abnormal, but subsequent testing showed a normal pattern [2]. Unlike Monquio s disease, there was no corneal clouding, they were severely retarded mentally, and the radiographic changes in the skeleton differed. In 1968 McKusick [3] listed the Dyggve-Melchion-Clausen (DMC) syndrome as a distinct mendelian entity. Among the terms which have been used to describe these patients are Monquio-Ullnich and Morquio-Brailsfond disease [1, 4, 5], modified hyaluronic mucopolysacchanidosis [6], and pseudo-monquio disease type 1 [7]. In 1971, Kaufmann et al. [8] described an 18-year-old mentally retarded girl with short trunk dwarfism and distinctive skeletal radiographic features, in particular, a lacy appearance of the iliac crests. The possibility was raised that two DMC syndromes existed with similar radiologic signs-one characterized by mental retardation and the other by normal intelligence. In 1972, Banylak and Kozlowski [9] described a 5-year-old female with mental retardation and generalized platyspondyly and emphasized the diagnostic nature of the radiologic signs in the spine and pelvis in the DMC syndrome. Spranger et al. [2] have recently reported several additional cases. To our knowledge, 21 DMC patients in 1 6 unrelated families have been reported. Affected siblings, including a pair of dizygotic twins, have been described in three of these families [1, 7, 101. Three pairs of parents were consanguineous [1, 2, 7]. Two patients with similar skeletal changes had normal intelligence [1 1, 1 2]. Nevertheless, the classical picture of DMC syndrome would appear to include moderately severe mental retardation. This paper describes the natural course of radiologic changes in the skeleton. The study is based on clinical and radiologic follow-up of two families with a total of eight affected members whose ages range from 4 to 25 years. The patients were dwarfed, mentally retarded, and had normal urinary mucopolysacchanide excretion. Family 1 Case Material The parents are Jews who emigrated from Morocco to Israel. They are healthy, of normal height and intelligence, and unrelated. Of 1 1 pregnancies, four resulted in normal offspring, one of whom died in infancy, and there was one spontaneous abortion at 5 months. Six pregnancies resulted in children with Dyggve-Melchior-Clausen syndrome (patients Mo., Al., S., Y., Mn., and El.). The birth order of the affected individuals was one, four through seven, and 10, respectively. Mo. (fig. 1A), a 25-year-old male, weighed 3.5 kg at birth, sat alone at 1 year, walked unaided at 2 years, and began talking at 3 years. At this age he was diagnosed as dwarfed, microcephalic, and mentally retarded. At present, his height is 125 cm, span 127 cm, crown-pubis to pubisheel ratio 0.71, and head circumference 49 cm. He has a short neck, thonacic kyphoscoliosis, protuberant abdomen, liver palpable 4 cm below the costal margin, normal sexual development, limitation of full extension of wrists, elbows, and knees, a waddling, shuffling gait, and short. broad thumbs (fig. 2) and great toes. His first, fourth, and fifth toes are foreshortened. The development of the other five affected children is stnikingly similar to Mo., except that they did not have hepatomegaly. S., at 18 years of age, also showed short, broad thumbs and first toes. Her menstrual periods commenced at 12 years and were regular. Y. (fig. 18), age 15 years, did not have shortened thumbs on great toes and had long limbs in relation to her short trunk. Mr., age 12, showed marked genu valgus, muscular wasting, hypenextensibility of knees, and deformity of the elbow joint with rhizomelic shortening of arm and Presented as the 13th annual Leo G. Rigler Lecture, Tel Aviv, June Department of Radiology, Tel Aviv University School of Medicine and Tel Aviv/Yaffo Medical Center, lchilov Hospital. Tel Aviv. Israel. 2 Department of Pediatrics, Tel Aviv University School of Medicine. and Genetic Service, Tel Aviv/Yaffo Medical Center, lchilov Hospital. Tel Aviv, Israel. 3 Department of Internal Medicine. Tel Aviv/Yaffo Medical Center. Ichilov Hospital, Tel Aviv, Israel. 4 Department of Radiology, Beer Sheva University School of Medicine and Central Hospital for the Negev. Beer Sheva, Israel. 5 Department of Pediatrics, Beer Sheva University School of Medicine and Central Hospital for the Negev. Beer Sheva, Israel. 6 Department of Pediatrics. Nasr Hospital. Gaza. Am J Ro.ntg.nol 128: , January

2 108 SCHORR ET AL. Fig Photographs of patient Mo. (A). age 25. and his sister Y. (B), age 15. both with long limbed, short trunk dwarfism. Fig 2. - Hand of patient Mo. showing short broad thumbs. thigh. El., age 5 years, had a crown-pubis to pubis-heel ratio of Special investigations including slit lamp examination of the cornea, fundoscopy, blood chromosomes, urinary amino acids. and urinary mucopolysacchanides (Ames spot test and total uronic acid content) were repeatedly normal. No abnormalities of serum electrolyte levels on blood chemistry were detected. The electrocardiograms were normal. Liven biopsy (Al.), bone marrow examination, and repeated blood Fig Patient A. at age 6 h. A. Characteristic double hump. B. Frontal view showing indistinct end plates. wide disc spaces, normal interpediculate distances, and flared concave posterior ends of ribs. counts were essentially normal. No significant findings were noted on a dermatoglyphic study of the family, and linkage studies were noncontnibutony. Family 2 The parents, healthy Arabs from Gaza, are related through common great-grandparents. Two of their three children (boys) are affected; the girl was unaffected but died of an infection at the age of 2 years. M. (birth rank 1 ) was modenately retarded and his psychomotor development had been slow. At the age of 9, his height was 102 cm (50th percentile for 4 years). The crown-pubis to pubis-heel ratio was There was no conneal clouding. His features were somewhat coarse and the mouth was relatively large. He had a short neck, short trunk, flared nibs with a bulging sternum, and a thonacic kyphosis with dorsal lordosis. The large joints were enlarged. There was no hepatosplenomegaly and no genu valgum. His younger brother A., at age 61/2 years, had a height of 85 cm (50th percentile for 2.5 years) and a crown-pubis to pubis-heel ratio of Physical findings as well as psychomotor and mental development were similar to those of his brother. All biochemical parameters examined, including quantitative and semiquantitative evaluations of urinary mucopolysaccharides, were normal for both boys. Radiologic nostic features are discussed. Findings The radiologic findings in affected members of both families are described and the salient differential diag-

3 DYG GVE-M ELCH IOR-CLAUSEN SYNDRO ME 109 TABLE 1 Radiologic Findings in DMC Syndrome Spine Pelvis and Hip Joints Generalized platyspondyly Os ilium crest with semi- Double vertebral hump with lunar lacy appearance and constriction in center at irregular thickening both vertebral end plates Os ilium small, diminished Anterior vertebral cutoff or vertical height pointing Wide and irregular sacroiliac Posterior scalloping joint Elongation of vertebral lam- Small sacroiliac notch mae Hypoplastic acetabulum Hypoplastic odontoid process Delayed, hypoplastic de- No hypoplastic vertebrae formed femoral head and Normal interpediculan dis- neck tance Femonal neck beaked medially Bilateral dislocation of hip Spine joint, laterally and supenionly Bilateral coxa valga Delayed deficient ossification of ischiopubic synchondrosis Plump, deformed, widened superior and inferior pubic ramus Wide symphysis pubis There is generalized platyspondyly (fig. 3). During childhood the disc spaces are rather wide and become narrowed with age (fig. 4). The characteristic double! Fig. 4.-Lumbar and dorsal spine of patient S. A, Age 5. Central constriction, wide intervertebral spaces, mild posterior vertebral scalloping. and elongated Iaminae. B. Age 1 1. Square vertebral body, sclerosed end plates, and marked posterior scalloping. C, Age 18. Rectangular vertebral bodies and bony appositional layers at both vertebral surfaces Fig. 5.-Cervical spine of patient Y. at age 1 5. Vertebral bodies show anterior wedging. Note slight irregularity of end plate surfaces and hypoplastic odontoid process. No double humping or scalloping present. hump is already noticeable at the age of 4 years. The changes are most apparent between the ages of 8 and 12 years (fig. 4B). With adolescence, appositional bone layers appear distinctly, and the vertebral bodies become almost rectangular in shape (fig. 48). The postenor scalloping persists from the age of 4 to 25 years, when the layers of appositional bone have fused and the bodies are rectangular. The previous end plates

4 110 SCHORR ET AL. TABLE 2 Differential Diagnosis Spinal Findings I..o;; i D M C Syndrome Fig. 6.-Pelvis and hip joints of patient S. A. Age 6. Characteristic semilunar lacy appearance of iliac crests and typical femoral heads and symphysis pubis. B, Age Morquio s Disease Spondyloepiphyseal Dysplasia Tarda Platyspondyly Vertebral hump Double - Posterior, - single, dense Spondylometaphyseal Dysplasia Hypoplasia of thonacolumban vertebrae Odontoid hypoplastic process + + Normal Normal Increased anterior-posterior diameter Wide disc space + + Narrow - Gibbus Kyphosis Sclerotic irregular end plates Anterior pointing I- 91 Fig. 7.-Pelvis and hip joints of patient Mo. A. Age 18. Acetabular roofs almost vertical. B. Age 25. Remnants of iliac crest still visible. Hips are dislocated to level of iliac crests. lschiopubic synchondrosis fused yet symphysis pubis still wide open.

5 DYGGVE-MELCHIOR--CLAUSEN SYNDROME 111 Fig 8 -Shoulder of patient Mr.. age 5. remain as ruptured dense lines. The radiologic findings in the spine are summarized in table 1. Other bone dysplasias must be taken into consideration in the differential diagnosis. In Morquio s disease, both end plates of the vertebral bodies are flattened, irregular, and without a humplike elevation. The thonacolumbar vertebrae are hypoplastic, and central tonguing or hook-shaped bodies are present during childhood. During adulthood the vertebral bodies became flattened and rectangular in shape. The hypoplastic odontoid process is present in both Morquio s disease and DMC syndrome (fig. 5). In spondyloepiphyseal dysplasia tarda, the flattened vertebral bodies have a humplike area of dense bone at the central and posterior part of both end plates, but the double hump with central constriction is absent. The disc spaces are narrowed with premature degenerative changes. In spondylometaphyseal dysplasia ( Kozlowski ), the flattened bodies have irregular sclerotic end plates, no humplike elevation is seen, and well defined tonguing or pointing at the anterior aspect of the vertebral body is usually present. Moreover, there is a marked increase in the anteropostenion diameter, a lateral extension external to the pedicles in the transverse diameter, and dorsal kyphosis. The differential signs are listed in table 2. Pelvis and Hip Joints In our experience, the peculiar radiographic signs in the pelvis as well as in the spine represent the most consistent diagnostic skeletal findings in DMC syndrome. The semilunar lacy appearance of the iliac crests, the wide sacroiliac joints, and a small acute sacroiliac notch are characteristic (fig. 6A). The acetabulum is flat, hypoplastic, and irregular, the head of the femur is small and dislocated with many supernumerary centers; and the neck of the femur is thick and plump. The ischiopubic synchondrosis is much wider than normal and the pubic nami as well as the symphysis pubis are also widened (fig. 6A). The evolution of these findings over time can be seen in figures 6B and 78. The hypoplastic deformed femoral heads tend to point laterally and superiorly. Figure 7B shows the remains of the somewhat disrupted, dense lines at the iliac crests. Marked dislocation of both femurs in later years is well shown. The nadiologic findings in the pelvis and hip joints are summarized in table 1. On lateral view of the sternum, the ends of the ribs flare with wide costochondral junctions. The sternal bones bulge forward slightly. Upper Extremities The height of the scapula is decreased and its inferior angle is concave. The glenoid fossa is flat. The metaphyseal end of the acromion is flared (fig. 8). The humeri are short and broad with rather marked deformities in both the shoulder and the elbow joints. The development of the hand abnormalities is well shown in figure 9. The major changes are best seen at 5 years of age (fig. 9A). The carpal bones are small and irregular with severe involvement of the proximal row. Accessory ossification centers at the distal ends of the first metacarpal and the distal ends of the proximal phalanges are apparent. By age 18 (fig. 98), the tubular bones of the hands are short and thick, and the carpal bones, especially the navicular and lunate, are irregular and rather small. With advancing age there is epiphyseal fusion and disappearance of the described epiphyseal peculiarities. Similar changes are seen in patient A. at 61/2 years (fig. 10). Accessory ossification centers, irregularity of length, and cone-shaped epiphyses, especially in the thumb, are apparent. Here, too, the carpal bones are small and irregular with severe changes in the proximal row. The marked shortening of the metatarsals and phalanges with flaring of their ends are well demonstrated in patient S. at 18 years of age (fig. 11). Discussion The patients described by Dyggve et al. [1] as haying Monquio-Ullnich disease in fact had a separate and distinct entity characterized by mental retardation, short trunked dwarfism, and pathognomic radiologic features in the bony skeleton. The skeletal abnormalities include peculiarly shaped vertebrae with the appearance of a

6 112 SCHORR ET AL. Fig. 10.-Hand of patient A., age 6. showing characteristic first metacarpal distal accessory ossifi cation centers, notched phalangeal ends. and coneshaped epiphyses. double hump and a central constriction, becoming more distinct in late childhood; a lacelike appearance of the iliac crests, persisting until adulthood; and an unusual growth pattern of the long bones of the hand and feet. The absence of proximal metacarpal pointing, the absence of distal radial and ulnan obliquity at the wrist joint, and the absence of hypoplasia of one on more dorsolumbar vertebrae with gibbus formation and kyphosis all clearly differentiate DMC syndrome from the Fig. 9.-Hand of patient S. A, Age 5. Small and irregular carpal bones with more severe involvement of proximal row. Accessory ossification centens at distal ends of second through fifth proximal phalanges and first metacarpal. B, Age 18. Tubular bones of hands are short and thick. Carpal bones irregular; navicular and lunate bones disproportionately small. Fig. 11.-Foot of patient S.. age 18. Metatarsals and phalanges short and with flared ends. Hunter-Hurler dysostosis multiplex group of diseases and Morquio s disease. DMC syndrome does not produce corneal clouding, hyperextensibility of joints, changes in the dental enamel, or an increase in urinary mucopolysacchanide excretion, as seen in Morquio s disease. This report adds a further eight patients with DMC syndrome to the medical literature and increases the total number to 29. The fact that these families had

7 DYGGVE-MELCHIOR-CLAUSEN SYNDROME 113 several affected children, together with the presence of parental consanguinity in one case, makes autosomal recessive inheritance extremely likely. Chromosomes appear to be normal, and no biochemical lesion has yet been identified which could be used to detect carriers. Intrafamilial variation of gene expression is slight. Intrauterine diagnosis by radiography has not been attemped in this disease. The diagnosis may be made within the first months of life. Although the prognosis for survival is better than in Morquio s disease and the physical disability slightly less, the moderate to severe mental retardation makes it an even more handicapping disease. The patients described are trainable but not educable. They have not suffered unduly from intercurrent infections on medical problems other than those related to the disturbed growth of bone. Our oldest patient has completed almost three decades and is in relatively good health. Although genetic counseling has been repeatedly and painstakingly given to these two families, their cultural and religious attitudes have precluded the use of adoption or artificial insemination. Curtailment of further reproduction was elected by the Muslim family but not by the Jewish family. Rimoin et al. [13] have examined costochondral junction and pelvic crest specimens from DMC patients by light microscopy and have noticed small foci of multinucleated cells, surrounded by a dense-staining ring of collagen, scattered within a very fibrous-appearing matrix. Storage vacuoles were not observed on electron microscopic examination of cartilage cells taken from DMC patients [13]. Linker et al. [12] detected a slowmoving spot, possibly a glycoprotein, on urine electrophorosis, but the basic defect remains unknown. ACKNOWLEDGM ENTS We thank Prof. J. Spranger for helpful comments on the radiologic aspects of the hands, wrists, and feet of these patients. We also thank Mn. 0. Pollack for work on the illustrations. REFERENCES 1. Dyggve HV, Melchior JC, Clausen J: Morquio-Ullrich s disease. Arch Dis Child 37: , Spranger J, Maroteaux P. Der Kaloustian UM: The Dyggve-Melchior-Clausen syndrome. Radiology 114: , McKusick VA: Mendelian Inheritance in Man, 2d ed. Baltimore, Johns Hopkins Press, Smith R, McCort JJ: Osteochondrodystrophy (Morquio- Brailsfond type): occurrence in three siblings. Calif Med 88:55-59, Gwinn JL, Barnes GR Jr: Radiological case of the month: Morquio-Brailsford disease. Am J Dis Child 1 1 5: , Langer LO Jr: Short stature: check list of conditions associated with retarded longitudinal growth. Clin Pediatr 8: , Maroteaux P, Wiedermann R, Spranger J. Kozlowski K, Lenzi L: Essai de classification des dysplasies spondyloepiphysaines. Lyon, France, Symep Editions, Kaufmann RL, Rimoin DL, McAlisten WH: The Dyggve- Melchior-Clausen syndrome, in Birth Defects: Original Articles Series. Pant VI. The Nervous System, edited by Bengsma D, Baltimore, Williams & Wilkins, 1971, pp Barylak A, Kozlowski K: Dyggve disease. Austral Pediatr J 8: , : Linker A, Evans LA, Langen LO Jr: Monquio s disease and mucopolysacchanide excretion. J Pediatr 77: , Hobaek A: Problems of Hereditary Chondnodysplasias. Oslo, Oslo University Press, Linker A, Evans LA, Langer LO: Monquio s disease and mucopolysacchanide excretion. J Pediatr 77: , Rimoin DL, Hollister DW, Lachman AS, Kaufman AL, McAlister WH, Rosenthal RE, Hughes GNF: Histologic studies in the chondrodystrophies. Birth Defects: Onig Ant Sen 10(12): , 1974