American Journal of Medical Genetics 132A:68 – 75 (2005)
Clinical Report A Novel Syndrome Resembling Desbuquois Dysplasia Ali Al Kaissi,1 N. Nessib,1 M.B. Ghachem,1 A. Hammou,2 N. Guiddana,3 and K. Kozlowski4* 1
Department of Paediatric Orthopaedics, Children’s Hospital, Tunis, Tunisia Department of Paediatric Radiology, Children’s Hospital, Tunis, Tunisia 3 Department of Pediatrics, Children’s Hospital, Tunis, Tunisia 4 Department of Medical Imaging, New Children’s Hospital, Westmead, Sydney, Australia 2
We report on three Tunisian siblings with a rare assortment of clinical and radiographic abnormalities closely resembling Desbuquois dysplasia. However, the siblings have had normal facies, normal hands, and were mentally normal. There were severe musculo-skeletal distinguishing fea-
tures such as joint stiffness, severe kyphoscoliosis, and multiple large joint dislocations. Moreover, the patients had an additional remarkable radiographic feature not reported in Desbequois dysplasia—multiple carpal ossification centers. The diagnosis of Desbuquois dysplasia is more difficult in older children and adults as the characteristic facial features of early childhood may recede, and the metaphyseal growth plates obliterate. This condition of these patients represents a novel Desbuquois-like syndrome. ß 2004 Wiley-Liss, Inc.
Fig. 1. Clinical findings in the patients. Frontal view of the patients. From left to right: Patients I (14-year-old), II (11-year-old), and III (27-yearold). Note normal faces and equinovarus deformity of the feet in patient III. [Color figure can be viewed in the online issue which is available at www.interscience.wiley.com.]
*Correspondence to: Dr. K. Kozlowski, New Children’s Hospital, Locked Bag 4001, Westmead NSW 2145, Australia. E-mail:
[email protected] Received 11 December 2003; Accepted 6 July 2004 DOI 10.1002/ajmg.a.30344
ß 2004 Wiley-Liss, Inc.
Fig. 2. A–C: Radiographs of the hands of the patients I, II, and III showing shortening of the metacarpals, hypoplastic/dysplastic carpal bones with supernumerary carpal bones, medial dislocation of the ulna and additional small, round intermetacarpal sesamoid bones in patients II and III.
Desbuquois Dysplasia
Fig. 2.
KEY WORDS:
Desbuquois syndrome; kyphoscoliosis; advanced bone age; multiple carpal ossification centers
INTRODUCTION Desbuquois dysplasia is a rare, but well described syndrome with remarkable clinical and radiographic variability ranging from mild skeletal involvement with normal intelligence to those with early fatal outcome [Desbuquois et al., 1966; Nishimura et al., 1999; Hall, 2001]. Up to the year 2003 about 50 cases had been described in the literature. The three siblings reported here have a rare assortment of severe skeletal abnormalities resembling Desbuquois dysplasia (Fig. 1). Absence of some important clinical signs of Desbuquois dysplasia such as characteristic facies and hyperlaxity as well as absence of some important abnormalities such as additional phalanges and axial deviation of the fingers were distinctive features in this family. X-ray examination documented absence of two consistent Desbuquois dysplasia features—flat acetabula and proximal elongation of the fibulae. There was severe kyphoscoliosis, multiple long bones dislocations, and the ribs were thin. Additionally they have abnormalities not previously reported—multiple carpal ossification centers. These patients represent a novel Desbuquoislike syndrome.
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CLINICAL REPORT Patient I This 8-year-old girl presented to the Department of Paediatric Orthopaedics at the Children’s Hospital, Tunis because of joint laxity and walking difficulties. She was a product of normal pregnancy and uncomplicated delivery. The 33-yearold, gravida 6, mother measured 148 cm in height and her face was normal—similar to her offspring. Her skeletal survey was normal. Two of her children died of unknown causes soon after the birth. The oldest brother, 27-years-old who has a similar face to the affected siblings measures 162 cm and does not have kyphoscoliosis or joint dislocations and refused to be investigated. The parents were second degree relatives. Birth weight was 2,400 g (400 g below 3rd centile), length 44 cm (5 cm below 3rd centile), OCF 35 cm (25th centile). Hypotonia was noted after birth and she remained in intensive care unit for 2 weeks because of feeding difficulties and persisting chest infections. Her motor development was retarded. In her first year of life scoliosis was noted. It was thought to be due to muscular dystrophy, but this diagnosis was excluded. At the age of 8 years her height was 5 SD. Her face was normal. The neck was very short. The thorax was narrow. There was kyphoscoliosis and generalized ligamentous hyperlaxity with multiple dislocations—elbows, wrists, hips, and knees. Re-examination at the age of 14 years revealed a marked decrease in mobility. The previously noted joint
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Fig. 3. A–D: Radiographs of the spine of the patients I, II, and III showing severe kyphosis of the thoracic spine. Note marked osteopenia and narrowing of the intervertebral disc spaces. Radiograph 3C: Patient II—showing scoliosis.
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Fig. 4. A–C: Radiographs of the pelvis of patients I, II, and III showing coxa valga and severe hip dislocations. Note marked osteopenia and pseudoacetabula in A and B.
hyperlaxity had changed into joint stiffness. There was progression of her spine deformity to increased kyphoscoliosis. Her walking had deteriorated and became waddling. Her height was 105 cm (6.7 SD) and OFC 52 cm (50th centile). The routine blood and urine examinations were normal.
his musculo-skeletal status deteriorated and the joint laxity changed into painful joint stiffness. At age 11 years his height was 113 cm (4.5 SD), weight 42 kg (þ1 SD), OFC 52 cm (50th centile). Patient III
Patient II A younger brother of patient I, was delivered normally at full-term gestation after an uneventful pregnancy. Birth weight was 3,100 g (3rd centile), length 49 cm (1 cm below 3rd centile), OFC 37 cm (50th centile). Hypotonia and increased joint laxity were noted in the first year of life. The motor development was delayed, and he started to walk at the age of 19 months. In the first few years of life bilateral elbow dislocations were noted and at the age of 6 years recurrent knee dislocation. He was seen at the Department of Paediatric Orthopaedics at the age 7 years because of short stature, multiple joint dislocations, and kyphoscoliosis. His face was similar to that of his older sister—normal. In spite of intensive physiotherapy
An older sister of patients I and II, was delivered normally at full term gestation after an uneventful pregnancy. Birth weight was 2,600 g (200 g below 3rd centile), length 44 cm (5 cm below 3rd centile), OFC 35 cm (25th centile). Equinovarus deformity of the feet, hypotonia, and joint laxity were noted at birth. Because of hypotonia and increased joint laxity muscular dystrophy was suspected. This was excluded by EMG, muscle biopsy, and enzymatic studies. Her motor development was delayed. She started to walk at the age of 22 months. In the following years multiple joint dislocations and progressive kyphoscoliosis developed. Her musculo-skeletal status deteriorated with age and the joint laxity changed into painful joint stiffness. At the age of 28 years her height was 87cm (10 SD),
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Fig. 5. A and B: Radiographs of the elbows patients II and III showing radial and ulnar dislocations. Note similarity of the changes in both siblings.
Fig. 6. Radiograph of the skull of patient I showing narrow cranial sutures.
weight 40 kg (2 SD), OFC 55 cm (50th centile). Her face was normal. There was severe kyphoscoliosis with marked shortening of the trunk and small thorax. Radiographic examinations. Skeletal surveys were done when the patients were aged 14 years (patient I), 11 years (patient II), and 28 years (patient III). All the siblings showed similar radiographic appearances, any differences being the result of age (Figs. 2–7). There was generalized osteopenia with narrowing of the joint spaces and intervertebral discs. In the skull the posterior cranial fossa was prominent and the cranial sutures were narrow (Fig. 6). All siblings showed very severe kyphoscoliosis of the thoraco lumbar spine (Fig. 3A–D). The cervical spine was flexed anteriorly which with slightly flattened vertebral bodies gave the impression of the ‘‘head sitting on the chest.’’ The thorax was narrow with thin ribs. There were dislocations of the wrists (Fig. 2A–C), elbows (Fig. 5A,B), and hips (Fig. 4A–C). There was narrowing of the joint spaces and the epiphyses were hypoplastic/dysplastic. The lesser trochanters were prominent. In the hands there was shortening of the metacarpals. The distal forearm epiphyses were small and flattened. The carpal bone age was advanced. The carpal bones were hypoplastic/dysplastic with multiple accessory carpal ossification centers (Fig. 2A–C). In patient II, 11-year-old boy and patient III, 28-year-old female—sesamoid bones were present at the distal ends of the metacarpals (Fig. 2B,C). In the patient III besides hallux valgus with large 1st metatarsal there was a small sesamoid bone at the distal end of
Desbuquois Dysplasia
Fig. 7. Radiograph of the foot of patient III showing hallux valgus with hypoplastic/dysplastic proximal phalanx and shortening of the 4th and 5th metatarsals. There is a sesamoid bone at the distal, medial aspect of the 5th metatarsal.
the 5th metatarsal (Fig. 7). The probant’s spinal MR documented syringomyelia in the thoraco-lumbar spinal cord. DISCUSSION Desbuquois dysplasia is a short limb type of dwarfism characterized by a dysmorphic face (prominent eyes, round face with flat nasal bridge, long upper lip, and micrognathia), joint hyperlaxity with joint dislocation in severe cases, axial deviation of the fingers, foot and spine deformities. Mental retardation may be present [Maroteaux and Le Merrer, 2002; Spranger et al., 2002]. Although clinical criteria remain of particular importance for the diagnosis, radiographic examination helps diagnosing Desbuquois dysplasia. The major radiographic criteria include five consistent features, namely ‘‘Swedish key’’ appearance of the proximal femur, flat acetabular roof, elevated greater trochanter, precocious carpal and tarsal ossification, and proximal fibular overgrowth [Faivre et al., 2004]. There is some correlation between the abnormal hand, kyphoscoliosis, and big joint dislocation. Among the 35 patients with Desbuquois syndrome of Faivre et al. [2004], Table I, 16 were with, and 19 without typical hand abnormalities. Typical hands (extraossification center distal to the second metacarpal, delta phalanx of the thumb and/or bifid
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distal phalanx of the thumb) were present in less than 50%. Patients with abnormal hands presented more often with kyphoscoliosis (8/16–50%) and long bone dislocations (10/16– 62%) than patients with normal hands (2/17–12%) and (3/19– 16%). Distinctive features in these siblings include normal facies. Specifically they did not show the facial features of Desbuquois syndrome—round face, prominent eyes, flat nasal bridge, long philtrum, and micrognathia. They were of normal intelligence with no school problems. Notable is the clinical course that in spite of physiotherapy joint hyperlaxity changed into joint stiffness. Stiffness is a rare finding in Desbuquois dysplasia. All of four patients of Faivre et al. [2004] with Desbuquois syndrome, aged 16–22 years showed persistent hyperlaxity. Further noteworthy features of our patients, sporadically reported in Desbuquois syndrome include severe kyphoscoliosis [Piussan et al., 1975], and multiple large joints dislocations (hips, knees, elbows, wrists). Severe kyphoscoliosis in our siblings was associated with narrowing of the intervertebral disc spaces. Of note is that the hands in our patients were normal. All have bilateral hip dislocation which can produce Desbuquois like proximal femoral changes. However, no flat acetabulae, anterior widening of the ribs, a common finding in Desbuquois syndrome after the first few years of life, nor proximal fibular overgrowth were present in our family. The most important differential diagnosis feature in our patients were multiple carpal ossification centers. Although multiple carpal ossification centers have been mentioned no radiograms with multiple hypoplastic/dysplastic carpal ossification centers have been presented [Le Merrer et al., 1991]. A hand radiograph of a 2-month-old child with six ossification centers is consistent with advanced bone age rather than with supernumerary carpal bones. Supernumerary carpal bones can only be counted when there are more than eight of them. Multiple sesamoid bones (patients I and III) have not yet been reported as well as narrow cranial sutures. The short tubular bones apart from shortening of the metacarpals and metatarsals were normal. Review of the literature does not show cases with exactly matching clinical and radiographic changes [Anderson et al., 1982; Beemer et al., 1985; Meinecke et al., 1989; Jequier et al., 1992; Ogle et al., 1994; Shohat et al., 1994; Gillessen-Kaesbach et al., 1995; Al-Gazeli et al., 1996]. Patients who show most similar pattern of skeletal abnormalities are two sisters of Pazzaglia et al. [1988], who suggested that their cases represented a new and distinct syndrome. Their patients had severely shortened stature and the radiographic appearances of the spine, elbows, pelvis, and skull were similar to those of our patients. Although Pazzaglia et al. [1988] claim that in their second case the carpal ossification centers were normal for age, eight carpal ossification centers in a 4-year-old child documents an accelerated bone age. Their patients are accepted as a severe form of Desbuquois syndrome. They showed characteristic ‘‘Desbuquois faces.’’ Consanguinity in our family supports autosomal recessive inheritance. The differential diagnosis of Desbuquois dysplasia is with multiple joint dislocation syndromes (especially Larsen, the Reunion Island variant of Larsen syndrome and Diastrophic dysplasia), and Catel–Manzke syndrome which show similar hand abnormalities. This topic has been discussed extensively in previous publications [Maroteaux, 1975; Shohat et al., 1994]. We believe that other syndromes with multiple joint dislocations should be considered in the differential diagnosis such as spondylo-epi-metaphyseal dysplasia with joint laxity [Beighton and Kozlowski, 1980], spondylo-epimetaphyseal dysplasia with leptodactyly [Spranger et al., 2002], and ill defined Larson-like entities [Maroteaux, 1975]. All present with joint dislocation and abnormal spinal curvature. We would also like to stress that although the
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Al Kaissi et al. TABLE I. Clinical and Radiographic Findings of Desbuquois Dysplasia and of Our Patients Trait
Desbuquois dysplasia (number 43)
Our patients (number 3)
þ þþþ þþþ þþþ þþ þþþ þ þþ þþ þþ þþ þþ
Yes Yes No No No Yes (early) Yes (later) No Yes Yes Yes No
þþþ þþþ þþ þþþ þ þþþ þþþ þþþ þþþ þþ þþ þ þþþ
Yes Yes No No Yes Yes Yes No No No (later) Yes Yes No Yes ?
Clinical Consanguinity Short stature Round face Prominent eyes Micrognathia Hyperlaxity Joint stiffness Hand deformity Displaced hips Displaced knees Foot deformity Developmental delay Radiological Osteoporosis Advanced carpal/tarsal bone age Supernumerary phalanges Large or double thumb Accessory carpal bones Sesamoid bones Prominent lesser trochanter Broad metaphyses Flat acetabular roofs Proximal fibular overgrowth Scoliosis/kyphosis Narrowing disc spaces Square vertebral bodies Platyspondyly Coronal clefts
þþþ, present in >50% of the cases; þþ, present in 25%–50% of the cases; þ, present in