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Anauxetic dysplasia, a spondylometaepiphyseal dysplasia with extreme dwarfism

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Editor—The term spondylometaepiphyseal dysplasia (SMED) embraces a group of skeletal disorders characterised by abnormalities of the metaphyses, epiphyses, and vertebral bodies. The various entities which fall within this spectrum are differentiated on the basis of clinical and radiological anomalies. Following a recent report by Menger et al 1 of sibs with an unknown type of SMED, we wish to report the phenotype of two brothers affected with a similar pattern of clinical and skeletal anomalies. The designation anauxetic dysplasia (from the Greek term for not growing, not permitting growth) is proposed.

The patients are the offspring of healthy, non-consanguineous German parents. The family history was unremarkable. The mother and father were both 22 years of age at the time of the first pregnancy.

Patient 1, the proband, was born after an uneventful pregnancy at 40 weeks of gestation. His weight was 2400 g (−2.0 SD) and length 43 cm (−3.4 SD). Short limbs with short hands, short feet, and flexion contractures of the elbows were noted. His early psychomotor development was retarded. He sat without support at 12 months, began to walk at the age of 19 months, and used a few words at 24 months. At 12 months, kyphosis of the thoracic spine was noted.

Examination at 38 months showed a height of 62 cm (−9.4 SD), weight of 6.5 kg (−5.2 SD), muscular hypotonia, and short limbs (fig 1). Additional findings included prognathism, small teeth, a large tongue, barrel chest, thoracic kyphosis, lumbar hyperlordosis, and limited extension of the elbows but marked laxity of the other joints. Radiographic findings at the age of 23 months are shown in fig2.

Figure 1

Front view of patient 1 at 23 months showing depressed nasal bridge, short neck, short limbs, and prominent heels.

Figure 2

Skeletal changes of patient 1 at 23 months. (A) The vertebral bodies are slightly flattened in the thoracic spine and foreshortened with concave dorsal borders in the lumbar spine. (B) Ossification of the femoral metaphyses is abnormal showing cystic areas reaching into the diaphyses and irregular margins. The femoral heads are small and in varus position. (C) The metaphyseal borders are irregular and delta shaped in the distal femora and distal tibiae. Note forefoot adduction. (D) Carpal and epiphyseal ossification is severely delayed and the middle phalanges are bullet shaped. (E) Radiograph of the skull taken at 23 months showing an enlarged, J shaped sella.

At 4 years, respiratory insufficiency and quadriplegia spontaneously occurred, which was attributed to cervical cord compression. After 4 months of ventilation, the patient died of myocardial infarction. Pathological examination showed a height of 63 cm (−9.8 SD) and weight of 6750 g (−5.3 SD). Postmortem studies of the cervical spine showed an anterior displacement of C1 on C2 and indentation of the spinal cord at C1. Signs of infection resulting in aortic stenosis were present. Light microscopy of specimens from the iliac crest, vertebral bodies, and femoral and tibial growth plates showed marked hypocellularity of the resting cartilage, somewhat rounded chondrocytes, and a reduced number of proliferating chondrocytes with diminished columnisation of the hypertrophic zone.

Patient 2, the brother of patient 1, was born by caesarean section at 42 weeks of gestation with a length of 46 cm (−2.1 SD) and weight of 2500 g (−1.8 SD). Growth retardation had been diagnosed by ultrasound at 20 weeks of gestation. His early psychomotor development was unremarkable; he was able to sit without support at 7 months, to walk at 12 months, and to speak his first words at 12 months. He was toilet trained at 3 years. Then retarded speech development was noted. He attended a school for mentally handicapped children.

Examination at 11 years showed a height of 74 cm (−11.8 SD), weight of 10.3 kg (weight for length, 75th centile), and OFC of 49.5 cm (−2.7 SD), short limbs with short hands and feet, barrel chest, lumbar hyperlordosis, flexion contractures of the elbow and hip, and laxity of the other joints (fig 3).

Figure 3

(A) Patient 2 at 11 years. Note depressed nasal bridge, slightly prominent chin, short trunk, and short limbs. (B) The pithecoid stance and lumbar hyperlordosis point to flexion contractures of the hips.

Craniofacial anomalies included a pointed chin, macroglossia, and small teeth. An orthopantomogram showed first permanent maxillary incisors but absence of the remaining permanent dentition (fig 4).

Figure 4

Orthopantomogram of patient 2 at 11 years. Note absence of permanent teeth, generally short dental roots, taurodontism of the premolars, and “pearls” of dental enamel between the roots of the mandibular incisors and canines.

Radiographic examinations at 7 and 11 years showed the bone changes illustrated in fig 5.

Figure 5

Skeletal changes of patient 2 at 7 years. (A) The vertebral bodies are slightly flattened with convexity of the upper and lower plates and concave anterior and posterior borders. (B) The capital femoral epiphyses are small and in varus position with marked hypoplasia of the femoral necks. The acetabular fossae are shallow and slanted with a wide iliac angle. (C) The metaphyses are mildly flared with abnormal mineralisation and irregular margins. (D) At 11 years the distal metaphysis of the radius is slightly flared. The tubular bones of the hands are short and thick and irregularly mineralised. Note bullet shape of the middle phalanges. Ossification of the carpal bones and epiphyses is grossly retarded.

Laboratory studies showed normal values of Ca, P, alkaline phosphatase, vitamin D3, and urinary mucopolysaccharides. Enzyme studies of blood and skin fibroblasts excluded mucopolysaccharidoses types VI and VII, mucolipidoses types II and III, and α-fucosidosis. Chromosome analysis indicated a normal male karyotype. Audiometry showed normal hearing and ophthalmological examination showed no abnormalities. On echocardiographic examination at 11 years, an aortic stenosis was diagnosed. At that time he underwent cervical fusion because of atlantoaxial subluxation documented on CT scans and an MRI of the cervical region.

Judging from the clinical, radiological, and histological appearance, the two sibs in this report and the sibs described by Mengeret al 1 seem to constitute a distinct bone dysplasia. Clinical characteristics are an extremely severe dwarfism with standard deviation scores of −9 to −13 after the first year of life and an adult height of approximately 85 cm in females. Other features include a pointed chin, oligodontia, mental retardation, congenital contractures of the elbows with hyperlaxity of the remaining large and small joints, and occasional dislocated hips. Atlantoaxial instability, macroglossia, and aortic stenosis were described in two patients. Radiographic signs include a J shaped sella, rounded vertebral bodies with mild platyspondyly, progressive metaphyseal irregularities of the shortened tubular bones, markedly retarded epiphyseal maturation with defective ossification of the femoral head and neck, often slanted acetabula with dislocated hips, and short, bullet shaped middle phalanges. Histological studies of the growth plates show hypocellularity of the resting cartilage and absent columnisation.

The observation of multiple affected children of unaffected parents and the consanguinity of the parents of the sibs described by Mengeret al 1 are compatible with autosomal recessive inheritance.

We think that mental retardation constitutes part of the condition and is not the consequence of the physical handicap. It is also found in the Dyggve-Melchior-Clausen syndrome. However, that disorder is easily differentiated by the different aspect of the spine, pelvis, and proximal femur. An X linked spondyloepimetaphyseal dysplasia with mental retardation was described by Bieganski et al.2 In our opinion, our patients do not share the clinical and radiological symptoms of this entity.

The association of a spondyloepimetaphyseal dysplasia and abnormal dentition has been described by Rao et al.3 However, the spondylar and epimetaphyseal abnormalities in that condition are much milder and the tubular bones of the hands are slender. Dental anomalies in the Goldblatt syndrome are associated with spondylar and metaphyseal abnormalities but not with such severe epiphyseal changes as seen here.4 5

The clinical and radiographic signs of the disorder described here are sufficiently characteristic to differentiate it from other rare spondylometaepiphyseal dysplasias including SMED, short limb-abnormal calcification type,6-8spondyloepimetaphyseal dysplasia (SEMD) with eczema and hypogammaglobulinaemia,9 micromelic SMED,10micromelic dwarfism, humerus, femur, tibia type,11 SEMD Irapa type,12 SEMD Shohat type,13 or SEMD caused by ATP sulphurylase kinase 2 deficiency.14 15

In conclusion, the observation of two affected sibs confirms and expands the identity of a bone dysplasia which we propose to name anauxetic dysplasia on the basis of the extreme dwarfism resulting from a severe pre- and postnatal disturbance of skeletal growth and differentiation.


We thank Professor C Opitz for providing the orthopantomogram of patient 2.