We report on the association of epiphyseal, vertebral, and ear dysplasia in two sisters with normal stature and psychomotor development born to distantly related, healthy parents. This distinctive association has not been reported previously and is likely to represent a new condition with an autosomal recessive mode of inheritance. For this syndrome, we propose the acronym EVE standing for epiphyseal,vertebral, andear dysplasia.
- and ear (EVE) dysplasia
- new syndrome
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We have observed the unusual association of epiphyseal, vertebral, and ear dysplasia in two sibs with normal stature and psychomotor development. To our knowledge, this association has not been reported previously. We propose the acronym EVE (epiphyseal-vertebral-ear) for this novel dysplasia syndrome. Overlap with the CODAS syndrome is discussed.
Case 1, a girl, was born after an uneventful pregnancy and term delivery to distantly related healthy parents (F<1/128) of Algerian origin (birth weight 2580 g, length 46.5 cm, OFC 33.5 cm). At 4 months of age, she was referred to our genetics unit because of facial dysmorphism. Dysmorphic features included a flat face, high forehead, depressed nasal bridge, short nose with anteverted nares, midface hypoplasia, and prominent philtrum. The ears were dysplastic with strikingly hypoplastic helices and antihelices (fig 1A-C). The neck was short with a normal posterior hairline. Mild anomalies of the extremities consisted of bilateral single palmar creases and short, overriding toes. She could spontaneously dislocate her elbows although passive joint mobility was normal. Growth and OFC were on the 50th centile. Psychomotor development was satisfactory for her age. Ophthalmological examination including the fundi was unremarkable.
Cardiac and renal ultrasound were normal. G banded lymphocyte chromosome analysis showed a normal 46,XX karyotype. Radiological findings included severely delayed bone age with absent ossification of the epiphyses of both long and short tubular bones, midcoronal clefts of vertebrae from T10 to S1, and hypoplasia of the odontoid (fig1D, E).
Case 2, her older sister, was 3 years 9 months of age when first examined. Her facial features were strikingly similar to those of her sister, namely symmetrical dysplastic ears, flat face, high forehead, depressed nasal bridge, and prominent philtrum (fig 2A, B). She had a unilateral patch of skin aplasia above the ear. Tooth eruption was adequate for age and the teeth were of normal shape. There was minor fifth finger camptodactyly, fingernail hypoplasia, and short, overriding toes (fig 2D). Joint mobility was normal, except for lumbar spine rigidity. She could no longer dislocate her elbows as she used to. Growth and OFC were on the 50th centile although she was as small for gestational age at birth as her younger sister (birth weight 2510 g, length 43 cm, OFC 32 cm at term). Psychomotor development was satifactory for her age. Ophthalmological examination was normal.
Radiological findings included delayed bone age and dysharmonic ossification with accelerated metacarpophalangeal maturation as compared to that of the carpal bones (carpal bone age <1 year, metacarpophalangeal bone age 2.5-3 years according to Pyle). In addition, x rays showed polyepiphyseal dysplasia with flat microepiphyses, mild metaphyseal dyspasia, persistent midcoronal clefts of vertebral bodies from T11 to L5 in the spine, and odontoid hypoplasia with abnormal mobility between C1 and C2 (fig 2D-H). The skull was normal. Normal results were obtained for peripheral blood creatinine, calcium, phosphate, very long chain fatty acids, and urinary excretion of calcium. Transient evoked otoacoustic emissions, as well as cardiac and renal ultrasound, were normal. Cytogenetic analysis showed a normal 46,XX karyotype in lymphocytes. Both parents were healthy, of normal height (1.60 m and 1.80 m, respectively), and had normal skeletal xrays.
Here, we describe a hitherto unreported association of malformations including epiphyseal, vertebral, and ear dysplasia in two sisters with delayed bone age and similar dysmorphic features. Mild intrauterine growth retardation followed by early postnatal catch up growth was noted in both children. Psychomotor development was normal and no hearing loss could be detected. At present, medullary compression owing to odontoid hypoplasia and arthrosis of early onset are the main causes of concern. Because of distant consanguinity, an autosomal recessive mode of inheritance is likely, especially as both parents were normal and two female sibs were affected. However, an autosomal dominant disorder with germline mosaicism in one parent cannot be excluded.1
To our knowledge, none of the known MCA syndromes previously reported could account for the cases reported here, yet this association shares several clinical features with the CODAS syndrome (forcerebral, ocular,dental,auricular,skeletal; table 1).2 3 The bone anomalies were quite similar, with delayed bone age, epiphyseal dysplasia, and vertebral clefts. Midface hypoplasia, anteverted nares, and ear anomalies affecting the first branchial arch are also consistent with both entities. However, additional features of the CODAS syndrome were not found in our patients, namely neonatal hypotonia, postnatal growth retardation, mental retardation, and eye and dental anomalies. Therefore, although variable expression of a single gene defect could be possible, we feel that the familial cases reported here are more likely a distinct entity. Both midface hypoplasia and depressed nasal bridge are non-specific dysmorphic facial features also seen in Stickler and SPONASTRIME(spondylar andnasal alterations withstriation of themetaphyses) syndromes. However, ear dysplasia is present in none of these bone dysplasia syndromes and the bone anomalies are distinct from our patients (table1).4 5 Chondrodysplasia punctata was also considered but no radiological evidence could be found in either girl and plasma long chain fatty acids were in the normal range in case 2. Finally, a search in the dysmorphic human-mouse homology database (DHMHD) did not show any mouse mutant reminiscent of this syndrome.6
In summary, we report a novel bone dysplasia syndrome with striking epiphyseal and vertebral anomalies in two sisters. Additional observations are needed to refine the phenotypic delineation of EVE syndrome and confirm whether we are dealing with a distinct entity.
We thank the family for cooperation, and Drs Maroteaux and Le Merrer for helpful discussions.