An animal model of the Hypoglossia-Hypodactylia syndrome

Abstract

The Hypoglossia-Hypodactylia syndrome is a congenital abnormality of the orofacial structures combined with asymmetric reduction deformities of the limbs. The principal features are a micrognathic profile, microglossia, and limb anomalies of varying severity ranging from syndactyly to peromelia or hemimelia. Other anomolies in the oral and visceral regions may also occur. The etiology and pathogenesis of the syndrome has been obscured by controversy for over two centuries. The currently favoured theory of etiology involves focal necrosis in utero with subsequent localised failure of fetal development in the orofacial and Iimb regions. This concept 'is however solely based on the non familial nature of the syndrome and the clinical features of affected individuals. No direct experimental evidence for this theory has been presented for humans or animals. The purpose of this study was to attempt to produce similar deformities, consistent with those recognised in the human syndrome, by inducing areas of localised developmental failure by means of focal necrosis in fetal rats. An area of focal necrosis was created in the anterior mandible and forelimb regions of 19 day fetal Sprague Dawley rats using a fine electrodessicating probe. Groups of fetuses were obtained at 24 hourly intervals over 4 days post surgery. Gross examination of specimens demonstrated an increasing tendency toward a micrognathic profile and complete absence of the affected forelimb. Examination of the skeletal morphology by Alizarin Red-S stain showed marked underdevelopment of the mandible and absence of bony tissue in the affected forelimb by 96 hours postsurgery. Histological examination of fetal head specimens in both sagittal and coronal planes was undertaken, supporting the previous morphologic descriptions¡ in addition the tendency towards microglossia was illustrated. The histological study also demonstrated healing of a relatively extensive area of necrosis in utero. Repair and regeneration of tissues in the oromandibular region was rapid. This was consistent with previous studies on fetal wound healing. Description of healing of an area of focal necrosis (infarct) in utero has not been previously reported. Thus the overall result of this experiment as illustrated by gross, skeletal and histological examination was that of a malformed rat was produced, with orofacial and limb anomalies similar to those described for the human Hypoglossia-Hypodactylia syndrome. This study supports the concept that the human syndrome of Hypoglossia-Hypodactylia is produced by localised developmental arrest secondary to focal necrosis. It does not indicate how the focal necosis is produced although several possibilities are suggested. The study contributes also to the available information on the mechanisms and dynamics of fetal wound healing. Furthermore, it is predicted from this investigation that the orofaci al deformity 'in the Hypoglossia-Hypodactylia syndrome would 'increase until cessation of the active growth period. Clinical application of this prognosis indicates that definitive reconstructive orofacial surgery should be delayed, until the cessation of skeletal growth.