PHENOTYPIC VARIABILITY IN CRANIOFACIAL AND ORGAN SYSTEM DEVELOPMENT IN HOLOPROSENCEPHALY

Objectives: To describe and compare similarities and differences in craniofacial and other organ system involvement between syndromic and non-syndromic cases of HPE in Manitoba. Methods: Cases of HPE were selected from the clinic database maintained at the Department of Genetics using the following inclusion criteria: HPE confirmed radiologically or by autopsy; or presence of a strongly suggestive clinical sequence (including hypotelorism, cleft lip/palate, microcephaly, cyclopia, proboscis, ethmocephaly, cebocephaly, or a single central incisor) without available radiologic confirmation or autopsy, and with or without a family history of HPE. Data on a predetermined list of clinical variables were abstracted from hospital and clinic records. Using two-by-two tables, categorical variables were analyzed for statistical significance (p<0.05).

Results: 47 cases of HPE were identified. 24 cases were considered syndromic and the remaining 23, non-syndromic. Craniofacial features (head size, shape and position of eyes, nose, midline anomalies, lips) were similar across the two groups (p>0.05). Crude odds ratios for anomalies of the neck (OR 9.05, 1.02 to 80.84), respiratory system (OR 5.25, 0.98 to 28), gastrointestinal tract (OR 13.2, 1.51 to 115.3), genitourinary tract (OR 6.00, 1.65 to 21.8), and musculoskeletal system (OR 4.57, 1.33 to 15.6) suggested significant associations with the syndromic group. Autopsy and imaging data confirmed variability in the extent of anomalies affecting the cerebral cortex, corpus callosum, deep nuclei, olfactory lobes, and the posterior fossa.

Conclusion: The findings suggest widespread variation in craniofacial and organ system development in patients with holoprosencephaly. Implications of these findings in terms of causation and dysmorphogenetic mechanisms need to be explored.