Holoprosencephaly and facial dysmorphia: nosology, etiology and pathogenesis

Holoprosencephaly is frequently associated with facial dysmorphia and together these anomalies constitute a single developmental field. Because the abnormalities within this field represent a spectrum and because they may be associated with various patterned groups of extracephalic anomalies, they should not usually be considered a disorder sui generis, but a "symptom-complex" which may occur in a variety of disorders. Etiologic heterogeneity is a sine qua non of holoprosencephaly with facial dysmorphia. At the present time it is not known how many distinct formal genesis syndromes with holoprosencephaly and facial dysmorphia may exist for reasons cited in this paper. However, three distinct causal genesis syndromes (trisomy 13 syndrome, 18p- syndrome and Dq- syndrome) are known to occur. An autosomal recessive form also seems likely. Cytogenetic findings and various genetic possibilities are discussed. A pathogenetic hypothesis is presented in which holoprosencephaly with severe facial dysmorphia (synophthalmia or ocular hypotelorism, proboscis formation) is thought to arise from faulty embryonic interaction between the cephalic tip of the notochordal plate, the neuroectoderm of the brain plate and the oral plate.