Holoprosencephaly: The Maastricht experience

Holoprosencephaly. the Maastricht experience: Holoprosencephaly (HPE) is a developmental field defect with impaired cleavage of the embryonic forebrai n as the cardinal feature. The prevalence is about I in 11.000-20.000 in li ve births and 1 in 250 during embryogenesis. In most cases, craniofacial ab normalities are associated and reflect in 80% of cases the degree of severi ty. The severity is of marked variability and ranges from cyclopia to minim al craniofacial dysmorphism, such as mild microcephaly with a single centra l incisor. The etiology of HPE is very heterogeneous and comprises environm ental factors (e.g. maternal diabetes) and genetic causes. Approximately 50 % of HPE cases are associated with a cytogenetic abnormality (the most comm on of which is trisomy 13) or a monogenic syndrome, Based on recurrent cyto genetic abnormalities, there are at least 12 genetic loci that likely conta in genes implicated in the pathogenesis of HPE. Currently, four human HPE g enes are known: SHH at 7q36, ZIC2 at 13q32, SIX3 at 2p21 and TGIF at 18p11. 3. Over the past 13 years, 16 patients with HPE have been observed at the D epartment of Clinical Genetics at Maastricht. Some of them are briefly pres ented in order to emphasize the spectral nature of HPE and the etiological heterogeneity. One patient appeared to have a partial 18p deletion due to a maternal cryptic translocation t(1; 18) and, in addition, a SHH mutation. The mildest affected patient presented with microcephaly and a single maxil lary incisor; she had a submicroscopic 7q deletion. Finally, we propose a p rotocol of etiological work-up of HPE cases.