SHH classically lead to defects in midline structures, particularly the face and eyes, and a lack of hemisphere separation of the brain, a disorder termed holoprosencephaly (HPE).
The clinical spectrum of HPE is wide, ranging from most to less severe brain phenotypes called alobar, semilobar and lobar HPE, generally associated with facial anomalies. The most emblematic is the cyclopy known since Homer’s Odyssey. Moreover, HPE patients usually present delayed development and seizure disorder.
There are four categories of facial abnormality, in descending order of medical severity:
- Very severe phenotypes, such as cyclopia, ethmocephaly (proboscis), cebocephaly.
- Premaxillary agenesis, cleft lip or palate and less severe eye abnormalities (coloboma, retinal dysplasia).
- Mild midface malformations, such as pyriform sinus stenosis and choanal stenosis.
- The mildest abnormalities, such as hypotelorism, solitary median maxillary incisor (SMMI), other mild non-specific defects and normal faces.
Microforms in patients with SHH variants were, above all, associated with pyriform sinus and choanal stenosis (74% category 3). The proportion of coloboma cases was relatively high (15% of the series as a whole). Associated brain malformations mostly concerned posterior fossa abnormalities (7%). Extracraniofacial abnormalities included five cases of multiple congenital malformations, mostly visceral and renal/urinary defect.