Etiopathogenetic advances and management of holoprosencephaly: from bench to bedside

Holoprosencephaly (HPE) is a complex brain malformation caused by impaired or incomplete midline division of the prosencephalon. It's characterized by cerebral and facial anomalies of different levels of severity. Both genetic and environmental factors are known to cause HPE, but they cover only few cases. Genetic causes are responsible for about 20% of cases: they are chromosomal abnormalities and gene mutations: up to date, nine genes (SHH, ZIC2, SIX3, TGIF, PATCHED1, TDGF1/CRIPTO, FAST1, GLI2 and DHCR) are definitely associated with HPE, but many others candidate gene are under investigation. The diagnosis of HPE is usually prenatal and is based on systematic ultrasound scan (US) and magnetic resonance imaging (MRI). Children with HPE have many medical problems in agreement with the severity of the brain malformation: craniofacial abnormalities, neurological signs, endocrine disorders, oromotor and dysautonomic dysfunction, thus requiring a multidisciplinary team for symptomatic treatment of manifestations, prevention of complications and parental support. Genetic counselling is an important step, often made difficult by extreme phenotypic variability, genetic heterogeneity, and a high risk of recurrence in apparently sporadic cases. In conclusion it can be concluded that we are far from a complete explanation of the etiopathogenesis. Future researches on genomic rearrangements all over the genome with techniques like the CGH array should lead to the identification of other causal genes and could improve diagnosis and prognosis. A skill multidisciplinary approach is mandatory to offer the better clinical assistance to patients and their parents.