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Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and the 28th day of gestation and affecting both the forebrain and the face. It is estimated to occur in 1/16,000 live births and 1/250 conceptuses. Three ranges of increasing severity have been described: lobar, semi-lobar and alobar HPE. Another milder subtype of HPE, called the middle interhemispheric variant (MIHF) or syntelencephaly, has also been reported. In most of the cases, facial anomalies are observed in HPE, such as cyclopia, proboscis and median or bilateral cleft lip/palate in severe forms, and ocular hypotelorism or solitary median maxillary central incisor in minor forms. These latter midline defects can occur without the cerebral malformations and then are called microforms. Children with HPE have many medical problems: developmental delay and feeding difficulties, epilepsy, and instability of temperature, heart rate and respiration. Endocrine disorders like diabetes insipidus, adrenal hypoplasia, hypogonadism, thyroid hypoplasia and growth hormone deficiency are frequent. To date, seven genes have been positively implicated in HPE: Sonic hedgehog (SHH), ZIC2, SIX3, TGIF, PTCH, GLI2 and TDGF1. A molecular diagnosis can be performed by gene sequencing and allele quantification for the four main genes (SHH, ZIC2, SIX3 and TGIF). Major rearrangements of the subtelomeres can also be identified by multiplex ligation-dependent probe amplification (MLPA). Nevertheless, in about 70% of cases, the molecular basis of the disease remains unknown, suggesting the existence of several other candidate genes or environmental factors. Consequently, a multiple-hit hypothesis of genetic and/or environmental factors (like maternal diabetes) has been proposed to account for the extreme clinical variability. Prenatal diagnosis is based on ultrasound and magnetic resonance imaging (MRI) rather than on molecular diagnosis. Treatment is symptomatic and supportive, and requires multidisciplinary management. Child outcome depends on the HPE severity and on the medical and neurological complications associated. Severely affected children have a very poor prognosis. Mildly affected children may exhibit few symptoms and may live a normal life. |