Abstract
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 are described: lobar, semi-lobar and alobar HPE. Another milder subtype of HPE called middle interhemispheric variant (MIHF) or syntelencephaly is also reported. In most of the cases, facial anomalies are observed in HPE, like cyclopia, proboscis, median or bilateral cleft lip/palate in severe forms, 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, 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. In a practical approach, prenatal diagnosis is based on ultrasound and magnetic resonance imaging (MRI) rather than on molecular diagnosis. Treatment is symptomatic and supportive, and requires a multidisciplinary management. Child outcome depends on the HPE severity and 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.
Highlights
(HPE, MIM 236100) is a complex human brain malformation resulting from incomplete cleavage of the prosencephalon into right and left hemispheres, occurring between the 18th and the 28th day of gestation
The forebrain malformations are generally associated with facial anomalies, ranging from anophthalmia, cyclopia or proboscis in the most severe cases, to midline cleft lip, a simple hypotelorism or even no anomalies in the less severe HPE forms [5,6] (Table 2)
Due to recent molecular data, the HPE phenotypic spectrum is very large ranging from severe cerebral malformations to a microform. This latter form can be defined by magnetic resonance imaging (MRI) normal brain, but with facial anomalies including ocular hypotelorism, midline cleft lip and/or flat nose
Summary
(HPE, MIM 236100) is a complex human brain malformation resulting from incomplete cleavage of the prosencephalon into right and left hemispheres, occurring between the 18th and the 28th day of gestation. The OMIM classification shows that HPE can be associated in about 25% of the cases with several defined multiple malformation syndromes with a normal karyotype, like Smith-Lemli-Opitz [38], (page number not for citation purposes) http://www.OJRD.com/content/2/1/8
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