Holoprosencephaly

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.

Clinical Features and Outcomes of Holoprosencephaly in Korea

“…The lobar or middle interhemispheric variant types are associated with milder facial dysmorphisms, including single central incisor and cleft lip and/or palate. The severity of facial malformation was demonstrated to correlate with brain anomalies [6,9,17], and our results indicated a similar tendency. However, many exceptions occur.…”

“…Although holoprosencephaly is divided into four types according to severity of the disease, these types should be envisioned as nodes on a continuous spectrum of abnormal hemispheric separation, rather than as clear and distinct divisions [9]. The most severe type of holoprosencephaly is alobar, and children with this type can present with severe craniofacial malformations, such as cyclopia or proboscis.…”

“…Although we were unable to conduct a molecular analysis in this study, more than seven genes are positively implicated in holoprosencephaly thus far: SHH, ZIC2, SIX3, TGIF, PTCH, GLI2, and TDGF1. However, only 20-30% of isolated cases of holoprosencephaly can be explained by searching for alterations in the four main holoprosencephaly genes, including SHH, ZIC2, SIX3, and TGIF, and subtelomeric regions [9,10]. More than 65% of isolated cases of holoprosencephaly remain unexplained, thus suggesting the involvement of many other unidentified genes in holoprosencephaly.…”

“…Eighteen percent to 25% of individuals with monogenic holoprosencephaly manifest a recognizable syndrome, and the remainder exhibit nonsyndromic holoprosencephaly [9]. Thus far, more than seven genes have been positively implicated in nonsyndromic holoprosencephaly: SHH, ZIC2, SIX3, TGIF, PTCH, GLI2, and TDGF1 [10][11][12][13].…”

NODAL and SHH dose-dependent double inhibition promotes an HPE-like phenotype in chick embryos

“…It results from failed or incomplete forebrain cleavage between days 18 and 28 of gestation (Dubourg et al, 2007;Marcorelles and Laquerriere, 2010).…”