Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation. Normally, the forebrain is formed and the face begins to develop in the fifth and sixth weeks of human pregnancy. The condition also occurs in other species.
Holoprosencephaly is estimated to occur in approximately 1 in every 250 conceptions; However, holoprosencephaly is still estimated to occur in approximately 1 in every 8,000 live births.
When the embryo's forebrain does not divide to form bilateral cerebral hemispheres (the left and right halves of the brain), it causes defects in the development of the face and in brain structure and function.
The severity of holoprosencephaly is highly variable. In less severe cases, babies are born with normal or near-normal brain development and facial deformities that may affect the eyes, nose, and upper lip.
; Microform
: Mild phenotypic presentation with reduced distance between eyes, sharp nasal bridge, single maxillary central incisor. According to one hypothesis, the holoprosencephalic brain is due to an incomplete axial twisting. According to the axial twist theory, each side of the brain represents its opposite body side because the anterior part of the head, including the forebrain, is turned around by a twisting along the body axis during early development. Accordingly, holoprosencephaly is possibly an extreme form of Yakovlevian torque.
The exact cause(s) of HPE are yet to be determined. Mutations in the gene encoding the SHH protein, which is involved in the development of the central nervous system (CNS), can cause holoprosencephaly. In other cases, it often seems that there is no specific cause at all.
thumb|Ultrasound scan of a fetal head at 14 weeks of pregnancy with partial absence of the midline
Genetics
Armand Marie Leroi describes the cause of cyclopia as a genetic malfunctioning during the process by which the embryonic brain is divided into two. Only later does the visual cortex take recognizable form, and at this point an individual with a single forebrain region will be likely to have a single, possibly rather large, eye (when fetuses with separate cerebral hemispheres would have two eyes).
Increases in expression of such genes as Pax-2, as well as inhibition of Pax-6, from the notochord have been implicated in normal differentiation of cephalic midline structures. Inappropriate expression of any of these genes may result in mild to severe forms of holoprosencephaly. Other candidate genes have been located, including the SHH (holoprosencephaly type 3 a.k.a. HPE3), TGIF1, ZIC2, SIX3 and BOC genes.
Although many children with holoprosencephaly have normal chromosomes, specific chromosomal abnormalities have been identified in some patients (trisomy of chromosome 13, also known as Patau syndrome). There is evidence that in some families, HPE is inherited (autosomal dominant as well as autosomal or X-linked recessive inheritance). Features consistent with familial transmission of the disease (e.g., a single central maxillary incisor) should be carefully assessed in parents and family members.
Non-genetic factors
Numerous possible risk factors have been identified, including gestational diabetes, transplacental infections (the "TORCH complex"), first trimester bleeding, and a history of miscarriage. As well, the disorder is found twice as often in female babies.