Holoprosencephaly is a cephalic disorder in which the prosencephalon fails to develop into two hemispheres. 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. The condition can be mild or severe. Most cases are not compatible with life and result in fetal deathin utero. When the embryo's forebrain does not divide to form bilateral cerebral hemispheres, it causes defects in the development of the face and in brain structure and function. 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.
Signs and symptoms
Symptoms of holoprosencephaly range from mild to moderate to severe. There are four classifications of holoprosencephaly. specimen from a case of alobar holoprosencephaly.
Alobar holoprosencephaly, the most serious form, in which the brain fails to separate, is usually associated with severe facial anomalies, including lack of a nose and the eyes merged to a single median structure, see Cyclopia
Semilobar holoprosencephaly, in which the brain's hemispheres have somewhat divided, is an intermediate form of the disease.
Lobar holoprosencephaly, in which there is considerable evidence of separate brain hemispheres, is the least severe form. In some cases of lobar holoprosencephaly, the patient's brain may be nearly normal.
Syntelencephaly, or middle interhemispheric variant of holoprosencephaly, in which the posterior frontal lobe and the parietal lobe are not properly separated, but the rostrobasal forebrain properly separates; it is possible that this is not a variant of HPE at all, but it is currently classified as such.
Agenesis of the corpus callosum, in which there is a complete or partial absence of the corpus callosum. It occurs when the corpus callosum, the band of white matter connecting the two hemispheres in the brain, fails to develop normally, typically during pregnancy. The fibers that would otherwise form the corpus callosum become longitudinally oriented within each hemisphere and form structures called Probst bundles.
Holoprosencephaly consists of a spectrum of defects or malformations of the brain and face. At the most severe end of this spectrum are cases involving serious malformations of the brain, malformations so severe that they often cause miscarriage or stillbirth. At the other end of the spectrum are individuals with facial defects which may affect the eyes, nose, and upper lip - and normal or near-normal brain development. Seizures and intellectual disabilities may occur. The most severe of the facial defects is cyclopia, an abnormality characterized by the development of a single eye, located in the area normally occupied by the root of the nose, and a missing nose or a nose in the form of a proboscis located above the eye. The condition is also referred to as cyclocephaly or synophthalmia, and is very rare.
Causes
The exact cause of HPE are yet to be determined. Mutations in the gene encoding the Sonic Hedgehog protein, which is involved in the development of the central nervous system, can cause holoprosencephaly. In other cases, it often seems that there is no specific cause at all.
Genetics
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. 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, TGIF, ZIC2, SIX3 and BOC genes. Although many children with holoprosencephaly have normal chromosomes, specific chromosomal abnormalities have been identified in some patients. There is evidence that in some families, HPE is inherited. Features consistent with familial transmission of the disease should be carefully assessed in parents and family members.
HPE is not a condition in which the brain deteriorates over time. Although serious seizure disorders, autonomic dysfunction, complicated endocrine disorders and other life-threatening conditions may sometimes be associated with HPE, the mere presence of HPE does not mean that these serious problems will occur or develop over time without any previous indication or warning. These abnormalities are usually recognized shortly after birth or early in life and only occur if areas of the brain controlling those functions are fused, malformed or absent. Prognosis is dependent upon the degree of fusion and malformation of the brain, as well as other health complications that may be present. The more severe forms of encephalopathy are usually fatal. This disorder consists of a spectrum of defects, malformations and associated abnormalities. Disability is based upon the degree in which the brain is affected. Moderate to severe defects may cause intellectual disability, spastic quadriparesis, athetoid movements, endocrine disorders, epilepsy and other serious conditions; mild brain defects may only cause learning or behavior problems with few motor impairments. Seizures may develop over time with the highest risk before 2 years of age and the onset of puberty. Most are managed with one medication or a combination of medications. Typically, seizures that are difficult to control appear soon after birth, requiring more aggressive medication combinations/doses. Most children with HPE are at risk of having elevated blood sodium levels during moderate-severe illnesses, that alter fluid intake/output, even if they have no previous diagnosis of diabetes insipidus or hypernatremia.
