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Holoprosencephaly
Specialty	Medical genetics

Holoprosencephaly is a type of cephalic disorder. This is a disorder characterized by the failure of the prosencephalon (the forebrain of the embryo) to develop. During normal development 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, as with Cy, the Cyclops kitten.) Holoprosencephaly is caused by a failure of the embryo's forebrain to divide to form bilateral cerebral hemispheres (the left and right halves of the brain), causing defects in the development of the face and in brain structure and function.

Symptoms

Symptoms of holoprosencephaly range from mild (no facial/organ defects, anosmia, or only a single central incisor) to moderate (cleft lip or cleft palate) to severe (synophthalmia proboscis or cyclopia).

There are four classifications of holoprosencephaly.

• Alobar holoprosencephaly, the most serious form in which the brain fails to separate, is usually associated with severe facial anomalies.
• Semilobar holoprosencephaly, in which the brain's hemispheres have a slight tendency to separate, 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.
• Middle Interhemispheric Variant of Holoprosencephaly (MIHV) -- where the middle of the brain (posterior frontal and parietal lobes) are not well separated with babies.

Presentation

Holoprosencephaly, once called arhinencephaly, 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 mental retardation may occur.

The most severe of the facial defects (or anomalies) 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 (a tubular appendage) located above the eye. The condition is also referred to as cyclocephaly or synophthalmia and is very rare.

Causes

The cause of holoprosencephaly (HPE) is currently unknown. Often, no specific cause can be identified. Suggested risk factors include maternal diabetes, infections during pregnancy (syphilis, toxoplasmosis, rubella, herpes, cytomegalovirus), and various drugs taken during pregnancy (alcohol, aspirin, lithium, thorazine, anticonvulsants, hormones, retinoic acid). Women with previous pregnancy loss and first trimester bleeding are also more likely to have a child diagnosed with holoprosencephaly.

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 (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.

Several genes have been identified that play a role in holoprosencephaly, specifically SHH, ZIC2, TGIF, and SIX3.

Source: The Carter Center for Research in holoprosencephaly http://www.stanford.edu/group/hpe/ and http://www.holoprosencephaly.net

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 (at such a time, individuals with separate cerebral hemispheres would form 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.

Prognosis

Holoprosencephaly (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 holoprosencephaly 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 mental retardation, spastic quadriparesis, atheoid movements, endocrine disorders, epilepsy and other serious conditions. Whereas, 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 yrs 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.

References

1. Armand Marie Leroi, Mutants: On the Form, Varieties and Errors of the Human Body, 2003, Harper Perennial, London. ISBN 0-00-653164-4

External links

• holoprosencephaly at NINDS
• http://www.holoprosencephaly.net

See also

• cephalic disorder

• Congenital disorders