SNP Browser for Human [Homo sapiens] Genetic Disorders

DiseaseID	HGD56
Genetic Disorder	Holoprosencephaly
Gene Name	SIX homeobox 3
Description	Holoprosencephaly (HPE) is a relatively common birth defect of the brain, which often can also affect facial features, including closely spaced eyes, small head size, and sometimes clefts of the lip and roof of the mouth, as well as other birth defects. Holoprosencephaly is a disorder caused by the failure of the prosencephalon (the embryonic forebrain) to sufficiently divide into the double lobes of the cerebral hemispheres. The result is a single-lobed brain structure and severe skull and facial defects. In most cases of holoprosencephaly, the malformations are so severe that babies die before birth. 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. This birth defect occurs soon after conception. It has a prevelance of 1 in 250 during early embryo development, and 1 in 10,000 to 1 in 20,000 at term. Classification:- Alobar, in which the brain has not divided at all, is usually associated with severe facial features. Semilobar, in which the brain's hemispheres have somewhat divided, causes an intermediate form of the disorder. Lobar,in which there is considerable evidence of separate brain hemispheres, is the least severe form. In some cases of lobar holoprosencephaly the baby's brain may be nearly normal. The milder craniofacial characteristics of HPE include microcephaly, midface flattening, hypotelorism (closely spaced eyes), flat nasal bridge, and single maxillary central incisor. Approximately 80 percent of severe HPE have characteristic facial features. The least severe of the facial anomalies in holoprosencephaly is the median cleft lip (premaxillary agenesis). The most severe is cyclopia, an abnormality characterized by a single eye located in the area normally occupied by the root of the nose, and a missing nose or a proboscis (a tubular-shaped nose) located above the eye. The least common facial anomaly is ethmocephaly, in which a proboscis separates closely-set eyes. Cebocephaly, another facial anomaly, is characterized by a small, flattened nose with a single nostril situated below incomplete or underdeveloped closely-set eyes. Not all individuals with HPE are affected to the same degree, even in families where more than one individual has this predisposition. This is why it is often helpful to discuss these issues with a professional in genetics who is trained to recognize features that might suggest that HPE is, or is not, likely to occur again in a family. The risk of reoccurrence is small in most families. There are a number of causes of HPE, including genetic alterations and environmental effects. The cause of HPE in any individual family is often unknown
Symptoms	Symptoms of holoprosencephaly range from mild (no facial/organ defects, anosmia, or only a single central incisor) to moderate (cleft lip or 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.
Causes	Holoprosencephaly has no single cause, but about half of all cases are associated with abnormal karyotype (abnormal numbers of chromosomes), especially trisomy 13 (extra copy of chromosome 13) and trisomy 15 (extra copy of chromosome 15). It can also run in families as an autosomal dominant, autosomal recessive, or X-linked recessive trait. Currently, researchers believe that holoprosencephaly might be linked to as many as 12 chromosomal regions on 11 chromosomes. Risk is increased if the mother has diabetes or has an infection during pregnancy such as syphilis, herpes, cytomegalovirus, rubella, or toxoplasmosis. Use of certain drugs or other substances during pregnancy (e.g., alcohol, aspirin, lithium, thorazine, anticonvulsants, hormones, retinoic acid) has also been suggested as a risk factor. Women who have had previous miscarriages and bleeding in the first trimester are also more likely to have fetuses with holoprosencephaly.
Diagnosis	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.
Treatment	Each child has a unique degree of malformations. Treatment must be individualized, although common problems occur. In general, treatment is largely symptomatic and supportive. Involvement in support groups and HPE Conferences are helpful .