About holoprosencephaly

What is holoprosencephaly?

Holoprosencephaly (HPE) is the failure of the prosencephalon, or forebrain, to develop normally. The forebrain is a region of the brain in the fetus that develops into parts of the adult brain, including the cerebral cortex. Instead of the normal complete separation of the left and right halves of the forebrain, there is an abnormal continuity between the two sides.
There are several different types of holoprosencephaly. In the alobar form, there is no separation between the right and left halves at all. In semilobar HPE, at least some of the brain has separated into different halves. In the lobar form, most of the brain has separated into right and left sides, though there is incomplete division into the two halves.

What are the symptoms for holoprosencephaly?

Holoprosencephaly is a malformation sequence with a very variable degree of severity for both the brain and facial abnormalities. Intellectual disability is associated with HPE and Seizures are often present.

Children diagnosed with this disorder may have a Small head (microcephaly), excessive fluid in the brain (hydrocephalus), facial abnormalities, tooth abnormalities (single central incisor), cleft lip and/or palate, epilepsy, and/or endocrine abnormalities. The most severely affected individuals may have cyclopia, a single central eye that is the most severe eye finding seen in holoprosencephaly, though this is very rare. Abnormalities in the formation of the nose may also occur.

Holoprosencephaly may also affect other systems in the body. Defects in the pituitary gland can cause an abnormally low level of sugar in the blood (hypoglycemia), low levels of sodium in the blood, or genital abnormalities.

What are the causes for holoprosencephaly?

Holoprosencephaly is a birth defect that arises during the first few weeks of the pregnancy. Diabetes in the mother during the pregnancy can increase the risk of holoprosencephaly in the fetus. However, for most children, no known intrauterine exposure is identified that is causally related to holoprosencephaly in that child.

Some children will have an identifiable genetic cause of holoprosencephaly. Approximately one-third of children born with holoprosencephaly have an abnormality of the chromosomes, which contain the genetic material (DNA). The most common chromosomal abnormality associated with HPE is when there are 3 copies of chromosome 13 (trisomy 13), although a number of other chromosomal changes can also cause holoprosencephaly.

In other children, holoprosencephaly is due to a change in a specific gene. These changes cause the genes and their proteins to function abnormally, and this affects the development of the brain, resulting in holoprosencephaly. Some of these genes are SHH, SIX3, TGIF1, ZIC2, PTCH1, FOXH1, NODAL, CDON, FGF8, and GLI2. Holoprosencephaly can also occur in certain genetic syndromes in which there are other medical issues besides those mentioned in this report that affect organs in addition to the brain and face (e.g., Smith-Lemli-Opitz syndrome).

Despite the above understanding of the causes of holoprosencephaly, the exact cause of the condition is not identified for many individuals. There are likely to be additional genetic causes other than those already known and mentioned above.

What are the treatments for holoprosencephaly?

The diagnosis of holoprosencephaly is usually made by MRI or CT of the brain. Holoprosencephaly can sometimes be detected prenatally through ultrasound or MRI, though mild forms may not be reliably detected prenatally.

Treatment and care for the issues associated with holoprosencephaly are supportive and based on the specific medical issues present for an individual child.

An endocrinology evaluation should be performed to assess for pituitary abnormalities. A neurologist should also be involved in the child’s care and can guide treatment for seizures if they are present. Plastic reconstructive surgery of cleft lip and palate or other facial features may be needed if indicated. A developmental pediatrician can help direct developmental therapies. Other treatments can be instituted as appropriate.

A clinical genetics evaluation and genetic counseling should be obtained for patients and their families once the diagnosis is made. Relatives of a child with holoprosencephaly may have an increased risk of having a child with holoprosencephaly, and this should be assessed and discussed by the child’s physicians, especially the neurologist and/or clinical geneticist. There are specific features that suggest an increased risk for having another child with holoprosencephaly (e.g., a single central upper incisor), and these should be carefully assessed in parents and family members. A chromosome analysis and gene testing is often performed.

Pediatricians, neurologists, dentists, special education teachers, surgeons, therapists, psychologists, developmental pediatricians, and others must systematically and comprehensively plan the child’s treatment for holoprosencephaly.

Is there a cure/medications for holoprosencephaly?

Holoprosencephaly is a neuroanatomical malformation of the forebrain or frontal lobe. Impaired signaling between the neural crest and neural ectoderm is the cause of the disorder. it occurs during the period of gastrulation, two or three weeks after conception. Incomplete midline cleavage of the forebrain and craniofacial midline defects are the primary clinical features. Many genetic defects have been attributed to the disease. Nongenetic causes include maternal diabetes, consistent folic acid use, exposure to teratogens, and drugs that reduce cholesterol synthesis. Treatment Treatment or management of holoprosencephaly requires a multidisciplinary approach and is symptomatic. Epilepsy is common in children with holoprosencephaly. Some patients may require multidrug anti-epileptic therapy. Motor anomalies cause spasticity and dystonia. Physical and occupational therapy is the first line of support. Some kids may need pharmacological interventions, including intrathecal baclofen pumps and oral trihexyphenidyl. Orofacial dysfunction may cause aspiration that leads to pneumonia. Structural surgical correction helps prevent possible infections. Malformed hypothalamus leads to a deficiency of pituitary hormones. Patients may require prednisone, thyroxine, and growth hormone supplements for diabetes insipidus and other overt symptoms. Patients with poor gastric and colonic motility may need the placement of a gastrostomy tube. Isolated gastroesophageal reflux disorder may warrant anti-reflux procedures or medications such as proton pump inhibitors.

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