NORD gratefully acknowledges Jeffrey E. Ming, MD, PhD, Division of Human Genetics, The Children's Hospital of Philadelphia, for assistance in the preparation of this report.
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 separation of the two halves is present. In the lobar form, most of the brain has separated into right and left sides, though there is incomplete division into the two halves.
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.
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.
Holoprosencephaly affects males and females in equal numbers before birth and has been reported in many ethnic groups. The incidence of holoprosencephaly has been estimated at 1 in 250 during early embryonic development, and approximately 1 in 16,000 live births.
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.
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Kauvar EF, Muenke M. Holoprosencephaly: recommendations for diagnosis and management. Curr Opin Pediatr. 2010; 22:687-95.
Levey EB, Stashinko E, Clegg NJ, Delgado MR. Management of children with holoprosencephaly. Am J Med Genet C Semin Med Genet. 2010; 154C:183-90.
Solomon BD, Gropman A, Muenke M. Holoprosencephaly Overview. 2000 Dec 27 [Updated 2013 Aug 29]. In: Adam MP, Pagon RA, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1530/ Accessed March 15, 2018.
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