Holoprosencephaly is a birth defect caused by failure of the forebrain (prosencephalon) to grow as two separate hemispheres in the first few weeks of fetal life. The more complete the failure to divide, the worse the resulting abnormalities of brain, skull, and face. In its most severe form, holoprosencephaly entails the development of a tiny, undivided forebrain and is fatal before birth. Equivalent terms are arhinencephaly, holotelencephaly, and telencephalosynapsis. The prefix holo means undivided.
There are three degrees of severity of holoprosencephaly: (1) alobar holoprosencephaly, in which a tiny, single-lobed, nonfunctional forebrain brain develops, along with other severe cerebral abnormalities and severe facial deformities including cyclopism, or formation of a single, nonfunctional eye where the bridge of the nose should be; (2) semilobar holoprosencephaly, in which the brain is partly divided and there may be significant facial deformities such as cleft palate; and (3) lobar holoprosencephaly, in which the brain is partly divided, but there is some fusion of structures along the midline. Some authorities distinguish a fourth category to include various mild abnormalities of prosencephalic division, namely olfactory aplasia (absence of olfactory bulbs and tracts) and middle interhemispheric variant, in which the posterior frontal and parietal lobes of the brain are not well-separated.
Holoprosencephaly occurs in a small number of live births, with estimates varying from one in 5,000 to one in 31,000. However, its actual incidence is much higher, since many fetuses with holoprosencephaly, approximately 97%, are either stillborn or spontaneously aborted (miscarried). The rate of holoprosencephaly among all
pregnancies may therefore be as high as 1:200 or 1:250. As of 2004, the medical literature did not note a higher prevalence of holoprosencephaly in any particular racial group or geographic area.
Causes and symptoms
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.
Alobar holoprosencephaly causes death, either before or soon after birth. Cyclopia or formation of a single eye often occurs, with the nose being absent, having only a single nostril, or being replaced by a proboscis (small, tubular nose) either above or below the eye. Less severe degrees of holoprosencephaly cause mental retardation ranging from profound to mild. The eyes may be closely set together, the nose may be malformed, and there may be cleft lip (premaxillary agenesis). Children who survive birth generally have facial deformities, spasticity , seizures , problems with regulating body temperature, apneic attacks (spells of stopped breathing), psychomotor retardation, sleep disorders, gastroesophageal reflux, and other problems. However, holoprosencephaly occurs along a continuum, and at the mild end of the spectrum development may be essentially normal.
Ultrasonic examination of the fetal brain has made early detection of holoprosencephaly common. In infants born live, a preliminary diagnosis may be based on extremely small head size (microcephaly ) and on examination of the face, which is often deformed by the underlying developmental defects of the brain and skull. In particular, midfacial hypoplasia (subnormal growth of the features along the midline of the face) is strongly correlated with holoprosencephaly. Half of all cases of agnathia (total or virtual absence of a lower jaw) are also associated with holoprosencephaly. However, about 30% of cases of severe holoprosencephaly occur with normal development of the face. Ultrasound may give early warning of holoprosencephaly during fetal development; magnetic resonance imaging is the definitive method for diagnosing holoprosencephaly in non-severe cases.
If holoprosencephaly is known to have occurred in the family, consultation with a geneticist before or during pregnancy may help a woman determine if she is at higher risk for conceiving infants with holoprosencephaly. If a woman has diabetes, she should see a doctor with expertise in diabetes care to obtain the best possible care before and during pregnancy, including help in achieving tight blood-glucose control, as this can reduce a diabetic woman's risk of having a child with birth defects to near normal.
There is no cure for holoprosencephaly. Severe forms are fatal. For children with milder forms, treatment is directed at the symptoms rather than the disease. For example, drugs such as diazepam (Valium) and baclofen can be used to moderate spasticity (involuntary muscle tightening). Dorsal rhizotomy (cutting of the sensory spinal nerve roots), often done for the relief of intractable pain , can also be used to treat spasticity. Difficulty sleeping, common in children with holoprosencephaly, may be helped by such medications as Valium, chloral hydrate, or Melatonin. Low muscle tone in the esophageal sphincter, leading to gastroesophageal reflux ("spitting up" of the stomach contents into the esophagus and possibly out of the mouth, as occurs normally in small infants), can be treated with drugs that increase the speed with which the stomach and intestines pass material along and with antacids, which decrease the acidity of stomach contents and make gastroesophageal reflux less harmful. Emotional and intellectual care must be adjusted to the degree of retardation in each case.
The prognosis for an infant born with holoprosencephaly depends on the severity of the cerebral and other defects. The prognosis for an infant with severe holoprosencephaly is poor; most do not survive past six months, and those that do are likely to suffer profound mental retardation. At the mild end of the spectrum, where brain development may be nearly normal, a normal lifespan is likely.
Graham, David I., and Peter L. Lantos. Greenfield's Neuropathology, 6th edition. Bath, UK: Arnold, 1997.
"Information about Holoprosencephaly." Carter Centers for Brain Research in Holoprosencephaly and Related Malformations. (March 6, 2004). <http://www.stanford.edu/group/hpe/about/>.
"NINDS Holoprosencephaly Information Page." National Institute of Neurological Disorders and Stroke. (March 6, 2004). <http://www.ninds.nih.gov/health_and_medical/disorders/holoprosencephaly.htm>.
Carter Centers for Research in Holoprosencephaly. c/o Texas Scottish Rite Hospital, P.O. Box 190567, 2222 Welborn Street, Dallas, TX 75219-9982. (214) 559-8411; Fax: (214) 559-7835. [email protected] <http://www.stanford.edu/group/hpe>.
Larry Gilman, Ph.D.
"Holoprosencephaly." Gale Encyclopedia of Neurological Disorders. . Encyclopedia.com. (August 14, 2018). http://www.encyclopedia.com/science/encyclopedias-almanacs-transcripts-and-maps/holoprosencephaly
"Holoprosencephaly." Gale Encyclopedia of Neurological Disorders. . Retrieved August 14, 2018 from Encyclopedia.com: http://www.encyclopedia.com/science/encyclopedias-almanacs-transcripts-and-maps/holoprosencephaly