Holoprosencephaly

Definition

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.

Description

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.

Demographics

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.

Diagnosis

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.

Treatment team

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.

Treatment

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.

Prognosis

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.

Resources

BOOKS

Graham, David I., and Peter L. Lantos. Greenfield's Neuropathology, 6th edition. Bath, UK: Arnold, 1997.

OTHER

"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.

ORGANIZATIONS

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. hpe@tsrh.org. http://www.stanford.edu/group/hpe.

Larry Gilman, Ph.D.

A congenital defect caused by the failure of the prosencephalon to divide into hemispheres during embryonic development. It is characterized by multiple midline facial defects, including cyclopia in severe cases.

Failure of the forebrain to divide into hemispheres or lobes causing insufficient development of facial characteristics such as the nose, lips, and palate; in severe cases, cyclopia can occur.

Developmental failure of cleavage of the prosencephalon with a deficit in midline facial development and with cyclopia in the severe form.

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Holoprosencephaly
Classification and external resources
Diagram depicting the main subdivisions of the embryonic vertebrate brain.
ICD-10	Q04.2
ICD-9	742.2
OMIM	236100
DiseasesDB	29610
eMedicine	radio/347
MeSH	D016142

Holoprosencephaly (HPE, once known as arhinencephaly) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres. Normally, the forebrain is formed and the face begins to develop in the fifth and sixth weeks of human pregnancy. Hox genes, which guide placement of embryonic structures, fail to activate along the midline of the head, allowing structures that are normally paired on the left and right to merge. The condition also occurs in other species, as with Cy, the Cyclops kitten.

The condition can be mild or severe. According to the National Institute of Neurological Disorders and Stroke (NINDS), "in most cases of holoprosencephaly, the malformations are so severe that babies die before birth.^[1]

When the embryo's forebrain does not divide to form bilateral cerebral hemispheres (the left and right halves of the brain), it causes defects in the development of the face and in brain structure and function.

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."

Contents 1 Symptoms 2 Presentation 3 Causes 3.1 Genetics 3.2 Non-genetic factors 4 Prognosis 5 See also 6 References 7 External links

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.

Gross pathology specimen from a case of alobar 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.
• Syntelencephaly, or middle interhemispheric variant of holoprosencephaly (MIHV), in which the posterior frontal lobe and the parietal lobe are not properly separated, but the rostrobasal forebrain properly separates; it is possible that this is not a variant of HCE at all, but is currently classified as such^[2]

Presentation

Holoprosencephaly 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 exact cause(s) of HPE are yet to be determined, although the presence of toxins may be suspected. However, it often seems that there is no specific cause at all.^[3]

Genetics

Armand Marie Leroi describes the cause of cyclopia as a genetic malfunctioning during the process by which the embryonic brain is divided into two.^[4] 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.^{[citation needed]} Other candidate genes have been located, including the SHH, TGIF, ZIC2 and SIX3 genes.^[5]

Although many children with holoprosencephaly have normal chromosomes, specific chromosomal abnormalities have been identified in some patients (trisomy of chromosome 13, also known as Patau syndrome). 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.

Non-genetic factors

Numerous possible risk factors have been identified, including gestational diabetes, transplacental infections (the "TORCH complex"), first trimester bleeding, and a history of miscarriage.^[3][6] As well, the disorder is found twice as often in female babies.^[6] However, there appears to be no correlation between HPE and maternal age.^[6]

There is evidence of a correlation between HPE and the use of various drugs classified as being potentially unsafe for pregnant and lactating mothers. These include insulin, birth control pills, aspirin, lithium, thorazine, retinoic acid, and the anticonvulsants.^[6] There is also a correlation between alcohol consumption and HPE, along with nicotine, the toxins in cigarettes and toxins in cigarette smoke when used during pregnancy).^[6]

Prognosis

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.

See also

• Cephalic disorder
• Prenatal development

References

1. ^ NINDS Holoencephalopathy Information Page
2. ^ Totori-Donati, Paolo; Rossi, Andrea; Biancheri, Roberta (2005). "Brain Malformations". in Totori-Donati, Paolo; Rossi, Andrea; Raybaud, C.. Pediatric Neuroradiology: Brain, Head, Neck and Spine. 1. Springer. pp. 92-95. ISBN 3540410775. 
3. ^ ^{a b} The Carter Centers for Brain Research in Holoprosencephaly and Related Malformations. "About Holoprosencephaly". http://www.stanford.edu/group/hpe/about/. 
4. ^ Armand Marie Leroi, Mutants: On the Form, Varieties and Errors of the Human Body, 2003, Harper Perennial, London. ISBN 0-00-653164-4
5. ^ The Carter Center for Research in holoprosencephaly [1] and [2]
6. ^ ^{a b c d e} "Risk Factors For Cytogenetically Normal Holoprosencephaly in California: A Population-Based Case-Control Study". American Journal of Medical Genetics (Wiley-Liss) 90: 320-325. 2000. doi:10.1002/(SICI)1096-8628(20000214)90:4<320::AID-AJMG11>3.0.CO;2-8. 

External links

• GeneReview/NIH/UW entry on Holoprosencephaly Overview
• holoprosencephaly at NINDS
• http://www.holoprosencephaly.net

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