Holoprosencephaly: Description, Causes and Risk Factors:
Presence of a single forebrain hemisphere or lobe; cyclopia occurs in the severest form. It is often accompanied by a deficit in median facial development.
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. Babies born with holoprosencephaly can have normal or near-normal brain development along with facial deformities that may affect the eyes, nose, and upper lip.
There are three classifications of holoprosencephaly:
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.
- Alobar, in which the brain has not divided at all, is usually associated with severe facial deformities.
- Semilobar, in which the brains hemispheres have somewhat divided, causes an intermediate form of the disorder.
Holoprosencephaly is a devastating defect of brain development that results from mutations in genes required for the normal formation of the forebrain. During brain development, the rostral neural tube, which begins as a single ?uid-?lled chamber, bifurcates into the two cerebral hemispheres. Holoprosencephaly disrupts this bifurcation and results in a fusion of the two hemispheres. Studies of genetic defects in human patients have identi?ed at least seven distinct genes that are mutated in holoprosencephaly; most of these are involved in known genetic pathways that govern the development of ventral brain structures. These two pathways involve the signaling molecules Sonic hedge-hog (SHH) and Nodal, both of which can induce ventral cell fates in a mirror-symmetrical manner on either side of the midline. Although mutations in genes required for ventral midline development go far in explaining some of the defects in holoprosencephaly, fundamental mysteries remain about why and how failures in dorsal midline formation also occur in this disorder.
Holoprosencephaly has both environmental and genetic causes. For example, ingestion of the teratogen cyclopamine causes holoprosencephaly by disrupting signaling through the SHH pathway, which patterns the ventral midline throughout the central nervous system (CNS). Genetic studies have identi?ed at least 12 loci associated with familial or sporadic forms of holoprosencephaly, and seven of these loci have been de?nitively identi?ed as speci?c genes. Three of the known genes encode members of the SHH signaling pathway, which regulates ventral development in both the forebrain and the spinal cord. Human mutations have been uncovered in SHH, which encodes a secreted signaling ligand localized at early stages to ventral domains in the developing neural tube, which encodes a receptor for SHH, and DispatchedA (DispA), which is required for the release and extracellular accumulation of Hedgehog (HH) proteins. Two additional holoprosencephaly mutations implicate the Nodal signaling pathway, which plays an important role in neural patterning. The transcriptional co-repressor tumor growth interacting factor (TGIF) represses the activity of SMAD transcription factors, which are activated by Nodal signaling, and Tdgf1/Cripto encodes a membrane-associated protein that serves as a co-receptor for Nodal signaling. The two other known holoprosencephaly genes do not play an obvious role in either of the above pathways. Six 3 encodes a homeodomain transcription factor expressed in the ventral forebrain, and Zic2 encodes a zinc-?nger transcription factor homologous to odd-paired in drosophila.
The etiology of holoprosencephaly is heterogenous. In most Cases it occurs sporadically but there is strong association with chromosomal anomalies. Autosomal recessive inheritance, diabetes mellitus, drugs, ethanol, retinoids and cytomegalovirus have been implicated.
The frequency of chromosome abnormalities in holoprosencephaly varies from 11% to 35% with the commonest chromosomal anomaly is trisomy 13. Others include 13q-, trisomy 18, 18p-, 21q- and triploidy.
Infants born to diabetic mothers may have an increased risk of having holoprosencephaly. Diabetic mothers can help reduce their risks of having children with birth defects and congenital disorders, such as holoprosencephaly, by strictly controlling their blood sugar levels. Therefore, expectant mothers with diabetes are encouraged to choose doctors with expertise in diabetes care. This helps ensure that the pregnant mother and the fetus obtain the best possible care before and during pregnancy.
Infants born to mothers who have infections, such as herpes, syphilis, cytomegalovirus, rubella, and toxoplasmosis, may have an increased risk of developing holoprosencephaly. Therefore, pregnant mothers who have symptoms of infections should seek prompt medical treatment.
In conclusion, holoprosencephaly carries a poor prognosis. Detailed ultrasound screening, genetic karyotyping, counselling and termination of abnormal fetuses may reduce the risk of stillbirth and perinatal mortality.
Holoprosencephaly is commonly associated with facial malformations. The degree of facial malformation often predicts the severity of the cranial anomalies. The mild degree has minimal midface anomalies, cleft lips, cleft palate, hypotelorism
, and trigonocephaly
. The severe malformations include cyclopia, proboscis, cebocephaly with single nostril.
Extracranial malformations and multiple anomaly syndromes are frequently found in both alobar and semilobar holoprosencephaly. Renal cysts, omphalocele, cardiovascular malformations, clubfoot, myelomeningocele, intestinal abnormalities, Meckel-Gruber syndrome, syndrome, campomelic dysplasia, Hall-Pallister and Vasadi syndromes have been identified.
The antenatal diagnosis of holoprosencephaly the absence of midline echo, single dilated midline ventricle replacing the two lateral ventricles, and fused thalami. The falx, corpus callosum and cavum septum pellucidum are usually absent. Additional demonstration of facial abnormalities of hypotelorism, cyclopia, cebocephaly, midline clefts make a more confident diagnosis. Sonographically, holoprosencephaly may be confused with other malformations; hydrocephalus, Dandy-Walker malformation, arachnoíd cyst, hydranencephaly and porencephaly.
There is no standard course of treatment for holoprosencephaly. Instead, treatment focuses on reducing the symptoms. The prognosis for individuals with the disorder depends on the severity of the brain and facial deformities and genetic abnormalities. The prognosis for most people is poor. Out of the three percent of babies with holoprosencephaly who are born alive, most die before the age of six months. However, patients with lobar holoprosencephaly may have normal life expectancies if the brain is only mildly affected by the disorder.
If a baby with holoprosencephaly has GERD (gastroesophageal reflux disease), a doctor may prescribe infant doses of medications commonly used to treat heartburn in adults. Commonly prescribed medications include H2 blockers, such as cimetidine (Tagamet®) or ranitidine (Zantac®), or proton pump inhibitors, such as esomeprazole (Nexium®) or omeprazole (Prilosec®). Although these drugs are considered safe for use in infants and children with GERD. Side effects positive.
In some cases, the muscles in the esophagus that prevent food in the stomach from being regurgitated may need to be surgically tightened. This is typically only performed if GERD interferes with breathing or prevents growth in the baby. Complications of this surgery are serious and may include persistent gagging during feedings.
Medications, called anticonvulsants, may be used to treat epilepsy in children with holoprosencephaly. These drugs are typically taken once daily to help prevent seizures from occurring. Phenobarbital (Luminal® Sodium) is one of the oldest and safest anticonvulsants for children. Valproic acid (Depakene® or Depakote®) has also been shown to be a safe and effective treatment for seizures in children.
NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.