What Is It, Causes, Signs, and More
Author: Lahav Constantini
Editors: Alyssa Haag, Józia McGowan, DO, Kelsey LaFayette, DNP
Illustrator: Jessica Reynolds, MS
Copyeditor: David G. Walker
What is holoprosencephaly?
Holoprosencephaly (HPE) is the most common birth defect of the forebrain (i.e., prosencephalon) and presents with manifestations of underdevelopment of the brain with a wide range of severity. More specifically, HPE is characterized by a failure of the forebrain to properly divide into two distinct cerebral hemispheres. This condition can occur as an isolated anomaly related to monogenic causes or as part of a genetic syndrome (e.g., trisomy 13 or 18). Children with HPE often present with additional midline facial defects, such as cleft lip and/or palate, and may have a dysfunctional pituitary gland. HPE is also typically associated with developmental delays, which correlate with the severity of the central nervous system malformation. Diagnosis and further classification of HPE can be made with an ultrasound or MRI either prenatally or postnatally.
In most cases, holoprosencephaly is incompatible with life and most die in utero. Only a small fraction of the fetuses that have HPE are born alive. Mortality remains high after birth and increases with age as well as severity of HPE. The small number of children that manage to survive until adulthood, live with various complications.
What causes holoprosencephaly?
Holoprosencephaly can be caused by both environmental and genetic factors. Nongenetic risk factors include pregestational maternal diabetes and exposure to teratogenic agents before the complete closure of the neural tube, which typically occurs by the fifth week from conception. The neural tube is an important embryological structure from which the central nervous system arises. Some medications may interfere with its closure and cause a variety of neural tube defects, including anencephaly (i.e. absence of most parts of the brain, skull, and scalp), spina bifida, and holoprosencephaly. For most children, however, there is no known intrauterine exposure directly related to development of holoprosencephaly.Genetic factors can be further distinguished into isolated, nonsyndromic monogenic causes and syndromic causes. Nonsyndromic monogenic causes, which are variants of a single gene, are most commonly inherited in an autosomal dominant pattern. Most typically, these variants occur in a part of the sonic hedgehog (SHH) signaling pathway, thereby resulting in disruption of this highly regulated embryological development pathway. Alternatively, syndromic causes of holoprosencephaly are associated with syndromes, such as Smith-Lemli-Opitz syndrome (SLOS), which is a multiorgan syndrome causing growth restriction, microcephaly, intellectual disability, and various bodily malformations; or a chromosomal abnormality, like trisomy 13 or trisomy 18.
What are the signs and symptoms of holoprosencephaly?
The main phenotypic features of holoprosencephaly include maldevelopment of the ventral forebrain, facial dysmorphism, and developmental delay.
There’s a wide range of brain structure malformations associated with holoprosencephaly that can include incomplete separation of the cerebral hemispheres; presence of a single ventricle; fused basal ganglia; or the absence of some structures, such as the corpus callosum and components of the olfactory pathway (e.g., arrhinencephaly). In milder forms, these changes are more subtle (e.g., only a partial absence of the corpus callosum). On the other hand, severe forms may present with additional midline defects and facial features, such as cleft lip and palate (i.e., labiopalatoschisis), hypotelorism (i.e., short distance between the eyes), cyclopia (i.e., presence of a single eye), or proboscis (i.e. a rare anomalous appendage protruding from the face). Some of these congenital defects may be associated with an orofacial motor dysfunction and feeding difficulties.
Furthermore, children with HPE may have an increased risk of pituitary gland dysgenesis and dysfunction, possibly resulting in various endocrinological issues, such as decreased growth leading to short stature, hypoglycemia, hyponatremia, and central diabetes insipidus (i.e., decreased release of antidiuretic hormone causing electrolyte imbalances).
There are other dysmorphic facial features, which are not diagnostic of HPE, however, may be associated with the condition. These include macro- or microcephaly, anophthalmia or microphthalmia (i.e., absence or small size of one or both eyes), dysmorphic nose, absence of a superior labial frenulum (i.e., the soft tissue that connects the inside of the upper lip to the midline of the upper gingiva), palatal anomalies, bifid uvula, and a single central incisor.
Lastly, children with HPE typically present with developmental delay. Due to the nature of their brain malformation, they are also predisposed to other neurodevelopmental issues, such as intellectual disability, seizures, hydrocephalus, brainstem dysfunction, and dysregulated sleep.
It’s important to note that there is a great variability in presentation, regardless of the apparent cause. For example, members of the same family with the same genetic variant may have a varied clinical presentation.
How is holoprosencephaly classified?
While the brain malformations in holoprosencephaly can occur on a spectrum, rather than distinct deformities, HPE can be generally classified into four different subtypes: alobar, semilobar, lobar, and middle interhemispheric. The alobar HPE form, which is the most common and severe form, is characterized by a total absence of the interhemispheric fissure as well as corpus callosum and olfactory bulbs. There is also only a single midline ventricle. The semilobar form is when there’s only partial separation as the posterior interhemispheric fissure exists, while some anterior parts are absent. In the lobar form, there is separation of the ventricles and nearly the whole cortex. Lastly, a recently recognized fourth pattern termed middle interhemispheric variant (MIHF), is the most mild form. This is characterized by abnormal midline union of the posterior aspect of the frontal and parietal lobes.Alobar HPE is linked with a poor prognosis and high mortality rate, while the other HPE forms, which are milder, may have a slightly better neurological outcome.
How is holoprosencephaly diagnosed?
Given that holoprosencephaly is related to dysfunctional brain development, diagnosis can typically occur during pregnancy. If the HPE is severe, it can be identified with an ultrasound during the first trimester—while in the third trimester, MRI can assist with diagnosis. In an infant, ultrasound can be performed if the anterior fontanelles are still open, while an MRI or a CT can be used in older children. Apart from diagnosis, neuroimaging allows classification of HPE into the different forms based on the brain structure affected. Neuroimaging is also performed when children present with typical morphology, family history, and environmental factors associated with holoprosencephaly.Nonetheless, genetic testing is commonly completed in order to identify the presence of genetic variants or chromosomal abnormalities. If genetic variants are found and the parents wish to conceive again, genetic counseling is usually recommended.
How is holoprosencephaly treated?
Holoprosencephaly should be promptly diagnosed and evaluated in the first days of life by a multidisciplinary team in order to optimize management, which is mainly symptomatic and supportive. Treatment also depends on the severity of the individual's symptoms. Some examples of possible treatment options include antiepileptic drugs for recurring seizures, shunt (i.e., ventriculoperitoneal shunt) surgery in cases of hydrocephalus, management of spasticity and dystonia with medications (e.g., intrathecal baclofen pump or oral trihexyphenidyl, respectively), and physical therapy—as well as hormonal supplements when hormone dysregulation is significant. Additionally, surgical correction of some facial defects, such as cleft lip and palate, is commonly performed. Identification of the underlying cause as well as counseling and support for parents are also recommended.
What are the most important facts to know about holoprosencephaly?
Holoprosencephaly (HPE) is a congenital defect of the forebrain (i.e., prosencephalon) and midline structures, resulting in incomplete separation of the cerebral hemispheres in the midline, neurologic impairment, and additional sequelae. Most cases of holoprosencephaly have poor prognosis and are often incompatible with life. HPE is associated with a varying spectrum of brain structure malformations, dysmorphic facial features, pituitary dysfunction, developmental delay, and other related signs and symptoms. HPE can be caused by environmental or genetic causes. In many cases, diagnosis can be made prenatally with an ultrasound or MRI, and further neuroimaging upon birth can help identify the pattern and severity of the HPE. Management is based on a multidisciplinary approach and focuses on symptomatic and supportive treatment as well as genetic counseling for the parents.
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