Holoprosencephalies, Related Disorders, and Mimics
Main Text
Preamble
Holoprosencephalies and variants, such as syntelencephaly, are classified as anomalies of ventral prosencephalon development. Other anomalies of the ventral prosencephalon include septo-optic dysplasia (with or without anomalies of the hypothalamic-pituitary axis) and arrhinencephaly, both of which are discussed in this chapter.
We conclude the chapter with a brief discussion of hydranencephaly, an in utero acquired destruction of the cerebral hemispheres that can sometimes be confused with alobar holoprosencephaly or severe “open-lip” schizencephaly.
Holoprosencephaly
Preamble
Holoprosencephaly (HPE) spans a continuum from alobar to lobar forms. Although each is delineated separately, keep in mind that the HPEs are really a spectrum with no clear boundaries that reliably distinguish one type from another.
Overview and Etiology
The fetal forebrain starts as a featureless, mostly fluid-filled sac. Outpouchings from the neural tube initially form a single central fluid-filled cavity (“monoventricle”). The fetal forebrain and monoventricle subsequently divide into the two cerebral hemispheres, also forming the definitive ventricles. Failure of this process leads to HPE. “Holoprosencephaly” literally means a single (“holo”) ventricle involving the embryonic forebrain (prosencephalon).
HPE is divided into three subtypes based on severity, although HPE is a continuum that ranges from the most severe type [alobar HPE (aHPE)] to milder lobar forms. In the most severe forms, a central monoventricle is present, and structures, such as the basal ganglia, are fused in the midline.
An intermediate type, semilobar HPE (sHPE), is more severe than aHPE but not nearly as well differentiated as the lobar variety. The distinction between these three forms is based primarily on the presence or absence of a midline fissure separating the hemispheres.
Clinical Issues
HPE is the most common human forebrain malformation. Craniofacial malformations, such as cyclopia or single proboscis, hypotelorism, nasal anomalies, solitary median maxillary central incisor (SMMCI), and facial clefts, occur in ~ 75-80% of cases. The statement “the face predicts the brain” means that the most severe facial defects generally are associated with the most severe intracranial anomalies.
Nearly 3/4 of HPE patients have endocrinopathies. Pituitary insufficiency and congenital anosmia with absent CNI [arrhinencephaly (ARR)] are other common clinical features of HPE.
General Imaging Features
Imaging findings range from a pancake-like holosphere with central monoventricle (aHPE) to well-differentiated, almost completely separated hemispheres with minimal abnormalities (lobar HPE). The septum pellucidum is absent in all cases of HPE.
Alobar Holoprosencephaly
Terminology and Pathology
aHPE is the most severe form of HPE. No midline fissure divides the brain into two separate cerebral hemispheres and no identifiable lobes are seen. The basal ganglia are fused. The falx and sagittal sinus are absent, as are the olfactory bulbs and tracts.
The brain configuration varies from flat (“pancake”) to cup- or ball-shaped. The sylvian fissures are unformed, and the brain surface often appears completely agyric or minimally sulcated with shallow sulci and flat, disordered gyri (43-1).
Cut sections demonstrate a single crescent-shaped monoventricle that opens dorsally into a large CSF-filled dorsal cyst.
Clinical Issues
aHPE has a high intrauterine lethality and stillbirth rate. Prognosis in surviving infants is poor. At least 1/2 of all patients with aHPE die in < 5 months, and 80% die before one year of age.
Imaging
The cardinal feature of aHPE is a CSF-filled, horseshoe-shaped cavity (43-2) (“central monoventricle”) that is often continuous posteriorly with a large dorsal cyst. Severe facial anomalies, such as cyclopia and proboscis, are more likely in those cases with a more severe spectrum of HPE.
The septum pellucidum and third ventricle are absent, as are the falx cerebri and interhemispheric fissure. The brain is completely fused across the midline without evidence of an anterior interhemispheric fissure. The brain appears thin and almost agyric, although a few shallow sulci may be present. The basal ganglia are small and fused across the midline. There are no discernible commissures. Associated vascular anomalies, such as azygous anterior cerebral artery, are common.
Differential Diagnosis
The major differential diagnosis of aHPE is hydranencephaly. In hydranencephaly, the face is normal. A falx is present, but most of the cerebral tissue has been destroyed, usually by an intrauterine vascular accident or infection.
Semilobar Holoprosencephaly
Terminology and Pathology
sHPE is intermediate in severity between aHPE and lobar HPE. A gradation of findings is present. The most severe sHPE shows a rudimentary interhemispheric fissure and incomplete falx (43-3). The temporal horns of the lateral ventricle may be partially formed, but the septi pellucidi are absent. A dorsal cyst is often present.
Imaging
With progressively better-differentiated sHPE, more of the interhemispheric fissure appears formed (43-4). The deep nuclei exhibit various degrees of separation. If a rudimentary third ventricle is present, the thalami may be partially separated. The basal ganglia and hypothalami are still largely fused (43-5). The caudate heads are continuous across the midline.
A corpus callosum splenium is present, but the body and genu are absent. Associated abnormalities include a dorsal cyst (present in 1/3 of cases) and vascular anomalies, such as azygous anterior cerebral artery and rudimentary deep veins.
Differential Diagnosis
The major differential diagnoses of sHPE are aHPE and lobar HPE, depending on the severity of the sHPE.
Lobar Holoprosencephaly
Terminology and Pathology
Lobar HPE is the best differentiated of the HPEs. The interhemispheric fissure and falx are clearly developed. The third ventricle and lateral ventricular horns are generally well formed, although the septum pellucidum is absent and the frontal horns almost always appear dysmorphic. The hippocampi are present but often more vertically oriented than normal.
Clinical Issues
Patients with lobar HPE are less severely affected compared with individuals with sHPE. Mild developmental delay, hypothalamic-pituitary dysfunction, and visual disturbances are the most common symptoms.
Imaging
In lobar HPE, the cerebral hemispheres—including the thalami and most of the basal ganglia—are mostly separated. At least some of the most rostral and ventral portions of the frontal lobes are continuous across the midline (43-6). The anterior columns of the fornix are fused. The thalami and basal ganglia are separated, although the caudate heads may remain fused.
The frontal horns of the lateral ventricles are present but dysplastic-appearing. The temporal and occipital horns are better defined, and the third ventricle generally appears normal. There is no septum pellucidum.
The corpus callosum is present and can be normal, incomplete, or hypoplastic. The splenium and most of the body can usually be identified, although the genu and rostrum are often absent. In contrast to isolated or syndromic corpus callosum dysgenesis, there are no Probst bundles in any of the HPEs.
The walls of the hypothalamus remain unseparated, and the optic chiasm is often smaller than normal. The olfactory bulbs are present in well-differentiated lobar HPE. The pituitary gland can be flattened, hypoplastic, or ectopic. Associated vascular anomalies include an azygous anterior cerebral artery.
Differential Diagnosis
The major differential diagnosis of lobar HPE is septo-optic dysplasia (SOD). Some authors consider SOD the best differentiated of the HPE spectrum. In contrast to lobar HPE, the frontal horns are well formed in SOD. ARR may resemble lobar HPE, but the olfactory bulbs are usually present in lobar HPE.
In the rare middle interhemispheric variant of HPE (MIH) (syntelencephaly) (43-7), the corpus callosum genu and splenium are formed; however, the body is missing, and the posterior frontal lobes are continuous across the midline.
Holoprosencephaly Variants
Preamble
Several holoprosencephaly (HPE) variants have been identified, including syntelencephaly and the septopreoptic HPEs. ARR, which some authors consider a variant of HPE, is considered together with SOD in the related midline disorders section later in the chapter.
Middle Interhemispheric Variant of Holoprosencephaly
Terminology
MIH is a mild HPE subtype that is also known as syntelencephaly.
Etiology
HPE is a disorder of ventral induction that results from incomplete midline cleavage of the prosencephalon. In MIH, there is failure of separation of the posterior frontal and parietal lobes (43-7).
Mutations in the ZIC2 gene have been recognized as a potential cause of MIH.
Pathology
The MIH variant represents 2-15% of HPE cases. In classic MIH, the callosal genu and splenium are normally formed, but the middle part (the body) is absent.
Clinical Issues
Patients with MIH often have closely spaced eyes and a depressed or narrowed nasal bridge but otherwise relatively normal facial appearance.
Imaging
Imaging findings in MIH are diagnostic. Sagittal T1 and T2 scans show that the corpus callosum splenium and genu are present, but the body is absent (43-9).
Axial scans show the anterior and posterior parts of the interhemispheric fissure are present, but the midsection is absent, so the hemispheres are fused across the midline (43-8B). The anterior falx is present or mildly dysplastic but then narrows and disappears in the posterior frontal and anterior parietal regions. In 85% of cases, the sylvian fissures course superiorly and meet in a coronally oriented, cortically lined fissure that is continuous across the midline (43-8A).
On coronal scans, the posterior frontal lobes are continuous across the midline, while the lateral ventricle bodies appear narrow and fused. A single common ventricle without a septum pellucidum is present. The third ventricle is well formed. A nodule of heterotopic gray matter is often perched along the dorsal aspect of the fused lateral ventricles, forming a characteristic central ventricular “notch”(43-9B). Other foci of heterotopic gray matter are also common.
The hypothalamus and basal ganglia are normally separated in MIH, while the caudate nuclei and thalami are partially fused. An azygous anterior cerebral artery is present in most cases. Other common associated anomalies include cerebellar abnormalities and polymicrogyria.
DTI shows that the callosal body and central cingulum fibers are absent, but all other major white matter tracts have a normal course, thickness, and integrity. The horizontal white matter tracts cross the midline just under the fused cortex (43-9C).
Differential Diagnosis
In contrast to classic HPE, in syntelencephaly, the ventral aspects of the basal forebrain are largely spared, so the basal ganglia and olfactory sulci appear normal.
Septopreoptic Holoprosencephaly
Several very mild forms of HPE have been described where failure of hemispheric separation is restricted to the septal (subcallosal) &/or preoptic regions or both. Patients with septopreoptic HPE often present with mild midline craniofacial malformations. These include solitary median maxillary central incisor (SSMCI) and congenital nasal pyriform aperture stenosis (CNPAS) (43-10).
Neonates with SMMCI often present with breathing difficulties secondary to nasal obstruction. Imaging findings range from isolated dental abnormalities with a single maxillary incisor and V-shaped palate to more complex abnormalities that also involve the brain. Anomalies of the fornix, septi pellucidi, and corpus callosum are often present. An azygous anterior cerebral artery is common. Some cases have pituitary stalk hypoplasia.
Related Midline Disorders
Septo-Optic Dysplasia
Terminology and Etiology
Some authors consider SOD simply a very well-differentiated form of lobar HPE.
Several genes connected to the development of the forebrain and related midbrain structures have been implicated in the development of SOD. These include HESX1, SOX2, SOX3, FGF1, and FGF8.
Pathology
SOD is characterized by any combination of the following: (1) Optic nerve hypoplasia, (2) pituitary hypofunction, and (3) midline brain abnormalities. Brain abnormalities include dysgenesis of the septum pellucidum &/or corpus callosum or hypoplasia of the pons, vermis, or medulla. Ventral midline fusions are absent. Approximately 1/3 of SOD patients have the full spectrum of manifestations (43-11A).
Clinical Issues
Individuals with SOD have different manifestations of visual and pituitary-hypothalamic dysfunction. The most common clinical feature of SOD is visual impairment. Nearly 2/3 of SOD patients also develop endocrine abnormalities from hypothalamic-pituitary insufficiency (e.g., hypoglycemic seizures).
Imaging
Thin-section coronal T1- and T2-weighted images show absent or hypoplastic septum pellucidum. The frontal horns appear “squared-off” or box-like with distinct inferior pointing. The optic chiasm and one or both optic nerves appear small in most cases (43-11). Sagittal images show that the septum pellucidum is absent and the fornices are low-lying, giving the lateral ventricles an empty appearance. The optic nerves and chiasm are hypoplastic.
Isolated absence of the septum pellucidum is relatively rare, so look carefully for other anomalies midline anomalies, such as pituitary malformations (anterior pituitary hypoplasia, ectopic posterior pituitary, and thin/interrupted or absent infundibulum). When associated with malformations of cortical development (e.g., schizencephaly and polymicrogyria), this constellation of findings is referred to as SOD plus (43-12).
SEPTO-OPTIC DYSPLASIA: IMAGING
Imaging Findings
• Absent septum pellucidum
“Squared-off” frontal horns, pointed inferiorly on coronal T2WI
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