the frontal horns are well formed in SOD. Arrhinencephaly may resemble lobar HPE, but the olfactory bulbs are usually present in lobar HPE.

In the middle interhemispheric variant of HPE (syntelencephaly), the corpus callosum genu and splenium are formed; however, the body is missing, and the posterior frontal lobes are continuous across the midline.

HOLOPROSENCEPHALIES (BASED ON DEMYER'S THREE DEGREES OF SEVERITY)

Classic Holoprosencephaly

•Alobar holoprosencephaly

○Most severe; high intrauterine lethality

○"Pancake" brain with central monoventricle

○Basal ganglia fused; no falx, no interhemispheric fissure (IHF)

•Semilobar holoprosencephaly

○Rudimentary falx, posterior IHF

○Primitive ventricular horns, third ventricle

○Thalami often separated, but basal ganglia fused

•Lobar holoprosencephaly

○Best-differentiated form of classic HPE

○Basal ganglia separated, falx/IHF present except anteroinferiorly

○Ventral frontal lobes remain fused across midline

Variant Holoprosencephaly

•Midline (middle) interhemispheric holoprosencephaly

•Septopreoptic holoprosencephaly

Holoprosencephaly Variants

Several holoprosencephaly (HPE) variants have been identified, including syntelencephaly and septopreoptic HPEs. Arrhinencephaly, which some authors consider a variant of HPE, is considered together with septooptic dysplasia later in the chapter.

Middle Interhemispheric Variant of

Holoprosencephaly

The middle interhemispheric variant of HPE (MIH) is also known as syntelencephaly. Here the anterior and posterior hemispheres are separated by the falx and interhemispheric fissure, but their midsections are fused across the midline (38-10). In contrast to classic HPE, the ventral aspects of the basal forebrain are largely spared, so the basal ganglia and olfactory sulci appear normal.

Imaging findings in MIH are diagnostic. Sagittal T1 and T2 scans show that the corpus callosum splenium and genu are present but that the body is absent. The posterior frontal lobes are continuous across the midline on coronal images. The lateral ventricle bodies appear narrow and fused.

Axial scans show the anterior and posterior parts of the interhemispheric fissure and the absence of the midsection. The falx also narrows and disappears in both 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 (3811A) (38-11B) (38-11D).

On coronal imaging, a single common ventricle lacking a septum pellucidum is present. A nodule of gray matter is perched along the dorsal aspect of the fused lateral ventricles, forming a characteristic central ventricular "notch"

(38-11C). The third ventricle is well formed.

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(38-9A) Sagittal T2WI of lobar HPE shows welldifferentiated brain, nearly normal-appearing third ventricle , and azygous ACA .

(38-9B) Axial T2WI shows well-developed occipital horns , third ventricle , and minimal anterior midline fusion .

(38-9C) Coronal T2WI shows that the anteroinferior frontal cortex is fused across the midline .

DTI shows that the callosal body and central cingulum fibers are absent, but all other major WM tracts have a normal course, thickness, and integrity. The horizontal white matter tracts cross the midline just under the fused cortex (38-11E).

Septopreoptic Holoprosencephaly

Several very mild forms of HPE have been described in which the failure of hemispheric separation is restricted to the septal (subcallosal) and/or preoptic regions or both. Patients with these types of HPE—termed septopreoptic holoprosencephaly—often present with mild midline craniofacial malformations. These variants include solitary median maxillary central incisor (SMMCI) and congenital nasal pyriform aperture stenosis (CNPAS). Both are briefly discussed here.

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Solitary Median Maxillary Central Incisor Syndrome

SMMCI syndrome is a rare malformation that consists of multiple (mainly midline) defects. Most authors suggest that SMMCI is an HPE variant, although others consider it a distinct entity.

Neonates with SMMCI often present with breathing difficulties secondary to nasal obstruction. Neurodevelopmental delay and endocrine abnormalities such as short stature and precocious puberty are common associated findings.

Imaging findings in SMMCI range from isolated dental abnormalities with a single maxillary incisor and V-shaped palate to more complex abnormalities that involve the brain (38-12). Anomalies of the fornix, septi pellucidi, and anterior

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(38-13) Coronal graphic shows SOD with absent cavum septi pellucidi with flat-roofed anterior horns and small optic chiasm .

(38-14) Cavum septi pellucidi are absent ; boxlike lateral ventricles with inferiorly pointed frontal horns are seen. (J. Townsend, MD.)

corpus callosum are often present. An azygous anterior cerebral artery is common. Pituitary stalk hypoplasia occurs in some cases.

Congenital Nasal Pyriform Aperture Stenosis

CNPAS can exist as an isolated abnormality with choanal atresia, midnasal stenosis, or pyriform aperture stenosis. CNPAS may also coexist with SMMCI. CNPAS is associated with a high incidence of hypothalamic-pituitary-adrenal axis dysfunction, cleft palate, and inner ear anomalies.

VARIANT HOLOPROSENCEPHALY

Middle Interhemispheric Variant Holoprosencephaly

•Also known as syntelencephaly

•Corpus callosum genu, splenium present; middle absent

○Only brain malformation with that morphology

•Midsections of falx, interhemispheric fissure absent

•Posterior frontal gray/white matter fused across midline

Septopreoptic Holoprosencephaly

•Solitary median maxillary central incisor syndrome (SMMCI)

○Single midline incisor

○Often coexists with nasal anomalies

○Brain anomalies of fornix, septi pellucidi, corpus callosum common

•Congenital nasal pyriform aperture stenosis (CNPAS)

○Choanal atresia, midnasal stenosis, pyriform aperture stenosis

○Often coexists with SMMCI

○Hypothalamic-pituitary-adrenal axis dysfunction common

Related Midline Disorders

Septooptic Dysplasia

Some authors consider septooptic dysplasia (SOD) simply a very welldifferentiated form of lobar holoprosencephaly (HPE). However, the lack of ventral midline fusion and the heterogeneous nature of the disorder are more consistent with a separate but related midline malformation.

Terminology and Pathology

SOD is also known as de Morsier syndrome. Two cardinal pathologic features define SOD: (1) absence of the septum pellucidum and (2) optic nerve hypoplasia (38-13) (38-14).

When SOD occurs with other anomalies such as schizencephaly or callosal dysgenesis, the syndrome is sometimes called SOD plus (38-15).

Etiology and Genetics

Most SOD cases are sporadic. Some are autosomal-dominant or -recessive cases. Mutation of the homeobox gene HESX1 has been identified in a few cases.

Clinical Issues

(38-15) Coronal T2WI in newborn shows absent cavum septi pellucidi , schizencephaly , extensive polymicrogyria , fused fornices .

The most common clinical feature of SOD is visual impairment. Nearly twothirds of SOD patients also develop endocrine abnormalities from hypothalamic-pituitary insufficiency (e.g., hypoglycemic seizures).

SEPTOOPTIC DYSPLASIA: PATHOLOGY AND CLINICAL FEATURES

Pathology

•Cardinal pathologic features

○Absent septi pellucidi

○Optic nerve/chiasm hypoplasia

Clinical Features

•Hormonal dysfunction in nearly two-thirds

○Pituitary insufficiency

○Growth hormone deficiency, hypothyroid most common

○Rare = precocious puberty

•Neurodevelopmental delay common

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Imaging

Imaging findings in SOD are diagnostic. Three orthogonal planes are crucial to identifying all the findings. Thin-section coronal T1and T2-weighted images show absent or hypoplastic septi pellucidi. The frontal horns appear "squaredoff" or box-like with distinct inferior pointing. The optic chiasm and one or both optic nerves appear small in most cases (3816).

Sagittal images show that the septi pellucidi are absent and the fornices are low-lying, giving the lateral ventricles an "empty" appearance (38-17A).

Isolated absence of the septi pellucidi is relatively rare, so look carefully for other anomalies. The majority of patients with SOD have malformations of cortical development (e.g., heterotopias, schizencephaly (38-17B), and polymicrogyria) in addition to optic nerve hypoplasia. Others exhibit a small pituitary gland with thin or absent stalk and an ectopic

(38-16A) Sagittal T2WI in a 13m boy with septooptic dysplasia (SOD) shows an empty-appearing lateral ventricle with low-lying fornix . The optic chiasm appears small. (38-16B) Coronal T2WI shows the hypoplastic optic chiasm , absent septi pellucidi , and the peculiar box-like or "squared-off" appearance of the frontal horns. The inferior pointing of both frontal horns is also characteristic of SOD.

(38-17A) Sagittal T1WI in a 26y woman with SOD shows extreme hypoplasia of the optic chiasm , small pituitary gland with inapparent stalk , and low-lying fornices that give a striking "empty" appearance to the lateral ventricle . (38-17B) Coronal IR in the same case shows unilateral schizencephaly with dysplastic gray matter lining the cleft . Note contralateral polymicrogyria .

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neurohypophysis. Olfactory tract/bulb hypoplasia and incomplete hippocampal rotation are common.

SEPTOOPTIC DYSPLASIA: IMAGING

Imaging Findings

•Absent septum pellucidum

○"Squared-off" frontal horns, pointed inferiorly on coronal T2WI

•Hypoplastic optic nerves, chiasm

•Look for

○Malformations of cortical development

○Thin stalk, small gland, ectopic posterior pituitary

Differential Diagnosis

The major differential diagnosis of SOD is well-differentiated lobar HPE. The olfactory bulbs are present in lobar HPE but

(38-18) Submentovertex graphic depicts the normal olfactory bulbs , trigones , and lateral olfactory stria passing into the temporal lobes. (38-19) Coronal T2WI in a normal newborn shows olfactory bulbs and normal olfactory sulci .

(38-20) Autopsy case of arrhinencephaly shows absent olfactory bulbs and shallow, deformed olfactory sulci .

(Courtesy R. Hewlett, MD.) (38-21) Coronal T2WI in a newborn with multiple congenital anomalies demonstrates arrhinencephaly with absent olfactory bulbs and no olfactory sulci . (Courtesy S. Blaser, MD.)

are frequently absent in SOD. The cerebral hemispheres and basal ganglia are completely separated in SOD.

Arrhinencephaly

Arrhinencephaly (ARR) is a congenital malformation in which the olfactory bulb and tracts are absent (38-18) (38-19) (3820) (38-21). Although ARR can exist in isolation, most cases occur with multiple other midline facial anomalies such as cleft palate, cleft lip, and nasal and/or ocular malformations.

Common associated intracranial abnormalities include abnormalities of the hypothalamic-pituitary axis, callosal dysgenesis, and alobar and semilobar HPE.

When olfactory aplasia/hypoplasia occurs with hypogonadotropic hypogonadism, it is termed Kallmann syndrome. Olfactory agenesis occurs in approximately 25% of patients with CHARGE (coloboma, heart malformations,