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Selected References

Normal Development and Anatomy of the Cerebral Commissures

Normal Development

Jamuar SS et al: Biallelic mutations in human DCC cause developmental split-brain syndrome. Nat Genet. 49(4):606-612, 2017

Scola E et al: Fetal development of the corpus callosum: insights from a 3T DTI and tractography study in a patient with segmental callosal agenesis. Neuroradiol J. 29(5):323-5, 2016

Normal Gross and Imaging Anatomy

Vannucci RC et al: Development of the corpus callosum: an MRI study. Dev Neurosci. ePub, 2016

Andronikou S et al: Corpus callosum thickness in children: an MR pattern-recognition approach on the midsagittal image. Pediatr Radiol. 45(2):258-72, 2015

Di Ieva A et al: The indusium griseum and the longitudinal striae of the corpus callosum. Cortex. 62:34-40, 2015

Commissural Anomalies

Callosal Dysgenesis Spectrum

Unterberger I et al: Corpus callosum and epilepsies. Seizure. 37:5560, 2016

Filippi CG et al: Lesions of the corpus callosum and other commissural fibers: diffusion tensor studies. Semin Ultrasound CT MR. 35(5):445-58, 2014

Thick Corpus Callosum

Nguyen LS et al: A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy. Eur J Hum Genet. 24(3):455-8, 2016

Budai C et al: Polymicrogyria, large corpus callosum and psychomotor retardation in four-year-old girl: potential association based on MR findings. A case report and literature review. Neuroradiol J. 27(5):590-4, 2014

Malformations of Cortical Development Overview

Barkovich AJ et al: Pediatric Neuroimaging, 5th ed. Philadelphia, PA: Lippincott, Williams & Wilkins, 2012

Malformations With Abnormal Cell Numbers/Types

Focal Cortical Dysplasias

Knerlich-Lukoschus F et al: Clinical, imaging, and immunohistochemical characteristics of focal cortical dysplasia Type II extratemporal epilepsies in children: analyses of an institutional case series. J Neurosurg Pediatr. 19(2):182-195, 2017

Siedlecka M et al: Focal cortical dysplasia: molecular disturbances and clinicopathological classification (Review). Int J Mol Med. 38(5):1327-1337, 2016

Crino PB: Focal cortical dysplasia. Semin Neurol. 35(3):201-8, 2015

Taylor DC et al: Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry. 34(4):369-87, 1971

Hemimegalencephaly

Crino PB: The enlarging spectrum of focal cortical dysplasias. Brain. 138(Pt 6):1446-8, 2015

Oikawa T et al: Utility of diffusion tensor imaging parameters for diagnosis of hemimegalencephaly. Neuroradiol J. 28(6):628-33, 2015

Abnormalities of Neuronal Migration

Heterotopias

Seniaray N et al: PET MRI coregistration in intractable epilepsy and gray matter heterotopia. Clin Nucl Med. 42(3):e171-e172, 2017

Hung PC et al: Clinical and neuroimaging findings in children with gray matter heterotopias: a single institution experience of 36 patients. Eur J Paediatr Neurol. 20(5):732-7, 2016

Kobayashi Y et al: Megalencephaly, polymicrogyria and ribbon-like band heterotopia: a new cortical malformation. Brain Dev. 38(10):950-953, 2016

Jamuar SS et al: Somatic mutations in cerebral cortical malformations. N Engl J Med. 371(8):733-43, 2014

Lissencephaly Spectrum

Fry AE et al: The genetics of lissencephaly. Am J Med Genet C Semin Med Genet. 166C(2):198-210, 2014

Malformations Secondary to Abnormal Postmigrational Development

Polymicrogyria

Bahi-Buisson N et al: The wide spectrum of tubulinopathies: what are the key features for the diagnosis? Brain. 137(Pt 6):1676-700, 2014

In this chapter, we discuss the holoprosencephalies and related disorders. Holoprosencephalies and variants such as syntelencephaly are classified as anomalies of ventral prosencephalon development. Other anomalies of the ventral prosencephalon include septooptic dysplasia (with or without anomalies of the hypothalamic-pituitary axis) and arrhinencephaly, both of which are discussed in this chapter.

We also consider two midline facial anomalies—solitary median maxillary central incisor syndrome and congenital pyriform aperture stenosis/choanal atresia spectrum—that are often present in holoprosencephaly or arrhinencephaly.

Finally, 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.

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(38-1) Autopsy shows total failure of neural tube closure with complete spine dysraphism and anencephaly . (Courtesy R. Hewlett, MD.)

(38-2A) Fetal sagittal T2WI in aprosencephaly shows no supratentorial brain , absent nose, and small remnant of cerebellum .

(38-2B) Autopsy of same case, seen from above, shows no supratentorial tissue . Only cerebellum is present (T. Winters, MD).

Overview

In HPE, the fetal forebrain fails to bifurcate into two hemispheres. "Holoprosencephaly" literally means a single ("holo") ventricle involving the embryonic prosencephalon ("pros") of the brain ("encephaly"). As ventral induction is closely related to facial development, HPE is also associated with a number of characteristic facial anomalies.

Although the phenotype of HPE is quite variable, it can be grouped into two major classes, namely classic HPE and an HPE variant known as middle interhemispheric variant of holoprosencephaly (MIH HPE) or syntelencephaly.

Classic HPE as described by DeMyer (1977) can be further subdivided into three subtypes based on severity although HPE is a continuum that ranges from the most severe type (alobar HPE) to milder lobar forms. In the most severe forms, a central monoventricle is present, whereas diencephalicderived structures such as the basal ganglia remain fused in the midline.

An intermediate type, semilobar HPE, is more severe than alobar HPE 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.

Etiology

Embryology. The fetal forebrain starts as a featureless, fluid-filled frontal sac. In the earliest stages, bilateral outpouchings from the neural tube initially form a single central fluid-filled cavity ("monoventricle"). A key group of specialized cells called the roof plate is involved in the division of this single forebrain vesicle into the two cerebral hemispheres. Failure of this process leads to some forms of holoprosencephaly.

General Concepts. Between one-quarter and one-half of HPE patients have a recognized syndrome (e.g., Pallister-Hall) or a single gene defect. Nonsyndromic HPE has previously been associated with a number of environmental teratogens (e.g., retinoic acid and alcohol) and maternal factors such as prepregnancy diabetes, smoking, and substance abuse. However, recent studies have cast doubt on these assertions.

Genetics. Genetically determined proteins are involved in normal forebrain roof plate function. Among the most prominent are members of the fibroblast growth factor (Fgf), Bmp, and Wnt proteins as well as Shh, Zic2, Neurogenin2, Six3, and TGIF.

Studies have shown that mutations in any of at least nine genes involved in the Shh signaling pathway can cause HPE in humans although this pathway accounts for only 17% of familial HPE. Variations in the homeobox protein Six3 have been shown to result in different forms of HPE.

Clinical Issues

Epidemiology and Demographics. HPE is the most common human forebrain malformation. The overall incidence of HPE varies from 1:250 aborted conceptuses to 1:10,000-20,000 live births.

Presentation. Presentation and prognosis in HPE both vary widely. Craniofacial malformations such as cyclopia or single proboscis, hypotelorism, nasal anomalies, and facial clefts occur in approximately 7580% of cases. The statement "the face predicts the brain" means that the most severe facial defects generally (although not invariably) are found with the most severe intracranial anomalies (38-3).

Nearly three-quarters of HPE patients have endocrinopathies; severity generally correlates with the degree of hypothalamic nonseparation. An association between HPE and hypothalamic hamartoma also exists.

Natural History. Fetuses with severe alobar HPE are often spontaneously aborted, and severely affected children frequently die as neonates. Surviving individuals usually exhibit variable mental retardation and seizures. Pituitary insufficiency and congenital anosmia with absent CN I ("arrhinencephaly") are other common clinical features of HPE.

Imaging

Imaging findings range from a pancake-like holosphere with central monoventricle (alobar HPE) to well-differentiated, almost completely separated hemispheres with minimal abnormalities (lobar HPE). The septum pellucidum is absent in all cases of HPE.

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Alobar Holoprosencephaly

Terminology and Pathology

Alobar holoprosencephaly (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 usually present but fused. The falx and sagittal sinus are absent, as are the olfactory bulbs and tracts. The optic nerves can be normal, fused, or absent.

The brain itself is often smaller than normal. Its configuration varies from flat ("pancake") to cupor ball-shaped. The sylvian fissures are unformed, and the brain surface often appears completely agyric (38-3B) or minimally sulcated with shallow sulci and flat, disordered gyri.

Cut sections demonstrate a single crescent-shaped monoventricle that opens dorsally into a large CSF-filled dorsal cyst (38-4).

(38-3A) Clinical photograph of aborted fetus with alobar holoprosencephaly shows extreme facial anomalies with central proboscis , cyclops , and slit-like oral cavity . (38-3B) View of autopsied brain in the same case shows completely smooth, featureless brain with no evidence of sulcation, gyration, or midline structures such as the falx or interhemispheric fissure. (Courtesy R. Hewlett, MD.)

(38-4A) Autopsy of alobar holoprosencephaly shows large dorsal cyst , fused thalami , and rudimentary hemisphereswith minimal sulcation and gyration. (38-4B) Coronal cut section in the same case demonstrates no evidence of midline fissure with fusion of the rudimentary hemispheres across the midline. The central monoventricle has a "horseshoe" shape. (Courtesy J. Townsend, MD.)

(38-5A) NECT scan shows holoprosencephaly. Small rim of cortex surrounds "horseshoe" central monoventricle . Thalami are fused .

Clinical Issues

aHPE has a high intrauterine lethality and stillbirth rate. It is found in 1:250 terminated pregnancies and approximately 1:15,000 live births. In utero demise and stillbirths are common.

With severe facial deformities such as cyclopia and proboscis, survival is often less than 1 week. Prognosis in surviving infants is poor. At least half of all patients with aHPE die in less than 5 months, and 80% die before 1 year of age.

Imaging

No normal ventricles can be identified. NECT scans show a CSF-filled horseshoe-shaped cavity that is usually continuous posteriorly with a large dorsal cyst (38-5).

Sagittal T1 scans show a thin anteroinferior pancake of tissue with poor gyration and no discernible midline fissure. Most of the calvaria appears CSF-filled and virtually featureless. In contrast, the brainstem and cerebellum often seem relatively normal.

Coronal scans best demonstrate the central monoventricle. The septi pellucidi and third ventricle are absent, as are the falx cerebri and interhemispheric fissure. The cerebral mantle is fused across the midline anteriorly. 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.

Axial scans show that the brain is completely fused across the midline without evidence of an anterior interhemispheric fissure. The monoventricle opens dorsally into a large CSFfilled cyst.

(38-5B) More cephalad scan in the same patient shows a large dorsal cyst and central monoventricle with thin rim of surrounding brain . No falx or interhemispheric fissure is present.

Vascular anomalies associated with aHPE include a rete of vessels and azygous anterior cerebral artery.

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

Semilobar holoprosencephaly (sHPE) is intermediate in severity between alobar HPE and lobar HPE. A gradation of findings is present. The most severe sHPE shows a rudimentary interhemispheric fissure and incomplete falx (38- 6). 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 (38-7). 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. The caudate heads are continuous across the midline

(38-8).

A corpus callosum splenium is present, but the body and genu are absent. Barkovich points out that (1) holoprosencephaly is the only malformation in which the posterior corpus callosum

(38-6) Coronal autopsy case of severe semilobar HPE shows H- shaped central ventricle with primitive-appearing temporal horns , fused basal ganglia , and rudimentary interhemispheric fissure . (Courtesy R. Hewlett, MD.)

forms while the anterior aspects are absent and (2) the farther anteriorly the corpus forms, the better the brain is developed.

Associated abnormalities include a dorsal cyst (present in onethird of cases) and vascular anomalies, such as azygous anterior cerebral artery and rudimentary deep veins.

Differential Diagnosis

The major differential diagnoses of sHPE are alobar HPE 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, although their most anterior aspects are often somewhat shallow and dysplastic-appearing.

The third ventricle and lateral ventricular horns are generally well formed, although the septi pellucidi are 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.

(38-7) Axial T2WI shows severe sHPE with rudimentary posterior interhemispheric fissure , primitive ventricular horns , and anterior midline fusion. Diffuse frontal migration arrest with subcortical heterotopic GM is also present.

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 (38-9). 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 are no septi pellucidi.

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 septooptic dysplasia (SOD). Some authors consider SOD the best differentiated of the HPE spectrum. In contrast to lobar HPE,