Elsevier

Molecular Genetics and Metabolism

Volume 80, Issues 1–2, September–October 2003, Pages 36-53
Molecular Genetics and Metabolism

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Human malformations of the midbrain and hindbrain: review and proposed classification scheme

https://doi.org/10.1016/j.ymgme.2003.08.010Get rights and content

Abstract

Although a great deal of interest in the genetics and etiology of cerebral, particularly forebrain, malformations has been generated in the past decade, relatively little is known about the basis of congenital malformations of the structures of the posterior fossa, namely the midbrain, cerebellum, pons, and medulla. In this review, we present a classification scheme for malformations of the midbrain and hindbrain based on their embryologic derivation, highlight four of the conditions associated with such abnormalities, and describe the genetics, prognosis, and recurrence risks for each. We describe several disorders in addition to Joubert syndrome with the distinctive radiologic sign known as the “molar tooth sign,” comprised of midbrain and hindbrain malformations. We discuss Dandy–Walker malformation, its classical definition, and the surprisingly good outcome in the absence of other brain malformations. We consider the heterogeneous entity of cerebellar vermis hypoplasia and describe the recently identified gene associated with an X-linked form of this condition. Finally, the pontocerebellar hypoplasias are discussed in the context of their generally progressive degenerative and severe course, and the differential diagnosis is emphasized. We anticipate that as imaging technologies improve, differentiation of the various disorders should aid in efforts to identify the causative genes.

Introduction

While significant progress has been made in recent years in our understanding of forebrain development and malformations, much less attention has been given to the midbrain and hindbrain. These are the posterior fossa structures that comprise the brainstem, which consists of the midbrain, pons, and medulla, as well as the cerebellum and related cerebrospinal fluid (CSF) spaces including the aqueduct of Sylvius, 4th ventricle, and the foramina of Luschka and Magendie, comprising the lateral and medial outflow tracts, respectively [1]. The embryologic development of these structures is complex, beginning at about 3 weeks gestation and continuing until 20 months of postnatal life for complete cellular differentiation of the cerebellar layers in humans [2]. These structures are primarily derivatives of the primitive hindbrain or rhombencephalon, with the cerebellum derived from the most rostral segment of the hindbrain (rhombomere 1), the pons from the rostral half of the hindbrain (the metencephalon), and the medulla from the lower half of the hindbrain (the myelencephalon). Further details are available in the accompanying review by Chizhikov and Millen [3]. In contrast, the midbrain is derived from the mesencephalon.

Malformations of the posterior fossa have been recognized much more frequently during the past decade or more, based on rapid advances in technology. The first imaging modality to identify these malformations was pneumoencephalography, where air injected into the CSF spaces of the brain could identify displaced, occluded, or dysplastic structures. With the advent of computerized tomography (CT), and more recently, magnetic resonance imaging (MRI), the resolution of cranial structures including the mid-hindbrain regions has improved greatly [4]. However, with improved brain imaging technologies has arisen perplexing problems of categorization and syndrome delineation, as more subtle structural anomalies can now be identified, often of uncertain significance. In fact, the ability to predict the degree of motor and cognitive impairment based on the gross appearance of brain images has been problematic. Cerebellar symptoms such as ataxia and motor incoordination or brainstem impairment have been equally difficult to prognosticate. Even more challenging has been the prenatal identification of a posterior fossa malformation, with resultant inability to accurately predict the outcome, often resulting in poorly informed decisions regarding pregnancy termination [5]. Several different classification schemes for malformations of posterior fossa structures have been proposed [2], [4], [6], [7]. However, none of these approaches consistently relates malformations to the embryological structures involved.

In this review, we present our preferred classification scheme, which is based as much as possible on the embryologic derivation of midbrain and hindbrain structures (Table 1). Although a comprehensive summary of all posterior fossa malformations included in this scheme is beyond the scope of this mini-review, we choose to focus on four of the relatively more common malformations, and those in which there has been considerable confusion regarding delineation and/or prognosis. Our emphasis is on abnormalities that primarily affect only the midbrain and/or hindbrain, although supratentorial structural abnormalities and cerebral dysfunction may also be a component. We will highlight four malformations that primarily involve posterior fossa structures: the molar tooth sign (MTS) and associated mid-hindbrain malformations that occur in Joubert and related syndromes; Dandy–Walker malformation (DWM); cerebellar vermis hypoplasia and dysplasia (CVH); and pontocerebellar hypoplasias (PCH). We will discuss the structural manifestations seen on MRI, the clinical features, the inheritance and causative genes (if known), the prognosis, and recurrence risks for each of these conditions (Table 2).

Section snippets

Embryology and classification scheme

The available methods of classifying congenital malformations of the posterior fossa all have limitations, in part because of poor understanding of the molecular basis of human midbrain and hindbrain development. Some schemes emphasize categorization on an anatomical basis, such as midline versus hemispheric cerebellar changes or abnormalities of cerebellar foliation and fissuration [2], [7], [8]. While anatomic landmarks can be very helpful for delineating the abnormal structures that

Molar tooth sign (MTS) and associated mid-hindbrain malformation disorders

Joubert syndrome (JS) is the best known and probably most common syndrome associated with the molar tooth sign (MTS). JS has been defined on the basis of clinical features which include hypotonia in infancy with later development of ataxia, developmental delays/mental retardation, an abnormal breathing pattern characterized by alternating tachypnea and apnea, abnormal eye movements typified by oculomotor apraxia, and the presence of the MTS on cranial MRI [22], [23]. The MTS is a distinctive

Conclusions

We have provided an overview of some of the major categories of posterior fossa malformations, as well as their outcomes and genetic bases (summarized in Table 1, Table 2). Given the scope of this review, we have provided only a cursory discussion of the metabolic conditions often associated with hindbrain abnormalities and many of the brain malformation syndromes in which cerebellar involvement is only a part of the entire process, such as the cobblestone lissencephaly conditions and

Acknowledgements

We are grateful for the many patients and their families who have participated in clinical surveys to enhance knowledge of these rare disorders. We thank Ian A. Glass, William O. Walker, Jr., David B. Shurtleff, Kathleen J. Millen, and A. James Barkovich for helpful discussions during the preparation of this manuscript.

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