Developmental Neuropathology

Homa Adle-Biassette, Brian N. Harding, Jeffrey A. Golden, Homa Adle-Biassette, Brian N. Harding, Jeffrey A. Golden, Francoise Gray, Katy Keohane

• Publisher: Wiley-Blackwell
• Year: 2018
• Print ISBN: 9781119013082
• eBook ISBN: 9781119013105
• Edition: 2
• Topic: Medicine
• Subtopic: Neurology

A definitive, clinically oriented guide to the pathology of genetics of developmental neuropathology

Developmental neuropathology relates to the wide range of disorders affecting the developing brain or pre- and post-natal life, with emphasis on the genetic and molecular mechanisms involved. This book provides a practical guide to diagnosing and understanding these disorders affecting this vulnerable population and potentially stimulates further advances in this exciting area. It also addresses the controversies in inflicted head injury in infants.

The fourth major title to be approved by the International Society of Neuropathology (ISN), Developmental Neuropathology offers in-depth chapter coverage of brain development; chromosomal changes; malformations; secondary malformations and destructive pathologies; developmental vascular disorders; acquired metabolic and exogenous toxins; metabolic disorders; Rett syndrome and autism; and infectious diseases. The text provides:

• Clinical, disease-oriented approach to the pathology and genetics developmental neuropathology
• Fuses classical and contemporary investigative approaches
• Includes genetic and molecular biological pathogeneses
• Fully illustrated
• Approved and endorsed by International Society of Neuropathology

Developmental Neuropathology is the perfect book for practicing neuropathologists, pediatric pathologists, general pathologists, neurologists, and geneticists in deciphering the pathology and pathogenesis of these complex disorders affecting the nervous system of the embryo, fetus, and child.

1
Central Nervous System Manifestations of Chromosomal Change

Joseph R. Siebert

Department of Laboratories, Seattle Children's Hospital and Departments of Pathology and Pediatrics, University of Washington, Seattle, WA, USA

Introduction

A wide variety of morphologic and functional abnormalities have been identified in the central nervous systems (CNS) of patients with chromosomal defects. These are reviewed for the more commonly encountered karyotypes, with emphasis given to those aberrations in chromosome number (e.g., trisomy, monosomy) or chromosome morphology (i.e., large deletions and duplications) that affect the CNS. Disorders associated with mosaicism, lesser chromosomal changes (including translocations), or single gene mutations are not included.

Chromosomal changes are encountered in early pregnancy loss, but their true incidence is hard to determine. A commonly used estimate is 50%. Alterations like trisomy 16 (estimated to occur in 1% of all conceptuses) are unlikely to come to the attention of neuropathologists because of early fetal demise. The prevalence of chromosomal defects is summarized for common CNS anomalies in Table 1.1. Because of genetic mechanisms (e.g., incomplete penetrance and variable expressivity) and other factors, phenotypes do not always correlate precisely with specific karyotypes. For this reason, the tables in this chapter are limited to general summaries.

Table 1.1 Prevalence of chromosomal abnormalities in common central nervous system (CNS) anomalies.

CNS anomaly	Estimated Prevalence of Abnormal Karyotype (%)	Predominant Karyotypic Abnormality	Reference
Anencephaly	9	Variable, including trisomy 13, 18, and triploidy	26
Holoprosencephaly	50	Trisomy 13, 18	27
Dandy-Walker malformation	45–55	Trisomy 9, 13, 18, 21; triploidy; del(6p)	28
Complete vermian agenesis	32		28
Inferior vermian agenesis	53		28
Chiari malformation	Occasional	Trisomy 13, 18	26
Microcephaly/micrencephaly	Frequent	Trisomy 9, 13, 18, 21; sex chromosome trisomy or monosomy	26
Isolated ventriculomegaly	12	Trisomy 21; 47XXY	29
Agenesis of corpus callosum	18	Trisomy 8, 13, 18; del(11q)	26,30
Spina bifida/myelomeningocele	17	Trisomy 13, 18; triploidy	31
Coloboma	Often unspecified; 10% in 1993 study	Trisomy 13, 18; triploidy; 5p-; 4p-	32
Micro-/anophthalmia	25+	Trisomy 13	33

The craniofacial complex

While this chapter is oriented toward the description of changes in the CNS, the cranium can scarcely be ignored. The embryogenesis of brain and cranium proceeds in tandem and anomalies of one structure are almost always reflected by changes in the other.

The pathologist whose study of the CNS is hampered by severe autolysis, commonplace in stillbirth, or delivery by dilatation and evacuation, does well to examine the cranium to get clues to CNS pathology [1]. Two examples are anencephaly and holoprosencephaly. In the former, the cranial base is markedly flattened, much of the calvaria is absent, and sphenoidal anomalies are common. In specimens altered by holoprosencephaly, the anterior cranial fossa is flattened, cribriform plates are small, obscured, or absent, the crista galli is reduced in size or absent, and the anterior falx cerebri is absent or hypoplastic (Figure 1.1). Axial anomalies are especially common in trisomy 13 and 18. Identifying any of these changes is of great help in achieving a diagnosis, or at least in attempting to corroborate prenatal imaging studies.

Figure 1.1 Close view of cranial base, showing anterior and middle cranial fossae of patient with holoprosencephaly and trisomy 13. Note absence of ethmoid derivatives (crista galli, cribriform plates) and falx cerebri. In cases of ocular hypotelorism, the basisphenoid and sella turcica may be narrowed.

Genetic counseling and the neuropathologist

Affected individuals and/or their families desire to understand both present and future issues surrounding their condition. Families are concerned about implications for present and future care, as well as prevention, recurrence risk, and family planning. Neuropathologists should be integral members of the team that provides information to patients and their families. Specialists will serve their patients well by providing information that is of direct use to the genetic counselor. In addition to written reports, the pathologist should provide photographs, especially of external phenotypic features (face, head, hands, and so forth), that have diagnostic value. Ethical ramifications are considerable, but beyond the scope of this review.

Autosomal trisomy

A trisomic cell is defined by the presence of three homologous chromosomes. The condition is serious and often associated with prenatal demise, or live birth with multiple anomalies, some of which are life-threatening. Females with trisomy 13 or 18 have severe ovarian dysgenesis, resulting germ cell failure, and cannot reproduce, should they survive to reproductive age [2]. Women with trisomy 21 who become pregnant give birth to infants with trisomy 21 in about one-third of cases; affected males are sterile. Trisomic conditions with associated changes of the craniofacial complex and CNS are described below and summarized in Table 1.2.

Table 1.2 Craniocerebral findings in selected autosomal aneuploid conditions.

Karyotype	Craniofacial Findings	Morphologic and Functional Abnormalities of CNS
Trisomy 8	Scaphocephaly; prominent forehead; ocular hypertelorism; deeply set eyes; bulbous nose; thickened, everted lower lip; high or cleft palate; low set, dysplastic ears; micrognathia	Variable psychomotor restriction; personality disorder/psychosis; agenesis of the corpus callosum; spina bifida occulta; less frequent CNS...

Table of contents

• Cover
• Title page
• Copyright
• List of Contributors
• Introduction
• Chapter 1: Central Nervous System Manifestations of Chromosomal Change
• Chapter 2: Neural Tube Defects
• Chapter 3: Midline Patterning Defects
• Chapter 4: Microcephaly
• Chapter 5: Hemimegalencephaly and Dysplastic Megalencephaly
• Chapter 6: Lissencephaly, Type I
• Chapter 7: Lissencephaly, Type II (Cobblestone Lissencephaly)
• Chapter 8: Polymicrogyria
• Chapter 9: Cerebral Heterotopia
• Chapter 10: Hippocampal Sclerosis, Granule Cell Dispersion, and Cortical Dysplasia
• Chapter 11: Tuberous Sclerosis Complex
• Chapter 12: Chiari Malformations
• Chapter 13: Dandy–Walker Malformation, Mega Cisterna Magna, and Blake's Pouch Cyst
• Chapter 14: Joubert Syndrome
• Chapter 15: Cerebellar Heterotopia and Dysplasia
• Chapter 16: Brainstem Malformations
• Chapter 17: Spinal Cord Lesions
• Chapter 18: Hydrocephalus
• Chapter 19: Antenatal Disruptive Lesions
• Chapter 20: Hemorrhagic Lesions
• Chapter 21: White Matter Lesions in the Perinatal Period
• Chapter 22: Gray Matter Lesions
• Chapter 23: Pediatric Head Injury
• Chapter 24: Pediatric Vascular Malformations
• Chapter 25: Sudden Infant Death Syndrome
• Chapter 26: Kernicterus
• Chapter 27: Lesions Induced by Toxins
• Chapter 28: Disorders of Carbohydrate Metabolism
• Chapter 29: Sphingolipidoses and Related Disorders
• Chapter 30: The Neuronal Ceroid Lipofuscinoses
• Chapter 31: Peroxisomal Disorders
• Chapter 32: Mitochondrial Disorders
• Chapter 33: Disorders of Amino Acid Metabolism and Canavan Disease
• Chapter 34: Pelizaeus–Merzbacher Disease
• Chapter 35: Cockayne Syndrome
• Chapter 36: Vanishing White Matter Disease
• Chapter 37: Alexander Disease
• Chapter 38: Neuroaxonal Dystrophy/Neurodegeneration with Brain Iron Accumulation
• Chapter 39: Spinal Muscular Atrophy
• Chapter 40: Autism Spectrum Disorders
• Chapter 41: Intrauterine Infections
• Chapter 42: Perinatal and Postnatal Infections
• Chapter 43: Rasmussen Encephalitis
• Index
• EULA