Neurodevelopmental Disorders: Comprehensive Developmental Neuroscience

By Bin Chen

Neurodevelopmental Disorders, the latest release in the Comprehensive Developmental Neuroscience series, presents the most thorough coverage available, addressing all aspects on how the nervous system and its components develop. This book brings together the latest research in this rapidly evolving field, with section editors discussing the technological advances that are enabling the pursuit of new research on brain development. This volume focuses on neurodevelopmental disorders in humans and experimental organisms. Particular attention is paid to the effects of abnormal development and on new psychiatric/neurological treatments being developed based on our increased understanding of developmental mechanisms.

• Features leading experts in various subfields as section editors and article authors
• Presents articles that have been peer reviewed to ensure accuracy, thoroughness and scholarship
• Covers disorders of the nervous system that arise through defects in neural development

• Language: English
• Publisher: Academic Press
• Release date: May 24, 2020
• ISBN: 9780128144107

Book preview

Neurodevelopmental Disorders

Comprehensive Developmental Neuroscience

Editors

John Rubenstein

Department of Psychiatry & Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States

Pasko Rakic

Department of Neuroscience & Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, United States

Bin Chen

Department of Molecular, Cell & Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA, United States

Kenneth Y. Kwan

Michigan Neuroscience Institute & Department of Human Genetics, University of Michigan, Ann Arbor, MI, United States

Table of Contents

Cover image

Title page

Copyright

Contributors

Chapter 1. Neurocutaneous disorders

1.1. Introduction

1.2. Neurofibromatosis type 1

1.3. Clinical features

1.4. Neurofibromatosis type 2

1.5. Clinical features

1.6. Schwannomatosis

1.7. Clinical features

1.8. Tuberous sclerosis complex

1.9. Clinical features

Chapter 2. Azetidine-2-carboxylic acid and other nonprotein amino acids in the pathogenesis of neurodevelopmental disorders

2.1. Introduction

2.2. Discussion

Chapter 3. Autisms

3.1. Introduction

3.2. The clinical framework of autism spectrum disorder

3.3. The pathophysiology of autism spectrum disorder

3.4. The autisms: syndromic forms

3.5. Nonsyndromic autisms: genetic and genomic forms

3.6. Nonsyndromic autisms: environmental factors

3.7. Pharmacological and behavioral therapies for autism spectrum disorder

3.8. Conclusions

Chapter 4. Developmental basis of Zika virus-induced neuropathology

4.1. Introduction

4.2. ZIKV virology

4.3. Vertical transmission

4.4. Modeling exposure to ZIKV in the nervous system

4.5. Mechanisms of ZIKV pathogenesis

4.6. Therapeutic development

4.7. Future of ZIKV research

4.8. Summary

Glossary

List of acronyms and abbreviations

Chapter 5. Induced pluripotent stem cells as models of human neurodevelopmental disorders

5.1. Introduction: need for human disease models

5.2. Description of human induced pluripotent stem cells

5.3. Differentiation and disease modeling: organoids, monolayers

5.4. Conclusions

Glossary

List of acronyms and abbreviations

Chapter 6. Cornelia de Lange Syndrome: insights into neural development from clinical studies and animal models

6.1. What is Cornelia de Lange Syndrome?

6.2. Clinical manifestations of neurodevelopmental deficits in man

6.3. Insights into neurodevelopmental and neurological deficits from studies of model systems

6.4. CdLS, transcriptomopathies, and the future of therapeutics

Glossary of terms

List of acronyms and abbreviations

Chapter 7. Fetal alcohol spectrum disorders

7.1. Introduction: prenatal alcohol exposure and fetal alcohol spectrum disorders

7.2. Consequences of alcohol exposure

7.3. Structural changes to the brain

7.4. Peripheral effects of PAE that impact brain function

7.5. Behavioral changes

7.6. Genetic risk factors and epigenetic changes

7.7. Interventions and management of secondary disabilities

7.8. Summary

Chapter 8. Neural tube defects

8.1. Neural tube defects

8.2. Vertebrate neurulation

8.3. Genetic approaches in mice to uncover regulators of neural tube closure

8.4. Molecular basis of neural tube defects

8.5. Future directions

Chapter 9. Developmental disabilities, autism, and schizophrenia at a single locus: complex gene regulation and genomic instability of 15q11-q13 cause a range of neurodevelopmental disorders

9.1. Complex genomics and gene regulation at the human 15q locus

9.2. Epigenetic control of gene expression across 15q11-q13

9.3. Genes known to cause disease in the region

9.4. Contiguous gene deletion/duplication syndromes on 15q

9.5. Complex diseases

9.6. Animal models of 15q region disorders

9.7. Conclusions

Nomenclature

Glossary

Chapter 10. Lissencephalies and axon guidance disorders

10.1. Introduction: disorders of axon guidance

10.2. Ligand/receptor systems mediating axon guidance

10.3. Downstream signaling mechanisms and other proteins involved in axon guidance

10.4. Introduction: neuronal migration

10.5. Overview of neuronal migration disorders

Chapter 11. Rett syndrome and MECP2-related disorders

11.1. Introduction

11.2. Clinical aspects of Rett syndrome

11.3. Concluding remarks

Chapter 12. Focal cortical dysplasia

12.1. Introduction

12.2. Classification and pathology

12.3. Electroclinical presentation

12.4. Imaging

12.5. Etiology

12.6. Management and outcomes

12.7. Conclusion

12.8. Application

Glossary

List of acronyms and abbreviations

Chapter 13. Disorders of myelin

13.1. Introduction

13.2. Functions of myelin

13.3. Inflammatory disorders of myelin

13.4. Genetic disorders of myelin

13.5. Environmental stress-induced disorders of myelin

13.6. Therapeutics for disorders of myelin

13.7. Conclusion

List of acronyms and abbreviations

Chapter 14. Language impairments

14.1. Introduction

14.2. Language disorder and related disabilities

14.3. Behavioral features of language learning disability

14.4. Neuropathology of language disability

14.5. Candidate language disability and dyslexia susceptibility genes

14.6. Conclusions

Chapter 15. Fragile X clinical features and neurobiology

15.1. Introduction

15.2. Clinical description

15.3. Genetics and neurobiology

15.4. Testing

15.5. Targeted treatments

15.6. Behavioral interventions

15.7. Summary and future perspectives

Abbreviations

Chapter 16. Congenital and postnatal microcephalies

16.1. Introduction

16.2. Basic principles of cortical development relevant to microcephaly

16.3. Congenital microcephalies and potential mechanisms

16.4. Postnatal microcephalies and potential mechanisms

16.5. Summary

Glossary

List of acronyms and abbreviations

Index

Copyright

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Contributors

Alexej Abyzov,     Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States

Kevin Cameron Allan,     Case Western Reserve University School of Medicine, Department of Genetics and Genome Sciences, Cleveland, OH, United States

Anahita Amiri,     Child Study Center, Yale University, New Haven, CT, United States

Heather M. Brown,     Graduate Program in Cell Biology, Stem Cells and Development, University of Colorado Denver, Aurora, CO, United States

Anne L. Calof

Center for Complex Biological Systems, University of California, Irvine, CA, United States

Department of Anatomy & Neurobiology, School of Medicine, University of California, Irvine, CA, United States

Department of Developmental & Cell Biology, University of California, Irvine, CA, United States

Qiang Chang,     Waisman Center, University of Wisconsin Madison, Madison, WI, United States

Kimberly M. Christian

Department of Neuroscience, Philadelphia, PA, United States

Mahoney Institute for Neurosciences, Philadelphia, PA, United States

Benjamin L.L. Clayton,     Case Western Reserve University School of Medicine, Department of Genetics and Genome Sciences, Cleveland, OH, United States

Francesca Cucinotta,     Interdepartmental Program Autismo 0-90, Child & Adolescent Neuropsychiatry Unit, Gaetano Martino University Hospital, University of Messina, Messina, Italy

Alissa M. D'Gama

Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, United States

Departments of Neurology and Pediatrics, Harvard Medical School, Boston, MA, United States

Broad Institute of MIT and Harvard, Cambridge, MA, United States

Mathew Sean Elitt,     Case Western Reserve University School of Medicine, Department of Genetics and Genome Sciences, Cleveland, OH, United States

L. Fernandez,     University of California, San Francisco, CA, United States

R. Holly Fitch,     University of Connecticut, Department of Psychological Sciences/Behavioral Neuroscience, Storrs, CT, United States

Jeffrey A. Golden,     Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States

Laura Groves,     Cerebra Center for Neurodevelopmental Disorders, School of Psychology, University of Birmingham, Birmingham, United Kingdom

R.J. Hagerman,     University of California at Davis, MIND Institute, Sacramento, CA, United States

Eric Jaffe,     Graduate Program in Molecular Biology, University of Colorado Denver, Aurora, CO, United States

B.L. Johnson-Kerner,     University of California, San Francisco, CA, United States

Alexandre Jourdon,     Child Study Center, Yale University, New Haven, CT, United States

Arthur D. Lander

Center for Complex Biological Systems, University of California, Irvine, CA, United States

Department of Developmental & Cell Biology, University of California, Irvine, CA, United States

M.J. Leigh,     University of California at Davis, MIND Institute, Sacramento, CA, United States

Youngshin Lim,     Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States

A.H. Mahnke,     Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, Bryan, TX, United States

Jessica Mariani,     Child Study Center, Yale University, New Haven, CT, United States

Guo-li Ming

Department of Neuroscience, Philadelphia, PA, United States

Mahoney Institute for Neurosciences, Philadelphia, PA, United States

Department of Developmental and Cell Biology, Philadelphia, PA, United States

Institute for Regenerative Medicine, Philadelphia, PA, United States

Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

R.C. Miranda,     Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, Bryan, TX, United States

S.M. Mooney,     UNC Nutrition Research Institute, Department of Nutrition, University of North Carolina at Chapel Hill, Kannapolis, NC, United States

Jeffrey L. Neul,     Vanderbilt Kennedy Center, Nashville, TN, United States

Zachary Scott Nevin,     Case Western Reserve University School of Medicine, Department of Genetics and Genome Sciences, Cleveland, OH, United States

Lee Niswander,     University of Colorado Boulder, Department of Molecular, Cellular and Developmental Biology, Boulder, CO, United States

Christopher Oliver,     Cerebra Center for Neurodevelopmental Disorders, School of Psychology, University of Birmingham, Birmingham, United Kingdom

Antonio M. Persico,     Interdepartmental Program Autismo 0-90, Child & Adolescent Neuropsychiatry Unit, Gaetano Martino University Hospital, University of Messina, Messina, Italy

Sofia A. Pezoa,     Graduate Program in Cell Biology, Stem Cells and Development, University of Colorado Denver, Aurora, CO, United States

Christina Pyrgaki,     The Rockefeller University, Biological Imaging Resource Center, New York, NY, United States

Lawrence T. Reiter

Department of Neurology, UTHSC, Memphis, TN, United States

Department of Pediatrics, UTHSC, Memphis, TN, United States

Department of Anatomy and Neurobiology, UTHSC, Memphis, TN, United States

Arianna Ricciardello,     Interdepartmental Program Autismo 0-90, Child & Adolescent Neuropsychiatry Unit, Gaetano Martino University Hospital, University of Messina, Messina, Italy

Edward Rubenstein,     Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States

Mustafa Sahin

Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States

Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States

Rosaysela Santos,     Department of Pathology, Anatomy, & Laboratory Medicine, School of Medicine, West Virginia University, Morgantown, WV, United States

Soraya Scuderi,     Child Study Center, Yale University, New Haven, CT, United States

E.H. Sherr,     University of California, San Francisco, CA, United States

Hongjun Song

Department of Neuroscience, Philadelphia, PA, United States

Mahoney Institute for Neurosciences, Philadelphia, PA, United States

Department of Developmental and Cell Biology, Philadelphia, PA, United States

Institute for Regenerative Medicine, Philadelphia, PA, United States

Institute for Epigenetics, Philadelphia, PA, United States

Siddharth Srivastava,     Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States

Paul J. Tesar,     Case Western Reserve University School of Medicine, Department of Genetics and Genome Sciences, Cleveland, OH, United States

Laura Turriziani,     Interdepartmental Program Autismo 0-90, Child & Adolescent Neuropsychiatry Unit, Gaetano Martino University Hospital, University of Messina, Messina, Italy

Flora M. Vaccarino

Child Study Center, Yale University, New Haven, CT, United States

Department of Neuroscience, Yale University, New Haven, CT, United States

Christopher A. Walsh

Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, United States

Departments of Neurology and Pediatrics, Harvard Medical School, Boston, MA, United States

Broad Institute of MIT and Harvard, Cambridge, MA, United States

Feinan Wu,     Child Study Center, Yale University, New Haven, CT, United States

Eunice Y. Yuen,     Child Study Center, Yale University, New Haven, CT, United States

Chapter 1

Neurocutaneous disorders

Siddharth Srivastava ¹ , and Mustafa Sahin ¹ , ²       ¹ Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States      ² Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States

Abstract

This chapter will cover neurocutaneous disorders, which are genetic disorders associated with cutaneous manifestations as well as varying presentations of neurological, developmental, and systemic features. Neurofibromatoses in particular are associated with increased prevalence of certain types of cancers affecting the central and peripheral nervous system. There are three types of neurofibromatoses: neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis. Tuberous sclerosis complex is characterized by tissue overgrowths affecting multiple organ systems, accompanying a complex and diverse neurodevelopmental profile. All four disorders have distinct genetic causes, and insight into mechanisms of disease for each has paved the way for potential targeted therapeutics.

Keywords

Mechanistic target of rapamycin; mTOR; Neurofibromatosis; Schwannomatosis; Tuberous sclerosis complex

1.1 Introduction

1.2 Neurofibromatosis type 1

1.2.1 Introduction

1.2.2 Diagnosis

1.3 Clinical features

1.3.1 Neurofibromas

1.3.2 Malignant peripheral nerve sheath tumors

1.3.3 Optic pathway gliomas

1.3.4 Cognition and behavior

1.3.5 Dermatological features

1.3.6 Ophthalmological findings

1.3.7 Cardiovascular features

1.3.8 Skeletal features

1.3.9 Genetics

1.3.10 Mechanisms

1.3.11 Targeted treatments

1.4 Neurofibromatosis type 2

1.4.1 Introduction

1.4.2 Diagnosis

1.5 Clinical features

1.5.1 Vestibular schwannomas

1.5.2 Meningiomas

1.5.3 Spinal cord tumors

1.5.4 Peripheral neuropathy

1.5.5 Ophthalmological features

1.5.6 Dermatological features

1.5.7 Pediatric presentation

1.5.8 Genetics

1.5.9 Mechanisms

1.5.10 Targeted treatments

1.6 Schwannomatosis

1.6.1 Introduction

1.6.2 Diagnosis

1.7 Clinical features

1.7.1 Schwannomas

1.7.2 Meningiomas

1.7.3 Pain

1.7.4 Genetics

1.7.5 Mechanisms

1.7.6 Targeted treatments

1.8 Tuberous sclerosis complex

1.8.1 Introduction

1.8.2 Diagnosis

1.9 Clinical features

1.9.1 Neurological features

1.9.2 Dermatological features

1.9.3 Ophthalmological features

1.9.4 Cardiac features

1.9.5 Pulmonary features

1.9.6 Renal features

1.9.7 Genetics

1.9.8 Mechanisms

1.9.9 Targeted treatments

References

1.1. Introduction

This chapter will cover neurocutaneous disorders, which are genetic disorders associated with cutaneous manifestations as well as varying presentations of neurological, developmental, and systemic features. Neurofibromatoses in particular are associated with increased prevalence of certain types of cancers affecting the central and peripheral nervous system. There are three types of neurofibromatoses: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. Tuberous sclerosis complex (TSC) is characterized by tissue overgrowths affecting multiple organ systems, accompanying a complex and diverse neurodevelopmental profile. All four disorders have distinct genetic causes, and insight into mechanisms of disease for each has paved the way for potential targeted therapeutics.

1.2. Neurofibromatosis type 1

1.2.1. Introduction

NF1 is an autosomal dominant genetic syndrome associated with a spectrum of neurological and systemic features (Jett and Friedman, 2010). The estimated prevalence of this disorder is 1 in ∼5000, while the estimated incidence is ∼1 in 3000 (Evans et al., 2010). The disorder is due to pathogenic variants in NF1 (neurofibromin; located on chromosome 17q11.2) that cause loss of function in the gene. Although the range of symptoms is widespread, some of the characteristic manifestations are cutaneous neurofibromas, multiple café au lait macules, axillary and inguinal freckling, Lisch nodules (iris hamartomas), and learning disabilities (Jett and Friedman, 2010).

1.2.2. Diagnosis

There are established criteria for the clinical diagnosis of NF1, based on a consensus development conference by the National Institutes of Health in 1998. The diagnosis is based on the presence of at least two of the following features:

(a) at least six café au lait macules (with diameter >5mm before puberty and >15mm after puberty)

(b) at least two neurofibromas (of any type) or at least one plexiform neurofibroma

(c) freckling (axillary or inguinal)

(d) optic glioma

(e) at least two Lisch nodules (iris hamartomas)

(f) skeletal dysplasia (i.e., sphenoid dysplasia or tibial pseudoarthrosis)

(g) a first-degree relative with NF1 (Gutmann et al., 1997; Neurofibromatosis. NIH Consensus Statement 1987 Jul 13–15, 6(12), 1–19, https://consensus.nih.gov/1987/1987Neurofibramatosis064html.htm).

Confirmation with sequencing and deletion/duplication analysis of NF1 can support the diagnosis, but it is not required (Friedman, 1993). Genetic testing may be helpful if an individual meets only one of the two diagnostic criteria (Radtke et al., 2007).

1.3. Clinical features

1.3.1. Neurofibromas

Neurofibromas are neoplasms affecting peripheral nerve sheathes. They are composed of mixture of cell types including Schwann cells, perineurial cells, and fibroblasts (Jouhilahti et al., 2011). They appear as multiple types: dermal neurofibromas (also called discrete neurofibromas), spinal neurofibromas, and plexiform neurofibromas (Cimino and Gutmann, 2018). Dermal neurofibromas grow from peripheral cutaneous nerves, with age of onset in affected individuals sometime during late childhood and adolescence. After this period of time, there can be continued appearance of these lesions throughout life (Korf, 2002), sometimes numbering in the thousands (Friedman, 1993). Dermal neurofibromas usually do not require resection unless they cause issues such as significant pain or functional impairment (Ferner et al., 2007). Spinal neurofibromas affect the spine, causing symptoms such as spinal cord compression and kyphotic deformity in NF1. This may lead to progressive neurological deficits that warrant surgical management (Taleb et al., 2011).

The third subtype of neurofibromas is plexiform neurofibromas, which affect longitudinal segments of nerves and their branches (Korf, 2002). These lesions affect 56% of NF1 patients, based on a study involving whole-body magnetic resonance imaging (MRI) (Mautner et al., 2008); the percentage of individuals with NF1 who have clinically detectable plexiform neurofibromas is about half of this number (Huson et al., 1988). Unlike dermal neurofibromas, which are encapsulated, plexiform neurofibromas are unencapsulated, which allows them to disrupt normal tissue development (Radtke et al., 2007). Symptoms may be due to compression of nerves or soft tissue, and skin covering plexiform neurofibroma may have pigmentary changes and abnormal hair growth (Cimino and Gutmann, 2018). Resection of plexiform neurofibromas can be challenging because of how integrated these lesions become with nearby structures and vasculature, and significant bleeding can be a complication from surgical removal, especially of facial plexiform neurofibromas (Ferner et al., 2007). Although plexiform neurofibromas are benign, one of the significant complications of these lesions is the increased risk for transformation into malignant peripheral nerve sheath tumors (Ferner and Gutmann, 2002).

1.3.2. Malignant peripheral nerve sheath tumors

Malignant peripheral nerve sheath tumors carry a significant risk for adverse outcomes. These malignant neoplasms can present with pain, focal neurological deficits, and systemic symptoms such as weight loss (Ferner and Gutmann, 2002). Commonly, they arise in the abdominal paraspinal regions, extremities, and head and neck (Radtke et al., 2007). In NF1, the lifetime risk for developing malignant peripheral nerve sheath tumors is 8%–13% (Evans et al., 2002). Not only are they difficult to discover, but also they are associated with negative outcomes (Ferner and Gutmann, 2002). Treatment of these malignancies requires total resection and adjuvant radiotherapy (Ferner et al., 2007).

1.3.3. Optic pathway gliomas

Optic pathway gliomas are a significant concern for affected individuals, especially children with NF1 (Fig. 1.1). Typically, they are pilocytic astrocytomas which affect the optic nerve and/or chiasm in one eye or both eyes. In a prospective cohort of 217 individuals with NF1, 33/217 (15%) had gliomas of the optic nerve and/or chiasm (Lewis et al., 1984). Although optic pathway gliomas may be asymptomatic in NF1, they can also cause complications such as vision loss, proptosis, optic disk atrophy, and precocious puberty (Guillamo et al., 2003; Thiagalingam et al., 2004). Children with NF1 who are younger than 7 years old are at increased risk for having optic pathway gliomas that cause symptoms (Listernick et al., 1997). Given the indolent nature of these lesions, close monitoring without intervention may be sufficient, unless they start to cause symptoms such as progressive visual loss or proptosis. When indicated, treatment is usually with chemotherapy (vincristine and cisplatinum), although surgical debulking may be necessary in certain circumstances, such as significant proptosis or widespread involvement. In children, radiotherapy can lead to secondary cancers, neurodevelopmental impairment, vascular damage (moyamoya angiopathy), and endocrine dysfunction, so it is avoided if possible for treatment of optic pathway gliomas (Ferner et al., 2007; Ullrich et al., 2007).

1.3.4. Cognition and behavior

The neurodevelopmental profile of NF1 is characterized by variable deficits in cognition, learning, and behavior. Formal neuropsychological testing and educational assessment should be part of the care for an individual affected by NF1. Management of these deficits, which are further delineated below, is the same as in the general population.

Figure 1.1 Mixed cystic and solid mass (arrow) involving the optic chiasm, hypothalamus, optic tracts, and optic radiation, reflecting an optic tract glioma.

The cognitive profile of NF1 is characterized by low average to average full-scale IQ. In one study, the average full-scale IQ of affected individuals was 88.6 (compared to 101 among controls who were matched for age, sex, and socioeconomic status) (Ferner et al., 1996). Likewise, affected individuals have lower full scale IQs than their unaffected siblings (Eldridge et al., 1989). About 6% of individuals with NF1 may have intellectual disability, defined by a full-scale IQ <70 (Hyman et al., 2005). In contrast to NF1 as a whole, those with a large NF1 deletion have a higher prevalence of intellectual disability (38%) (Mautner et al., 2010a).

About one in five children with NF1 has a specific learning disability, defined as a discrepancy in achievement in an academic subject compared to an individual's full cognitive potential. However, more than half of children with NF1 have impairments in reading, mathematics, and spelling. Other challenges noted on neuropsychological testing conduced on individuals with NF1 include impairments in perceptual skills, executive functioning, and attention (Hyman et al., 2005).

Attention deficit hyperactivity disorder and other behavioral concerns are common in children with NF1. Attention deficit hyperactivity disorder occurs in close to 40% of children with NF1, although an even greater percentage of affected individuals may have attentional concerns (Hyman et al., 2005). Autism spectrum disorder has a higher prevalence among children with NF1, affecting 11% (Eijk et al., 2018), compared to a prevalence of 1%–2% in the general population.

1.3.5. Dermatological features

Café au lait macules are one of the characteristic dermatological features of NF1. Café au lait macules are typically ovaloid, uniformly hyperpigmented lesions 1–3   cm in size. Apart from the palms or soles, they can affect any part of the body (Friedman, 1993). Café au lait macules are seen in more than 90% of individuals with NF1 (Corsello et al., 2018). These lesions can be one of the first manifestations of NF1, appearing during infancy and growing in number until about 2 years of age (Korf, 2002).

Axillary and inguinal freckling is another characteristic dermatological manifestation of NF1. They resemble smaller, clustered versions of café au lait macules. By age 7 years, up to 90% of children with NF1 may have axillary or inguinal freckling (DeBella et al., 2000). In affected individuals, they start to emerge at 3–5 years of age. There may be a typical progression of appearance of the freckling, starting with the inguinal area, followed by the neck, face, and underneath the breasts in females (Korf, 2002).

1.3.6. Ophthalmological findings

Ophthalmological manifestations of NF1 include Lisch nodules and choroidal abnormalities. Lisch nodules are raised, pale brown hamartomatous lesions affecting the iris. The prevalence of Lisch nodules in NF1 increases with age: about half of 5-year-old children with NF1 have Lisch nodules, while nearly all affected adults over 30 years of age have these lesions (Ragge et al., 1993). Lisch nodules do not impact vision in NF1 (Lewis and Riccardi, 1981). They require slit lamp examination for proper detection (Radtke et al., 2007). Choroidal nodules consist of hyperplastic Schwann cells organized around axons. They may be difficult to detect with routine ophthalmological examination, requiring alternative modalities such as near-infrared reflectance imaging (Viola et al., 2012).

1.3.7. Cardiovascular features

NF1 is associated with a vasculopathy which can manifest in different forms. Stenoses, occlusions, aneurysms, pseudoaneurysms, and fistulas can occur, affecting small to large vessels in both the arterial and venous circulation (Friedman et al., 2002). There can be stenoses/occlusions of vessels in the cerebrovascular system, including the internal carotid artery, middle cerebral artery, and anterior cerebral artery (Friedman, 1993), which may lead to collateralization of blood vessels around the areas of stenosis—so-called moyamoya angiopathy—and subsequent strokes (Koss et al., 2013). Renal artery dysplasia is an example of NF1-related vasculopathy outside of the cerebrovascular system (Friedman et al., 2002).

There is an increased prevalence of congenital heart defects in NF1. Pulmonary stenosis and, to a smaller extent, aortic coarctation are two types of congenital heart defects seen in NF1 (Lin et al., 2000). Pulmonary hypertension is a serious health consideration in NF1, especially for older, female affected individuals (Montani et al., 2011).

Affected individuals are at risk for hypertension, which can occur throughout the lifespan (Friedman et al., 2002). In children with NF1, hypertension may be secondary to renovascular disease, such as renal artery stenosis (Fossali et al., 2000).

1.3.8. Skeletal features

Up to 20% of individuals with NF1 have scoliosis (Vitale et al., 2002). Scoliosis associated with NF1 has two presentation types: a dystrophic type, which has a quick rate of progression, and a nondystrophic type, which has a much slower rate of progression. One contributing factor to the development of dystrophic scoliosis is the presence of a paraspinal neurofibroma encroaching on an adjacent vertebra. In contrast, nondystrophic scoliosis in NF1 has similar characteristics as idiopathic scoliosis seen in the general population, although it may transform into dystrophic scoliosis (Elefteriou et al., 2009).

Dysplasia of long bones affects 3%–4% of individuals with NF1, and this commonly affects the tibia and fibula (Fig. 1.2). In NF1, manifestations of long bone dysplasia include the presence of fracture or pseudarthrosis (false joint anomaly) around the time of birth, as well as bowing of the affected extremity in infancy. Dysplasia of long bones can predispose affected individuals to fractures in early childhood due to even mild injury, which can result in pseudoarthrosis. Bracing may be helpful for dyplasia of long bones in NF1, to prevent fractures. If pseudarthrosis occurs, management can be challenging, sometimes requiring multiple surgical interventions (Elefteriou et al., 2009).

Sphenoid wing dysplasia—one of the diagnostic criteria for NF1—is characterized by underdevelopment of the sphenoid wing. This finding affects 3%–7% of individuals with NF1 (Radtke et al., 2007). Typically, sphenoid wing dysplasia does not cause symptoms (Alwan et al., 2005). When symptomatic, it can lead to distortion of the bony architecture in the surrounding orbit. Herniation of the temporal lobe can be a consequence, manifesting as exophthalmos (Jacquemin et al., 2003).

Impaired bone mineral metabolism remains a strong concern for individuals with NF1. There is a high prevalence of both osteopenia, affecting 44% of patients, and osteoporosis, affecting 18% of patients (Petramala et al., 2012). The mechanisms leading to altered bone health in NF1 are not entirely clear, but several factors may be implicated, such as hypomineralization as well as altered osteocyte porosity and matrix formation (Kühnisch et al., 2014).

1.3.9. Genetics

Up to 95% of cases may have a pathogenic germline variant in NF1 (which encodes neurofibromin protein), constituting a wide spectrum of variant types. Examples of reported intragenic pathogenic variants include nonsense, frameshift, splice site, and missense variants, as well as small in-frame deletions (Messiaen et al., 2000). Although the majority of cases are due to intragenic pathogenic variants, up to 10% of affected individuals may have microdeletions that contain NF1 as well as a number of other surrounding genes (Pasmant et al., 2010; Kluwe et al., 2004). A small fraction of cases may be due to translocations such as t(14;17) (q32;q11.2) (Messiaen et al., 2000). Individuals affected by localized, as opposed to generalized, features of NF1 may have somatic mosaicism (García-Romero et al., 2016).

Figure 1.2 Anterolateral tibial dysplasia (arrow) of tibia and fibula in 5-year-old boy with neurofibromatosis type 1.

In general, NF1 is characterized by a high level of intrafamilial and interfamilial variable expressivity (Friedman, 1993). However, a small number of studies have highlighted specific genotype–phenotype correlations. For example, the presence of a 3-bp, in-frame deletion of NF1 (c.2970-2972 delAAT) confers reduced likelihood of developing cutaneous neurofibromas or plexiform neurofibromas (Upadhyaya et al., 2007). The NF1 missense variant, c.5425C>T (p.Arg1809Cys), is linked to a milder phenotype characterized by lack of development of neurofibromas, Lisch nodules, osseous lesions, and symptomatic optic gliomas (Pinna et al., 2015). Pathogenic missense variants affecting the residues Leu844, Cys845, Ala846, Leu847, and Gly848 may lead to more severe disease (Koczkowska et al., 2018). Individuals with microdeletions encompassing NF1 may have greater risk of complications such as learning disabilities and dysmorphic facial features (Pasmant et al., 2010).

1.3.10. Mechanisms

The NF1 gene is large, comprising 335   kb and 60 exons, and it encodes a polypetide with 2818 amino acids (Gutmann et al., 1991). Out of the 60 exons contained within the gene, several undergo alternative splicing (Barron and Lou, 2012). Furthermore, within one of its intronic segments, NF1 contains three genes (EVI2A (Cawthon et al., 1990), EVI2B (Cawthon et al., 1991), and OMGP (Viskochil et al., 1991)) whose function and impact on NF1 itself remain under investigation.

NF1 is expressed in multiple cell types, especially those located in the central and peripheral nervous system. NF1 is highly expressed in neurons, oligodendrocytes, and Schwann cells (Daston et al., 1992). Moreover, NF1 is expressed in neural crest derivatives (Gitler et al., 2003), which include cutaneous pigment cells, craniofacial bones, and parts of the peripheral nervous system—tissue types impacted in NF1.

Neurofibromin has several key functional domains. Exons 11–17 encode the CSRD (cysteine and serine-rich domain), which contains a MAP (microtubule-associated protein) domain. The CSRD is involved in actin binding. Exons 21–27 encode the GRD (Ras GTPase-activating protein related domain), essential for its action on Ras GTPase, which converts Ras-GTP (active form) into Ras-GDP (inactive form). Exons 28 and 32 encode two CBDs (caveolin-1 binding domains), which associate with caveolin-1. The complex consisting of neurofibromin and caveolin-1 regulates downstream effectors like protein kinase C and p21ras (Barron and Lou, 2012).

Effectively, neurofibromin plays a critical role in regulating two important downstream signaling pathways: the Ras-GAP (guanosine triphosphatase (GTPase)–activating protein) pathway and the cAMP-PKA (cyclic adenosine 3′,5′-monophosphate–protein kinase A) pathway. Typically, activation of RTK (receptor tyrosine kinase) induces phosphorylation of Ras-GDP, converting it into Ras-GTP. In opposition of this process, neurofibromin stimulates the activity of Ras GTPase, which converts Ras-GTP into Ras-GDP, rendering Ras inactive (Diggs-Andrews and Gutmann, 2013). Because neurofibromin inhibits Ras signaling, NF1-associated loss of function variants in neurofibromin lead to overactivity of the Ras signaling pathway (Fig. 1.3), which has downstream implications on cell growth and differentiation (Simanshu et al., 2017) as well as various facets of cognition, learning, and memory (Diggs-Andrews and Gutmann, 2013). Downstream targets of Ras signaling include MAPK (mitogen-activated protein kinase)/ERK (extracellular signal–regulated kinase) and PI3K (phosphoinositide 3-kinase)/AKT/mTOR (mammalian target of rapamycin) signaling (Yap et al., 2014).

Neurofibromin also regulates the cAMP–PKA pathway. Specifically, neurofibromin promotes activity of adenylyl cyclase (Tong et al., 2002), which is the precursor to intracellular cAMP. In murine models of NF1, levels of cAMP are reduced in astrocytes (Dasgupta et al., 2003). PKA has a number of downstream targets, including enzymes involved in cellular metabolism, as well as other signaling pathways (Sassone-Corsi, 2012).

A double-hit model may be responsible for tumorigenesis in NF1, based on multiple lines of evidence. Early studies showed there was somatic loss of function of NF1 in tumor tissue in individuals with NF1 with peripheral nerve sheath tumors (Legius et al., 1993) and neurofibromas (Serra et al., 2000). In mice with germline copies of only one functional Nf1 allele, conditional knockout of the other Nf1 allele in Schwann cells resulted in the development of neurofibromas (Zhu et al., 2002). In humans with NF1, loss of heterozygosity (LOH) causing inactivation of NF1 in somatic cells is a significant factor for this double-hit model of tumorigenesis. LOH may be due to interstitial deletions affecting chromosome 17q or mitotic recombination leading to isodisomy of 17q (Garcia-Linares et al., 2011).

Additional factors may contribute to neoplastic proliferation in NF1. One such factor is upregulation of cell growth signaling pathways induced by neurofibromin loss. In a study analyzing astrocytoma tissue and unaffected white matter from an individual with NF1, the tumor demonstrated loss of neurofibromin expression, coupled with increased levels of Ras-GTP as well as evidence of increased Raf-MAPK and PI3K/Akt signaling (Lau et al., 2000). In addition, reduced NF1 expression may lead to enhanced astrocyte growth as one of the steps in tumor development (Gutmann et al., 1999). Based on data from a rat model, Nf1 is overexpressed in response to cerebral ischemia (Giordano et al., 1996), inhibiting factors that lead to growth and differentiation (Cichowski and Jacks, 2001). Therefore, loss of NF1 may disrupt the typical cascade of events unleashed after injury, and this altered response may play a role in astrocyte generation.

Figure 1.3 Signaling pathways involving NF1, NF2, and TSC1/TSC2.

Apart from tumorigenesis, one of the primary manifestations of NF1 is neurodevelopmental impairments, which may be due in part to reduced synaptic plasticity (Mainberger et al., 2016). In Nf1 +/− mice, there are deficits in long-term potentiation related to enhanced GABA-mediated inhibition. Interestingly, administration of a farnesyl transferase inhibitor, which blocks farnesylation and reduces Ras signaling, reversed some of these deficits (Costa et al., 2002). In a study of humans with NF1 compared to healthy controls, paired associative stimulation led to a rise in motor-evoked potential amplitudes in the controls, but not the affected individuals, suggesting an impairment in synaptic plasticity (Mainberger et al., 2013).

1.3.11. Targeted treatments

Better understanding of the pathophysiology of NF1 has led to clinical trials targeting various pathways, although results have been mixed. Simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, has been of interest in NF1. HMG-CoA reductase inhibitors decrease cholesterol, which is necessary for production of farnesyl, which in turn facilitates binding of Ras to the plasma membrane and its subsequent activation by various extracellular signals. Therefore, use of simvastatin may in theory target the overactive Ras signaling seen in NF1. However, a randomized, placebo-controlled clinical trial of 12 months of simvastatin in children with NF1 failed to show improvement in full-scale IQ, attentional issues, or internalizing behavioral problems (van der Vaart et al., 2013).

Plexiform neurofibromas in NF1 have been the subject of therapeutic trials targeting mTOR and MAPK signaling. Clinical trials examining the use of the mTOR inhibitor rapamycin (sirolimus) did not show an improvement in tumor size for nonprogressive plexiform neurofibromas (Weiss et al., 2014) but did modestly increase time to progression in cases of progressive plexiform neurofibromas (Weiss et al., 2015). A phase 1 clinical trial for children with NF1 and inoperable plexiform neurofibromas revealed that treatment with selumetinib, an inhibitor of MAPK kinase (MEK) 1 and 2, decreased tumor volume in more than 70% of the cohort (Dombi et al., 2016). In early 2018, selumetinib received orphan drug designation from the Food and Drug Administration (FDA) for use in individuals with NF1.

1.4. Neurofibromatosis type 2

1.4.1. Introduction

NF2 is associated with the development of specific tumor types in the nervous system, especially vestibular schwannomas, along with characteristic ocular and dermatological findings. The prevalence of this syndrome is about 1:60,000 (Evans et al., 2010), and the incidence at birth is about 1:33,000 (Evans, 1993).

1.4.2. Diagnosis

Diagnosis of NF2 is based on fulfillment of consensus diagnostic criteria and/or detection of a pathogenic variant in NF2. The current Baser criteria is a modification of, and improvement over, previous diagnostic criteria. To arrive at a clinical diagnosis of NF2, an individual must have at least one of the following:

(a) bilateral vestibular schwannomas

(b) a first-degree relative with NF2, as well as either

(i) unilateral vestibular schwannoma or

(ii) any two NF2-associated clinical features (meningioma, schwannoma, glioma, neurofibroma, and posterior subcapsular or cortical cataract)

(c) unilateral vestibular schwannoma and any two NF2-associated clinical features (meningioma, schwannoma, glioma, neurofibroma, and posterior subcapsular or cortical cataract)

(d) multiple meningiomas and either

(i) unilateral vestibular schwannoma or

(ii) any two NF2-associated clinical features (schwannoma, glioma, neurofibroma, and posterior subcapsular or cortical cataract) (Baser et al., 2011; Evans, 1993).

Individuals suspected of having NF2 should undergo sequencing and deletion/duplication analysis of NF2.

1.5. Clinical features

1.5.1. Vestibular schwannomas

The most common presentation of NF2 is the development of bilateral vestibular schwannomas, which are usually benign neoplasms that develop from Schwann cells. In NF2, schwannomas most commonly affect the vestibular branch of the vestibulocochlear nerve (cranial nerve VIII) (Evans, 1993), although they can affect other cranial nerves (close to 30% of affected individuals have trigeminal schwannomas (Mautner et al., 1996)), as well as spinal and peripheral nerves (Evans, 2009b). Affected individuals can present with varying combinations of hearing loss, tinnitus, and dizziness/unsteadiness (Evans, 2009b); symptoms of hearing loss and tinnitus can be unilateral at first (Asthagiri et al., 2009).

Definite treatment of vestibular schwannomas is surgery, but the risks of the intervention itself heavily influence if/when to proceed with surgery. With surgery, there is a risk for injuring the facial nerve (Asthagiri et al., 2009), which can lead to problems with blinking or tearing that may exacerbate existing ophthalmological manifestations of NF2. Over time, vestibular schwannomas may expand into the brainstem, causing compression of this structure and hydrocephalus. Thus, indications for removal of vestibular schwannomas include significant lesion growth, impact on hearing, and/or impact on the facial nerve (Evans, 2009a). For those individuals with NF2 in whom surgery is indicated for vestibular schwannomas, one specific surgical modality that may be safe and effective is stereotactic radiosurgery (Mathieu et al., 2007).

After removal of vestibular schwannomas, if hearing is compromised, then cochlear implantation and auditory brainstem implantation are interventions to potentially restore hearing. If the affected individual has significant hearing loss, but has an anatomically intact cochlear nerve not impacted during surgery, then cochlear implantation may result in improved hearing, even years after surgery (Neff et al., 2007). However, if the cochlear nerve is disrupted, then auditory brainstem implantation is a safe means of improving auditory function, although the outcomes can be unpredictable compared to cochlear implantation (Sanna et al., 2012).

1.5.2. Meningiomas

Meningiomas are present in 58% of individuals with NF2 (Mautner et al., 1996), affecting the intracranial space and the intradural extramedullary spinal compartment. Symptoms of meningiomas are due to factors such as size and anatomical location. Just as large meningiomas in the cerebral convexity can produce neurological deficits, so do can smaller tumors in close proximity to important intracranial structures such as the optic nerve sheath and skull base (Asthagiri et al., 2009). In addition to the symptoms they cause, meningiomas confer an approximately 2.5× increased relative risk of mortality in individuals with NF2 (Baser et al., 2002). Treatment of meningiomas is surgical resection, which is usually safe; however, if the lesion infiltrates cranial nerves or other anatomically precarious locations, then there is increased risk for adverse outcomes (Asthagiri et al., 2009). If the meningioma is not easily resectable, radiation therapy (Shaikh et al., 2018) and stereotactic radiosurgery (Liu et al., 2015) may be alternative treatment options, although there is need for long-term data on safety and efficacy of these interventions.

1.5.3. Spinal cord tumors

Spinal cord tumors affect up to 90% of individuals with NF2 (Mautner et al., 1995). Examples of extramedullary spinal tumors seen in NF2 include schwannomas and meningiomas, while examples of intramedullary tumors are ependymomas, astrocytomas, and schwannomas (Patronas et al., 2001). Symptoms of spinal cord tumors can include back pain, muscle weakness, and paresthesias (Asthagiri et al., 2009).

1.5.4. Peripheral neuropathy

Peripheral neuropathy is a common complication affecting individuals with NF2. In one study of 15 individuals with NF2, 7/15 (47%) had clinical evidence of motor/sensory distal peripheral neuropathy, while 10/15 (67%) had electrophysiological evidence of peripheral neuropathy, particularly axonal neuropathy (Sperfeld et al., 2002). The cause of this peripheral neuropathy is not necessarily related to mass effect from compressive tumor. If the cause of the neuropathy is not related to the presence of a tumor, then treatment is supportive addressing pain and comfort (Asthagiri et al., 2009).

1.5.5. Ophthalmological features

Decreased visual acuity is a notable concern for individuals by NF2, especially for those with childhood-onset disease. In a retrospective observational case series which consisted of individuals with NF2 who underwent initial (n   =   30) and follow-up (n   =   23) neuro-ophthalmological examinations, 2/14 (14%) of individuals with childhood-onset NF2 had visual acuity of 1.0 in both eyes by the end of the study, in contrast to 7/9 (78%) of individuals with adult-onset NF2 (Bosch et al., 2006).

One factor which may contribute to progressive visual difficulties in NF2 is the development of tumors in the visual pathway. A retrospective analysis found that 73/467 (16%) of individuals with NF2 had tumors residing next to the anterior visual pathway, potentially impairing vision. Among these 73 individuals, intraorbital tumors were present in 31/73 (42%), suprasellar meningiomas were present in 21/73 (29%), and sphenoid ridge meningiomas were present in 21/73 (29%). The intraorbital tumors consisted of, in decreasing order of frequency, optic nerve sheath meningiomas, intraorbital schwannomas, spheno-orbital meningiomas, anterior cranial fossa-orbital meningiomas, and cranio-orbital schwannomas. Vision loss was present in 43/73 (59%) of the cohort. Early detection and surgical resection of these lesions may help prevent progressive vision deterioration; however, one exception is optic nerve sheath meningiomas. Optic nerve sheath meningiomas become intertwined with the optic nerve and its vasculature; therefore, surgical removal is difficult and can lead to vision complications such as blindness (Li et al., 2017).

Retinal manifestations are commonplace in individuals with NF2. In one study of 48 individuals with NF2, retinal complications affected 25/48 or more than half of the subjects. Specifically, 17/48 (35%) had epiretinal membranes (semitranslucent membranes found on the inner retina); 24/48 (50%) had retinal microaneurysms; 19/48 (40%) had intraretinal fluorescein leakage; and 3/48 (6%) had retinal hamartomas (slightly raised malformations of retinal and epiretinal tissue) including one individual who had combined pigment epithelial and retinal hamartoma (Feucht et al., 2008). Epiretinal membranes (Asthagiri et al., 2009) and retinal microaneurysms (Feucht et al., 2008) usually do not contribute to vision loss in NF2. Retinal hamartomas, on the other hand, can impact vision in NF2 (Asthagiri et al., 2009). In light of these findings, retinal evaluation should be part of the annual ophthalmological exam for surveillance purposes in individuals with NF2.

In addition to retinal abnormalities, cataracts—including posterior subcapsular cataracts, cortical cataracts, and mixed posterior subcapsular/cortical cataracts—occur in up to about 83% of affected individuals (Feucht et al., 2008). Due to their diminutive size and peripheral location within the lens of the eye, cortical wedge cataracts may require careful investigation by an ophthalmologist for appropriate discovery. When cataracts impact vision, which can happen in up to 25% of cases of NF2, they may require removal (Asthagiri et al., 2009).

1.5.6. Dermatological features

The dermatological manifestations of NF2 include skin plaques, subcutaneous tumors, and intradermal tumors. Skin tumors predominate in NF2. In a case series of 88 individuals with NF2, 52/88 (59%) had cutaneous tumors (Mautner et al., 1997). NF2 plaques are intracutaneous, minimally raised, hyperpigmented, and hypertrichotic lesions (Ruggieri et al., 2015). Subcutaneous tumors are nodular or spindle-shaped tumors that are often palpable and occur along peripheral nerves. Finally, intradermal tumors include cutaneous schwannomas and, to a lesser extent, neurofibromas (Evans, 2009b).

1.5.7. Pediatric presentation

The pediatric presentation of NF2 differs from adult presentation of NF2. In a retrospective review of a pediatric tumor registry data from the United Kingdom, 18% of 334 patients with NF2 had initial symptom onset on or before 15 years of age. Of the 30 children with NF2 who presented with symptoms on or before 10 years of age, 8/30 or 26% had vestibular schwannoma as their NF2 feature (not including an additional 2 individuals with question of vestibular schwannoma), in contrast to adults with NF2, in whom vestibular schwannoma is the first sign of the disorder in a majority of patients. In this NF2 pediatric cohort ≤10   years of age, 12/30 (40%) had meningioma as NF2 feature; 3/10 (10%) had spinal schwannoma; and 1/30 (3%) had cutaneous schwannoma. Some of these affected children with vestibular schwannoma presented initially with facial paralysis, but in a subset of cases, there was a long period of time, up to 15   years, between facial paralysis that did not completely recover and eventual diagnosis of vestibular schwannoma, suggesting mononeuropathy as the cause (Evans et al., 1999). Furthermore, some children with NF2 may develop polio-like lower limb atrophy (Evans, 2009b). Ophthalmologic features associated with pediatric presentations of NF2 include cataracts, retinal hamartomas, and strabismus or amblyopia. Sometimes children with NF2 can develop NF2 skin plaques as described above (Ruggieri et al., 2015).

1.5.8. Genetics

NF2 is transmitted in an autosomal dominant fashion and results from germline pathogenic variants in the NF2 (merlin) gene, which is located on chromosome 22q12.2 (Rouleau et al., 1993). There is nearly complete penetrance with the disorder (by some estimates, >95% (Kanter et al., 1980)), and interfamilial variability is more common than intrafamilial variability (Evans, 1993). About half of cases result from de novo variants, with somatic mosaicism responsible for up to 30% of sporadic cases (Evans, 1993; Evans et al., 2007).

A number of research studies have highlighted various genotype–phenotype correlations in NF2 pertaining to clinical measures. A decreased number of intracranial meningiomas, spinal tumors, and peripheral nerve tumors is related to the presence of somatic mosaicism or certain types of germline pathogenic NF2 variants (splice site, missense, or large deletions), as opposed to nonsense or frameshift NF2 variants (Baser et al., 2004). Specifically, the prevalence of spinal tumors is increased in those with germline frameshift or nonsense pathogenic variants in NF2 (Dow et al., 2005). In NF2, the location of the pathogenic variant within the gene influences the predilection for developing meningioma: individuals with pathogenic variants in the 5′ half of NF2 have an increased likelihood of developing cranial meningiomas, compared to those with pathogenic variants in the 3′ portion of the gene (Smith et al., 2011). Furthermore, relative mortality risk in NF2 is lower in individuals who have a germline pathogenic missense variant, compared to those with germline pathogenic nonsense variants, frameshift variants, splice site variants, or large deletions (Baser et al., 2002).

1.5.9. Mechanisms

NF2 encodes the protein merlin. Merlin contains 595 amino acids, and its secondary structures comprise three parts: an N-terminal FERM domain (4.1 protein/ezrin/radixin/moesin), which itself is divided into three subdomains, an alpha-helical coiled-coil domain, and a C-terminal domain. There are two isoforms encoded by NF2, with the canonical isoform containing 17 exons, the last of which encodes hydrophilic C-terminal residues that play a role in intraprotein interaction with the FERM domain. The noncanonical isoform has 16 exons and lacks this extended C-terminal domain (Cooper and Giancotti, 2014).

Merlin plays an important role in development and organization of the plasma membrane and cytoskeletal architecture (McClatchey and Giovannini, 2005). Merlin shares structural elements with ERM (ezrin, radixin, and moesin) proteins, and not surprisingly, it functions like this class of proteins, which connect elements from the plasma membrane to the cell cytoskeleton (Sainio et al., 1997). Merlin localizes to the inner surface of the cell membrane (Shaw et al., 1998), where it interacts with various molecular players. For example, merlin helps establish and mature adherens junctions in epidermal cells through its interaction with α-catenin, causing it to associate with Par3 (Gladden et al., 2010). Merlin helps organize the actin cytoskeleton (Lallemand et al., 2009) and travels along microtubules by kinesin-1 and dynein motors (Benseñor et al., 2010).

Some of the interactions between merlin and other partners mediate its effect on cell growth. Merlin induces cell growth inhibition by binding to part of CD44, which is a receptor for hyaluronate, an extracellular signal (Morrison et al., 2001). Merlin also serves as a component of the protein complex that includes angiomotin, PATJ (Pals1-associated tight junction), and PALS1 (protein associated with Lin seven 1) and is associated with cellular tight junctions. Merlin inhibits angiomotin, which inhibits RICH1 (RhoGAP interacting with CIP4 homologues, a GTPase-activating protein), which in turn inactivates the protein RAC1 (Ras-related C3 botulinum toxin substrate 1). Given that RAC1 is involved in activation of Ras-MAPK pathways, merlin is effectively an inhibitor of RAC1 and Ras-MAPK signaling (Yi et al., 2011) (Fig. 1.3). Merlin regulates the Hippo signaling pathway, which mediates cell proliferation and organ size via inhibition of YAP (yes-associated protein) (Zhang et al., 2010). When bound by lipids, merlin undergoes conformational change to an open, active configuration, which allows it to regulate cell proliferation through these pathways (Chinthalapudi et al., 2018).

In light of the role of merlin in these downstream signaling pathways controlling cell proliferation, NF2 likely serves as a tumor suppressor, and tumorigenesis in NF2 may follow a two-hit model. Analysis of tumor tissue from individuals with NF2 (and from individuals with sporadic schwannomas) has shown that there is loss/inactivation of both copies of NF2 contributing to vestibular schwannoma development (Irving et al., 1994). Loss of both copies of NF2 also occurs in sporadic meningiomas (Ueki et al., 1999). Mice with inactivation of both copies of Nf2 in Schwann cells or arachnoidal cells develop features of schwannomas (Giovannini et al., 2000) and meningiomas (Kalamarides et al., 2002), respectively. In affected humans, on top of the germline defect in NF2, there may be an intragenic variant affecting NF2 in somatic cells, or LOH such as from mitotic recombination (Hadfield et al., 2010), supporting a two-hit hypothesis of tumor development in NF2.

1.5.10. Targeted treatments

Knowledge of the various pathways implicated in NF2 has led to investigation of targeted treatments. Schwannomas and meningiomas overexpress EGFR (epidermal growth factor receptor) and ErbB2, and small studies have demonstrated various treatment responses to lapatinib, an EGFR/ErbB2 blocker, for meningiomas (Osorio et al., 2018) and progressive vestibular schwannomas (Karajannis et al., 2012) in NF2. Given that vestibular schwannomas express VEGF (vascular endothelial growth factor), researchers have studied the effects of bevacizumab, a VEGF inhibitor, in NF2, showing that it can lead to improvement in hearing and tumor size (Blakeley et al., 2016; Mautner et al., 2010b). In contrast, the mTOR inhibitor everolimus has failed to show significant effect for growing vestibular schwannomas in NF2 (Karajannis et al., 2014), and bevacizumab has shown less effect for NF2-related meningiomas (Nunes et al., 2013).

1.6. Schwannomatosis

1.6.1. Introduction

Schwannomatosis is a genetic syndrome that leads to the development of multiple schwannomas affecting various sites except for the vestibular nerve. The prevalence of this condition is around 1/70,000, although this number may be an underestimate (Dhamija et al., 1993). Although schwannomatosis is considered a third type of neurofibromatosis, its clinical features and genetic causes are distinct from NF1 and NF2.

1.6.2. Diagnosis

To make a diagnosis of schwannomatosis, there are both clinical criteria and combined molecular and clinical criteria. A diagnosis based on clinical criteria involves satisfaction of either of the following two conditions: (1) at least two nonintradermal schwannomas (one of which must have histologic confirmation), along with confirmed absence of bilateral vestibular schwannomas (using MRI, with/without gadolinium, with slice thickness   ≤ 3   mm, including focus on the internal auditory canal) and (2) at least one pathologically confirmed schwannoma (can be unilateral vestibular but not bilateral vestibular) or intracranial meningioma, plus a first-degree relative with schwannomatosis (Dhamija et al., 1993; Kehrer-Sawatzki et al., 2017). Combined molecular and clinical criteria require either of the following two conditions:

(a) germline pathogenic variant in SMARCB1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1) or LZTR1 (leucine zipper-like transcriptional regulator 1) plus at least one schwannoma or meningioma confirmed on biopsy

(b) at least two schwannomas/meningiomas with LOH of 22q (with different deletion breakpoints) and two unique somatic pathogenic NF2 variants, plus at least two schwannomas/meningiomas confirmed on pathology, plus absence of any of the exclusion criteria.

The exclusion criteria are fulfillment of criteria for NF2, germline pathogenic variant in NF2, and occurrence of schwannomas only in previously radiated locations (Dhamija et al., 1993; Kehrer-Sawatzki et al., 2017).

1.7. Clinical features

1.7.1. Schwannomas

One of the core features of schwannomatosis is the presence of multiple schwannomas. In a retrospective study of 87 individuals with schwannomatosis, peripheral schwannomas were present in 89%, spinal schwannomas were present in 74%, and intracranial schwannomas not affecting the vestibular nerve were present in 9% (Merker et al., 2012). In affected individuals with spinal schwannomas, there is a predilection for affecting the lumbar region (Li et al., 2016). Segmental schwannomatosis, in which the schwannomas affect only one limb or only one part of the spine (≤5 contiguous spinal segments), occurs in one out of three affected individuals (Koontz et al., 2013).

1.7.2. Meningiomas

Meningiomas can occur in scwhannomatosis, although much less frequently than schwannomas. In the aforementioned retrospective case series of 87 individuals with schwannomatosis, intracranial meningiomas were present in 5% (Merker et al., 2012). In individuals with schwannomatosis, the presence of multiple meningiomas suggests an underlying germline pathogenic variant in SMARCB1 (van den Munckhof et al., 2012).

1.7.3. Pain

Pain is often the most common presenting symptom of schwannomatosis. Pain occurs in 75% of affected individuals, based on an international registry of schwannomatosis. The pain can occur by itself, in the context of a mass, and/or in the context of neurological deficit. In some cases, the presence of a mass without any symptoms can be the only presenting symptom (Ostrow et al., 2017). The chronic pain associated with schwannomatosis can be quite disabling and difficult to treat. Individuals with chronic pain related to schwannomatosis have received treatment with neuropathic medications, antiinflammatory medications, opioids, muscle relaxants, among others (Merker et al., 2012). Surgical resection of schwannomas is reserved for only specific circumstances, when other treatment options have been exhausted. Such scenarios include pain refractory to medical management and compression of the spine and other structures (Merker et al., 2012; Huang et al., 2004).

1.7.4. Genetics

Schwannomatosis is an autosomal dominant genetic disorder caused by a germline pathogenic variant in either SMARCB1 (located on 22q11.23) (Hulsebos et al., 2007) or LZTR1 (located on chromosome 22q11.21) (Piotrowski et al., 2014). There are both familial and sporadic cases. In comparing SMARCB1 variant-related familial cases to sporadic cases, there is an increased likelihood of a nontruncating variant, particularly at the N- or C-terminus, in the former, whereas there is an increased likelihood of a truncating variant in the latter (Dhamija et al., 1993).

1.7.5. Mechanisms

SMARCB1 encodes one of the components of SWI/SNF chromatin remodeling complexes implicated in cell growth and differentiation. Within this context, SMARCB1 functions as a tumor suppressor, preventing excessive cell growth (Roberts and Orkin, 2004). LZTR1 helps stabilize the Golgi apparatus (Nacak et al., 2006) and also associates with the CUL3 ubiquitin ligase complex (Frattini et al., 2013). Like SMARCB1, LZTR1 serves as a tumor suppressor in cells.

Figure 1.4 Three-step and four-hit model of tumorigenesis implicated in schwannomatosis.

The pathogenesis of schwannomatosis may involve a four-hit model of tumor development (Fig. 1.4). According to this hypothesis, a germline pathogenic variant in SMARCB1 or LZTR1 serves as the first hit. Subsequently, in somatic tissue, there is LOH of 22q (heterozygous deletion of part of chromosome 22q), affecting the nonmutated copy of SMARCB1 and LZTR1 (second hit), as well as one of the two wild-type NF2 alleles (third hit) which is adjacent to SMARCB1 and LZTR1. Finally, in the nondeleted copy of 22q, the fourth hit is a mutation of NF2 (Plotkin et al., 2013; Kehrer-Sawatzki et al., 2017).

1.7.6. Targeted treatments

Currently, there are a limited number of effective targeted treatments for schwannomatosis. There is a case report of an individual with schwannomatosis who had treatment response with the VEGF antagonist bevacizumab (Blakeley et al., 2014), but this finding needs replication in larger cohorts.

1.8. Tuberous sclerosis complex

1.8.1. Introduction

TSC is a genetic disorder affecting multiple organ systems, including the central nervous system, eyes, heart, lungs, kidneys, liver, and skin (Curatolo et al., 2008). About 1 in 6000 live births is affected by TSC (Osborne et al., 1991). The disorder is inherited in an autosomal dominant fashion (Hyman and Whittemore, 2000).

1.8.2. Diagnosis

The diagnosis of TSC is based on establishment of a pathogenic variant in TSC1 or TSC2, or satisfaction of consensus-based clinical criteria. The diagnostic criteria include major and minor features, with a definite diagnosis resulting from the presence of two or more major features or one major and at least two minor features. Major neurological features include cortical dysplasias, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs). Major dermatological features include hypomelanotic macules (≥3, at least 5   mm in diameter), angiofibromas (≥3) or fibrous cephalic plaque, ungula fibromas (≥2), and shagreen patches. Major features in other organ systems are multiple retinal hamartomas, cardiac rhabdomyomas, lymphangioleiomyomatosis (LAM), angiomyolipomas (AMLs) (≥2). Minor features are the following: confetti skin lesions, dental enamel pits (>3), intraoral fibromas (≥2), retinal achromatic patches, multiple renal cysts, and nonrenal hamartomas (Krueger and Northrup, 2013).

1.9. Clinical features

1.9.1. Neurological features

Cortical/subcortical tubers, SENs, and SEGAs are gross structural abnormalities affecting the brain in TSC (Mizuguchi and Takashima, 2001) (Fig. 1.5). Cortical tubers are glioneuronal hamartomas which affect parts of the cortex and extend into the subcortical white matter (Grajkowska et al., 2010). Their microstructural architecture can evolve over time (Peters et al., 2015), and sometimes they can develop cystic changes, which occurs more commonly in individuals with a TSC2 pathogenic variant (Chu-Shore et al., 2009). In TSC, cortical tubers can affect both the supratentorial areas and the cerebellum (Martí-Bonmatí et al., 2000). By 36 months of age, 94% of infants with TSC may develop tubers or other cortical dysplasias (Davis et al., 2017).

Most of the time, the tubers themselves do not require intervention; however, in some circumstances, they may become a hotspot for epileptic activity warranting surgical resection. Such a scenario may present as an individual with TSC who has refractory epilepsy, in whom the combination of MRI, EEG, and nuclear medicine modalities has identified a specific epileptogenic focus within a tuber (Chandra et al., 2006).

SENs are abnormal collections of glial and vascular components that usually line the wall of the lateral and third ventricles in the brains of individuals with TSC. Up to 90% of patients with TSC have SENs (Davis et al., 2017). Over time, these lesions can calcify (Islam and Roach, 2015). Although they are usually small (<1   cm in size), they can transform into SEGAs (Radhakrishnan and Verma, 2011).

SEGAs can cause significant neurological symptoms in individuals with TSC. SEGAs are low-grade tumors, possibly mixed glioneuronal in composition (Goh et al., 2004; Buccoliero et al., 2009). They affect nearly 25% of individuals with TSC. A common location for SEGAs is the foramen of Monro (Radhakrishnan and Verma, 2011). One of the more serious consequences of SEGAs is they can grow rapidly to the point of causing acute obstructive hydrocephalus from blockage of cerebrospinal fluid flow in the ventricular system. This constitutes a neurosurgical emergency and requires surgical resection of the lesion (Radhakrishnan and Verma, 2011).

Epilepsy is a common neurological manifestation of TSC. Close to three-quarters of neonates with TSC develop epilepsy by 12 months of age (Davis et al., 2017), and the prevalence of infantile spasms, a particularly severe form of epilepsy, is about 30%–40% (Chu-Shore et al., 2010; Wilbur et al., 2017), although often hypsarrhythmia is not seen with infantile spasms in TSC (Wu et al., 2016).

There is a spectrum of cognitive, behavioral, and psychiatric manifestations in TSC known as TSC-associated neuropsychiatric disorders (de Vries et al., 2015). Intellectual disability affects about 45% of affected individuals, with mild-to-severe levels in 14% of patients and profound severity in 31% (Joinson et al., 2003). The prevalence of autism spectrum disorder (ASD) in TSC is about 40% (Richards et al., 2015). Other behavioral and psychiatric features of the disorder include attention deficit hyperactivity disorder, anxiety, and depression (de Vries et al., 2015; Prather and de Vries, 2004). Formal neuropsychological testing and educational evaluation is often necessary to develop a treatment plan for these manifestations. Treatment of these neurodevelopmental manifestations is the same as for individuals without TSC.

Figure 1.5 Cortical/subcortical tubers, subependymal nodules, and subependymal giant cell astrocytoma in a 10-year-old with tuberous sclerosis complex.

1.9.2. Dermatological features

There are a host of dermatological and dental manifestations of TSC. Cutaneous features include facial angiofibromas (reddish papules on nose and cheeks); fibrous cephalic plaques (yellowish brown or skin-colored plaques on the forehead or scalp); hypomelanotic macules (hypopigmented patches which enhance on Wood lamp examination) and confetti-like hypopigmentation; shagreen patches (skin-colored patches often found on the back or dorsal surfaces, with texture akin to an orange peel); and periungual fibromas (reddish or skin-colored nodules found in the nail groove, plate, or folds). Dental features include gingival fibromas (benign tumors of the oral cavity) and dental pitting (Teng