Meet the editors

Dr. Juichiro Nakayama graduated from the Faculty of Medicine, Kyushu University, Japan. After completing his clinical residency, he attended the Post Graduate School of Medicine. He studied skin carcinogenesis at the National Institutes of Health, USA. He then became an associate professor in the Department of Dermatology, Kyushu University. He was a member of Research on Measures for Intractable Diseases supported by Japanese

Health and Labor Sciences Research Grants. He served as the head of the Neurocutaneous Syndrome Research Group for six years. He was then appointed professor and chairman of the Department of Dermatology, Fukuoka University School of Medicine, where he has been Professor Emeritus since 2019.

Dr. Yuichi Yoshida graduated from the Faculty of Medicine, Kyushu University, Japan. He obtained a Ph.D. in Immune Dermatology and worked as a Ph.D. student at the Department of Dermatology, Case Western Reserve University, Cleveland, USA. He became an assistant professor at Kyushu University in 2001 and a lecture at Fukuoka University in 2005. He has also been an associate professor at Tottori University Hospital since 2006. Dr.

Yoshida has served on many different boards and commissions.

Contents

**Section 1**

**Section 2**

**Section 3**

of Neurofibromatosis Type 1

Bone Lesions in Children with Neurofibromatosis

Seizures in Adult with Neurofibromatosis Type 1 *by Demet İlhan Algin and Oğuz Osman Erdinç*

Endocrine Conditions in Neurofibromatosis 1 *by Shilpa Mehta and Resmy Palliyil Gopi*

Type 1 - Diffuse Neurofibromatous Tissue

*by Juichiro Nakayama*

*by Nikolaos Laliotis*

**Preface XI**

Fundamental Aspects of Neurofibromatosis Type 1 **1**

**Chapter 1 3**

Clinical Aspects of Neurofibromatosis Type 1 **7**

**Chapter 2 9**

**Chapter 3 35**

**Chapter 4 49**

**Chapter 5 57**

Basic Aspects of Neurofibromatosis Type 1 **67**

**Chapter 6 69**

Clarifying the Pathophysiological Mechanisms of Neuronal Abnormalities

of NF1 by Induced-Neuronal (iN) Cells from Human Fibroblasts

*by Noriaki Sagata, Yasunari Sakai and Takahiro A. Kato*

Introductory Chapter: Toward a More Comprehensive Understanding

Characterisation of a Novel Radiological Entity in Neurofibromatosis

*by Venkata Amruth Nadella, K. Joshi George and Calvin Soh*

### Contents



Preface

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is an autosomal dominant disorder affecting 1 in about 3,000 people. NF1 is defined as a major monogenic neurocutaneous disorder. The NF1 gene was identified and reported in 1990. Since then, genetic analysis and cellular and molecular biological studies on the pathogenesis and pathophysiology of NF1 have rapidly progressed. The NF1 gene encodes a Ras GTPase-activating protein (Ras-GAP) named neurofibromin. Neurofibromin is a large protein that includes up to 2,818 amino acids and 57 exons. Dysfunction of this gene by germline mutations causes constitutive activation of Ras-mitogen activated protein kinase (MAPK) signaling, which promotes tumorigenesis in central and peripheral neuronal tissues. The classical cutaneous lesions of NF1 include pigmented café-au-lait macules and small axillar or inguinal freckles, and dermal, subcutaneous, and plexiform nodular and diffuse

Germline mutations of the NF1 gene are completely penetrated. Therefore, NF1 gene mutation occurs in a wide variety of cells and tissues. Consequently, in addition to the classical cutaneous lesions described above, NF1 affects multiple organ systems exhibiting neurological and psychiatric disorders, abnormal orthopedic manifestations, and impaired endocrine functions. However, the appearance of organ-specific lesions varies in patients with NF1. The quality of life in patients

This book is organized into three sections covering the fundamental, clinical, and basic aspects of NF1. An introductory chapter in the first section supplements and introduces the text, indicating the point of view to be adopted by the reader.

The second section includes four chapters. The first chapter discusses bone lesions in children with NF1, with a focus on dysplastic patterns of scoliosis in the spinal lesions. The second chapter presents a retrospective and descriptive study on a novel radiological entity in NF1-diffuse neurofibromatous tissue called DNFT, which is distinct from commonly reported neurofibromas. This is the first reported descriptive study of DNFT in NF1. The third chapter reports on the prevalence, association with brain tumors or cortical malformations, types, and management of seizures in adults with NF1. It also discusses a possible association with the defective neurofibromin function on the mechanism of epilepsy. The final chapter in this section describes several endocrine disorders that are characteristic in children or adolescents with NF1. Mechanisms for the greater incidence of short stature in patients with NF1 are discussed, focusing on the dysregulation of intracellular

The third section includes four chapters. The first chapter in this section describes NF1-induced neuronal (NF1-iN) cells from cultured fibroblasts of patients with NF1 by direct conversion technologies. This technology enables the investigation of NF1 neuronal cells directly instead of using a mouse system. NF1-iN-cells show significantly different aberrant gene expression and quite different morphology from that of human control iN-cells. The chapter authors present their important

with NF1 is severely affected by this wide range of symptoms.

cAMP in the brain due to neurofibromin dysfunction.

types of neurofibromas.

*by Ionica Masgras and Andrea Rasola*
