Genetics of Bone Biology and Skeletal Disease

Cover
GENETICS OF
BONE BIOLOGY
AND SKELETAL
DISEASE
Copyright
List of Contributors
Preface to the Second Edition
Preface to the First Edition
Section 1: General Background to Genetics
Chapter 1 - Introduction to Genetics of Skeletal and Mineral Metabolic Diseases
	1 - Introduction
	2 - Genetics of skeletal and mineral metabolic diseases
		2.1 - Modes of Inheritance
		2.2 - Genetic Heterogeneity and Monogenic Skeletal Diseases
		2.3 - Identifying Genetic Abnormalities Causing Monogenic Diseases
		2.4 - Identifying Genes Causing Polygenic Traits
		2.5 - Molecular Insights From the Investigation of Monogenic Disorders and Polygenic Traits
		2.6 - Genetic Understanding and Application to Development of Novel Therapeutics
	3 - Approach to the patient with genetic skeletal/mineral metabolic disease
		3.1 - Clinical Approach
		3.2 - Medical History and Physical Examination
		3.3 - Family Medical History for Determining Mode of Disease Inheritance
	4 - Current genetic tests, their clinical utility, and interpretation
		4.1 - Clinical Value of Genetic Testing
		4.2 - Pretest Considerations—Which Test?
		4.3 - Detection of Chromosomal Abnormalities, Copy Number Variations, and Mutations Causing Disease
			4.3.1 - Karyotype
			4.3.2 - Fluorescence In Situ Hybridization (FISH)
			4.3.3 - Multiplex-Ligation Dependent Probe Amplification (MLPA)
			4.3.4 - Whole Genome Arrays
			4.3.5 - Microarray-Comparative Genomic Hybridization (aCGH)
			4.3.6 - Single Nucleotide Polymorphism Arrays
			4.3.7 - Single Gene Testing (Sanger Sequencing)
			4.3.8 - Next-Generation Sequencing or Second-Generation Sequencing
		4.4 - Challenges of Data Interpretation and Approaches to the Analysis of Variants Identified by NGS Platforms
			4.4.1 - Variant Identification
			4.4.2 - Variant Interpretation
		4.5 - Special Circumstances for Genetic Testing
			4.5.1 - Detection of Mosaicism
			4.5.2 - Prenatal Diagnosis
		4.6 - Informed Consent and Ethical Considerations
	5 - Conclusions
	References
Chapter 2 - Epigenetics
	1 - Introduction
	2 - Epigenetic control mechanisms
		2.1 - Histone Modifications and Chromatin Remodeling
		2.2 - Histone Variants
		2.3 - DNA Methylation
		2.4 - Noncoding RNAs (ncRNAs)
	3 - Transgenerational epigenetic inheritance
	4 - Epigenetics and human disease
		4.1 - Imprinting Disorders
		4.2 - Cancer
		4.3 - Other Diseases
		4.4 - Epigenetic Therapy
	5 - Conclusions
	References
Chapter 3 - Genome-Wide Association Studies
	1 - Introduction
	2 - Linkage disequilibrium mapping
	3 - Study design issues in genome-wide association studies
		3.1 - Quality Control
	4 - The “missing heritability” question
	5 - Rare variant study designs
	6 - Conclusions
	References
Chapter 4 - Copy Number Variation
	1 - Introduction
		1.1 - Potential Mechanisms for Formation of CNVs
	2 - CNV detection
	3 - CNV and disease
		3.1 - Obesity
		3.2 - Schizophrenia
		3.3 - Autism
		3.4 - Cancer
		3.5 - Congenital Heart Disease
	4 - CNV and osteoporosis
	5 - Conclusions
	Acknowledgments
	References
Chapter 5 - Genomic Profiling in Bone
	1 - Introduction
		1.1 - Profiling Skeletal Cells and Bone Metabolism
		1.2 - Profiling Location and Age Dependent Changes in Skeletal Gene Expression
		1.3 - Profiling Biomechanical Effects on Bone
		1.4 - Profiling Gene Expression Changes Occurring as a Function of Altered Bone Metabolism
			1.4.1 - Profiling Bone in Animal Models With Impaired Bone Metabolism
			1.4.2 - Profiling Osteoporosis in Humans
		1.5 - Profiling Noncoding RNA Expression in Bone
	2 - Conclusions
	Acknowledgments
	References
Chapter 6 - Functional Genomics
	1 - What is functional genomics?
	2 - Annotating the genome—an emerging picture
		2.1 - Encode and Roadmap: An Overview
		2.2 - DNase-seq
		2.3 - ChIP-seq and Chromatin Profiling
			2.3.1 - SP7/Osterix is Restricted to Bone-Forming Vertebrates Where it Acts as a Dlx Cofactor in Osteoblast Specification
			2.3.2 - Distinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte
			2.3.3 - The Osteoblast-to-Osteocyte Transition: Epigenetic Changes and Response to the Vitamin D3 Hormone
			2.3.4 - The Binding of Runx2 During Osteoblastogenesis
			2.3.5 - Chromatin Profiling of Parathyroid Glands
	3 - From annotated sequences to function
		3.1 - In Situ Saturating Mutagenesis With CRISPR/Cas9
		3.2 - Multiplexed Reporter Assays (MPRA) to Assess Function of Expression-Modulating Variants
	4 - Interrogation of cellular function: genome-wide gain- and loss-of-function screening in mammalian cells
		4.1 - RNAi-Based Functional Genomics
		4.2 - The Orfeome: A Tool for Gain-of-Function Screening
		4.3 - Genetic Screens Using CRISPR/Cas9: The Next Frontier
	5 - Outlook
	6 - Summary
	References
Chapter 7 - Mouse Models: Approaches to Generate In Vivo Models for Hereditary Disorders of Mineral and Skeletal Homeostasis
	1 - Introduction
	2 - Methods for generating mouse models
		2.1 - Nontargeted Strategies
		2.2 - Targeted Knock-Out Strategies
		2.3 - Targeted Knock-In Strategies
	3 - Genetic bone diseases associated with defective calcium homeostasis
		3.1 - Disorders of Parathyroid Development
		3.2 - Models for the DiGeorge Syndrome Type 1 Due to TBX1 Mutations
		3.3 - Models for Familial Isolated Hypoparathyroidism Due to PTH and GCMB Mutations
		3.4 - Disorders of PTH Signaling
		3.5 - Blomstrand’s Chondrodysplasia
		3.6 - Jansen’s Disease
		3.7 - Pseudohypoparathyroidism
		3.8 - Disorders of the Calcium-Sensing Receptor (CaSR)
		3.9 - FHH and NSHPT Due to Loss-of-Function CaSR Mutations
		3.10 - ADHH Due to Gain-of-Function CaSR Mutations
	4 - Conclusions
	References
Chapter 8 - Prospects of Gene Therapy for Skeletal Diseases
	1 - Introduction
	2 - Vectors in skeletal gene therapy
		2.1 - Adenovirus
		2.2 - Adeno-Associated Virus
		2.3 - Retrovirus and Lentivirus
		2.4 - Nonviral Vectors
		2.5 - Conclusions
	3 - Methods of gene delivery
		3.1 - In Vivo Delivery
		3.2 - Ex Vivo Delivery
	4 - The immune response to gene therapy vectors
		4.1 - The Innate Immune Response
		4.2 - The Adaptive Immune Response
		4.3 - Strategies to Limit Immune Reactions to Gene Therapy Vectors
	5 - Gene therapy for pathologies of the skeletal system
		5.1 - Bone
			5.1.1 - Bone Healing and Osteogenesis
			5.1.2 - Implant Stability and Aseptic Loosening
			5.1.3 - Osteoporosis
			5.1.4 - Osteogenesis Imperfecta
		5.2 - Cartilage
			5.2.1 - Osteoarthritis
			5.2.2 - Rheumatoid Arthritis
		5.3 - Tendon
		5.4 - Intervertebral Disc
	6 - Conclusions
	References
Chapter 9 - Pharmacogenetics and Pharmacogenomics of Osteoporosis: Personalized Medicine Outlook
	1 - Complexity of phenotypes
	2 - Genetics of osteoporosis
		2.1 - Candidate Genes
		2.2 - Genome-Wide Studies
		2.3 - Pathways
	3 - Gene–gene interaction and “missing heritability”
	4 - Pharmacogenetics of therapeutic response
	5 - Toward individualized assessment and individualized treatment decisions
	6 - Conclusions
	References
Chapter 10 - Genetic Testing and Counseling
	1 - Genetic testing
		1.1 - Small-Scale Variants
		1.2 - Large-Scale Variants
		1.3 - Evolving Approaches to DNA-Based Genetic Testing
	2 - Genetic testing for skeletal disorders
		2.1 - Genetic Tests Available
		2.2 - When to Order Genetic Testing
	3 - Genetic counseling
		3.1 - History
		3.2 - The Genetic Counseling Process
		3.3 - The Genetic Counseling Session
			3.3.1 - Family History
			3.3.2 - Genetic Testing
			3.3.3 - Communicating the Facts
			3.3.4 - Counseling and Support
	References
Section 2: General Background to Bone Biology
Chapter 11 - Biology of Bone and Cartilage
	1 - Introduction
	2 - Osteoclasts
		2.1 - Regulation of Osteoclast Formation: The RANKL–RANK–OPG Pathway
		2.2 - Transcription Factor Regulation of Osteoclastogenesis
		2.3 - Costimulatory Signaling-Mediated Osteoclastogenesis
		2.4 - RANKL/RANK Downstream Signaling
		2.5 - Regulation of Osteoclast Activation
		2.6 - Negative Regulation of Osteoclast Formation and Function
		2.7 - Osteoclast Apoptosis
	3 - Osteoblasts
		3.1 - Transcription Factors and Signal Pathways
			3.1.1 - BMP/RUNX2 Signaling
			3.1.2 - Wingless (Wnt)-β-Catenin
			3.1.3 - Notch
		3.2 - Epigenetic Modifications
			3.2.1 - DNA Methylation
			3.2.2 - Histone Modification
			3.2.3 - Micro-RNA
		3.3 - Regulation of Osteoblast/Osteoclast Communication
			3.3.1 - Ephrins
			3.3.2 - Semaphorins
	4 - Cartilage
		4.1 - Chondrocyte Formation
		4.2 - Endochondral Ossification
		4.3 - Endochondral Ossification in the Adult Skeleton
		4.4 - Formation of Articular Cartilage
		4.5 - Cartilage Degeneration
	5 - Conclusions
	References
Chapter 12 - Overview of Bone Structure and Strength
	1 - Introduction
	2 - Bone biomechanics and the determinants of whole-bone strength
		2.1 - Structural Versus Material Properties of Bone
		2.2 - Mechanical Properties of Bone Tissue Depend on Loading Direction
		2.3 - Determinants of Biomechanical Properties of Trabecular and Cortical Bone
	3 - Contribution of bone geometry to bone strength
		3.1 - Age-Related Changes in Bone Size and Shape
	4 - Age-related changes in trabecular and cortical bone microarchitecture
	5 - Contribution of bone microarchitecture to bone strength
		5.1 - Trabecular Microarchitecture
		5.2 - Age-Related Changes in Cortical and Trabecular Bone Material Properties
		5.3 - Contribution of Bone Structure to Vertebral Strength
		5.4 - Contribution of Bone Structure to Proximal Femoral Strength
	6 - Contribution of bone structure to fracture risk in humans
	7 - Conclusions
	References
Chapter 13 - Overview of Joint and Cartilage Biology
	1 - Introduction
	2 - Joint development
		2.1 - Joint Development as a Part of Skeletal Development
		2.2 - Joint Site Determination
		2.3 - What Happens in the Joint Interzone?
		2.4 - Joint Cavitation
		2.5 - The Differentiation of the Articular Cartilage and Other Joint Structures
		2.6 - Integration of the Joints with the Skeleton and Joint Shape Morphogenesis
	3 - Joint anatomy
		3.1 - The Articular Cartilage
			3.1.1 - Collagens
			3.1.2 - Proteoglycans
			3.1.3 - Noncollagenous Matrix Proteins
			3.1.4 - Organization of the Articular Cartilage
				3.1.4.1 - Soft Tissues of the Joint
				3.1.4.2 - The Enthesis
	4 - Joint homeostasis
	5 - Joint disease
		5.1 - Rheumatoid Arthritis
			5.1.1 - Spondyloarthritis
			5.1.2 - Osteoarthritis
	6 - Joint repair
		6.1 - Tissue Repair by Enhancing the Endogenous Healing Response
		6.2 - Joint Resurfacing by Tissue Engineering
	References
Chapter 14 - Osteocyte Biology
	1 - Introduction
	2 - The fundamental role of osteocytes in skeletal homeostasis
		2.1 - The Osteocyte Network
		2.2 - Osteocytes as Mechanosensory Cells
		2.3 - Osteocytes and the Skeletal Response to PTH
	3 - Molecular and functional signature of osteocytes
		3.1 - Formation and Maintenance of the Osteocytic Network
		3.2 - Regulation of Bone Formation by Osteocytes
		3.3 - Regulation of Bone Resorption by Osteocytes and the Role of Osteocyte Apoptosis in Targeted Remodeling
	4 - Gene deletion and mutations affecting osteocytes
		4.1 - Sclerostin, Sclerosteosis, and van Buchem’s Disease
		4.2 - LRP Mutations
		4.3 - Mutations Leading to Disturbance of Phosphate Homeostasis
	5 - Cross talk of bone with other organs/tissues
		5.1 - Cross Talk of Bone With Kidney and Heart
		5.2 - Cross Talk of Bone With Muscle
		5.3 - Cross Talk of Bone and Hematopoietic Cells
		5.4 - Cross Talk of Bone and Fat
	6 - The dying and aging osteocyte
	7 - Conclusions
	References
Chapter 15 - Skeletal Stem Cells/Bone Marrow Stromal Cells
	1 - History and definitions of postnatal stem cells
		1.1 - Definitions
		1.2 - Identification of Skeletal Stem/Progenitor Cells
		1.3 - From SSCs/BMSCs to “Mesenchymal Stem Cells”—A Source for all Mesodermal Derivatives?
		1.4 - From Bone Marrow–Derived “MSCs” to Ubiquitous “MSCs”?
		1.5 - “MSCs” are Pluripotent?
	2 - Origins of skeletal stem cells/bone marrow stromal cells
	3 - Practical considerations—preparation and assessment of SSCs/BMSCs
		3.1 - Isolation
		3.2 - Culture Conditions
		3.3 - Characterization of the Biological Nature of SSCs/BMSCs
			3.3.1 - Cell Surface Markers
			3.3.2 - Colony-Forming Efficiency
			3.3.3 - Demonstration of Bona Fide Stem Cell Characteristics
				3.3.3.1 - Differentiation Potential—In Vitro
				3.3.3.2 - Differentiation Potential—In Vivo
				3.3.3.3 - Self-Renewal
	4 - The role of SSCs/BMSCs in postnatal bone turnover
	5 - The role of SSCs/BMSCs in disease
	6 - Regulation of SSC/BMSC fate
		6.1 - Hormonal Regulation
		6.2 - Signaling Pathways and Transcription Factors
		6.3 - Epigenetic Controls
		6.4 - MicroRNAs
		6.5 - Cell–Cell and Cell–Substrate Interactions, Cell Shape, and Mechanical Forces
		6.6 - Iatrogenic Effects
	7 - SSCs/BMSCs in tissue engineering and regenerative medicine
		7.1 - Regeneration of the Bone/Marrow Organ
		7.2 - SSCs/BMSCs in Another Form of Regenerative Medicine
	8 - Conclusions
	Acknowledgments
	References
Chapter 16 - Osteoimmunology
	1 - Introduction
	2 - The RANKL/RANK system in bone metabolism
		2.1 - RANKL is Essential for Osteoclastogenesis
		2.2 - The Cellular Source of RANKL in Bone Remodeling
		2.3 - The Role of RANKL in the Mammary Gland and Cancer
	3 - Immunological role of the RANKL/RANK system
	4 - Intracellular signaling for osteoclastogenesis
		4.1 - RANKL Signaling for Osteoclast Differentiation
		4.2 - NFATc1, the Master Transcription Factor of Osteoclast Differentiation
		4.3 - Costimulatory Signal for RANK
		4.4 - Negative Regulators of Osteoclastogenic Signaling
		4.5 - Cell–Cell Communication Between Osteoclasts and Osteoblasts
	5 - Mechanisms underlying bone destruction in arthritis
		5.1 - Th17 Cells and Treg Cells in Autoimmune Arthritis
		5.2 - Therapeutic Strategies for RA
	6 - Bone marrow microenvironment
	7 - Conclusions
	References
Chapter 17 - Integrating Endocrine and Paracrine Influences on Bone; Lessons From Parathyroid Hormone and Parathyroid Hormone-Re...
	1 - Bone remodeling and modeling
	2 - Parathyroid hormone and parathyroid hormone-related protein
	3 - PTHrP in bone; production in osteoblasts
	4 - PTHrP function in bone; lessons from PTHrP null mice
	5 - Anabolic actions of PTH and PTHrP
	6 - Endocrine PTH, paracrine PTHrP; relationships in development and postnatal life
	7 - Are osteoclasts involved in the anabolic action of PTH?
	8 - Growth factors in the local actions of PTH and PTHrP
	9 - gp130 cytokines as agents of local control of PTH action
	10 - Sclerostin as a local factor promoting PTH action
	11 - Other influences of PTH/PTHrP on bone through the bone marrow microenvironment
	12 - The PTH–PTHrP relationship in vasculature and bone
	13 - Conclusions
	References
Chapter 18 - Genetics of Bone Fat and Energy Regulation
	1 - Introduction
	2 - The complex relationship of adipose tissue to bone mass
	3 - A common origin for fat and bone cells
	4 - Bioenergetics of cells in the bone marrow niche in relation to energy needs and whole body metabolism
	5 - Control of skeletal and adipose tissue remodeling
		5.1 - Adipokine Regulation of Bone Remodeling
		5.2 - Sympathetic Nervous System Control Over Fat and Bone Remodeling
	6 - Anorexia nervosa: energy, bone, and adipose deficiencies
	7 - Genetics of fat and bone in animal models
		7.1 - Shared Genetic Determinants of Bone and Fat in Animal Models
	8 - Genetics of fat and bone in humans
		8.1 - Shared Genetic Determinants of Fat and Bone in Humans
	Acknowledgments
	References
Chapter 19 - The Cross Talk Between the Central Nervous System, Bone, and Energy Metabolism
	1 - Introduction
	2 - Specific features of bone and whole-organism physiology
		2.1 - Coordinated Control of Bone Mass and Energy Metabolism: Regulation of Bone Mass by Adipocytes
		2.2 - Coordinated Regulation of Bone Mass and Energy Metabolism: The Central Mode of Action of Leptin
	3 - Expanding bone biology without premeditation
	4 - The anticipated functions of osteocalcin
		4.1 - The Other Side of Osteocalcin
	5 - Questions raised by the functions of osteocalcin
	References
	Further Reading
Chapter 20 - Fetal Control of Calcium and Phosphate Homeostasis
	1 - Introduction
	2 - Overview of fetal and neonatal mineral metabolism
		2.1 - Animal Data
		2.2 - Human Data
	3 - Overview of placental mineral transport
		3.1 - Animal Data
		3.2 - Human Data
	4 - Overview of endochondral bone development
		4.1 - Animal and Human Data
	5 - Role of PTHrP
		5.1 - Animal Data
			5.1.1 - Regulation of Serum Minerals
			5.1.2 - Regulation of Placental Mineral Transfer
			5.1.3 - Regulation of Endochondral Bone Formation
		5.2 - Human Data
	6 - Role of PTH
		6.1 - Animal Data
			6.1.1 - Regulation of Serum Minerals
			6.1.2 - Regulation of Placental Mineral Transfer
			6.1.3 - Regulation of Endochondral Bone Formation
		6.2 - Human Data
	7 - Role of PTHrP and PTH in combination
		7.1 - Animal Data
			7.1.1 - Regulation of Serum Minerals
			7.1.2 - Regulation of Placental Calcium Transfer
			7.1.3 - Regulation of Endochondral Bone Formation
		7.2 - Human Data
	8 - Role of estradiol
		8.1 - Animal and Human Data
	9 - Role of calcitonin
		9.1 - Animal and Human Data
	10 - Role of vitamin D and calcitriol
		10.1 - Animal Data
			10.1.1 - Regulation of Serum Minerals
			10.1.2 - Regulation of Placental Mineral Transport
			10.1.3 - Regulation of Endochondral Bone Development
		10.2 - Human Data
			10.2.1 - Observational Studies and Case Reports
			10.2.2 - Intervention Studies
			10.2.3 - Associational Studies
	11 - Role of FGF23
		11.1 - Animal Data
		11.2 - Human Data
	12 - Conclusions
	References
Chapter 21 - Control of Mineral and Skeletal Homeostasis During Pregnancy and Lactation
	1 - Introduction
	2 - Skeletal and mineral physiology during pregnancy
		2.1 - Mineral Ions and Calciotropic Hormones (Fig. 21.2)
		2.2 - Intestinal Absorption of Calcium
		2.3 - Renal Handling of Calcium
		2.4 - Skeletal Calcium Metabolism
	3 - Disorders of bone and mineral metabolism during pregnancy
		3.1 - Osteoporosis in Pregnancy
		3.2 - Primary Hyperparathyroidism
		3.3 - Familial Hypocalciuric Hypercalcemia
		3.4 - Hypoparathyroidism
		3.5 - Pseudohypoparathyroidism
		3.6 - Pseudohyperparathyroidism
		3.7 - Vitamin D Deficiency and Genetic Vitamin D Resistance Syndromes
		3.8 - Calcitonin Deficiency
		3.9 - Low Calcium Intake
		3.10 - Hypercalcemia of Malignancy
		3.11 - FGF23-Related Disorders
	4 - Skeletal and mineral physiology during lactation
		4.1 - Mineral Ions and Calciotropic Hormones (Fig. 21.3)
		4.2 - Calcium Pumping and Secretion in Mammary Tissue
		4.3 - Intestinal Absorption of Calcium
		4.4 - Renal Handling of Calcium
		4.5 - Skeletal Calcium Metabolism
		4.6 - Brain–Breast–Bone Circuit
	5 - Disorders of bone and mineral metabolism during lactation
		5.1 - Osteoporosis of Lactation
		5.2 - Primary Hyperparathyroidism
		5.3 - Familial Hypocalciuric Hypercalcemia
		5.4 - Hypoparathyroidism
		5.5 - Pseudohypoparathyroidism
		5.6 - Pseudohyperparathyroidism
		5.7 - Vitamin D Deficiency and Genetic Vitamin D Resistance Syndromes
		5.8 - Calcitonin Deficiency
		5.9 - Low Calcium Intake
		5.10 - FGF23-Related Disorders
	6 - Conclusions
	References
Section 3: Disorders of Bone and Joint
Chapter 22 - Osteoporosis Genes Identified by Genome-Wide Association Studies
	1 - Introduction
	2 - Genome-wide association studies of osteoporosis
	3 - Genes identified by genome-wide association studies on bone mineral density
		3.1 - 1p31.3 WLS
		3.2 - 1p36.12 ZBTB40 and WNT4
		3.3 - 2p16.2 SPTBN1
		3.4 - 2q14.2 EN1
		3.5 - 2q24.3 GALNT3
		3.6 - 3p22.1 CTNNB1
		3.7 - 4q22.1 IBSP, MEPE, and SPP1
		3.8 - 5q14.3 MEF2C
		3.9 - 6p22.3 SOX4
		3.10 - 6q22.33 RSPO3
		3.11 - 6q25.1 ESR1
		3.12 - 7p14.1 SFRP4 and STARD3NL
		3.13 - 7q21.2 COL1A2
		3.14 - 7q21.3 SHFM1 and C7orf76
		3.15 - 7q31.31 FAM3C, CPED1, and WNT16
		3.16 - 8q24.12 TNFRSF11B (OPG)
		3.17 - 9q22.32 PTHC1
		3.18 - 11p11.2 LRP4 and ARGHAP1
		3.19 - 11p14.1 DCDC5, LIN7C, and LGR4
		3.20 - 11p15.1 SOX6
		3.21 - 11q13.2 LRP5
		3.22 - 12q13.12 DHH
		3.23 - 12q13.13 SP7
		3.24 - 13q14.11 TNFSF11 (RANKL)
		3.25 - 14q32.32 MARK3
		3.26 - 16p13.3 CLCN7 and AXIN1
		3.27 - 16q24.1 FOXL1 and FOXC2
		3.28 - 17q12-22 CRHR1
		3.29 - 17q21.31 SOST and HDAC5
		3.30 - 18q21.33 TNFRSF11A
		3.31 - 20p12 JAG1
	4 - GWAS in other ethnic groups and for other osteoporosis phenotypes
	5 - Conclusions
	References
Chapter 23 - Osteogenesis Imperfecta
	1 - Introduction
	2 - Clinical description
	3 - Genetic description
	4 - Molecular genetics
		4.1 - Defects in Collagen Synthesis and Structure (Types I–IV)
		4.2 - Bone Mineralization Defects (Types V and VI OI)
		4.3 - Defects in Collagen Modification: The Prolyl 3-Hydroxylase Complex (Types VII, VIII, and IX OI)
		4.4 - Defects in Collagen Processing and Crosslinking (Types X–XII OI)
		4.5 - Defects in Osteoblast Differentiation and Function (Types XIII–XVIII OI)
	5 - Animal models
		5.1 - Dominant Type I Collagen Murine Models
		5.2 - Recessive Murine Models
	6 - Diagnostic aspects
	7 - Treatment
	8 - Conclusions
	References
Chapter 24 - Osteoarthritis: Genetic Studies of Monogenic and Complex Forms
	1 - Brief clinical description
		1.1 - Diagnosis
		1.2 - Mortality of OA
		1.3 - Economic burden of OA
		1.4 - Risk factors
	2 - Genetics description
		2.1 - Familial Aggregation and Heritability of OA
	3 - Molecular genetics
		3.1 - Monogenic Syndromes
			3.1.1 - Osteochondritis Dissecans
			3.1.2 - Multiple Epiphyseal Dysplasia
			3.1.3 - Pseudoachondroplasia
			3.1.4 - Spondyloepiphyseal Dysplasia Tarda
			3.1.5 - Otospondylomegaepiphyseal Dysplasia
			3.1.6 - Stickler Syndrome
			3.1.7 - Marshall Syndrome
			3.1.8 - Progressive Pseudorheumatoid Displasia
			3.1.9 - Dyggve–Melchior–Clausen Syndrome and Smith–McCort Dysplasia
			3.1.10 - Spondyloepiphyseal Dysplasia
			3.1.11 - Spondyloepimetaphyseal Dysplasias
		3.2 - Genetic Association Studies and Genome-Wide Scans
			3.2.1 - Candidate Gene Studies
			3.2.2 - Genome-Wide Association Studies
	4 - Functional and molecular pathology
		4.1 - Comparison Between OA Genes and Monogenic Syndromes
		4.2 - A Disease of the Whole Joint
		4.3 - Molecular Pathways Implicated in OA Genetic Risk
			4.3.1 - Functional Validation of GWAS Hits
			4.3.2 - Bone Morphogenetic Proteins
				4.3.2.1 - GDF5
			4.3.3 - Inflammation and Immune Response
		4.4 - Wnt Signaling
		4.5 - Pain in OA and Its Genetic Contribution
	5 - Diagnostic aspects
	6 - Treatment
		6.1 - Surgical Options
	7 - Conclusions
	References
	Futher Reading
Chapter 25 - Genetics of Paget’s Disease of Bone
	1 - Clinical features
	2 - Genetic architecture of Paget’s disease
	3 - Environmental factors
	4 - Molecular genetics
		4.1 - CSF1
		4.2 - OPTN
		4.3 - SQSTM1
		4.4 - TNFRSF11A
		4.5 - TNFRSF11B
		4.6 - VCP
		4.7 - HNRNPA2B1 and HNRNPA1
		4.8 - DCSTAMP
		4.9 - RIN3
		4.10 - PML
		4.11 - 7q33 Locus
		4.12 - Other Susceptibility Genes and Loci
	5 - Animal models
		5.1 - Models of PDB Mimicking Measles Infection
		5.2 - Genetic Models of PDB
			5.2.1 - SQSTM1
			5.2.2 - VCP
			5.2.3 - OPTN
		5.3 - Complex Disease Models
	6 - Molecular pathology
		6.1 - Cellular Abnormalities
		6.2 - Cytokines and Growth Factors
		6.3 - Intracellular Signaling Pathways
		6.4 - Somatic Mutations
	7 - Molecular diagnosis
	8 - Conclusions
	References
Chapter 26 - Mendelian Disorders of RANKL/OPG/RANK/NF-kB Signaling
	1 - Introduction
	2 - Disorders from constitutive RANK activation
		2.1 - Familial Expansile Osteolysis
			2.1.1 - FEO(Ger)
			2.1.2 - FEO(NI)
			2.1.3 - FEO(Am)
			2.1.4 - FEO(Sp)
			2.1.5 - Additional Reports of FEO
			2.1.6 - FEO Treatment
		2.2 - Early-Onset Paget’s Disease of Bone (PDB2)
			2.2.1 - PDB2(Jpn)
			2.2.2 - PDB2(Chn)
		2.3 - Expansile Skeletal Hyperphosphatasia
		2.4 - Panostotic Expansile Bone Disease
		2.5 - Juvenile Paget’s Disease, Type 2 (JPD2)
		2.6 - Other Phenotypes
		2.7 - Pathogenesis From Constitutive RANK Activation
		2.8 - Phenotype Variation of FEO, PDB2, ESH, PEBD, and JPD2
	3 - Disorders of OPG deficiency
		3.1 - Juvenile Paget’s Disease
		3.2 - Acquired OPG Deficiency
	4 - Disorders of the NF-kB complex
	5 - Disorders Of RANKL and RANK deactivation
	6 - Conclusions
	Acknowledgments
	Abbreviations
	References
Chapter 27 - Skeletal Dysplasias
	1 - Introduction
	2 - Classification of skeletal dysplasias
	3 - Diagnosis
	4 - Multiple epiphyseal dysplasias
	5 - Metaphyseal dysplasias
	6 - Conclusions
	References
Chapter 28 - Hypophosphatasia and How Alkaline Phosphatase Promotes Mineralization
	1 - Introduction
	2 - Molecular biology and biochemistry of alkaline phosphatase
	3 - Physiology of skeletal mineralization
	4 - Hypophosphatasia
		4.1 - History
		4.2 - Clinical Features
			4.2.1 - Perinatal Hypophosphatasia
			4.2.2 - Infantile Hypophosphatasia
			4.2.3 - Childhood Hypophosphatasia
			4.2.4 - Adult Hypophosphatasia
			4.2.5 - Odontohypophosphatasia
			4.2.6 - Pseudohypophosphatasia
			4.2.7 - Benign Prenatal Hypophosphatasia
		4.3 - Laboratory Findings
			4.3.1 - Biochemical
				4.3.1.1 - ALP Activity
				4.3.1.2 - Minerals
				4.3.1.3 - Routine Studies
				4.3.1.4 - TNSALP Natural Substrates
		4.4 - Radiological Findings
		4.5 - Histopathological Findings
			4.5.1 - Skeleton
			4.5.2 - Dentition
		4.6 - Biochemical and Genetic Defect
			4.6.1 - TNSALP Deficiency
			4.6.2 - Genetic Defect in HPP
			4.6.3 - Inheritance
			4.6.4 - Epigenetic and Nongenetic Effects
		4.7 - Treatment
			4.7.1 - Prognosis
			4.7.2 - Supportive
			4.7.3 - Experimental
			4.7.4 - Prenatal Diagnosis
		4.8 - Mouse Model for Hypophosphatasia
	5 - Enzyme replacement therapy for HPP
	6 - Physiological role of alkaline phosphatase explored in hypophosphatasia
		6.1 - Phosphoethanolamine
		6.2 - Pyridoxal 5′-Phosphate
		6.3 - Inorganic Pyrophosphate
		6.4 - Alkaline Phosphatase in Serum
		6.5 - Overview for Tissue-Nonspecific Alkaline Phosphatase Function
	Acknowledgments
	Abbreviations
	References
Chapter 29 - Sclerosing Bone Disorders
	1 - Introduction
	2 - Clinical aspects of the sclerosing bone disorders
	3 - Molecular genetics and pathogenic mechanisms
		3.1 - Disorders Caused by Bone Resorption Defects
			3.1.1 - Osteopetroses
			3.1.2 - Pycnodysostosis
			3.1.3 - Osteosclerotic Metaphyseal Dysplasia
		3.2 - Disorders Caused by Increased Bone Formation
			3.2.1 - High–Bone Mass Phenotype, Sclerosteosis, and van Buchem’s Disease
			3.2.2 - Osteopathia Striata With Cranial Sclerosis
			3.2.3 - Osteopoikilosis and Melorheostosis
			3.2.4 - Craniometaphyseal Dysplasia
			3.2.5 - Camurati–Engelmann Disease
			3.2.6 - Lenz–Majewski Syndrome
			3.2.7 - Tricho–Dento–Osseous Syndrome
			3.2.8 - Raine Syndrome
	4 - Diagnostics, treatment, and genetic counseling
	References
Chapter 30 - Fibrodysplasia (Myositis) Ossificans Progressiva
	1 - Introduction
	2 - Clinical description: fibrodysplasia ossificans progressiva
		2.1 - Heterotopic Endochondral Ossification in FOP
		2.2 - Histopathology of FOP Lesions
		2.3 - Skeletal Development in FOP
		2.4 - Additional Clinical Features of FOP
		2.5 - Atypical FOP Phenotypes
	3 - Genetics and molecular genetics of FOP
		3.1 - ACVR1 (ALK2) R206H Mutations in FOP
		3.2 - ACVR1 Mutations in Atypical FOP
		3.3 - Phenotypic Variability
		3.4 - ACVR1 Mutations in Diffuse Intrinsic Pontine Gliomas (DIPGs)
	4 - Animal models
		4.1 - In Vivo Models for BMP Signaling
			4.1.1 - Drosophila and Mutations in Sax
			4.1.2 - Zebrafish Models and the Alk8 Receptor
			4.1.3 - BMP Signaling in Genetically-Engineered Mouse Models
		4.2 - BMP Induction of Endochondral Ossification in Nongenetic and Genetic Models
			4.2.1 - Nongenetic Induction of HO: BMP Implants
			4.2.2 - Transgenic Mice Overexpressing BMP: Nse-BMP4
			4.2.3 - Constitutively Active Alk2 Mice (Alk2Q207D)
			4.2.4 - Acvr1 R206H Knock-In and Conditional Knock-In Mice
		4.3 - Nongenetic Injury-Induced Models of Heterotopic Ossification
		4.4 - Naturally Occurring Animal Models of Heterotopic Ossification
		4.5 - Osteochondromas and Mouse Models
	5 - Functional and molecular pathology
		5.1 - BMP Signaling and ACVR1/ALK2
			5.1.1 - Structural Modeling of Mutant ALK2 Receptors
			5.1.2 - BMP Pathway Signaling in FOP Patient Cells
			5.1.3 - Effects of ACVR1/ALK2 Mutations on BMP Pathway Signaling
			5.1.4 - Activin A Induction of TGFβ/BMP Signaling Pathway
		5.2 - Effects of FOP ACVR1/ALK2 Mutation on Lesion Progression
			5.2.1 - Immunological Contributions to Heterotopic Ossification Development in FOP
			5.2.2 - Role of Activin A in FOP Lesion Pathology
			5.2.3 - Role of Hypoxia in Heterotopic Ossification Pathology
			5.2.4 - Origin of Progenitor Cells Contributing to HO Formation
			5.2.5 - Chondrogenesis and Osteogenesis
	6 - Diagnostic aspects
	7 - Counseling and treatment
		7.1 - Blocking Activity of the Mutant Receptor in FOP
		7.2 - Altering the Cellular Microenvironment Supporting Heterotopic Ossification
		7.3 - Diverting Progenitor Cells From an Osseous to a Soft Tissue Fate
	8 - Conclusions
	Acknowledgments
	References
Chapter 31 - Thyroid Hormone in Bone and Joint Disorders
	1 - Introduction
	2 - Thyroid hormone physiology and action
		2.1 - Hypothalamic-Pituitary-Thyroid Axis
		2.2 - TSH Action
		2.3 - Thyroid Hormone Transport
		2.4 - Thyroid Hormone Metabolism
		2.5 - Nuclear Actions of Thyroid Hormones
		2.6 - Nongenomic Actions of Thyroid Hormones
	3 - Role of thyroid hormones in skeletal growth and development
		3.1 - Skeletal Cell Types
		3.2 - Intramembranous and Endochondral Ossification
		3.3 - Linear Growth and Bone Modeling
		3.4 - Expression of TSH, TSHR, Thyroid Hormone Transporters, Deiodinases, and Thyroid Hormone Receptors in Skeletal Cells
		3.5 - Pediatric Consequences of Thyroid Dysfunction
		3.6 - Genetic Disorders of Thyroid Signaling
			3.6.1 - TSHB
				3.6.1.1 - Loss-of-Function Mutations
			3.6.2 - TSHR
				3.6.2.1 - Loss-of-Function Mutations
				3.6.2.2 - Gain-of-Function Mutations
			3.6.3 - SBP2
				3.6.3.1 - Loss-of-Function Mutations
			3.6.4 - THRB
				3.6.4.1 - Dominant-Negative Mutations
			3.6.5 - THRA
				3.6.5.1 - Dominant-Negative Mutations
				3.6.5.2 - Mutations Affecting TRα1
				3.6.5.3 - Mutations Affecting Both TRα1 and α2
		3.7 - TSH Action in the Growth Plate
		3.8 - Thyroid Hormone Action in the Growth Plate
	4 - Role of thyroid hormones in bone maintenance and mass
		4.1 - Bone Remodeling Cycle
		4.2 - Clinical Consequences of Thyroid Dysfunction
			4.2.1 - Discriminating Thyroid Hormone and TSH Effects on the Skeleton
			4.2.2 - Consequences of Variation of Thyroid Status Within the Reference Range
			4.2.3 - Consequences of Hypothyroidism
			4.2.4 - Consequences of Subclinical Hypothyroidism
			4.2.5 - Consequences of Subclinical Hyperthyroidism
			4.2.6 - Consequences of Hyperthyroidism
		4.3 - Human Population Studies
		4.4 - TSH Action in Osteoblasts and Osteoclasts
		4.5 - Thyroid Hormone Action in Osteoblasts and Osteoclasts
			4.5.1 - Osteoblasts
			4.5.2 - Osteoclasts
	5 - Genetically modified mice
		5.1 - Targeting TSHR Signaling
			5.1.1 - Skeletal Development and Growth
			5.1.2 - Adult Bone Maintenance
		5.2 - Targeting Thyroid Hormone Transport and Metabolism
			5.2.1 - Thyroid Hormone Transporters
			5.2.2 - Deiodinases
		5.3 - Targeting TRα (Fig. 31.4)
		5.4 - Targeting TRβ (Fig. 31.4)
			5.4.1 - Cellular and Molecular Mechanisms
			5.4.2 - Downstream Signaling Responses in Skeletal Cells
	6 - Role of thyroid hormones in osteoarthritis
		6.1 - Human Population Studies
		6.2 - Rodent Models of Osteoarthritis
		6.3 - Thyroid Hormone Action in Articular Chondrocytes
	7 - Conclusions
	Acknowledgments
	References
Chapter 32 - Disorders and Mechanisms of Ectopic Calcification
	1 - Introduction
	2 - Disorders of ectopic calcification
		2.1 - Generalized Arterial Calcification of Infancy (GACI)
			2.1.1 - Clinical Presentation and Diagnostic Aspects
			2.1.2 - Molecular Genetics
			2.1.3 - Treatment
		2.2 - Arterial Calcification due to Deficiency of CD73 (ACDC)
			2.2.1 - Clinical Presentation and Diagnostic Aspects
			2.2.2 - Molecular Genetics
			2.2.3 - Treatment
		2.3 - Pseudoxanthoma Elasticum (PXE)
			2.3.1 - Clinical Presentation and Diagnostic Aspects
			2.3.2 - Molecular Genetics
			2.3.3 - Treatment
		2.4 - Familial Chondrocalcinosis Type 2
			2.4.1 - Clinical Presentation and Diagnostic Aspects
			2.4.2 - Molecular Genetics
			2.4.3 - Treatment
		2.5 - Familial Tumoral Calcinosis (FTC)
			2.5.1 - Clinical Presentation and Diagnostic Aspects
			2.5.2 - Molecular Genetics
			2.5.3 - Treatment
		2.6 - Idiopathic Basal Ganglia Calcification (IBGC)
			2.6.1 - Clinical Presentation and Diagnostic Aspects
			2.6.2 - Molecular Genetics
			2.6.3 - Treatment
		2.7 - Keutel Syndrome
			2.7.1 - Clinical Presentation and Diagnostic Aspects
			2.7.2 - Molecular Genetics
			2.7.3 - Treatment
		2.8 - Singleton–Merten Syndrome (SMS)
			2.8.1 - Clinical Presentation and Diagnostic Aspects
			2.8.2 - Molecular Genetics
			2.8.3 - Treatment
		2.9 - Mönckeberg Medial Calcific Sclerosis
	3 - Animal models
		3.1 - GACI, PXE, and ACDC
		3.2 - Chondrocalcinosis and Craniometaphyseal Dysplasia
		3.3 - Tumoral Calcinosis
		3.4 - Idiopathic Basal Ganglia Calcification
		3.5 - Keutel Syndrome
		3.6 - Singleton–Merten Syndrome
		3.7 - Chronic Kidney Disease, Diabetes, and Aging
	4 - Disease mechanisms
		4.1 - Regulators of Calcification: Phosphate, Pyrophosphate, and Matrix Gla Protein
		4.2 - Phosphate
		4.3 - Pyrophosphate
		4.4 - Matrix Gla Protein
		4.5 - Local Versus Circulating Hypotheses
		4.6 - Osteochondrogenic Differentiation
		4.7 - Viral Mechanisms
	5 - Conclusions
	References
Section 4: Parathyroid and Related Disorders
Chapter 33 - Hyperparathyroidism
	1 - Familial hyperparathyroidism
		1.1 - MEN1
		1.2 - MEN2
		1.3 - MEN4
		1.4 - HPT-JT
		1.5 - FIHPT
		1.6 - FHH/NSHPT
	2 - Sporadic hyperparathyroidism
		2.1 - Parathyroid Adenoma
			2.1.1 - MEN1
			2.1.2 - CCND1
			2.1.3 - CDKN1B/CDKIs
			2.1.4 - β-Catenin
			2.1.5 - EZH2
			2.1.6 - ZFX
			2.1.7 - CDC73
			2.1.8 - Calcium-Sensing Receptor
			2.1.9 - Mitochondrial DNA
			2.1.10 - Additional Genetic Aspects
			2.1.11 - Epigenetics
		2.2 - Parathyroid Carcinoma
			2.2.1 - CDC73
			2.2.2 - Additional Genetic Considerations
	3 - Ectopic PTH production
	References
Chapter 34 - Hypoparathyroidism
	1 - Introduction
	2 - Clinical and Diagnostic Aspects
	3 - Complex syndromes associated with hypoparathyroidism
		3.1 - DiGeorge Syndrome
			3.1.1 - Mouse Models for DGS1
		3.2 - Hypoparathyroidism, Deafness, and Renal Anomalies Syndrome
			3.2.1 - Mouse Model for HDR
		3.3 - Mitochondrial Disorders Associated With Hypoparathyroidism
		3.4 - Kenny–Caffey, Sanjad–Sakati, and Kirk–Richardson Syndromes
			3.4.1 - Mouse Models With Tbce Abnormalities
		3.5 - Additional Familial Syndromes
		3.6 - Pluriglandular Autoimmune Hypoparathyroidism
			3.6.1 - Mouse Model With Aire1 Deletion
	4 - Abnormalities of the calcium-sensing receptor and G-protein subunit α11
		4.1 - ADH1 and Bartter Syndrome Type V
			4.1.1 - Mouse Models for ADH1
		4.2 - ADH2
			4.2.1 - Preclinical Studies and Early Clinical Trial of Calcilytics for Treatment of ADH
		4.3 - Autoimmune Acquired Hypoparathyroidism (AH)
	5 - Isolated hypoparathyroidism
		5.1 - Autosomal Hypoparathyroidism, and PTH Gene Abnormalities
			5.1.1 - Mouse Model With Pth deletion
		5.2 - Autosomal Hypoparathyroidism and GCMB Abnormalities
			5.2.1 - Mouse Model With Gcm2 Deletion
		5.3 - X-linked Recessive Hypoparathyroidism
	6 - Gene Testing in Clinical Practice
	7 - Treatment
	8 - Conclusions
	Acknowledgments
	References
Chapter 35 - Gsα, Pseudohypoparathyroidism, Fibrous Dysplasia, and McCune–Albright Syndrome
	1 - Introduction
	2 - Pseudohypoparathyroidism/Albright hereditary osteodystrophy
		2.1 - Brief Clinical Description
		2.2 - Genetics Description
		2.3 - Molecular Genetics
		2.4 - Animal Models
		2.5 - Functional and Molecular Pathology
		2.6 - Diagnosis
		2.7 - Counseling
		2.8 - Treatment
	3 - Fibrous dysplasia/McCune–Albright syndrome
		3.1 - Brief Clinical Description
		3.2 - Genetics Description
		3.3 - Molecular Genetics
		3.4 - Animal Models
		3.5 - Functional and Molecular Pathology
		3.6 - Diagnostic
		3.7 - Counseling
		3.8 - Treatment
	References
Chapter 36 - Genetic Disorders Caused by Mutations in the PTH/PTHrP Receptor, its Ligands, and Downstream Effector Molecules
	1 - Introduction
	2 - The PTH/PTHrP receptor system
		2.1 - Parathyroid Hormone (PTH)
		2.2 - Parathyroid Hormone-Related Peptide (PTHrP)
		2.3 - The PTH/PTHrP receptor and its role in endochondral bone formation
	3 - Human disorders caused by mutations in the PTH-PTHrP signaling pathway
		3.1 - PTH, GCM2, and GNA11 Mutations
		3.2 - PTHLH Mutations
		3.3 - PTH1R Mutations
			3.3.1 - Jansen’s Metaphyseal Chondrodysplasia
				3.3.1.1 - Jansen’s Disease is Caused by Activating PTH/PTHrP Receptor Mutations
			3.3.2 - Blomstrand’s Lethal Chondrodysplasia
				3.3.2.1 - Blomstrand’s Disease is Caused by Inactivating PTH/PTHrP Receptor Mutations
			3.3.3 - Eiken Familial Skeletal Dysplasia
			3.3.4 - Enchondromatosis (Ollier’s Disease)
			3.3.5 - Delayed Tooth Eruption Due to PTH/PTHrP Receptor Mutations
	4 - Mutations in genes down-stream of the PTH/PTHrP receptor
		4.1 - GNAS Mutations
		4.2 - PRKAR1A Mutations
		4.3 - PDE4D Mutations
		4.4 - HDAC4 Mutations
	5 - Conclusions
	References
Chapter 37 - Genetically Determined Disorders of Extracellular Calcium (  ) Sensing and    Homeostasis
	1 - Introduction
	2 - Clinical and genetic features of familial hypocalciuric hypercalcemia, including FHH, type 1 (FHH1) (OMIM #145980; alte...
		2.1 - Clinical Features of FHH
		2.2 - Genetics of FHH
		2.3 - Molecular Genetics
		2.4 - Animal Models
		2.5 - Functional and Molecular Pathology
		2.6 - Diagnostic Aspects
		2.7 - Counseling
		2.8 - Treatment
	3 - Clinical and genetic features of neonatal severe primary hyperparathyroidism [OMIM 239200]
		3.1 - Clinical Description
		3.2 - Genetics
		3.3 - Molecular Genetics
		3.4 - Functional and Molecular Pathology
		3.5 - Diagnostic Aspects
		3.6 - Counseling
		3.7 - Treatment
	4 - Clinical and genetic features of autosomal dominant hypoparathyroidism caused by activating mutations of the CaSR [OMIM...
		4.1 - Clinical Description
		4.2 - Genetics and Molecular Genetics
		4.3 - Animal Model
		4.4 - Functional and Molecular Pathology
		4.5 - Diagnostic Aspects
		4.6 - Counseling
		4.7 - Treatment
	5 - Clinical and genetic features of Bartter’s syndrome subtype V arising from activating mutations of the CaSR: [OMIM - #6...
		5.1 - Clinical Description
		5.2 - Genetic, Molecular Genetic, Functional, and Molecular Pathology
		5.3 - Diagnostic Aspects, Counseling, and Treatment
	References
Chapter 38 - Multiple Endocrine Neoplasia Syndromes
	1 - Introduction
	2 - Multiple endocrine neoplasia type 1
		2.1 - Parathyroid Tumors
			2.1.1 - Clinical Findings
			2.1.2 - Treatment
		2.2 - MEN1-Associated Primary Hyperparathyroidism and Relevance to Skeletal Disease
		2.3 - Pancreatic Tumors
			2.3.1 - Gastrinoma
				2.3.1.1 - Clinical Findings
				2.3.1.2 - Treatment
			2.3.2 - Insulinoma
				2.3.2.1 - Clinical Findings
				2.3.2.2 - Treatment
			2.3.3 - Glucagonoma
				2.3.3.1 - Clinical Findings
				2.3.3.2 - Treatment
			2.3.4 - Vasoactive Intestinal Peptide (VIP) Tumors (VIPomas)
				2.3.4.1 - Clinical Findings
				2.3.4.2 - Treatment
			2.3.5 - Other Rare Functioning Pancreatic NETs
			2.3.6 - Nonfunctioning Pancreatic Neuroendocrine Tumors
				2.3.6.1 - Clinical Findings
				2.3.6.2 - Treatment
		2.4 - MEN1-Associated Pancreatic NETs and Relevance to Skeletal Disease
		2.5 - Pituitary Tumors
			2.5.1 - Clinical Findings
			2.5.2 - Treatment
		2.6 - MEN1-Associated Pituitary Tumors and Relevance to Skeletal Disease
			2.6.1 - Prolactinoma
			2.6.2 - Somatotrophinomas and Growth Hormone
			2.6.3 - Corticotrophinomas and Glucocorticoid Excess
		2.7 - Carcinoid Tumors
			2.7.1 - Clinical Findings
			2.7.2 - Treatment
		2.8 - MEN1-Associated Carcinoid Tumors and Relevance to Skeletal Disease
		2.9 - Adrenocortical Tumors
			2.9.1 - Clinical Findings
			2.9.2 - Treatment
		2.10 - MEN1-Associated Adrenal Tumors and Relevance to Skeletal Disease
		2.11 - Other Clinical Manifestations of MEN1
		2.12 - MEN1 Gene Function and Clinical Applications
		2.13 - Function of MEN1 Protein (Menin) and Relevance to Bone Biology
		2.14 - MEN1 Mutational Analysis in Clinical Practice
	3 - Multiple endocrine neoplasia types 2 and 3 (MEN2 and MEN3)
		3.1 - Medullary Thyroid Cancer
			3.1.1 - Clinical Findings
			3.1.2 - Treatment
			3.1.3 - Prophylactic Surgery
		3.2 - MEN2- and MEN3-Associated MTC and Relevance to Skeletal Disease
			3.2.1 - Skeletal Involvement in Metastatic MTC
			3.2.2 - Role of Calcitonin on Bone Metabolism
			3.2.3 - Hypoparathyroidism Following Thyroid Surgery
			3.2.4 - Ectopic Cushing’s/Osteoporosis
			3.2.5 - Use of TKIs and Effects on Bone
		3.3 - Pheochromocytoma
			3.3.1 - Clinical Findings
			3.3.2 - Treatment and Screening
		3.4 - Primary Hyperparathyroidism
			3.4.1 - Clinical Features and Treatment
		3.5 - Other Manifestations: Hirschsprung’s Disease and Cutaneous Lichen Sclerosis
		3.6 - Genetics
		3.7 - Functions of the RET Oncogene and Relevance to Skeletal Biology
	4 - Multiple endocrine neoplasia type 4 (MEN4)
		4.1 - Clinical Findings and Treatment
		4.2 - Genetics and Screening
	5 - Multiple endocrine and other organ neoplasias (MEONs) syndromes
	6 - Hyperparathyroidism-jaw tumor syndrome
		6.1 - Clinical Findings and Treatment
		6.2 - HPT-JT and Relevance to Skeletal Disease
		6.3 - Genetics and Screening
		6.4 - Parafibromin: Function and Relevance to Bone Biology
	7 - Neurofibromatosis type 1
		7.1 - Clinical Findings and Treatment
			7.1.1 - Endocrine Abnormalities
		7.2 - NF-1 and Relevance to Skeletal Disease
		7.3 - Genetics and Screening
		7.4 - Neurofibromin Function and Bone
	8 - Von Hippel–Lindau disease
		8.1 - Clinical Findings and Treatments
		8.2 - VHL and Relevance to Skeletal Disease
		8.3 - Genetics and Screening
		8.4 - Role of VHL in Bone Biology
	9 - Carney complex
		9.1 - Clinical Findings and Treatment
		9.2 - Carney Complex and Relevance to Skeletal Disease
		9.3 - Genetics and Screening
		9.4 - Role of cAMP-Protein Kinase A Signaling and PRKAR1A in Bone Biology
	10 - Cowden syndrome
		10.1 - Clinical Findings and Treatment
		10.2 - Cowden’s Syndrome and Relevance to Skeletal Disease
		10.3 - Genetics and Screening
		10.4 - PTEN and Relevance to Skeletal Biology
	11 - McCune–Albright syndrome
		11.1 - Clinical Findings and Treatment
		11.2 - McCune–Albright Syndrome and Relevance to Skeletal Disease
		11.3 - Genetics and Screening
		11.4 - MAS and Relevance to Skeletal Biology
	References
Section 5: Vitamin D and Renal Disorders
Chapter 39 - Genetic Disorders Of Vitamin D Synthesis and Action
	1 - Introduction
	2 - Biosynthesis of 1,25-dihydroxyvitamin D
		2.1 - Overview of Vitamin D Biosynthetic Enzymes
		2.2 - Vitamin D 25-Hydroxylases
		2.3 - Vitamin D 24-Hydroxylase
		2.4 - Vitamin D 1α-Hydroxylase
		2.5 - 1α-Hydroxylase Deficiency
		2.6 - CYP27B1 Mutations Causing 1α-Hydroxylase Deficiency
		2.7 - Treatment of 1α-Hydroxylase Deficiency
		2.8 - Other Pathways of Vitamin D Metabolism
	3 - Hereditary vitamin D–resistant rickets
		3.1 - Structure of the Vitamin D Receptor
		3.2 - Clinical Picture
		3.3 - Mutations in the VDR Gene That Lead to HVDRR
		3.4 - Animal Models
		3.5 - Treatment
		3.6 - Alopecia
	4 - Conclusions
	References
Chapter 40 - Heritable Renal Phosphate Wasting Disorders
	1 - Introduction
	2 - Phosphate homeostasis
	3 - Phosphate regulation of vitamin D metabolism
	4 - The heritable renal phosphate wasting disorders
		4.1 - Autosomal Dominant Hypophosphatemic Rickets
			4.1.1 - Clinical Presentation and Diagnostic Aspects
			4.1.2 - Genetic Abnormality
			4.1.3 - Molecular Genetics and Animal Model
			4.1.4 - Genetic Testing
			4.1.5 - Treatment
		4.2 - X-Linked Hypophosphatemia
			4.2.1 - Clinical Presentation and Diagnostic Aspects
			4.2.2 - Genetic Abnormality
			4.2.3 - Molecular Genetics and Animal Models
			4.2.4 - Genetic Testing
			4.2.5 - Treatment
		4.3 - Autosomal Recessive Hypophosphatemic Rickets
			4.3.1 - Clinical Presentation and Diagnostic Aspects
			4.3.2 - Genetic Abnormality
			4.3.3 - Molecular Genetics and Animal Models
			4.3.4 - Genetic Testing
			4.3.5 - Treatment
	5 - Other disorders
	6 - Conclusions
		6.1 - Model
		6.2 - Predictions
		6.3 - Clinical Implications
	Acknowledgments
	References
Chapter 41 - Renal Fanconi Syndrome, Dent Disease, and Bartter Syndrome
	1 - Brief clinical description
	2 - Pathophysiology of the disease
		2.1 - General Considerations
		2.2 - Metabolic Bone Disease: Rickets and Osteomalacia
		2.3 - Polyuria, Polydipsia, and Dehydration
		2.4 - Urinary Bicarbonate Loss and Acidemia
		2.5 - Glucosuria
		2.6 - Phosphaturia and Hypophosphatemia
		2.7 - Urinary Sodium Loss and Secondary Potassium Loss
		2.8 - Uricosuria and Hypouricemia
		2.9 - Generalized Aminoaciduria
		2.10 - Low-Molecular-Weight Proteinuria
		2.11 - Decreased Urinary Excretion of Osteopontin and Uromodulin
	3 - Etiologies
		3.1 - Idiopathic Fanconi Syndrome
		3.2 - Hereditary Fanconi Syndrome
			3.2.1 - Phosphate Transporter NaPi-IIa Deficiency
			3.2.2 - Mitochondriopathies
			3.2.3 - Lowe Syndrome
			3.2.4 - Cystinosis
			3.2.5 - Galactosemia
			3.2.6 - Hereditary Fructose Intolerance
			3.2.7 - Glycogen Storage Disease Type I (von Gierke Disease)
			3.2.8 - Fanconi–Bickel Syndrome
			3.2.9 - Tyrosinemia Type I
			3.2.10 - Wilson Disease
			3.2.11 - Maturity-Onset Diabetes of the Young (MODY) Types 1, 3, and 5
			3.2.12 - Microvillous Inclusion Disease
			3.2.13 - Lysinuric Protein Intolerance
		3.3 - Acquired Fanconi Syndrome
		3.4 - Exogenous Factors
			3.4.1 - Drugs
			3.4.2 - Chemical Compounds
			3.4.3 - Heavy Metals
			3.4.4 - Honeybee Stings
	4 - Diagnostic aspects
	5 - Genetic counseling
	6 - Treatment
		6.1 - Specific Treatments
		6.2 - Correction of Fluid and Electrolyte Disturbances
		6.3 - Treatments of Metabolic Bone Diseases and Growth Failure
	7 - Dent disease
		7.1 - Clinical Description
			7.1.1 - Dent Disease 1
			7.1.2 - Dent Disease 2
		7.2 - Genetics
		7.3 - Pathophysiology
			7.3.1 - Dent Disease 1
			7.3.2 - Dent Disease 2
		7.4 - Diagnostic Aspects
		7.5 - Genetic Counseling
		7.6 - Treatment
	8 - Bartter’s Syndrome
	References
Chapter 42 - Inherited Magnesium Disorders
	1 - Introduction
	2 - Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)
		2.1 - Clinical Features
		2.2 - Molecular Genetics of Claudins-16 and -19
		2.3 - Claudins and Renal Physiology
		2.4 - Animal Models
		2.5 - Diagnosis and Treatment
	3 - Primary hypomagnesemia and secondary hypocalcemia (HSH)
		3.1 - Physiology of TRPM6
		3.2 - Animal Model
		3.3 - Treatment Considerations
	4 - Isolated autosomal recessive hypomagnesemia (IRH)
		4.1 - Role of Epidermal Growth Factor
	5 - Autosomal dominant renal hypomagnesemia with hypocalciuria
		5.1 - FXYD2
		5.2 - HNF1B/PCBD1
	6 - Gitelman syndrome
		6.1 - Molecular Defect and Genetics in Gitelman Syndrome: SLC12A3 and NCCT
		6.2 - Pathophysiology
		6.3 - Phenotype Variability and Clinical Features
		6.4 - Treatment of Gitelman Syndrome
	7 - Hypomagnesemia in Bartter syndrome
	8 - Autosomal dominant hypocalcemia
	9 - Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME Syndrome)/epilepsy, ata...
		9.1 - Role of Kir4.1 in Kidney
		9.2 - Genetics and Clinical Features
	10 - KCNA1/Kv1.1 mutation and its association with isolated hypomagnesemia
		10.1 - Mechanism for the Associated Hypomagnesemia
	11 - Hypomagnesaemia with mitochondrial inheritance
	12 - CNNM2 mutations in dominant hypomagnesemia
	13 - Treatment and counseling
	References
Chapter 43 - Genetic Hypercalciuria: A Major Risk Factor in Kidney Stones
	1 - Introduction
	2 - Clinical description and definition
	3 - Human kidney stones and hypercalciuria: a complex genetic trait
		3.1 - A Formidable Problem
		3.2 - Familial Aggregation
		3.3 - Twin Studies
		3.4 - Classical Nature versus Nurture
		3.5 - Candidate Gene Approach
		3.6 - Genome-Wide Associations
		3.7 - Summary
	4 - Monogenetic causes of hypercalciuria
	5 - Animal models
		5.1 - A Rodent Model of Polygenic Hypercalciuria
		5.2 - Stone Formation in Genetic Hypercalciuric Rats
		5.3 - Decreased Bone Density in Hypercalciuria
			5.3.1 - Humans
			5.3.2 - Hypercalciuric Rats
	6 - Clinical pathophysiology
	7 - Counseling and treatment
	References
Index
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