Shafer's Textbook of Oral Pathology 7th Edition PDF

Shafer Hine Levy Shafer’s Textbook of Oral Pathology Seventh Edition R Rajendran, MDS, PhD, FRCPath Professor and Consultant, Division of Oral Pathology, College of Dentistry, King Saud Bin Abdul Aziz University for Health Sciences, National Guard Health Affairs (NGHA), Riyadh, Kingdom of Saudi Arabia Formerly Professor and Head, Department of Oral Pathology and Microbiology, Government Dental College, Trivandrum, INDIA B Sivapathasundharam, MDS Professor and Head, Department of Oral Pathology, Meenakshi Ammal Dental College, Chennai, INDIA 2 Table of Contents Cover image Title page Copyright Dedication Foreword Preface to the Seventh Edition Preface to the First Edition Contributors Acknowledgements Section I: Disturbances of Development and Growth Chapter 1: Developmental Disturbances of Oral and Paraoral Structures Craniofacial Anomalies Developmental Disturbances of Jaws Abnormalities of Dental Arch Relations 3 Developmental Disturbances of Lips And Palate Hereditary Intestinal Polyposis Syndromen Developmental Disturbances of Oral Mucosa Developmental Disturbances of Gingiva Developmental Disturbances of Tongue Developmental Disturbances of Oral Lymphoid Tissue Developmental Disturbances of Salivary Glands Developmental Disturbances in Size of Teeth Developmental Disturbances in Shape of Teeth Developmental Disturbances in Number of Teeth Developmental Disturbances in Structure of Teeth Disturbances of Growth (Eruption) of Teeth Fissural (Inclusion, Developmental) Cysts of Oral Region Chapter 2: Benign and Malignant Tumors of the Oral Cavity Benign Tumors of Epithelial Tissue Origin ‘Premalignant’ Lesions/Conditions of Epithelial Tissue Origin Malignant Tumors of the Epithelial Tissue Origin 4 Benign Tumors of Connective Tissue Origin Malignant Tumors of Connective Tissue Origin Benign Tumors of Muscle Tissue Origin Malignant Tumors of Muscle Tissue Origin Benign Tumors of Nerve Tissue Origin Malignant Tumors of Nerve Tissue Origin Chapter 3: Tumors of the Salivary Glands Benign Tumors of the Salivary Glands Malignant Tumors of the Salivary Glands Other Carcinomas Chapter 4: Cysts and Tumors of Odontogenic Origin Inflammatory Cysts Tumors of odontogenic origin Odontogenic epithelium with odontogenic ectomesenchyme with or without hard tissue formation Odontogenic ectomesenchyme with or without included odontogenic epithelium Malignant odontogenic tumors 5 Odontogenic Carcinomas Section II: Diseases of Microbial Origin Chapter 5: Bacterial Infections of the Oral Cavity Chapter 6: Viral Infections of the Oral Cavity Oral Manifestations of Hiv Infection Human Immunodeficiency Virus Chapter 7: Mycotic Infections of the Oral Cavity Chapter 8: Diseases of the Periodontium The Healthy Periodontium Classification of Periodontal Disease Gingival Diseases Enlargement Associated with Systemic Factors Periodontitis Peri-Implantitis Chapter 9: Dental Caries Etiology of Dental Ca ries Clinical Aspects of Dental Caries 6 Histopathology of Dental Caries Diagnosis of Dental Caries Methods of Caries Control Chapter 10: Diseases of the Pulp and Periapical Tissues Diseases of Dental Pulp Classification of Pulpitis Diseases of Periapical Tissues Osteomyelitis Chapter 11: Spread of Oral Infection Infections of Specific Tissue Spaces Ludwig’s Angina Maxillary Sinusitis Focal Infection Section III: Injuries and Repair Chapter 12: Physical and Chemical Injuries of the Oral Cavity Injuries of Teeth Associated with Tooth Preparation Effect of Heat 7 Effect of Restorative Materials Physical Injuries of the Teeth Physical Injuries of the Bone Occupational Injuries of the Oral Cavity Occlusal Trauma Chapter 13: Regressive Alterations of the Teeth Attrition, Abrasion and Erosion Abfraction Dentinal Sclerosis: (Transparent Dentin) Dead Tracts Secondary Dentin Reticular Atrophy of Pulp Pulp Calcification Resorption of Teeth Hypercementosis: (Cementum Hyperplasia) Cementicles Chapter 14: Healing of Oral Wounds 8 Factors Affecting Healing of Oral Wounds Complications of Wound Healing Biopsy and Healing of Biopsy Wound Exfoliative Cytology Healing of Extraction Wound Complications in Healing of Extraction Wounds Healing of Fracture Complications of Fracture Healing Replantation and Transplantation of Teeth Implants Section IV: Disturbances of the Metabolism and Immunologic Diseases Chapter 15: Oral Aspects of Metabolic Diseases Disturbances in Mineral Metabolism Disturbances in Protein Metabolism Individual Amino Acids Lysosomal Storage Diseases Disturbances in Carbohydrate Metabolism 9 Hurler Syndrome: (Mucopolysaccharidosis I, MPS IH, gargoylism) Disturbances in Lipid Metabolism Avitaminoses Disturbances in Hormone Metabolism Chapter 16: Allergic and Immunologic Diseases of the Oral Cavity Recurrent Aphthous Stomatitis: (Aphthous ulcers, aphthae, canker sores) Behçet’s Syndrome Reiter’s Syndrome Sarcoidosis: (Boeck’s sarcoid, Besnier-Boeck-Schaumann disease) Uveoparotid Fever: (Uveoparotitis, Heerfordt’s syndrome) Midline Lethal Granuloma: (Malignant granuloma, lethal granuloma, midline lethal granulomatous ulceration) Wegener’s Granulomatosis Chronic Granulomatous Disease Angioedema: (Angioneurotic edema, Quincke’s edema, giant urticaria) 10 Drug Allergy: (Drug idiosyncrasy, drug sensitivity, stomatitis or dermatitis medicamentosa) Contact Stomatitis and Dermatitis: (Stomatitis and dermatitis venenata) Contact Stomatitis from Cinnamon Flavoring Contact Stomatitis from Chronic Oral Mucosal Contact with Dental Amalgam Lichenoid Reaction: (Lichenoid mucositis, lichenoid drug reaction, lichenoid lesions) Perioral Dermatitis Latex Allergy Section V: Diseases of Specific Systems Chapter 17: Diseases of Bone and Joints Group I: Defects in Extracellular Structural Proteins (Based on Molecular Pathogenetic Classification of Genetic Disorders of Skeleton) Diseases of Bone of Questionable Etiology Diseases of Temporomandibular Joint Chapter 18: Diseases of the Blood and Blood-forming Organs Diseases Involving Red Blood Cells 11 Diseases Involving White Blood Cells Leukocytosis Diseases Involving Blood Platelets Thrombocytasthenia Diseases Involving Specific Blood Factors Chapter 19: Diseases of the Skin Pemphigus Bullous Pemphigoid (Parapemphigus) Epidermolysis Bullosa Dermatitis Herpetiformis (Duhring-Brocq disease) Acrodermatitis Enteropathica: (Zinc deficiency) Systemic Lupus Erythematosus Systemic Sclerosis: (Scleroderma, dermatosclerosis, hidebound disease) Ehlers-Danlos Syndrome: (Tenascin-X deficiency syndrome, lysyl hydroxylase deficiency syndrome, cutis hyperelastica) Focal Dermal Hypoplasia Syndrome: (Goltz's syndrome) Solar Elastosis: (Senile elastosis, actinic elastosis) 12 Chapter 20: Diseases of the Nerves and Muscles Diseases of the Nerves Diseases of the Muscles Heterotopic Ossification Section VI: Forensic Odontology Chapter 21: Forensic Odontology Personal Identification Dental Identification Procedures Identification in Disasters Identification from Dental Dna Palatal Rugae in Identification Dental Profiling The Dentist as an Expert Witness Acknowledgements Appendix I: Introduction to Laboratory Analyses in Oral and Maxillofacial Pathology Appendix II: Mucosal Response to Oral Prostheses: Some Pathological Considerations 13 Appendix III: Routine Histotechniques Staining and Notes on Immunohistochemistry Appendix IV: Tables of Normal Values Index 14 Copyright Shafer’s Textbook of Oral Pathology, 7/e Rajendran and Sivapathasundharam ELSEVIER A division of Reed Elsevier India Private Limited Mosby, Saunders, Churchill Livingstone, Butterworth Heinemann and Hanley & Belfus are the Health Science imprints of Elsevier. © 2012 Elsevier Fourth Edition 1983 © Saunders Fifth Edition 2006 © Elsevier Sixth Edition 2009 © Elsevier Seventh Edition 2012 © Elsevier All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means—electronic or mechanical, including photocopy, recording, or any information storage and retrieval system—without permission in writing from the publisher. 15 This adaptation of Textbook of Oral Pathology, 4/e by William G. Shafer, Maynard K. Hine and Barnet M. Levy is published by an arrangement with Elsevier Inc. Original ISBN: 978-07-216-8128-3 Indian Adaptation ISBN: 978-81-312-3097-8 Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and the duration of administration, and the contraindications. It is the responsibility of the practitioners, relying on their own experience and knowledge of the patient, and to take diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Authors assume any liability for any injury and/or damage to persons or property arising out or related to any use of the material contained in this book. Please consult full prescribing information before issuing prescription for any product mentioned in this publication. The Publisher 16 Published by Elsevier, a division of Reed Elsevier India Private Limited Registered Office: 305, Rohit House, 3 Tolstoy Marg, New Delhi-110 001 Corporate Office: 14th Floor, Building No. 10B, DLF Cyber City, Phase II, Gurgaon-122 002, Haryana, India Publishing Manager: Ritu Sharma Commissioning Editor: Nimisha Goswami Managing Editor (Development): Anand K Jha Copy Editor: Isha Bali Manager-Publishing Operations: Sunil Kumar Production Manager: NC Pant Cover Designer: Raman Kumar Typeset by Chitra Computers, New Delhi Printed and bound at Thomson Press (India) Ltd. 17 Dedication Dedicated to Prof Mansour Faris Hussein, PhD, FRCPath Department of Pathology College of Food Sciences and Agriculture King Saud University, Riyadh, Saudi Arabia For being a source of inspiration to me during this arduous journey R Rajendran my wife Dr S Rohini B Sivapathasundharam 18 Foreword It is a distinct honor and privilege to have been asked to write the foreword for this edition of Shafer's Textbook of Oral Pathology. Dr Shafer, through the text that he co-authored with Drs Maynard Hine and Barnet Levy, made a tremendous impact on the practice of dentistry from the first edition, published in 1958, to the last edition, published in 1983. It is likely that no other text has ever had such a widespread influence on the perception of a specialty of dentistry, essentially establishing that the clinical and histopathologic diagnosis of oral disease belonged to the practice of dentistry, and the practice of oral and maxillofacial pathology specifically. I was fortunate to have been one of more than 60 individuals who were trained under ‘the Chief’, as he was widely known by the people who passed through his department. Understand that he was a stern taskmaster, and he was serious about the practice of oral pathology. When a resident made a diagnosis, Dr Shafer expected that resident to know everything about that disease, and we spent hours in the library (this was in the days before computers!) tracking down who first reported that specific disease, in what year, and in what journal, as well as the most recent references related to the disease. He never allowed any of his residents to use his text as a reference, either. Perhaps he imparted the most significant concept, consciously or unconsciously, to us: knowledge and understanding of disease is an ever-changing, evolving process, and the practitioner must continually keep up with 19 the dental and medical literature in order to remain current and provide the most accurate, up-to-date patient care. This textbook, then, provides the dental clinician with some of the most current viewpoints related to the vast spectrum of disease that is encountered in the oral and maxillofacial region. The editors are to be commended on continuing Dr Shafer’s legacy to the dental and oral pathology communities. By updating and amplifying the textbook, the authors will ensure that this knowledge will be handed down to future generations of practitioners. Future editions will include the inevitable advances in our understanding of disease processes, and hopefully will provide the stimulus for new investigators wishing to advance the science of oral and maxillofacial pathology. Undoubtedly, this textbook will maintain the tradition of excellence in oral pathology education that was established by Dr Shafer and will serve as a valuable resource for students, instructors and clinicians alike. Carl M. Allen, DDS, MSD Professor and Director, Oral and Maxillofacial Pathology, College of Dentistry, The Ohio State University, Columbus, Ohio Professor, Department of Pathology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio 20 Preface to the Seventh Edition The periodic and timely revisions of Shafer’s Textbook of Oral Pathology have brought out a treatise, well conceived and written with the aim of updating the student all necessary nuances of the specialty. The scope of the present edition is an extension of this goal aimed at understanding the disease processes at a more fundamental level, the impetus being those in the maxillofacial region. While the subject appears more of loco-regional nature, as the text unfolds, its wider ramifications become more apparent and the disease entities described here appear wider in scope and nature. As in the past, this edition has also undergone an extensive revision and new topics have been included. A well thought out decision of incorporating ‘cutting edge’ technologies of relevance such as molecular markers and disease profiling, continues to be incorporated in the text with the aim of updating the subject and making it more contemporary. Scattered throughout the text one finds highlighted ‘boxes’ which stand out, yet merge imperceptibly with the rest, denoting advanced information perhaps beyond the ambit of the undergraduate curriculum. In this way, the text has been user friendly, though discriminatory of the scope and choice of its contents. We believe this approach is sensible and will be well taken by the readership. This textbook represents a treasury of information based for the most part, on the publications of our contemporaries and predecessors. In order to present the material in an informal manner, continuous referencing to 21 these sources have been discarded. However, the reader will find a list of suggested references of wider scope at the end of each chapter. This edition is peculiar in having new pieces of four-color art schematics, flowcharts and diagrams primarily aimed at comprehension of its contents and to facilitate reasoning of concepts such as the molecular basis of cancer. A change which is far reaching and marked is the hard copy format of the text which intends to minimize structural fatigue and maximize ease of usage. Finally, as was true of the fifth and sixth editions, all of our associations with the publisher, Elsevier India were pleasant and helpful. We want to thank the editorial staff of Elsevier India for their skilled and friendly assistance in helping us publish this project to completion successfully. Deficiencies and shortcomings are rather inevitable in an effort of this magnitude and for which we shall be solely responsible. This textbook is dedicated to our contemporaries and predecessors who have made this effort a reality. R. Rajendran and B. Sivapathasundharam 22 Preface to the First Edition ORAL PATHOLOGY represents the confluence of the basic sciences and clinical dentistry. Since it has no methods of its own, knowledge in this field is acquired through the adaptation of methods and disciplines of those sciences basic to dental practice, such as gross and microscopic anatomy, chemistry, microbiology and physiology, and through information obtained by clinical histories and observation of patients. Through the science of oral pathology, an attempt is made to correlate human biology with the signs and symptoms of human disease. The oral pathologist attempts to understand oral disease so that it can be properly diagnosed and adequately treated. In this text we have attempted to bring the reader to an understanding of the patient and his problems through applied basic science. We have tried to explain clinical signs and symptoms in the light of known histologic, chemical and physiologic alterations. Where possible, the prognosis of each disease is considered as a reflection of the underlying tissue changes and what we know can be done about them today. In numerous sections of the text we have attempted to integrate information from many of the basic sciences for adequate diagnosis of oral disease. This approach is a departure from that of the usual textbook of oral pathology, representing an effort to place more emphasis on the physiologic and chemical aspects of oral disease. 23 The references at the end of each chapter are extensive enough to be of value to those interested in additional reading. Only those papers which constitute good review articles or exceptional discussions or which are of historical importance are included. Because the field of oral pathology is large, much of the bibliographic material has had to be curtailed or omitted. The highlights alone have been stressed. It is our hope that this book will prove to be a stimulus to study as well as a guide for undergraduate and postgraduate students and practitioners of both dentistry and medicine. The Authors 24 Contributors Ashith B. Acharya, Assistant Professor, Department of Forensic Odontology, SDM Dental College, Dharward N. Gururaj, Reader, Department of Oral Pathology, CSI Dental College, Madurai Mahesh Verma, Director and Dean, Maulana Azad Institute of Dental Sciences, New Delhi Praveen R. Arany, National Cancer Institute National Institutes of Health, Bethesda, Maryland, USA A.R. Raghu, Professor and Head, Department of Oral Pathology, Manipal College of Dental Sciences, Manipal K. Ranganathan, Professor and Head, Department of Oral Pathology, Ragas Dental College, Chennai Anil Sukumaran, Professor and Consultant, Division of Periodontics, College of Dentistry, King Saud University, Riyadh, Saudi Arabia Nasser Nooh, Associate Professor and Chairman, Division of Maxillofacial Surgery, College of Dentistry, King Saud University, Riyadh, Saudi Arabia 25 Mansur Ahmad, Associate Professor and Director, Oral and Maxillofacial Radiology, University of Minnesota School of Dentistry, Minneapolis, USA 26 Acknowledgements The editors wish to acknowledge, with extreme gratitude, the unstinted support provided by way of literature and photograph search, website browsing, proof correction and data entry by the following friends and colleagues: Anisha Cynthia Sathyasekar, Anirudh Acharaya, Balasundaram T, Dulkanti Santhosh Reddy, Einstein T Bertein, Helen James, Jose Joy Idicula, Karthigakannan S, Kavitha B, Liza Thakur Suchdeva, Manikandhan R, Capt. Neelakandan RS, Poornima Kumar, Pritham Panja, Ramakrishnan T, Ramya Ganesh, Sriram G, Sujatha G, Saraswathi TR, Saravanakumar, Surapaneni Sunilkumar, Spencer Lilly D, Anna P Joseph, C Venugopal, PK Rajeesh Mohammad, Sabu Paul, Saleem Shaikh, Sivakumar G, Sunil Kumar Kothawar, S Sunil, Twinkle S Prasad, Vidyarani Bhat. Without their active participation and help, this edition would have been impossible to complete. In addition, Dr B Sivapathasundharam would especially like to thank Dr Rohini Sivapathasundharam, his wife for her continuous help, support and encouragement, and postgraduate students of department of oral pathology, Meenakshi Ammal Dental College for correcting the proofs; Thiru AN Radhakrishnan, Chancellor, Dr E Munirathnam Naidu, Former Vice Chancellor, Meenakshi University; and Dr P Jayakumar, Principal, Meenakshi Ammal Dental College for their constant encouragement and support. The editor also wishes to thank Dr Kavitha Bottu, Dr Thubashini 27 Kannan, Dr M Preethi, Dr B Sabari, Dr Manoj Prabhakar, Dr M Sivaramakrishnan, Dr K Karthik and Dr R Kalpana. 28 Section I Disturbances of Development and Growth 29 Chapter 1 Developmental Disturbances of Oral and Paraoral Structures R. Rajendran. Craniofacial Anomalies. Developmental Disturbances of Jaws. Abnormalities of Dental Arch Relations. Developmental Disturbances of Lips and Palate. Hereditary Intestinal Polyposis Syndrome. Developmental Disturbances of Oral Mucosa. Developmental Disturbances of Gingiva. Developmental Disturbances of Tongue. Developmental Disturbances of Oral Lymphoid Tissue. Developmental Disturbances of Salivary Glands. Developmental Disturbances in Size of Teeth 30. Developmental Disturbances in Shape of Teeth. Developmental Disturbances in Number of Teeth. Developmental Disturbances in Structure of Teeth. Disturbances of Growth (Eruption) of Teeth. Fissural (Inclusion, Developmental) Cysts of Oral Region Craniofacial Anomalies Craniofacial anomalies (CFA) are a diverse group of deformities in the growth of the head and facial bones. Anomaly is a medical term meaning ‘irregularity’ or ‘different from normal’. These abnormalities are congenital (present at birth) and have numerous variations: some are mild, others are severe and require surgery. There is no single factor that causes these abnormalities. Instead, there are many factors that may contribute to their development, including the following: Combination of genes. A child may receive a particular combination of gene(s) from one or both parents, or there may be a change in the genes at the time of conception, which results in a craniofacial anomaly. Environmental. There is no data that shows a direct correlation between any specific drug or chemical exposure 31 causing a craniofacial anomaly. However, any prenatal exposure should be evaluated. Folic acid deficiency. Folic acid is a B vitamin found in orange juice, fortified breakfast cereals, enriched grain products, and green, leafy vegetables. Studies have shown that women who do not take sufficient folic acid during pregnancy, or have a diet lacking in folic acid, may have a higher risk of having a baby with certain congenital anomalies, including cleft lip and/or cleft palate. Some of the most common types of craniofacial anomalies (Table 1-1) include: Table 1-1 Examples of most common craniofacial anomalies 32 Source: Rovin et al, 1964; Temple, 1989; Cohen et al, 1992; Lewanda et al, 1992; Croen et al, 1996; Derijcle et al, 1996; Sampson et al, 1997; Blate et al, 1998. Cleft lip and/or cleft palate. A separation that occurs in the lip or the palate or both. Cleft lip and cleft palate are the most common congenital craniofacial anomalies seen at birth. Cleft lip. An abnormality in which the lip does not completely form. The degree of the cleft lip can vary greatly, from mild (notching of the lip) to severe (large opening from the lip up through the nose). 33 Cleft palate. Occurs when the roof of the mouth does not completely close, leaving an opening that can extend into the nasal cavity. The cleft may involve either side of the palate. It can extend from the front of the mouth (hard palate) to the throat (soft palate). The cleft may also include the lip. Craniosynostosis. A condition in which the sutures in the skull of an infant close too early, causing problems with normal brain and skull growth. Premature closure of the sutures may also cause the pressure inside the head to increase and the skull or facial bones to change from a normal, symmetrical appearance. Hemifacial microsomia. A condition in which the tissues on one side of the face are underdeveloped, affecting primarily the ear (aural), mouth (oral), and jaw (mandibular) areas. Sometimes, both sides of the face can be affected and may involve the skull as well as the face. Hemifacial microsomia is also known as Goldenhar syndrome, brachial arch syndrome, facio-auriculovertebral syndrome (FAV), oculo-auriculovertebral spectrum (OAV), or lateral facial dysplasia. Vascular malformation. A birthmark or a growth, present at birth, which is composed of blood vessels that can cause functional or esthetic problems. Vascular malformations may involve multiple body systems. There are several different types of malformations, named after the type of blood vessel that is predominantly affected. Vascular malformations are 34 also known as lymphangiomas, arteriovenous malformations, and vascular gigantism. Hemangioma. A type of birthmark; the most common benign (noncancerous) tumor of the skin. Hemangiomas may be present at birth (faint red mark) or appear in the first month after birth. A hemangioma is also known as a port wine stain, strawberry hemangioma, and salmon patch. Deformational (or positional) plagiocephaly. A misshapen (asymmetrical) shape of the head (cranium) from repeated pressure to the same area of the head. Plagiocephaly literally means ‘oblique head’ (from the Greek ‘plagio’ for oblique and ‘cephale’ for head). Collectively they affect a significant proportion of the global society (Table 1-1). Global Epidemiology The frequency of occurrence of cleft lip, with or without cleft palate, has been computed on a global scale and is estimated to be 1 in every 800 newborn babies (Tables 1-2 and 1-3). A child is therefore born with a cleft somewhere in the world approximately every two-and-half minutes. Accurate data on the frequency of occurrence of these disorders is relevant for implementing strategies aimed at primary prevention and effective management of these disabled children (Table 1-2). Like anywhere else, the epidemiological data in this situation is also inherently handicapped by: 35 Table 1-2 Cleft lip with or without cleft palate Source: WHO (1998), World Atlas of Birth Defects (1st Edition). * Abortion for birth defect not permitted. ↑ = 99% significantly higher than the mean. 36 ↓ = 99% significantly lower than the mean. Table 1-3 Cleft palate without cleft lip Source: WHO (1998), World Atlas of Birth Defects (1st Edition). * 37 Abortion for birth defect not permitted. ↑ = 99% significantly higher than the mean. ↓ = 99% significantly lower than the mean. The heterogeneity of orofacial clefting, The lack of standard criteria for collection of data, and In particular, the lack of and/or failure to apply an internationally comparable classification for orofacial clefting. Defining the affected population is also problematic because, on many occasions, the terminology is so vague that it is not clear whether it denotes all birth, or all live births. The word ‘births’ is again somewhat ambiguous because it usually includes stillbirths, a term which lacks clarity. Registration of Targeted Craniofacial Anomalies in India 1. Three multicenter studies in India have provided almost similar frequency of CFA: meta-analysis of 25 early studies from 1960–1979, involving 407,025 births, showed: 38 CL/P = 440 cases, 1.08 per 1,000 births, CP = 95 cases, 0.23 per 1,000 births. 2. A prospective national study of malformations in 17 centers from all over India from September 1989 to September 1990 involving 47,787 births showed: CL/P = 64 cases, 1.3 per 1,000 births, CP = 6 cases, 0.12 per 1,000 births. 3. The latest three-center study, conducted in 1994–1996, involved 94,610 births in Baroda, Delhi and Mumbai, and showed a frequency of: CL/P = 0.93 per 1,000 births, CP = 0.17 per 1,000 births. This was the most rigorously conducted study and it found the number of infants born every year with CLP to be 28,600; this means 78 affected infants are born every day, or three infants with clefts are born every hour (Table 1-4)! 39 Table 1-4 Number of infants with common malformations born every year in India Source: Global registry and database on craniofacial anomalies: Report of a WHO registry on craniofacial anomalies, 2001. CFA are not lethal but they are disfiguring, and thus cause a tremendous social burden. However, these disorders have an excellent outcome if surgical repair is carried out competently. Recent information regarding the etiology of CFA provides the means to carry out primary or secondary prevention. Maintaining a registry would be very useful as a benefit to the community and in reducing the burden of these anomalies, either by prevention or surgical repair. Another reason why a registry would be desirable is the changing pattern of morbidity and mortality in India emerging as a result of the achievements in immunization, the success in providing primary health care and the existence of a 40 well-developed health infrastructure. In many university and city hospitals congenital malformations and genetic disorders have become important causes of illness. All these reasons show that starting a registry of these disorders deserves high priority in India. Existing epidemiological data on CFA The epidemiological information that exists on CFA anomalies in India needs to be examined to decide what data should be collected for the registry: Higher frequency of CL+CP among Indian males is similar to that observed among Caucasians. The ratio is more than that observed in Africans and Japanese. The higher prevalence of CL+CP as compared with CL among Indians is like that observed in Africans, and is more than that observed in Caucasians. Children born prematurely are more frequently affected in India, as elsewhere. About 10.9% of 459 cases of all clefts are syndromic in Chennai. Of these, about 50 % are due to single-gene disorders, about 18% due to chromosomal disorders, and the rest due to undetermined causes. 41 Chromosomal studies would be desirable in cases with associated abnormalities. Syndromes are more commonly associated with CP than with CL, as elsewhere. Lateralization (more clefts on the left side) in India is similar to that observed in other races. In one study in India, the intake of drugs was observed in 18% of parents — mostly steroidal compounds (progestogens as tests for pregnancy). A greater history of terminated pregnancies has been observed among cases, as compared with controls. History of severe vomiting has been observed to be about six times more common among case mothers than among controls. There is some difference in the frequency of orofacial clefts in different states in India; however, this needs verification. The state of origin (or mother tongue) of the parents should be recorded. 42 Clefts are more commonly found in certain caste groups among Hindus. In India CP has less frequency in those with blood group A. CL occurs more in those with group O and AB. Association of clefts with certain HLA types has been documented in India. In a study in Chennai, significantly more consanguinity was observed among couples having children with clefts as compared with controls. Genetics: Principles And Terminology Genotype and Phenotype The science of genetics is concerned with the inheritance of traits, whether normal or abnormal, and with the interaction of genes and the environment. This latter concept is of particular relevance to medical genetics, since the effects of genes can be modified by the environment. Table 1-5 Genes involved in craniofacial and dental disorders, sorted by acronym gene name 43 Acronym Full name ACTC Actin, Alpha, Cardiac Muscle APP Amyloid Beta A4 Precursor Protein (APP) ARVCF Armadillo Repeat Gene Deleted in VCFS ATPhase, H+ Transporting, Lysosomal, ATP&E Subunit E CA1 Carbonic Anhydrase 1 CLTCL1 Clathrin, Heavy Polypeptide-Like 1 COL01A1 Collagen, Type I, Alpha-1 COL01A2 Collagen, Type I, Alpha-2 COL02A1 Collagen, Type II, Alpha-1 COL04A4 Collagen, Type IV, Alpha-4 COL04A5 Collagen, Type IV, Alpha-5 COL05A1 Collagen, Type V, Alpha-1 COL06A1 Collagen, Type VI, Alpha-1 COL10A1 Collagen, Type X, Alpha-1 COMT Catechol-O-Methyltransferase CYLN2 Cytoplasmic Linker 2 DCN Decorin DGSI DiGeorge Syndrome Critical Region Gene ELN Elastin FBLN2 Fibulin 2 FBN1 Fibrillin 1 FGF8 Fibroblast Growth Factor 8 FGFR1 Fibroblast Growth Factor Receptor 1 FGFR2 Fibroblast Growth Factor Receptor 2 FGFR3 Fibroblast Growth Factor Receptor 3 Guanine Nucleotide-Binding Protein, GNAS1 Alpha-Stimulating Activity Polypeptide 44 GOLGA1 Golgi Autoantigen, Golgin Subfamily A, 1 GP1BB Glycoprotein Ib, Platelet, Beta Polypeptide GPC3 Glypican 3 GPC4 Glypican 4 GPR1 G Protein-Coupled Receptor 1 GTF2I General Transcription Factor II-I HIP1 Huntingtin-interacting Protein 1 Histone Cell Cycle Regulation Defective, S. HIRA Cerevisiae, Homolog of, A HOXD10 Homeo Box D10 ITGB2 Integrin, Beta-2 KRT04 Keratin 4 KRT06A Keratin 6A KRT06B Keratin 6B KRT13 Keratin 13 KRT16 Keratin 16 KRT17 Keratin 17 LAMB1 Laminin, Beta-1 MEOX2 Mesenchyme Homeo Box 2 MSX1 MSH, Drosophila, Homeo Box, Homolog of, 1 MSX2 MSH (Drosophila) Homeo Box Homolog 2 PNUTL1 Peanut-Like 1 PTHR1 Parathyroid Hormone Receptor 1 RO60 Autoantigen Ro/SSA, 60–KD SCZD Schizophrenia SCZD4 Schizophrenia 4 SCZD8 Schizophrenia 8 V-SRC Avian Sarcoma (Schmidt-Ruppin A-2) SRC Viral Oncogene 45 SRY Sex-Determining Region Y SSA1 Sjögren Syndrome Antigen A1 SSB Sjögren Syndrome Antigen B Tumor Necrosis Factor Receptor Superfamily, TNFRSF11B Member 11B TTPA Tocopherol Transfer Protein, Alpha TWIST Twist, Drosophila, Homolog of Williams-Beuren Syndrome Chromosome WBSCR1 Region 1 Source: Report of the National Institutes of Dental and Craniofacial Research Genetics Workgroup, Meeting held November 14–16, 1999. Consideration of the heritability of a particular feature or trait requires a consideration of the relationship between genotype and phenotype. Genotype is defined as the genetic constitution of an individual, and may refer to specified gene loci or to all loci in general. An individual’s phenotype is the final product of a combination of genetic and environmental influences. Phenotype may refer to a specified character or to all the observable characteristics of the individual. The proportion of the phenotypic variance attributable to the genotype is referred to as heritability. Genetic variation in man may be observed at two levels: In specific traits, individual genotypes are readily identified and differences are qualitative (discrete), for example, the ABO blood antigen system. Gene frequencies can be estimated and the Mendelian type of analysis can be applied. 46 In continuous traits such as height, weight or tooth size, differences are characterized quantitatively between individuals. These quantitative traits in man are more elusive to study because they are determined by the alleles of many gene loci, and therefore, the Mendelian type of analysis is not appropriate. They are further modified by environmental conditions which obscure the genetic picture. If the genetic variation of a particular phenotypic trait is dependent on the simultaneous segregation of many genes and affected by environment it is referred to as being subject to multifactorial inheritance. Genetic differences caused by the segregation of many genes is referred to as polygenic variation and the genes concerned are referred to as polygenes. These genes are, of course, subject to the same laws of transmission and have the same general properties as the single genes involved in qualitative traits, but segregation of genes is translated into genetic variations seen in continuous traits through polygenes. Different types of genetic ‘product’ can be thought of as being different distances from the fundamental level of gene activity. Enzymes, for instance, are almost direct products of gene action, and in most cases where genetic variation of enzyme structure has been demonstrated, it has been shown that a single locus is responsible for the structure of a single enzyme. The structure, and consequently, the activity of an enzyme is therefore usually simply and directly related to allele substitutions at a single locus. Morphological characters, on the other hand, such as the numerous dimensions used to describe the shape of the face and jaws, are furthest removed from the fundamental genetic level and are the end results of a vast complexity of interacting, hierarchical, biochemical, and developmental 47 processes. Each gene is therefore likely to influence many morphological characters so that a deleterious mutation, although producing a unitary effect at the molecular level, almost always results in a syndrome of morphological abnormalities. When a gene is known to affect a number of different characters in this way its action is said to be pleiotropic. A reverse hierarchy also exists, making each morphological character dependent on many different genes (Mossey, 1999). Modes of Inheritance Population genetics deals with the study of the mode of inheritance of traits and the distribution of genes in populations. All chromosomes exist in pairs so our cells contain two copies of each gene, which may be alike or may differ in their substructure and their product. Different forms of genes at the same locus or position on the chromosome are called alleles. If both copies of the gene are identical, the individual is described as homozygous, while if they differ, the term used is heterozygous. The exception to the rule that cells contain pairs of chromosomes applies to the gametes, sperm and ovum, which contain only single representatives of each pair of chromosomes, and therefore, of each pair of genes. When the two gametes join at fertilization, the new individual produced again has paired genes, one from the father and one from the mother. If a trait or disease manifests itself when the affected person carries only one copy of the gene responsible, along 48 with one normal allele, the mode of inheritance of the trait is called dominant (Fig. 1-1A). If two copies of the defective gene are required for expression of the trait, the mode of inheritance is called recessive (Fig. 1-1B). 49 50 Figure 1-1 (A) Autosomal dominant pedigree. (B) Autosomal recessive pedigree. (C) X-linked recessive pedigree. Courtesy of PA Mossey, 1999. The special case of genes carried on the X chromosome produces yet different pedigrees. Since male-to-male transmission is impossible and since females do not express the disease when they carry only one copy of the diseased gene (since it is modified by the homologous X chromosome), the usual pedigree consists of an affected male with clinically normal parents and children, but with affected brothers, maternal uncles, and other maternal male relatives (Fig. 1-1C). This mode of inheritance is described as X-linked recessive. It has been long appreciated that many normal traits, such as height, intelligence, and birth weight, have a significant genetic component, as do a number of common diseases, such as diabetes mellitus, schizophrenia, hypertension, and cleft lip and palate. However, the pattern of inheritance of these traits does not follow the simple modes just described. Mathematical analysis of many of these has led to the conclusion that they follow the rules of polygenic inheritance, i.e. determined by a constellation of several genes, some derived from each parent. The determination of heritability for polygenic or multifactorial characters is difficult, as a feature of continuous variation is that different individuals may occupy the same position on the continuous scale for different reasons. Using mandibular length as an example, micrognathia can occur in chromosomal disorders, such as Turner’s syndrome, in 51 monogenic disorders such as Treacher Collins syndrome or Stickler syndrome, or due to an intrauterine environmental problem, such as fetal alcohol syndrome. Combined with this the concept of etiological heterogeneity encompasses the principle of the same gene defect producing different phenotypic anomalies, and syndromes can be due to defective gene activity in different cells. Conversely, different gene defects or combinations of defective genes can produce a similar phenotypic abnormality. Genetic lethality or reduced reproductive fitness can also complicate the diagnostic picture and genomic imprinting can result in a gene defect ‘skipping’ a generation. These complexities serve to hamper progress in the understanding of polygenic or multifactorial disorders such as orofacial clefting (Mossey, 1999). Multifactorial Inheritance In contrast to single-gene inheritance, either autosomal or sex-linked, the pedigree pattern does not afford a diagnosis of multifactorial inheritance. In multifactorial traits, the trait is determined by the interaction of a number of genes at different loci, each with a small, but additive effect, together with environmental factors (i.e., the genes are rendering the individual unduly susceptible to the environmental agents). Many congenital malformations (Table 1-6) and common diseases of adult life are inherited as multifactorial traits and these are categorized as either continuous or discontinuous. Table 1-6 Causes of deformations 52 Extrinsic Mechanical Unstretched uterine and abdominal muscles Small maternal size Amniotic tear Unusual implantation site Uterine leiomyomas Unicornuate uterus Bicornuate uterus Twin fetuses Intrinsic Malformational Spina bifida Other central nervous system malformations Bilateral renal agenesis Severe hypoplastic kidneys Severe polycystic kidneys 53 Urethral atresia Functional Neurologic disturbances Muscular disturbances Connective tissue defects Source: MM Cohen Jr, The Child with Multiple Birth Defects. Raven Press, New York, 1982, p 10. Cited by RJ Gorlin, MM Cohen, LS Levin. Syndromes of the Head and Neck, 3rd Ed, Oxford University Press; 1990, New York. Molecular Genetics in Dental Development The first sign of tooth development is a local thickening of oral epithelium, which subsequently invaginates into neural crest derived mesenchyme and forms a tooth bud. Subsequent epithelial folding and rapid cell proliferation result in first the cap, and then the bell stage of tooth morphogenesis. During the bell stage, the dentine producing odontoblasts and enamel secreting ameloblasts differentiate. Tooth development, like the development of all epithelial appendages, is regulated by inductive tissue interactions between the epithelium and mesenchyme (Thesleff, 1995). There is now increasing evidence that a number of different mesenchymal molecules and their receptors act as mediators of the epithelial-mesenchymal interactions during tooth development. Of the bone morphogenetic proteins (BMPs) 2, 54 4, and 7 mRNAs shift between the epithelium and mesenchyme in the regulation of tooth morphogenesis (Aberg et al, 1997). The fibroblast growth factor (FGF) family have also been localized in epithelial and mesenchymal components of the tooth by immunohistochemistry (Cam et al, 1992); and in dental mesenchyme tooth development and shape is regulated by FGF8 and FGF9 via downstream factors MSX1 and PAX9 (Kettunen and Thesleff, 1998). Control of Tooth Development Homeobox genes have particular implications in tooth development. Muscle specific homeobox genes Msx-1 and Msx-2 appear to be involved in epithelial mesenchymal interactions, and are implicated in craniofacial development, and in particular, in the initiation developmental position (Msx-1) and further development (Msx-2) of the tooth buds (MacKenzie et al, 1991; Jowett et al, 1993). Further evidence of the role of Msx-1 comes from gene knock-out experiments which results in disruption of tooth morphogenesis among other defects (Satokata and Maas, 1994). Pax-9 is also transcription factor necessary for tooth morphogenesis (Neubuser et al, 1997). BMPs are members of the growth factor family (TGF) and they function in many aspects of craniofacial development with tissue specific functions. BMPs have been found to have multiple roles not only in bone morphogenesis, (BMP 5, for example, induces endochondral osteogenes is in vivo), but BMP 7 appears to induce dentinogenesis (Thesleff, 1995). Disorders in Tooth Morphogenesis 55 Advances in the field of molecular genetics have made great progress in the understanding of a number of dental anomalies with a genetic component. Congenital Deformations Of Head And Neck These are common, and mostly resolve spontaneously within the first few days of postnatal life. When they do not, further evaluation may be necessary to plan therapeutic interventions that may prevent long-term consequences. Approximately 2% of infants are born with extrinsically caused deformations that usually arise during late fetal life from intrauterine causes. Approximately 30% of deformed infants have two or more deformations. Deformed infants tend to show catch-up growth during the first few postnatal months after release from the intrauterine environment. The common deformations considered under the craniofacial category are nasal, auricular and mandibular deformities. Teratogenic Agents Teratogens are agents that may cause birth defects when present in the fetal environment. Included under such a definition are a wide array of drugs, chemicals, and infectious, physical, and metabolic agents that may adversely affect the intrauterine environment of the developing fetus. Such factors may operate by exceedingly heterogeneous pathogenetic mechanisms to produce alterations of form and function as well as embryonic and/or fetal death (Gorlin et al, 1990). 56 The mechanisms of teratogenesis are selective in terms of the target and effect. Thus, characteristic patterns of abnormalities can be expected to be associated with particular teratogenic agents. However, the extent to which an individual may be adversely affected by exposure to a given teratogen varies widely. This depends on the following four factors: 1. Differences in dose 2. Developmental timing of exposure 3. Differences in susceptibility 4. Interactions among environmental exposures. It is of considerable interest to the dental profession that experimental studies of teratogenic agents have almost invariably revealed a variety of head, neck and oral malformations. Conway and Wagner have compiled a list of the most common malformations of the head and neck as shown in Table 1-7. Table 1-7 Classification of cleft lip Type Occurrence (%) Unilateral incomplete 33 57 Unilateral complete 48 Bilateral incomplete 7 Bilateral complete 12 Source: V Veau: Division palatine; anatomie, chirurgie, phonetique. Paris, Masson et Cie, 1931. Stem cells Stem cells are clonogenic cells that have the capacity for self-renewal and multilineage differentiation. The microenvironment in which stem cells reside is called a stem cell niche and is composed of heterologous cell types, extracellular matrix and soluble factors to support the maintenance and self-renewal of the stem cells. Stem cells have been isolated and characterized from a wide variety of sources. Adult progenitor cellular populations have been isolated from distinctive tissues and fluids, such as bone marrow, peripheral blood, umbilical cord blood, Wharton’s jelly, placenta, amniotic fluid and membrane, adipose tissue, dermis, hair follicles, synovial membrane, skeletal muscle, central nervous system, olfactory bulb, retina, and liver among others. From these biological sources, progenitors of the mesenchymal, epithelial, hematopoetic (discussed elsewhere), neural, endothelial and trophoblastic lineages have been identified (Fig. 1-2). 58 Figure 1-2 Mandibular micrognathia. Courtesy: Prof Anil Sukumaran, Prof R Rajendran. King Saud University, Riyadh, KSA. In tissue engineering applications, mesenchymal stem cells are among the most used populations because of the wide variety of sources from which they can be harvested, their ability to self-renew, and their multilineage potential following adequate induction. Moreover, the vast majority of the tissues relevant in surgical repair / regeneration are of mesenchymal origin. This is of particular relevance in the craniofacial area because during development cells originating from the neural crest are known to migrate, differentiate, and participate in the morphogenesis of virtually all structures of the region including muscle, ligament, bone, cartilage, periodontal tissues and teeth. 59 There are two major categories of stem cells, which are of relevance to dentistry: 1. Embryonic stem cells 2. Adult or somatic stem cells. Totipotent embryonic stem cells are derived from the inner cell mass of mammalian blastocyst and can be maintained indefinitely in culture. Somatic stem cells have a limitation in their potential of differentiation. The differentiation potential of dental stem cells lies in the formation of dentin or periodontium associated tissues, whether these cells are derived from pulp, periodontal ligament or dental follicle. It is obvious that dental ectomesenchymal stem cells can be classified into two different groups with respect to their differentiation potential. The first group is associated with the dental pulp, consisting of dental pulp stem cells (DPSCs), stem cells from exfoliated deciduous teeth (SCEDs), and stem cells from apical papilla (SCAPs); the second group contains periodontal ligament stem cells (PLSCs) and dental follicle progenitor cells (DFPCs), related to the periodontium. The odontogenic stem cells are further divided into: 1. Epithelial stem cells (ESCs) 2. Mesenchymal stem cells (MSCs). 60 Dental epithelial stem cells Embryonic dental epithelium is capable of inducing the development of a tooth germ in combination with non-dental ectomesenchymal tissue. However, oral ectomesenchyme in combination with non-dental epithelium did not induce tooth development. Later steps in tooth development are driven by a complex interaction of both ectodermal and ectomesenchymal tissues along with growth promoting factors of bone morphogenic protein-4 (BMP-4) and fibroblast growth factor-8 (FGF-8), produced by the oral ectoderm for the initiation of tooth development. Oral ectoderm derived ameloblasts are unable to proliferate or regenerate once they have reached the maturation stage of development. Continuously growing mouse incisors and molars in some mammalian species show replenishing populations of enamel organs composed of stellate reticulum, stratum intermedium and enamel epithelial cells which provide models for dental epithelial stem cells. Mice have an epithelial stem cell niche located at their incisor labial apical ends, known as the cervical loop. The cervical loop has been considered to be a determinative region in odontogenesis due to its ability to produce enamel and dentin. One specialized structure found at the apical region of the labial cervical loop in mouse incisors, “apical bud” (Ohshima H et al, 2003), is suggested as stem cell compartment that could differentiate into ameloblast through interaction with mesenchymal cells and growth factors. In humans, these dental epithelial stem cells are lost after tooth eruption; therefore, are not available for studies on dental development. In contrast to dental epithelial stem cells, 61 undifferentiated cells of the oral ectomesenchyme are not entirely lost after tooth eruption in humans. It became possible to isolate precursor cells from the dental pulp and ectomesenchymal stem cells were isolated from the dental pulp of extracted wisdom teeth. Dental mesenchymal stem cells They are a heterogeneous population of multipotent self-renewal cells that possess clonogenic competence and the capacity to differentiate into all cell lineages of the mesenchymal and connective tissue elements. They also seem to be able to differentiate into epithelial cells and lineages derived from neuroectoderm. Mesenchymal stem cells have been shown to produce a wide range of bioactive molecules capable of immunomodulatory functions along with the ability to modulate the regenerative processes in the human body (Ohshima H et al, 2001). Developmental Disturbances of Jaws Agnathia (Otocephaly, holoprosencephaly agnathia) Agnathia is a lethal anomaly characterized by hypoplasia or absence of the mandible with abnormally positioned ears having an autosomal recessive mode of inheritance. More commonly, only a portion of one jaw is missing. In the case of the maxilla, this may be one maxillary process or even the premaxilla. Partial absence of the mandible is even more common. The entire mandible on one side may be missing, or more frequently, only the condyle or the entire ramus, although bilateral agenesis of the condyles and of the rami 62 also has been reported. In cases of unilateral absence of the mandibular ramus, it is not unusual for the ear to be deformed or absent as well. It is probably due to failure of migration of neural crest mesenchyme into the maxillary prominence at the fourth to fifth week of gestation (postconception). The prevalence is unknown and less than 10 cases are described. The prognosis of this condition is very poor and it is considered to be lethal. Micrognathia Micrognathia literally means a small jaw, and either the maxilla or the mandible may be affected. Many cases of apparent micrognathia are not due to an abnormally small jaw in terms of absolute size, but rather to an abnormal positioning or an abnormal relation of one jaw to the other or to the skull, which produces the illusion of micrognathia. True micrognathia may be classified as either congenital, or acquired. The etiology of the congenital type is unknown, although in many instances it is associated with other congenital abnormalities, including congenital heart disease and the Pierre Robin syndrome (q.v.) This form of the disease has been discussed by Monroe and Ogo. It occasionally follows a hereditary pattern. Micrognathia of the maxilla frequently occurs due to a deficiency in the premaxillary area, and patients with this deformity appear to have the middle third of the face retracted. Although it has been suggested that mouth-breathing is a cause of maxillary micrognathia, it is more likely that the micrognathia may be one of the predisposing factors in mouth-breathing, owing to the 63 associated maldevelopment of the nasal and nasopharyngeal structures. True mandibular micrognathia of the congenital type is often difficult to explain. Some patients appear clinically to have a severe retrusion of the chin but, by actual measurements, the mandible may be found to be within the normal limits of variation. Such cases may be due to a posterior positioning of the mandible with regard to the skull or to a steep mandibular angle resulting in an apparent retrusion of the jaw. Agenesis of the condyles also results in a true mandibular micrognathia. The acquired type of micrognathia is of postnatal origin and usually results from a disturbance in the area of the temporomandibular joint. Ankylosis of the joint, for example, may be caused by trauma or by infection of the mastoid, of the middle ear, or of the joint itself. Since the normal growth of the mandible depends to a considerable extent on normally developing condyles as well as on muscle function, it is not difficult to understand how condylar ankylosis may result in a deficient mandible. The clinical appearance of mandibular micrognathia is characterized by severe retrusion of the chin, a steep mandibular angle, and a deficient chin button (Fig. 1-3). 64 Figure 1-3 Mandibular micrognathia Courtesy of Dr G Thaddeus Gregory and Dr J William Adams. Micrognathia may be caused by or may be a feature of several conditions (Table 1-8). Table 1-8 Causes of micrognathia Congenital conditions Catel-Manzke syndrome Cerebrocostomandibular syndrome 65 Cornelia de Lange syndrome Femoral hypoplasia—unusual facies syndrome Fetal aminopterin-like syndrome Miller-Dieker syndrome Nager acrofacial dysostosis Pierre Robin syndrome Schwartz-Jampel-Aberfeld syndrome van Bogaert-Hozay syndrome Intrauterine acquired conditions Syphilis, congenital Chromosomal abnormalities 49, XXXXX syndrome Chromosome 8 recombinant syndrome Cri du chat syndrome 5p Trisomy 18 Turner’s syndrome Wolf-Hirschhorn syndrome 66 Mendelian inherited conditions CODAS (cerebral, ocular, dental, auricular, skeletal) syndrome Diamond-Blackfan anemia Noonan’s syndrome Opitz-Frias syndrome Autosomal dominant conditions Camptomelic dysplasia Cardiofaciocutaneous syndrome CHARGE syndrome DiGeorge’s syndrome Micrognathia with peromelia Pallister-Hall syndrome Treacher Collins-Franceschetti syndrome Trichorhinophalangeal syndrome type 1 Trichorhinophalangeal syndrome type 3 Wagner vitreoretinal degeneration syndrome Autosomal recessive conditions 67 Bowen-Conradi syndrome Carey-Fineman-Ziter syndrome Cerebrohepatorenal syndrome Cohen syndrome Craniomandibular dermatodysostosis De la Chapelle dysplasia Dubowitz syndrome Fetal akinesia-hypokinesia sequence Hurst’s microtia-absent patellae-micrognathia syndrome Kyphomelic dysplasia Lathosterolosis Lethal congenital contracture syndrome Lethal restrictive dermopathy Marden-Walker syndrome Orofaciodigital syndrome type 4 Postaxial acrofacial dysostosis syndrome Rothmund-Thomson syndrome 68 Smith-Lemli-Opitz syndrome ter Haar syndrome Toriello-Carey syndrome Weissenbacher-Zweymuller syndrome Yunis-Varon syndrome X-linked inherited conditions Atkin-Flaitz-Patil syndrome Coffin-Lowry syndrome Lujan-Fryns syndrome Otopalatodigital syndrome type 2 Autoimmune conditions Juvenile chronic arthritis Source: www.diseasesdatabase.com, Health on the Net Foundation, 2005. Macrognathia Macrognathia refers to the condition of abnormally large jaws. An increase in size of both jaws is frequently proportional to a generalized increase in size of the entire skeleton, e.g. in pituitary gigantism. More commonly only the 69 jaws are affected, but macrognathia may be associated with certain other conditions, such as: Paget’s disease of bone, in which overgrowth of the cranium and maxilla or occasionally the mandible occurs, Acromegaly, in which there is progressive enlargement of the mandible owing to hyperpituitarism in the adult, or Leontiasis ossea, a form of fibrous dysplasia in which there is enlargement of the maxilla. Cases of mandibular protrusion or prognathism, uncomplicated by any systemic condition, are a rather common clinical occurrence (Fig. 1-4). The etiology of this protrusion is unknown, although some cases follow hereditary patterns. In many instances the prognathism is due to a disparity in the size of the maxilla in relation to the mandible. In other cases the mandible is measur-ably larger than normal. The angle between the ramus and the body also appears to influence the relation of the mandible to the maxilla, as does the actual height of the ramus. Thus prognathic patients tend to have long rami which form a less steep angle with the body of the mandible. The length of the ramus, in turn, may be associated with the growth of the condyle. It may be reasoned, therefore, that excessive condylar growth predisposes to mandibular prognathism. 70 Figure 1-4 Macrognathia (prognathia) of the mandible. (A) The protrusion of the mandible is obvious. (B) The same patient after surgical correction (ostectomy) (Courtesy of Dr G Thaddeus Gregory and Dr J William Adams. General factors which conceivably would influence and tend to favor mandibular prognathism are as follows: Increased height of the ramus Increased mandibular body length Increased gonial angle Anterior positioning of the glenoid fossa 71 Decreased maxillary length Posterior positioning of the maxilla in relation to the cranium Prominent chin button Varying soft-tissue contours. Surgical correction of such cases is feasible. Ostectomy, or resection of a portion of the mandible to decrease its length, is now an established procedure, and the results are usually excellent from both a functional and a cosmetic standpoint. Facial Hemihypertrophy (Hyperplasia) Hemihyperplasia is a rare developmental anomaly characterized by asymmetric overgrowth of one or more body parts. Although the condition is known more commonly as hemihypertrophy, it actually represents a hyperplasia of the tissues rather than a hypertrophy. Hemihyperplasia can be an isolated finding, but it also may be associated with a variety of malformation syndromes (Table 1-9). Almost all cases of isolated hemihyperplasia are sporadic. Table 1-9 Malformation syndromes associated with hemihyperplasia Beckwith-Wiedemann syndrome 72 Neurofi bromatosis Klippel-Trenaunay-Weber syndrome Proteus syndrome McCune-Albright syndrome Epidermal nevus syndrome Triploid/diploid mixoploidy Langer-Giedion syndrome Multiple exostoses syndrome Maffucci’s syndrome Ollier syndrome Segmental odontomaxillary dysplasia Source: HE Hoyme et al, 1998. Hoyme et al (1998) provided an anatomic classification of hemihyperplasia: Complex hemihyperplasia is the involvement of half of the body (at least one arm and one leg); affected parts may be contralateral or ipsilateral, 73 Simple hemihyperplasia is the involvement of a single limb, and Hemifacial hyperplasia is the involvement of one side of the face. Etiology The cause is unknown, but the condition has been variously ascribed to vascular or lymphatic abnormalities; CNS disturbances; and chromosomal abnormalities. Clinical Features Patients affected by facial hemihypertrophy exhibit an enlargement which is confined to one side of the body, unilateral macroglossia and premature development, and eruption as well as an increased size of dentition. Familial occurrence has been reported on a few occasions, according to the excellent review of the condition by Rowe, who described four additional cases. Of all reported cases, females are affected somewhat more frequently than males (63% versus 37%), according to the review by Ringrose. There is an almost equal involvement of the right and left sides. Oral Manifestations The dentition of the hypertrophic side, according to Rowe, is abnormal in three respects: crown size, root size and shape, and rate of development. Rowe has also pointed out that not 74 all teeth in the enlarged area are necessarily affected in a similar fashion. There is little information about the effects on the deciduous dentition, but the permanent teeth on the affected side are often enlarged, although not exceeding a 50% increase in size. This enlargement may involve any tooth, but seems to occur most frequently in the cuspid, premolars, and first molar. The roots of the teeth are sometimes proportionately enlarged but may be short. Characteristically, the permanent teeth on the affected side develop more rapidly and erupt before their counterparts on the uninvolved side (Fig. 1-5). Coincident to this phenomenon is premature shedding of the deciduous teeth. The bone of the maxilla and mandible is also enlarged, being wider and thicker, sometimes with an altered trabecular pattern. Figure 1-5 Facial hemihypertrophy. The difference in the eruption pattern of the teeth on each side is apparent. The teeth on the affected side, where all deciduous teeth have already been lost, are not appreciably 75 larger than those on the unaffected side (Courtesy of Dr John B Wittgen. The tongue is commonly involved by the hemihypertrophy and may show a bizarre picture of enlargement of lingual papillae in addition to the general unilateral enlargement and contralateral displacement. In addition, the buccal mucosa frequently appears velvety and may seem to hang in soft, pendulous folds on the affected side. Histologic Features Tissue examination has been infrequently reported but is generally uninformative. In those cases reported, true muscular hypertrophy was not found. Treatment and Prognosis There is no specific treatment for this condition other than attempts at cosmetic repair. Cosmetic surgery is advised after cessation of growth. Effect on life expectancy is not certain, but in some cases patients have lived a normal life span. Periodic abdominal ultrasound/ MRI is recommended to rule out tumors. Differential Diagnosis There are certain diseases of the jaws, such as neurofibromatosis and fibrous dysplasia of the jaws, that may give the clinical appearance of facial hemihypertrophy, but 76 these can usually be differentiated readily by the lack of effect on tooth size and rate of eruption. Facial Hemiatrophy (Parry-Romberg syndrome, Romberg-Parry syndrome, progressive facial hemiatrophy, progressive hemifacial atrophy) Hemifacial atrophy remains almost as much an enigma today as it was when first reported by Romberg in 1846. Hemifacial atrophy, originally described by Parry and Henoch and Romberg consists of slowly progressive atrophy of the soft tissues of essentially half the face, which is characterized by progressive wasting of subcutaneous fat, sometimes accompanied by atrophy of skin, cartilage, bone and muscle. Although the atrophy is usually confined to one side of the face and cranium, it may occasionally spread to the neck and one side of the body and it is accompanied usually by contralateral Jacksonian epilepsy, trigeminal neuralgia, and changes in the eyes and hair. Evidence of a mendelian basis is lacking. Lewkonia and Lowry reported the case of a 16-year-old boy who developed facial changes at age seven and had localized scleroderma on one leg and the trunk. The presence of antinuclear antibodies in his serum suggested that the Parry-Romberg syndrome may be a form of localized scleroderma. Hemifacial atrophy is a form of localized scleroderma and is supported by its concurrence with scleroderma. Hemifacial atrophy is a rare condition that occurs sporadically although some familial distribution has been found. The majority of cases are sporadic with no definite inheritance being proven in the literature. 77 Etiology The etiology has been the subject of considerable debate. Wartenburg considered the primary factor to be a cerebral disturbance leading to increased and unregulated activity of sympathetic nervous system, which in turn produced the localized atrophy through its trophic functions conducted by way of sensory trunks of the trigeminal nerve. Other workers suggested extraction of teeth, local trauma, infection and genetic factors could also be a cause. In a paper published in 1973, Poswillo attributed the development of facial deformities to the disruption of the stapedial artery. Poswillo fed pregnant rats with triazine and pregnant monkeys with thalidomide and showed the consistent maldevelopment of first and second branchial arch structures. Robinson, in 1987, supported Poswillo’s theory by demonstrating carotid flow abnormalities in two and defects related to vascular disruption in a third child with craniofacial microsomia. Clinical Features Hemifacial atrophy is a syndrome with diverse presentation. The most common early sign is a painless cleft, the ‘coup de sabre,’ near the midline of the face or forehead. This marks the boundary between normal and atrophic tissue. A bluish hue may appear in the skin overlying atrophic fat. The affected area extends progressively with the atrophy of the skin, subcutaneous tissue, muscles, bones, cartilages, alveolar bone and soft palate on that side of the face. In addition to facial wasting that may include the ipsilateral salivary glands and hemiatrophy of the tongue, unilateral 78 involvement of the ear, larynx, esophagus, diaphragm, kidney and brain have been reported. It starts in the first decade and lasts for about three years before it becomes quiescent. The final deformity varies widely, burning itself out in some patients with minimal atrophy, while in others progressing to marked atrophy. Neurological disorders are found in 15% of patients, while ocular findings occur in 10–40%, the most common being enophthalmos. Rarely, one half of the body may be affected. This condition may be accompanied by pigmentation disorders, vitiligo, pigmented facial nevi, contralateral Jacksonian epilepsy, contralateral trigeminal neuralgia and ocular complications. The disease occurs more frequently in women; female to male ratio is 3 : 2. It has a slight predilection for the left side and appears in the first or second decades of life. It progresses over a period of two and 10 years, and atrophy appears to follow the distribution of one or more divisions of the trigeminal nerve. The resulting facial flattening may be mistaken for Bell’s palsy (Fig. 1-6). 79 Figure 1-6 Facial hemiatrophy. Oral Manifestations Dental abnormalities include incomplete root formation, delayed eruption and severe facial asymmetry, resulting in facial deformation and difficulty with mastication. Hemiatrophy of the lips and the tongue is reported, as are dental effects. Foster has reported that growth of the teeth may be affected just as other tissues are involved. Eruption of teeth on the affected side may also be retarded. Differential Diagnosis Post-traumatic fat atrophy, hemifacial microsomia (first and second branchial arch syndrome), Goldenhar’s syndrome, and partial lipodystrophy which is; however, always bilateral. 80 Treatment and Prognosis There is no specific treatment for the condition. It has been found that, typically, the disease will be progressive for a period of several years and then remain unchanged for the remainder of the patient’s life. Abnormalities of Dental Arch Relations In the preceding sections the conditions discussed are those in which there is an actual or apparent abnormal variation in size of one or both jaws. Of far greater importance than a simple disparity in size is the disparity in relation of one jaw to the other and the difficulties in occlusion and function that result. A great many different types of malocclusion exist, and many classifications have been evolved in an attempt to unify methods of treatment. The classification of Angle, proposed in 1899, is the most universally known and used. That classification, with the approximate percentage occurrence as determined by Angle in a large group of orthodontic patients, is as follows: Class I. Arches in normal mesiodistal relations 69.0%. Class II. Mandibular arch distal to normal in its relation to the maxillary arch. 81 Division 1. Bilaterally distal, protruding maxillary incisors 9.0. Subdivision. Unilaterally distal, protruding maxillary incisors 3.5. Division 2. Bilaterally distal, retruding maxillary incisors 4.0. Subdivision. Unilaterally distal, retruding maxillary incisors 10.0. Class III. Mandibular arch mesial to normal in its relation to the maxillary arch. Division.Bilaterally mesial 3.5. Subdivision.Unilaterally mesial 1.0. Since these abnormal jaw relations constitute a separate course of study, no further allusion to this subject will be made here. Developmental Disturbances of Lips And Palate Congenital Lip and Commissural Pits and Fistulas 82 Congenital lip pits and fistulas are malformations of the lips, often following a hereditary pattern, that may occur alone or in association with other developmental anomalies such as various oral clefts. Both Taylor and Lane and McConnel and his associates have emphasized that in 75–80% of all cases of congenital labial fistulas, there is an associated cleft lip or cleft palate, or both. The association of pits of the lower lip and cleft lip and/or cleft palate, termed van der Woude’s syndrome, has been reviewed by Cervenka and his associates. Commissural pits are an entity probably very closely related to lip pits, but occur at the lip commissures, lateral to the typical lip pits. Everett and Wescott have described this entity and noted that it is also frequently hereditary, possibly a dominant characteristic following a Mendelian pattern, and may be associated with other congenital defects. Etiology Many theories of the etiology of congenital lip pits have been offered, but none has been universally accepted. Pits may result from notching of the lip at an early stage of development, with fixation of the tissue at the base of the notch, or from failure of complete union of the embryonic lateral sulci of the lip, which persist and ultimately develop into the typical pits. Commissural pits are also difficult to explain, but they occur at the site of the horizontal facial cleft and may represent defective development of this embryonic fissure. Clinical Features 83 The lip pit or fistula is a unilateral or bilateral depression or pit that occurs on the vermilion surface of either lip but far more commonly on the lower lip (Fig. 1-7A). In some cases a sparse mucous secretion may exude from the base of this pit. The lip sometimes appears swollen, accentuating the appearance of the pits. Figure 1-7 (A) Congenital lip pits. (B) Congenital commissural pits. Courtesy of Dr Spencer Lilly, Meenakshi Ammal Dental College, Chennai. 84 Commissural pits appear as unilateral or bilateral pits at the corners of the mouth on the vermilion surface (Fig. 1-7B). An actual fistula may be present from which fluid may be expressed. Whether this tract, either in lip or commissural fistulas, represents a true duct is not clear. Interestingly, in several cases preauricular pits have been reported in association with commissural pits. Treatment Surgical excision of these various pits has been recommended but primarily for academic information, since the pits are harmless and seldom manifest complications. van der Woude Syndrome (Cleft lip syndrome, lip pit syndrome, dimpled papillae of the lip) van der Woude syndrome is an autosomal dominant syndrome typically consisting of a cleft lip or cleft palate and distinctive pits of the lower lips. The degree to which individuals carrying the gene are affected is widely variable, even within families. These variable manifestations include lip pits alone, missing teeth, or isolated cleft lip and palate of varying degrees of severity. Other associated anomalies have also been described. Etiology The most prominent and consistent feature of van der Woude syndrome is orofacial anomalies. They are due to an abnormal fusion of the palate and lips, at days 30–50 postconception. 85 The van der Woude syndrome can be caused by deletions in chromosome band 1q32, and linkage analysis has confirmed this chromosomal locus as the disease gene site. The gene has been localized to chromosome band 1q32. Further studies have raised the possibility that the degree of phenotypic expression of a gene defect at this locus may be influenced by a second modifying gene that has been mapped to chromosome band 17p11. Clinical Features In general, van der Woude syndrome affects about 1 in 100,000–200,000 people. About 1–2% of patients with cleft lip or palate have van der Woude syndrome. The van der Woude syndrome affects both genders equally and no difference among them have been reported. The severity of the van der Woude syndrome varies widely, even within families. About 25% of individuals with the van der Woude syndrome have no findings or minimal ones, such as missing teeth or trivial indentations in the lower lips. Others have severe clefting of the lip or palate. The hallmark of the van der Woude syndrome is the association of cleft lip and/or palate with distinctive lower lip pits. This combination is seen in about 70% of those who are overtly affected but in less than half of those who carry the gene. The cleft lip and palate may be isolated. They may take any degree of severity and may be unilateral or bilateral. Submucous cleft palate is common and may be easily missed on physical examination. Hypernasal voice and cleft or bifid uvula are clues to this diagnosis. It is possible as well that a bifid uvula is an isolated finding in certain individuals with the van der Woude syndrome. The lower lip pits seen in this syndrome are fairly 86 distinctive (Fig. 1-8). The pits are usually medial, on the vermilion portion of the lower lip. They tend to be centered on small elevations in infancy, but are simple depressions in adults. These pits are often associated with accessory salivary glands that empty into the pits, sometimes leading to embarrassing visible discharge. Occasionally lip pits may be the only manifestation of the syndrome. Affected individuals may have maxillary hypodontia; missing maxillary incisors or missing premolars. Again, this may be the only manifestation of the syndrome. Although infrequently reported, other oral manifestations include syngnathia (congenital adhesion of the jaws); narrow, high, arched palate; and ankyloglossia (short glossal frenulum or tongue-tie). Figure 1-8 Bilateral lip pits. Extraoral Manifestations The reported incidence of extraoral manifestations are rare but include limb anomalies, popliteal webs, and brain 87 abnormalities. Accessory nipples, congenital heart defects, and Hirschsprung disease have also been reported. It is uncertain whether these extraoral manifestations are unassociated additional anomalies or infrequently expressed aspects of van der Woude syndrome. Treatment Along with a thorough orofacial examination, a thorough general physical examination helps to determine if there are other associated anomalies of the cardiovascular system, genitourinary system, limbs, or other organ systems. Examination and genetic counseling by a pediatric geneticist (dysmorphologist) is suggested for families that may be affected by the van der Woude syndrome. This should include an examination of as many potentially affected family members (probands) as possible. Surgical repair of the cleft lip and palate or other anomalies may be required, when planning surgical intervention, imaging studies of affected areas, such as CT scanning of the oropharynx, may be appropriate. Even among those less severely affected, surgical excision of lip pits is often performed, either to alleviate discomfort or for cosmetic reasons (e.g. improving the appearance of lip pits or reducing mucous discharge). Cleft Lip and Cleft Palate The term cleft lip and palate is commonly used to represent two types of malformation, i.e., cleft lip with or without cleft palate (CL/P) and cleft palate (CP). Cleft lip and palate are common congenital malformations. The reported incidence of clefts of the lip and palate varies from 1 in 500 to 1 in 2500 88 live births depending on geographic origin, racial and ethnic background and socioeconomic status. In general, Asian population have the highest frequencies, often at 1 in 500 or higher, with Caucasian population intermediate, and Africanderived population the lowest at 1 in 2500. An understanding of the normal human maxillofacial development is necessary before a discussion of cleft lip and palate. During the fourth week of gestation, the maxillary processes emerge from the first branchial arch on each side and the nasal placodes form from the frontal prominence. By the fifth week, all the primordia for the lip and palate are present. The medial, lateral nasal and the frontonasal processes are formed from the nasal placodes and the maxillary processes continue to enlarge. During the seventh week the medial nasal, frontonasal and maxillary processes fuse to form the primary palate, which becomes the medial portion of the upper lip, alveolus and the anterior part of hard palate up to the incisive foramen. When the primary palate is completely formed, the maxillary processes enlarge intraorally to form the palatine processes. During the 8th week of gestation, the palatal shelves fill up the space on both sides of the tongue. During the 9th and 10th weeks, the mandibular arch enlarges and the tongue drops. The palatal shelves transpose horizontally and fuse with each other and with the anterior part of the palate. Palatal fusion occurs anteroposteriorly and the process is completed by the 11th to 12th weeks (Shapiro, 1976). Failure in the fusion of the nasal and maxillary processes leads to the cleft of the primary palate, which can be unilateral or bilateral. The degree of cleft can vary from a slight notch on the lip to complete cleft of the primary palate. 89 Cleft of the secondary palate is medial. It varies from bifid uvula to complete cleft palate up to the incisive foramen. When it is associated with the primary palate, a complete uni- or bilateral cleft lip and palate is formed. Etiology It has been clearly established by Fogh-Andersen and confirmed by numerous other investigators that two separate and distinct entities exist: Cleft lip with or without associated cleft palate, and Isolated cleft palate. Heredity is undoubtedly one of the most important factors to be considered in the etiology of these malformations. However, there is increasing evidence that environmental factors are important as well. According to Fogh-Andersen, slightly less than 40% of the cases of cleft lip with or without cleft palate are genetic in origin, whereas slightly less than 20% of the cases of isolated cleft palate appear to be genetically derived. Most investigations indicate that the inheritance pattern in cleft lip with or without cleft palate is different from that in isolated cleft palate. The mode of transmission of the defect is uncertain. This has been discussed by Bhatia, who pointed out that the possible main modes of transmission are either by a single mutant gene, producing a large effect, or by a number of genes (polygenic inheritance), each producing a small effect which together 90 create this condition. It should be pointed out that cytogenetic studies have failed to reveal visible alterations in chromosomal morphology of the affected individuals. Bixler more recently has expanded upon this concept and reiterated that there are two forms of clefts. The most common is hereditary, its nature being most probably polygenic (determined by several different genes acting together). In other words, when the total genetic liability of an individual reaches a certain minimum level, the threshold for expression is reached and a cleft occurs. Actually, it is presumed that every individual carries some genetic liability for clefting, but if this is less than the threshold level, there is no cleft. When the individual liabilities of two parents are added together in their offspring, a cleft occurs if the threshold value is exceeded. However, even though this is the most common form of cleft, the threshold value is sufficiently high that it is a low-risk type. The second form of cleft is monogenic or syndromic and is associated with a variety of other congenital anomalies. Since these are monogenic, they are of a high-risk type. Bixler has pointed out that, fortunately, the clefting syndromes are rare and probably make up only 5% of all cleft cases even though, according to Cohen, there are now over 300 clefting syndromes reported in the literature. Although there is insufficient evidence that nutritional disturbances cause cleft palates in human beings, abnormal dietary regimens have caused developmental clefts in animals. Cleft palate has been experimentally produced in newborn rats by feeding diets either deficient or excessive in vitamin A to maternal rats during pregnancy. Riboflavin-deficient diets fed to pregnant rats have also 91 produced offspring with a high incidence of cleft palate. The administration of cortisone to pregnant rabbits has induced similar clefts in their young. Strean and Peer reported that physiologic, emotional, or traumatic stress may play a significant role in the etiology of human cleft palate, since stress induces increased function of the adrenal cortex and secretion of hydrocortisone. Their study, based on histories of 228 mothers of children with cleft palate, confirms the experimental findings of cleft palate in animals due to the action of stressor agents or the administration of cortisone. However, Fraser and Warburton have reported data which indicate that neither maternal emotional stress nor the lack of a prenatal nutritional supplement was causally related to the occurrence of cleft lip or cleft palate. Other factors that have been suggested as possible causes of cleft palate include: A defective vascular supply to the area involved A mechanical disturbance in which the size of the tongue may prevent the union of parts Circulating substances, such as alcohol and certain drugs and toxins 92 Infections Lack of inherent developmental force. Despite the numerous clinical and experimental investigations, the etiology of cleft palate in the human being is still largely unknown. It must be concluded; however, that heredity is probably the most important single factor. Clinical Features Cleft lip with or without palate is more common in males than in females. Males have also been reported to have more severe defects, whereas the isolated cleft palate is more common in females. Clefts can be divided into nonsyndromic and syndromic forms. Syndromic forms of clefts include those cases that have additional birth defects like lip pits or other malformations, whereas nonsyndromic clefts are those cases wherein the affected individual has no other physical or developmental anomalies and no recognized maternal environmental exposures. At present, most studies suggest that about 70% of cases of cleft lip with or without palate and 50% of isolated cleft palate are nonsyndromic. The remaining syndromic cases can be subdivided into chromosomal anomalies, teratogens and uncategorized syndromes. Cleft lip can occur as a unilateral (on the left or right side) or as a bilateral anomaly. The line of cleft always starts on the lateral part of the upper lip and continues through the 93 philtrum to the alveolus between the lateral incisor and the canine tooth. The clefting anterior to the incisive foramen (i.e. lip and alveolus) is also defined as a cleft of primary palate. Cleft lip may occur with a wide range of severity, from a notch located on the left or right side of the lip to the most severe form, bilateral cleft lip and alveolus that separates the philtrum of the upper lip and premaxilla from the rest of the maxillary arch. When cleft lip continues from the incisive foramen further through the palatal suture in the middle of the palate, a cleft lip with palate (either unilateral or bilateral) is present (Figs. 1-9, 1-10). A wide range of severity may be observed. The cleft line may be interrupted by skin or mucosa bridges, hard (bone) bridges, or both, corresponding to a diagnosis of an incomplete cleft. This occurs in unilateral and bilateral CLP. Figure 1-9 Cleft involving both the hard and the soft palates. Courtesy of Dr R Manikandan, Meenakshi Ammal Dental College, Chennai) 94 Figure 1-10 Cleft involving the soft palate only. Courtesy of Dr John M Tondra and Harold M Trusler. Isolated cleft palate is etiologically and embryologically different from cleft lip with or without cleft palate. Several subtypes of isolated cleft palate can be diagnosed based on severity. The uvula is the place where the minimal form of clefting of the palate is observed (Fig. 1-11). A more severe form is a cleft of the soft palate. A complete cleft palate constitutes a cleft of the hard palate, soft palate, and cleft uvula. The clefting posterior to the incisive foramen is defined as a cleft of secondary palate. 95 Figure 1-11 Cleft or biid uvula. Courtesy of Dr Manikandan R, Meenakshi Ammal Dental College, Chennai. Classification of CLP Various classification schemes have been devised in the last 70 years, but few have received widespread clinical acceptance. Four of the more accepted schemes are depicted: Davis and Ritchie classification. Each of the following subgroups is further subdivided into the extent of the cleft (1/3, 1/2, etc.): Group I: Clefts anterior to the alveolus (unilateral, median, or bilateral CL) Group II: Postalveolar clefts (CP alone, soft palate alone, soft palate and hard palate, or submucous cleft). 96 Veau classification The Veau classification system is illustrated in: Group I (A): Defects of the soft palate only Group II (B): Defects involving the hard palate and soft palate Group III (C): Defects involving the soft palate to the alveolus, usually involving the lip Group IV (D): Complete bilateral clefts. Kernahan and Stark symbolic classification This classification highlights the anatomic and embryonic importance of the incisive foramen formed during weeks 4–7 GA. The secondary palate forms the roof of the mouth from the incisive foramen to the uvula during weeks 7–12 GA. This system provides a graphic classification scheme using a Y-configuration, which can be divided into 9 areas: Areas 1 and 4: Lip Areas 2 and 5: Alveolus 97 Areas 3 and 6: Palate between the alveolus and the incisive foramen Areas 7 and 8: Hard palate Area 9: Soft palate. International confederation of plastic and recon-structive surgery classification. This system uses an embryonic framework to divide clefts into 4 groups, with further subdivisions to denote unilateral or bilateral cases. Group I: Defects of the lip or alveolus Group II: Clefts of the secondary palate (hard palate, soft palate, or both) Group III: Any combination of clefts involving the primary and secondary palates. A median maxillary anterior alveolar cleft is a relatively common defect, occurring in approximately 1% of the population, according to Stout and Collett, but this is unrelated to cleft lip or cleft palate. This type of cleft has been discussed by Gier and Fast, who suggested that it might be 98 due to precocious limitation of the growth of the primary ossification centers on either side of the midline at the primary palate, or to their subsequent failure to fuse. In addition, Miller and his coworkers have suggested that at least some cases may represent an incomplete manifestation of the median cleft-face syndrome (hypertelorism, median cleft of the premaxilla and palate, and cranium bifidum occultum). This syndrome has no clinical manifestations and is usually detected only on routine intraoral radiographic examination (Fig. 1-12). 99 Figure 1-12 Median maxillary anterior alveolar cleft. All degrees of severity of the cleft may occur (Copyright by the American Dental Association. Reprinted by permission and by courtesy of Dr Arthur S Miller. From AS Miller, JN Greeley and DL Catena: Median maxillary anterior alveolar cleft: report of three cases. J Am Dent Assoc, 79: 896, 1969. Clinical Significance 100 Most cases of cleft lip can be surgically repaired with excellent cosmetic and functional results. It is customary to operate before the patient is one month old or when he has regained his original birth weight and is still gaining. Both the physical and psychologic effects of cleft palate on the patient are of considerable concern. Eating and drinking are difficult because of regurgitation of food and liquid through the nose. The speech problem is also serious and tends to increase the mental trauma suffered by the patient. Most individuals with CL, CP, or both, require the coordinated care of providers in many fields of medicine and dentistry, as well as those in speech pathology, otolaryngology, audiology, genetics, nursing, mental health, and social medicine. Treatment Treatment of CLP anomalies requires years of specialized care. Although successful treatment of the cosmetic and functional aspects of orofacial cleft anomalies is now possible, it is still challenging, lengthy, costly, and dependent on the skills and experience of a medical team. This especially applies to surgical, dental, and speech therapies. Undoubtedly, closure of the CL is the first major procedure that tremendously changes children’s future development and ability to thrive. Variations occur in timing of the first lip surgery; however, the most usual time occurs at approximately three months of age. Pediatricians used to strictly follow a rule of ‘three 10s’ as a necessary requirement for identifying the child’s status as suitable for surgery (i.e. 10 101 lb, 10 mg/L of hemoglobin, and age 10 weeks). Although pediatricians are presently much more flexible, and some surgeons may well justify a neonatal lip closure, the rule of three 10s is still very useful. Anatomical differences predispose children with CLP and with isolated CP to ear infections. Therefore, ventilation tubes are placed to ventilate the middle ear and prevent hearing loss secondary to otitis media with effusion (OME). In multidisciplinary teams with significant participation of an otolaryngologist, the tubes are placed at the initial surgery and at the second surgery routinely. The hearing is tested after the first placement when ears are clear with tubes. If no cleft surgery is planned early, placing the tubes by age six months and monitoring hearing with repeated testing is recommended. Complications include eardrum perforation and otorrhea, particularly in patients with open secondary palates in which closure is planned for a later date. Cheilitis Glandularis (Actinic cheilitis, squamous cell carcinoma) Cheilitis glandularis (CG) is a clinical diagnosis that refers to an uncommon and poorly understood inflammatory disorder of the lip. The condition is characterized by progressive enlargement and eversion of the lower labial mucosa that results in obliteration of the mucosal-vermilion interface. With externalization and chronic exposure, the delicate labial mucous membrane is secondarily altered by environmental influences, leading to erosion, ulceration, and crusting. Most significantly, susceptibility to actinic damage is increased. Therefore, CG can be considered a potential predisposing 102 factor for the development of actinic cheilitis and squamous cell carcinoma. Etiology CG is an unusual clinical manifestation of cheilitis that evolves in response to one or more diverse sources of chronic irritation. Lip enlargement is attributable to inflammation, hyperemia, edema, and fibrosis. Surface keratosis, erosion, and crusting develop consequent to longstanding actinic exposure, unusual repeated manipulations that include self-inflicted biting or other factitial trauma, excessive wetting from compulsive licking, drying (sometimes associated with mouth-breathing, atopy, eczema, and asthma), and any other repeated stimulus that could serve as a chronic aggravating factor. Clinical Features In 1870, von Volkman introduced the term cheilitis glandularis. He described a clinically distinct, deeply suppurative, chronic inflammatory condition of the lower lip characterized by mucopurulent exudates from the ductal orifices of the labial minor salivary glands. In 1914, Sutton proposed that the characteristic lip swelling was attributable to a congenital adenomatous enlargement of the labial salivary glands. This remained the prevailing hypothesis until 1984 when Swerlick and Cooper reported five new cases and a retrospective analysis of all cases of CG reported until that time. Their studies revealed no evidence to support the 103 assertion that salivary gland hyperplasia is responsible for CG. Cheilitis glandularis is a chronic progressive condition. Patients typically present for diagnostic consultation within 3–12 months of onset. Complaints vary

Shafer's Textbook of Oral Pathology 7th Edition PDF

Document Details

Tags

Related

Summary

Full Transcript

Upgrade to continue