Khe Hở Môi Và Vòm Miệng: Chẩn Đoán Và Quản Lý Điều Trị (Cleft Lip and Palate)

13/10/2026 • by Bs CKI Phẫu thuật tạo hình, tái tạo và thẩm mỹ Trương Hoài Anh •

Sách hướng dẫn đa chuyên khoa toàn diện về điều trị dị tật khe hở môi và vòm miệng. Cung cấp các kỹ thuật phẫu thuật tạo hình nụ cười, phục hồi chức năng phát âm, chỉnh hình răng hàm mặt và theo dõi sự phát triển của trẻ theo từng giai đoạn.

📂 Chuyên mục: Tài liệu thẩm mỹ, Phẫu thuật tái tạo, Thẩm mỹ khuôn mặt

🏷️ Từ khóa: khe hở môi vòm, cleft lip and palate, phẫu thuật tạo hình, dị tật bẩm sinh, sứt môi hở hàm ếch

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Samuel Berkowitz Editor Cleft Lip and Palate Diagnosis and Management Third Edition 2 Springer

Cleft Lip and Palate

(Trang không có chữ)

Samuel Berkowitz
Editor
Cleft Lip and Palate
Diagnosis and Management
Third Edition

ISBN 978-3-642-30769-0 ISBN 978-3-642-30770-6 (eBook)
DOI 10.1007/978-3-642-30770-6
Springer Heidelberg New York Dordrecht London
Library of Congress Control Number: 2012954868
© Springer-Verlag Berlin Heidelberg 2013
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While the advice and information in this book are believed to be true and accurate at the date of
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for any errors or omissions that may be made. The publisher makes no warranty, express or
implied, with respect to the material contained herein.
Printed on acid-free paper
Springer is part of Springer Science+Business Media ()
Editor
Samuel Berkowitz , DDS, M.S., FICD
Adjunct Professor
Department of Orthodontics
College of Dentistry
University of Illinois
Chicago, IL
USA
Clinical Professor of Surgery
and Pediatrics (Ret)
Director of Research (Ret)
South Florida Cleft Palate Clinic
University of Miami School
of Medicine
Miami, FL
USA
Consultant (Ret)
Craniofacial Anomalies Program
Miami Children’s Hospital
Miami, FL
USA

My professional growth has been nurtured by my
understanding wife, Lynn, who made it possible for me to
spend endless uninterrupted evenings at my desk, while at the
same time encouraging me to “stay with it.” Warm hugs to my
two daughters, Beth and Debra, Ruben and Edward, and my
eight outstanding grandchildren for their endless expressions
of support and love.
Last, but by no means least, I cannot say enough for the
countless children with various palatal and facial clefts whom
I have treated over the past four decades and for their
understanding parents. This book is dedicated to all of them
as a token of my appreciation for their enduring perseverance
and fortitude. My young patients have taught me much about
the human spirit and the joy that can spring from surmounting
nature’s adversities.
Finally, my work was made possible by the support of
D. Ralph Millard, Jr., who appreciated the value of serial
records starting at birth. S.A. Wolfe and I have differed on
a few areas of treatment, but we strongly agreed that only
through the analyses over time of objective growth records
could progress in treatment be accomplished. J.D. Subtelny,
Chairman of the Department of Orthodontics at Eastman
Dental Center and author of many articles on clefts, and
I have been friends for 40 years and at many of our meetings
it was a pleasure to hear of his experience treating children
born with clefts of the lip and palate.

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vii
Foreword
I am deeply honored by the opportunity to write the foreword to this new
edition of Dr. Samuel Berkowitz’s classic volume on cleft lip and palate.
As a lifelong student of past and current cleft palate literature on facial
palatal growth and development he is a strong advocate for good record
keeping and carefully conducted clinical studies. He possesses extensive
knowledge and insight in the effects of treatment interventions on cleft lip
and palate patients and their parents which has led to this book.
Samuel Berkowitz wrote his master’s thesis in cleft palate under the super-
vision and guidance of Samuel Pruzansky at the Cleft Palate-Craniofacial
Program at the University of Illinois School of Dentistry in 1959. From there
he went to the University of Miami School of Medicine to help develop, with
Dr. D. Ralph Millard Jr., Chief of Plastic Surgery, a craniofacial anomalies
program and clinic (1960–1998). They collaborated in developing an exten-
sive collection of longitudinal clinical records of dental casts, cephaloradio-
graphs, panorexes and photographs from birth to adolescence. These records
are now housed at the Museum of Health and Medicine associated with
the Institute of Pathology at Walter Reed Hospital in Washington, D.C.
Dr. Berkowitz’s main goal was to create lasting treatment concepts based on
a better understanding of the natural history of cleft palate and facial growth
and development. This book discusses in detail the resulting treatment con-
cepts, which are supported by in-depth case analyses.
During his and my time as clinician providers committed to care of chil-
dren with congenital facial differences, we have seen major improvements in
the overall long-term outcomes in the young adult with a cleft, managed from
infancy in an interdisciplinary team setting. Our expectations for the ﬁ nal
outcome are normal speech, harmonious facial features, well and stable occlu-
sion and good self esteem. The improvements are due to several factors, many
of which are the result of careful clinical studies, long-term observations and
the learning and experience that the providers obtain by working together in
a team. We have also experienced waves of new clinicians professing new
insights into how tissues will respond to certain new or reinvented techniques
or manipulations, only many years later to ﬁ nd no improvement in outcomes
or even detrimental effects on growth and development. The clinical records,
long memory and experience that are found in an established team can have a
moderating effect on new members without curbing enthusiasm and creative
thinking. It remains a fact that treatment interventions must proceed stepwise

viii
Foreword
according to biologic development and that there are wide individual varia-
tions among individuals with clefts.
In this new edition, Sam Berkowitz has assembled the most outstanding
specialists in their speci ﬁ c area of experience and expertise and some new
talents. The student of this text will ﬁ nd solid data where that exists and well
founded theories where data is not yet available. This text and the teaching
materials that Sam has produced to be used in orthodontic specialty programs,
attest to his burning desire and commitment to educate future clinical special-
ists in the care of individuals born with a cleft. He strongly believes that all
specialists should know each others problems to better design a meaningful
solution.
San Francisco, USA
Karin Vargervik

ix
About the Editor

Dr. Berkowitz , an orthodontist, was a Clinical Professor of Pediatrics and
Surgery associated with the South Florida Craniofacial Anomalies Program
at the University of Miami School of Medicine. He was also Adjunct Clinical
Professor at Nova Southeastern University College of Dentistry – Orthodontic
Department, and Adjunct Clinical Professor of Orthodontics at the University
of Illinois College of Dentistry. His main goal is to develop teaching materi-
als in cleft palate for professionals in plastic and oral surgery, orthodontics,
and speech language pathology. He is a past President of the American
Cleft Palate Association Educational Foundation, the Florida Cleft Palate
Association, was President of the Miami Craniofacial Anomalies Foundation.
Dr. Berkowitz was active in the American Association of Orthodontics,
Florida Cleft Palate Association, and The Edward Angle Society of
Orthodontists. He has published widely in medical and cleft palate journals
and is the author of Volume I and the editor of Volume II of Cleft Lip and

x
About the Editor
Palate Perspectives in Management – First Edition; he coauthored Plastic
Surgery of the Facial Skeleton with S. A. Wolfe, M. D, and wrote The Cleft Palate
Story for parents of a child born with a cleft. Dr. Berkowitz is a popular
speaker on cleft lip/palate topics and has presented many workshops and
seminars in the USA and abroad.
His research interest focused on improving surgical-orthodontic treatment
planning for cleft lip and palate children as well as those with other craniofa-
cial anomalies. Dr. Berkowitz was project director of a clinical research pro-
gram that was studying the long-term effects of various surgical treatment
procedures on palatal and facial growth and development. He created a quan-
titative method for determining when to close the palatal cleft space, based on
the 10 % ratio of the cleft space to the area of the surrounding palatal surface
medial to the alveolar ridges. He has created an audiovisual PowerPoint lec-
ture series for surgeons and orthodontists to enable them to better understand
and teach others the effects of surgery on the face from birth through
adolescence.
Dr. Berkowitz has been awarded the title “Honoree” by the Edward Angle
Society of Orthodontists, and “Honoree” by the First World Congress of the
International Cleft Lip and Palate Foundation for his many contributions to
the ﬁ eld of cleft lip and palate treatment. His extensive serial clinical records
of dental casts, lateral cephaloradiographs, facial and intraoral photographs,
and panorexes are in the National Museum of Health and Medicine (associ-
ated with Walter Reed Hospital’s Institute of Pathology in Washington DC),
where they will be available for continued study.

xi
Preface
In the ﬁ rst page of the ﬁ rst edition of this book, I quoted Samuel Pruzansky
who, after participating at an International Symposium on Cleft Lip and
Palate held in 1969, and re ﬂ ecting on what he heard at that meeting, stated,
“The same tired questions have been asked as at every similar clinical meet-
ing. And I despair at the general unfamiliarity with the pertinent literature.”
Fortunately, since the 1950s, many clinical investigators in the ﬁ eld of
cleft palate have performed excellent clinical studies of the management of
cleft lip and palate that have contributed to the intellectual ferment over the
last 50 years. To these studies we are indebted, since to know this literature is
vital for correct treatment planning.
When selecting signi ﬁ cant references for this text, every attempt was made
to carry out an exhaustive literature search to include all of the excellent arti-
cles on each subject covered. That, however, has been an insurmountable
task. To investigators whose research articles were not included, I apologize
and I advise readers to conduct their own literature search, which must include
papers on the “opposing schools” of thought. There is no doubt in my mind
that their ﬁ nal conclusions will be the same as mine when they consider the
results of long-term palatal and facial growth studies that involved the analy-
sis of objective records.
To familiarize clinicians with the appropriate literature and its importance
to the treatment of cleft lip and cleft palate, the chapters in this book are struc-
tured to improve clinicians’ understanding of the natural history of the cleft
defect, the face in which it exists, the in ﬂ uence of surgery on palatal growth
and development, and equally importantly in developing an appreciation for
the heterogeneity that exists even within a single cleft type.
These chapters will show that chronological age is not the parameter that
really matters in determining the age at which to close the cleft in the palate.
What is important is morphologic age and physiologic ﬁ tness, that is, whether
the tissues are adequate in quantity and quality and whether the geometric
relationship of cleft parts is favorable or unfavorable for reconstruction. Some
questions incidental to growth, which date back 25 years, concern the rela-
tionship of the malformed palatal segments to the contiguous skeletal anat-
omy, which, in turn, may be anomalous. These following questions are also
addressed: Are the palatal segments static in their de ﬁ ciency or does the
de ﬁ ciency diminish in time, that is, is “catch-up-growth” a predictable phe-
nomenon? And if so, what surgical procedures (as to age and type) make it
possible?

xii
Preface
Many of Pruzansky’s thoughts, written so many years ago, still hold true
today and are worth repeating. He stated that whoever sees things from their
beginning will have the most advantageous view of them. To that end, most
of the serial cases presented in this volume start soon after birth when plaster
casts and photographs of the palatal and facial defect are taken. Serial lateral
cephaloradiographs are added as soon as the child is manageable, and again
taken periodically through adolescence.
It is hoped that clinicians who are just beginning their involvement in cleft
palate will learn the pathology and its natural history of cleft palate from the
cases presented in this book and appreciate the need to keep careful records
(casts, cephaloradiographs, photographs, and panorexes) which are of vital
importance to both the processing of knowledge and self-criticism.
One last note of great importance – it is rare that two members of a team,
such as I, an orthodontist, and D. Ralph Millard Jr., a plastic surgeon, can
successfully work together even when some differences in treatment philoso-
phy exist. We succeeded because we were professionally compatible and
because we shared an obsessive need to determine why some procedures are
successful and why others fail even when the same treatment procedures were
used. Failures, we discovered, occur principally because of misinterpretation
of physiological principles and/or a lack of technical pro ﬁ ciency.
Dr. Millard understood the value of serial objective records dating from
birth as the essential starting point in determining the long-term utility of any
surgical cleft treatment program. Although I was always free to voice a con-
trary opinion as to what surgery should be performed (and when), our work-
ing relationship was based on recognizing the right of the surgeon to reject
recommendations and follow his own dictates. And it was my right, as a
member of a team involved in growth studies, to document the anatomical
changes to the face and palate for future analysis. Respecting our mutual
rights and responsibilities was no simple task. Strong emotional and concep-
tual barriers had to be overcome in the process of communicating with each
other.
Our 40-year search for a better understanding of the natural history of cleft
lip/palate growth and development and the effects of various surgical-orth-
odontic treatment procedures ultimately led Dr. Millard to a conservative
approach of staged surgical treatment without the intercession of maxillary
orthopedics with periosteoplasty, which he tried and found wanting.
Reference
Pruzansky S (1969) Early treatment of cleft lip and palate. In: Cole RM (ed) Proceedings
of the second international symposium. Cleft Lip and Cleft Palate Institute, Northwestern
University School of Dentistry, Chicago, p 116

xiii
Preface
Advertisement
An Audio-Visual PowerPoint 7 hour online lecture is available from Dr. Samuel
Berkowitz and the University of Illinois, College of Dentistry, Orthodontic
Department, for all specialist on a cleft palate team. It consists of a tutorial of
over 400 illustrations utilized in the 3rd edition of Cleft Lip and Palate:
Diagnosis and Management .
Biological Concepts that underlie Cleft Palate Treatment: The E-Learning
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This course is designed as supplemental material for any program cover-
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Individual enrollments and bulk university class enrollments are
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To enroll or view a free trial module, visit
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Topics covered include:
Embryopathogenesis of cleft palate development
•
The natural history of cleft palate growth and development from birth to
•
adolescence (with or without presurgical orthopedics)
Complete bilateral cleft lip and palate
–
Complete unilateral cleft lip and palate
–
Isolated cleft palate
–
Use
and
abuse
of
presurgical
orthopedics
with/without
•
gingivoperiosteoplasty
The velopharyngeal mechanism and variations in the pharyngeal architec-
•
ture which in ﬂ uences nasal air ﬂ ow
The use of a pharyngeal ﬂ ap versus pharyngioplasty to control air ﬂ ow
•
Timing of palatal closure as it in ﬂ uences occlusion, speech, and facial
•
growth
The use of a protraction facial mask to avoid midfacial surgical
•
advancement
Craniofacial surgery and distraction osteogenesis
•
Samuel Berkowitz, DDS, M.S., FICD
Editor

(Trang không có chữ)

xv
Acknowledgements
Since the Third Edition involves the assistance of those who aided in the
creation of the Second Edition I am happy to list their names again. I extend
heartfelt thanks to Dr. Maria Camila Caro, Leslie Gagnon, Gillian Kelley,
George Diaz, Ms. Marta Mejia, Juan Hernandez, Pedro Ibarra, Ana Belmonte
and the late Francis Fink for his excellent photography. For the Third Edition
I want to give special thanks to Jay Abbott and Howard Siegel for their com-
puter skills involved in this edition.
Also, immeasurable thanks to my many colleagues in The American Cleft
Palate-Craniofacial Association and those involved in various cleft palate
clinics in the USA, Europe and Asia for contributing to my understanding of
cleft lip and palate patient management. To them, too many to recognize by
name, I shall be forever grateful for their professional knowledge and per-
sonal friendship.
Special acknowledgement needs to be given to my mentor, Dr. Samuel
Pruzansky, orthodontist who was director of the Cleft Palate-Craniofacial
program at the University of Illinois College of Dentistry when I was a resi-
dent in orthodontics. There is no question he motivated me as well as all of
those with whom he made contact to go in the right direction to understand
the natural history of the face with the cleft palate defect. His aim was to be
able to uncover signi ﬁ cant information to perform differential diagnosis in
treatment planning.

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xvii
Contents
Part I Facial Embryology and Neonatal Palatal Cleft Morphology
1 Embryogenetics of Cleft Lip and Palate . . . . . . . . . . . . . . . . . .
3
Geoffrey H. Sperber and Steven M. Sperber
2 The Value of Longitudinal Facial and Dental Casts Records
in Clinical Research and Treatment Analysis . . . . . . . . . . . . .
35
Samuel Berkowitz
3 Facial and Palatal Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
Samuel Berkowitz
Part II Types of Clefts
4 The Effect of Clefting of the Lip and Palate
and the Palatal Arch Form . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61
Samuel Berkowitz
5 Alternative Method Used to Correct Distorted Neonatal
Cleft Arch Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
87
Samuel Berkowitz
6 Complete Unilateral Cleft of the Lip and Palate . . . . . . . . . . .
95
Samuel Berkowitz
7 Complete Bilateral Cleft Lip and Palate . . . . . . . . . . . . . . . . . . 133
Samuel Berkowitz
8 Lip Pits: Orthodontic Treatment, Dentition,
and Occlusion – Associated Skeletal Structures. . . . . . . . . . . . 227
Samuel Berkowitz
Part III Facial Growth in Cleft Palate Children
9 Characteristics of Facial Morphology and Growth
in Infants with Clefts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
Sven Kreiborg, Nuno V. Hermann, and Tron A. Darvann

xviii
Contents
10 A 25-Year Longitudinal Facial Growth Study
of Unilateral Cleft Lip and Palate Subjects
from the Sri Lankan Cleft Lip and Palate Project. . . . . . . . . . 259
Brijesh Patel and Michael Mars
11 Airway Management in Patients with Robin Sequence . . . . . 279
Kevin D. Han, Mitchel Seruya, Diego A. Preciado,
and Albert K. Oh
12 Pierre Robin Sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
Samuel Pruzansky and Julius B. Richmond
Part IV Audiology/Otology
13 Management of Otopathology and Hearing Loss
in Children with Cleft Palate and Craniofacial Anomalies. . . 299
Amelia F. Drake and Jackson Roush
Part V Effects of Surgery and How It Was Utilized
14 Palatal Wound Healing: The Effects of Scarring
on Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
Johannes W. Von den Hoff, Jaap C. Maltha,
and Anne Marie Kuijpers-Jagtman
15 Facial Growth Related to Surgical Methods . . . . . . . . . . . . . . 325
Gunvor Semb and William C. Shaw
Part VI Lip and Palate Surgery: Millard–Berkowitz Protocol
16 The Inﬂuence of Conservative Surgery on Growth
and Occlusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
Samuel Berkowitz
17 Choosing the Best Time for Palatal Surgery . . . . . . . . . . . . . . 389
Samuel Berkowitz
Part VII Another Tested Good Surgical Procedure
18 Two-Stage Palatal Surgery with Early Veloplasty
and Delayed Hard Palate Repair: A Balanced View
on Speech and Midfacial Growth Outcome . . . . . . . . . . . . . . . 413
Hans Friede, Jan Lilja, and Anette Lohmander
Part VIII Facial Growth: Time Is the Patient’s Ally
19 Management of the Premaxilla/Maxilla in Bilateral
Cleft Lip and Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441
Karin Vargervik and Snehlata Oberoi

xix
Contents
Part IX Presurgical Orthopedics
20 Neonatal Maxillary Orthopedics: Past to Present . . . . . . . . . . 455
Anne Marie Kuijpers-Jagtman and Charlotte Prahl
21 A Comparison of the Effects of the Latham–Millard
POPLA Procedure with a Conservative Treatment
Approach on Dental Occlusion and Facial Aesthetics
in CUCLP and CBCLP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473
Samuel Berkowitz and Martha Mejia
Part X Midfacial Orthodontic/Orthopedic and/or
Surgical Changes
22 Protraction Facial Mask . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511
Samuel Berkowitz
23 Protraction Facial Mask for Early Correction
of Midfacial Retrusion: The Bergen Rationale . . . . . . . . . . . . 519
Rolf S. Tindlund
24 LeFort I Osteotomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
S.A. Wolfe and Samuel Berkowitz
Part XI Orthognathic Surgery
25 Cleft Jaw Deformities and Their Management . . . . . . . . . . . . 557
Jeffrey C. Posnick
26 Secondary Bone Grafting of Alveolar Clefts . . . . . . . . . . . . . . 601
Frank E. Abyholm, Sayuri Otaki, and Masatomo Yorimoto
27 The Need for Differential Diagnosis in Treatment Planning . . . 613
Samuel Berkowitz
Part XII Distraction Osteogenesis
28 Rigid External Distraction: Its Application
in Cleft Maxillary Deformities . . . . . . . . . . . . . . . . . . . . . . . . . . 633
John W. Polley and Alvaro A. Figueroa
29 Remodeling the Mandible by Distraction Osteogenesis . . . . . 649
Fernando Molina
30 Management of Maxillary Deformities
in Growing Cleft Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
Eric J.W. Liou and Philip K.T. Chen
31 Preventing Relapse Following Distraction Osteogenesis
for the Cleft Midface in Adults . . . . . . . . . . . . . . . . . . . . . . . . . 693
N.K. Koteswara Prasad, Syed Altaf Hussain,
and Jyotsna Murthy

xx
Contents
Part XIII Speech
32 Diagnostic Procedures and Instruments Used
in the Assessment and Treatment of Speech . . . . . . . . . . . . . . . 707
Samuel Berkowitz
33 Variations in Nasopharyngeal Skeletal Architecture . . . . . . . . 715
Samuel Berkowitz
34 The Velopharyngeal Mechanism . . . . . . . . . . . . . . . . . . . . . . . . 741
Robert J. Shprintzen
35 Surgical Management of Velopharyngeal Dysfunction . . . . . . 759
Richard E. Kirschner and Adriane L. Baylis
36 Velopharyngeal Dysfunction Management Algorithms . . . . . 777
Jeffrey L. Marsh
37 Optimal Age for Palatoplasty to Facilitate Normal
Speech Development: What Is the Evidence? . . . . . . . . . . . . . 787
Sally J. Peterson-Falzone
38 Speech, Language, and Velopharyngeal Dysfunction:
Management Throughout the Life of an Individual
with Cleft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 803
John E. Riski
39 Prosthetic Speech Appliances for Patients
with Cleft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 821
Mohammed Mazaheri
40 Palatal Lift Prosthesis for the Treatment of Velopharyngeal
Incompetency and Insufﬁciency . . . . . . . . . . . . . . . . . . . . . . . . 839
Mohammed Mazaheri
Part XIV Third World Cleft Treatment
41 Cleft Palate Treatment in Developing Countries of Africa . . . 855
Fadekemi O. Oginni and Wasiu L. Adeyemo
42 Birthing and Building Nascent Cleft Teams
in Developing Countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 871
Emad Hussein, Hala Borno, and John van Aalst
43 Challenges in Cleft Care in Underdeveloped Countries . . . . . 879
Isaac L. Wornom III
Part XV Psychological/Team Function
44 Examining the Team Process: Developing
and Sustaining Effective Craniofacial Team Care . . . . . . . . . . 885
Lynn M. Fox and Patricia Ann Stone

xxi
Contents
45 Living with a Cleft: Psychological Challenges,
Support and Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907
Nichola Rumsey and Nicola Marie Stock
46 Managing Teasing and Bullying . . . . . . . . . . . . . . . . . . . . . . . . 917
Sara Shavel-Jessop, Joanna Shearer, Elizabeth McDowell,
and Daniela Hearst
Part XVI Multicenter Clinical Reports
47 Eurocleft and Americleft Studies: Experiments
in Intercenter and International Collaboration . . . . . . . . . . . . 929
Ross E. Long Jr., William C. Shaw, and Gunvor Semb
Part XVII Recording Patient Orthodontic/Surgical Findings
48 Berkowitz Recording Patient Information Form . . . . . . . . . . . 947
Samuel Berkowitz
Part XVIII The Patient’s World
49 Social, Ethical, and Health Policy Issues in the Care
of Children with Major Craniofacial Conditions . . . . . . . . . . 955
Ronald P. Strauss
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967

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xxiii
Contributors
Frank E. Abyholm , M.D., DDS, Ph.D. Department of Plastic Surgery ,
Rikshopitalet National Hospital , Oslo , Norway
Wasiu L. Adeyemo , BDS (Ib), FMCDS (Nig), FWACS, Ph.D., Cologne,
FICS Department of Oral and Maxillofacial Surgery, Faculty of Dental
Sciences, College of Medicine, University of Lagos, Lagos , Nigeria
Adriane L. Baylis , Ph.D., CCC-SLP Director, Resonance Disorders
Program , Nationwide Children’s Hospital , Columbus , OH , USA
Assistant Professor of Clinical Plastic Surgery, Speech and Hearing Science,
and Pediatrics , The Ohio State University , Columbus , OH , USA
Samuel Berkowitz , DDS, M.S., FICD Adjunct Professor, Department of
Orthodontics , College of Dentistry, University of Illinois , Chicago , IL , USA
Clinical Professor of Surgery and Pediatrics (Ret), Director of Research
(Ret), South Florida Cleft Palate Clinic, University of Miami School of
Medicine , Miami , FL , USA
Consultant (Ret), Craniofacial Anomalies Program , Miami Children’s
Hospital , Miami , FL , USA
Hala Borno School of Medicine , University of North Carolina
at Chapel Hill , Chapel Hill , NC , USA
Philip K. T. Chen Section of Craniofacial Surgery, Department of Plastic,
and Reconstruction Surgery, Chang Gung Memorial Hospital,
Taipei, Taiwan
Tron A. Darvann , M.Sci., Ph.D. 3D Craniofacial Image Research
Laboratory , School of Dentistry, University of Copenhagen , Copenhagen ,
Denmark
Department of Oral and Maxillofacial Surgery, Centre of Head and Orthopaedics,
Copenhagen University Hospital Rigshospitalet, Copenhagen , Denmark
Amelia F. Drake , M.D., FACS Department of Otolaryngology ,
The University of North Carolina School of Medicine, UNC Hospitals ,
Chapel Hill , NC , USA
Alvaro A. Figueroa , DDS, M.S. Rush Craniofacial Center , Chicago ,
IL , USA

xxiv
Contributors
Lynn M. Fox , M.A., Med Department of Dental Ecology, University of
North Carolina School of Dentistry , Chapel Hill , NC , USA
Hans Friede , DDS Department of Orthodontics ,
Sahlgrenska Academy at University of Gothenburg , Gothenburg , Sweden
Kevin D. Han , M.D. Department of Plastic Surgery, 1PHC ,
Georgetown University Hospital , Washington, DC , USA
Daniela Hearst Psychosocial and Family Services , Great Ormond Street
Hospital for Children NHS Trust and the North Thames Cleft Lip
and Palate Service , London , UK
Nuno V. Hermann , DDS, Ph.D. Department of Pediatric Dentistry
and Clinical Genetics , School of Dentistry, University of Copenhagen ,
Copenhagen , Denmark
Syed Altaf Hussain , M.S., FRCS, DNB Department of Plastic Surgery,
Cleft and Craniofacial Centre , Sri Ramachandra University , Chennai , India
Emad Hussein , M.S., FRCS, DNB Department of Orthodontics and
Pediatric Dentistry, Faculty of Dentistry , Arab American University ,
Jenin , Palestine
Richard E. Kirschner , M.D., FACS, FAAP Chief, Section for Plastic and
Reconstructive Surgery , Director, Cleft Lip and Palate Center,
Nationwide Children’s Hospital , Columbus , OH , USA
Professor of Clinical Plastic Surgery and Pediatrics , The Ohio State
University College of Medicine , Columbus , OH , USA
Sven Kreiborg , DDS, Ph.D., DrOdont Department of Pediatric Dentistry
and Clinical Genetics , School of Dentistry, University of Copenhagen ,
Copenhagen , Denmark
Anne Marie Kuijpers-Jagtman , DDS, Ph.D. Department of Orthodontics
and Craniofacial Biology , Cleft Palate Craniofacial Unit, Radboud
University Nijmegen Medical Centre , Nijmegen , The Netherlands
Jan Lilja , M.D., DDS, Ph.D. Department of Plastic Surgery, Sahlgrenska
University Hospital , Gothenburg , Sweden
Eric J. W. Liou , DDS, M.S. Department of Orthodontics & Craniofacial
Dentistry, Chang Gung Memorial Hospital, Taipei , Taiwan
Anette Lohmander , SLP, Ph.D. Division of Speech and Language
Pathology , Karolinska Institute , Stockholm, Sweden
Previously af ﬁ liated with Sahlgrenska Academy at University of
Gothenburg, Sweden
Ross E. Long Jr., DMD, M.S., Ph.D. Lancaster Cleft Palate Clinic ,
Lancaster , PA, USA

xxv
Contributors
Jaap C. Maltha , Ph.D. Department of Orthodontics and Craniofacial
Biology , Radbound University Nijmegen Medical Center , Nijmegen ,
The Netherlands
Michael Mars , DSc (Hon), Ph.D., BDS, FDS, D.Orth, FRCSLT (Hon),
FSLCP (Hon) North Thames Cleft Centre – Great Ormond Street
Hospital for Children , London , UK
Faculty of Medicine, Peradeniya , Sri Lanka
Jeffrey L. Marsh , M.D. Department of Surgery, Plastic
and Reconstructive , St. Louis University School of Medicine ,
St. Louis , MO , USA
Department of Pediatric Plastic Surgery , Cleft Lip/Palate and Craniofacial
Deformities Center, Mercy Children’s Hospital , St. Louis , MO , USA
Kids Plastic Surgery , St. Louis , MO , USA
Mohammed Mazaheri , MDD, DDS, M.Sc. Professor of Surgery
Pennsylvania State University , Hershey Medical Center, Past Medical and
Dental Director, Lancaster Cleft Palate Clinic, Lancaster, PA , USA
Elizabeth McDowell Psychosocial and Family Services ,
Great Ormond Street Hospital for Children NHS Trust and the North
Thames Cleft Lip and Palate Service , London , UK
Marta Mejia , DDS Division of Plastic Surgery , Miami Children’s
Hospital , Miami , FL , USA
Fernando Molina , M.D. Department of Plastic and Reconstructive
Surgery, Hospital General “Dr. Manuel Gea Gonzalez”, Delegacion Tlalpan ,
Mexico
Jyotsna Murthy , M.S., Mch (Plastic) Department of Plastic Surgery,
Cleft and Craniofacial Centre , Sri Ramachandra University ,
Chennai , India
Snehlata Oberoi , DDS Department of Orofacial Sciences, Center for
Craniofacial Anomalies, University of California, San Francisco ,
San Francisco , CA , USA
Fadekami O. Oginni , BChD (Ife), FMCDS (Nig), FWACS Department of
Oral and Maxillofacial Surgery, Faculty of Dentistry , College of Health
Sciences, Obafemi Awolowo University , Ile-Ife , Osun , Nigeria
Albert K. Oh , M.D. Department of Surgery and Pediatrics , The George
Washington University School of Medicine , Washington, DC , USA
Department of Plastic and Reconstructive Surgery ,
Children’s National Medical Center , Washington, DC , USA

xxvi
Contributors
Sayuri Otaki , M.D., DDS, Ph.D. Department of Plastic Surgery ,
Tane General Hospital , Osaka-Shi , Japan
Department of Plastic Surgery , Osaka City University Medical School ,
Osaka-Shi , Japan
Brijesh Patel , BDS (Hons), M.Sc., MFDS, M. Orth, FDS (Orth)
North Thames Cleft Centre – Great Ormond Street Hospital for Children ,
London , UK
St. Andrew’s Hospital, Chelmsford, UK
Sally J. Peterson-Falzone , Ph.D., CCC-Sp, FASHLA Clinical Professor
Emerita, University of California , San Francisco , CA , USA
John W. Polley , M.D. Craniofacial Clinic, Rush University Medical
Center , Chicago , IL , USA
Jeffrey C. Posnick , DMD, M.D., FRCS (C), FACS Director, Posnick
Center for Facial Plastic Surgery , Chevy Chase , MD , USA
Clinical Professor of Surgery and Pediatrics , Georgetown University ,
Washington, DC , USA
Adjunct Professor of Orthodontics , University of Maryland, Baltimore
College of Dental Surgery , Baltimore , MD , USA
Adjunct Professor of Oral and Maxillofacial Surgery , Howard University
College of Dentistry , Washington, DC , USA
Charlotte Prahl , DDS, Ph.D. Department of Orthodontics ,
Academic Centre for Dentistry , Amsterdam , The Netherlands
Orthodontist Cleft Palate Team , Free University Medical Centre ,
Amsterdam , The Netherlands
N. K. Koteswara Prasad , MDS, FCFD Department of Orthodontics,
Faculty of Dental Sciences, Cleft and Craniofacial Centre ,
Sri Ramachandra University , Chennai , India
Diego A. Preciado , M.D., Ph.D. Department of Otolaryngology,
Pediatrics, and Integrative Systems Biology , The George Washington
University School of Medicine , Washington, DC , USA
Division of Pediatric Otolaryngology, Department of Otolaryngology ,
Children’s National Medical Center , Washington, DC , USA
Samuel Pruzansky , DDS (Deceased) Cleft Palate Craniofacial Center ,
University of Illinois, Chicago , IL , USA
Julius B. Richmond , M.D. (Deceased) Department of Plastic Surgery,
University of Illinois, Chicago, IL, USA
John E. Riski , Ph.D., CCC-S, FASHA Speech Pathology Laboratory ,
Center for Craniofacial Disorders, Children’s Healthcare of Atlanta ,
Atlanta , GA , USA

xxvii
Contributors
Jackson Roush , Ph.D. Division of Speech and Hearing Sciences,
Department of Allied Health Sciences , University of North Carolina
School of Medicine , Chapel Hill , NC , USA
Nichola Rumsey Department of Psychology , Centre for Appearance
Research, University of the West of England , Bristol , UK
Gunvor Semb , DDS, Ph.D. Department of Orthodontics, University of
Manchester, School of Dentistry , Manchester , UK
Mitchel Seruya , M.D. Department of Plastic Surgery, 1PHC ,
Georgetown University Hospital , Washington, DC , USA
Sara Shavel-Jessop Psychosocial and Family Services , Great Ormond
Street Hospital for Children NHS Trust and the North Thames Cleft Lip
and Palate Service , London , UK
William C. Shaw , BDS, Ph.D. Department of Orthodontics, University of
Manchester, School of Dentistry, The University of Manchester ,
Manchester , UK
Joanna Shearer Psychosocial and Family Services , Great Ormond Street
Hospital for Children NHS Trust and the North Thames Cleft Lip
and Palate Service , London , UK
Robert J. Shprintzen , Ph.D. President and Chairman of the Board, The
Virtual Center for Velo-Cardio-Facial Syndrome Inc., NY, USA
Geoffrey H. Sperber , BDS, M.S., Ph.D., FICD, Dr Med Dent
(Hon causa) Faculty of Medicine and Dentistry , Edmonton Clinic
Health Academy, University of Alberta , Edmonton , AB , Canada
Steven M. Sperber , M.S., Ph.D., FACMG Denver Genetic Laboratories,
Department of Pediatrics , School of Medicine, University of Colorado ,
Aurora , CO , USA
Nicola Marie Stock Department of Psychology, Faculty of Health
and Life Sciences , Centre for Appearance Research, University of the West
of England , Bristol , UK
Patricia Ann Stone , M.A., CCC-SLP Department of Plastic and
Reconstructive Surgery, Akron Children’s Hospital, Akron Children’s
Hospital, One Perkins Square, Akron, OH, USA
Ronald P. Strauss , DMD, Ph.D. Departments of Dental Ecology and of
Social Medicine, The University of North Carolina at Chapel Hill,
Schools of Dentistry and Medicine , Chapel Hill , NC , USA
The UNC Craniofacial Center , Chapel Hill , NC , USA
Rolf S. Tindlund , DDS, Ph.D. Department of Orthodontics and Facial
Orthopedics, Faculty of Medicine and Dentistry , University of Bergen ,
Bergen , Norway

xxviii
Contributors
John van Aalst Division of Plastic Surgery, Department of Surgery ,
The University of North Carolina at Chapel Hill , Chapel Hill , NC , USA
Karin Vargervik , DDS Department of Orofacial Sciences,
Center for Craniofacial Anomalies, University of California,
San Francisco , San Francisco , CA , USA
Johannes W. Von den Hoff , Ph.D. Department of Orthodontics and
Craniofacial Biology , Radbound University Nijmegen Medical Center ,
Nijmegen , The Netherlands
S. A. Wolfe , M.D. Chief, Division of Plastic Surgery, Miami Children’s
Hospital, Miami , FL , USA
Isaac L. Wornom III, M.D., FACS Richmond Plastic Surgeons,
Virginia Commonwealth University , Richmond , VA , USA
Masatomo Yorimoto , DDS Yorimoto Dental Clinic , Osaka-Shi , Japan

xxix
Introduction
The general aim of this volume is to present recognized experts from the
clinical sciences of dentistry, medicine, speech, audiology, psychology, social
work, nurses, genetics, ethics, and biology, so that all aspects of the treatment
of cleft palate and other craniofacial anomalies can be scrutinized from a
particular point of view: long-term clinical experience.
For the sake of brevity, many variations in cleft type and their treatment
alluded to in this book were not presented. Because of the multiplicity of
variables, no simple description or classi ﬁ cation and treatment plan could
possibly satisfy everyone concerned with this problem.
Pruzansky (1953) was once asked, “When should the orthodontist’s,
speech pathologist’s, or prosthodontist’s interest in the cleft palate child
begin?” His response: “The answer is quite clear. Everyone who seeks to
serve the needs of the child with a cleft should begin at the beginning.” An
interest in all events affecting these children is essential to the training and
educational experience that each member of the team must obtain. Each spe-
cialist emerges not only better informed in his/her own ﬁ eld, but with an
increased perspective regarding the means available for providing an inte-
grated program of care for the handicapped child.
The material presented examines the face with a cleft in all aspects as a
biologic continuum from birth through postnatal growth and development to
maturity at various stages of treatment. In the past several decades, many
advances have taken place in cleft habilitation procedures. Unfortunately,
many of these changes have not ful ﬁ lled all of their stated objectives, and in
some instances, these procedures were found to be either injurious or at best
unnecessary. These errors will be discussed in detail.
This book also brings together clinicians and biological scientists from the
United States, Asia, Europe, and Africa, each of whom in his or her own way
has been seeking answers to the multifaceted problem of cleft palate, regard-
ing its embryopathogenesis, craniofacial growth, maxillary orthopedics, sur-
gery, protraction of the maxilla, dental speech prostheses, secondary alveolar
bone grafting, speech, hearing, genetics, psychosocial development, and
craniofacial surgery.
Each contributor presents pertinent concepts so that a broad perspective of
the entire habilitative process can be obtained. The conclusions the reader
will reach will be the result of well-documented literature of selected well-
controlled clinical research that has withstood the test of review and
reexamination.

xxx
Introduction
Because space limitations prevent thorough penetration of all aspects of
each subject, a large bibliography is included for additional source material.
In no way could these chapters be expected to cover all aspects of this
complex subject.
It is my hope that, through a better understanding of the cleft palate defect
and face, all clinicians will be better able to evaluate present-day treatment
practices and concepts to better plan their own treatment procedures.
We fully acknowledge the important contributions made by the authors
and research programs from the institutions which have strongly in ﬂ uenced
much of what has been written in these volumes.
All lip and palate surgery of my cases were performed by Dr. Ralph
Millard, Jr., except where otherwise indicated; S.A. Wolfe performed all skel-
etal surgery and secondary alveolar bone grafting. They both performed
superior-based pharyngeal ﬂ aps. No presurgical orthopedics were used unless
speci ﬁ cally indicated.
Reference
Pruzansky S (1953) Description, classi ﬁ cation, and analysis of unoperated clefts of the lip
and palate. Am J Orthod 39:590

Part I
Facial Embryology
and Neonatal Palatal Cleft Morphology

3
S. Berkowitz (ed.), Cleft Lip and Palate,
DOI 10.1007/978-3-642-30770-6_1, © Springer-Verlag Berlin Heidelberg 2013
1
1.1
Introduction
The human features and countenance, although
composed of some ten parts or a little more, are
so fashioned that among so many thousands of
men there are no two in existence who cannot be
distinguished from one another. Pliny the Elder,
Book 7, Sect 8. AD 23–79 (Harvey 1847 )
The basis for most congenital malformations
must be found, I think, in hampered development,
that is, in arrest at different periods of develop-
ment. In order to provide evidence for this, it was
necessary to complement the pictures of malfor-
mations with illustrations of the normal develop-
ment of the embryo (Vrolik quoted in Oostra
et al. 2004 ) (Fig. 1.1 ).
Embryogenetics of Cleft Lip
and Palate
Geoffrey H. Sperber and Steven M. Sperber
G. H. Sperber , BDS, M.S., Ph.D., FICD, Dr Med Dent
(Hon causa) ()
Faculty of Medicine and Dentistry , Edmonton Clinic
Health Academy, University of Alberta ,
Edmonton , AB T6G 1C9 , Canada
e-mail: gsperber@ualberta.ca
WNT
PAX6
DLX
BARX
GSE
BMP
FGF8
PAX9
Fig. 1.1 Schematic
depiction of gene signaling
patterns in a 7-week-old
human fetus. The regional
colors represent transient
gene expression patterns at
different stages of embryo-
genesis (Courtesy of B.
Lozanoff, University of
Hawaii
S. M. Sperber , M.S., Ph.D., FACMG
Denver Genetic Laboratories, Department of Pediatrics ,
School of Medicine, University of Colorado ,
Aurora , CO 80045 , USA
e-mail: steven.sperber@ucdenver.edu

4
G.H. Sperber and S.M. Sperber
Thus did Vrolik, more than 150 years ago,
lay the foundation for understanding the causes
of orofacial clefts. The challenge for modern
molecular medicine is to translate the clinically
observed clefting defects, the phenotype, back
through the intricate developmental phenom-
ena that created them, to the coding genotype.
The identi ﬁ cation of the genetic predisposition
to clefts and the environmental factors that
determine and alter the varying threshold of
normal versus dysmorphic development are
among the central challenges for developmen-
tal biologists to decipher. Variations of gene
expression regulated by epigenetic mechanisms
and variable environments may cause differing
expressions of genetic traits (polyphenisms),
among which are clefting syndromes. The pre-
natal diagnostic capabilities of chorionic villus
sampling, amniocentesis, fetoscopy, magnetic
resonance imaging, and ultrasonography have
vaulted gestational developmental phenomena
into the ﬁ eld of concern to the clinician
(Fig. 1.2 ) (Liou et al. 2011 ; Stoll and Clementi
2003 ; Wang et al. 2011 ) . A new three-dimen-
sional sonographic technique (OmniView)
allows study of the fetal hard and soft palates
and prenatal diagnosis of clefting (Tonni and
Lituania 2012 ) . The maldeveloped intrauterine
fetus has now become a potential patient
(Jones 2002 ) .
The potential for clefting will ideally be
diminished from its initial pathogenetic determi-
nation by prevention rather than by post hoc
treatment. The basics of biology and molecular
medicine will be translated from the laboratory
bench to the bedside in the clinical practice of the
future.
1.2
Genetics
The mélange of molecular mechanisms involved
in the cascading events of embryogenesis are
predicated by the expression patterns of speci ﬁ c
genes contained in the human genome, con-
strained by impacting environmental factors.
Gene expression patterns are revealing regions of
the emerging embryo that have been previously
observed histologically and anatomically but not
heretofore realized as genetically distinct entities
during development. Studies of animal model
systems have contributed to our understanding of
the molecular determinants that contribute to
facial patterning (Swartz et al. 2011 ) . Herein is
the marriage of genetics with developmental biol-
ogy becoming of potential clinical signi ﬁ cance.
Current investigations are delineating the com-
plex molecular embryology of development.
Speci ﬁ c defects in molecular pathways and net-
works may provide insights into the etiology of
clefting. While embryologists focus on the mech-
anisms of malformation, deformation, disruption,
and dysplasia, clinicians focus on the etiology,
diagnosis, treatment, prognosis, and prevention of
clefting. The incidence and epidemiology of oro-
facial clefts provide some clues to the etiology of
these malformations (Mossey 2007 ) . The combi-
nation of basic and clinical sciences should pro-
vide the ideal goal of comprehensive cleft care.
In establishing etiology, it would be useful to
have available the gene expression patterns and
ﬂ ow of biochemical pathways underlying mor-
phogenic events. Understanding the local regula-
tion of cellular behaviors and misregulation of
any step in these processes can provide insights
into clefting consequences. The recognition of
Fig. 1.2 Intrauterine ultrasonography of cleft lip fetus
(Courtesy of Dr. Eileen Wang, University of Pennsylvania;
Reproduced by kind permission of McGraw-Hill from
Losee and Kirschner ( 2009 ) )

5
1 Embryogenetics of Cleft Lip and Palate
the molecular and tissue elements responsible for
normal labiopalatogenesis will allow prognosti-
cation of clefting defects in their de ﬁ ciencies.
The therapeutic application of growth factors and
gene therapy has the potential for biomimetic
preventive and healing regimens (Scheller and
Krebsbach 2009 ) . Scarless repair of clefts is now
potentially feasible (Larson et al. 2010 ) .
Of the estimated 25,000 protein-coding genes
in the human genome, some 17,000 genes have
been identi ﬁ ed in contributing to craniofacial
development (International Human Genome
Sequencing Consortium 2004 ) . Engineering
advancements in genome sequencing technology
with the advent of next-generation massively par-
allel sequencing platforms has made possible the
1,000 Genomes Project which is cataloguing
human genotypic variations in all of these genes
(Nielsen 2010 ) . The application of whole exome
sequencing has proven to be a powerful tool in its
ability to identify genes that in ﬂ uence craniofacial
patterning (Ng et al. 2010 ) , with whole genome
sequencing being the goal of personal medicine
for genetic risk assessment and prevention.
The complexity of contributions of the hundreds
of genes to facial formation is being elucidated by
identifying each gene’s individual expression for
each stage of development (Feng et al. 2009 ) .
Identi ﬁ cation of gene mutations responsible for
craniofacial syndromes provides clues to the
genetic basis for craniofacial clefting. However,
detailed molecular and cellular analyses of the
chronology and loci of gene expression patterns,
upon which are superimposed epigenetic phenom-
ena, make unraveling the complexity of craniofa-
cial morphogenesis a daunting challenge. The
ever-constant new identi ﬁ cation of gene expression
pro ﬁ les of embryonic craniofacial and oral struc-
tures has led to the development of a consortium
titled COGENE ( C raniofacial and O ral G ene
E xpression N etwork) that can be accessed online at
Cogene: (Cai et al.
2005 ) . Therein is contained a list of all hitherto
identi ﬁ ed genes, growth factors, and signals
involved in the expression pro ﬁ les of structures
between the 4th and 8.5 weeks of human develop-
ment. It is in the mutation or silencing of genes or
the misappropriation of growth factors and signals
that the source of some developmental defects is
revealed. The intricacies of RNA editing, complex
regulatory networks, crisscrossing molecular path-
ways, together with overlapping and redundancies
of gene expression patterns make unravelling the
skein of individual in ﬂ uences particularly dif ﬁ cult.
A FaceBase consortium providing a comprehen-
sive program of craniofacial research has been
established (Hochheiser et al. 2011 ) .
Some of the genes implicated in craniofacial
development through human and animal model
studies are listed in Table 1.1 .
Ascribing speci ﬁ c functions to all these genes is
the aim of molecular biology, but it is the realiza-
tion of the biology encoded within each gene that
will provide comprehension of developmental phe-
nomena and their aberrations. Genomic analyses
are revealing the molecular architecture behind
complex developmental pathways (Brito et al.
2011 ; Swartz et al. 2011 ) , and the multifactorial
basis of the etiology of clefts (Abu-Hussein 2012 ) .
Human genetics can lead to insights of pheno-
typic diagnosis and provide understanding of the
relationships of components of molecular cir-
cuitry that will improve the ability of genotypic
information to predict the phenotype of complex
clefting traits (Dixon et al. 2011 ; Rahimov et al.
2011 ; Stuppia et al. 2011 ; Yuan et al. 2011 ) .
The majority of orofacial clefting cases are non-
syndromic and have no identi ﬁ ed cause. Genetic and
phenotypic heterogeneity of facial clefting has com-
plicated the identi ﬁ cation of the responsible phe-
nomena. Research studies have identi ﬁ ed genetic
variants associated with cleft lip and palate through
linkage analysis, candidate gene approaches, direct
sequencing, deletion and duplication analysis by
array comparative genomic hybridization (aCGH),
and genome-wide association studies (GWAS)
(Rahimov et al. 2011 ; Weatherley-White et al. 2011 ) .
A genome-wide association study has identi ﬁ ed ﬁ ve
genetic loci in ﬂ uencing facial morphology in
Europeans: PRDM16, PAX3, TP63, C5o rf 50 and
COL17A1 (Liu et al. 2012 ) . This study established
links between DNA variants previously associated
with non-syndromic cleft lip/palate at 2p21, 8q24,
13q31 and 17q22. The complexity of clefting is
illustrated in the numerous different types of genes
associated with the phenotype. Such studies have led

6
G.H. Sperber and S.M. Sperber
Table 1.1 Selected genes implicated in craniofacial development
Gene
Gene/protein
OMIM
Associated syndrome (OMIM)/functional role
Location
ALX3
Aristaless-like homeobox 3
606014
Frontonasal dysplasia type 1 (136760)
1p13.3
ARHGAP29/PARG1 Rho GTPase-activating protein
610496
Candidate gene associated with nonsyndromic CL/P
1p22.1
BMP4
Bone morphogenetic protein 4
112262
Orofacial cleft 11 (600625)
14q22-q23
CLPTM1
Cleft lip and palate transmembrane
protein 1
604783
t(2;19)(q11.2;q13.3) translocation described in three-generation pedigree with
nonsyndrome CL/CP
19q13
CRISPLD2
Cysteine-rich secretory protein LCCL
domain containing 2
612434
Candidate gene associated with cleft lip/palate
16q24.1
DLX5
Distal-less homeobox 5
600028
Proximodistal patterning of the pharyngeal arches; oronasal patterning
7q21.3
EFNB1
EPH-related receptor tyrosine kinase
ligand 2
300035
Craniofrontonasal dysplasia (304110)
Xq13.1
FAF
FAS-associated factor 1
604460
Pierre Robin sequence, cleft palate only
1p32.3
FGF8
Fibroblast growth factor 8
600483
Kallmann syndrome 6 (612702); cleft lip/palate
10q24
FGF10
Fibroblast growth factor receptor 10
602115
Aplasia of lacrimal and salivary glands (180920); lacrimoauriculodentodigital
syndrome (LADD; 149730)
5p13-p12
FGFR1
Fibroblast growth factor receptor 1
136350
Pfeiffer syndrome (101600), Kallmann syndrome type 2 (147950)
8p11.23-p11.22
FGFR2
Fibroblast growth factor receptor 2
176943
Apert syndrome (101200), Pfeiffer syndrome (101600); craniosynostosis and
midfacial hypoplasia syndromes; LADD syndrome (149730)
10q26.13
FOXE1 (TTF-2)
Forkhead homolog-like 15/thyroid
transcription factor 2
602617
Bamforth-Lazarus syndrome (241850)
9q22.33
GLI2
GLI-Kruppel family member 2
165230
Holoprosencephaly type 9 (610829), cleft lip and palate
2q14.2
GSC
Goosecoid
138890
Homozygous knockout mouse model exhibits aplastic nasal apparatus
14q32.1
GSCL
Goosecoid-like
601845
Located in the DiGeorge syndrome deletion region
22q11.21
HOXA1
Homeobox A1
142955
Athabaskan brainstem dysgenesis (601536); Bosley-Salih-Alorainy syndrome
(601536)
7p15.3
IRF6
Interferon regulatory factor 6
607199
Van der Woude syndrome type 1 (119300); popliteal pterygium syndrome
(119500); oralfacial cleft 6 (IRF6 enhancer; 608864)
1q32.3-q41
JAG2
Jagged2
602570
Alagille syndrome; association with cleft palate
14q32
LHX6
Lim homeobox protein 6
608215
Expressed in palatogenesis
9q33.2
LHX8
Lim homeobox gene 8
604425
Associated with cleft lip
1p31.1
MEOX2
Mesenchyme homeobox 2
600535
Posterior palate expression in mouse models
7p21.2
MIR140
MicroRNA 140
611894
Regulates PDGFA expression; cleft palate
16q22.1
MSX1
Muscle segment homeobox 1
142983
Oralfacial cleft type 5 (608874); tooth agenesis (106600); Witkop syndrome
(189500)
4p16.2

7
1 Embryogenetics of Cleft Lip and Palate
MSX2
Muscle segment homeobox 2
123101
Craniosynostosis type 2; enlarged parietal foramina (168500)
5q35.2
OFC1
Unknown
119530
Oralfacial cleft type 1 (119530)
6p24.3
ORS2
Odd-skipped related 2
611297
Cleft palate in knockout mouse
8q22.2
OTX2
Orthodenticle homolog 2
600037
Anophthalmia, micro-ophthalmia (610125)
14q22.3
PAX7
Paired box homeobox gene 7
167410
Neural crest speci ﬁ cation; possible in ﬂ uence on CL/P risk
1p36.13
PDGFC
Platelet-derived growth factor C
608452
Mitogen, associated with CLP
4q32.1
PLCB4
Phospholipase C, beta-4
600810
Auriculocondylar syndrome (602483)
20p12
PTCH1
Patched 1
601309
Holoprosencephaly type 7 (610828), basal cell carcinoma (605462), CLP
9q22.32
PVRL1
Poliovirus receptor-like 1/NECTIN-1
600644
Cleft lip/palate-ectodermal dysplasia syndrome/Zlotogora-Ogur/Margarita
Island syndrome (orofacial cleft 7; 225060)
11q23.3
RUNX2
Runt-related transcription factor 2
600211
Cleidocranial dysplasia (119600); implicated in CLP
6p21.1
RYK1
Receptor-like tyrosine kinase
600524
Implicated in oral cleft studies
3q22.1
SATB2
Special AT-rich binding protein 2
608148
Implicated in orofacial clefting
2q33.1
SHH
Sonic hedgehog
600725
Holoprosencephaly type 3 (142945)
7q36
SPRY2
Sprouty homolog 2
602466
Candidate gene for nonsyndromic cleft lip and palate
13q31.1
SUMO1
SMT3 suppressor of mif two 3 homolog
1
601912
Oral facial cleft type 10 (601912)
2q33.1
TCOF1
TREACLE
606847
Treacher Collins-Franceschetti syndrome I (154500)
5q32.q33.1
TBX22
T-box 22
300307
X-linked cleft palate with ankyloglossia (303400)
Xq21.1
TBX10
T-BOX 10
604648
Associated with cleft lip with or without cleft palate
11q13.2
TFAP2A
Transcription factor AP-2 alpha
107580
Branchio-oculo-facial syndrome (113620)
6p24.3
TGFB3
Transforming growth factor beta 3
190230
Cleft palate in mouse model
14q24.3
TGFBR1
Transforming growth factor, beta
receptor I
190181
Loeys-Dietz syndrome type 2A (608967), cleft palate
9q22.33
TGFBR2
Transforming growth factor, beta
receptor II
190182
Loeys-Dietz syndrome type 2B (610380), cleft palate
3p24.1
TP63
Tumor protein p63
603273
Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (604292);
OFC8 (129400)
3q28
WDR65
WD-repeat domain 65;
614259
Van der Woude syndrome type 2 (606713)
1q34.2
YPEL1
Yippee-like 1
608082
Located in the commonly deleted DiGeorge (188400)/velocardiofacial
(192430) region
22q.11.2

8
G.H. Sperber and S.M. Sperber
to the characterization of several genes with variants
that convey an increased risk of orofacial clefting
including MSX1, a transcription factor expressed in
the anterior palate (Jezewski et al. 2003 ; van den
Boogaard et al. 2000 ) , and TGF b 3, a signaling cue
involved in cell migration and palatal shelf fusion
(Ashique et al. 2002 ; Iordanskaia and Nawshad
2011 ; Lidral et al. 1998 ) . TBX22, which functions in
conjunction with SUMO1 (Shi et al. 2009 ) as a tran-
scriptional repressor, participates in posterior palate
osteogenesis (Andreou et al. 2007 ) and whose muta-
tions cause X-linked cleft palate and ankyloglossia
(Kantaputra et al. 2011 ) . Another transcription fac-
tor is SATB2, which contributes to osteoblastogen-
esis and in ﬂ uences expression of transcription factors
Alx4 , Pax9 , and Msx1 in the base of the developing
palates of mouse models (Britanova et al. 2006 ;
FitzPatrick et al. 2003 ; Zhang et al. 2011b ) . The
genetic variants contributing to the highest incidence
of CL/P (~2 % of all cases) are found in the inter-
feron regulatory factor 6 ( IRF6 ) gene, a transcription
factor that participates in the differentiation of kera-
tinocytes in the developing epidermis (Ingraham
et al. 2006 ; Kondo et al. 2002 ; Richardson et al.
2006 ) . Mutations or microdeletions in IRF6 are
responsible for Van der Woude and popliteal ptery-
gium syndromes, both of which exhibit variable
phenotypic expression of labiopalatal clefting and
lip pit depressions (Jobling et al. 2011 ; Kondo et al.
2002 ) . A genome-wide meta-analysis of non-syn-
dromic cleft lip with or without cleft palate has
identi ﬁ ed six new susceptibility regions viz. 1p36,
2p21, 3p11.1, 8q21.3, 13q31.1 and 15q22 (Ludwig
et al. 2012 ) . Variants of SKI have been proposed as
a candidate gene for non-syndromic clefts of the lip
and palate (Mangold et al. 2012 ).
Genetically determined elements such as
facial and nasal width, bizygomatic distances
(Boehringer et al. 2011 ) , palatal height, and jaw
growth constitute an additive to the genotype that
approaches a cleft palate threshold, whereby each
element contributes only a small increase in risk.
This threshold may be crossed by external factors
that include environmental in ﬂ uences, such as
smoking, and potential epidemiological factors
including maternal stress and age (Fraser 1976 ;
Jagomagi et al. 2010 ; Wallace et al. 2011 ; Wehby
et al. 2011 ; Zhang et al. 2011a ; Wu et al. 2012 ) .
Maternal smoking during pregnancy implicates
TGFB3 and MN1 in the etiology of submucous
cleft palate (Reiter et al. 2012 ) .
The functional role of many of these genes has
yet to be fully established. Before a link between
a gene and its expressed phenotype is recognized,
there needs to be extensive characterization of
the gene’s products. The topographical areas and
timing of gene expression need to be known for
speci ﬁ c regions of orofacial development.
Interruption of components of the genetic-meta-
bolic machinery responsible for normal embry-
onic development can lead to malformations.
Disharmonic growth between embryonic compo-
nents occasioned by subtle differences in the
number of cell divisions or in the onset or offset
times or rates of cellular activities may variably
contribute to dysplasias. The biochemical basis
of development and growth changes with time
during different stages of development.
In a clinically oriented text, consideration of
the very early stages of embryogenesis involving
molecular biological mechanisms, induction by
signaling factors, tissue differentiation, histogen-
esis, and organ morphogenesis and growth, each
of which constitute enormous ﬁ elds of study,
must be greatly condensed. Appreciation of these
underlying developmental phenomena is neces-
sary in understanding the series of cascading
events leading from the initial zygote formed by
the union of parental gametes to the fully ﬂ edged
infant (Fig. 1.3 ). Aberrations or variations from
the normal morphogenetic patterns, whether of
genetic, epistatic, or environmental origin, are
responsible for many of the congenital anomalies
that constitute clinical syndromes. Currently,
there are no speci ﬁ c tests available for genetic
susceptibility to orofacial clefts. The revelation
of associated congenital anomalies with cleft lip
and palate may further identify the interrelation-
ships of diverse embryonic developments with
genetic mutations held in common.

9
1 Embryogenetics of Cleft Lip and Palate
1.3
Early Embryology
The relevance of embryological understanding of
facial development is becoming increasingly
signi ﬁ cant not only for seeking the etiology of
orofacial anomalies but also for the application of
the molecular mechanisms of normal embryo-
genesis to the emerging ﬁ elds of genetic engi-
neering and tissue regeneration. The exploding
ﬁ eld of stem cell research for reparative tissue
and organ replacement demands an understand-
ing of the morphogenetic mechanisms occurring
during facial formation. The recipe for differen-
tiation of stem cells in therapeutic cloning is sim-
ilar to that of the pathways taken by the
multilineage pluripotential cells of the early
embryo. The same genes, growth factors, and sig-
naling pathways that operate in the embryo are
replicated in directed stem cell differentiation for
therapeutic tissue replacement. Fundamental
insights into pathophysiology, diseases, and dys-
morphology are being revealed by molecular
biology (Fig. 1.4 ).
The ﬁ eld of craniofacial embryology is cur-
rently undergoing a paradigmatic period of read-
justment and discovery. The last decade has
revealed a host of previously unknown factors in
embryogenesis. During development, cells are
monitored by genetically determined pathways
and adjust their rates of accumulation, apoptosis,
and hyperplasia to produce organs of predeter-
mined size. The precise control of growth is of
inestimable importance for, if each cell in our
faces was to undergo just one more cell division,
we would be horribly malformed.
The prior presence of the brain determines the
subsequent development of the craniofacies. The
rostral parts of the brain—the prosencephalon
and mesencephalon—are speci ﬁ ed by the ortho-
denticle homologues OTX1 and OTX2, while the
HOX genes specify the rhombencephalon and
establish spatial identity of prospective craniofa-
cial compartments (Dixon et al. 2011 ; Larsen
et al. 2010 ; Vieille-Grosjean et al. 1997 ) . It is the
brain underlying the future face that is a key com-
ponent of cephalogenesis (Marcucio et al. 2011 ) .
a
e
f
g
h
b
3 days
6 days
Inner cell mass
Cloacal plate
Trophoblast
Amnion
Germ disk
Yolk sac
Chorion
14 days
9 months
28 days
24 days
18 days
Body stalk
(Umbilicus)
Cut edge of
amnion (ectoderm)
Prechordal plate
Yolk sac (endoderm)
Head
Prechordal plate
Heart
Heart
Lens placode
Otic placode
Pharyngeal arches
c
d
Fig. 1.3 Diagrammatic
synopsis of embryogenesis.
( a ) Spermatozoon
penetrating ovum to form
zygote. ( b ) Morula stage
of blastula. ( c ) Blastocyst
with inner cell mass.
( d ) Fetal membranes in
chorion. ( e ) Primary germ
layers forming in germ disk.
( f ) Some stage embryo.
( g ) Postsomite stage
embryo. ( h ) Full-term fetus
(Reproduced by kind
permission of McGraw-Hill
from Losee and Kirschner
( 2009 ) )

10
G.H. Sperber and S.M. Sperber
1.3.1 Organizing Centers
Human and animal model studies show develop-
ment of the head depends on the inductive activi-
ties of the prosencephalic and rhombencephalic
organizing centers, which are regulated by the
expression of the sonic hedgehog (SHH) gene as
a signaling protein in the neural ﬂ oor plate cells
(De Robertis et al. 1991 ; Odent et al. 1999 ) .
These organizing centers are the sites of origin of
signaling factors that diffuse into surrounding
areas to create “fate maps” that predetermine the
details of differentiation of adjacent cells to form
particular facial elements. Thus, the rostral
prosencephalic center, derived from prechordal
mesoderm, located at the rostral end of the noto-
chord, induces the visual and inner-ear apparatus
and upper third of the face (the neurocranium).
Genetic factors
Genotype
Diploid chromosomes
Genes
DNA activation & inactivation
Inductors
Induction
Organization
Histodifferntiation
Development of tissue types;
epithelia: muscle, nerve,
connective tissue
Positioning
Patterning
Development of “fields”, organs
and systems - phenotype
Transductions
Signal
Genome
imprinting
(Dysplasias)
(Deformations)
Growth factors; morphogens
receptors
(Aneuploidies, inversions,
translocations, deletions)
(Variable penetrance,
expressivity, pleiotropy,
heterogeneity, mutations)
(Mis-timing of reactions)
(Failed receptor interactions)
(Hyper-and hypoplasias)
(Italicized parenthesized type indicates defective development)
(misplaced organizational fields;
Dysmorphology)
Morphodifferentiation
Development of cell types: ecto-,
meso-, endoderm
Cytodifferentiation
(Immaturity; Necrosis)
Cell adhesion, Repulsion; Migration;
Proliferation, Apoptosis
Environmental factors
Spatial position of cells
metabolism. hormones
(Teratogens)
Cytoplasmic factors
RNA organelle activity
(Transcription defects)
Malformations
Disruptions
Transcription
Fig. 1.4 Schema of embryogenesis (Reproduced by kind permission of McGraw-Hill from Losee and Kirschner
( 2009 ) )

11
1 Embryogenetics of Cleft Lip and Palate
The caudal rhombencephalic center induces the
middle and lower thirds of the face, the viscerofa-
cial skeleton (Fig. 1.5 ). The gradients of chemi-
cal and physical properties emanating from the
organizing centers regulate craniofacial pattern-
ing by inducing a range of responses from uncom-
mitted populations of neural crest tissue (Hu et al.
2003 ) .
1.3.2 Neural Crest Tissue
The major contributor to facial formation is the
peculiarly derived mesenchymal tissue that arises
from the crests of the ectodermal neural folds that
create the brain. Speci ﬁ cation of the neural crest
by the transcription factor PAX7 occurs very
early in embryonic development, even before the
neural plate appears (Basch et al. 2006 ; Betters
et al. 2010 ) . The transition of the ectoderm into
mesenchyme is a key factor in creating ectomes-
enchyme that provides a lineage of pluripotential
cells that gives rise to diverse tissues (Table 1.2 ).
Facial morphogenesis is controlled by multistep
reciprocal interactions between the ecto- and
endodermal epithelia and neural crest cells.
Rhombencephalic
organizing center
Hindbrain
Midbrain
Forebrain
Notochord
Heart
Prosencephalic
organizing center
Fig. 1.5 Schematic
depiction of prosencephalic
and rhombencephalic
organizing centers
(Reproduced by kind
permission of McGraw-Hill
from Losee and Kirschner
( 2009 ) )
Connective tissues
Ectomesenchyme of facial prominences and
pharyngeal arches
Bones and cartilages of skull and face
Dermis of face
Stroma of salivary, thymus, thyroid, parathyroid, and
pituitary glands
Dental papilla, dentin, periodontal ligament, cementum
Muscle tissues
Ciliary muscles
Perimysium, epimysium, endomysium of pharyngeal
arch muscles (masticatory, facial, faucial, laryngeal)
Nervous tissues
Supporting tissues
Leptomeninges of prosencephalon and part of
mesencephalon
Glia
Schwann sheath cells
Sensory ganglia
Autonomic ganglia
Sensory ganglia of trigeminal, facial,
glossopharyngeal, and vagal nerves
Parasympathetic ganglia (ciliary, ethmoid,
sphenopalatine, submandibular, enteric system)
Pigment cells
Melanocytes in all tissues
Melanophores of iris
Table 1.2 Neural crest derivatives

12
G.H. Sperber and S.M. Sperber
The cranial neural crest cells migrate from
their initial dorsal location above the rhombom-
eres of the brain to ventral destinations that are
either predetermined by homeobox transcription
factor (HOX) genes that constrain their
distribution or by responding to local cues from
overlying or underlying epithelia (Cordero et al.
2011 ; Eberhart et al. 2006 ; Le Douarin et al.
2004 ; Wilkie and Morriss-Kay 2001 ) . Collagen
type I and periostin expression are implicated in
the role of cranial neural crest during soft palate
development (Oka et al. 2012 ) .
Segmentation of the rhombencephalon into
eight rhombomeres delineates the stepwise
sequence of cascading streams of migrating ecto-
mesenchyme to create six pharyngeal arches and
ﬁ ve facial prominences (Fig. 1.6 ). Neural crest
mesenchyme migrates in the median plane over the
prosencephalon to create the frontonasal promi-
nence. Neural crest tissue from the ﬁ rst two rhom-
bomeres migrates ventrally on either side of the
rhombencephalon into the ﬁ rst pharyngeal arch
that will give rise to both the maxillary and man-
dibular arches and their derived skeletal elements.
Crest tissue from the fourth rhombomere con-
tributes to forming the second pharyngeal arch,
while rhombomeres 6 and 7 contribute to the third,
fourth, and sixth arches. The neural crest overlying
rhombomeres 3 and 5 suffers an apoptotic fate
mediated by bone morphogenetic protein-4 (BMP4)
signaling before migrating and therefore does not
contribute to the arches (Smith and Graham 2001 ) .
Developmental studies have shown platelet-
derived growth factor A (PDGFA) is required for
normal migration of a subset of neural crest cells
toward the oral ectoderm that will participate in
palate development (Eberhart et al. 2008 ) .
Inadequate neural crest mesenchymal prolifera-
tion, migration, or excessive apoptosis would
result in de ﬁ ciencies of tissues, causing clefts,
among other hypoplasias (Le Douarin et al. 2004 ;
Noden and Trainor 2005 ; Wilkie and Morriss-
Kay 2001 ) . Treacher Collins syndrome is such an
example resulting in apoptosis of the speci ﬁ ed
cranial neural crest due to disruption of RNA bio-
synthesis caused by mutations in the TCOF1
gene that encodes for the TREACLE, a nucleolar
phosphoprotein (Dixon et al. 2006 ) .
Fig. 1.6 A Stage 15, 33-day-old human embryo upon
which are depicted the neural crest streams emanating
from the rhombomeres ( r1-8 ), in ﬂ uenced by the homeo-
box ( HOX ) gene expression patterns. FNP frontonasal
prominence, FB forebrain, E eye, MB midbrain, HRT
heart, OV otic vesicle, pa1/2 pharyngeal arches 1/2 (SEM
by Prof. Steding, Gottingen. By permission of Springer
Verlag; Reproduced by kind permission of McGraw-Hill
from Losee and Kirschner ( 2009 ) )

13
1 Embryogenetics of Cleft Lip and Palate
1.3.3 Facial Formation
The orofacial region is identi ﬁ ed very early in
embryonic development at the 28th day postcon-
ception, by the appearance of the prechordal
plate in the embryonic trilaminar germ disk. This
disk is composed of the three primary germ lay-
ers, ecto-, meso-, and endoderm. The prechordal
plate is characterized by lack of the intermediate
mesoderm. The contiguous ectoderm and endo-
derm at the site of the prechordal plate combine
to form a tenuous and temporary bilaminar
oropharyngeal membrane that demarcates the
location of the future mouth. The ectoderm will
form the mucosa of the future oral cavity, while
the endoderm will coat the pharyngeal walls.
The oropharyngeal membrane identi ﬁ es the top-
ographic center of facial development by lining a
central depression, the stomodeum, the primitive
mouth around which there migrate ﬁ ve facial
prominences during the fourth week of embryo-
genesis (Fig. 1.7 ). The prescient mouth is bor-
dered rostrally by the developing median
frontonasal prominence, laterally by the maxil-
lary prominences, and caudally by the mandibu-
lar prominences, the latter two both derived from
the ﬁ rst pharyngeal arches (Fig. 1.8 ) (Sperber
et al. 2010 ) .
The tissues that constitute the frontonasal,
maxillary, and mandibular prominences are com-
prised of cells of different lineages that have
migrated, relocated, and been displaced by epi-
thelial-mesenchymal interactions. Neural crest
mesenchyme contributes the major tissue type
that combines with core mesoderm and is cov-
ered by surface epithelia. The neural crest tissues
give rise to the facial skeleton, while the meso-
derm will form the facial muscles. Four key mor-
phogens control facial development by regulation
of cell proliferation, differentiation, survival,
and apoptosis (cell death). Extensive studies
have shown that these signaling cues include
endothelin (ET1) (Clouthier et al. 2010 ) ,
ﬁ broblast growth factors (FGFs) (Liu et al. 2010 ;
Szabo-Rogers et al. 2008 ) , sonic hedgehog
(SHH) (Hu and Marcucio 2009 ; Welsh and
O’Brien 2009 ) , the wingless (WNT) family
(Chiquet et al. 2008 ; Lin et al. 2011 ; Reid et al.
2011 ; Mostowska et al. 2012 ) , and the trans-
forming growth factor beta (TGF- b ) family
(Iwata et al. 2011 ) which include the bone mor-
phogenetic proteins (BMPs) (Francis-West et al.
2003 ; Paiva et al. 2010 ; Spears and Svoboda
2005 ) .
These morphogens direct signaling pathways
that interact coordinately and interdependently to
regulate the growth, patterning, and shaping of the
Fig. 1.7 Frontal view of face of a 24-day-old human
embryo. ×36 (Courtesy of Prof. Nishimura, Kyoto
Collection; Reproduced by kind permission of McGraw-
Hill from Losee and Kirschner ( 2009 ) )

14
G.H. Sperber and S.M. Sperber
developing face (Fig. 1.9 ) (Boehringer et al. 2011 ;
Farlie and Moody 2011 ; Sperber 2006 ; Szabo-
Rogers et al. 2010 ) . Mutations of genes or misregu-
lation of the signaling pathways results in
misappropriated tissue interactions that are the
source of facial maldevelopment. The molecular
basis for variable expressivity of these genes and
factors has not been fully elucidated, but is respon-
sible for the epigenetic spectrum of phenotypic
facial malformations. Developmental instability and
teratogenic disruption of genetic signaling are other
sources of dysmorphic development. Moreover,
mechanical pressures must operate within the
con ﬁ nes of the epithelial constraints placed upon
the expanding mesenchymal components of the
facial prominences, in ﬂ uencing their architecture
and developing facial features (Radlanski and Renz
2006 ) . A precise mechanistic understanding of the
numerous steps involved in signal transductions and
migrations is as yet ill-de ﬁ ned.
The mesodermal core of the ﬁ rst pharyngeal
arch condenses into myogenic elements that
become innervated by the motor branch of the
trigeminal nerve. These muscles migrate to their
disparate destinations to perform masticatory
and swallowing activities. Similarly, second pha-
ryngeal arch mesodermal myogenic elements,
innervated by the facial nerve branches, viz.,
the occipital, temporal, zygomatic, mandibular,
and cervical, migrate through the mesenchymal
milieu of the facial prominences to establish
all the mimetic muscles of the face (Noden and
Francis-West 2006 ) . All these dispersed muscles
retain their initially established nerve supply.
The lingual musculature is derived from migra-
tion and elongation of the hypoglossal cord of
somatic mesodermal origin, retaining its original
hypoglossal (cranial nerve XII) innervation.
Appropriate distribution of all these elements of
tissue components will formulate a face of nor-
mal physiognomy. De ﬁ ciencies of the perioral
muscles have been demonstrated in microforms
and in full- ﬂ edged clefts of the upper lip (Jiang
et al. 2006 ; Landes et al. 2006 ) .
The frontonasal prominence, innervated by
the frontal branch of the trigeminal nerve, con-
tributes to the forehead and the nose. On the
inferolateral corners of the frontonasal promi-
nence, there develop bilateral nasal placodes
that differentiate into the olfactory epithelium
that interacts with the underlying olfactory
nerves. Defective or absent nasal placodal
development not only will result in anosmia but
has a devastating effect on nasal and central
facial development.
Fig. 1.8 Frontal view of face of a 32-day-old human
embryo. ×22 (Courtesy of Prof. Nishimura. Kyoto
Collection; Reproduced by kind permission of McGraw-
Hill from Losee and Kirschner ( 2009 ) )

15
1 Embryogenetics of Cleft Lip and Palate
Fig. 1.9 Scanning electron micrographs of the face of a
Stage 15, 33-day-old human embryo depicting the gene
expression patterns derived from mouse embryos (Faces
from Hinrichsen: By kind permission of Springer Verlag;
Reproduced by kind permission of McGraw-Hill from
Losee and Kirschner ( 2009 ) )

16
G.H. Sperber and S.M. Sperber
The sinking of the nasal placodes to form nasal
pits is the result of the development of the elevated
horseshoe-shaped medial and lateral nasal promi-
nences (Fig. 1.10 ). The posterior aspect of each
nasal pit, initially in communication with the sto-
modeum, becomes separated from the oral cavity
by the transient oronasal membrane. This mem-
brane normally disintegrates by the end of the 5th
week postconception to open the posterior
choanae connecting the nostrils to the posterior
oral cavity. Failure of membrane disintegration
leads to choanal atresia, a potentially fatal asphyx-
iating neonatal congenital anomaly.
Elevation of the lateral nasal prominences cre-
ates the alae of the nose. The expression patterns
of 36 genes are manifested in the medial nasal
prominences and those of some 45 genes in the
lateral nasal prominences. The location of these
genes can be identi ﬁ ed on the gene resource loca-
tor (Ref: ) (Honkura
et al. 2002 ) . Defects of medial nasal prominence
development may result in arhinia, or a bi ﬁ d
nose, varying from a simple depression to com-
plete separation of both nostrils. Other nasal mal-
formations include degrees of aplasia of the alae
as well as atresia of the nasal fossa(e).
1.3.4 Upper Lip Development
Formation of the upper lip is a complex process
involving factors that include PAX9, MSX1, as
well as WNT, SHH, FGF, and BMP signaling
pathways that pattern cell proliferation and tissue
con ﬁ guration (Jiang et al. 2006 ; Nakatomi et al.
2010 ) . The upper and lateral boundaries of the
primitive oral cavity are formed by the freely pro-
jecting maxillary, medial nasal, and lateral nasal
prominences. Initial fusion between the lower
edges of the horseshoe-shaped medial and lateral
nasal prominences completes the large rotund
nostril openings. Maxillary prominence growth
pushes the widely spaced nostrils medially and
converts them into slits. Upper lip completion
requires fusion of the bilateral maxillary and the
two medial nasal prominences, with the lateral
nasal prominences excluded but wedged in
between (Fig. 1.11 ).
The medial tip of each maxillary prominence
is initially separated from the inferolateral aspect
of each medial nasal prominence by an interven-
ing epithelial “nasal ﬁ n” that degenerates, allow-
ing mesenchymal migration across the former
boundaries, and seals the initial cleft. Development
Medial nasal
process
Nasal fin
61/2 weeks
6 weeks
Maxillary
process
Lateral nasal
process
Fig. 1.10 Schematic depiction of breakdown of nasal ﬁ n
and formation of nostrils. Arrows indicate disintegration
of the nasal ﬁ n between the medial nasal and maxillary
prominences (Courtesy of J. Avery and Oxford University
Press; Reproduced by kind permission of McGraw-Hill
from Losee and Kirschner ( 2009 ) )
Fig. 1.11 Horizontal section of embryonic lip showing
incipient clefting on one side and fusion on the other side
(Courtesy of Dr. V. Diewert, University of British
Columbia; Reproduced by kind permission of McGraw-
Hill from Losee and Kirschner ( 2009 ) )

17
1 Embryogenetics of Cleft Lip and Palate
of the fusing tissues is the result of cell prolifera-
tion, vascular invasion, extracellular matrix
production, and ﬂ uid accumulation, all of which
are subject to variations that may predispose to
clefting conditions. Persistence of the nasal ﬁ n
may contribute to clefting of the upper lip and
anterior palate (Fig. 1.10 ). Although the lateral
nasal prominences do not contribute to the upper
lip, failure of their initial fusion with the medial
nasal prominences is implicated where clefts of
the upper lip extend into the nostril (Jiang et al.
2006 ) . All these fusions incur programmed cell
death (apoptosis) of the periderm of surface epi-
thelia, epithelial-mesenchymal transformations,
ﬁ lopodial, and adhering interactions. Epithelial
ﬁ lopodia project and anchor into the opposing
prominences, followed by mesenchymal fusion.
These phenomena are all exquisitely timed and
precisely geometrically coordinated to effect the
fusions. Inexact contacts by topographic diver-
gences of the prominences or delayed sequences
of hierarchical cascading events will inevitably
result in clefting of the upper lip.
The initially widely separated median nasal
prominences merge in the midline to form an inter-
vening intermaxillary segment, from which is
derived the tip of the nose, the columella, the phil-
trum, the labial tuberculum of the upper lip, the
frenulum, and the entire primary palate. The cen-
tral intermaxillary segment provides continuity to
the upper lip, accounting for its maxillary nerve
innervation. Upper lip formation commences at
24 days postconception and is completed by
37 days, well within the ﬁ rst trimester of preg-
nancy. The philtrum and cupid’s bow shape of the
upper lip form between the third and fourth intra-
uterine months (i.e., much later than the melding
of the maxillary prominences) as a result of colla-
gen condensation in the midline to produce the
philtral groove. The philtrum may be congenitally
absent when the upper lip lacks a cupid’s bow out-
line, as in the fetal alcohol syndrome. Failure of
normal disintegration of the nasal ﬁ n by apoptotic
cell death or epithelial-mesenchymal transforma-
tion is a cause of cleft upper lip, alveolar clefting,
and anterior primary palate clefting by preventing
the merging of the medial nasal and maxillary
mesenchyme. This merging defect may be
described as a “differentiation defect,” as opposed
to a “fusion defect,” that becomes clinically
signi ﬁ cant in the varying degree of dysmorphol-
ogy exhibited in cleft lip, alveolar clefting, and
primary palate clefting. These different degrees of
anomalous formation are the result of different
time frames in their embryological development
that are related to different genes and molecular
biological mechanisms operating on lip, alveolus,
and primary palate formation (Krapels et al. 2006 ;
Meng et al. 2009 ; Luijsterburg and Vermeij-Keers
2011 ) . Alteration of developmental timing (het-
erochrony) accounts for various gradations of
severity of anomalous development, from incom-
plete forme fruste to complete clefting.
1.3.5 Cheiloschisis
Clefting of the upper lip (cheiloschisis) is one of
the most frequent of all congenital anomalies; its
unilateral incidence (usually on the left) varies
among different racial groupings, indicating its
inherited character: it is highest in frequency
among peoples of Asian descent, intermediate in
incidence among whites, and least frequent in
blacks (varying from 1:500 to 1:2,000 births)
(Derijcke et al. 1996 ; Mossey and Little 2002 ) .
The anomaly appears more commonly in males
and has been ascribed to inadequate neural crest
tissue migration to the lip area. The degree of
clefting varies enormously; the anomaly is rarely
median, a characteristic of a major holoprosen-
cephaly syndrome (Mansouri Hattab et al. 2011 ) .
A median cleft lip is associated with agenesis of
the primary palate and other midline defects. Lip
clefts may be coincidentally associated with cleft
palate, which has a separate inheritance pattern
and a different etiopathogenic pathway (see
Sect. 1.5 ). However, failure of upper lip fusion

18
G.H. Sperber and S.M. Sperber
may implicate the much later-occurring second-
ary palate conjunctions, accounting for combined
cleft lip and cleft palate defects.
Perturbation of the maxillary and mandibular
prominences leads to other rare facial anoma-
lies. Normally, the primitive wide stomodeal
aperture is reduced by migrating mesenchyme
fusing the maxillary and mandibular promi-
nences to form the “corners” of the de ﬁ nitive
mouth. Inadequate ectomesenchyme results in
macrostomia (unilateral or bilateral), a form of
facial clefting, while excessive fusion produces
microstomia or astomia usually associated with
other congenital anomalies such as agnathia and
synotia (Fig. 1.12 ).
1.4
Lower Lip Formation
Fusion of the bilateral mandibular prominences
in the midline creates the continuity of the lower
lip. The lower lip is rarely defective, but if so, it
is clefted in the midline, contrasting with the
more usual unilateral clefting of the upper lip. A
rare congenital anomaly of the lower lip
(1:100,000 births) is the presence of bilateral pits
or ﬁ stulae that are pathognomonic of the Van der
Woude syndrome, frequently manifesting cleft
lip and palate and caused by mutations in the
IRF6 and WDR65 genes (Baghestani et al. 2010 ;
Birkeland et al. 2011 ; Etoz and Etoz 2009 ; Jobling
a
b
c
d
e
f
Fig. 1.12 Schematic
depiction of potential clefts
of the face. ( a ) unilateral cleft
lip; ( b ) bilateral cleft lip; ( c )
oblique facial cleft and
unilateral cleft lip; ( d )median
cleft lip; ( e ) median
mandibular cleft; ( f )
unilateral macrostomia.
(Courtesy of G.H. Sperber;
Reproduced by kind
permission of McGraw-Hill
from Losee and Kirschner
( 2009 ) )

19
1 Embryogenetics of Cleft Lip and Palate
et al. 2011 ; Rorick et al. 2011 ) . The embryo-
pathogenetic mechanisms of the associations
between upper and lower lip and palate formation
in the Van der Woude syndrome are presently
unknown.
The rare persistence of the lines of fusion
between the maxillary and lateral nasal promi-
nences leads to potential oblique facial cleft(s) in
the line of the naso-optic canal. Another potential
source of clefting of the face may occur when
amniotic bands or strands of connective tissue
detach in utero from the amniotic sac, and which
the fetus then swallows, tethering the fetal face to
the amnion and tearing through the face to form
congenital disruption clefts that are unrelated to
embryonic fusion lines (Fig. 1.13 ).
1.5
Palatogenesis
The development of the intact human palate is an
evolutionary advance in separating the respira-
tory and masticatory chambers over the common
oronasal chamber (the embryonic stomodeum)
that occurs in reptilian and avian antecedents.
The hard palate forms a rigid platform against
which the tongue can manipulate food and allow
pumping action of the linguofaucial muscles
to create a vacuum for suckling and swallow-
ing. The soft palate acts as a ﬂ exible obturator,
closing the nasopharynx from the oropharynx
in speech and swallowing. The primary pal-
ate develops as a projection into the stomodeal
chamber from the median frontonasal promi-
nence with contributions from the medial, lat-
eral, and maxillary prominences (Piotrowski
et al. 2011 ) . The secondary mammalian palate
is developed as bilateral projections from the
maxillary prominences into the stomodeum. The
initially separate elements are programmed to
fuse. If fusion fails, clefting occurs, and the per-
sistence of the clefted condition may a priori be
considered an atavistic phenomenon. Cleft pal-
ates are the norm in reptiles and birds (Ferguson
1988 ) . Mammalian palatogenesis is directed by
an extensive network of interacting transcription
factors and signaling molecules emanating from
several molecular pathways and different cell
types (Bush and Jiang 2012 ) .
The separation of the respiratory chamber (the
nasal fossae) from the food ingestion chamber
(the mouth) has enabled the development of
speech and of leisurely mastication with its
accompanying epicurean enjoyment and hence
the “palatability” of food. Paradoxically, the hard
palate contains no taste buds, although the soft
palate does. The anterior oronasal chamber sepa-
ration de ﬁ nes the palate, whereas the unseparated
posterior oronasal chamber serves both respira-
tion and ingestion, accounting for momentary
asphyxiation during swallowing. In contrast to
mammalian mastication, birds and reptiles char-
acteristically gulp their food to minimize airway
impedance.
Fig. 1.13 Amniotic band disruption clefts in the face of
a fetus (Courtesy of G.A. Machin; Reproduced by kind
permission of McGraw-Hill from Losee and Kirschner
( 2009 ) )

20
G.H. Sperber and S.M. Sperber
The intact palate is composed of three embryo-
logical elements derived respectively from the
median frontonasal prominence, the primary pal-
ate, and the two lateral palatal shelves from the
maxillary prominences forming the secondary pal-
ate. These elements are initially widely separated
in the con ﬁ ning stomodeal chamber by the intru-
sive developing tongue. The continually growing
lateral palatal shelves are de ﬂ ected down vertically
on either side of the tongue, prior to the eighth
week of development (Fig. 1.14 ). As a result of
growth of the stomodeum at the beginning of the
fetal period (8th week), and the occurrence of
mouth opening re ﬂ exes, the tongue is withdrawn
from between the vertical shelves. The mechanical
withdrawal of the tongue requires functioning of
the hyoglossus muscle, necessitating neuromuscu-
lar and jaw joint activity (Fig. 1.15 ). All these
factors are gene initiated and environmentally
dependent on critical timing, which, if perturbed,
disrupts the precision of palatal fusion.
The palatal shelves, in a short period, ﬂ ow like
a wave into the horizontal plane, enabling them to
establish contact with each other in the midline,
with the primary palate anteriorly and with the
lower edge of the perpendicular nasal septum.
Thereby, the single stomodeal chamber is
subdivided into the upper nasal fossae and the
lower oral cavity (Figs. 1.16 and 1.17 ). The con-
junction of the shelves with the nasal septum may
be unilateral, leading to asymmetrical cleft palate,
with only one nasal fossa opening into the mouth.
Shelf elevation occurs by a number of mech-
anisms, including biochemical transformations
of the physical consistency of the connective tis-
sue of the shelves, blood ﬂ ow into the shelves
increasing tissue turgor, and differential pro-
liferation of mesenchyme, creating mechanical
elevating forces. The increase in tissue tur-
gor pressure depends on a critical role played
by hyaluronic acid that interacts with several
extracellular matrix proteins. The gene CD44,
7 weeks
12 weeks
Vomer (paired ossification centers)
Nasal fossa
Nasal capsule
Eye
Nasal septum
Oronasal chamber
Lateral palatal shelf
Ossifying maxilla
Fused palatal shelves
Tongue
Mandible
Meckel’s cartilage
Hyoid cartilage
1st branchial groove
Fused eyelids
Fig. 1.14 Schematic depiction of midcoronal sections of heads at 7 and 12 weeks depicting palatal lifting (Courtesy of
G. H. Sperber; Reproduced by kind permission of McGraw-Hill from Losee and Kirschner ( 2009 ) )