Cleft lip and palate managementA comprehensive atlas

Cleft lip and palatemanagementA comprehensive atlas

Edited by

Ricardo D. Bennun, MD, MS, PHDDirector, Cleft Lip/Palate ProgramAsociacion PIEL & Maimonides UniversityBuenos Aires, Argentina

Julia F. Harfin, DDS, PHDProfessor and Chairman, Orthodontics DepartmentMaimonides UniversityBuenos Aires, Argentina

George K. B. Sándor, MD, DDS, PHD, DR. HABILOral and Maxillofacial, Plastic and Craniofacial SurgeonProfessor of Tissue Engineering, Professor of Oral and Maxillofacial SurgeryUniversity of Oulu, Oulu University HospitalOulu, Finland;Director of ResearchBioMediTechUniversity of TampereTampere, Finland

David Genecov, MD, FACS, FAAPInternational Craniofacial InstituteCleft Lip & Palate Treatment CenterDallas, TX, USA

Copyright © 2016 by John Wiley & Sons, Inc. All rights reserved

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Library of Congress Cataloging-in-Publication Data:

Cleft lip and palate management : a comprehensive atlas/edited by Ricardo D. Bennun, Julia F. Harfin, George K.B. Sándor, DavidGenecov.

p. ; cm.Includes bibliographical references and index.ISBN 978-1-118-60754-1 (cloth: alk. paper)I. Bennun, Ricardo D., editor. II. Harfin, Julia F. de, editor. III. Sándor, George K. B., editor. IV. Genecov, David, editor.[DNLM: 1. Cleft Lip–surgery–Atlases. 2. Cleft Palate–surgery–Atlases. 3. Cleft Lip–diagnosis–Atlases. 4. Cleft

Palate–diagnosis–Atlases. 5. Oral Surgical Procedures–methods–Atlases. 6. Reconstructive Surgical Procedures–methods–Atlases.WV 17]

RD524617.5′22059–dc23

2015026543

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

Contents

Contributors, vii

Preface, ix

Acknowledgments, xi

Part 1: Principles

1 Mechanisms of cleft palate: developmental fieldanalysis, 3Michael H. Carstens

2 Tissue engineering and regenerative medicine:evolving applications towards cleft lip and palatesurgery, 23George K. B. Sándor

3 The nasolabial region: a revision of the vascularanatomy, 41Ricardo D. Bennun

4 Epidemiological data about nonsyndromic oralclefts in Argentina, 47Ricardo D. Bennun

5 International multicenter protocol, 53Ricardo D. Bennun, Suvi P. Tainijoki, Leena P.Ylikontiola, George K. B. Sándor, and Vanesa Casadio

Part 2: Present primary surgicalreconstruction

6 Dynamic presurgical nasoalveolar remodeling inunilateral and bilateral complete cleft: the DPNRtechnique, 65Ricardo D. Bennun and Analia C. Langsam

7 Pediatric anesthesia considerations, 79Luis Moggi, Diofre Ponce, and María Bevilacqua

8 Developmental field reassignment cleft surgery:reassessment and refinements, 83Michael H. Carstens

9 Unilateral cleft lip and nose repair, 113Ricardo D. Bennun and David Genecov

10 Bilateral cleft lip and nose repair, 143Ricardo D. Bennun and George K. B. Sándor

11 Cleft palate repair, 163Ricardo D. Bennun and Luis Monasterio Aljaro

Part 3: Orthodontic treatment

12 Correction of transverse problems in cleft patientsusing the Maimonides protocol, 177Julia F. Harfin

13 Changes in arch dimension after orthodontictreatment in cleft palate patients, 187Julia F. Harfin

14 Real orthodontic treatment in adult cleft patients, 201Julia F. Harfin

15 Strengthening surgical/orthodonticinterrelationships, 227Julia F. Harfin and Ricardo D. Bennun

Part 4: Improving results in cleft lip andpalate interdisciplinary management

16 To what extent could dental alveolar osteogenesisbe achieved solely with orthodontic treatment inflap patients?, 245Julia F. Harfin

17 Laser treatment of cleft lip scars, 253Agustina Vila Echague

18 3D photography in cleft patients, 257Virpi Harila, Tuomo Heikkinen, Ville Vuollo, GeorgeK.B. Sándor, and Pertti Pirttiniemi

Index, 263

v

List of contributors

Luis Monasterio Aljaro, MD, Fundacion Gantz,Santiago de Chile

María Bevilacqua, MD Anesthesiologist Asociacion PIEL,Buenos Aires, Argentina

Michael H. Carstens, MD, FACS, Clinical Associate Professorof Plastic Surgery, Saint Louis University; Profesor de Cirugía Plástica(Honoris Causa), Universidad Nacional Autonoma de Nicaragua, Leon,Nicaragua; Attending Surgeon, Hospital Metropolitano Vivian PellasManagua, Nicaragua

Vanesa Casadio, PhD, Speech Therapist Asociacion PIEL,Buenos Aires, Argentina

Agustina Vila Echagüe, MD, PhD, Dermatologist AsociacionPIEL, Buenos Aires, Argentina

Virpi Harila, DDS, PhD, Oulu University, Finland

Tuomo Heikkinen, DDS, PhD, Oulu University, Finland

Analia Langsam, DMD, Pediatric Dentist Asociacion PIEL,Buenos Aires, Argentina

Luis Moggi, MD Anesthesiologist Asociacion PIEL, Buenos Aires,Argentina

Pertti Pirttiniemi, DDS, PhD, Oulu University, Finland

Diofre Ponce, MD, Anesthesiologist Asociacion PIEL, Buenos Aires,Argentina

Suvi P. Tainijoki, Clinical Nurse Specialist, Oulu University Hospital,Oulu, Finland

Ville Vuollo, MSc, Oulu University, Finland

Leena P. Ylikontiola, MD, DDS, PhD, Oulu University, Finland

vii

Preface

A nonsyndromic oral cleft delivery not only creates an emotionalburden on the family and the medical team, but also compro-mises the physical and psychological development of the patientas well as disadvantaging their social insertion.

This affliction, characterized by misplaced central facial pieces,occurs on average in 1/800 live newborns. Added to the initialproblems of feeding and suction are the encumbering complica-tions in hearing.

The overwhelming complexity of the problems to be treated inan oral cleft patient induced the organization of the first interdis-ciplinary team by Cooper in Lancaster, Pennsylvania, in 1939.

Although the first references to oral cleft repair in the liter-ature were written by Ambroise Paré and Gaspare Tagliacozziin the sixteenth century, a large number of authors have pub-lished diverse techniques, using different skin incisions and agreat variety of flaps, arguing for better cosmetic results.

In all aspects of plastic surgery, there is an equal measure of artand knowledge. However in the repair of the cleft lip, art seemsto take the upper hand. In art, there is no excellence: you must gothrough knowledge, to reach a privileged level of achievement.

Unfavorable results in unilateral and bilateral cleft lip, nose,and palate repair are often easy to score, and probably less easyto prevent, but are really difficult to treat.

It is not the intention of this Atlas to report a historicalrevision; our aim is to transmit to you more than 20 years ofpractical experience from different teams working but con-nected throughout the world, showing both successful as wellas unsuccessful results with the intention of avoiding unwantedsequels.

What we have attempted to do in this book is to try and dealwith the more common problems, explain our point of viewregarding their causation, and define their best possible man-agement – mostly from our personal experiences over manyyears, and never forgetting Sir Harold Gillies’ words: “Diagnosebefore you treat.”

Meticulous documentation and follow-up are uniquely validactions that have allowed us to choose and recommend sometechniques over other less-effective procedures, and to discardmany of them as being really dangerous.

Today, the accepted universal goal is to obtain excellent aes-thetic and functional results during primary reconstruction ofthe lip and nose, and normal speech, in 85–90% of cases.

Using less aggressive techniques, conserving and respectinggrowth centers, innervations, and blood supply, will allow us toprevent the growth and development of facial alterations.

With the introduction of presurgical orthopedics, reconstruc-tive surgery in cleft patients has entered a period of inductivesurgery or regeneration of missing anatomic parts. This alsocoincides with two other phenomena currently observed inall surgical disciplines: (i) the simplification or minimizationof surgery and (ii) recognition of the need for delivery ofhealthcare services at a lower cost.

Although we are aiming to outline principles, we feel thata problem as complex as the 45 variants of cleft presentationdescribed in epidemiological research realized in Argentinacannot be solved using one technique. We need to know howthe deformity occurs and what normal looks like. Only withnormal as a guide can we repair the misplaced central facialpieces.

This book’s intention is to provide a selection of the best pro-cedures and resources performed by experienced surgeons thathave shown the best results over the years. Milestones and diffi-culties are analyzed in this book in a step by step manner.

With regard to the large number of untoward sequels createdby surgeons, the aim of this book will be to show the readerhow to arrive at a normal appearance using the least invasiveprocedure. Post-surgical evaluation by the interdisciplinaryteam is transcendental to prevent hipoacusia, speech, and bitealterations.

Ensuring the safety of the patients must be the number one pri-ority and the guiding force behind every treatment plan. In thisway, we share Smile Train’s Safety and Quality Protocol, togetherwith over 400 cleft centers from 72 countries around the worldas an important tool helping to advance the excellence of carefor all cleft patients.

The authors also wish to show that it is possible to employ sim-ilar treatment protocols, in a number of different places in theworld, with diametrically opposite cultural, social, and scientificinsights. In recent years, our collaboration has even extended tomolecular biologists and geneticists, who have done so muchto shed light on the etiopathogenesis; and tissue engineeringresearchers who work for the future in tissue culturing.

Unquestionably the answers to cleft causation and its preven-tion are the goals of the future.

ix

x Preface

There are few surgeons who meet their patients before birth, aswhen the parents present the surgeon with an ultrasonic imageof their unborn child. We are privileged to work with parents,as the geneticist attempts to help them answer the inevitablequestion, “Why?” and, with the help of the psychosocial team

recruited to encourage the parents in their frustration andworry, to help them relish the joy of having brought a child intothe world.

Ricardo D. Bennun, MD, MS, PhD

Acknowledgments

Our international project receives the human and scientificsupport of multidisciplinary teams from Buenos Aires,Argentina; Santiago de Chile; Oulu, Finland; and Dallas, USA.

We are indebted to our families, friends, patients, as well asour professors, institutions, and colleagues. Special thanks to ouradministrative staff and contributors for making our passion forthis work a reality.

The present book represents a huge effort to condenseexperiences and suggestions. Our intention is to facilitate the

multidisciplinary treatment of cleft patients, improve results,and prevent sequels. This work is aimed at young professionalsin different places in the world dealing with different realities.

Our achievements would not be possible without the invalu-able support of The Smile Train and The World of Childrenfoundations.

The Editors

xi

PART 1

Principles

CHAPTER 1

Mechanisms of cleft palate: developmentalfield analysis

Michael H. CarstensSaint Louis University and Universidad Nacional Autonoma de Nicaragua, Nicaragua

The purpose of this chapter is to present concepts of cleft palaterepair based on a single unifying concept: the embryology ofthe oronasopharynx. We shall begin with an in-depth discus-sion of how the bone and soft tissue structures are assembled,based upon the developmental field model. Next, we shall con-sider how this normal process is altered when a disruption ofthe neurovascular pedicle to an individual field results in a defi-ciency state such that the affected field is unable to fuse with itspartner fields. Attention will also be give to the effect that such adeficiency state has on the subsequent development of the part-ner fields. Surgical procedures based on the embryologic modelare designed to restore functional tissue relationships.

Craniofacial development: the Lego® model

The anatomic structures of the head and neck are assembledfrom tissue units known as developmental fields, each of whichhas a distinct neurovascular pedicle providing sensory and/orautonomic control and blood supply. Fields are often compositestructures containing mesenchymal elements such as cartilage,bone, fascia, muscle and so on. They may have an associatedepithelium such as skin or mucosa. Adjacent fields interact.Muscles with a primary attachment to bone or cartilage withinone field may have a secondary attachment site in an adjacentfield.

Fields develop in a strict spatio-temporal sequence. Congeni-tal conditions that reduce the size or content of a field will affectsubsequent growth. In the Pierre Robin sequence, the relativedecrease in volume of the mandibular ramus leads to a poste-rior position of the chin and subsequent relationships of theinfrahyoid musculature. The reduction of the frontal process ofthe premaxilla seen in the typical orofacial cleft causes a relativenarrowing of the nasal fossa, malposition of the internal nasalvalve, and respiratory dysfunction (Figure 1.1).

Cleft Lip and Palate Management: A Comprehensive Atlas, First Edition. Edited by Ricardo D. Bennun, Julia F. Harfin, George K. B. Sándor, and David Genecov.© 2016 John Wiley & Sons, Inc. Published 2016 by John Wiley & Sons, Inc.

The anatomic defects seen in clefts of the hard and soft palatepresent as a spectrum involving several fields. Many casesinvolve deficiency states of the piriform fossa and/or premaxillaand soft tissues of the lip and nose. In other, rarer conditions,such as the Tessier 3 cleft, a cleft palate defect coincides withdefects in seemingly unrelated anatomic zones, such as the infe-rior turbinate and medial maxillary wall. For this reason, it isnecessary to have a comprehensive picture of the neurovascularanatomy of the oronasopharynx.

The zones of anatomic interest are all supplied by arterial axesrunning in parallel with the various sensory branches of V1and V2. Development of the pedicles is a reciprocal process.Neuronal growth cones secrete vascular endothelial growthfactor (VEGF) while the arterial growth cone secretes nervegrowth factor (NGF). Like all cranial nerves, the trigeminalcomplex is constructed from neural crest, whereas the histo-logic composition of the arteries consists of a tubular conduitof endothelial cells made from paraxial mesoderm embraced bypericytes. These latter cells are contractile and control capillarypermeability. Pericytes are ubiquitous throughout the humanbody (Figure 1.2). They are the precursor for mesenchymal stemcells. They also elaborate paracrine factors that are essential forsurvival of the vascular growth cone. Thus, we come to a verysimple and powerful idea: dysfunction of a vascular growthcone will result in either a reduction of volume of mesenchymalstructures within the target field, or the outright loss of the fielditself. In the first case, the physical effect of the small field is toconstrain subsequent growth of surrounding fields. If a franktissue defect exists (i.e., a cleft) adjacent fields actually collapseinto the site.

The reader will note here terminology that may be unfamiliar:it harkens back to those embryology lectures that we endured… an endless list of structures that morphed into a final resultvia mechanisms that were unknown. The molecular revolutiontransformed the science into developmental biology with a

3

4 Chapter 1

Figure 1.1 Craniofacial fields are composite blocks of tissue supplied by aspecific neurovascular pedicle. Fields grow in relation to each other overtime, each with a different volume and rate of growth. Deficiency orabsence of a field results in collapse of adjacent partner fields. The leaningtower of Pisa is a classic example of what happens when a supporting fieldis absent – the entire complex is displaced and, if the upper stories of thetower were made of soft plastic, would become distorted as well. A “cleft” isreally a condition of excess or deficiency in a given field that results indisplacement and/or distortion of adjacent fields.

tight connection to genetics (these fields formerly co-existed invirtual isolation from each other). In the following section weshall consider the tissue composition of developmental fields,how they are arranged in the intermediate state as pharyngealarches, and how, with growth-driven folding of the embryo,these fields become physically repositioned and interactive(Carlson, 2013; Gilbert, 2013).

The embryonic period lasts 8 weeks and is divided into 23anatomic stages (see Figure 1.3). In the first three stages, theembryo is a rapidly dividing ball of cells. Stages 4–5 are allabout survival as the embryo implants itself into the uterinewall and begins the process by which blood supply will comefrom the mother. The stage 4 embryo secretes fluid into itscenter, becoming a hollow blastocyst with a single layer ofcells, the epiblast, becoming segregated to one side of the ball.Thus there is an inner cell mass (the future organism) andenveloping wall (the trophoblast) that will eventually form theextraembryonic structures, such as the placenta (O’Rahilly& Müller, 1996). The tightly-bound cells of the epiblast thenbecome transiently “loose,” allowing some of the epiblast cellsto drop down below their previous plane, coalesce and forma new second layer, the hypoblast. By the end of stage 5, thehypoblast has proliferated and formed a lining layer around theinner wall of the trophoblast. The hypoblast now secretes a new

layer, extraembryonic mesoderm (EEM), interposed between itand the trophoblast. This geometry allows the EEM to surroundthe entire embryo and move into the zone of the future placenta.Since blood vessels are formed exclusively from mesoderm, theEEM becomes the source for the entire extraembryonic bloodsupply.

Stages 6–7 involve a transformation of the intraembryonic tis-sues into three layers (ectoderm, mesoderm, and endoderm) viaa process called gastrulation: “the single most important eventin the life of every organism.” There are excellent videos of gas-trulation available on YouTube. Note that at the completion ofgastrulation, the hypoblast is pushed out of the way; it has norole in the formation of the organism per se. In point of fact, theepiblast contributes first to endoderm, then to mesoderm. Whenthe gastrulation process is complete, the cells remaining behindon the surface are known as the ectoderm proper.

The concept of three germ layers is outmoded and inapplica-ble to understanding craniofacial development. For simplicity,let’s leave the epithelial germ layers (ecto- and endoderm)behind and concentrate on mesoderm. This layer outside thehead and neck is responsible for all striated muscles, bone,cartilage, brown fat (white fat is more complex), fascia, andthe non-neural internal organs. Furthermore, as mesodermfans out over the surface of the embryo, its identity becomesdetermined by the interplay of gene products expressed eitherfrom the midline (i.e., the neural tube) such as sonic hedgehog(SHH) and wingless (WNT) or from the peripheral epithelialsurfaces of future skin (ectoderm) and mucosa (endoderm)such as BMP-4 (Carstens, 2000, 2002).

Depending upon location, mesoderm assumes three basicfates. Paraxial mesoderm (PAM) lies next to the neural tube. Itbecomes segmented into individual tissue blocks called somites,each one of which is developmentally related to the segmentof the nervous system from which it derives its innervation.Somites construct the entire axial skeleton, related striatedmuscles, and the major axial arteries (aorta, carotids, etc.).Intermediate mesoderm (IM) is also segmentally organized; itforms the genito-urinary system. Finally, lateral plate mesoderm(LPM) forms the entire appendicular skeleton, the remainder ofthe arteries, smooth muscle, and the viscera (Carstens, 2008a,2008b) (Figure 1.4).

Left out from this equation is the fourth germ layer, the neuralcrest. The vast majority of all facial soft tissues in the face andall the craniofacial membranous bones arise from neural crest.These cells substitute for mesoderm in the head. They also formthe ensheathing Schwann cells of the peripheral nervous systemand the entire autonomic nervous system.

During stages 8–9 neurulation takes place. First, a flat neuralplate is formed; this then rolls up like a cigar to form the neuraltube. Neural crest cells develop at the interface between the out-lying ectoderm and the neural plate. These rapidly multiply andare distributed over the entire organism, immediately subjacentto the epithelia (ectoderm and endoderm) and throughout the

Mechanisms of cleft palate: developmental field analysis 5

(a)

Arteriole Actin filaments

Basement membrane

Peg-socket

Caveolae

Adhesion

plaques

(b)

(c)

P

E

Precapillary arteriole

Postcapillary arteriole

Capillary

Venule

1

2

3

4

5

Regulation of tight and

adherens junctions

and bulk flow fluid

transcytosis

Regulation of capillary

diameter and blood flow

Phagocytosis

Regulation of vascular

stability and architecture

Regulation of extracellular matrix

protein secretion and levels

Figure 1.2 (a, b) Pericytes are ubiquitous throughout the body. They surround all vessels, especially capillaries, providing control of diameter andpermeability. Pericytes have contractile fibers. They are interconnected, including between adjacent vessels. Pericytes may have a connection withneural crest, can detach under conditions of inflammation, are the source of white fat, and also give rise to all mesenchymal stem cells of the body.(c) Demonstrated are the multiple physiologic functions of pericytes.

mesoderm. Neural crest cells are critical for craniofacial devel-opment (Figure 1.5).

Stages 8–9 are also notable for the segmentation of thezone of paraxial mesoderm flanking the neural tube. PAMforms into distinct blocks called somites. There are names fortheir respective locations: 4 occipital, 8 cervical, 12 thoracic,5 lumbar, 5 sacral, and 3–4 coccygeal. The appearance of thefirst three occipital somites alongside the hindbrain definesstage 9. Somitogenesis is a cranial-caudal process in whichone somite appears approximately every 4 hours (Figure 1.6).However, there is an additional zone of PAM which lies cranialto the somites alongside the midbrain and forebrain in whichthe segmentation is incomplete, forming seven somitomeres.Somitomeres (Sms) have very limited developmental potential.They produce the striated muscles of the orbit and the first

three pharyngeal arches; Sm1 and Sm2 also contribute to theposterior wall of the orbit.

So what we have now is a critical mass of tissues that willmix together to form a series of five intermediate structures,the pharyngeal arches, each of which is innervated by a specificcranial nerve. These structures first develop at a stage whenthe embryo is still flat; at stage 9 the embryo begins a complexfolding process. The first pharyngeal arch can be seen at thisstage. It hangs downward like a sock filled with neural crest andPAM. At each stage thereafter a new pharyngeal arch makes itsformal appearance. The process of making the five pharyngealarches is thus complete by stage 14 (Figures 1.7 and 1.8). Allpharyngeal arches are organized into distinct zones by a seriesof distal-less (Dlx) genes: proximal/distal, cranial/caudal, andmedial/lateral. All arches have the same organizational pattern.

6 Chapter 1

9–10 days

Primary villusAmniotic

cavityTrophoblastic

lacuna

Syncytiotrophoblast

Epiblast

Primary yolk sacExtraembryonic

mesoderm

Hypoblast

Cytotrophoblast

Figure 1.3 At stage 5, 9–10 days, the embryo is a hollow ball (blastocyt)consisting of the embryo proper surrounded by trophoblast (green) thatwill eventually make non-embryonic tissues such as the placenta. From theoriginal inner cell mass a second layer of cells develops beneath. Theembryo now has an epiblast (blue), and a hypoblast (yellow), also termedthe primitive endoderm. Hypoblast spreads out to line the entire blastocystcavity. It then secretes the primitive mesoderm (red) which will flow upinto the future placenta and make the extra-embryonic circulation.

Arch 1 has a rostral maxillary zone innervated by V2 and acaudal mandibular zone supplied by V3. Muscles of mastica-tion in the first arch all arise from somitomere 4. Arch 2 fuseswith arch 1; it contains the muscles for facial expression. The

upper division of VII supplies facial muscles from somitomere5 distributed over the maxillary zone while the lower division ofVII innervates muscles from somitomere 6 distributed over themandible (see Figure 1.9).

Embryonic folding driven largely by explosive brain growthcauses the pharyngeal arches to swing upward into the adultposition. They subsequently fuse. Growth of the vascular chan-nels into the arches proceeds concomitant with penetration ofthe arches by cranial nerves from the brain. We will now brieflyexplore how the individual neurovascular pedicles associatedwith the nasopharynx and oropharynx are organized. This willgive us insight into the manner in which the developmentalfields are assembled (O’Rahilly & Müller, 1999).

The final configuration of craniofacial arteries is the result of astep-wise process by which primitive structures meld into morecomplex forms. Arteries are mesodermal structures, the earli-est ones appear after gastrulation is complete. The forebrain andmidbrain are supplied by a primitive head plexus while primitivehindbrain channels supply the remainder of the brain. The dorsalaortae run alongside the body axis and supply non-neural tis-sues. Anterior extensions of the dorsa aortae connect with oneanother anterior to the brain and to the oropharyngeal mem-brane, greater complexity is assumed. The arteries to the brainand spinal cord assume a segmental pattern to supply each devel-opmental unit of the CNS, that is neuromeres. Each of the fivepharyngeal arches is supplied by a segmental aortic arch arteryconnecting the primitive outflow tract with the paired dorsalaortae above. The fifth aortic arch artery atrophies with AA4supplying both pharyngeal arch 4 and 5. AA6 is dedicated exclu-sively to the pulmonary circulation (Figures 1.10–1.12).

Hensen’s node

Primitive streak

Epiblast (ectoderm)

Endoblast

Endoderm displacing

endoblastEctoderm

Mesoderm

Prospective endoderm

Endoblast

MesodermMigrating cells

(a)

(b)

Ectoderm

Neural

tube

Neural

canalWolffian duct

Somite

Celom Somatic mesoderm

Splachnic mesodermAortaNotochord

Endoderm

Figure 1.4 (a) Note here that the primitive endoderm/hypoblast (green) will be pushed out of the way by the definitive endoderm (yellow). Hypoblast thushas no biologic role in development other than to serve as a temporary layer. (b) Mesoderm will have specific roles depending upon its location in theembryo. This is because at each physical location a unique combination of gene products from ectoderm and endoderm act as signals to the mesoderm,“instructing” it as to its ontogenic fate. Paraxial mesoderm (red) forms: somites, dermis, striated muscle, the axial skeleton. Intermediate mesoderm (notseen) is a long thin rod of tissue extending along the axis of the embryo. It is neuromerically organized. It produces the entire genito-urinary system.Lateral plate mesoderm (purple) forms: the cardiovascular system, smooth muscle, the appendicular skeleton, and the mesenchyme for all internal organs.

Mechanisms of cleft palate: developmental field analysis 7

(a) (b)

NFB

BA1

BA2

BA3

BA4

DiA Mes

Diencephalic and anterior mesencephalic NC

Posterior mesencephalic NC

r1 NC

r2 NC

r3 NC

r4 NC

r5 NC

r6 NCr7 NC

r8 NC

P Mes

r1r2r3r4r5r6r7r8

r1

r2

r3

r4

r5

r6

r7

r8

Figure 1.5 (a) Neuromeres are developmental units of the nervous system,the boundaries of which are established by unique combination of productsfrom homeotic genes (Hox). In humans there are 38 Hox genes distributedover four chromosomes. Common to each is a 60 amino acid sequence thatunlocks DNA. Hox genes code for the CNS as far forward as themidbrain/hindbrain junction. Recently discovered additional Hox-relatedgenes code for the neuromeres of the midbrain and forebrain. Carlson BM.Human Embryology and Developmental Biology, 3rd edn. Reproducedwith permission of Elsevier. (b) Neural crest at any given level of the CNShas exactly the same Hox code as the neuromere above which it originates.Color coding shows contributions as follows. PROSENCEPHALON(forebrain) = pink. Non-neural ectoderm (not truly neural crest) lies aboveprosomeres p5 and p6. P6 produces the nasopharyngeal mucosa suppliedby V1. P5 produces the epidermis supplied by V1. Prosomeres p4-p1 areunclear but probably flow beneath p6 and p5 to produce (respectively)nasopharyngeal submucosa and dermis. MESENCEPHALON (midbrain)= red. M1 goes to membranous bone. M2 goes to meninges, orbit, and firstarch. First arch contains m2, r1, r2, and r3; second arch contains r4 and r5;third arch has r5 and r6; fourth arch has r7 and r8. NB: each arch has alongitudinal axis with equal numbers of neuromeres represented on eitherside. The coordinates of the arches are determined by the distal-less (Dlx)system of genes.

Within the pharyngeal arches, the aortic arch arteries consti-tute primitive vascular cores. These rapidly involute, each onebeing replaced with a plexus, the confluence of which formsthe external carotid system. At Carnegie stage 17 an entirelynew system of stapedial arteries develops, the initial stem ofwhich runs upward from internal carotid through the temporalbone. The timing of stapedial development precisely matchesthe emergence of the cranial nerves, each nerve serving as thetemplate for a respective artery. These dural arteries connectexternally to the external carotid system via the trigeminalganglion. In the orbit the V1-related stapedial (StV1) plugs intothe ophthalmic. The latter supplies the ocular apparatus whilethe former supplies all the periocular structures (muscle, fascia,bone, etc.). When the parent stem of stapedial involutes, thefinal anatomy takes shape: the dural arteries are now supplied

Figure 1.6 Somitomeres and somites develop from paraxial mesoderm.Somitomeres are hollow balls with a somitocoele in the center; they areincompletely separated from each other, so mesenchyme can be shared.Somites are discrete units with epithelial boundaries. They have regionalspecializations for axial bone (sclerotome), muscle (myotome), and epaxialdermis (dermatome). Humans have 7 somitomeres and 39 somites. Theprocess of somitogenesis in mammals takes approximately 4 hours persomite. Gilbert SF, Developmental Biology, 10th edn., Sinauer, 2014. SinauerAssociates, Inc.

Figure 1.7 Only four arches (the fifth is diminuitive) and no sixth arch.Aortic arch arteries span the four arches, AA4 supplying pharyngeal arch 5.Arteries to the sixth “arch” are dedicated to pulmonary circulation.http://creatureandcreator.ca/. Reproduced with permission of TerryPicton. Last accessed December 2014.

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Figure 1.8 Note the longitudinal fissure in the first pharyngeal archseparating the maxillary (green) and mandibular (blue) fields. Eachpharyngeal arch has a similar axis which is specified by the distal-less (Dlx)genes.

by the external carotid system. The ophthalmic is a hybrid; theoriginal stem from the internal carotid is dedicated to the eyewhile StV1 serves the orbital structures exclusively (Figures 1.13and 1.14).

The extension of the stapedial downward through the trigem-inal ganglion gives it access to the distal extent of the externalcarotid system, to which it attaches just beyond the take-off ofthe facial artery. Those branches associated with StV2 supply themaxilla. Each of these is distributed through the pterygopalatineplexus while StV3 supplies the mandible.

Developmental fields of thenaso-oropharynx containing membranousbones

We come now to the crucial concept. Each of the StV2 branchesis responsible for supplying one or more fields within the max-illa. Thus, a reduction or knock-out in any one of these brancheswill create a tissue deficiency state (cleft). Each of the Tessier cleftzones contains specific bone and cartilagenous structures. Thusit is possible to use the reduction in size or absence in a markerstructure to define the presence of a Tessier cleft.• Internal medial nasal (StV1), Tessier zone 1: nasal bones and

upper septum.• External medial nasal (anterior ethmoid) (StV1), Tessier zone

1: distally these extend down through the columella and intothe philtrum. Collaterals to central incisor.

• Internal lateral nasal (StV1), Tessier zone 3: upper turbinateand middle turbinate.

• External lateral nasal (StV1). Tessier zone 4: piriform fossa.• Lacrimal (StV1), Tessier zone 9: lateral orbit – anastomoses

with orbital branch of middle meningeal.• Supraorbital (StV1), Tessier zone 10–11.• Supratrochlear artery (StV1), Tessier zones 12–13.• Medial nasopalatine (StV2), Tessier zone 2: lower septum,

vomer, and premaxilla.• Lateral nasopalatine (StV2), Tessier zone 3: inferior turbinate,

medial maxillary wall, and the nasal mucosa of the secondaryhard palate.

• Descending palatine (StV2), Tessier zone 3: palatine bone, oralmucosa of the secondary hard palate.

• Medial infraorbital (anterior alveolar) (StV2), Tessier zone 4:frontal process of maxilla, canine, anterior maxilla medial tothe foramen.

• Lateral infraorbital artery (middle alveolar) (StV2), Tessierzone 5: premolars, anterior maxilla lateral to foramen.

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Figure 1.9 Mesoderm from the first seven somitomeres has a very limited role in craniofacial development. Somitomere 4 supplies the muscles ofmastication. Somitomeres 5–6 supply the muscles of facial expression. Somitomere 7 supplies all muscles of the palate except the tensor. Adapted fromButler AB, Hodos W. Comparative Vertebrate Neuroanatomy, 2nd edn., Wiley-Liss, 2005. Reproduced with permission of John Wiley & Sons.

Mechanisms of cleft palate: developmental field analysis 9

5cm 7X

VIIIVII

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vesicle

Figure 1.10 Dorsal aortae (purple), aortic arch arteries (green) with AA1well developed and AA2 in formation, primitive internal carotid (red)connects via the trigeminal artery with the neural arcade consisting of headplexus covering forebrain and midbrain (pink) and the primitive hindbrainchannels (pink). Four occipital somites are depicted.

• Posterior alveolar (StV2), Tessier zone 6: molars, posteriormaxillary wall.

• Zygomatico - facial (StV2), Tessier zone 7: malar bone (lowerzygoma).

• Zygomatico - temporal (StV2), Tessier zone 8: post-orbitalbone (upper zygoma).(NB: Tessier zone 9 is the rarest cleft, most likely because of its

dual blood supply – the anastomosis between the lacrimal andzygomatico-temporal.)

All of the above fields contain one or more membranousbones, all of which are derived from neural crest. (NB: in cran-iofacial development the only bones that are derived frommesoderm (lateral plate) are the basisphenoid, part of the tem-poral bone, and the occipital bone complex below the superiornuchal line. All remaining bones arise from neural crest.)

Developmental fields of thenaso-oropharynx containing muscle

What about fields that are composed exclusively of muscle? Thiswould include the muscles of the soft palate and pharynx. Howdo we categorize their blood supply? What could go wrong indevelopment to produce the pathologies associated with cleftpalate?

The physiology of speech depends upon muscles that are bothintrinsic to the soft palate and those that are extrinsic to it. Thefollowing concepts are essential for understanding the develop-mental anatomy of this integrated muscle system.(1) Craniofacial muscles arise from paraxial mesoderm (PAM).(2) PAM is segmentally organized into 7 somitomeres and 35

somites. The process of mesoderm segmentation takes place

(a)

(b)

Figure 1.11 (a) shows the internal carotid artery has extended up to theforebrain and midbrain; it has segmental branches. PHCs have morphedinto longitudinal neural arteries (still pink). These will later on move to themidline and fuse to form the basilar system. Paired segmental branchesfrom the dorsal aortae supply the cervical somites and spinal cord. Thesewill later break down and form a new secondary vertical axis, the vertebralartery which will, in turn, anastomose with the segmentalized basilartrunk. (b) shows four aortic arch arteries connecting the outlet tract withthe dorsal aortae. The arrowhead is the primitive trigeminal. Thepharyngeal arch remnants form a plexus that will morph into the externalcarotid system. Hiruma T. Formation of the pharyngeal arch arteries in thechick embryo. Observations of corrosion casts by scanning electronmicroscopy. Anat Embryol 1995; 191:415–424. Reproduced withpermission of Springer Science and Business Media.

during stages 7–8 and proceeds in a cranio-caudal direction.Each segment will be supplied by a designated motor nerve.

(3) Craniofacial mesenchyme is predominantly neural crest,not mesoderm. From stages 9 to 14 this mesenchymebecomes itself segmented into five pharyngeal arches.

(4) Located in the core of each arch is an aortic arch artery thatspans from the cardiac outflow tract located below the futurepharynx to the dorsal aorta lying above the pharynx. Thefifth aortic arch artery involutes and the fourth takes over thesupply for the structures of both pharyngeal arches 4 and 5.

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Figure 1.12 Scanning electron microscopy shows embryo in reversedposition (head to right). At this stage the pharyngeal arch plexus is verydense. Just caudal to the fourth aortic arch artery, arrowheads indicate thestumps of the involuting fifth aortic arch artery. AA4 will subsequentlysupply both pharyngeal arches 4 and 5. There is no sixth pharyngeal arch inmammals (in fish, yes). The artery assigned to this mesnchyme, AA6, willbe incorporated into the pulmonary circulation. Hiruma T. Formation ofthe pharyngeal arch arteries in the chick embryo. Observations of corrosioncasts by scanning electron microscopy. Anat Embryol 1995; 191:415–424.Reproduced with permission of Springer Science and Business Media.

Figure 1.13 Dural arteries are all derivatives of the intracranial stapedialsystem. Upon involution of the stem these all form anastomoses withbranches of the internal and external carotid systems. Diamond MK.Homologies of the stapedial artery in humans, with a reconstruction of theprimitive stapedial artery configuration in euprimates. Am J Phys Anthro1991; 84:433–462. Reproduced with permission of John Wiley & Sons.

(5) Despite textbook dogma, there is no sixth pharyngeal arch.The sixth aortic arch artery becomes incorporated into thepulmonary circulation.

(6) The muscles that develop within the pharyngeal archesoriginate from paraxial mesoderm that becomes physicallyincorporated into the arch system. Hypoplasia or aplasia ofpalate musculature can occur from an intrinsic defect of the

Figure 1.14 The stapedial system develops at stage 17 precisely when thecranial nerves emerge. The stem ascends through the tympanic cavity, goesintracranial, and follows the intracranial sensory nerves throughout thedura. A forward branch to the trigeminal ganglion picks up intracrancialV1 and gains access to the orbit where it supplies all extraocular structures.From the trigeminal ganglion a branch goes extracranial to connect to themaxillary system as the middle meningeal. From the typanic cavity abranch tracks extracranial following chorda tympani until it connects withthe external carotid system. When the stem involutes, all the branches ofstapedial survive on anastomoses with other systems, such as the opthalmicfrom the internal carotid, the external carotid distal to facial artery to formthe internal maxillary, and multiple connections with other branches of theexternal carotid system, such as occipital. Huang C-H, Hu DK. Nogginheterozygyous mice: an animal model for congenital conductive hearingloss in humans. Hum Mol Genet 2008; 17(6):844–853. Reproduced withpermission of Oxford University Press.

mesoderm or from a failure of the arterial axis that suppliesit. Such defects can be isolated to a single muscle or can bemore global as in hemi-palate.

Craniofacial mesoderm assigned to the orbit and to the firstthree pharyngeal arches comes from seven somitomeres (Sm).These are incompletely separated balls of mesoderm with a hol-low center. The first three somitomeres produce the extraocularmuscles (Figure 1.15). The remaining somitomeres are assignedas follows. Sm4 gives rise to the muscles of mastication in thefirst pharyngeal arch; these are innervated by the Vth cranialnerve. Sm5 and Sm6 produce the muscles of facial expression inthe second phayrngeal arch; these are innervated by the VIIthcranial nerve. Sm7 contains the muscles of the soft palate; incontrast to dogma, these are innervated by the IXth cranial nervevia the Xth cranial nerve, the vagus. Somites are completely sep-arate from one another. Somites 1 and 2 provide the musclesof phonation in the fourth and fifth pharyngeal arches; theseare supplied by the Xth cranial nerve. Mesoderm from S1–S4that is not incorporated into the pharyngeal arches producesthe muscles of the tongue, the sternocleidomastoid, and thetrapezius.

The pharyngeal arch system is transient; so too are the aorticarch arteries that originally supplied each pharyngeal arch.These break down, reorganize, and eventually are connected

Mechanisms of cleft palate: developmental field analysis 11

Cerebellum

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3

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Figure 1.15 The pathways of extraocular muscles from somitomeres 1, 2, 3,and 5 to their insertion sites on the sclera are depicted.

to the carotid; thus is formed the external carotid artery andall its derivatives serving the pharyngeal arch structures ofthe face – but not the maxilla. Recall that the V2-associatedstapedial artery system forms an anastomosis distal to the facialartery and to the superficial temporal artery – thus is born thesystem of arteries emanating from the pterygo-palatine fossathat supplies the maxilla and inferior oro-nasopharynx. Theseare responsible for the bone-bearing fields of the maxilla.

Let us look at the arterial axes that supply the soft palate.The primary axis of the soft palate is the ascending pharyngealartery. It supplies the most primitive muscles, that is thosethat develop first, but are last to be affected. The absence ofa soft palate is a survivable condition; not so the absence ofpharyngeal muscles. The palatal branch of ascending pharyn-geal supplies the palatoglossus. The pharyngeal branch of theascending pharyngeal supplies the superior constrictor, middleconstrictor, salpingopharyngeus, and stylopharyngeus, andpalatopharyngeus. These are all important for swallowing; thefirst two constrict the pharynx while the latter two function aselevators of the pharynx. The secondary axes of the soft palate are:the descending (a.k.a. greater) palatine branch of the StV2 distalinternal maxillary artery and the ascending palatine branch ofthe facial artery. These axes supply the more recent additionsto the soft palate: levator veli palatini, tensor veli palatini,and uvulus. The first two have attachments to the tympanictube while uvulus relates to the posterior spine of the palatinebone.

Where do these muscles originate? Tensor veli palatini arisesfrom somitomere 4; it is supplied by the Vth cranial nerve.Levator veli palatini arises from somitomere 7; it is sup-plied – with controversy – by cranial nerve IX vs. the cranialportion of the spinal accessory nerve: cranial nerve XI. Allof the pharyngeal muscles under consideration here are sup-plied by the cranial portion of spinal accessory nerve: cranialnerve XI. The reason for the overlap between cranial nerves

IX and XI is that they are in register with the same zone of thebrain stem; their nuclei simply represent two parallel columnsreflecting different functions. The constrictors are likely to arisefrom somites 2 and 3; their motor supply is cranial nerve XI.Stylopharyngeus relates to the second arch and therefore islikely to arise from somitomere 5 (or 6). Salpingopharyngeusrelates to the portion of the tympanic tube that is develop-mentally related to the third arch; thus it likely comes fromsomitomere 7.

Knowing the above facts, we can make some general state-ments about muscle pathologies in cleft palate. All defects of thehard palate, either primary (the premaxilla), from the incisiveforamen forward, or secondary, from the incisive foramenbackward, involve deficiencies in membranous bone. These arereadily diagnosed by physical examination and 3D CT scan-ning. Such bone defects involve one or more arterial axes of theStV2 stapedial system supplying the maxilla. The nucleus of V2resides within the second rhombomere of the hindbrain (r2).Thus defects of the maxillary complex represent deficiencies inthe population of neural crest cells arising from that segmentof the neural fold in genetic register with r2. Strictly by logic abone defect occurs when something is intrinsically wrong withthe r2 mesenchymal population or there is defective formationof a neurovascular axis supplying a portion of the r2 population.The latter mechanism is more specific; it explains isolated bonedefects at later stages in development rather than a global failureof neural crest mesenchyme in the first arch.

Mandibular defects associated with cleft palate, as in thePierre Robin sequence, can be diagnosed in a similar way.Defects involving any developmental zone of the mandibleinvolve one or more arterial axes of the StV3 stapedial system.The nucleus of V3 resides within the third rhombomere ofthe hindbrain (r3). Thus, defects of the mandibular complexrepresent deficiencies in the population of neural crest cellsarising from that segment of the neural fold in genetic registerwith r3. Tensor veli palatini is the sole palate muscle belongingto the first arch; it comes from somitomere Sm4 (which alsobears the muscles of mastication). For this reason, any form ofcleft palate involving TVP implies a more proximal “hit” to theStV2–StV3 system or a more global involvement of first archneural crest.

Summary of neural crest and mesodermalderivatives that contribute to cleft palate

• r0/r1 = bone fields from stapedial V1: perpendicular plate ofthe ethmoid, septum, columella, prolabium.

• r2 = bone fields from stapedial V2: vomer, premaxilla, palatalshelf, inferior turbinate.

• r3 = bone fields from stapedial V3: mandible.• r5 = neural crest to arterial wall of ascending palatine branch

of facial > soft palate muscles.

12 Chapter 1

• r7 = neural crest to arterial wall of ascending pharyngeal tosoft palate/pharynx muscles.

• Sm4 = mesoderm of tensor veli palatini.• Sm7 = mesoderm of levator veli palatini, palatoglossus,

palatopharyngeus, uvulus.

Mechanisms of developmental field failure

Now that we have an idea of the various neurovascular axes, letus consider a first mechanism of failure, alteration of function ofthe growth cone. Because growth of the axes proceeds outward,the earlier in time the failure occurs the more structures willbe affected. For example, the premaxilla is the terminal field forthe medial nasopalatine axis. It has three sub-fields: the centralincisor, lateral incisor, and the frontal process of the premaxilla(which lies tucked beneath the frontal process of the maxilla).Any perturbation of the nasopalatine axis will show up first as adeformation in the inferolateral rim of the piriform fossa. Nextthe lateral incisor and its bony housing are affected. Finally, atotal loss of premaxilla can occur (Figure 1.16).

A simplifying concept involves failure of the vascular growthcone (Figures 1.17 and 1.18). The growth cone of the artery con-sists of an endothelial tip sprout that produces PDGF-B whichis chemoattractive for pericytes and positive for the receptorPDGFRB. These cells distribute themselves along the ablumi-nal wall of the vessel along which they secrete cytoplasmicprocesses.

We turn our attention to the specific anatomic variations ofcleft palate. We postulate that fusion of these mesenchymal tissueunits (partner fields) requires that they be physically positionedrelative to each other within a critical contact distance. If the tis-sue volume of one of the fields is reduced, and the critical contactdistance is exceeded, fusion will not occur and a cleft will result.A second mechanism involves the alteration of fusion potential ofthe epithelial surface. The stability of the epithelium is controlledby sonic hedgehog (SHH). As long as this is active, the epithe-lial surface will be incapable of fusion. SHH is itself inhibitedby BMP-4 of the underlying mesenchyme. The total amount ofBMP-4 produced by a field is proportional to its mesenchymalvolume. Thus, any reduction in BMP-4 production will promotethe stability of the epithelial surface and prevent its fusion.

b

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Figure 1.16 The alveolar walls of the premaxilla (PMx) are supplied by medial nasopalatine artery; the labial alveolar wall receives collateral supply fromthe medial infraorbital. Premaxilla has three subfields: the medial incisor, lateral incisor, and the frontal process. Since the frontal process is the most distal,it is always affected first in deficiency states. Bartezko K, Jacob M. A re-evaluation of the premaxillary bone in humans. Anat Embryol 2004; 207:417–437.Reproduced with permission of Springer Science and Business Media.

Mechanisms of cleft palate: developmental field analysis 13

Growth Cone (Axon)

Schwann Cell

Neurotrophic Factors

Figure 1.17 Schwann cells pick up nutrients and growth factors from the environment and transmit them back into the axon. NGF (nerve growth factor)produced by the pericytes promotes growth of the neural axis in register with the vascular axis. Adapted from: May F et al. Nerve replacement strategeisfor cavernous nerves. Europ Urol 2005; 48:372–378.

Tip cell

Recruitment of pericytes by PDGF. B

released by endothelial (tip) cell

PDGF receptor

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inter-endothelial junctions and

EC quiescence

Figure 1.18 Vascular endothelial growth factor (VEGF) produced by the nerve cone causes outgrowth of endothelial cells from a vascular axis. Theseendothelial cells form the core of the new vessel or they add on to an existing vessel to elongate it. But stabilization of the new vessel by pericytes is nowrequired. Tip cells produce PDGF-Beta that recruits pericytes to come alongside the endothelial axis and stabilize it. Adapted from: Quaegebeur A,Lange C, Carmeliet P. The neurovascular link in health and disease: molecular mechanisms and therapeutic implications. Neuron 2011; 71:406–424.Reproduced with permission of Elsevier.

Fusion of the palate is bi-directional, proceeding both forwardand backward from the incisive foramen. Closure of the primarypalate involves interaction between the alveolar processes of thepremaxilla (medial nasopalatine artery) and the canine-bearingmesial maxilla (lateral nasopalatine artery). In addition, thefrontal process of premaxilla fuses with the overlying frontal

process of the maxilla. This latter structure is supplied by themedial branch of the infraorbital and belongs to the Tessier cleftzone 4.

Fusion of the secondary hard palate takes place concomitantly.It involves union between the vomer and the horizontal palatalshelf. The vomer is the proximal tissue field along the medial

14 Chapter 1

nasopalatine shelf. Its partner field, the horizontal palatine shelf,is actually supplied by two distinct neurovascular axes: lateralnasopalatine on the nasal side and greater palatine artery on theoral side. Sinus formation within the horizontal shelf has beenpreviously reported. All sinuses represent the separation of adja-cent fields from one another.

It is useful to think of field development as a flow of mes-enchyme into a geometric space. Flow into the palatal shelfappears to follow an anterior-to-posterior gradient. Thus, insuf-ficiency will always manifest itself in the “newest” zone, that is,posteriorly. The fusion process of the secondary hard palate isanterior-to-posterior.

Cleft palate: analysis by zones

Tessier cleft zone 14: a misleading conceptThe zone does not exist. This was a trompe l’oeil for Tessier. Thefontal bone is not singular; it is two halves which fuse in themidline. Each hemi-frontal bone is a bilaminar structure withfour develomental fields, all of which are organized around fourStV1 neurovascular axes. Zones 13 and 12 are supplied by thesupraorbital externally and internally these zones are supportedby the medial meningeal flowing over the ethmoid plate. Zones11 and 10 are supplied externally by the supraorbital, whileinternally the lacrimal supplies the lateral orbital. Developmentof the frontal bone takes place by the membranous ossifica-tion of the neural crest which migrates from rhombomere 0(zones 13–12) and from rhombomere 1 (zones 11–10). Thisectomesenchyme follows a pathway alongside the midbrain andforebrain, forward over the orbit and downward to form thenasal process. This mesenchyme is the source of the dura anddermis within which the membranous bone fields develop. The

neural crest populates and pushes forward a unique ectodermalenvelope which is described below (Figure 1.19).

The epidermis of the zones overlying the forehead and noseis likewise unique. As the r0/r1 neural crest flows forward ittracks beneath the overlying non-neural ectoderm to producethe skin of the V1 region. Non-neural ectoderm (NNE) is alayer of tissue overlying the prosencephalon (forebrain). NNEacts like ectoderm; it is in genetic register with the six under-lying prosomeres of the forebrain (p1–p6). The interactionbetween the r0/r1 beneath the NNE covering the most rostralprosomeres, p5 and p6, produces frontonasal skin, a structureradically different from the remainder of facial skin and body.(NB: The reader will recall that the source of dermis of all headand neck skin down to the level of C2 is not mesodermal, butneural crest.) For this reason, in frontonasal dysplasia the skinappears different in thickness and consistency.

Closure of the frontal bone zones takes place by a processof apoptosis, a controlled breakdown of tissue that allows thefrontal fields to move forward into the midline. Of course,the driving force for this is the medialization of the orbits, aprocess that is dictated by the growth pattern of the brain andthe anterior cranial base. The ethmoid complex is interposedbetween the orbits. Failure of apoptosis in the ethmoid zoneswill lead to hypertelorisim. Since the ethmoid is a bilateralstructure, such hypertelorism can be unilateral or bilateral.Probably the apoptosis process required of the frontal bone issubject to whatever degree of apoptosis is taking place in theethmoid complex.

Midline pathologies can manifest as a simple excess of tissueor as a fusion failure or cleft (sic). For this reason, it appeared toTessier as if this were truly an autonomous zone. Recall that thepituitary sits in a cavity between two bones: the anterior neuralcrest presphenoid and a posterior mesodermal post-sphenoid

PD.

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Figure 1.19 (a) Non-neural ectoderm overlying prosomeres p5 (blue) and p6 (red) is not formally neural crest; it is responsible for the frontonasalepidermis. Frontonasal dermis results from sub-epidermal forward flow of more posterior neural crest. (b) Note neural crest contributions to craniofacialarterial systems. Etchevers HC, Couly G, Le Douarin NM. Morphogenesis of the branchial vascular sector. Trends Cardiovasc Med 2002; 12(7):299–306.Reproduced with permission of Elsevier.

Mechanisms of cleft palate: developmental field analysis 15

(basisphenoid). The former has a sinus while the latter is solid.Fusion failures extending backward into the sphenoid have abiologic limit to viability. Failure of apoptosis in the midline ofzone 13 also leads to a residual excess of mesenchyme in themidline; this is normal orbital approximation and results inhypertelorism.

Medialization can also be altered by the presence of anencephalocoele that can seek out a field failure between anyof the zones to achieve an extracranial position and therebyblock the closure. The escape routes of encephalocoeles are welldocumented, be they forward through the frontal bone zones,in the midline or in paramedian positions.

Neuroembryologic simplification of zones 1and zone 13/zone 2 and zone 12Tessier originally perceived that a fundamental differenceexisted between clefts (states of mesenchymal deficiency and/orexcess) involving the maxilla and those involving the orbit. Atthe time, neuroembryology of the area was not recognized. Inour correspondence, Tessier was impressed by the correlationbetween his findings and the regional sensory neuroanatomy(Flores-Sarnat, et al., 2007). The structures of the nose areunique in that the topology of the fields supplied by the neu-rovascular axes of StV1 and StV2 is not one of simple planarseparation, rather these fields are interlocking. This makes theinterpretation of congenital field defects difficult. The best wayto keep things straight is for us to consider these zones by theirneuroanatomy, with 1–2 supplied by StV2 axes while those ofzones 13 and 12 are supplied STV1 axes. For this reason, weare going to violate the traditional way of describing Tessier

clefts in this region. In the end, as he himself commented, theobservations will be clearer (Ewings and Carstens, 2009).

Tessier cleft zone 1Zone 1 consists of the structures in the midline of the nose andmouth, the paried vomer and perpendicular ethmoid bones.The nasal cavity is supplied by two neurovascular pedicles:StV2 medial nasopalatine axis, and StV1 internal medial nasalaxis. The medial zone of dorsal nasal skin and nasal bones aresupplied by the StV1 external medial nasal axis (Figures 1.20and 1.21).

Paired medial nasopalatine arteries supply paired vomerinebones. Occasionally, these bones may fail to fuse. Alternatively,the intervomerine space may allow for the descent of a tumoror encephalocoele into the oral cavity. Such situations requireconcomitant pathology of the perpendicular plates of the eth-moid. In the routine case, a deficiency of vomerine mesenchymewill impair the inhibition of sonic hedgehog (SHH) and thusthe epithelial surface of that vomer front-to-back fusion processwith the palatal shelf. If the palatal shelf is normal the cleft willbe narrow (Figure 1.22). In the minimal state, the palate cleft isvery posterior, at the posterior nasal spine, but as the degree ofvomer deficiency increases, the palate cleft will extend forwarduntil it reaches the incisive foramen.

When a minimal vomerine deficiency exists in isolation, thewidth of the palate cleft will be fairly narrow and uniform. Thevomer develops in posterior-to-anterior sequence; as it does so,it descends from front to back into the palatal plane like a scim-itar. Thus, the most vulnerable zone of the vomer is posterior

Medial internal nasal branch of

anterior ethmoidal artery

Septal branch of

posterior ethmoidal artery

Septal branch of

superior labial artery

Kiessellbach’s plexus

Posterior septal branch of

sphenopalatine artery

Figure 1.20 The obliquely-oriented midline of the septum is a vascular interface zone between StV1 posterior and anterior ethmoid and StV2 medialnasopalatine arteries.