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 Craniosynostoses
Molecular Genetics, Principles of Diagnosis, and Treatment
Monographs in Human Genetics
Vol. 19

Series Editor

Michael Schmid Würzburg

Craniosynostoses
Molecular Genetics, Principles of Diagnosis, and Treatment

Volume Editors

Maximilian Muenke Bethesda, Md

Wolfram Kress Würzburg
Hartmut Collmann Würzburg
Benjamin D. Solomon Bethesda, Md

113 figures, 32 in color, and 17 tables, 2011

Basel · Freiburg · Paris · London · New York · Bangalore ·

Bangkok · Shanghai · Singapore · Tokyo · Sydney
Maximilian Muenke Wolfram Kress
Medical Genetics Branch Institut für Humangenetik
National Human Genome Research Institute Universität Würzburg
National Institutes of Health Biozentrum
35 Convent Drive, MSC 3717 Am Hubland
Building 35, Room 1B-203 97074 Würzburg (Germany)
Bethesda, MD 20892-3717 (USA)

Hartmut Collmann Benjamin D. Solomon

Neurochirurgische Klinik und Poliklinik der Medical Genetics Branch
Universität Würzburg National Human Genome Research Institute
Abteilung Pädiatrische Neurochirurgie National Institutes of Health
Josef-Schneider-Straße 11 35 Convent Drive, Building 35
97080 Würzburg (Germany) Bethesda, MD 20892-3717 (USA)

Library of Congress Cataloging-in-Publication Data

Craniosynostoses : molecular genetics, principles of diagnosis, and

treatment / Volume Editors, Maximilian Muenke, Bethesda, Md, Wolfram
Kress, Würzburg, Hartmut Collmann, Würzburg, Benjamin Solomon, Bethesda,
Md.
p. ; cm. -- (Monographs in human genetics, ISSN 0077-0876 ; vol.
19)
Includes bibliographical references and indexes.
ISBN 978-3-8055-9594-0 (hard cover : alk. paper) -- ISBN
978-3-8055-9595-7 (e-ISBN)
1. Craniosynostoses. I. Muenke, Maximilian, editor. II. Kress, Wolfram,
editor. III. Collmann, Hartmut, editor. IV. Solomon, Benjamin, editor. V.
Series: Monographs in human genetics ; v. 19. 0077-0876
[DNLM: 1. Craniosynostoses--genetics. 2. Craniosynostoses--diagnosis.
3. Craniosynostoses--therapy. W1 MO567P v.19 2011 / WE 705]
RJ482.C73C69 2011
616'.042--dc22
2010051327

Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents®.
Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of
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© Copyright 2011 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland)
www.karger.com
Printed in Switzerland on acid-free and non-aging paper (ISO 9706) by Reinhardt Druck, Basel
ISSN 0077–0876
ISBN 978–3–8055–9594–0
e-ISBN 978–3–8055–9595–7
Contents

VII Editorial
Schmid, M. (Würzburg)
VIII Preface
Muenke, M. (Bethesda, Md.); Kress, W.; Collmann, H. (Würzburg); Solomon, B.D. (Bethesda, Md.)
IX Foreword
Cohen Jr., M.M. (Halifax, N.S.)

Chapter 1
1 Craniosynostosis: A Historical Overview
Solomon, B.D. (Bethesda, Md.); Collmann, H.; Kress, W. (Würzburg); Muenke, M. (Bethesda, Md.)
Chapter 2
8 Discovery of MSX2 Mutation in Craniosynostosis: A Retrospective View
Müller, U. (Gießen)
Chapter 3
13 Regulation of Calvarial Bone Growth by Molecules Involved in the Craniosynostoses
Benson, M.D.; Opperman, L.A. (Dallas, Tex.)
Chapter 4
28 Signal Transduction Pathways and Their Impairment in Syndromic Craniosynostosis
Connerney, J.J. (Boston, Mass.); Spicer, D.B. (Scarborough, Me.)
Chapter 5
45 The Molecular Bases for FGF Receptor Activation in Craniosynostosis and Dwarfism
Syndromes
Beenken, A.; Mohammadi, M. (New York, N.Y.)
Chapter 6
58 Recurrent Germline Mutations in the FGFR2/3 Genes, High Mutation Frequency, Paternal
Skewing and Age-Dependence
Arnheim, N.; Calabrese, P. (Los Angeles, Calif.)
Chapter 7
67 Apert, Crouzon, and Pfeiffer Syndromes
Cohen Jr., M.M. (Halifax, N.S.)
Chapter 8
89 Muenke Syndrome
Solomon, B.D.; Muenke, M. (Bethesda, Md.)

V
 Chapter 9
98 Saethre-Chotzen Syndrome: Clinical and Molecular Genetic Aspects
Kress, W.; Collmann, H. (Würzburg)
Chapter 10
107 Craniofrontonasal Syndrome: Molecular Genetics, EFNB1 Mutations and the Concept of
Cellular Interference
Wieland, I. (Magdeburg)
Chapter 11
119 Uncommon Craniosynostosis Syndromes: A Review of Thirteen Conditions
Raam, M.S. (Bethesda, Md./Chevy Chase, Md.); Muenke, M. (Bethesda, Md.)
Chapter 12
143 Metopic Craniosynostosis Syndrome Due to Mutations in GLI3
McDonald-McGinn, D.M.; Feret, H.; Nah, H.-D.; Zackai, E.H. (Philadelphia, Pa.)
Chapter 13
152 Craniosynostosis and Chromosomal Alterations
Passos-Bueno, M.R.; Fanganiello, R.D.; Jehee, F.S. (São Paulo)
Chapter 14
165 Nonsyndromic Craniosynostoses
Collmann, H. (Würzburg); Solomon, B.D. (Bethesda, Md.); Schweitzer, T.; Kress, W. (Würzburg);
Muenke, M. (Bethesda, Md.)
Chapter 15
177 Molecular Genetic Testing of Patients with Craniosynostosis
Hehr, U. (Regensburg)
Chapter 16
184 Prenatal Sonographic Diagnosis of Craniosynostosis
Schramm, T. (Munich)
Chapter 17
199 Clinical Approach to Craniosynostosis
Gripp, K.W. (Wilmington, Del.)
Chapter 18
216 Imaging Studies and Neurosurgical Treatment
Collmann, H.; Schweitzer, T.; Böhm, H. (Würzburg)
Chapter 19
232 Maxillofacial Examination and Treatment
Böhm, H.; Schweitzer, T.; Kübler, A. (Würzburg)

244 Author Index

245 Subject Index

VI Contents
Editorial

It is a great pleasure to introduce volume 19 of aim of Monographs in Human Genetics in dealing

the book series Monographs in Human Genetics with the molecular causes of important hereditary
entitled ‘Craniosynostoses: Molecular Genetics, diseases, their diagnosis, and their eventual pre-
Principles of Diagnosis and Treatment’. The ini- vention and clinical treatments. The volume has
tial idea for this book was born during a work- been organized in an exquisite way by Maximilian
shop on craniosynostoses held at the Academy Muenke, Wolfram Kress, Hartmut Collmann and
of Human Genetics in Würzburg (Germany). Benjamin Solomon. I express my gratitude to
Hartmut Collmann and Wolfram Kress brought them for all the time they invested and the ef-
together many seemingly diverse aspects of cra- forts they made in processing and refining all 19
niosynostoses, including clinical approaches, ge- chapters of this exciting book. The international-
netics, molecular mechanisms and, most impor- ly renowned authors have contributed excellent
tantly, treatments. As that course progressed, they manuscripts with astonishing illustrations. Their
realized how inspiring this subject was to their commitment has made the publication of this vo-
colleagues and medical students. lume possible. The constant support of Thomas
Craniosynostoses provide one of the best Karger with this ongoing and timely book series
examples of today’s molecular medicine, con- is highly appreciated.
necting simple anatomy and pathology with the Michael Schmid
structures of molecules that form the relevant si- Würzburg, November 2010
gnaling pathways. This book truly achieves the

VII
Preface

Craniosynostosis is a challenging and complex both as relates to syndromic and nonsyndromic

condition that has been recognized since the forms, as well as to normal cranial development
dawn of human history. Our understanding of more generally. This understanding is critical on
the clinical manifestations of the disease process many levels, but, most importantly perhaps, may
has advanced considerably in the last century, be able to inform modalities of medical and sur-
with molecular etiologies of many forms of syn- gical management to help improve the lives of af-
dromic craniosynostosis emerging in the last two fected patients and families.
decades. This increased knowledge has in turn en- We felt an international team of authors would
abled researchers and clinicians to probe normal be able to represent this difficult disorder in all
and abnormal sutural biology from the atomic to its complexity; these are authors of diverse back-
the population-based level. grounds, including clinicians and researchers
Just as important, and in parallel with the re- whose careers are intimately involved in under-
cent wave of basic biological understandings of standing the causes, effects, and treatments of
craniosynostosis, advances in clinical diagnosis craniosynostosis. Hence, this is a book intended
and treatment have been achieved, which include for colleagues from a wide variety of disciplines.
improvements in prenatal and postnatal imaging We hope this volume may prove useful wheth-
and craniofacial surgical techniques. These ad- er a researcher is devoted to basic science at the
vances have been important for many reasons, and bench or standing next to an operating table, and
have allowed functional corrections and achieve- at every point in between.
ment of acceptable cosmesis in a broad range of The editors would like to thank all the au-
patients. thors who graciously contributed to this volume
Thus, given the growth of our knowledge base and who took the time to share their expertise
about craniosynostosis, the editors of this volume and explain their most important discoveries to a
feel that the timing of publication comes at a very wide audience. We also would like to extend our
opportune moment. With the completion of the deepest gratitude to all the patients and families
Human Genome Project and with the more re- whom we have met over the course of our careers
cent availability of high-throughput investigative for their time, their generosity, and their compas-
methods, we are now able to couple knowledge sionate spirits.
from previous accomplishments to newly emerg- Maximilian Muenke, Wolfram Kress,
ing genomic technologies. We anticipate that Hartmut Collmann, and Benjamin D. Solomon
through the critical mass of knowledge achieved Bethesda and Würzburg, August 2010
to date, we can harness new tools of genome analy-
sis in order to better understand craniosynostosis,

VIII
Foreword

The Editors – Max Muenke, Ben Solomon, and TGFβ. In Chapter 4, Jeanette Connerney and
Hartmut Collmann, and Wolfram Kress – have Douglas Spicer raise the question of how differ-
produced an epic-making volume on craniosyn- ent signaling transduction pathways integrate
ostosis that is a tour de force. They have done a re- with one another to regulate the formation and
markable job of selecting and coordinating many morphogenesis of craniofacial structures, which
highly respected authorities in the field to write is only starting to be understood. In Chapter 5,
19 chapters covering a wide range of subjects. It Andrew Beenken and Moosa Mohammadi ad-
is also remarkable that these four editors have, in dress the molecular mechanisms of FGFR activa-
addition, written or been coauthors of six excel- tion in craniosynostosis and in some of the skel-
lent articles, so that each one of them is magister etal dysplasias, and discuss ligand-independent
mundi of craniosynostosis. gain-of-function mutations, and also ligand-
The rate of discovery in the molecular ad- dependent gain-of-function mutations for those
vances in craniosynostosis is very exciting, but few disorders in the linker region between IgII
it is equally true for the remarkable advances in and IgIII. In Chapter 6, Norman Arnheim and
craniofacial biology, imaging studies, neurosurgi- Peter Calabrese discuss recurrent germline muta-
cal treatment, craniofacial surgical treatment, and tions in FGFR2 and FGFR3, which are paternally
therapeutics and it means clearly that the future is derived and age-dependent. The process is driven
now! However, we all know that advances in these by a selective advantage of spermatogonial cells,
fields will continue to flower tomorrow! as demonstrated in Apert syndrome.
Chapter 1 by Ben Solomon, Hartmut Collmann, Several chapters deal with various syndromes.
Wolfram Kress, and Max Muenke provides a his- Each of these is remarkably extensive and very
torical review of craniosynostosis. The authors thorough, analyzing both clinical and molecular
take us on a tour of ancient times, later histori- aspects of the disorders. I have dealt with Apert
cal developments, the advent of modern classifi- syndrome, Crouzon syndrome, and Pfeiffer syn-
cations, and the evolution of the molecular causes drome in Chapter 7. Ben Solomon and Max
of craniosynostosis, and management. In Chapter Muenke have analyzed the condition named af-
2, Ulrich Müller discusses Boston-type cranio- ter Max, namely Muenke syndrome in Chapter
synostosis and its molecular mutation on MSX2 8. Wolfram Kress and Hartmut Collmann have
(p.Pro148His). Saethre-Chotzen syndrome as their subject in
Some basic biological and molecular studies Chapter 9. Ilse Wieland writes about craniofron-
are grouped next. In Chapter 3 Douglas Benson tonasal syndrome in Chapter 10.
and Lynne Opperman focus on the molecular reg- In Chapter 11, Manu Raam and Max Muenke
ulation of calvarial bone growth by Ephrins, FGFs, tackle a large group of uncommon syndromes

IX
with craniosynostosis (Antley-Bixler syndrome, search for the causes of the craniosynostosis as-
Baller-Gerold syndrome, Beare-Stevenson cutis sociated with other anomalies together with their
gyrata syndrome, Bohring-Opitz syndrome, C more complicated medical needs.
syndrome (or Opitz trigonocephaly syndrome), The final two chapters discuss surgical treat-
Carpenter syndrome, Crouzon syndrome with ment in the craniosynostoses. In Chaper 18,
acanthosis nigricans, Jackson-Weiss syndrome, Hartmut Collmann and his colleagues deal with
Jacobsen syndrome, Loeys-Dietz syndrome type imaging studies and neurosurgical treatment.
I, osteoglophonic dysplasia, P450 oxidoreductase They indicate that the diagnosis of craniosynos-
deficiency, and Shprintzen-Goldberg syndrome). tosis is primarily a matter of careful clinical ex-
In Chapter 12, Donna McDonald-McGinn, amination with the use of imaging to verify the
Elaine Zackai and their colleagues present two clinical diagnosis, to detect other possible sutures
patients with trigonocephaly, one with postaxial involved, to look for signs of intracranial hyper-
polydactyly, the other with polysyndactyly. Both tension, and to assess possible associated anoma-
were shown to have GLI3 mutations. lies. The earlier craniectomy techniques used have
Chapters 13–17 deal with general problems of now been partially replaced by plastic surgical
various kinds. In Chapter 13, Maria Rita Passos- techniques. Long term postoperative surveillance
Bueno and her colleagues deal with the difficult is mandatory. In Chapter 19, Hartmut Böhm and
problems of analyzing chromosomal alterations his colleagues discuss maxillofacial treatment.
associated with craniosynostosis. In Chapter 14, Procedures developed have included Le Fort III
Hartmut Collman and his colleagues review non- distraction, frontoorbitomaxillary advancement,
syndromic craniosynostoses. In Chapter 15, Ute monobloc frontofacial advancement, and orbital
Hehr discusses the molecular genetic testing of transposition.
patients with craniosynostosis, and in Chapter Finally, let me say that all these highly respect-
16, Thomas Schramm discusses prenatal ultra- ed authorities have written remarkably excellent
sonography, pointing out that there are no data chapters, which are so provocative that this vol-
on the validity of prenatal ultrasound screening ume will be read by many clinicians, many resi-
for craniosynostosis, although to a certain degree, dents, many craniofacial biologists, many mo-
syndromic forms of craniosynostosis with cran- lecular geneticists, and many students. This will
iofacial and limb involvement may allow ultra- be the definitive volume on craniosynostosis for
sonic differentiation between syndromes. Karen many years to come!
Gripp in Chapter 17 provides a wonderful clini- M. Michael Cohen Jr.
cal approach to craniosynostosis and distinguish- Halifax (Canada), July 2010
es isolated synostosis from the more complicated

X Foreword
Chapter 1
Muenke M, Kress W, Collmann H, Solomon BD (eds): Craniosynostoses: Molecular Genetics, Principles of Diagnosis, and Treatment.
Monogr Hum Genet. Basel, Karger, 2011, vol 19, pp 1–7

Craniosynostosis: A Historical Overview

B.D. Solomona ⭈ H. Collmannb ⭈ W. Kressc ⭈ M. Muenkea
aMedical Genetics Branch, National Human Genome Research Institute, National Insitutes of Health, Bethesda, Md., USA;
bDepartment of Neurosurgery, cInstitute of Human Genetics, Julius-Maximilians University, Würzburg, Germany

Abstract individual at death was estimated to be at least

Craniosynostosis has been recognized since ancient five to eight years of age (and likely at least sev-
times, and the condition has a colorful and diverse his- eral years older than that). The authors argue that
tory. In this introductory chapter, we include a descrip-
tion of historical aspects of craniosynostosis, which
the individual’s age is evidence that the society to
touches upon ancient depictions of the condition, the which this individual belonged cared for handi-
advent of modern classification schemes, more recent capped and otherwise impaired members, which
gene discoveries involving the molecular causes of many has certainly not always been the rule, even in
types of craniosynostosis, and evolving aspects of the modern cultures [1].
management of affected patients.
There is good evidence to believe that since
Copyright © 2011 S. Karger AG, Basel
prehistoric times, humankind has associated de-
viated head shape with magic ideas and mythic
General History imaginations, as well as with both positive and
negative aesthetic appearances. Unintentional
Descriptions and definitions of craniosynos- deformation of the head by external forces, for
tosis have a long and complicated history that instance from tight fixing of an infant’s head to
stretches over many millenia. Depictions of af- a cradle board, may have resulted in the prac-
fected individuals have appeared in numerous tice of intentional deformation by wrapping the
cultures spanning every part of the globe where head or applying pads or boards to the infantile
investigations have been undertaken. The ear- head. The aim likely was to create an extraordi-
liest evidence comes from an at least 500,000 nary outer appearance in order to emphasize the
year-old Middle Pleistocene human skull found terrifying appearance of a warrior or the noble
in modern Spain, which was noted to have uni- image of an aristocrat, or by simply following lo-
lateral lambdoid synostosis (a relatively rare type cal cultural criteria of beauty. In fact, intention-
of sutural fusion) and consequent predicted de- al deformation of the head has been practiced in
formities in the shape of the skull. The skull also almost all cultures for many hundreds of years,
showed evidence for elevated intracranial pres- and was customary even in Europe until the 18th
sure (ICP). Most interestingly, the age of the century [2].
 Less ancient but equally interesting (and more [7]. However, it was not until the late 1700s that
speculative) examples abound. It has been hy- Samuel Thomas Sömmering first clearly identi-
pothesized that the Egyptian pharaoh Akhenaten, fied the sutures themselves as the sites of early
who ruled around 1350 BCE, may have had cran- cranial growth, and concluded that premature su-
iosynostosis as a manifestation of a disorder sim- tural fusion would consequently result in cranial
ilar to Antley-Bixler syndrome, as he and his deformity [8].
family were also depicted as having features con- Modern concepts of craniosynostosis are
sistent with abnormal steroidogenesis [3]. Certain based on the works of Otto and Virchow [5]. In
Chinese deities such as the god of longevity, Nan- 1851, the famed German scientist and physician
ji-xian-weng, are sometimes shown with severe Rudolf Virchow described a logical classification
frontal bossing consistent with craniosynostosis of deformities resulting from monosutural fusion.
[4, 5]. In the Iliad, Homer, who is thought to have According to Virchow’s law, expansion of the cra-
lived around the 8th century BCE, though the ex- nial vault is restricted in a direction perpendicu-
act date is controversial, described Thersites, a lar to the fused suture, while compensatory over-
soldier in the Greek army during the Trojan war, growth occurs along the fused suture [9]. Virchow
as having a ‘pointed head,’ which may have been coined the related term ‘craniostenosis’, which im-
a reference to oxycephaly, a condition resulting plicates the potentially harmful effect that growth
from craniosynostosis of the lambdoid, sagittal, restriction due to craniosynostosis can have on
and coronal sutures. Thersites’ odd behavior is brain function. Later, the Austrian radiologist
sometimes attributed to neurocognitive impair- Arthur Schüller confined the term to intracra-
ment secondary to severe craniosynostosis. Busts nial hypertension resulting from craniosynosto-
of the renowned Athenian politician Pericles, sis [10]. Of note, in his 1851 study, Virchow did
who led Athens during the city’s Golden Age in not clearly separate microcephaly due to primary
the 5th century BCE, show features consistent osseous growth failure from deficient brain bulk
with sagittal synostosis, and he was described as growth (micrencephaly) resulting in secondary
‘handsome. . .but with the head enormously long.’ sutural fusion, which remains a critical distinc-
Indeed, the great general was typically depicted tion both in terms of diagnosis and treatment (see
wearing a helmet, presumably to hide the shape the discussion below on aspects of management)
of his skull. Pericles was a brilliant polymath in [9].
many respects, and many individuals with isolat-
ed types of craniosynostosis have unaffected cog-
nitive development even without the availability Syndromic Craniosynostosis and Genetic
of surgical treatment [6]. Discoveries
Early systematic descriptions of craniosynos-
tosis appear in the writings of Hippocrates, who Like craniosynostosis more generally, syndromic
around the 4th century BCE described cranial su- craniosynostosis also has a complex and fascinat-
tures as they relate to a broad spectrum of head ing history. Many of these syndromes were first
shapes. Several centuries later, at the turn of the clinically defined in Europe in the first half of the
millennia, the Roman encylcopedist Cornelius 20th century. However, it was not until the end of
Celsus described skulls with absent sutures [5]. the century that the precise molecular causes were
Much later, in the 1500s, the Brussels-born physi- unearthed, largely within a few years in the 1990s
cian and anatomist Andreas Vesalius, who spent during a period in which emerging technology al-
his professional career in Italy, outlined a variety of lowed for rapid discovery of the genetic causes of
skull deformities characteristic of craniosynostosis most Mendelian disorders. As several chapters in

2 Solomon · Collmann · Kress · Muenke

 Fig. 1. Drawing of a child (approximately 18 months of age) with Apert
syndrome, by Max Brödel, 1920. Brödel, who was trained in Germany, was
brought to the Johns Hopkins School of Medicine in the United States in the
1890s in order to work with clinicians such as William Halsted, Howard Kelly,
and Harvey Cushing, and is considered by some to be the father of modern
medical illustration. Original art is #506 and #507 in the Walters Collection of
the Max Brödel Archives in the Department of Art as Applied to Medicine, The
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

this book demonstrate, there remains active and early illustration of a child with Apert syndrome).
healthy debate on both clinical and molecular defi- Almost exactly 100 years after Wheaton’s descrip-
nitions related to syndromic craniosynostosis (see tion, in 1995, Wilkie et al. used a positional can-
Chapters 7 and 11 in this volume). While this his- didate gene approach to show that the genetic ba-
torical introduction is not intended to exhaustive- sis of the syndrome was due to specific mutations
ly describe the history of every aspect and type of in FGFR2 [14].
craniosynostosis, a discussion of the discovery of In 1912, Louis Edouard Octave Crouzon, a
a number of craniosynostosis-related syndromes French neurologist who specialized in heredi-
is nonetheless valuable and informative. tary neurological diseases such as spinocerebel-
First, in 1906, Eugène Charles Apert, a French lar ataxia, described a mother and her young son
pediatrician, described a child affected with ac- who both exhibited features of the syndrome that
rocephaly and syndactyly of the hands and feet would take his name. After the initial description,
[11]. (On a related but unfortunate side note, Crouzon remained engaged with this entity and
Apert was a vocal proponent of eugenics and eu- added several other studies to his first description
thanasia, and in fact was a founding member and [15]. As with many other craniosynostosis syn-
later secretary general of the French Society of dromes, linkage analysis established that FGFR2
Eugenics [12]). Apert noted that 8 similar cas- was the gene associated with this condition [16].
es had already been reported, one of them by The history of Saethre-Chotzen syndrome
Wheaton in 1894 [13]. Apert termed the condi- is especially interesting, both in terms of the
tion acrocephalosyndactyly [11] (see fig. 1 for an presentation of the patients and in terms of

Craniosynostosis History 3
the eponymous physicians. Haakon Saethre, a to his decision to pursue a career in genetics. In
Norwegian neurologist and psychiatrist, and Fritz 1991, Max Muenke, after whom Muenke syn-
Chotzen, a German psychiatrist, independent- drome is named, visited this family in their small
ly described patients with hereditary turriceph- Westphalian hometown (which is very close to his
aly associated with additional minor abnormali- own childhood home) in order to obtain the nec-
ties [17, 18]. In 1930, Saethre saw a 32-year-old essary samples for linkage. Linkage analysis and
woman, who had been admitted to the psychiatric sequencing of candidate genes led to the determi-
department of Oslo because of a catatonic crisis. nation that Pfeiffer syndrome was due to muta-
He noticed characteristic craniofacial and limb tions in FGFR1 and FGFR2 [21–24]. Interestingly,
features, as well as signs of intracranial hyperten- the mutation in the original Pfeiffer syndrome
sion. Her mother and sister were similarly affect- family, described years later, was in an unusual
ed, suggesting autosomal dominant inheritance. location in FGFR2 [25].
In the same study, he reported another adult Finally, Muenke syndrome offers an example
woman who appeared to be similarly affected. In of a craniosynostosis syndrome that was first de-
1932, Chotzen reported a father and his 2 sons fined molecularly, rather than clinically. Muenke
with similar findings. Chotzen also noted signs syndrome, which is due to a specific mutation in
of elevated intracranial pressure in 2 members of FGFR3, was established when in a number of kin-
this family. Chotzen categorized this family along dreds who were previously clinically diagnosed
with the acrocephalosyndactylies, emphasizing a with Pfeiffer syndrome, the disease was shown
commonality with Apert syndrome and Crouzon to be linked to markers on chromosome 4 and to
cranio-facial dysostosis. The molecular cause of segregate with a common mutation in FGFR3 [26,
Saethre-Chotzen syndrome was defined by both 27].
cytogenetic mapping and linkage analysis, in con- The case of Muenke syndrome highlights ten-
trast to other syndromic forms of craniosynosto- sions within the field of genetics between histor-
sis. While the first cytogenetic clues emerged in ic clinical diagnoses and more recent molecular
the 1970s, mutations in TWIST were shown to be definitions. Only within the last few decades has
causative only in 1997 [19, 20]. the latter become possible for the vast majority
Saethre-Chotzen syndrome particularly car- of Mendelian disorders, and even now, there are
ries the stigma of German political history. Fritz many syndromic forms of craniosynostosis whose
Chotzen, the chairman of the Breslau hospital for etiologies remain unknown (see Chapter 11 in
nervous diseases, was Jewish. In 1933, he was ex- this volume). Continued advances in genomic
pelled from his position by the Nazis, and died in research will certainly accelerate the process of
1937 at age 66. In Norway, Saethre was kept hos- molecular definitions, but careful clinical dissec-
tage and shot by German occupiers in February tions remain critical to understanding of the dis-
1945, only a few short months before the end of ease, and must continue in a fashion coupled to
WWII, in reprisal for an attack on a police officer purely genetic knowledge. Indeed, the lesson of
by the Norwegian resistance movement. the discovery of Muenke syndrome is that thor-
It was not until 1964 that Rudolf Pfeiffer, a con- ough clinical and molecular investigations must
temporary German geneticist, described 8 mem- proceed together in order to advance our under-
bers of a family who were affected with acro- standing of rare diseases.
cephaly and striking first digit anomalies. Pfeiffer Overall, the FGFR-associated craniosynostoses
saw the first member of this family, an affected are a prime example of current trends in ‘molecular
child, during his pediatric residency in Münster, medicine’, which allow clinicians and researchers
Germany, and this experience at least contributed a glimpse of the future of genetic medicine. Using

4 Solomon · Collmann · Kress · Muenke

molecular medicine, clinical problems might be on your hands and sins on your souls. No ocean
addressed on the molecular and even the atomic of soap and water will clean those hands. . .’ [2, 31,
level. The highly complex and likely redundant 32]. Thereafter, surgery on craniosynostosis was
network of signal transduction pathways con- abandoned for nearly two decades.
trolling growth, differentiation, demarcation and Today, neurosurgery (in cooperation with
apoptosis of cells in the sutures is only partly un- maxillofacial or plastic surgery) is a mainstay of
derstood. However, crystallographic data makes treatment, though the optimal technique contin-
use of atomic information in order to explore how ues to evolve and remain controversial at times.
differences in hydrogen bridges affect receptor sta- An important related consideration has been the
bilization and ligand binding. This type of data has ability to assess for the presence of elevated in-
been used to clarify how specific phenotypes may tracranial pressure (ICP) and to precisely define
result from specific atomic changes, as in the case the involved sutures (see Chapter 18 for a more
of FGFR2 and Apert syndrome (see Chapter 5 in in-depth analysis of these issues). Naturally, these
this volume for detailed discussion). Further, the techniques are intimately connected with treat-
observation that the same signal transduction cas- ment approaches. In the patients they first de-
cades are important both in embryologic develop- scribed, both Saethre and Chotzen were able to as-
ment and later on in life (for example, in cancer) has sess intracranial hypertension via ophthalmologic
led to fascinating hypotheses, such as the idea that examination and by detecting signs on plain ra-
cancer therapies designed to impede a certain sig- diographs. At this time, elevated ICP was evident
naling cascade might also be used in the treatment only in its more advanced stages. Improvements
of birth defects [28]. The future will undoubtedly in ophthalmologic instruments allow for the abil-
bring many exciting developments in this field. ity to detect earlier and less obvious degrees of
elevated ICP, as does the ability to perform in-
tracranial pressure monitoring. In addition, the
History of Treatment Aspects of widespread availability of more sophisticated
Craniosynostosis neuroimaging techniques, including plain radio-
graphs, ultrasonography, computerized tomogra-
The first attempts to surgically treat craniosynos- phy, and magnetic resonance imaging, allows for
tosis were performed on microcephalic children better detection. As discussed by Collmann et al.
with deficient brain bulk growth [29, 30]. In these (Chapter 18 this volume), all or any of these tech-
cases, the mortality was extremely high. Since niques may be useful in a given scenario, and it
the problem of micrencephaly was well known is up to the clinicians’ expertise to select the ap-
at that time, surgical enthusiasm soon met with propriate modality. Finally, the value of dedicat-
harsh criticism. The most famous voice was that ed teams of professionals and dedicated services
of Abraham Jacoby, a New York pediatrician, who to care for affected patients cannot be overstated.
at the American Annual Meeting in 1893 accused These services include intensive care units famil-
the surgeons with the following declaration: ‘The iar with caring for patients in the postoperative pe-
hands take too frequently the place of brains. . . Is riod, diverse craniofacial and neurosurgical teams
it sufficient glory to let daylight into a deformed who are capable and willing to manage a wide va-
cranium and on top of a hopelessly defective brain, riety of needs, ranging from genetic counseling to
and to proclaim a success because a victim con- precise neurosurgical techniques, and laboratory-
sented not to die of the assault?. . . Such rash feats based researchers dedicated to dissecting the pre-
of indiscriminate surgery, if continued, moreover cise pathogenetic mechanisms in order to design
in the presence of 14 deaths in 33 cases, are stains molecularly-derived treatments.

Craniosynostosis History 5
Concluding Remarks and accompanying severe facial deformities who
lived half-a-million years ago, underscores the
From human ancestors and relatives living long most important lesson that can be taken from
before recorded history to cutting-edge research- this dramatic and fascinating disease: we must
ers using the most precise instruments avail- strive to care for the less fortunate to the extent
able in the modern laboratory setting, count- of our collective abilities.
less aspects of craniosynostosis provide a view
on many facets of the human condition. In the
last few decades, new treatment and diagnostic Acknowledgements
modalities allow a dramatically improved under-
This work was supported in part by the Division of
standing of the condition. Further, the progno-
Intramural Research, National Human Genome Research
sis for affected individuals continues to improve. Institute, National Institutes of Health, Department of
Still, the story of the earliest known affected pa- Health and Human Services, United States of America.
tient, a child with lambdoid craniosynostosis

References
1 Gracia A, Arsuaga JL, Martínez I, 9 Virchow R: Über den Cretinismus, 17 Saethre H: Ein Beitrag zum Turmschä-
Lorenzo C, Carretero JM, Bermúdez de namentlich in Franken, und über delproblem (Pathogenese, Erblichkeit
Castro JM, Carbonell E: Craniosynosto- pathologische Schädelformen. Verhandl und Symptomatologie). Dtsch Z Nerven-
sis in the Middle Pleistocene human Phys Med Ges Würzburg 1851;2:230– heilk 1931;117:533–555.
Cranium 14 from the Sima de los Hue- 270. 18 Chotzen F: Eine eigenartige familiäre
sos, Atapuerca, Spain. Proc Natl Acad Sci 10 Schüller A: Craniostenosis. Radiology Entwicklungsstörung (Akrocephalosyn-
USA 2009;106:6573–6578. 1929;13:377–382. daktylie, Dysostosis craniofacialis und
2 Goodrich JT, Tutino M: An annotated 11 Apert E: De l’acrocéphalosyndactylie. Hypertelorismus). Monatsschr Kinder-
history of craniofacial surgery and inten- Bull Soc Méd Paris 1906;23:1310–1330. heilk 1932;55:97–122.
tional cranial deformation. Neurosurg 12 Strous RD, Edelman MC: Eponyms and 19 el Ghouzzi V, Le Merrer M, Perrin-
Clin N Am 2001;12:45–68. the Nazi era: time to remember and time Schmitt F, Lajeunie E, Benit P, et al:
3 Braverman IM, Redford DB, Mackowiak for change. Isr Med Assoc J 2007;9:207– Mutations of the TWIST gene in the
PA: Akhenaten and the strange phy- 214. Saethre-Chotzen syndrome. Nat Genet
siques of Egypt’s 18th dynasty. Ann 13 Wheaton SW: Two specimens of congen- 1997;15:42–46.
Intern Med 2009;150:556–560. ital cranial deformity in infants associ- 20 Howard TD, Paznekas WA, Green ED,
4 Wang HS, Kuo MF: Nan-ji-xian-weng: ated with fusion of the fingers and toes. Chiang LC, Ma N, et al: Mutations in
the god of longevity. Childs Nerv Syst Trans Path Soc London 1894;45:238– TWIST, a basic helix-loop-helix tran-
2010;26:1–2. 241. scription factor, in Saethre-Chotzen syn-
5 Cohen MM Jr: History, terminology, and 14 Wilkie AO, Slaney SF, Oldridge M, Poole drome. Nat Genet 1997;15:36–41.
classifications of craniosynostosis, in MD, Ashworth GJ, et al: Apert syndrome 21 Muenke M, Schell U, Hehr A, Robin NH,
Cohen MM Jr, MacLean RE (eds): Cran- results from localized mutations of Losken HW, et al: A common mutation
iosynostosis: Diagnosis, Evaluation, and FGFR2 and is allelic with Crouzon syn- in the fibroblast growth factor receptor 1
Management, ch 9, pp 103–111 (Oxford drome. Nat Genet 1995;9:165–172. gene in Pfeiffer syndrome. Nat Genet
University Press, New York, Oxford 15 Crouzon O: Dysostose cranio-faciale 1994;8:269–274.
2000). héréditaire. Bull Soc Méd Paris 1912;33: 22 Lajeunie E, Ma HW, Bonaventure J,
6 Di Rocco C: Craniosynostosis in old 545–555. Munnich A, Le Merrer M, Renier D:
Greece: political power and physical 16 Jabs EW, Li X, Scott AF, Meyers G, Chen FGFR2 mutations in Pfeiffer syndrome.
deformity. Childs Nerv Syst 2005;21:859. W, et al: Jackson-Weiss and Crouzon Nat Genet 1995;9:108.
7 Vesalius A: De humanis corporis fabrica syndromes are allelic with mutations in 23 Rutland P, Pulleyn LJ, Reardon W,
(Oporinus, Basel 1543). fibroblast growth factor receptor 2. Nat Baraitser M, Hayward R, et al: Identical
8 Sömmering ST: Vom Baue des menschli- Genet 1994;8:275–279. Erratum in: Nat mutations in the FGFR2 gene cause
chen Körpers. Erster Teil: Knochenlehre Genet 1995;9:451. both Pfeiffer and Crouzon syndrome
(Warentrapp & Brenner, Frankfurt/M phenotypes. Nat Genet 1995;9:173–176.
1791).

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24 Schell U, Hehr A, Feldman GJ, Robin 26 Bellus GA, Gaudenz K, Zackai EH, 29 Lane LC: Pioneer craniectomy for relief
NH, Zackai EH, et al: Mutations in Clarke LA, Szabo J, Francomano CA, of imbecillity due to premature sutural
FGFR1 and FGFR2 cause familial and Muenke M: Identical mutations in three closure and microcephalus. JAMA
sporadic Pfeiffer syndrome. Hum Mol different fibroblast growth factor recep- 1892;18:49–50.
Genet 1995;4:323–328. tor genes in autosomal dominant cranio- 30 Lannelongue O: De la craniectomie dans
25 Kan SH, Elanko N, Johnson D, Cornejo- synostosis syndromes. Nat Genet la microcéphalie. L’Union Medicale
Roldan L, Cook J, et al: Genomic screen- 1996;14:174–176. 1890;50:42–45.
ing of fibroblast growth-factor receptor 2 27 Muenke M, Gripp KW, McDonald- 31 Jacobi A: Nil nocere. Med Report
reveals a wide spectrum of mutations in McGinn DM, Gaudenz K, Whitaker LA, 1894;45:609–618.
patients with syndromic craniosynosto- et al: A unique point mutation in the 32 Fisher RG: Surgery of the congenital
sis. Am J Hum Genet 2002;70:472–486. fibroblast growth factor receptor 3 gene anomalies, in Walker AE (ed): A history
(FGFR3) defines a new craniosynostosis of neurological surgery, pp 334–361
syndrome. Am J Hum Genet (Hafner, New York 1967).
1997;60:555–564.
28 Wilkie AO: Cancer drugs to treat birth
defects. Nat Genet 2007;39:1057–1059.

Maximilian Muenke
NIH, MSC 3717
Building 35, Room 1B-203
Bethesda, MD, 20892–3717 (USA)
Tel. +1 301 402 8167, Fax +1 301 496 7184, E-Mail [email protected]

Craniosynostosis History 7
Chapter 2
Muenke M, Kress W, Collmann H, Solomon BD (eds): Craniosynostoses: Molecular Genetics, Principles of Diagnosis, and Treatment.
Monogr Hum Genet. Basel, Karger, 2011, vol 19, pp 8–12

Discovery of MSX2 Mutation in Craniosynostosis:

A Retrospective View
U. Müller
Institut für Humangenetik, Justus-Liebig-Universität, Gießen, Germany

Abstract family. Together with Matt Warman, then a fellow

This is a historical review of the discovery of the first muta- in medical genetics, and John B. Mulliken, profes-
tion detected in autosomal dominant craniosynostosis. sor of craniofacial surgery at Children’s hospital, I
The mutation was found in one large family in whom
craniosynostosis segregated as an autosomal dominant
decided to study the genetic basis of the disorder
trait. Craniosynostosis in this family was highly variable in this family. The three of us contacted the fam-
and could present as frontal recession, turribrachyceph- ily, who was excited to participate in an investi-
aly, frontal bossing, or clover-leaf malformation. Cranio- gation and invited us to what they called a ‘DNA
synostosis is the only or main sign in this syndrome, now party’ at their home. This gave us an opportunity
referred to as craniosynostosis, Boston type, based on the
to clinically examine all affected family members
location of its discovery. A gain-of-function mutation was
identified in the gene MSX2 in this disorder. The mutation from 3 generations (fig. 1). The phenotype varied
results in replacement of an evolutionarily highly con- dramatically in affected persons (fig. 2). While the
served proline within the homeodomain of the gene by grandmother was affected only slightly, mainly
a histidine (p.Pro148His). The causative role of the muta- displaying fronto-orbital recession and absence of
tion in craniosynostosis was borne out in transgenic midface hypoplasia, persons in subsequent gen-
mice. To date affected members of the Boston family
are the only ones in whom a mutation in MSX2 has been
erations were more severely affected. Their find-
shown to cause craniosynostosis. ings included frontal bossing, turribrachycephaly,
Copyright © 2011 S. Karger AG, Basel and clover-leaf anomaly. Seven affected mem-
bers of the family required surgical intervention.
Three had turribrachycephaly, 2 clover-leaf skulls,
Family Identification 1 fronto-orbital recession, and 1 frontal bossing.
Figure 3 shows the radiograph of a severely affect-
A patient with a clinically undescribed form of ed patient with turribrachycephaly, who later un-
craniosynostosis was presented at medical ge- derwent surgery. Almost all affected individuals
netics rounds at Children’s Hospital in Boston in had myopia or hyperopia and 2 had tunnel vision
1991. The family history revealed many affected and visual field loss. In addition, several patients
members in several generations, consistent with suffered from severe headaches and 4 had seizures.
autosomal dominant inheritance of the trait in this A triphalangeal thumb was found in 1 individual
 I
RF

II
TB TB RF RF TB RF TB RF RF

III
TB RF TB CL CL FB RF TB FB

Fig. 1. Pedigree of the Boston family. CL, clover-leaf skull; FB, frontal bossing; RF, fronto-orbital recession; TB,
turribrachycephaly.

B D

Fig. 2. Phenotypic spectrum in affected members of the Boston family. A Fronto-orbital recession and absence of
midface hypoplasia. B Frontal bossing. Lateral photograph shows markedly retropositioned supraorbital rims without
midface retrusion. C Turribrachycephaly as the result of pancraniosynostosis. Lateral photograph shows retrusion of
the supraorbital rims in presence of normal midface position. D Clover-leaf skull. The malformation is still apparent de-
spite coronal, lambdoidal and temporal craniectomies were performed during infancy (from [1, 2]).

MSX2 and Craniosynostosis 9

Fig. 3. Frontal (left) and lateral
(right) radiograph of a patient from
the Boston family, demonstrating
signs of turribrachycephaly. Note
bony extensions between frontal
and middle lobes (frontal view) and
frontal and supraorbital retrusion,
short cranial base, platybasia, and
marked convolutional impressions
on the endocranial surface (lateral
view) (from [1]).

and radiographs revealed short first metatarsals in at the Institute for Genetic Medicine of the Kenneth
3 out of 4 patients examined. Taken together, limb R. Norris Cancer Hospital, Los Angeles, had cloned
involvement was very mild if present at all in this the human homologue of the mouse Msx2 gene and
mainly ‘pure’ form of craniosynostosis [1]. assigned it to the distal long arm of human chro-
mosome 5. MSX2, composed of 2 exons separat-
ed by a large intron, is a member of the vertebrate
Discovery of the Causative Mutation Msx family of homeobox genes that were origi-
nally identified on the basis of their homology to
DNA was available from 23 members of the fam- the Drosophila gene Msh (muscle segment homeo-
ily. In order to chromosomally assign the disease box gene) (summarized in [3]). The chromosom-
locus by linkage analysis, I joined Jim Weber’s al location of MSX2 and its function in epithelial-
lab in Marshfield Wisconsin for several weeks in mesenchymal interactions made it a good candidate
1992. Jim had established a panel of short tan- gene for craniosynostosis, Boston type. In collabo-
dem repeat polymorphic (STRP) markers that ration with the Baltimore/Los Angeles groups, we
allowed investigation of the entire genome. At identified a C-A transversion at nucleotide 64 in
this time STRPs were amplified in the presence exon 2 of MSX2. This mutation results in an amino
of a radiolabeled nucleotide (α-32P-dCTP) and acid change from proline (Pro, encoded by CCC)
investigated by autoradiography after gel elec- to histidine (His, encoded by CAC) at position 7
trophoretic separation. Time to perform a whole of the homeodomain of MSX2 (p.Pro148His) and
genome scan was dramatically abbreviated by segregated with the disorder in the family.
finding highly significant linkage to the first
marker tested (Mfd 154 at locus D5S211). With
a maximum logarithm of the odds (LOD) score Functional Analyses of the Mutation
(Zmax) of 4.82 at zero recombination (θ = 0.00)
the craniosynostosis locus was assigned to the Proline has been highly conserved during evolu-
distal long arm of chromosome 5 in this Boston tion and occurs at a position that has been invari-
family [2]. ant in Msx homeodomains of numerous phyla
At the same time, Ethlyn Jabs at Johns Hopkins for approximately 600 million years [4]. These
Medical School in Baltimore and Robert Maxson, observations together with expression of Msx2 in

10 Müller
 A B

Fig. 4. A Skull of a 1-day-old normal mouse. B Skull of a 1-day-old transgenic animal expressing the mouse counterpart
of the human p.Pro148His mutation in the Msx2 gene. Skulls were stained with alcian blue to demonstrate cartilage
(blue) and with alizarin red S to reveal mineralized bone (red). Note complete occlusion of coronal and sagittal sutures
and partial closure of lambdoid suture in the transgenic animal (Photograph kindly provided by Dr. R.E. Maxson; see
also [5]). als, lambdoid suture; cs, coronal suture; ms = metopic suture; ss = sagittal suture.

membranous bone of the calvaria and in adjacent Conclusion

mesenchymal cells in the mouse convincingly
suggested that the MSX2 mutation causes cran- MSX2 was the first gene found to be associated
iosynostosis, Boston type [4]. A role of the MSX2 with autosomal dominant craniosynostosis in the
(p.Pro148His) mutation was borne out in trans- absence of gross limb deformities. Ironically, no
genic mice. Both, overexpression of human MSX2 additional families with craniosynostosis and an
in mice and introduction of the murine counter- MSX2 mutation have been identified to date. It
part of the p.Pro148His mutation, result in cran- appears that only the specific mutation at posi-
iosynostosis [5, 6]. Figure 4 depicts the skull of tion 7 of the homeodomain of MSX2 found in the
a normal mouse and of a transgenic animal with Boston family results in increased binding, over-
synostosis of the coronal and sagittal suture and stimulation of target sequences, and eventually in
partial occlusion of the lambdoid suture. craniosynostosis. Other mutations might not have
The mutation increases the affinity of Msx2 such an effect. Interestingly, haploinsufficiency of
for its target sequence without interfering with MSX2 causes the opposite of craniosynostosis, i.e.
site specificity of Msx2 binding. In comparison to parietal foramina (delayed ossification along the
wild-type Msx2, gel shift analysis revealed drasti- sagittal sutures) [9, 10].
cally enhanced binding of p.Pro148His Msx2 to a
sequence containing the consensus Msx binding
site, TAATTG [7]. This suggests that the domi- Acknowledgement
nant mutation acts by a gain-of-function mecha-
The enthusiastic participation of the Boston family in the
nism by overstimulating Msx2 target sequences.
work reported is highly appreciated.
Interestingly, some patients with partial trisomy of
the long arm of chromosome 5 have craniosynos-
tosis [8]. This may thus be caused by the increased
dosage of MSX2 expected in these patients.

MSX2 and Craniosynostosis 11

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