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  • CRANIOSYNOSTOSIS:

    CLINICAL AND FUNDAMENTAL ASPECTS

    CRANIOSYNOSTOSE:

    KLINISCHE EN FUNDAMENTELE ASPEKTEN

    PROEFSCHRIFT

    TER VERKRIJGING V AN DE GRAAD V AN DOCTOR AAN DE

    ERASMUS UNIVERSITEIT ROTTERDAM OP GEZAG VAN DE

    RECTOR MAGNIFICUS

    PROF.DR.IR. J.H. VAN BEMMEL

    EN VOLGENS BESLUIT V AN HET COLLEGE VOOR

    PROMOTIES

    DE OPENBARE VERDEDIGING ZAL PLAATSVINDEN OP

    WOENSDAG 25 OKTOBER 2000 OM 9.45 UUR

    DOOR

    IRENE MARGREET JACQUELINE MATHIJSSEN

    GEBOREN TE BREDA

  • PROMOTIECOMMISSIE

    PROMOTOR:

    OVERIGE LEDEN:

    COPROMOTOR:

    PROF.DR. S.E.R. ROVIUS

    PROF.DR. B.A. OOSTRA

    PROF.DR. D. TIBBOEL

    PROF.DR. A.O.M. WILKIE

    DR. CRR. VERMEIJ-KEERS

    This study has been financially supported by an AGIKO grant from NWO

    (AGI 920.03.011, 1996) and a grant from "Het Van Leersumfonds" from KNA W

    (5510702,1998).

    Additional sponsoring by Esser Stichting, Jnamedical, Mediprof, Nederlandse

    Vereniging voor Plastische Chirurgie, Stopler, and Carl Zeiss B.V.

    Printed by Wyt Document Services, Rotterdam.

    ISBN 90-76580-06-5.

    All rights reserved. This book is protected by copyright. No part of this book may

    be reproduced in any form or by any means, including photocopying, or utilized by

    any information storage and retrieval system without written permission from the

    copyright owner.

  • CONTENTS

    page

    I. Introduction 5

    I.1. Historical and clinical perspectives on craniosynostosis 5

    Defmition, classification, and incidence 5

    Diagnosis and treatment 13

    Literature overview on pathogenesis 17

    1.2. Genetic background of syndromic craniosynostosis 21

    Genes and craniosynostosis 21

    FGFRI mutations 24

    FGFR2 mutations 25

    FGFR3 mutations 29

    TWIST mutations 31

    Expression and function of FGFRs and TWIST

    during skull development 41

    1.3. Aim of this study 45

    n. Morphologic study ofthe human calvaria in craniosynostosis 65

    11.1. The role of bone centers in the pathogenesis of

    craniosynostosis: An embryologic approach using

    CT measurements in isolated craniosynostosis and

    Apert and Crouzon syndromes. 67

  • 11.2. Tracing craniosynostosis to its developmental stage

    through bone center displacement. 79

    m. Histologic study of the developing murine coronal suture: Normal and abnormal 89

    IlL I. Apoptotic cell death during normal embryogenesis of

    the coronal suture: Early detection of apoptosis in mice

    using Annexin V. 91

    III.2. Simultaneous induction of apoptosis, collagen type I

    expression and mineralization in the developing

    coronal suture following FGF4 and FGF2 application. 99

    IV. FGFR-mutations and their phenotypes 129

    IV. I. Pfeiffer syndrome resulting from a Ser351 Cys mutation

    in the fibroblast growth factor receptor-2 gene. 131

    IV.2. Additional phenotypic features of the FGFRJ

    Pr0250Arg mutation in two Dutch families. 137

    V. General discussion 157

    VI. Summary 173

    VII. Samenvatting 177

  • Publications used in this thesis 183

    Publications related to this thesis 185

    Other publications 187

    Curriculum vitae 188

  • I. INTRODUCTION

    Prior to the discovery of the genetic background of craniosynostosis,

    its classification was purely based on clinical features. This

    classification system did however have its pitfalls which became more

    obvious after comparing it with the detected genetic mutations.

    Because this classification has been the basis for clinical practice for

    years and still is applied world wide, this chapter will begin by giving

    a historical and clinical view on craniosynostosis before discussing the

    genetic aspects.

    1.1. Historical and clinical perspectives on craniosynostosis

    Definition, classification, and incidence

    Craniosynostosis is generally defined as the premature (pre- or

    postnatally) closure of one or more cranial suture(s). This condition

    can arise primarily as a congenital malformation, and secondary to

    certain metabolic disorders (e.g., hyperthyroidism, rickets, and

    mucopolysaccharidoses), hematological disorders (e.g., thalassemia,

    sickle cell anemia, and polycythemia vera), holoprosencephaly, and

    microcephaly, or have iatrogenic origin such as following ventricular

    shunting. The focus ofthis thesis is on congenital craniosynostosis.

    Figure la depicts the cranial sutures. The sutures are the sites at which

    the skull can expand to accommodate itself to the enlarging brain.

    Growth takes place in the direction perpendicular to the suture. For

    example, the coronal sutures allow the skull to grow in the

    5

  • anteroposterior direction, while the sagittal sutnre offers the potential

    to expand in the bilateral direction. Most volume expansion of the

    skull occurs in utero and within the fIrst two years of life, although

    most sutures do not ossify before adulthood. OssifIcation of the

    coronal suture, for instance, starts at about 24 years of age (Kokich,

    1986).

    metopic suture

    anterior fontanelle coronal suture --II" .~~¥

    sagittal suture --1fI{----;

    posterior fontanelle ~~_

    lan~bdoid suture

    Figure I a. The cranial sutnres as seen from a birds' eye view.

    Premature closure of a sutnre will cause the cessation of growth

    within the associated direction. Subsequently, compensatory growth is

    observed in the remaining sutnres. If the coronal sutures were to be

    synostotic, insuffIcient growth in the anteroposterior direction would

    occur and additional growth takes place at the non-affected sutures,

    thus resulting in a broad skull with reduced anteroposterior

    dimensions. Figure I b illustrates the associated skull confIgurations

    for each synostotic suture and the commonly applied nomenclatnre.

    6

  • Although the lambdoid sutures can be synostotic too, this is a very

    rare condition (Huang et ai., 1996). Most patients presenting with a

    flattened occiput do not suffer from craniosynostosis. This

    dysmorphology appears to be induced by the commonly advised

    supine position for neonates to sleep in, and seems to reflect a

    molding effect rather than an intrinsic abnormality of the lambdoid

    suture. The most severe skull deformity in syndromic craniosynostosis

    is the cloverleaf skull, referring to the image seen on X-ray (fig. lc).

    This is often a life-threatening condition due to respiratory failure. In

    most cases, all cranial suture have fused.

    F'klgi1x:~pl:rnly !)X:[pwlll plagi~balr

    Figure lb. The associated skull configurations resulting from specific synostotic sutures and the commonly applied nomenclature.

    7

  • Figure 1c. X-ray of a patient with a cloverleaf skull. In anteroposterior direction the skull has the shape of the three leaves of a clover, formed by the bulging temporal bones bilaterally. The lateral view shows impressiones digitatae, suggestive of increased intracranial pressure.

    One of the major distinctions that is made in craniosynostosis is

    whether or not this anomaly arises solitarily, i.e. isolated, or combined

    with other congenital malformations, constituting a craniosynostosis

    syndrome. Sagittal suture synostosis or scaphocephaly represents the

    most common isolated form of craniosynostosis with a male: female

    ratio of3.5:1, showing the male predominance (Lajeunie et aI., 1996).

    Very rarely, familial cases with 2 or more affected scaphocephalic

    members occur (Hunter and Rudd, 1976; Berant and Berant, 1973;

    Lajeunie et aI., 1996). In 1996, a new designated autosomal dominant

    craniosynostosis syndrome was suggested, being the Philadelphia

    8

  • type, which is characterized by sagittal synostosis and soft tissue

    syndactyly of the fingers and toes (Robin et ai., 1996).

    Isolated synostosis of either the metopic suture, i.e., trigonocephaly,

    or one or both coronal sutures, i.e., plagiocephaly or brachycephaly

    respectively, does occur but one needs to rule out an underlying

    syndrome (chapter 1.2). Analysis of a series of 237 patients with

    trigonocephaly resulted in 184 cases with an isolated synostosis and

    53 cases with a syndromic form (Lajeunie et ai., 1998). Of these 53,

    13 concerned well-delineated syndromes, while the remaining 40

    couldn't be assigned to any of the known syndromes. As with isolated

    sagittal suture synostosis, an increased incidence of twinning (7.8 %,

    both monozygotic and dizygotic) was observed, up to about three

    times higher compared to the normal population (Lajeunie et ai.,

    1998). Of the monozygotic twins two were concordant and three were

    disconcordant for synostosis.

    In craniosynostosis syndromes, the coronal sutures are usually

    affected and the most commonly associated malformations involve the

    upper and lower extremities. Limb abnormalities