Noonan Syndrome and Related Disorders - A Matter of Deregulated Ras Signaling

178 Pages·2008·3.122 MB·English

by  Martin Zenker

Noonan Syndrome and Related Disorders
A Matter of Deregulated Ras Signaling
Monographs in Human Genetics
Vol. 17
Series Editor
Michael Schmid
Würzburg
Noonan Syndrome and
Related Disorders –
A Matter of Deregulated
Ras Signaling
Volume Editor
Martin Zenker
Erlangen
25 figures, 17 in color, and 16 tables, 2009
Basel · Freiburg · Paris · London · New York · Bangalore ·
Bangkok · Shanghai · Singapore · Tokyo · Sydney
Martin Zenker
Institute of Human Genetics
University Hospital Erlangen
University of Erlangen–Nuremberg
Schwabachanlage 10
D–91054 Erlangen
Library of Congress Cataloging-in-Publication Data
Noonan syndrome and related disorders : a matter of deregulated ras
signalling / volume editor, Martin Zenker.
p. ; cm. -- (Monographs in human genetics, ISSN 0077-0876 ; v. 17)
Includes bibliographical references and indexes.
ISBN 978-3-8055-8653-5 (alk. paper)
1. Genetic disorders. 2. Ras oncogenes. 3. Ras proteins. I. Zenker,
Martin. II. Series.
[DNLM: 1. Noonan Syndrome--genetics. 2. Noonan
Syndrome--physiopathology. 3. Signal Transduction. 4. ras
Proteins--genetics. W1 MO567P v.17 2009 / WD 375 N817 2009]
RB155.5.N66 2009
616(cid:2).042--dc22
2008035626
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ISSN 0077–0876
ISBN 978–3–8055–8653–5
e-ISBN 978–3–8055–8654–2
Contents
VII Editorial
Schmid, M. (Würzburg)
IX Preface
Zenker, M. (Erlangen)
1 History of Noonan Syndrome and Related Disorders
Noonan, J.A. (Lexington, Ky.)
9 The Clinical Phenotype of Noonan Syndrome
Allanson, J.E. (Ottawa)
20 Molecular Genetics of Noonan Syndrome
Tartaglia, M. (Rome); Gelb, B.D. (New York, N.Y.)
40 Genotype-Phenotype Correlations in Noonan Syndrome
Sarkozy, A.; Digilio, M.C.; Marino, B.; Dallapiccola, B. (Rome)
55 LEOPARD Syndrome: Clinical Aspects and Molecular Pathogenesis
Sarkozy, A.; Digilio, M.C.; Zampino, G.; Dallapiccola, B.; Tartaglia, M. (Rome); Gelb, B.D. (New York, N.Y.)
66 The Clinical Phenotype of Cardiofaciocutaneous Syndrome (CFC)
Roberts, A.E. (Boston, Mass.)
73 Molecular Causes of the Cardio-Facio-Cutaneous Syndrome
Tidyman, W.E.; Rauen, K.A. (San Francisco, Calif.)
83 The Clinical Phenotype of Costello Syndrome
Kerr, B. (Manchester)
94 The Molecular Basis of Costello Syndrome
Sol-Church, K.; Gripp, K.W. (Wilmington, Del.)
104 Endocrine Regulation of Growth and Short Stature in Noonan Syndrome
Binder, G. (Tübingen)
109 The Heart in Ras-MAPK Pathway Disorders
Digilio, M.C.; Marino, B.; Sarkozy, A.; Versacci, P.; Dallapiccola, B. (Rome)
119 Myeloproliferative Disease and Cancer in Persons with Noonan
Syndrome and Related Disorders
Kratz, C. (Freiburg)
128 Neurofibromatosis Type 1-Noonan Syndrome: What’s the Link?
Denayer, E.; Legius, E. (Leuven)
138 Animal Models for Noonan Syndrome and Related Disorders
Araki, T.; Neel, B.G. (Toronto, Ont.)
151 Towards a Treatment for RAS-MAPK Pathway Disorders
Joshi, V.A.; Roberts, A.E.; Kucherlapati, R. (Boston, Mass.)
165 Author Index
166 Subject Index
VI Contents
Editorial
This volume 17 of Monographs in Human Genetics is an in-depth discourse on the disorders of the
Ras-MAPK pathway (Noonan-, cardio-facio-cutaneous-, Costello-, and LEOPARD syndromes). Like
the two preceding volumes of this book series, it deals with important hereditary diseases with high
clinical impact, and whose molecular causes have been unravelled in recent years. Noonan syndrome
belongs to one of the most frequent monogenic disorders occurring in approximately one in 1,000 to
2,500 children and therefore has significant importance in public health genomics. Molecular analyses
have led to the surprising result that all four syndromes can be traced back to specific mutations in
genes coding for molecules that interact in the Ras-MAPK pathway. This exciting discovery does not
only permit the precise diagnosis of the diseases, but also clears promising ways for potential therapies
in the future.
Martin Zenker, the Editor of the present volume, succeeded in bringing together the leading experts
working on these diseases and received their contributions in a very short space of time. The articles
treat both the clinical and molecular data exhaustively and give the reader a very timely update and out-
line of these related disorders. I thank Martin Zenker and all the authors for their time and effort to ren-
der possible the publication of this book. Furthermore, I gratefully acknowledge the constant
promotion of this book series by Thomas Karger.
Michael Schmid
Würzburg, August 2008

Preface
Noonan syndrome (NS), which is recognized as one of the most common monogenic disorders, was
defined as a separate entity by Jacqueline Noonan in 1968. Thirty-three years later, the first gene for
NS was identified by Marco Tartaglia and colleagues. Their discovery represented the spark for a series
of new gene discoveries eventually showing that mutations that alter the function of molecules inter-
acting in a common signalling cascade, the Ras-MAPK pathway, are responsible for NS and the clini-
cally related disorders cardio-facio-cutaneous syndrome (CFCS), LEOPARD syndrome (LS), and
Costello syndrome (CS). Together, these findings unexpectedly related this group of disorders to a sig-
nalling pathway which was previously known for its involvement in tumorigenesis. Thereby, the asso-
ciation of certain types of malignancies and tumor-like lesions with NS, LS, CFCS, and particularly CS
has been elucidated. Vice versa, studies on the significance of somatic mutations in the same genes in
sporadic tumors have been stimulated and yielded exciting new findings. Notably, the genes mutated
in Neurofibromatosis 1 and a newly defined Neurofibromatosis 1-like phenotype encode negative reg-
ulators of the same pathway. Thus, the known clinical relations between all these conditions have
become intelligible through the achievements of molecular research.
The Editor of this volume of Monographs in Human Genetics greatly acknowledges the contribu-
tions of excellent experts in the field. Their comprehensive reviews provide most updated data on the
various clinical and molecular aspects of known disorders of the Ras-MAPK pathway. Jacqueline
Noonan herself is giving an historical overview in the first chapter. The book ends with a chapter on
current and possible future treatment options for this group of disorders. Together the contributions
to this volume nicely show the close relationship between clinical issues and molecular research and
the mutual benefit for people working in either of these fields. It is of note that the previously estab-
lished clinical entities are strongly correlated with certain mutated genes or – in the case of LS – spe-
cific functional consequences of certain mutations. The proposed term neuro-cardio-facial-cutaneous
syndromes for all disorders caused by germline mutations in components of the Ras-MAPK pathway
may be useful as a superordinate, but currently there is no need to replace the established nosology,
which is also used in this book.
The content of this volume certainly does not represent a story that has been completed, but it is much
more than a progress report. The chase for genes for NS and related disorders seems to have reached a
IX