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Epstein’s Inborn Errors of Development
 OXFORD MONOGRAPHS ON MEDICAL GENETICS

GENERAL EDITORS:
JUDITH G. HALL
PETER S. HARPER
LOUANNE HUDGKINS
EVAN EICHLER
CHARLES J. EPSTEIN (DECEASED 2011)
ARNO G. MOTULSKY (RESIGNED 2011)

1. R. B. McConnell: The genetics of gastrointestinal 29. R. J. M. Gardner and G. R. Sutherland: Chromosomes

disorders
2. A. C. Kopéc: The distribution of the blood groups in the
United Kingdom
3. E. Slater and V. A. Cowie: The genetics of mental
disorders
4. C. O. Carter and T. J. Fairbank: the genetics of locomotor
disorders
5. A. E. Mourant, A. C. Kopéc, and K. Domaniewska-​
Sobezak: The distribution of the human blood groups and
other polymorphisms
6. A. E. Mourant, A. C. Kopéc, and K. Domaniewska-​
Sobezak: Blood groups and diseases
7. A. G. Steinbert and C. E. Cook: The distribution of the
human immunoglobulin allotypes
8. D. Tills, A. C. Kopéc, and R. E. Tills The distribution
of the human blood groups and other polymorphisms:
Supplement I
10. D. Z. Loesch: Quantitative dermatoglyphics: classifica-
tion, genetics, and pathology
11. D. J. Bond and A. C. Chandley: Aneuploidy
12. P. F. Benson and A. H. Fensom: Genetic biochemical
disorders
13. G. R. Sutherland and F. Hecht: Fragile sites on human
chromosomes
14. M. d’A Crawfurd: The genetics of renal tract disorders
16. C. R. Scriver and B. Child: Garrod’s inborn factors in
disease
18. M. Baraitser: The genetics of neurological disorders
19. R. J. Gorlin, M. M. Cohen, Jr. and L. S. Levin: Syndromes
of the head and neck, third edition
21. D. Warburton, J. Byrne, and N. Canki: Chromosome
anomalies and prenatal development: an atlas
22. J. J. Nora, K. Berg, and A. H. Nora: Cardiovascular
disease: genetics, epidemiology, and prevention
24. A. E. H. Emery: Duchenne muscular dystrophy, second
edition
25. E. G. D. Tuddenham and D. N. Cooper: The molecular
genetics of haemostasis and its inherited disorders
26. A. Boué: Foetal medicine
27. R. E. Stevenson, J. G. Hall, and R. M. Goodman: Human
malformations
28. R. J. Gorlin, H. V. Toriello, and M. M. Cohen, Jr.:
Hereditary hearing loss and its syndromes
abnormalities and genetic counseling, second edition
30. A. S. Teebi and T. I. Farag: Genetic disorders among
Arab populations
31. M. M. Cohen, Jr.: The child with multiple birth defects
32. W. W. Weber: Pharmacogenetics
33. V. P. Sybert: Genetic skin disorders
34. M. Baraitser: Genetics of neurological disorders, third
edition
35. H. Ostrer: Non-​Mendelian genetics in humans
36. E. Traboulsi: Genetic factors in human disease
37. G. L. Semenza: Transcription factors and human disease
38. L. Pinsky, R. P. Erickson, and R. N. Schimke: Genetic
disorders of human sexual development
39. R. E. Stevenson, C. E. Schwartz, and R. J. Schroer: X-​
linked mental retardation
40. M. J. Khoury, W. Burke, and E. & Thomson: Genetics
and public health in the 21st century
41. J. Weil: Psychosocial genetic counseling
42. R. J. Gorlin, M. M. Cohen, Jr., and R. C. M. Hennekam:
Syndromes of the head and neck, fourth edition
43. M. M. Cohen, Jr., G. Neri, and R. Weksberg: Overgrowth
syndromes
44. R. A. King, J. I. Rotter, and A. G. Motulsky: & e genetic
basis of common diseases, second edition
45. G. P. Bates, P. S. Harper, and L. Jones: Huntington’s
disease, third edition
46. R. J. M. Gardner and G. R. Sutherland: Chromosome
abnormalities and genetic counseling, third edition
47. I. J. Holt: Genetics of mitochondrial disease
48. F. Flinter, E. Maher, and A. Saggar-​Malik: & e genetics of
renal disease
49. C. J. Epstein, R. P. Erickson, and A. Wynshaw-​
Boris: Inborn errors of development: the molecular basis
of clinical disorders of morphogenesis
50. H. V. Toriello, W. Reardon, and R. J. Gorlin: Hereditary
hearing loss and its syndromes, second edition
51. P. S. Harper: Landmarks in medical genetics
52. R. E. Stevenson and J. G. Hall: Human malformations
and related anomalies, second edition
53. D. Kumar and S. D. Weatherall: Genomics and clinical
medicine
54. C. J. Epstein, R. P. Erickson, and A. Wynshaw-​Boris:
Inborn errors of development: the molecular basis of
clinical disorders of morphogenesis, second edition
55. W. Weber: Pharmacogenetics, second edition
56. P. L. Beales, I. S. Farooqi, and S. O’Rahilly: The genetics
of obesity syndromes
57. P. S. Harper: A short history of medical genetics
58. R. C. M. Hennekam, I. D. Krantz, and J. E. Allanson:
Gorlin’s syndromes of the head and neck, fifth edition
59. D. Kumar and P. Elliot: Principles and practices of car-
diovascular genetics
60. V. P. Sybert: Genetic skin disorders, second edition
61. R. J. M. Gardner, G. R. Sutherland, and L. C. Shaffer:
Chromosome abnormalities and genetic counseling,
fourth edition
62. D. Kumar: Genomics and health in the developing world
63. G. Bates, S. Tabrizi, L. Jones: Huntington’s Disease,
fourth edition
64. B. Lee, F. Scaglia: Inborn errors of Metabolism: from
neonatal screening to metabolic pathways
65. D. Kumar, C. Eng: Genomic Medicine, second edition
66. R. Stevenson, J. Hall, D. Everman, B. Solomon: Human
Malformations and Related Anomalies, third edition
67. R. Erickson and A. Wynshaw-​Boris: Epstein’s inborn
errors of development: the molecular basis of clinical dis-
orders of morphogenesis, third edition
In memory of Charles J. Epstein, MD
 EDITORIAL BOARD

Han Brunner, MD, PHD

Department of Human Genetics
Radboud University Nijmegen Medical Center

Michael J. Gambello, MD, PHD

Division of Medical Genetics
Emory University School of Medicine

Ophir Klein, MD, PHD

Departments of Orofacial Sciences and Pediatrics
Institute for Human Genetics and Regeneration Medicine
UCSF Helen Diller Family Comprehensive Cancer Center

Julie R. Korenberg, PHD, MD

Center for Integrated Neuroscience and Human Behavior
The Brain Institute Department of Pediatrics University of Utah

Ian Krantz, MD
Division of Human Genetics
The Children’s Hospital of Philadelphia

Michael Lovett, PHD

Faculty of Medicine
National Heart and Lung Institute

Katherine A. Rauen, MD, PHD

Genomic Medicine Division
UCSF Helen Diller Family Comprehensive Cancer Center

Val C. Sheffield, MD, PHD

Department of Pediatrics
Howard Hughes Medical Institute

Joseph Shieh, MD, PHD

Division of Medical Genetics
Department of Pediatrics
Institute for Human Genetics
University of California San Francisco

Anne Slavotinek, MD, PHD

Department of Pediatrics
University of California, San Francisco
EPSTEIN’S INBORN ERRORS
OF DEVELOPMENT
The Molecular Basis of Clinical
Disorders of Morphogenesis
Third Edition

Edited by

Robert P. Erickson
Anthony J. Wynshaw-​Boris

1
1
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Library of Congress Cataloging-in-Publication Data

Inborn errors of development.
Epstein’s inborn errors of development : the molecular basis of clinical disorders of morphogenesis / edited by Robert P. Erickson,
Anthony J. Wynshaw-Boris.—Third edition.
p. ; cm.
Preceded by: Inborn errors of development / edited by Charles J. Epstein, Robert P. Erickson, Anthony Wynshaw-Boris. 2nd ed. 2008.
Includes bibliographical references and index.
ISBN 978–0–19–993452–2
I. Erickson, Robert P., 1939– , editor. II. Wynshaw-Boris, Anthony Joseph, editor. III. Title.
[DNLM: 1. Genetic Diseases, Inborn—genetics. 2. Congenital Abnormalities—genetics. 3. Morphogenesis—genetics. QZ 50]
RB155.5
616′.042—dc23
2015025320

9 8 7 6 5 4 3 2 1
Printed by Sheridan Books, Inc., United States of America
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ix
Preface to the Third Edition

Charlie J. Epstein (Charlie), a founding co-​editor of Inborn Errors of Development, passed away on
February 15, 2011. With his passing we lost a good friend and outstanding colleague. The facts of his life
and career have been well summarized elsewhere (Wynshaw-​Boris et al., 2011). We would like to add some
more personal reminisces here. One of us, Robert P. Erickson (RPE), first met Charlie in in 1967 in Christian
B. Anfinsen’s lab at the National Institutes of Health while interviewing for a research associate position.
Although Charlie was leaving for the University of California, San Francisco (UCSF), Dr. Anfinsene inter-
viewed him as a potential fellow/​junior faculty for his new Division of Pediatric Genetics there. Charlie and
he had a conversation about early mouse development and the t-​alleles, with which both were fascinated.
Not surprisingly, RPE was an easy recruit and later became Charlie’s first fellow.
Those early years at UCSF (in the early 1970s) were exciting for both basic research and clinical efforts.
Charlie timed X-​inactivation in the early mouse embryo by careful G6PD dosage studies (Epstein, 1972),
which presaged his human chromosome 21 dosage studies. Charlie’s lab’s techniques helped RPE start
studies on t-​allele–​induced alterations in early embryo metabolism (Erickson et al., 1974). An extensive
satellite genetics program was developed, which became a model for many such programs (Epstein et al.,
1975). Early research fellows were Horst Spielmann, MD, now a major leader in European Community
toxicology, and Franco Mangia, PhD, currently Professor of Neuroscience at La Sapienza University in
Rome. Soon to follow were Edward Schneider, PhD, who became a major figure in aging research, and
Peter Tischfield, PhD, who has been a major contributor to human genetics. The spirit of cooperation and
intellectual exchange was high.
Clinics were run in a much more leisurely fashion than is now possible. All families scheduled for clinic
visit had a family history taken in advance by a genetics counselor, preferably by a home visit but, if that
was not possible, by telephone. On clinic day, the fellow or faculty member then spent an initial hour with
the family, taking medical histories of all affected members and examining them. Then the family was left
alone (they had been well warned of this gap) while cases were presented at a clinical conference for an
hour, with brief visits to each family to check details of physical examinations. After the hour’s discussion,
the best diagnoses or lack of them and decisions on what to counsel were made. Then the physician and
counselor (if available, since there were fewer counselors than physicians) returned to the room for an hour
of counseling. This was always followed by a letter to the referring physician, usually with recent references
to the medical genetics literature and a counseling letter to the family.
Charlie remained a towering figure in human genetics, but in spite of this stature he was always interested
in and supportive of younger geneticists. At one of Anthony Wynshaw-​Boris’s (AWB’s) first American
Society for Human Genetics meetings, Charlie came up to a group of trainees, including AWB, and wanted
to know what they found interesting and what they were working on. From that day on, Charlie was a men-
tor, then colleague and friend, even though AWB never trained with him. When Charlie retired, he could not
be replaced, but it was AWB’s great honor and good fortune to be asked to become the Charles J. Epstein
Professor of Human Genetics and Pediatrics as well as the Chief of the Division of Medical Genetics at
UCSF School of Medicine, which Charlie founded and ran until his retirement.
With Charlie’s death, we remaining “editors-​in chief” faced a dilemma. Since there has been a large
increase in the number of dysmorphology syndromes for which the gene has been cloned (going from 84
clinical chapters in the first edition of this book to 144 in the second edition and an anticipated 207 in this
edition), it has become impossible to have only 2 editors for the book. Thus, a group of senior editors, many

xi
xii Preface to the Third Edition
of them past associates of Charlie’s, have been recruited to help. We have also had to severely limit the
length of the clinical chapters, placing much material online, so as to keep the book in one printed volume.
In this we are following the trend of many journals that post less essential data online as supplements.
We again thank the excellent staff of Oxford University Press, especially Chad Zimmerman, for their
great help in bringing this edition to fruition. RPE and AWB wish to thank their best friends and life’s com-
panions, Sandra and Diane, for their loving support during this and all their other efforts.
Contents

Contributors xxvii

I. G E N E RA L CO N C EPTS
1. Human Malformations and Their Genetic Basis 3
Charles J. Epstein
2. Principles of Differentiation and Morphogenesis 9
Scott F. Gilbert and Ritva Rice
3. Model Organisms in the Study of Development and Disease 23
Ethan Bier and William Mcginnis
4. Human Genomics and Human Development 41
Robert Nussbaum

II. PAT T E RN S OF D EV EL O PM ENT

5. Development of Left-​Right Asymmetry 49
Hiroshi Hamada
6. Neural Crest Formation and Craniofacial Development 57
Kurt A. Engleka and Jonathan A. Epstein
7. Development of the Nervous System 63
John L. R. Rubenstein and Luis Puelles
8. Development of the Eye 77
David C. Beebe
9. Development of the Ear 85
Donna M. Fekete
10. Molecular Regulation of Cardiogenesis 107
Deepak Srivastava and Joseph T. C. Shieh
11. Update on the Development of the Vascular System and Its Sporadic Disorders 113
M. Michael Cohen Jr.
12. Muscle and Somite Development 121
Douglas M. Anderson and Alan Rawls

xiii
xiv CONTENTS
13. The Development of Bone and Cartilage 131
Shunichi Murakami, Haruhiko Akiyama, and Benoit De Crombrugghe
14. Limb Development 147
Malte Spielmann and Sigmar Stricker
15. The Sex-​Determination Pathway 161
Peter J. Ellis and Robert P. Erickson
16. Development of the Kidney 171
Kevin T. Bush, Mita M. Shah, Dylan L. Steer, Derina E. Sweeney, and Sanjay K. Nigam
17. Development of the Endodermal Derivatives in Lung, Liver, Pancreas, and Gut 189
Ben Z. Stanger
18. Development of Epidermal Appendages: Teeth and Hair 205
Atsushi Ohazama and Paul T. Sharpe

III. D E F IN E D C O R E D EV EL O PM ENTA L PATHWAY S L I NK ED TO C I LI A

A: Ciliary Functions: Genesis, Transport, and Reabsorbtion
19. Primary Ciliary Dyskinesia (Kartagener Syndrome) 221
Michal Witt and Zuzanna Bukowy-​Bieryłło
20. The Molecular Basis of Joubert Syndrome and Related Disorders 229
Jeong Ho Lee and Joseph G. Gleeson
21. The Bardet-​Biedl Syndrome 237
Val C. Sheffield, Qihong Zhang, Elise Heon, Arlene V. Drack, Edwin M. Stone,
and Rivka Carmi
22. The Molecular Basis of Oral-​Facial-​Digital Type I Syndrome 241
Brunella Franco
23. Meckel Syndrome 249
Amanda Leightner and Peter C. Harris
24. From Hydrolethalus to Acrocallosal Syndromes: A Spectrum of Disorders
Linked to the KIF7 Gene 255
Férechté Encha Razavi and Tania Attie-​Bitach
25. Sensenbrenner Syndrome (Cranioectodermal Dysplasia, CED): A Genetically
Heterogeneous Ciliopathy 259
Joanna Walczak-​Sztulpa and Anna Latos-​Bielenska
26. MKKS and the McKusick-​Kaufman and Bardet-​Biedl Syndromes 265
Leslie G. Biesecker

B: The Sonic Hedgehog Signaling Pathway

27. The Hedgehog Signaling Network 269
M. Michael Cohen Jr.
28. Smith-​Lemli-​Opitz Syndrome 279
Wen-​Hann Tan and Mira B. Irons
29. SHH and Holoprosencephaly 287
Khosrow S. Houschyar, Andrew A. Smith, and Jill A. Helms
30. IHH, Acrocapitofemoral Dysplasia, and Brachydactyly A1 293
Jan Hellemans and Geert R. Mortier
31. PTCH and the Basal Cell Nevus (Gorlin) Syndrome 297
Ervin Epstein Jr
32. GLI3 and the Pallister–​Hall and Greig Cephalopolysyndactyly Syndromes 303
Leslie G. Biesecker
 CONTENTS xv
33. SALL1 and the Townes-​Brocks Syndrome 309
Jürgen Kohlhase
34. MYCN and Feingold Syndrome 315
Hans Van Bokhoven and Han G. Brunner
35. Preaxial Polydactyly Type 2 and Associated Limb Defects 319
Robert Hill and Laura Lettice

C: The Wnt Signaling Pathway

36. The Wnt Signaling Pathway 323
Benjamin N. R. Cheyette and Kimberly A. Mulligan
37. AXIN2, Tooth Agenesis, and Colorectal Cancer 331
Pekka Nieminen, Laura Lammi, and Heikki J. Järvinen
38. WNT3 and Tetra-​Amelia 335
Stephan Niemann
39. ROR2, Brachydactyly Type B, and Recessive Robinow Syndrome 341
Andrew O. M. Wilkie
40. Cenani-​Lenz Syndrome 345
Nina Bögershausen and Bernd Wollnik
41. Goltz Syndrome (Focal Dermal Hypoplasia) 349
Ignatia B. Van Den Veyver and V. Reid Sutton
42. WNT10A and Odonto-​Onycho-​Dermal Dysplasia 355
Hala Mégarbané and André Mégarbané
43. Al-​Awadi-​Raas-​Rothschild Syndrome/​Fuhrmann Syndrome 359
Geoff Woods
44. AXIN1 and Caudal Duplication Anomaly 363
Christine R. Zhang and Suyinn Chong

D: T H E P L A N A R CE L L P OL A R I TY (PC P) PATH WAY

45. Role of Planar Cell Polarity Genes VANGL1 and VANGL2 in Neural Tube Formation
and Neural Tube Defects 365
Elena Torban, Alexandra Iliescu, and Philippe Gros

IV. OT HE R D E F IN E D CORE D E V EL O PM EN TA L PATHWAY S

A: The TGF-​β Signaling Pathway
46. An Introduction to TGF-​β Family Signaling 373
Jacqueline Nguyen and Tamara Alliston
47. NOG and Proximal Symphalangism (SYM1), Multiple Synostosis (SYN1),
Tarsal-​Carpal Coalition, and Isolated Stapes Ankylosis 381
Stefan Mundlos
48. NODAL Signaling and Heterotaxy 385
Stephanie M. Ware and John W. Belmont
49. ENG, ACVRL1, SMAD4, and Hereditary Hemorrhagic Telangiectasia
(Osler-​Weber-​Rendu Syndrome) 393
Sudha Srinivasan, Jonathan N. Berg, and Douglas A. Marchuk
50. RUNX2 and Cleidocranial Dysplasia 401
Lindsay C. Burrage, Yangjin Bae, Brendan H. Lee, and Dobrawa Napierala
51. AMH/​MIS and Its Receptors: The Persistent Müllerian Duct Syndrome 407
Jean-​Yves Picard
xvi CONTENTS
52. LEMD3 and Osteopoikilosis, the Buschke-​Ollendorff Syndrome and Melorheostosis 411
Jan Hellemans and Geert R. Mortier
53. TGFBR 1/​2 and Loeys-​Dietz Syndrome 417
Bart L. Loeys and Harry C. Dietz
54. ZEB2 and Mowat-​Wilson Syndrome 425
Meredith Wilson, Irina Giurgea, and David Mowat
55. LTBP4 and Autosomal Recessive Cutis Laxa Type IC 431
Zsolt Urban
56. ACVR1 and Fibrodysplasia Ossificans Progressiva 435
Frederick S. Kaplan, O. W. Towler, and Eileen M. Shore
57. The Role of the Latent TGF- β Binding Protein 3, LTBP3, in Tooth, Spine,
and Bone Density Abnormalities 439
Muhammad Ayub, Abdul Noor, and John B. Vincent

B : TH E TN F S I GNAL I NG PATH WAY

58. Signaling by TNF and Related Ligands 443
Pascal Schneider
59. The Ectodysplasin Signaling Pathway in Hypohidrotic Ectodermal Dysplasias 451
Jonathan Zonana and Kenneth Huttner

C : THE F G F S I GNAL I NG PATHWAY

60. Molecular and Cellular Biology of FGF Signaling 457
Jacob V. P. Eswarakumar
61. FGF Receptor Mutations: Bone Dysplasia, Craniosynostosis, and Other Syndromes 469
Andrew O. M. Wilkie
62. FGF10, FGFR2, and FGFR3 and the Lacrimo-​Auriculo-​Dental-​Digital (LADD) Syndrome 477
Jeff M. Milunsky
63. TWIST1 and the Saethre-​Chotzen Syndrome 479
64. FGFR1, FGF8, PROKR2, PROK2, ANOS1, and the Olfactogenital
(Kallmann) Syndrome 485
Jean-​Pierre Hardelin and Catherine Dodé
65. TIE2 (TEK) and Venous Malformation 493
Nisha Limaye, Melanie Uebelhoer, Laurence M. Boon, John B. Mulliken,
and Miikka Vikkula
66. FLT4 (VEGFR3) and Milroy Disease 497
Robert E. Ferrell, David N. Finegold, and Catherine J. Baty
67. Focal Facial Dermal Dysplasias 501
Anne M. Slavotinek, Beom Hee Lee, and Robert J. Desnick

D : G L IA CEL L – ​D ER I V ED N EU R O TR O PHI C FA C TO R S I G NALI NG

68. Signaling Pathways of Glial Cell–​Derived Neurotrophic Factor 507
Louis Reichardt
69. RET Mutation and Function in HSCR, MEN2, and Other Cancers 517
Sumantra Chatterjee, Zachary E. Stine, Andrew S. Mccallion, and Aravinda Chakravarti
 CONTENTS xvii
E : IN T ROD U CT ION T O E N D O TH EL I N -​B R EC EPTO R
A N D S OX 1 0 PATHWAY S
70. Introduction to Endothelin-​B Receptor and SOX10 Pathways 525
Monalee Saha and Cheryl E. Gariepy
71. EDNRB, EDN3, SOX10, and the Shah-​Waardenburg Syndrome (WS4) 531
Joke B. G. M. Verheij and Robert M. W. Hofstra

F : T H E N OT CH S IG N A L I N G PATHWAY
72. Introduction to Notch Signaling 537
Alison Miyamoto and Gerry Weinmaster
73. JAG1 and NOTCH2 and the Alagille Syndrome 553
Nancy B. Spinner, Laura D. Leonard, Alexandra M. Falsey, and Ian D. Krantz
74. DLL3, MESP2, LFNG, HES7, TBX6, RIPPLY2 and Spondylocostal Dysostosis 559
Peter D. Turnpenny, Kenro Kusumi, and Sally L. Dunwoodie

G : T H E P I3 K - L​ KB 1 PATH WAY
75. The PI3K-​LKB1 Pathway 571
Reuben J. Shaw and Lewis C. Cantley
76. PTEN and Cowden and Bannayan-​Riley-​Ruvalcaba Syndromes 577
Pauline Funchain and Charis Eng
77. STK11 (LKB1) and Peutz-​Jeghers Syndrome 583
Stylianos E. Antonarakis
78. TSC1, TSC2, and Tuberous Sclerosis 587
David J. Kwiatkowski

H : T H E RA S /​E RK/​M A PK PATHWAY

79. The RAS Pathway 597
Jeffrey Swensen and David Viskochil
80. Neurofibromatosis Type 1 605
Heather Riordan and David H. Gutmann
81. Noonan Syndrome and RAS Signaling Defects 611
Marco Tartaglia and Bruce D. Gelb
82. HRAS and Costello Syndrome 623
Yoko Aoki and Yoichi Matsubara
83. The Ras/​MAPK Pathway and the Cardio-​Facio-​Cutaneous Syndrome 629
Katherine A. Rauen
84. RASA1 and Capillary Malformation–​Arteriovenous Malformation 633
Nicole Revencu, Laurence M. Boon, John B. Mulliken, and Miikka Vikkula
85. SPRED1 and Legius Syndrome 639
Hilde Brems, Ludwine Messiaen, and Eric Legius

I: E P H /​E P H RIN S I GNAL I NG

86. Introduction to Eph/​Ephrin Signaling in Vertebrate Development 643
Audrey K. O’Neill and Jeffrey O. Bush
xviii CONTENTS
87. Craniofrontonasal Syndrome and EFNB1 Mutations 651
Peter Wieacker and Judit Horvath

V. T RA N S C R I PTI O N FAC TO R S AND C H R O M ATI N R EGUL AT O R S

A: The Homeobox Gene Family
88. The Role of Hox and Dlx Gene Clusters in Evolution and Development 659
Frank H. Ruddle
89. HOXA1 Deficiency Syndrome 663
Max A. Tischfield, Robert P. Erickson, and Elizabeth C. Engle
90. HOXA11 and Amegakaryocytic Thrombocytopenia With Radioulnar Synostosis 673
Amy E. Geddis
91. HOXA13 Hand-​Foot-​Genital Syndrome and Guttmacher Syndrome 675
Jeffrey W. Innis
92. HOXD10 Mutations Associated With Congenital Vertical Talus and Pes Cavus
Claw-Toe Limb Abnormalities 681
Antony E. Shrimpton and E. Mark Levinsohn
93. HOXD13 and Synpolydactyly 687
Frances R. Goodman and Peter J. Scambler
94. EMX2, HESX1, Type I Schizencephaly, and Septo-​Optic Dysplasia 693
Daniel Kelberman and Mehul T. Dattani
95. PDX1, Pancreatic Agenesis, and Type 2 Diabetes 699
Melissa K. Thomas and Joel F. Habener
96. MSX1, Hypodontia, Orofacial Clefting, and the Witkop Syndrome 703
Marie-​José H. Van Den Boogaard and Hans-​Kristian Ploos Van Amstel
97. MSX2 in Craniosynostosis and Defects of Skull Ossification 707
Mamoru Ishii, Robert Maxson, and Ulrich Muller
98. SHOX, Dyschondrosteosis, and Turner Syndrome 711
Jay W. Ellison
99. HLXB9 (MNX1), Sacral Agenesis, and the Currarino Syndrome 715
Stephen Scherer, Giuseppe Martucciello, Margherita Lerone, and Elena Belloni
100. Branchio-​Oto-​Renal (BOR) Syndrome 721
Fowzan S. Alkuraya and Richard L. Maas
101. PITX2 and PITX3: Axenfeld-​Rieger Syndrome, Anterior Segment Dysgenesis,
Posterior Polar Congenital Cataract (CPP4), and Microphthalmia with Neurological
Impairment 727
Linda M. Reis and Elena V. Semina
102. NKX2-​5 and Congenital Heart Disease 733
Avihu Z. Gazit, Susan N. Foerster, and Patrick Y. Jay
103. LMX1B and the Nail-​Patella Syndrome 741
Philippe M. Campeau, Nadejda A. Bespalova, and Brendan H. Lee
104. The ALX Homeobox Gene Family and Frontonasal Dysplasias 747
Arda Cetinkaya and Nurten A. Akarsu
105. Simplex and Complex Microphthalmia Genes—​OTX2, RAX, VSX2, VAX1, SIX6,
and HMX1 753
Anne M. Slavotinek
106. PRRX1 757
Joy Samanich and Elaine Pereira
 CONTENTS xix
107. Developmental Abnormalities Due to Mutations in the Aristaless-​Related
Homeobox Gene 761
Cheryl Shoubridge, Michael Field, Richard J. Leventer, and Jozef Gecz
108. PITX1-​Associated Congenital Lower Limb Malformations 767
Christina A. Gurnett and Matthew B. Dobbs

B: The Paired Box (PAX) Gene Family

109. The Paired Box (PAX) Gene Family: Introduction to Paired​Box Genes 771
Cherie Stayner, Caiyun G. Li, Petros P. Petrou, Peter Gruss, and Michael R. Eccles
110. PAX2 and the Renal-​Coloboma Syndrome 777
Michael R. Eccles, Matthew Bower, and Lisa A. Schimmenti
111. PAX3 and Waardenburg Syndrome Type 1 781
Kirby A. Ziegler, Gareth N. Corry, and D. Alan Underhill
112. PAX6, Aniridia, and Related Phenotypes 785
Veronica Van Heyningen and Kathleen Williamson
113. PAX9 and Hypodontia 791
Pragna I. Patel and Donald T. Brown

C: The Forkhead Gene Family

114. Introduction to Forkhead Genes 797
Naoyuki Miura
115. FOXC1, FOXL2, the Axenfeld–​Rieger Syndrome, and the Blepharophimosis, Ptosis,
and Epicanthus Inversus Syndrome 801
Fred B. Berry and Michael A. Walter
116. FOXC2, FOXF1, and the 16q24.1-​Region Microdeletions: Lymphatic, Vascular,
Cardiac, and Other Phenotypes 807
Robert P. Erickson
117. FOXE1: Bamforth-​Lazarus Syndrome, Thyroid Dysgenesis, and Thyroid Cancer
Predisposition 813
Masaru Katoh, Masuko Katoh, Mireille Castanet, Aurore Carré, and Michel Polak
118. AGGF1 and Vascular Disease: Klippel-​Trenaunay Syndrome 817
Qiuyun Chen, Mohammad Reza Amini, and Qing Kenneth Wang

D: The T-​Box Gene Family

119. Introduction to the T-​Box Genes: Their Evolution and Roles in Development 821
Virginia E. Papaioannou and Sarah N. Goldin
120. The 22q11.2 Deletion Syndrome and TBX1 827
Bernice E. Morrow, Donna M. Mcdonald-​Mcginn, and Beverly S. Emanuel
121. TBX3, TBX5, and the Ulnar-​Mammary and Holt-​Oram Syndromes 833
Michael J. Bamshad and Lynn B. Jorde
122. TBX22, X-​linked Cleft Palate, and Ankyloglossia 839
Erwin Pauws and Philip Stanier

E : T H E S OX G E NE FA M I LY
123. Sox Genes in Development and Disease 843
Peter Koopman
xx CONTENTS
124. SOX2 and Malformations of the Eye, Brain, Foregut, and Male Genital Tract 849
David R. Fitzpatrick
125. SOX3 and Infundibular Hypoplasia 855
Kyriaki S. Alatzoglou, Daniel Kelberman, and Mehul T. Dattani
126. SOX9, Campomelic Dysplasia, and Sex Reversal 861
Sahar Mansour
127. SOX18 and the Hypotrichosis-​Lymphedema-​Telangiectasia Syndrome 867
Pascal Brouillard, Koen Devriendt, and Miikka Vikkula

F : TR A NS C R I PTI O N FAC TO R S
128. MITF and the Waardenburg Type II and Albinism-​Deafness (Tietz) Syndromes 871
Lina Naga and Thomas J. Hornyak
129. POU3F4 and Mixed Deafness With Temporal Bone Defect (DFNX2) 875
Hannie Kremer, Cor W. R. J. Cremers, Erwin Van Wijk, and Frans P. M. Cremers
130. Char and Branchio-​Oculo-​Facial Syndromes: The AP-​2 Transcription Factor Defects 881
Matthew Bock and Bruce D. Gelb
131. GATA3, Hypoparathryoidism, Deafness, and Renal Disease 889
R. V. Thakker
132. FOG-​2 (now ZFPM2), GATA-​4, Congenital Heart Disease, and Diaphragmatic Hernia 895
Anne M. Slavotinek
133. PTF1A: Pancreatic and Cerebellar Agenesis 899
Jayne A. L. Houghton and Andrew T. Hattersley
134. RAI1, Smith-​Magenis Syndrome, and Potocki-​Lupski Syndrome 905
Melanie Lacaria, Weimin Bi, and James R. Lupski
135. SALL4 and the Duane Radial-​Ray/​Okihiro and Acro-​Renal-​Ocular Syndromes 915
Jürgen Kohlhase, Rosa Barrio, and James D. Sutherland
136. HNF1B-​MODY: A Disorder of Development With Diabetes and Congenital
Malformations in the Pancreas and Urogenital Tract Due to Mutations in HNF1B 921
Oddmund Søvik, Jørn V. Sagen, Ingfrid S. Haldorsen, Erling Tjora, and Pål R. Njølstad
137. ZIC1, ZIC4, and FOXC1 in Dandy-​Walker Malformation 927
Kathleen J. Millen
138. MED12 and Opitz-​Kaveggia Syndrome 931
Michael J. Lyons
139. Börjeson-​Forssman-​Lehmann Syndrome and PHF6 935
Mark A. Corbett, Matthew Hunter, and Jozef Gecz

G : R EGUL ATI O N O F C HR O M ATI N S TR U C TU R E

A ND G EN E EX PR ES S I O N
140. Mechanisms of Regulated Gene Transcription 941
Robert B. Weiss, Kristen Jepsen, Valentina Perissi, Victoria Lunyak,
Michael G. Rosenfeld, and Christopher K. Glass
141. CBP (CREBBP), the Rubinstein-​Taybi Syndrome, and the 16p13.3 Duplication Syndrome 947
Fred Petrij and Dorien J. M. Peters
142. ATRX, X-​Linked α-​Thalassemia Mental Retardation 957
Richard J. Gibbons, Takahito Wada, and Christopher A. Fisher
143. IGF2, H19, CDKNIC, KCNQ1OT1, and the Beckwith-​Wiedemann Syndrome 965
Marcel Mannens, I. Karen Temple, and Frederic Brioude
 CONTENTS xxi
144. Prader-╉Willi Syndrome 971
Shawn E. Mccandless and Suzanne B. Cassidy
145. Genetic and Clinical Heterogeneity in Immunodeficiency-╉Centromeric
Instability-╉Facial Anomalies Syndrome 979
Silvère Van Der Maarel and Corry Weemaes
146. RSK2 and the Coffin-╉Lowry Syndrome 983
Anne Schneider, Jean-╉Pierre Delaunoy, and André Hanauer
147. The BCL6 Corepressor (BCOR) and Oculofaciocardiodental Syndrome 989
Emma Hilton, Graeme C. M. Black, and Vivian Bardwell
148. CHD7 and CHARGE Syndrome 995
Donna M. Martin and Conny M. A. Van Ravenswaaij ╉Arts
149. Carboxy-╉Terminal Domain Phosphatase 1: Congenital Cataracts-╉Facial
Dysmorphism-╉Neuropathy Syndrome 1001
Luba Kalaydjieva, Teodora Chamova, and Rebecca Gooding
150. ESCO2 and Roberts Syndrome 1005
Hugo Vega, Miriam Gordillo, and Ethylin Wang Jabs
151. MS. 173/╉Pathways—╉Cohesinopathies 1009
Yaning Wu, Matthew A. Deardorff, and Ian D. Krantz
152. NSD1 and Sotos Syndrome 1015
Remco Visser and Naomichi Matsumoto
153. Kabuki Syndrome 1021
Margaret P. Adam and Louanne Hudgins
154. SETBP1 and Schinzel-╉Giedion Syndrome 1025
Kenichi Yoshida, Bregje W. M. Van Bon, and Seishi Ogawa
155. HDAC4 and 2q37 Deletion Syndrome 1029
Trang Le and Sarah Elsea
156. Warsaw Breakage Syndrome 1033
Johan P. De Winter

VI.╇ CE L L U L A R P ROCE S S E S AND D Y NAM I C S

A: RNA Localization and Control of Activity
157. Posttranscriptional Control: Nuclear RNA Processing 1037
Maurice S. Swanson and John P. Aris
158. FMR1 and the Fragile X Syndrome 1053
Kathryn B. Garber, Jeannie Visootsak, and Stephen T. Warren
159. TCOF1 (Treacle) and the Treacher-╉Collins Syndrome 1057
Jill Dixon, Paul A. Trainor, and Michael J. Dixon
160. RMRP and Cartilage-╉Hair Hypoplasia 1061
Pia Hermanns, Bernhard Zabel, and Brendan H. Lee

B : P OST TRA N S L AT ION A L CON T R O L A ND U B I Q UI TI N ATI O N

161. An Introduction to Posttranslational Control by Ubiquitin-╉Dependent Proteolysis 1065
Peter K. Jackson
162. UBE3A and the Angelman Syndrome 1077
Charles A. Williams
163. VHL and Von Hippel–╉Lindau Disease 1083
Eamonn R. Maher
xxii CONTENTS
164. PQBP1 and Renpenning Syndrome, Related XLID Syndromes,
and Nonsyndromic XLID 1087
Charles E. Schwartz
165. TBCE and the Hypoparathyroidism-​Retardation-​Dysmorphism (HRD) Syndrome 1095
George A. Diaz, Ruti Parvari, Eli Hershkovitz, and Monica Sentmanat
166. UBR1, the N-​End-​Rule Pathway, and the Johanson-​Blizzard Syndrome 1099
Martin Zenker
167. 3M Syndrome 1103
Céline Huber and Valérie Cormier-​Daire
168. Peters Plus Syndrome 1107
Saskia A. J. Lesnik Oberstein, Martine J. Van Belzen, and Raoul C. M. Hennekam
169. X-​linked Malformation and Infantile Lethality Syndrome, Provisionally Named Ogden
Syndrome 1111
Gholson J. Lyon, Lynne M. Bird, and Alan Rope

C: CEL L C Y C L E, PR O L I F ER ATI O N, AND A PO PTO S I S

170. An Introduction to the Mechanisms of Cell-​Cycle Regulation and Apoptosis 1115
Katrien Vermeulen, Dirk R. Van Bockstaele, Viggo F. I. Van Tendeloo,
and Zwi N. Berneman
171. Hutchinson-​Gilford Progeria Syndrome 1127
Frank G. Rothman and Leslie B. Gordon
172. Fanconi Anemia 1133
Henri Van De Vrugt and Markus Grompe
173. RECQL4-​Related Recessive Conditions 1141
L. Van Maldergem, J. Piard, L. Larizza, and L. L. Wang
174. TP63 and the Ectodermal Dysplasia, Ectrodactyly, and Cleft Lip and/​or Palate (EEC),
Limb-​Mammary (LMS), Ankyloblepharon, Ectrodactyly, and Cleft Lip/​Palate (AEC,
Ha​-​Wells), Acro-​Dermato-​Ungual-​Lacrimal-​Digit (Adult), and Rapp–​​Hodgkin
Syndromes and Ectrodactyly (Split Hand/​Foot Malformation) 1149
Michael J. Bamshad
175. Seckel Syndrome 1159
Mark O’Driscoll
176. Miller Syndrome 1163
Dagmar Wieczorek and David R. Fitzpatrick
177. Meier-​Gorlin Syndrome 1167
Mark E. Samuels, Cheri L. Deal, and David L. Skidmore
178. Desbuquois Dysplasia 1175
Céline Huber and Valérie Cormier-​Daire

D : G UANI N E NUC L EO TI D E-​B I N DI N G PR O TEI NS

179. GNAS and McCune-​Albright/​Fibrous Dysplasia, Albright Hereditary Osteodystrophy,
and Pseudohypoparathyroidism 1177
Lee S. Weinstein
180. FGD1 and Faciogenital Dysplasia (Aarskog-​Scott Syndrome); McKusick #305400 1183
Jerome L. Gorski
181. RAB3GAP1, RAB3GAP2, RAB18, TBC1D20, and the Warburg Micro and Martsolf
Syndromes 1191
Irene Aligianis and Mark Handley
 CONTENTS xxiii
182. GPR56 and Bilateral Frontoparietal Polymicrogyria 1197
Xianhua Piao
183. ARHGAP31, DOCK6, RBPJ, EOGT, and Adams-​Oliver Syndrome 1203
Laura Southgate and Richard C. Trembath

E : MIC ROT U BU L E MOT ORS A N D THE C Y TO S K EL ETO N

184. Microtubule Motors: Intracellular Transport, Cell Division, Ciliary Movement,
and Nuclear Migration 1211
Anthony J. Wynshaw-​Boris
185. Classic Lissencephaly 1217
Joseph G. Gleeson and Deborah J. Morris Rosendahl
186. Lissencephaly With Cerebellar Hypoplasia 1223
Eric C. Olson and Christopher A. Walsh
187. FLNA and FLNB and Periventricular Nodular Heterotopia, the Otopalatodigital
Spectrum Disorders, Spondylocarpotarsal Synostosis, Larsen Syndrome, and
Atelosteogenesis Types I and III 1227
Stephen P. Robertson and Deborah Krakow
188. Oblique Facial Clefts 1237
Valeriy Shubinets, Richard L. Maas , and Eric C. Liao
189. Deletion of 7q11.23 Genes and Williams Syndrome 1243
Li Dai, Anna Järvinen, Ursula Bellugi, Debra L. Mills, Timothy T. Brown, Eric Halgren,
Barbara R. Pober, and Julie R. Korenberg
190. SH3PXD2B and Frank–​Ter Haar Syndrome 1249
Hans Van Bokhoven

F: VE SICL E - ​M E D IAT E D T RA F F IC K I N G A ND ENDO C Y TO S I S

191. Inborn Defects of Membrane Trafficking 1253
Elina Ikonen
192. VPS13B and Cohen Syndrome 1259
Forbes D. C. Manson, Kate E. Chandler, Graeme C. M. Black,
and Deborah J. Morris-​Rosendahl
193. VPS33B, VIPAS39, and the Arthrogryposis, Renal Dysfunction,
and Cholestasis Syndrome 1265
Paul Gissen
194. SEC23A and Cranio-​Lenticulo-​Sutural Dysplasia 1269
Jinoh Kim and Simeon A. Boyadjiev
195. Griscelli Syndrome 1275
Haggit Hurvitz, Andrew R. Cullinane, Marjan Huizing, and Yair Anikster

G : E XT RA CE L L U L A R M ATR I X
196. Extracellular Matrix and Signaling During Development 1281
Joanna J. Phillips, Scott B. Selleck, and Sally E. Stringer
197. GPC3 and the Simpson-​Golabi-​Behmel Syndrome 1287
Michael R. Debaun, Rick A. Martin, and Scott Saunders
198. HSPG2 (Perlecan), the Silverman-​Handmaker Type of Dyssegmental Dysplasia, and
the Schwartz-​Jampel Syndrome 1293
Sophie Nicole and Bertrand Fontaine
xxiv CONTENTS
199. L1CAM and X-​Linked Hydrocephalus (L1 Syndrome) 1299
Yvonne Vos, Jean-​Pierre Fryns, and Connie Schrander-​Stumpel
200. COMP and Pseudoachondroplasia 1303
Matthew J. Rock and Daniel H. Cohn
201. ZIC3 Related Disorders: X-​linked Heterotaxy, Vacterl-​X, Situs Inversus
and Isolated CHD* 1309
Mardi J. Sutherland and Stephanie M. Ware
202. Human MMP-​2/​MT1-​MMP Deficiency: Multicentric Osteolysis With Nodulosis,
Arthropathy (MONA), and Winchester Syndromes 1313
Rebecca A. Mosig and John A. Martignetti
203. ADAMTS10, ADAMTS17, and FBN1: The Weill-​Marchesani Syndrome 1335
Carine Le Goff and Valérie Cormier-​Daire
204. Fraser Syndrome and Related Conditions 1339
Peter J. Scambler
205. TRPS1 and the Tricho-​Rhino-​Phalangeal Syndrome 1343
Hermann-Josef Lüdecke and Bernhard Horst Hemke
206. Walker-​Warburg Syndrome: Genetic Heterogeneity Converging at the Abnormal
Glycosylation of Alpha-​Dystroglycan 1349
Moniek Riemersma, Dirk J. Lefeber, and Hans Van Bokhoven
207. HPSE2, LRIG2, and the Urofacial Syndrome 1353
Helen M. Stuart, Adrian S. Woolf, and William G. Newman
208. Bifid Nose, Anorectal Malformation, and Renal Agenesis (BNAR) Syndrome 1357
Fowzan S. Alkuraya
209. CHST14, DSE, and the Musculocontractural Type of Ehlers-​Danlos Syndrome
(Adducted Thumb–​Clubfoot Syndrome) 1361
Andreas R. Janecke
210. Synpolydactyly and Mutations in the Hoxd13 Gene 1369
Philippe Debeer, Przemko Tylzanowski, and Nathalie Brison

H : J U NC TI O N S , TR ANS PO RTER S , A ND C H ANNEL S

211. GJA1 (Connexin 43) and the Oculodentodigital Syndrome 1375
Rebecca J. Richardson and Michael J. Dixon
212. KCNJ2 and the Andersen-​Tawil Syndrome 1383
David R. Renner, Rabi Tawil, Martin Tristani-Firouzi, and Louis J. Ptáček
213. ANKH and Craniometaphyseal Dysplasia 1389
Uwe Korank, Peter Nürnberg, and Sigrid Tinschert

VII. D YS M O R PH I C DI S EA S E G EN ES O F UNK NO W F UNC T I O N

O R U NC L A S S I F I ED
214. Role of EVC and EVC2 in Ellis-van Creveld Syndrome and Weyers Acrofacial
Dysostosis 1397
Marzena M. Galdzicka, Janice A. Egeland, and Edward I. Ginns
215. P450 Oxidoreductase Deficiency and Antley-​Bixler Syndrome 1405
Walter L. Miller
216. TRIM37 and Mulibrey Nanism 1413
Kaisa Kettunen, Niklas Karlberg, Susann Karlberg, Hannu Jalanko,
Marita Lipsanen-​Nyman, and Anna-​Elina Lehesjoki

* Chapter 201 belongs to the Section IV, Part A: The TGF-β Signaling Pathway
 CONTENTS xxv
217. KIAA1279 and Goldberg-​Shprintzen Syndrome 1417
Alice S. Brooks and Robert M. W. Hofstra
218. GLMN and Glomuvenous Malformation 1423
Pascal Brouillard, Laurence M. Boon, and Miikka Vikkula
219. The Roles of KRIT1, CCM2, and PDCD10 in the Pathogenesis of Cerebral Cavernous
Malformations 1429
David A. Mcdonald and Douglas A. Marchuk
220. Proteus Syndrome 1435
Leslie G. Biesecker
221. Microphthalmia 9 (PDAC) 1439
Julie Plaisancie and Nicolas Chassaing
222. Ichthyosis Prematurity Syndrome 1445
Joakim Klarjürgen Kohlhase, Anders Vahlqvist, and Niklas Dahl
223. Microphthalmia With Linear Skin Lesions (MLS) Syndrome: An Unconventional
Mitochondrial Disorder 1449
Alessia Indrieri and Brunella Franco
224. Mutations in SCARF2 Are Responsible for the Van Den Ende–​Gupta Syndrome
(VDEGS) 1453
Loydie A. Jerome-Majewska
Index 1457

REFERENCES
Complete references for this book are available online at:
www.oxfordmedicine.com/​inbornerrorsofdevelopment3e
Contributors

Margaret P. Adam, MD Tamara Alliston, PhD

Division of Genetic Medicine, Associate Professor,
Department of Pediatrics, Department of Orthopaedic Surgery,
University of Washington School of Medicine, University of California, San Francisco,
Seattle, WA San Francisco, CA

Nurten A. Akarsu MD, PhD Mohammad Reza Amini, MD

Hacettepe University, Department of Molecular Medicine,
Department of Medical Genetics, Cleveland Clinic Lerner College of Medicine,
Ankara, Turkey Case Western Reserve University,
Cleveland, OH
Haruhiko Akiyama MD, PhD
Gifu University, Douglas M. Anderson, PhD
Department of Orthopaedics, Department of Molecular Biology,
Gifu, Japan University of Texas Southwestern Medical Center at Dalla,
Dallas, TX
Kyriaki S. Alatzoglou MD, PhD
University College London Yair Anikster, MD PhD
Institute of Child Health Metabolic Disease Unit,
London, United Kingdom Edmond and Lily Safra Children’s Hospital,
Sheba Medical Center,
Irene Aligianis PhD Tel Hashomer and Sackler School of Medicine Tel-​Aviv, University,
School of Molecular, Tel-​Aviv, Israel
Genetic and Population Health Sciences,
The University of Edinburgh Stylianos E. Antonarakis, MD, DSc
Edinburgh, Scotland, United Kingdom Department of Genetic Medicine and Development
University of Geneva Medical School,and University Hospitals of
Fowzan S. Alkuraya, MD GenevaDirector,
College of Medicine, iGE3 Institute of Genetics and Genomics of Geneva President of
Alfaisal University, HUGO (Human Genome Organization)
Developmental Genetics Unit, Geneva, Switzerland
King Faisal Specialist Hospital and Research Center,
Riyadh, Kingdom of Saudi Arabia; Yoko Aoki, MD, PhD
Division of Genetics, Department of Medical Genetics,
Department of Pediatrics, Tohoku University School of Medicine,
Boston Children’s Hospital and Harvard Medical School, Sendai, Japan
Boston, MA

xxvii
xxviii CONTRIBUTORS
John P. Aris, PhD John W. Belmont, MD, PhD
Associate Professor, Department of Molecular & Human Genetics
Department of Anatomy and Cell Biology, Baylor College of Medicine
College of Medicine, Houston, TX
University of Florida,
Gainesville, FL Jonathan N. Berg, MD
School of Medicine,
Tania Attie-Bitach MD, PhD University of Dundee,
Hôpital Universitaire Necker Dundee, United Kingdom
Service de Génétique Médicale
Paris, France Zwi N. Berneman, MD, PhD, FRCP
Department of Hematology
Muhammad Ayub, MBBS, MRC. Psych, MSc, MD Universitair Ziekenhuis Antwerpen
Department of Psychiatry, Antwerp, Belgium
Queen’s University,
Kingston, ON, Canada Fred B. Berry, PhD
Department of Surgery,
Yangjin Bae, PhD University of Alberta,
Department of Molecular and Human Genetics, Edmonton, Alberta
Baylor College of Medicine, Alberta, Canada
Houston, TX
Nadejda A. Bespalova, MD
Michael J. Bamshad, MD Department of Pediatrics,
Professor of Pediatrics Baylor College of Medicine,
Adjunct Professor of Genome Sciences Houston, TX
Department of Pediatrics,
University of Washington, Weimin Bi, PhD
Seattle, WA Department of Molecular and Human Genetics,
Baylor College of Medicine,
Vivian Bardwell, PhD Houston, TX
Department of Genetics,
Cell Biology and Development, Ethan Bier, PhD
Masonic Cancer Center, Professor of Biological Sciences,
University of Minnesota, Division of Biological Sciences,
Minneapolis, MN University Of California, San Diego
La Jolla, CA
Rosa Barrio, PhD
Department of Functional Genomics, Leslie G. Biesecker, MD, FAAP, FACMG
CIC bioGUNE, Medical Genomics and Metabolic Genetics Branch,
Bizkaia, Spain National Human Genome Research Institute,
National Institutes of Health,
Catherine J. Baty, DVM, PhD Bethesda, MD
Renal Division,
Department of Medicine, Lynne M. Bird, MD
School of Medicine, Department of Pediatrics,
University of Pittsburgh, University of California, San Diego,
Pittsburgh, PA Rady Children’s Hospital
San Diego, CA
David C. Beebe, PhD, FARVO
Janet And Bernard Becker, Graeme C.M. Black, MA, MB, BCh, DPhil, FRCOphth
Department of Ophthalmology and Visual Sciences, Centre for Genetic Medicine,
Department of Cell Biology and Physiology, Institute of Human Development,
Washington University School of Medicine, University of Manchester,
St. Louis, MO Manchester, United Kingdom;
St Mary’s Hospital,
Elena Belloni Central Manchester University Hospitals NHS Foundation Trust,
Department of Experimental Oncology Manchester, United Kingdom
IEO -​Istituto Europeo di Oncologia
Milano, Italy Matthew Bock, MD
Department of Pediatrics,
Ursula Bellugi, EdD Icahn School of Medicine at Mount Sinai,
Laboratory for Cognitive Neuroscience, New York, NY
Salk Institute,
La Jolla, CA
Another random document with
no related content on Scribd:
 MRS. GASKELL

I
WE think of her habitually—do we not?—by her married title of “Mrs.
Gaskell.” Who Mr. Gaskell was this generation does not, in an
ordinary way, pause to enquire: a neglect which does injustice to a
gentleman of fine presence, noble manners and high culture. She
was a beautiful woman: they married in 1832, and had children, and
lived most happily.
So it is as “Mrs. Gaskell” that we think of her: and I dare to wager
that most of you think of her as Mrs. Gaskell, authoress of Cranford.
Now heaven forbid that anything I say this morning should daunt
your affection for Cranford, as heaven knows how long and sincerely
I have adored it. I have adored it at least long enough and well
enough to understand its devotees—for Cranford has not only
become popular in the sense, more or less, that Omar Khayyam has
become popular—by which I mean that, at this season or
thereabouts, numbers of people buy a copy in limp suède, with Hugh
Thomson’s illustrations, and only hesitate over sending it to the So-
and-So’s with best wishes on a chilling doubt that they sent it last
year, with the identical good wishes—if indeed they are not returning
the identical volume they received! Well, let us be merry and
careless!—in the course of a week or two these soft bricks will be
dropping on every hearth.
But seriously, one finds devotees of Cranford everywhere; and
especially, in my experience, among scholarly old men. They have
Cranford written on their hearts, sometimes hardly covering a
cherished solution of The Mystery of Edwin Drood. Cranford and the
novels of Jane Austen—you never know how many delightful
persons cherish them, have them by heart, pore over their text as
over an Ode of Pindar’s. And they are fierce, these devotees, as the
noble new edition of Jane Austen by Mr. Chapman of the Oxford
Press has recently been teaching us. Here are five volumes edited
with all the care that study and affection can lavish on the task. Yet
from here, there and everywhere lovers start up from firesides—
scattered widowers of this dear maiden—challenging over variae
lectiones, feeling for the hilt on the old hip to champion (we’ll say)
“screen” as the right word against “scene” as printed—

“Swerve to the left, Son Roger,” he said,

“When you catch his eyes through the helmet-slit.”

It is as serious, almost, as all that: and so it is with Cranford, and

Miss Jenkyns and Captain Brown and adorable Miss Matty.
Yet, let us admit there are certain works which conquer some of
us, we cannot tell why. To go a very long way from Cranford, take
Tristram Shandy. No one can really criticise Tristram Shandy, and all
pretence to do so is mere humbug. Either you like Tristram Shandy
(as I do, for one) or you don’t, and there’s an end to it. My sole
complaint against the devotees of Cranford is that, admiring it,
revelling in it, they imagine themselves to have the secret of Mrs.
Gaskell, stop there, and do not go on to explore her other works of
which one at any rate I shall presently dare to proclaim to you as the
most perfect small idyll ever written in English prose.

II
The sin is the worse because every one acknowledges the Life
of Charlotte Brontë to be—after Boswell’s Life of Johnson, admittedly
beyond competition—among the two or three best biographies in our
language. Conceive the Brontës—not Charlotte alone, but the whole
family—the whole of that terrible family in that terrible parsonage at
Haworth—as this staid lady, wife of a Unitarian minister, faithfully
depicts them—the wastrel son, Branwell: through long nights tearing
his own heart out, with his stern old father’s, in the bedroom they
had, for safety, to occupy together: in the end pulling himself up to
die standing: the shuddering sisters listening on the stairs; Emily,
doomed and fierce, she too in her turn standing up to die. Consider
—I will not say Wuthering Heights, or Charlotte’s well-known
magnificent description, in Villette, of Rachel and her tortured acting
—but consider if only by illustration of contrast this most maddened
poem by Emily—and there are others as tragic—
The Prisoner

Still let my tyrants know, I am not doom’d to wear

Year after year in gloom and desolate despair;
A messenger of Hope comes every night to me,
And offers for short life, eternal liberty.

He comes with Western winds, with evening’s wandering airs,

With that clear dusk of heaven that brings the thickest stars:
Winds take a pensive tone, and stars a tender fire,
And visions rise, and change, that kill me with desire.

Desire for nothing known in my maturer years,

When Joy grew made with awe, at counting future tears:
When, if my spirit’s sky was full of flashes warm,
I knew not whence they came, from sun or thunder-storm.

But first, a hush of peace—a soundless calm descends;

The struggle of distress and fierce impatience ends.
Mute music soothes my breast—unutter’d harmony
That I could never dream, till Earth was lost to me.

Then dawns the Invisible; the Unseen its truth reveals;

My outward sense is gone, my inward essence feels;
Its wings are almost free—its home, its harbour found;
Measuring the gulf, it stoops, and dares the final bound.
 O dreadful is the check—intense the agony—
When the ear begins to hear, and the eye begins to see;
When the pulse begins to throb—the brain to think again—
The soul to feel the flesh, and the flesh to feel the chain.

Yet I would lose no sting, would wish no torture less;

The more that anguish racks, the earlier it will bless;
And robed in fires of hell, or bright with heavenly shine,
If it but herald Death, the vision is divine.

Consider, I say, that the authoress of Cranford not only lived with
these fierce women and comforted them as their benign friend, with
a comfort that no soul can give to another without understanding, but
portrayed them (their struggles ended) in a book that combines the
English (even the Victorian English) with the Greek, a fidelity to awful
fact with a serene judgment, a tender mercy—the two so discovering
and covering all, that—whether it be in charity or in justice—its core
of truth has never been challenged: that it stands yet among the
noblest few of English biographies. I put it to you that, if you but set
together those two books—Cranford and the Life of Charlotte Brontë
—at once you must recognise the operating hand—the quietly
operating hand—of genius. But this, even when Mrs. Gaskell’s
longer novels are thrown into the scale, has avoided, I think—
because she herself is so equable, so temperate—its right
recognition. Yes, her very portrait has a Hellenic look, so beautiful it
is, so penetrating its calm gaze.

III
Yet maybe you think it strange that I find so much of high
Hellenic quality in this quiet lady—born a Stevenson, to be sure—but
christened Elizabeth Cleghorn, names not to us reminiscential of
Hybla or the Ilissus. Her father was a Unitarian minister, who
preached in that capacity, in Dob Lane Chapel, Manchester—which
again does not suggest the Acropolis. In 1832 she married a
Unitarian minister, son of a prosperous manufacturer, minister to a
Chapel in Cross Street, Manchester, and prominent on the Home
Missionary Board. For these and some particulars that follow I go to
4
the best sources known to me.

4
Sir Adolphus Ward’s various Introductions to
the Knutsford Edition (8 volumes, published by
John Murray) and the article on her in the
Dictionary of National Biography, by the same
writer, whose scholarship, when devoted to this
dead lady, reaches to a religious note of chivalry.

Her married life was one of unbroken happiness. Her husband

had literary leanings, and in 1838 she writes to Mrs. Howitt, “We
once thought of trying to write sketches among the poor, rather in the
manner of Crabbe (now don’t think this presumptuous), but in a more
beauty-seeing spirit: and one—the only one—was published in
5
Blackwood, January, 1837. But I suppose we spoke our plan near a
dog-rose, for it never went any further.”

5
The curious may read it in Blackwood’s
Magazine, Vol. XLI, No. CCIV, or in Sir Adolphus
Ward’s Biographical Introduction.

So you see that she had already made Manchester her home,
and was already interested in the poor.
Also one may interpose here that (without evidence of her
portrait) she was acknowledged by all who met her to be a person of
quite remarkable beauty, and as little conscious of it as any beautiful
woman has any right to be: since as Jaques noted:
 if ladies be but young and fair,
They have the gift to know it.

Above all, she had the ineffable charm of being the least
assertive, the most concerned with others, in any company. I think
that of her rather than of any other writing-woman one may quote
Mrs. Browning’s lines on her Kate—

I doubt if she said to you much that could act

As a thought or suggestion: she did not attract
In the sense of the brilliant or wise: I infer
’Twas her thinking for others made you think of her.

She never found fault with you, never implied

Your wrong by her right: and yet men at her side
Grew nobler, girls purer, as through the whole town
The children were gladder that pulled at her gown....

The weak and the gentle, the ribald and rude,

She took as she found them, and did them all good:
It always was so with her—see what you have!
She has made the grass greener even here ... with her grave.

Such a woman, as I trace her portrait, was Mrs. Gaskell, and I think
the end of the story will confirm my reading of her. She made no
show: without interfering she saw beauty in the lives of the poor: she
lived with the misery of Manchester and pitied it; and across a
personal bereavement—or (shall we say?) out of the very anguish of
her own breast—she relieved her heart in her first long book in pity
for that place.
In 1844 Mr. and Mrs. Gaskell revisited Festiniog, in North Wales,
a halt of their wedding tour. They took their children with them; and
at the inn there the eldest daughter caught the scarlet fever. Mrs.
Gaskell removed her with her infant brother to Portmadoc, where he
sickened of the fever and died. It was in search of an anodyne for
sorrow that the mother began to write Mary Barton. Read that book
with just these two or three facts in your mind, and you will find an
illustration—though it almost shames me to give you one so poignant
—of the way in which the sincerest art is begotten and brought forth:
that is, by lifting one’s own experience up to a Universal, and then
bringing it back to reclothe it in imaginary, particular, men and
women.

IV
In two previous lectures, Gentlemen, I have given you—it may
well be ad nauseam—the conditions of life among the industrial poor
of that period as they can be gathered from Blue Books and out of
Hansard. In my last lecture I tried to indicate how they affected the
ambitious (and to that extent selfish) but yet chivalrous mind of
Disraeli. I shall be shorter with Mrs. Gaskell, who invents no political
novel, but just tells the tale and passes on. But she tells it, and I
select here to read to you a passage to illustrate rather how gently
and charitably she tells it than to make out the worst of the case,
which yet may be found in her pages.

At all times it is a bewildering thing to the poor weaver to see

his employer removing from house to house, each one grander
than the last, till he ends in building one more magnificent than
all, or withdraws his money from the concern, or sells his mill, to
buy an estate in the country, while all the time the weaver, who
thinks he and his fellows are the real makers of this wealth, is
struggling on for bread for his children, through the vicissitudes
of lowered wages, short hours, fewer hands employed, etc. And
when he knows trade is bad, and could understand (at least
partially) that there are not buyers enough in the market to
purchase the goods already made, and consequently that there
is no demand for more; when he would bear and endure much
without complaining, could he also see that his employers were
bearing their share; he is, I say, bewildered and (to use his own
word) “aggravated” to see that all goes on just as usual with the
mill-owners. Large houses are still occupied, while spinners’ and
weavers’ cottages stand empty, because the families that once
filled them are obliged to live in rooms or cellars. Carriages still
roll along the streets, concerts are still crowded by subscribers,
the shops for expensive luxuries still find daily customers while
the workman loiters away his unemployed time in watching
these things, and thinking of the pale, uncomplaining wife at
home, and the wailing children asking in vain for enough of food,
—of the sinking health, of the dying life, of those near and dear
to him. The contrast is too great. Why should he alone suffer
from bad times?
I know that this is not really the case; and I know what is the
truth in such matters: but what I wish to impress is what the
workman feels and thinks.
But there are earnest men among these people, men who
have endured wrongs without complaining, but without ever
forgetting or forgiving those whom (they believe) have caused all
this woe.
Among these was John Barton. His parents had suffered; his
mother had died from absolute want of the necessaries of life.
He himself was a good, steady workman, and, as such, pretty
certain of steady employment. But he spent all he got with the
confidence (you may also call it improvidence) of one who was
willing, and believed himself able, to supply all his wants by his
own exertions. And when his master suddenly failed, and all
hands in the mill were turned back, one Tuesday morning, with
the news that Mr. Hunter had stopped, Barton had only a few
shillings to rely on; but he had good heart of being employed at
some other mill, and accordingly, before returning home, he
spent some hours in going from factory to factory, asking for
work. But at every mill was some sign of depression of trade!
Some were working short hours, some were turning off hands,
and for weeks Barton was out of work, living on credit. It was
 during this time that his little son, the apple of his eye, the
cynosure of all his strong power of love, fell ill of the scarlet
fever. They dragged him through the crisis, but his life hung on a
gossamer thread. Everything, the doctor said, depended on
good nourishment, on generous living, to keep up the little
fellow’s strength, in the prostration in which the fever had left
him. Mocking words! when the commonest food in the house
would not furnish one little meal. Barton tried credit; but it was
worn out at the little provision shops, which were now suffering
in their turn. He thought it would be no sin to steal, and would
have stolen; but he could not get the opportunity in the few days
the child lingered. Hungry himself, almost to an animal pitch of
ravenousness, but with bodily pain swallowed up in anxiety for
his little sinking lad, he stood at one of the shop windows, where
all edible luxuries are displayed; haunches of venison, Stilton
cheeses, moulds of jelly—all appetising sights to the common
passer by. And out of this shop came Mrs. Hunter, his late
employer’s wife! She crossed to her carriage, followed by the
shopman loaded with purchases for a party. The door was
quickly slammed to, and she drove way; and Barton returned
home with a bitter spirit of wrath in his heart, to see his only boy
a corpse!
You can fancy, now, the hoards of vengeance in his heart
against the employers. For there are never wanting those who,
either in speech or in print, find it their interest to cherish such
feelings in the working classes; who know how and when to
rouse the dangerous power at their command; and who use their
knowledge with unrelenting purpose to either party.

Now you know from actual evidence given you in my two

previous lectures that this account is not overstrained. You see how
the writer makes allowances; and how, all allowances made, her
thrust is as deadly as any in Disraeli’s Sybil.
 V
But now comes in the difference. Mrs. Gaskell knew these
people as Disraeli did not. She had lived among them, and to all the
angry protests evoked by Mary Barton she returned, of her
knowledge, gentle, but gently firm answers which could not be
6
refuted. The story, at any rate, exercised at once a “commanding
effect,” and the width of that effect was attested by translations into
many foreign languages—French, German, Spanish, Hungarian and
Finnish.

6
I should mention here, by the way, on Sir
Adolphus Ward’s authority, the virtual certainty
that before writing her own novel she “had
remained quite unacquainted with both
Coningsby and Sybil.”

She did not go on to exploit that success, that effect. She had
said what she had to say; and having found, in the saying of it, her
gift as a writer, she passed on to other things. A very beautiful
necklace of novels was the result. But this serene indifference to
what might with others have meant a very strong “literary” temptation
implied no failing devotion to the poor whose woes the book had,
once for all, championed. Some eighteen years later, in 1862–3, a
time of trouble came over Manchester and South-west Lancashire in
general, which

called forth one of the most notable, and certainly one of the
best-organized efforts of goodwill and charity which this country
has ever seen. In the long struggle between masters and men,
the times of the Lancashire Cotton Famine, due to the outbreak
and continuance of the American Civil War, brought about a
protracted truce, in which the kindly feelings inspired by the self-
 sacrificing efforts of many leading employers of manufacturing
labour cannot but have counted for much.

I am quoting from Sir Adolphus Ward:

Mrs. Gaskell, whose name had so good a sound among the

Lancashire working classes that we hear of an Oldham man
regularly bringing his children to gaze upon the house in
Plymouth Grove where dwelt the authoress of Mary Barton, gave
many proofs in these times of trouble of her readiness to help
suffering in every way in her power.

The relief problem, in short, claimed her almost entirely during

that long tribulation of her people. “We were really glad,” she writes
to a friend, “to check one another in talking of the one absorbing
topic, which was literally haunting us in our sleep, as well as being
our first thoughts in wakening and the last at night.” In organising,
superintending, working sewing-rooms, providing dinners, she would
work for six or seven hours of her day.
The shadow of these and other industrial troubles recurs,
indeed, in some of the later novels, particularly in North and South:
but always you see that with her there is no political axe to grind, nor
scarce a consciousness of there being any such thing: and this
disinterested charitableness leads her, as it were, imperceptibly into
regions of which Disraeli, with all his genius, never won ken. The first
incentive, I have tried to show, operated on both. But whereas he
went off into a life of action—great and powerful action, let all admit
—to return in his old age to revisit with Endymion the glimpses of the
moon and his boyish dreams, this unambitious Victorian lady, having
found her literary talent, went on to employ it with a serenity
unmoved to worship any idols of the market. Glad of course she was
to enjoy and use her gift: very modestly glad (as what true woman or
man is not?) of the recognition it brought, but following the path to
the end to bequeath to the world several noble novels and three
shining masterpieces. Of these, of course, the Life of Charlotte
Brontë is one and Cranford the second: and for the moment I leave
you to guess at the third. For the moment I wish you to picture this
woman. In her writing, as in her daily life, she had no mannerisms.
She copied neither Disraeli, nor Dickens, who also championed the
poor and was moreover her encourager and editor; nor the Brontës,
for all the spell of their genius; nor Trollope, nor George Eliot; though
all were great and flattered her with their admiration. Past them all
we see her quietly keeping the tenor of her way. Now and again she
seems to falter and ask herself—herself, mind you—Is this trouble to
speak the simple truth as best I can, without heat, really worth its
reward as set against the heat and acrimony it provokes? The
strictures passed on her Life of Charlotte Brontë gave her, for a time,
a distaste for it all. But she wrote on, after a little, and on Sunday,
November 12, 1865, killed of a sudden by a pang of the heart—
carried away, as her epitaph at Knutsford (which is “Cranford”) says,
“Without a moment’s warning”—she left her writings all just as clean
and bright as the bunch of her household keys.

Who sweeps a room, as for Thy laws,

Makes that, and the action, fine.

VI
I shall pass the catalogue of these writings very quickly in review.
The authoress of Mary Barton was hailed at that time, when novels
were yet few and even poetry but beginning to recover its strength,
by great men and by Dickens especially, who engaged her pen for
the first number of his serial adventure, Household Words. In 1853
appeared her second important novel, Ruth (which possibly
influenced Dickens’ own Hard Times, published a year later). Then in
June, 1853, came Cranford, made into a book from papers
contributed to Household Words between December, 1851, and
May, 1853. North and South ran in Household Words from
September, 1854, to January, 1855, and appeared as a book, with
some slight alterations, in that year. In that year also (on March 31st)
Charlotte Brontë died and Mrs. Gaskell consented, at the old father’s
urgent request, to write the Biography. She gave herself up to the
work and finished it in the spring of 1857. The strictures on it—truth,
as Milton says, never comes into the world but as a bastard—broke
her spirit for a while for all but occasional writing: and then came the
cotton famine, of which I have spoken, to tax all her energies. But
after the stress of this they revived. In 1863 appeared Sylvia’s
Lovers, in 1863–4 Cousin Phillis in the pages of the Cornhill
Magazine. In this magazine (August, 1864–January, 1866) followed
her last story, Wives and Daughters, published soon after in that
year as an unfinished work. So you see the whole tale of it lies within
the central years of the last century, beginning with Mary Barton in
1848 and ending sharply just eighteen years after.

VII
I do not propose to discuss the toll of her work this morning. I
wish that those of you who aspire to write, and are here learning to
write, would study it—for two reasons. For the first, while I admit
many flaws, it seems to me elementally of the best literary breeding,
so urbane it is, so disposedly truthful; so much of the world, quizzing
it; so well aware, all the while, of another. For my second, that here
you have, refuting, an exception to all hasty generalisations about
the nineteenth century, the Victorian Age, horsehair sofas, the
Evangelicals, the Prince Consort, the Great Exhibition of 1851 and
all that bagful of cheap rubbish. In 1851 this lady was writing
Cranford: in 1863 she was writing Cousin Phillis: and considering
that most lovely idyll, I am moved to ask, “Do you, at any rate, know
it, this Sicilian yet most English thing of the mid-nineteenth century?”
I am moved to say, “Yes, Keats is lovely, and was lovely to me alas!
before ever you were born: but quit your gushing and your talk about
‘romantic revivals’—which are but figments invented by fellows who
walk round and round a Grecian urn, appraising it scholastically. Quit
it, and try to make a Grecian urn. The horses on the frieze of the
Parthenon are good horses: but you have as good to study to-day or
to-morrow if you will but take a short journey out to Newmarket and
study them. Which is better?—to watch a gallop between two colts
on a heath, or to bend a congested nose over Ferrex and Porrex?”
To be classical is not to copy the classics: to be classical is to
learn the intelligence of the classics and apply just that to this
present world and particularly to this island of ours so familiar and
yet so romantic.

VIII
I spoke, a while back, of three masterpieces of Mrs. Gaskell,
naming two, leaving you to guess the third. Lay by your Cranford,
and take up and study Cousin Phillis.
I suppose its underlying sadness has kept it out of popular
esteem—this tale of scarcely more than a hundred pages—a pale
and shadowy sister of Cranford. It has none, or little of Cranford’s
pawky fun: it has not Cranford’s factitious happy ending. But it beats
me to guess how any true critic can pass it over and neglect a thing
with all that is best in Theocritus moving in rustic English hearts. And
it is not invented. It has in all its movements the suggestion of things
actually seen—of small things that could not have occurred to any
mind save that of an eye-witness—of small recognitions, each in its
turn a little flash of light upon the steady background of rural
England. It is England and yet pure Virgil—as purely Virgilian as the
vignette, in the Fourth Georgic, of the old man of Corycus tilling his
scanty acres:

nec fertilis ilia juvencis

Nec pecori opportuna seges nec commoda Baccho—

who yet brought home his own-grown vegetables at night and cast
them on the table, in his mind equal to the wealth of kings. I shall
read you two passages—the first of young Paul’s introduction, by his
cousin Phillis, to her father the ex-minister and Virgilian scholar
turned farmer and labouring with his hinds—

“There is father!” she exclaimed, pointing out to me a man in

his shirt-sleeves, taller by the head than the other two with whom
he was working. We only saw him through the leaves of the ash-
trees growing in the hedge, and I thought I must be confusing
the figures, or mistaken: that man still looked like a very powerful
labourer, and had none of the precise demureness of
appearance which I had always imagined was the characteristic
of a minister. It was the Reverend Ebenezer Holman, however.
He gave us a nod as we entered the stubble-field; and I think he
would have come to meet us, but that he was in the middle of
giving some directions to his men. I could see that Phillis was
built more after his type than her mother’s. He, like his daughter,
was largely made, and of a fair, ruddy complexion, whereas hers
was brilliant and delicate. His hair had been yellow or sandy, but
now was grizzled. Yet his grey hairs betokened no failure in
strength. I never saw a more powerful man—deep chest, lean
flanks, well-planted head. By this time we were nearly up to him;
and he interrupted himself and stepped forwards, holding out his
hand to me, but addressing Phillis.
“Well, my lass, this is cousin Manning, I suppose. Wait a
minute, young man, and I’ll put on my coat, and give you a
decorous and formal welcome. But—Ned Hall, there ought to be
a water-furrow across this land: it’s a nasty, stiff, clayey, dauby
bit of ground, and thou and I must fall to, come next Monday—I
beg your pardon, cousin Manning—and there’s old Jem’s
cottage wants a bit of thatch; you can do that job to-morrow,
while I am busy.” Then, suddenly changing the tone of his deep
bass voice to an odd suggestion of chapels and preachers, he
added, “Now I will give out the psalm: ‘Come all harmonious
tongues,’ to be sung to ‘Mount Ephraim’ tune.”
He lifted his spade in his hand, and began to beat time with
it; the two labourers seemed to know both words and music,
 though I did not; and so did Phillis: her rich voice followed her
father’s, as he set the tune; and the men came in with more
uncertainty, but still harmoniously. Phillis looked at me once or
twice, with a little surprise at my silence; but I did not know the
words. There we five stood, bareheaded, excepting Phillis, in the
tawny stubble-field, from which all the shocks of corn had not yet
been carried—a dark wood on one side, where the wood-
pigeons were cooing; blue distance, seen through the ash-trees,
on the other. Somehow, I think that, if I had known the words,
and could have sung, my throat would have been choked up by
the feeling of the unaccustomed scene.
The hymn was ended, and the men had drawn off, before I
could stir. I saw the minister beginning to put on his coat, and
looking at me with friendly inspection in his gaze, before I could
rouse myself.

And now let me read you this exquisite passage—there are many
almost as lovely—of Phillis in love, walking with her cousin Paul—
alas! not her beloved.

We talked about the different broods of chickens, and she

showed me the hens that were good mothers, and told me the
characters of all the poultry with the utmost good-faith; and in all
good-faith I listened, for I believe there was a great deal of truth
in all she said. And then we strolled on into the wood beyond the
ash-meadow, and both of us sought for early primroses and the
fresh green crinkled leaves. She was not afraid of being alone
with me after the first day. I never saw her so lovely, or so happy.
I think she hardly knew why she was so happy all the time. I can
see her now, standing under the budding branches of the grey
trees, over which a tinge of green seemed to be deepening day
after day, her sun-bonnet fallen back on her neck, her hands full
of delicate wood-flowers, quite unconscious of my gaze, but
intent on sweet mockery of some bird in neighbouring bush or
tree. She had the art of warbling, and replying to the notes of
different birds, and knew their song, their habits and ways, more
 accurately than any one else I ever knew. She had often done it
at my request the spring before; but this year she really gurgled,
and whistled, and warbled, just as they did, out of the very
fulness and joy of her heart. She was more than ever the very
apple of her father’s eye; her mother gave her both her own
share of love and that of the dead child who had died in infancy.
I have heard cousin Holman murmur, after a long dreamy look at
Phillis, and tell herself how like she was growing to Johnnie, and
soothe herself with plaintive inarticulate sounds, and many
gentle shakes of the head, for the aching sense of loss she
would never get over in this world.

My eyes, to be sure, are not what they were: but to them the
prose of this shimmers with beauty. In Mrs. Gaskell, as with many
another ageing writer, one can detect towards the close a certain
sunset softness—a haze, we may call it—in which many hard
experiences are reconciled. To take the highest, we agree that it so
happened to Shakespeare. To step down to the man with whom for a
study in the differences of literary genius starting from a like
incentive—the woes of the poor, and operating in the same literary
form, the novel—I have been—I hope, Gentlemen, not whimsically—
contrasting this very noble lady, we know that in his later days, in
Endymion, Disraeli saw his youth so, casting back to it. And you,
maybe, will say that these sunset softening colours are all a mirage.
Well, a great deal of it all is that. I believe that, as you grow older,
you will find yourselves more and more tending to make less, and
still less, account of definitions, of sharp outlines and judgments
based on them; of anybody’s positive assertions, be he never so
young.

IX
I have been speaking, however, to-day of one whose measure in
any light has never to my thinking been accurately taken. The crew
of Odysseus were Greeks. They beached their ship (says Homer) on
the isle of the Laestrygonians: and there came down to them the
Queen of the Laestrygonians, “a woman as tall as a mountain,” and
they hated her. The Victorian Age lent itself to excess; and its
excessive figures are our statues for some to deface or bedaub. But
I, who have purposely compared Elizabeth Gaskell with her most
ornate contemporary, dare to prophesy that when criticism has sifted
all out, she will come to her own, as a woman of genius, sweetly
proportioned as a statue, yet breathing; one of these writers we call
by that vain word—so vain, so pathetic even when used of the
greatest poet—“immortal.”
 ANTHONY TROLLOPE
THE BARSETSHIRE NOVELS

I
A few months ago I asked a publisher if he had ever thought of
venturing on a complete edition of Trollope, and was answered that
he had thought of it often, but doubted it would not pay. A few weeks
ago I referred this answer to an eminent bookseller, and he praised
the publisher’s judgment. I retain my belief that the pair of them are
mistaken: for let the name of Trollope be mentioned in any company
of novel-lovers, almost to a certainty one or two will kindle, avow a
passion for him, and start a chorus of lament that there exists no
complete worthy edition of him.
“All Balzac’s novels occupy one shelf”—and all Trollope’s would
occupy a plaguey long one. Some of them, too, are hasty, baddish
novels. None the less, I see that shelf as one of trusted and familiar
resort for such a number of my fellows as would fill a respectable
subscription-list: and, anyhow, it remains a scandal that certain good
works of his—The Eustace Diamonds, for instance—are
unprocurable save by advertising for second-hand copies. Mr.
Humphrey Milford, of the Oxford University Press, has recently
printed The Claverings and The Belton Estate in the World’s
Classics, with the Autobiography, which did, as it happened, about
as much harm as a perfectly honest book could do to an honest
man’s fame. Messrs. Chatto & Windus—whom, as Cicero would say,
“I name for the sake of honour,” as publishers who respect their
moral contract to keep an author’s books alive while they can—have
kept on sale some eight or nine, including The American Senator,
The Way We Live Now, and The Golden Lion of Grandpré; and the
famous Barsetshire six, of which Messrs. George Bell now offer us a
 7
cheap and pleasant reprint, have always been (as they say in
Barset) “come-at-able” in some form or another. But while three full
editions of Stevenson have been subscribed for since his death in
1894 (the first of them fetching far more than the original price), and
his sale in cheaper editions has been high and constant, Trollope,
who died in 1882, has, in these forty-odd years, received no
gratitude of public recognition at all answerable to his deserts.

7
Trollope’s Barsetshire Novels: (1) The
Warden, (2) Barchester Towers, (3) Dr. Thorne,
(4) Framley Parsonage, (5) The Small House at
Allington (2 vols.), (6) The Last Chronicle of
Barset (2 vols.) 8 vols. 25s. the set. (Bell &
Sons.)

It is a curious business in two ways. For the first, the rebirth of

Trollope’s fame, with the growing readiness of an admirer to cast
away apology and hail a fellow-admirer as a friend “by adoption
tried,” has nothing esoteric about it. A passion for Peacock, or for
Landor—as a passion for Pindar—you may share with a friend as a
half-masonic, half-amorous secret. But there can be no such
freemasonry over Trollope, who is as English as a cut off the joint or
a volume of Punch. For the second curiosity, I suppose that no man
ever wrote himself down at a more delicately ill-chosen time than did
Trollope by the publication (posthumous) of his Autobiography in
1883. It was a brave—if unconsciously brave—and candid book. But
it fell on a generation of young men fired in literature by Flaubert, in
painting (say) by Whistler; on a generation just beginning to be
flamboyant over “art for art’s sake,” the mot juste, and the rest. It all
seems vain enough at this distance, and the bigots of each
successive iron time will always be arraigning their fathers’ harmless
art, no doubt to the ultimate advancement of letters. But by young
men quite honestly and frenetically devoted to chiselling out English
as though (God rest them!) in obedience to a Higher Power, it may