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Velo-Cardio-Facial-Syndrome: A Model for Understanding Microdeletion Disorders
BOOK REVIEWS
Velo-Cardio-Facial-Syndrome: A Model for Understanding Microdeletion Disorders. Edited by Kieran C. Murphy and Peter J. Scambler. New York: Cambridge University Press, 2005, 243 pp., $120 (hardcover).
Please do not dismiss this tongue twister of a syndrome as an irrelevant zebra. Far from it, velocardiofacial syndrome (VCFS) provides one of the strongest predictive genetic risk factors for the development of schizophrenialike psychotic disorders. As such, it may provide a useful heuristic model to shed light on the frustrating Bblack box[ that remains the cause of schizophrenia. VCFS is about as common as autism and Tourette_s syndrome, and its manifestations are heterogeneous. In some instances, patients with VCFS may only have mild physical disability, but they almost always suffer from learning disabilities and psychiatric disorders. Hence, it is important for psychiatrists to be aware of the major manifestations of VCFS so they can refer suspected individuals for genetic evaluation. Although this new volume outlines almost 200 physical symptoms involving most organ systems, the authors have focused on its main clinical manifestations, rather than exhausting the reader with extraneous details. The syndrome was first described by Angelo DiGeorge during the 1960s and by Robert Shprintzen during the 1970s. The DiGeorge syndrome was defined as characterized by immunologic deficiencies secondary to thymus hypoplasia, hypocalcemia secondary to hypoparathyroidism, and congenital cardiac anomalies. By contrast, the syndrome bearing Shprintzen_s name and later VCFS, included major features suggested by its acronym: palate anomalies (velo), congenital cardiovascular defects (cardio), and mild facial dysmorphism (facial). In the early 1990s, it was Scambler and colleagues who discovered that both DiGeorge syndrome and VCFS are caused by a microdeletion in the same region of the long arm of chromosome 22 (at band 22q11.2). The cause of the phenotypic variability of this microdeletion syndrome is still not known. It could be related to genes in the homologous region on the intact chromosome 22 (such as COMT and PRODH) or to interaction with genes in other regions. In addition, it is probably related to yet unspecified environmental factors. The clinical diagnosis of 22q11 is verified by a cytogenetic test, fluorescent in situ hybridization. In most cases the syndrome is caused by the de novo microdeletion of a 3-Mb region, but there is also a 50% chance
J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 45:6, JUNE 2006
Assistant Editor: Andre´s Martin, M.D., M.P.H.
of transmitting the syndrome to the offspring of affected patients. This microdeletion comprises at least 27 genes expressed in the brain (including COMT), and occurs in about 1/4,000 livebirths. Interestingly, other common microdeletion syndromes also have unique behavioral phenotypes and are associated with learning disabilities and mental retardation. For example, fragile X syndrome is characterized by gaze aversion and a social disability, Williams syndrome by hypersocial behaviors, and Prader-Willi syndrome by excessive eating and compulsive behaviors such as skin-picking. The editors of this book have divided the volume into 12 chapters that provide basic science data on VCFS as a model disorder, as well as clinically relevant information about this complex syndrome. In the first chapter, Robert J. Shprintzen describes the historical overview of his formerly namesake condition. The second chapter provides a comprehensive list of the genes from the deleted region. The functions of the proteins encoded by the various genes are well described and remind us that the development of the brain and its functions are more complex than the simple balance between dopamine and serotonin. The next four chapters in the book are dedicated to the major physical manifestations, including cardiovascular, immunologic, and facial. Some cardiovascular anomalies, such as interrupted aortic arch, are almost pathognomonic, whereas others, such as ventricular septal defect, are common but hardly specific. Chapters 7 through 10 are most relevant to psychiatry. Supported by extensive research, they describe the high rates of schizophrenia in as many as one fourth of adolescents and adults with the syndrome. The authors also describe the association of VCFS with other psychiatric disorders, such as bipolar disorder, attention-deficit/hyperactivity disorder, affective disorders, and autism spectrum disorders. The psychiatric treatment section is understandably short, in contrast to the rich literature on psychiatric morbidity and cognitive profiles. Patients with VCFS have a varied range of cognitive impairment, with an average IQ in the mid-70s. Chapter 8 gives an in-depth and detailed overview of the cognitive deficit profile characteristic of individuals with VCFS, including in the areas of mathematics and numerical skills, visual object and spatial cognition, memory, executive function, attention, and communication skills. At the end of this chapter, authors Linda Campbell and Ann Swillen provide an excellent schematic representation of different research strategies to further investigate these deficits. There is also a comprehensive overview of the rich literature on
757
Copyright @ 2006 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
BOOK REVIEWS
structural neuroimaging in VCFS and its relevance to the neurobiology of schizophrenia. As in schizophrenia, VCFS is characterized by subtle reductions in brain volumes in cortical and subcortical regions. However, it is still not known which of these changes predict the onset of schizophrenia in affected patients. Longitudinal studies that are now being conducted will perhaps answer this question. It is surprising that there have been almost no functional neuroimaging studies in VCFS because it would seem that functional magnetic resonance imaging studies in VCFS could shed light on the interaction between specific genes (e.g., COMT ) and brain function. In Chapter 10, Karen J. Golding-Kushner, the president of the VCFS Educational Foundation, emphasizes that it is not only articulation (speech) that is aberrant in VCFS, but also the production of words (expressive language) and communication skills. She further elaborates on the mechanism of the velopharyngeal insufficiency leading to a characteristically hypernasal voice. With experience gained through decades of work with children with VCFS, her chapter provides practical measures used to improve the speech capabilities of affected individuals. Chapter 11 focuses on genetic counseling and provides sufficient information on what family members want to know and how their questions can be answered appropriately. The last chapter of the book, BFamily Issues,[ reminds the reader that the impact of having a child affected with a genetic syndrome goes far beyond the patient. It makes one realize the importance of staying attuned and sensitive to the needs of immediate and extended family members. In conclusion, VCFS should be familiar to child psychiatrists as a major genetic risk factor for serious neuropsychiatric morbidity, especially schizophrenia. To help facilitate a better understanding of VCFS, this book is comprehensive and balanced and will serve as a good reference for anyone involved in the care of individuals with this condition. Sunanda Muralee, M.D. Department of Psychiatry Yale University School of Medicine New Haven, CT
Doron Gothelf, M.D. Center for Interdisciplinary Brain Sciences Research Stanford University Stanford, CA Sackler School of Medicine Tel Aviv University Tel Aviv
Disclosure: The authors have no financial relationships to disclose.
758
Juvenile-Onset Schizophrenia: Assessment, Neurobiology and Treatment. Edited by Robert L. Findling, and S. Charles Schulz. Baltimore: The Johns Hopkins University Press, 2005, 311 pp., $49.99 (hardcover). In the field of psychiatric research, there has been increasing interest in the neurobiology and developmental course of schizophrenia and other psychiatric disorders. Mounting evidence demonstrates that schizophrenia is preceded by disordered neurodevelopment that begins in very early life. Because individuals with early-onset schizophrenia generally have a worse prognosis than patients with adult-onset schizophrenia, this group is particularly important to study. Despite research into schizophrenia precursors, risk factors, genetics, and neurobiology, we are still unable to reliably predict who will develop schizophrenia. We also lack clear methods for preventing full expression of the disorder in those who are thought to be at high risk. This book succeeds in bringing together information on diverse topics relevant to early-onset schizophrenia and in summarizing current knowledge in a concise and highly readable manner. Chapter authors include a number of top researchers in the areas of early-onset schizophrenia, childhood precursors to schizophrenia, and the schizophrenia prodrome. To understand schizophrenia and move toward better prevention and treatment, it is necessary to consider the course of the disorder across the life span. Schizophrenia research may benefit greatly from the efforts of psychiatry researchers who are familiar with childhood development in addition to adult psychopathology. Those psychiatrists who work mainly with adults are familiar with the present characteristics of their adult patients with schizophrenia, but some may not be aware of their patients_ childhood development and early psychopathology. Child psychiatrists see children who may be at risk of eventually developing schizophrenia, but they do not have a clear way to determine which young patients are showing symptoms that could be precursors to schizophrenia. The content of this book is relevant to all clinicians and researchers who work with psychiatric patients, whether they work mainly with children or adults. The book focuses mainly on adolescent-onset schizophrenia but also includes information on childhood-onset schizophrenia and other early-onset psychotic disorders, including affective disorders with psychotic features and psychosis not otherwise specified. The book provides a summary of current knowledge regarding risk factors, assessment, epidemiology, neurodevelopment, neurophysiology, neuroimaging, neuropsychology, genetics, and treatment. The book is useful for clinicians interested in evidence-based treatments and for researchers who need a
J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 45:6, JUNE 2006
Copyright @ 2006 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
Velo-Cardio-Facial-Syndrome: A Model for Understanding Microdeletion Disorders. Edited by Kieran C. Murphy and Peter J. Scambler. New York: Cambridge University Press, 2005, 243 pp., $120 (hardcover).
Please do not dismiss this tongue twister of a syndrome as an irrelevant zebra. Far from it, velocardiofacial syndrome (VCFS) provides one of the strongest predictive genetic risk factors for the development of schizophrenialike psychotic disorders. As such, it may provide a useful heuristic model to shed light on the frustrating Bblack box[ that remains the cause of schizophrenia. VCFS is about as common as autism and Tourette_s syndrome, and its manifestations are heterogeneous. In some instances, patients with VCFS may only have mild physical disability, but they almost always suffer from learning disabilities and psychiatric disorders. Hence, it is important for psychiatrists to be aware of the major manifestations of VCFS so they can refer suspected individuals for genetic evaluation. Although this new volume outlines almost 200 physical symptoms involving most organ systems, the authors have focused on its main clinical manifestations, rather than exhausting the reader with extraneous details. The syndrome was first described by Angelo DiGeorge during the 1960s and by Robert Shprintzen during the 1970s. The DiGeorge syndrome was defined as characterized by immunologic deficiencies secondary to thymus hypoplasia, hypocalcemia secondary to hypoparathyroidism, and congenital cardiac anomalies. By contrast, the syndrome bearing Shprintzen_s name and later VCFS, included major features suggested by its acronym: palate anomalies (velo), congenital cardiovascular defects (cardio), and mild facial dysmorphism (facial). In the early 1990s, it was Scambler and colleagues who discovered that both DiGeorge syndrome and VCFS are caused by a microdeletion in the same region of the long arm of chromosome 22 (at band 22q11.2). The cause of the phenotypic variability of this microdeletion syndrome is still not known. It could be related to genes in the homologous region on the intact chromosome 22 (such as COMT and PRODH) or to interaction with genes in other regions. In addition, it is probably related to yet unspecified environmental factors. The clinical diagnosis of 22q11 is verified by a cytogenetic test, fluorescent in situ hybridization. In most cases the syndrome is caused by the de novo microdeletion of a 3-Mb region, but there is also a 50% chance
J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 45:6, JUNE 2006
Assistant Editor: Andre´s Martin, M.D., M.P.H.
of transmitting the syndrome to the offspring of affected patients. This microdeletion comprises at least 27 genes expressed in the brain (including COMT), and occurs in about 1/4,000 livebirths. Interestingly, other common microdeletion syndromes also have unique behavioral phenotypes and are associated with learning disabilities and mental retardation. For example, fragile X syndrome is characterized by gaze aversion and a social disability, Williams syndrome by hypersocial behaviors, and Prader-Willi syndrome by excessive eating and compulsive behaviors such as skin-picking. The editors of this book have divided the volume into 12 chapters that provide basic science data on VCFS as a model disorder, as well as clinically relevant information about this complex syndrome. In the first chapter, Robert J. Shprintzen describes the historical overview of his formerly namesake condition. The second chapter provides a comprehensive list of the genes from the deleted region. The functions of the proteins encoded by the various genes are well described and remind us that the development of the brain and its functions are more complex than the simple balance between dopamine and serotonin. The next four chapters in the book are dedicated to the major physical manifestations, including cardiovascular, immunologic, and facial. Some cardiovascular anomalies, such as interrupted aortic arch, are almost pathognomonic, whereas others, such as ventricular septal defect, are common but hardly specific. Chapters 7 through 10 are most relevant to psychiatry. Supported by extensive research, they describe the high rates of schizophrenia in as many as one fourth of adolescents and adults with the syndrome. The authors also describe the association of VCFS with other psychiatric disorders, such as bipolar disorder, attention-deficit/hyperactivity disorder, affective disorders, and autism spectrum disorders. The psychiatric treatment section is understandably short, in contrast to the rich literature on psychiatric morbidity and cognitive profiles. Patients with VCFS have a varied range of cognitive impairment, with an average IQ in the mid-70s. Chapter 8 gives an in-depth and detailed overview of the cognitive deficit profile characteristic of individuals with VCFS, including in the areas of mathematics and numerical skills, visual object and spatial cognition, memory, executive function, attention, and communication skills. At the end of this chapter, authors Linda Campbell and Ann Swillen provide an excellent schematic representation of different research strategies to further investigate these deficits. There is also a comprehensive overview of the rich literature on
757
Copyright @ 2006 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
BOOK REVIEWS
structural neuroimaging in VCFS and its relevance to the neurobiology of schizophrenia. As in schizophrenia, VCFS is characterized by subtle reductions in brain volumes in cortical and subcortical regions. However, it is still not known which of these changes predict the onset of schizophrenia in affected patients. Longitudinal studies that are now being conducted will perhaps answer this question. It is surprising that there have been almost no functional neuroimaging studies in VCFS because it would seem that functional magnetic resonance imaging studies in VCFS could shed light on the interaction between specific genes (e.g., COMT ) and brain function. In Chapter 10, Karen J. Golding-Kushner, the president of the VCFS Educational Foundation, emphasizes that it is not only articulation (speech) that is aberrant in VCFS, but also the production of words (expressive language) and communication skills. She further elaborates on the mechanism of the velopharyngeal insufficiency leading to a characteristically hypernasal voice. With experience gained through decades of work with children with VCFS, her chapter provides practical measures used to improve the speech capabilities of affected individuals. Chapter 11 focuses on genetic counseling and provides sufficient information on what family members want to know and how their questions can be answered appropriately. The last chapter of the book, BFamily Issues,[ reminds the reader that the impact of having a child affected with a genetic syndrome goes far beyond the patient. It makes one realize the importance of staying attuned and sensitive to the needs of immediate and extended family members. In conclusion, VCFS should be familiar to child psychiatrists as a major genetic risk factor for serious neuropsychiatric morbidity, especially schizophrenia. To help facilitate a better understanding of VCFS, this book is comprehensive and balanced and will serve as a good reference for anyone involved in the care of individuals with this condition. Sunanda Muralee, M.D. Department of Psychiatry Yale University School of Medicine New Haven, CT
Doron Gothelf, M.D. Center for Interdisciplinary Brain Sciences Research Stanford University Stanford, CA Sackler School of Medicine Tel Aviv University Tel Aviv
Disclosure: The authors have no financial relationships to disclose.
758
Juvenile-Onset Schizophrenia: Assessment, Neurobiology and Treatment. Edited by Robert L. Findling, and S. Charles Schulz. Baltimore: The Johns Hopkins University Press, 2005, 311 pp., $49.99 (hardcover). In the field of psychiatric research, there has been increasing interest in the neurobiology and developmental course of schizophrenia and other psychiatric disorders. Mounting evidence demonstrates that schizophrenia is preceded by disordered neurodevelopment that begins in very early life. Because individuals with early-onset schizophrenia generally have a worse prognosis than patients with adult-onset schizophrenia, this group is particularly important to study. Despite research into schizophrenia precursors, risk factors, genetics, and neurobiology, we are still unable to reliably predict who will develop schizophrenia. We also lack clear methods for preventing full expression of the disorder in those who are thought to be at high risk. This book succeeds in bringing together information on diverse topics relevant to early-onset schizophrenia and in summarizing current knowledge in a concise and highly readable manner. Chapter authors include a number of top researchers in the areas of early-onset schizophrenia, childhood precursors to schizophrenia, and the schizophrenia prodrome. To understand schizophrenia and move toward better prevention and treatment, it is necessary to consider the course of the disorder across the life span. Schizophrenia research may benefit greatly from the efforts of psychiatry researchers who are familiar with childhood development in addition to adult psychopathology. Those psychiatrists who work mainly with adults are familiar with the present characteristics of their adult patients with schizophrenia, but some may not be aware of their patients_ childhood development and early psychopathology. Child psychiatrists see children who may be at risk of eventually developing schizophrenia, but they do not have a clear way to determine which young patients are showing symptoms that could be precursors to schizophrenia. The content of this book is relevant to all clinicians and researchers who work with psychiatric patients, whether they work mainly with children or adults. The book focuses mainly on adolescent-onset schizophrenia but also includes information on childhood-onset schizophrenia and other early-onset psychotic disorders, including affective disorders with psychotic features and psychosis not otherwise specified. The book provides a summary of current knowledge regarding risk factors, assessment, epidemiology, neurodevelopment, neurophysiology, neuroimaging, neuropsychology, genetics, and treatment. The book is useful for clinicians interested in evidence-based treatments and for researchers who need a
J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 45:6, JUNE 2006
Copyright @ 2006 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.