Handbook of Davis PEDIATRIC Neuropsychology Andrew S. Davis, PhD, Editor Handbook of P Neuropsychology The breadth and depth of this body of work is impressive. Chapters written by some of the best researchers and authors in the field of pediatric neuropsychology address every pos- EDIATRI Handbook of Handbook sible perspective on brain-behavior relationships culminating in an encyclopedic text…. This [book] reflects how far and wide pediatric neuropsychology has come in the past 20 PEDIATRIC years and the promise of how far it will go in the next. –Elaine Fletcher-Janzen, EdD, NCSP, ABPdN The Chicago School of Professional Psychology Neuropsychology his landmark reference covers all aspects of pediatric neuropsychology from a research- based perspective, while presenting an applied focus with practical suggestions and Tguidelines for clinical practice. Useful both as a training manual for graduate students and as a comprehensive reference for experienced practitioners, it is an essential resource for those dealing with a pediatric population. This handbook provides an extensive overview of the most common medical conditions that neuropsychologists encounter while dealing with pediatric populations. It also discusses school- based issues such as special education law, consulting with school staff, and reintegrating children C back into mainstream schools. It contains contributions from over 100 well-respected authors who are leading researchers in their respective fields. Additionally, each of the 95 chapters includes an up-to-date review of available research, resulting in the most comprehensive text on pediatric neuropsychology available in a single volume. Key features: Andrew S. Davis º Provides thorough information on understanding functional neuroanatomy and development, and on using functional neuroimaging Editor º Highlights clinical practice issues, such as legal and ethical decision making, dealing with child abuse and neglect, and working with school staff º Describes a variety of professional issues that neuropsychologists confront during their daily practice, such as ethics, multiculturalism, child abuse, forensics, and psychopharmacology With compliments of Springer Publishing Company, LLC 11 W. 42nd Street New York, NY 10036-8002 www.springerpub.com 65 Sex Chromosome Aneuploidies Rebecca Wilson, Elizabeth Bennett , Susan E. Howell, and Nicole Tartaglia OVERVIEW OF SEX CHROMOSOME features of sex chromosome aneuploidies are generally ANEUPLOIDIES much less distinct and more variable than other chromo- somal aneuploidy conditions such as Down syndrome, Approximately 1 in 400 births has a combination of sex leading to lower rates of diagnosis and lower public chromosomes that diff ers from the typical male karyo- awareness and recognition of these conditions. The neu- type of 46,XY or typical female karyotype of 46,XX. Sex ropsychological features of the most common sex chro- chromosome aneuploidy conditions are a group of genetic mosome aneuploidy conditions (including TS, XXY/KS, disorders characterized by an atypical number of X and/ XYY, Triple X) are also less severe, and cognitive abilities or Y chromosomes, and are also known as sex chromo- in the intellectual disability range are rare. However, indi- some abnormalities, sex chromosome anomalies, or X&Y viduals with sex chromosome aneuploidies are at higher chromosome variations. Examples of the most com- risk for developmental delays, learning disabilities, exec- mon sex chromosome aneuploidy conditions in males utive dysfunction, and adaptive functioning defi cits. An include 47,XXY (Klinefelter syndrome [KS]) and 47,XYY. understanding of the neuropsychological profi les associ- In females, sex chromosome aneuploidies include 45,X ated with sex chromosome aneuploidy conditions is very (Turner syndrome [TS]) and 47,XXX (Trisomy X). Less important in the evaluation and treatment of individuals common variations occur with the addition of more than with these syndromes. one extra sex chromosome (i.e., 48,XXYY or 49,XXXXX), The fi rst large studies on the developmental and psy- and the physical and neuropsychological features become chological features of these conditions were performed more signifi cant as additional chromosomes are added. from the 1970s to 1990s when newborns at many sites Table 65.1 includes a complete list of the sex chromosome around the world were screened at birth, and individuals aneuploidy conditions and their prevalence. with sex chromosome aneuploidy were identifi ed and fol- The absence or addition of sex chromosomes leads to lowed until young adulthood. The design of these studies syndromes with characteristic physical and medical fi nd- allowed for long-term evaluation of subjects ascertained ings, as well as associated characteristic profi les of devel- at birth, and results form the basis of our knowledge of opmental and neuropsychological fi ndings. The physical the neuropsychological profi les. Additional research in the 2000s has supplemented and expanded these original fi ndings. The most signifi cant distinction is in compari- son of neuropsychological profi les between TS/45,X where Table 65.1 ■ List of Sex Chromosome Aneuploidy Conditions there is a missing X chromosome and the conditions with extra X and Y chromosomes (XXY, XYY, XXX). TS is asso- Karyotype Also Known as Estimated Prevalence ciated with defi cits in visuo–perceptual abilities and rel- Males ative strengths in verbal skills, while the conditions with 47,XXY Klinefelter syndrome 1:650 extra X and/or Y chromosomes share language-based 47,XYY – 1:1,000 48,XXXY – 1:20,000 defi cits and relative strengths in nonverbal abilities. 48,XXYY – 1:18,000 The medical and psychological features in sex chro- 48,XYYY – ? mosome aneuploidy conditions are hypothesized to 49,XXXXY – 1:85,000 result from diff erences in the expression levels of genes 49,XXXYY – ? on the sex chromosomes. In cells with more than one X 49,XYYYY – ? chromosome, such as typical 46,XX cells in females or Females 45,X Turner syndrome 1:2,500 males with 47,XXY, the second X chromosome undergoes 47,XXX Triple X, Triplo-X, 1:1,000 a process called X-inactivation in order to maintain a bal- Trisomy X ance of gene expression in the cells. However, approxi- 48,XXXX Tetrasomy X 1:50,000 mately 10–20% of genes on the second X chromosome 49,XXXXX Pentasomy X 1:250,000 escape X-inactivation and these genes are expressed by Copyright Springer Publishing Company, LLC 806 ■ V: Pediatric Neuropsychological Disorders both X chromosomes. In TS (45,X), genes that escape or in the early cell divisions aft er fertilization. The addi- X-inactivation are then expressed at a lower level com- tional X chromosome has been shown to be paternal in pared to typical 46,XX females, while in 47,XXY or 47,XXX origin in approximately 50% of cases and maternal in they are expressed at a higher level. A good example to origin in approximately 50% of cases (Jacobs et al., 1988; illustrate this principle is the SHOX gene and its relation- Lorda-Sanchez, 1992). In approximately 16% of cases the ship to height in sex chromosome aneuploidy conditions. nondisjunction occurs aft er fertilization, which can lead Short stature is a characteristic feature of TS, while XXY/ to mosaicism, where an individual has a combination of KS and Triple X syndrome are associated with tall stature. both 46,XY and 47,XXY cells (Thomas & Hassold, 2003). The SHOX gene is located on the X and Y chromosomes, Mosaicism accounts for approximately 10% of males with escapes X-inactivation, and is known to be involved in Klinefelter syndrome, and typically leads to milder phys- bone growth of long bones that contribute to fi nal adult ical and psychological fi ndings (Paduch, Fine, Bolyakov, stature. Females with TS only express SHOX from one & Kiper, 2008). It is postulated that the physical and psy- X chromosome, and this decreased expression of SHOX chological features associated with 47,XXY result from in TS leads to short stature. In contrast, in 47,XXY and overexpression of genes from the extra X chromosome; 47,XXX, SHOX is expressed from all three sex chromo- however, the specifi c genes leading to psychological fea- somes contributing to tall stature in these conditions. tures have yet to be identifi ed. Thus, diff erences in the levels of gene expression from The diagnosis of Klinefelter syndrome is made genes on the sex chromosomes lead to characteristic fea- by a chromosome analysis (also called a karyotype) tures of the syndromes. These gene dosage eff ects are that shows the extra X chromosome. Approximately also hypothesized to be involved in the psychological 10% of cases are diagnosed by amniocentesis in the phenotypes of sex chromosome aneuploidy; however, the prenatal period, while the remaining identifi ed cases specifi c genes involved in neuropsychological features of are diagnosed in the postnatal period due to devel- these conditions have not yet been identifi ed. opmental delays or learning problems in childhood, pubertal delays in adolescence, or infertility in adult- hood. However, it is estimated that 64% of males with SEX CHROMOSOME ANEUPLOIDY IN MALES Klinefelter syndrome remain undiagnosed in their life- time (Abramsky & Chapple, 1997). KLINEFELTER SYNDROME (47,XXY) Physical and Medical Features of Background and History of Klinefelter Syndrome Klinefelter Syndrome Klinefelter syndrome was fi rst described in 1942 by In early childhood, physical and medical features of Dr. Harry Klinefelter and colleagues in an endocrinol- Klinefelter syndrome are oft en subtle or absent, but can ogy clinic at Massachusett s General Hospital in Boston, include early developmental delay (speech and/or motor Massachusett s. The fi rst description was a series of nine development), and physical features such as hypotonia postpubertal males with tall stature, sparse facial and (low muscle tone), hypertelorism (widely spaced eyes), body hair, small testes, testosterone defi ciency, and no clinodactyly (curvature of the fi ft h fi nger), hyperextensi- sperm production (Klinefelter, Reifenstein, & Albright, ble joints, and/or fl at feet. Tall stature can begin in child- 1942).