Mary Linden, M.S.
Research Associate

A. Sex chromosomal abnormalities (SCA): A prospective study.

Sex chromosome abnormalities (SCA) are common. Found in 1 in 400 live newborns, SCA are even more common than Down syndrome or fragile X syndrome. With normal life expectancy, it is estimated that close to three quarters of a million individuals with SCA live in the United States alone. Intriguingly, many if not most of these cases will go undiagnosed, not because SCA has no effect, but because its effects on human development are variable, sometimes subtle, and often difficult to distinguish from other developmental disorders. While SCA can include a variety of abnormalities of the sex chromosomes, by far the most commonly occurring SCA involve the deletion (45,X or partial X monosomy) or addition (47,XXY, 47,XYY, 47,XXX) of an X or Y chromosome. Of these conditions, only Turner syndrome, caused by the loss of all or part of an X chromosome, results in an easily identifiable physical phenotype.

The Denver Study of individuals with sex chromosome abnormalities (SCA) was the first to screen a large number of consecutive newborns for SCA and to follow them prospectively. Now in its 31st year of NIH funding, this study continues to document the developmental prognosis of individuals with SCA. We receive hundreds of calls each year from expectant parents of prenatally diagnosed SCA fetuses and their obstetricians and genetic counselors; information made available from this study has a significant impact upon the genetic counseling of these parents and their subsequent decision making. This is one of only two remaining projects in the world continuing the longitudinal study of this population into adulthood. No other study is likely to be able to provide a life-span prognosis for SCA individuals.

The unselected SCA cohort has provided a unique opportunity to investigate the relationship between the sex chromosomes, development, and behavior through childhood and adolescence. The effects of SCA are milder than those of any other chromosome lesion; nonetheless, an increased risk for language, learning, and behavioral impairment has been identified. Karyotype-specific patterns of development separate the primary SCA groups (47,XXY; 47,XXY; 47,XYY; 45,X and partial monosomy X; and mosaics) and help to define the role of the sex chromosomes in human development and naturally occurring sex differences. Evaluation of the families of propositi has helped to clarify the relationship between environment and developmental risk imposed by the SCA and to understand the observed variability in adaptation and ability within the SCA groups.

The emergence into young adulthood has been a difficult period of transition for many propositi, now twenty to thirty years of age. Progression through adolescent milestones, including finishing high school and achieving independence, has lingered into early adulthood. Problems observed in childhood, in particular language and learning impairments, have impeded educational, social, and vocational success, and likely have contributed to the presence of maladaptive behavior in some propositi. Psychiatric disorder, ranging from mild and acute to severe and chronic, has been diagnosed in a significant number of subjects. The group of 47,XXX women has demonstrated the greatest degree of psychological dysfunction in early adulthood. The 45,X and partial monosomy X women have demonstrated psychological decline, while the 47,XXY men appear to be improving in their overall adaptation. The presence of some individuals in each karyotype group with positive overall adaptation is a reminder that the effects of SCA are variable and sometimes quite subtle.

Our continuing evaluation of the SCA cohort into adulthood will provide the only currently available information on the natural history from birth to adulthood of individuals with SCA. The continuation of this study into adulthood is critical because, as noted by Cicchetti and Garmezy (1993) in their description of children in psychopathology risk groups: "vulnerabilities and/or strengths may emerge during developmental transitions throughout the life course as well as during periods of acute stress."

This is a multidisciplinary effort involving the expertise of several disciplines. It includes the evaluation of language impairments observed in childhood and carried into adulthood; the incidence, degree, and course of psychopathology; the frequency and quality of social, romantic, and sexual relationships; and broad markers of adaptation including educational and vocational progress and independent living. We believe it crucial to understand the developmental experiences which contribute to or interfere with successful adaptation, and to that end have included a retrospective interview about childhood experiences and family relationships. The natural physical development of SCA adults will be documented. Finally, we have planned a study of brain structures using magnetic resonance imaging to investigate the impact of SCA on neurological development, and to add to understanding of the biological variations which mediate the relationship between SCA and behavioral adaptation. Pilot neuroimaging data strongly suggest that we will detect specific structural changes in SCA brains.

We are continuing the evaluation of the value of testosterone therapy in adolescents with a 47,XXY karyotype, as well as the efficacy of a transdermal testosterone patch as a method of giving testosterone.

B. Follow-up of SCA born after being diagnosed by amniocentesis.

Because of the tremendously expanded use of prenatal diagnosis, the identification of children with SCA and their long-term prognosis have become vitally important. Until now, information about these individuals has come from studies of SCA children diagnosed through neonatal screening programs. We are now following another group of SCA individuals consisting of children who were diagnosed prenatally and whose parents chose to continue the pregnancy. The study of this latter group will help to increase appreciation for the phenotypic range in this population and the factors which ameliorate the effects of SCA. Pilot data suggest a more positive prognosis than previously recognized. I have received over 700 telephone calls from all over the United States and Canada from physicians and parents concerned about the prognosis of prenatally diagnosed SCA.

C. Molecular studies.

All patients with monosomy X that we are following or see in consultation are being checked with Y chromosome short arm probes to see if they have any Y chromosome DNA. If they do, this will have serious implications in management.

This work is carried out in collaboration with Bruce Bender, Ph.D.

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