Abstract
Trisomy X is a sex chromosome anomaly with a variable phenotype caused by the presence of an extra X chromosome in females (47,XXX instead of 46,XX). It is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births. As some individuals are only mildly affected or asymptomatic, it is estimated that only 10% of individuals with trisomy X are actually diagnosed. The most common physical features include tall stature, epicanthal folds, hypotonia and clinodactyly. Seizures, renal and genitourinary abnormalities, and premature ovarian failure (POF) can also be associated findings. Children with trisomy X have higher rates of motor and speech delays, with an increased risk of cognitive deficits and learning disabilities in the school-age years. Psychological features including attention deficits, mood disorders (anxiety and depression), and other psychological disorders are also more common than in the general population. Trisomy X most commonly occurs as a result of nondisjunction during meiosis, although postzygotic nondisjunction occurs in approximately 20% of cases. The risk of trisomy X increases with advanced maternal age. The phenotype in trisomy X is hypothesized to result from overexpression of genes that escape X-inactivation, but genotype-phenotype relationships remain to be defined. Diagnosis during the prenatal period by amniocentesis or chorionic villi sampling is common. Indications for postnatal diagnoses most commonly include developmental delays or hypotonia, learning disabilities, emotional or behavioral difficulties, or POF. Differential diagnosis prior to definitive karyotype results includes fragile X, tetrasomy X, pentasomy X, and Turner syndrome mosaicism. Genetic counseling is recommended. Patients diagnosed in the prenatal period should be followed closely for developmental delays so that early intervention therapies can be implemented as needed. School-age children and adolescents benefit from a psychological evaluation with an emphasis on identifying and developing an intervention plan for problems in cognitive/academic skills, language, and/or social-emotional development. Adolescents and adult women presenting with late menarche, menstrual irregularities, or fertility problems should be evaluated for POF. Patients should be referred to support organizations to receive individual and family support. The prognosis is variable, depending on the severity of the manifestations and on the quality and timing of treatment.
Highlights
Trisomy X is a sex chromosome anomaly with a variable phenotype caused by the presence of an extra X chromosome in females (47,XXX instead of 46,XX)
While newborn screening studies have demonstrated that the incidence of trisomy X is approximately 1/1000 female births, only approximately 10% of cases are ascertained clinically
There is considerable variation in the phenotype, with some individuals very mildly affected and others with more significant physical and psychological features. This manuscript reviews the current literature available describing features associated with trisomy X, with recognition that much of the literature is based on small sample sizes and clinical ascertainment of patients, and does not likely represent the full spectrum of females with trisomy X
Summary
Major medical problems are not present in most cases, other medical problems may be associated with trisomy X. For school-age children and adolescents, a multidisciplinary assessment, including evaluation with a child psychologist (for learning disabilities, social/emotional problems, and adaptive functioning assessment), as well as speech/language assessment and occupational therapy assessment, is important in order to identify strengths and weaknesses and to help develop educational supports and behavioral interventions. Prognosis The prognosis of trisomy X is variable, with some individuals doing extremely well with minimal manifestations of the disorder, and others with more significant cognitive and psychological involvement as described above Outcomes of those diagnosed in the prenatal period have been found to be better than those of patients described in the prospective studies (birth cohorts) and than those in case reports of girls identified after birth ascertained due to developmental delays [64].
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