A review of trisomy X (47,XXX)

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.

Figure 1

Variable facial features in girls with trisomy X. (a) Epicanthal folds and hypertelorism in 2 year old girl, (b) Hypertelorism in 9 year old girl, (c) Lack of dysmorphic features in a 19 year old girl with trisomy X.

Figure 2

Estimated Full-Scale IQ (FSIQ) distribution for females with 47,XXX compared to controls. In 47,XXX, there is a wide variation in IQ with the normal curve shifted to the left with the mean FSIQ at 85-90. The majority of females with 47,XXX have a FSIQ in the normal range, and many are above average compared to the general population. However, due to the shift of the curve, a larger percentage of females with 47,XXX fall in the intellectual disability range compared to controls. Adapted and reprinted with permission from Bender et. al. 1986 [42].