ReviewA review of trisomy X ( 47 , XXX )

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. Schoolage 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. Background/Definition Trisomy X (47,XXX) is a sex chromosome aneuploidy condition in which females have an extra X chromosome, compared to the 46,XX karyotype in typical females. It was first described in 1959 in a 35-year-old woman with normal intellectual abilities who presented with secondary amenorrhea at 19 years of age [1]. Since the initial description, only several hundred cases have been described, identifying a variety of associated developmental, psychological, and medical features. Most of the background literature on trisomy X comes from longitudinal prospective studies of females identified by newborn screening and followed into young adulthood. These studies were conducted in the 1970's and 80's at multiple centers across the U.S., Canada, and the U.K. [25]. 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. However, review of the current knowledge is necessary to provide a summary of background and treatment recommendations for patients and * Correspondence: tartaglia.nicole@tchden.org 1 Department of Pediatrics, University of Colorado Denver School of Medicine, 13123 East 16th Ave, Aurora, Colorado, 80045, USA Full list of author information is available at the end of the article BioMed Central © 2010 Tartaglia et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Tartaglia et al. Orphanet Journal of Rare Diseases 2010, 5:8 http://www.ojrd. com/content/5/1/8 Page 2 of 9 professionals, and to highlight the many areas of need for additional research in trisomy X. Disease Names/Synonyms Trisomy X is also commonly known as: 47,XXX Triple X, or Triplo-X Epidemiology Originally described as the "superfemale" in 1959, trisomy X occurs in approximately 1 in 1,000 female births, however, it is estimated that only approximately 10% of cases are diagnosed [6]. In identified cases, diagnosis occurs through prenatal amniocentesis or chorionic villi sampling (CVS), or in the postnatal period through a standard karyotype test or chromosome analysis performed for hypotonia, developmental delays, physical features, or cognitive/behavioral difficulties. Although nonmosaic 47,XXX karyotypes are the most frequent, mosaicism occurs in approximately 10% of cases and can occur in many combinations such as 46,XX/47,XXX or 47,XXX/48,XXXX, or in combinations including Turner syndrome cell lines such as 45,X/47,XXX or 45,X/46,XX/ 47,XXX[6]. Clinical Description A. Physical Characteristics Significant facial dysmorphology or striking physical features are not commonly associated with 47,XXX, however, minor physical findings can be present in some individuals including epicanthal folds, hypertelorism, upslanting palpebral fissures, clinodactyly, overlapping digits, pes planus, and pectus excavatum. Hypotonia and joint hyperextensibility may also be present [2,7]. Please see Figure 1 for photographs of girls with trisomy X, and Table 1 for a summary of physical and medical features. Length and weight at birth is usually normal for gestational age, however, stature typically increases in early childhood, and by adolescence most girls with 47,XXX are at or above the 75th percentile for height [2]. A few cases have been ascertained due to tall stature [8], and current evaluation of tall stature in females should include karyotype analysis to evaluate for 47,XXX. Cases of short stature have also been described (unrelated to a known 45,X mosaicism), and one prospective study identified a subgroup of 47,XXX girls with heights below the 50th percentile [9]. Body segment proportions typically show long legs, with a short sitting height [10]. Studies of bone age have shown no significant differences from 46,XX females [11]. The average head circumference is below the 50th percentile, however, there is a lot of individual variation. Microcephaly (<5th percentile) is rare [12,13]. B. Clinical characteristics Although major medical problems are not present in most cases, other medical problems may be associated with trisomy X. The most common are genitourinary abnormalities, ranging from unilateral kidney and renal dysplasia to ovarian malformations [14]. Congenital heart defects have also been described including cases of atrial and ventricular septal defects, pulmonic stenosis, and aortic coarctation [15-17]. Studies describing seizure disorders and EEG abnormalities in trisomy X vary from 0 to Table 1: Physical and Medical Features Associated with