Expanding the phenotype of Triple X syndrome: A comparison of prenatal versus postnatal diagnosis

Abstract

Triple X syndrome (47, XXX) occurs in approximately 1:1,000 female births and has a variable phenotype of physical and psychological features. Prenatal diagnosis rates of 47, XXX are increasing due to non-invasive prenatal genetic testing. Previous studies suggest that prenatal diagnosed females have better neurodevelopmental outcomes. This cross-sectional study describes diagnosis, physical features, medical problems, and neurodevelopmental features in a large cohort of females with 47, XXX. Evaluation included review of medical and developmental history, physical exam, cognitive, and adaptive testing. Medical and developmental features were compared between the prenatal and postnatal diagnosis groups using rate calculations and Fisher's exact test. Cognitive and adaptive tests scores were compared using t-tests. Seventy-four females age 6 months-24 years (mean 8.3 years) participated. Forty-four (59.5%) females were in the prenatal diagnosis group. Mean age of postnatal diagnosis was 5.9 years; developmental delay was the most common indication for postnatal genetic testing. Common physical features included hypertelorism, epicanthal folds, clinodactyly, and hypotonia. Medical problems included dental disorders (44.4%), seizure disorders (16.2%), genitourinary malformations (12.2%). The prenatal diagnosis group had higher verbal (P < 0.001), general ability index (P = 0.004), and adaptive functioning scores (P < 0.001). Rates of ADHD (52.2% vs. 45.5%, P = 0.77) and learning disabilities (39.1% vs. 36.3%, P = 1.00) were similar between the two groups. These findings expand on the phenotypic features in females with Triple X syndrome and support that prenatally ascertained females have better cognitive and functional outcomes. However, prenatally diagnosed females are still at risk for neurodevelopmental disorders. Genetic counseling and treatment recommendations are summarized. © 2016 Wiley Periodicals, Inc.

Sex chromosome aneuploidy detection by noninvasive prenatal testing: helpful or hazardous?

“…For children born with Turner syndrome or Klinefelter syndrome, early diagnosis, which might not have occurred without NIPT, can enable early treatment interventions and counseling. Better cognitive and functional outcomes are observed in prenatally ascertained females with triple X . Identification of a pregnancy with Turner syndrome and confirmation on prenatal karyotype can also help set expectations of clinical outcomes for families.…”

“…Taken together, rates of SCA are as high as for the autosomal trisomies, and advanced maternal age increases the likelihood of a positive NIPT result. However, the phenotypes of sex chromosome aneuploidies are often mild, especially when mosaic, and may be even milder when ascertained prenatally, especially in the absence of ultrasound abnormalities . Before embarking on a test, caregivers should have a clear picture of what to tell the patient about the disorder and the clinical utility of prenatal ascertainment.…”

MANAGEMENT OF ENDOCRINE DISEASE: Diagnostic and therapeutic approach of tall stature

“…Affected girls can present with mild ocular hypertelorism, epicanthal folds, pes planus and 5th finger clinodactyly (45,46,47). Height is normal until the age of 4, and they become taller because of longer legs, reaching a stature in the upper limit of the normal range or mildly above 2 s.d.…”

“…Fertility is not an issue, although premature ovarian failure has been reported in some cases. Learning disabilities, especially regarding expressive language, are also present, and many girls are diagnosed during an investigation for developmental delay (47). Diagnosis is achieved by a 47,XXX karyotype with or without mosaicism.…”

When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome

“…However, these estimates are clearly influenced by ascertainment, which often follows diagnostic evaluation for developmental delay or learning disability. The lack of a distinct and/or severe phenotype for 47,XXX means that many individuals remain undiagnosed, and these are probably females with less severe outcomes, in agreement with the observation that prenatally ascertained 47,XXX females generally had better cognitive and adaptive functioning [15]. While gain of an X chromosome seems detrimental to some cognitive abilities, it has limited impact, or may even be protective for autism spectrum disorders, which generally show a 4 : 1 male predominance [16].…”