Developmental delays affect 12–17% of the general pediatric population (Glascoe, 2000
). However, only 20–30% of the children with disabilities are identified prior to school entry, which suggests that early identification needs to be improved (AAP, 2006
; Sand et al., 2005
). Fragile X syndrome (FXS) is the most common inherited cause of delay affecting 1 in 4,000 males and 1 in 8,000 females (Crawford, Acuna, & Sherman, 2001
). FXS can be accurately diagnosed prenatally or at birth by genetic testing but the average age of diagnosis is 32 months due to a number of barriers (Bailey, Skinner, & Sparkman, 2003
) including a lack of information regarding the phenotype of FXS during the early years. Earlier identification would provide access to early intervention, help tailor specific health or educational treatments, identify recurrence risk in siblings, and provide family support to optimize outcomes (Bailey et al., 2003
; Srour, Mazer, & Shevell, 2006
The full mutation of FXS results from an expansion of ≥200 CGG repeats on the X-linked FMR1
gene. Reduction in fragile X mental retardation protein (FMRP) is associated with increased clinical involvement (Bailey, Hatton, Skinner, & Mesibov, 2001
; Hatton et al., 2006
). Due to random X chromosomal inactivation, females are more variably affected; approximately 50% display cognitive deficits and the remainder manifest mild to no cognitive or behavioral effects. Most males with the full mutation have a moderate intellectual disability, attention problems, and elevated risk for other co-occurring conditions (Bailey, Raspa, Olmsted, & Holiday, 2008
), but these features are not evident at birth. A decline in IQ standard scores (not loss of skill) has been documented (Bailey, Hatton, & Skinner, 1998
; Skinner et al., 2005
), but the age at which the decline is first evident is unclear.
A co-morbid diagnosis of autism occurs in at least 30% of children with FXS (Rogers, Wehner, & Hagerman, 2001
) with recent evidence that autistic behavior increases over time (Hatton et al., 2006
). A diagnosis of autism or the presence of elevated autistic behavior, regardless of meeting diagnostic criteria, is associated with poor developmental outcome (Hatton et al., 2006
; Rogers et al., 2001
). Likewise, maternal IQ and education have been examined as predicting developmental outcome in children with FXS, given that that mothers of boys with FXS could have the full mutation themselves or could be affected by subtle learning difficulties documented in females with the premutation (Minquez et al., 2008
). While preliminary, this work has shown that maternal education is related to academic achievement (Roberts et al., 2005
), and parental IQ is associated with performance IQs in school-aged boys with FXS and full scale IQs in girls with FXS (Dyer-Friedman et al., 2002
). In contrast, maternal education does not appear related to the nonverbal intelligence in school-aged children with FXS (Skinner et al., 2005
Research on young children with FXS is sparse. Since most children are not identified until nearly 3 years of age, it has been difficult to find an adequate sample of very young children. Some studies report average or borderline development (Freund, Peebles, Aylward, & Reiss, 1995
; Hagerman et al., 1994
) while others report moderate delays during the early childhood years (Bailey et al., 1998
; Roberts, Hatton, & Bailey, 2001
). Only three published studies include infants 12 months of age or younger. A longitudinal study of 26 boys with FXS (four were 12 months at entry) found that global developmental delays were evident as early as 12 months with language skills most delayed (Roberts et al., 2001
). Skills increased with age, and developmental scores at early ages were correlated with scores at older ages. A longitudinal study using developmental screening measures with 13 boys with FXS at 9, 12, and 18 months of age reported that scores on the Denver II identified 91% of the boys as delayed at 9 months of age and 100% as delayed at both 12 and 18 months of age (Mirrett, Bailey, Roberts, & Hatton, 2004
). In a retrospective video analysis of sensory-motor features of 12-month-old infants with FXS (n
= 11) when compared to age and developmental level matched controls with autism without FXS (n
= 11), nonspecific developmental delay (n
= 10), and typically developing children (n
= 11), infants with FXS were distinguishable by their lack of object play and increased leg stereotypes (Baranek et al., 2005
). Sensory-motor features strongly predicted early developmental milestones (e.g., level of object play predicted age of walking).
These results suggest that developmental delays may be detectable in very young children with FXS as early as the first year of life. However, further research is needed to determine when developmental delays are evident and the form in which they are expressed. Such information could help pediatric professionals refer children for FXS testing (Visootsak, Warren, Anido, & Graham, 2005
). Furthermore, given the recent policy statement by the American Academy of Pediatrics that developmental screening tests be administered at the 9-, 18-, and 30-month well-child visits (Council on Children with Disabilities, 2006
), it is important to examine if development in infants with FXS is clearly delayed by 9 month of age. If not, these infants are at risk for not being identified until the subsequent screening interval at 18 or 30 months. Additionally, in the absence of the diagnosis of FXS, which allows eligibility for early intervention based on an established condition, children must demonstrate a significant delay to meet criteria for early intervention services (IDEA, 2004
632[A]). Individual states have latitude in the determination of eligibility criteria and great variability across states currently exists. However, two primary means for defining a developmental delay include (a) a 25% delay in at least one area of development, and (b) 2 SD
(s) below the mean on a norm-referenced instrument.
While existing work provides important preliminary information about the phenotype of FXS during the first years of life, it has included small samples focused on a narrow age range with few assessments with children under 2 years of age, and failed to include predictors of development. Furthermore, there has been a reliance on screening measures that have elevated false-positive rates of developmental delay and are limited in providing detailed developmental information upon which to base phenotypic-specific profiles. Needed are studies with larger samples using comprehensive measures of development in a prospective longitudinal design.
The primary aim of this study is to describe the trajectories and examine predictors of development for boys with FXS during the first 5 years of life. We hypothesized that young children with FXS would demonstrate stable developmental gains over the first 5 years of life, that language skills would be less well developed than other domains, and that development would be negatively affected by increased autistic behaviors and lowered maternal IQ. Secondary aims of this study are to identify at what age development is clearly delayed and to determine the extent to which early developmental scores are associated with later measures. We hypothesize that development will be clearly delayed by 12 months of age. Furthermore, we predict that early developmental scores will be moderately related to later developmental scores.