Early development of infants with neurofibromatosis type 1: a case series

Background Prospective studies of infants at familial risk for autism spectrum disorder (ASD) have yielded insights into the earliest signs of the disorder but represent heterogeneous samples of unclear aetiology. Complementing this approach by studying cohorts of infants with monogenic syndromes associated with high rates of ASD offers the opportunity to elucidate the factors that lead to ASD. Methods We present the first report from a prospective study of ten 10-month-old infants with neurofibromatosis type 1 (NF1), a monogenic disorder with high prevalence of ASD or ASD symptomatology. We compared data from infants with NF1 to a large cohort of infants at familial risk for ASD, separated by outcome at age 3 of ASD (n = 34), atypical development (n = 44), or typical development (n = 89), and low-risk controls (n = 75). Domains assessed at 10 months by parent report and examiner observation include cognitive and adaptive function, sensory processing, social engagement, and temperament. Results Infants with NF1 showed striking impairments in motor functioning relative to low-risk infants; this pattern was seen in infants with later ASD from the familial cohort (HR-ASD). Both infants with NF1 and the HR-ASD group showed communication delays relative to low-risk infants. Conclusions Ten-month-old infants with NF1 show a range of developmental difficulties that were particularly striking in motor and communication domains. As with HR-ASD infants, social skills at this age were not notably impaired. This is some of the first information on early neurodevelopment in NF1. Strong inferences are limited by the sample size, but the findings suggest implications for early comparative developmental science and highlight motor functioning as an important domain to inform the development of relevant animal models. The findings have clinical implications in indicating an important focus for early surveillance and remediation in this early diagnosed genetic disorder

Early differences in auditory processing relate to Autism Spectrum Disorder traits in infants with Neurofibromatosis Type I

Abstract: Background: Sensory modulation difficulties are common in children with conditions such as Autism Spectrum Disorder (ASD) and could contribute to other social and non-social symptoms. Positing a causal role for sensory processing differences requires observing atypical sensory reactivity prior to the emergence of other symptoms, which can be achieved through prospective studies. Methods: In this longitudinal study, we examined auditory repetition suppression and change detection at 5 and 10 months in infants with and without Neurofibromatosis Type 1 (NF1), a condition associated with higher likelihood of developing ASD. Results: In typically developing infants, suppression to vowel repetition and enhanced responses to vowel/pitch change decreased with age over posterior regions, becoming more frontally specific; age-related change was diminished in the NF1 group. Whilst both groups detected changes in vowel and pitch, the NF1 group were largely slower to show a differentiated neural response. Auditory responses did not relate to later language, but were related to later ASD traits. Conclusions: These findings represent the first demonstration of atypical brain responses to sounds in infants with NF1 and suggest they may relate to the likelihood of later ASD

Development of tibia & fibula bone deficits in children with neurofibromatosis type I – A longitudinal case-control comparison

Neurofibromatosis type 1 (NF1) is associated with lower bone mass and increased risk of fracture. Children with NF1 display faltering growth from mid-childhood. However, to date tibia bone development in children with NF1 across childhood and the role of body size have not been explored. Therefore, we recruited 24 children with NF1 (12 girls, mean age 8.2 ± 1.1y) and 104 children without NF1 (52 girls, mean age 11 ± 1.7y). Tibia and fibula bone characteristics were assessed at 4% and 38% distal-proximal tibia length in all children at baseline using peripheral quantitative computed tomography (pQCT). Longitudinal scans were obtained in 21 children with NF1 (12 girls) over 3.4 ± 0.3y and 71 children without NF1 (34 girls) over 1.1 ± 0.1y, such that at follow-up mean age of both groups (NF1 10.9 ± 1.3y, controls 11.4 ± 1.4y) were similar. Effects of group (NF1/control) on bone outcomes as well as group-by-age interactions, indicating differences in rate of change in bone outcome bone outcomes were assessed via linear mixed effects models with adjustment for sex, age, pubertal status and in additional models with adjustment for height and weight Z-scores. Group (NF1/control)-by-age interactions indicated a slower rate of tibia and fibula bone mass accrual in children with NF1 at all measured sites. These associations were attenuated by 25–50% by adjustment for height and weight Z-scores. At the 4% site, deficits in bone mass at older ages were related to slower trabecular BMD accrual. At the 38% site, group-by-age interactions suggested that bone mass deficits resulted from poorer accrual of cortical CSA and to a lesser extent cortical BMD. Lower limb bone mass deficits evident in children with NF1 appear to be progressive and emerge in mid-childhood. In part, they are related to development of a similar pattern of deficits in longitudinal growth and body weight in NF1. Interventions promoting muscle development or physical activity may be partially effective in attenuating bone mass accrual deficits in this population