Neurodevelopmental Risks of Non-syndromic Craniosynostosis [electronic resource].

9781085619981

Ann Arbor : ProQuest Dissertations & Theses, 2019.

1 online resource (86 p.)

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Purpose: Nonsyndromic craniosynostosis may manifest with complex cognitive, language, behavioral, and emotional sequelae, depending on the suture fusion involved. De-novo or rare transmitted mutations in the SMAD6 gene affect midline synostosis in 7% of patients. Current standards of assessment, such as the Bayley Scales of Infant Development (BSID), may not be predictive of long-term development, paving the way for newer assessments such as functional magnetic resonance imaging (fMRI) and the event related potentials (ERP), which measures passive neurological responses to speech sounds. Methods: Cranially-mature, post-operative unilateral coronal, metopic, midline SMAD6 mutated and age/race/gender/synostosis/operation matched non-SMAD6 controls from the Yale Craniofacial Clinic and the Children’s Hospital of Philadelphia (CHOP) completed a double-blinded neurodevelopmental assessment, which included the Wechsler Fundamentals, Wechsler Abbreviated Scale of Intelligence, and Beery- Buktenica Developmental Test. Unilateral coronal (ULC) or metopic synostosis were age/gender/handedness matched to controls and participated in a GoNoGo task under fMRI. Craniosynostosis infants were given the BSID and ERP testing at two points (pre and post operatively), and after they reached >6 years of age, patients completed the Wechsler Abbreviated Scale of Intelligence and Wechsler Fundamentals to measure 5 language functional domains. Results: ULC patients had a mean verbal IQ of 117.3 and performance IQ of 106.4, performed above average on academic achievements except for numerical, but below average on all visual-motor tests. Right ULC had improved spelling compared to left ULC, controlled for exogenous influences (p=0.033). Metopic patients with mild phenotype (endocranial bifrontal angle <124) performed better in word reading (p=0.035) and reading composite (p=0.014) than patients with severe stenosis (>124). After controlling for exogenous factors, midline synostosis patients with SMAD6 mutations performed worse on numerical operations(p=0.046), performance IQ(p=0.018), full IQ(p=0.010), and motor coordination(p=0.043) than those without the mutation. Among seven ULC and six metopic patients that participated in fMRI, metopic patients had decreased bloodoxygenation- level-dependent signal in the posterior cingulate(p=0.017) and middle temporal gyrus(MTG;p=0.042). ULC had decreased signal in the posterior cingulate(p=0.023), MTG(p=0.027), and thalamus(p=0.033), but increased signal in the cuneus(p=0.009) and cerebellum(p=0.009). Among 10 craniosynostoses patients who received ERP/BSID testing in infancy followed by school-age neurocognitive testin, the left frontal ERP cluster strongly correlated with word reading (R 0.713, p=0.031), reading comprehension (R 0.745, p=0.021), and language composite scores (R=0.771, p=0.015). Correlations for BSID cognitive, expressive language, and language composite scores had no predictive value (R0.05) for neurocognitive scores. Conclusions: Post-operative cranially mature ULC patients have higher verbal IQ scores, but worse mathematical and visual-motor achievement. Left-sided ULC patients may perform worse in spelling. The severity of orbito-frontal dysmorphology in metopic synostosis significantly impacts long-term cognitive function and academic achievement. Neuropsychiatric development may be in whole or in part under genetic control. SMAD6 mutations led to poorer performance on mathematics, performance-IQ, full-IQ, and motor coordination, even after controlling for exogenous factors. ULC patients may have emotional dyregulation in response to frustration while metopic patients may have attenuated emotional reactions. ERP assessment in nonsyndromic craniosynostosis patients has significantly better predictive value for future neurocognitive assessment than the standard BSID test. Use of ERP assessment may help tailor treatment for language deficits earlier in development.

Dissertations & Theses @ Yale University.

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English

January 17, 2020

Thesis (M.D.)--Yale University, 2019.