Date of Award

January 2019

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

John A. Persing

Abstract

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 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 (R<0.5, p>0.05) 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.

Comments

This is an Open Access Thesis.

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