Prospective evaluation of the brain in asymptomatic children with neurofibromatosis type 1: relationship of macrocephaly to T1 relaxation changes and structural brain abnormalities

Abstract

Background and purpose: Mutation of the neurofibromatosis type 1 (NF-1) gene may be associated with abnormal growth control in the brain. Because macrocephaly could be a sign of abnormal brain development and because 30% to 50% of children with NF-1 display macrocephaly in the absence of hydrocephalus, we sought to determine the relationship between macrocephaly and other brain abnormalities in young subjects with NF-1. These subjects were free of brain tumor, epilepsy, or other obvious neurologic problems.

Methods: We prospectively screened 18 neurologically asymptomatic subjects with NF-1, ages 6 to 16 years, using clinical measures, psychometric testing, conventional MR imaging, and quantitative MR imaging to measure T1.

Results: Cranial circumference was 2 or more SDs above the age norm in seven (39%) of 18 subjects, a frequency of macrocephaly 17-fold higher than normal. Conventional MR imaging showed abnormalities in all 18 children, although there were more extensive abnormalities in subjects with macrocephaly. Macrocephaly in NF-1 was associated with enlargement of multiple brain structures, and brain T1 in macrocephalic subjects was reduced with respect to controls in the genu, frontal white matter, caudate, putamen, thalamus, and cortex. In normocephalic subjects, T1 was reduced only in the genu and splenium. Volumetric analysis showed that macrocephaly was associated specifically with enlargement of white matter volume.

Conclusion: Neurologically asymptomatic children with NF-1 showed macrocephaly, cognitive deficit, enlarged brain structures, and abnormally low brain T1. Macrocephaly in children with NF-1 may be associated with characteristic alterations in brain development, marked by more widespread and significant changes in T1, greater enlargement of midline structures, and greater volume of white matter.

fig 1.

A, T1-weighted sagittal midline image (266/6/3) in an 11-year old boy with NF-1 and macrocephaly shows where the measurements of midline structures were made (see Table 2). This boy had thickening of the corpus callosum and enlargement of the anteroposterior diameter of the pons and medulla. B, T2-weighted transverse image (3500/93/1) in an 8-year old girl shows bilateral lesions in the globus pallidus and tectum

fig 2.

Scatterplot of quantitative tissue T1 in the nucleus pulvinarus versus FSIQ in children with NF-1 (r = .58; P = .012 by ANOVA)