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. 2023;96(5):509-517.
doi: 10.1159/000529403. Epub 2023 Feb 1.

Infants with Congenital Adrenal Hyperplasia Exhibit Thalamic Discrepancies in Early Brain Structure

Vidya Rajagopalan  1   2 , Lloyd N Overholtzer  3 , William S Kim  3 , Jessica L Wisnowski  1   4 , Trevor A Pickering  5 , Nicole R Fraga  3 , Joyce Javier  6 , Liza Mackintosh  6 , Christine Mirzaian  6 , Mitchell E Geffner  2   3 , Mimi S Kim  2   3
Affiliations

Infants with Congenital Adrenal Hyperplasia Exhibit Thalamic Discrepancies in Early Brain Structure

Vidya Rajagopalan et al. Horm Res Paediatr. 2023.

Abstract

Introduction: Patients with classical congenital adrenal hyperplasia (CAH) have prenatal and postnatal hormonal imbalances. To characterize the ontogeny of reported brain and behavior changes in older children with CAH, we aimed to study the brain structure in infants with CAH compared to healthy controls.

Methods: We performed neuroimaging in 16 infants with classical CAH due to 21-hydroxylase deficiency (8 males, gestational age 38.2 ± 1.7 weeks, post-conceptional age [PCA] 42.2 ± 3.0 weeks) and 14 control infants (9 males, gestational age 38.5 ± 1.8 weeks, PCA 42.5 ± 2.4 weeks) utilizing 3-Tesla magnetic resonance imaging. Regional brain volumes were adjusted for PCA and sex, along with an additional adjustment for total brain volume (TBV), for group comparisons by regression analyses (mean, 95% confidence interval [CI]). The degree to which each brain region was differentiated between CAH and control infants was examined by relaimpo analyses, adjusting for all other brain regions, PCA, and sex.

Results: Infants with CAH had significantly smaller thalamic volumes (8,606 mm3, 95% CI [8,209, 9,002]) compared to age-matched control infants (9,215 mm3, 95% CI [8,783, 9,647]; β = -609; p = 0.02) which remained smaller after further adjustment for TBV. Upon further adjustment for TBV, the temporal lobe was larger in infants with CAH (66,817 mm3, CI [65,957, 67,677]) compared to controls (65,616 mm3, CI [64,680, 66,551]; β = 1,202, p = 0.03). The brain regions most differentiated between CAH versus controls were the thalamus (22%) and parietal lobe (10%).

Conclusions: Infants with CAH exhibit smaller thalamic regions from early life, suggesting a prenatal influence on brain development in CAH. Thalamic emergence at 8-14 weeks makes the region particularly vulnerable to changes in the intrauterine environment, with potential implications for later maturing brain regions. These changes may take time to manifest, meriting longitudinal study through adolescence in CAH.

Keywords: 21-Hydroxylase deficiency; Brain development; Congenital adrenal hyperplasia; Magnetic resonance imaging; Newborn; Pediatrics.

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Conflict of interest statement

M.S.K. receives unrelated research funding from Neurocrine Biosciences, Spruce Biosciences, Adrenas Therapeutics, and Diurnal. M.E.G. receives unrelated research support from Novo Nordisk, Adrenas Therapeutics, Neurocrine Biosciences, and Spruce Biosciences. M.E.G. serves on advisory boards or as a consultant for Adrenas Therapeutics, Ascendis, Eton Pharmaceuticals, Novo Nordisk, and Pfizer; serves on data safety monitoring boards for Ascendis; serves as an adjudication committee member for ICON Clinical Research, LLC/Aeterna Zentaris; and receives royalties from McGraw-Hill and UpToDate.

Figures

Figure 1.
Figure 1.. Acquisition and segmentation of brain structural images in infants with CAH and age-matched controls for volumetric analyses.
Prior to automated segmentation, 3D T1-weighted anatomical images were automatically skull-stripped (FSL) and then edited manually (ITK-SNAP) and inverted into pseudo-T2-weighted images to match the imaging modality of the ALBERTs atlases. The images were then bias-corrected and automatically segmented (NeBSS) into 50 brain tissue types. These 50 subregions were then refined into larger structural regions of interest (ROIs).
Figure 2.
Figure 2.. Relaimpo analysis to examine the degree to which each brain region was differentiated between CAH and control infants.
Relative Importance of Regressors in Linear Models (relaimpo) analyses were performed, adjusting for post-conceptional age and sex. The brain regions most differentiated between CAH and control infants were the thalamus (percent variance = 22%) and the parietal lobe (percent variance = 10%).
See this image and copyright information in PMC

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