Cognitive, Motor, and Brain Volume Deficits in Children with Growth Hormone Deficiency
Cognitive, Motor, and Brain Volume Deficits in Children with Growth Hormone Deficiency
Abstract & Commentary
By Sotirios Keros, MD, PhD, Instructor in Pediatrics, Division of Child Neurology, Weill Cornell Medical College. Dr. Keros reports no financial relationships relevant to this field of study.
Synopsis: Children with isolated growth hormone deficiency have lower IQ, worse motor skills, and several brain regions with smaller volumes than carefully selected controls.
Source: Webb EA, et al. Effect of growth hormone deficiency on brain structure, motor function, and cognition. Brain 2012;135(Pt 1): 216-227.
Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) receptors are located throughout the brain, and are particularly expressed in regions related to learning and memory, such as the hippocampus. GH deficiency leads to smaller brain volumes in animals and contributes to decreased neuronal and glial proliferation. There are a variety of existing studies in both animals and humans that suggest GH deficiency and low IGF-1 levels are correlated with decreased cognitive ability. In addition, exogenous growth factor has been noted to improve IQ in small-for-gestational-age children. The human cognitive data, however, are somewhat contradictory and are limited due to heterogeneous patient groups with multiple etiologies of GH deficiency, non-standard definitions, and wide ranges of the ages of included subjects. Few human studies have examined the role of GH deficiency on brain structure or on motor function.
In the present study, the authors prospectively recruited children aged 5-11 with isolated growth hormone deficiency (IGHD) (n = 15), but with otherwise normal endocrine function. To control for any confounding effects of short stature, children with idiopathic short stature (n = 14) were used as controls. IGHD was defined as a level below 6.7 mcg/L on tests of GH release in children with a height and growth velocity less than two standard deviations below the mean. Idiopathic short stature was defined as a height less than 2 standard deviations below the mean but with normal height velocity and a GH level of greater than 10 mcg/L with stimulation testing and normal brain MRIs and IGF-2 concentrations. In addition to GH levels, IGF-1 and its primary binding protein, insulin-like growth factor binding protein 3 (IGFBP-3), were measured. All patients had extensive cognitive testing, including Full-Scale IQ (Wechsler Intelligence Scales for Children 4th ed. or a subset of the Weschsler Preschool and Primary Scale of Intelligence 3rd ed.). Memory, as well as attention and executive function, were assessed using the NEPSY-II battery and Cambridge neuropsychological test automated battery (CANTAB). Parental checklists were used to assess behavioral differences, and motor skills were assessed using the Movement Assessment Battery for Children Test. 1.5 tesla brain MRIs were obtained to assess for the volume of total brain, basal ganglia, thalamus, hippocampus, and corpus callosum using Freesurfer software analysis. Diffusion tensor fractional anisotropy and mean diffusivity maps were extracted and calculated from the MRI data as markers of white matter tract integrity.
Webb et al discovered several statistically significant differences in the IGHD group compared to controls. Blood levels of IGF-1 and IGFBP-3 were lower in the IGHD group. Full-Scale IQ was lower in IGHD children (92.8 vs 102.6; P = 0.01). Lower scores in Verbal Comprehension Index and Processing Speed Index also were noted. Total motor scores were lower in IGHD, specifically in the subcategories of manual dexterity and balance. Total brain volume was similar in both groups, but the volumes of the splenium of corpus callosum, right palladum, right hippocampus, and left thalamus were lower in the IGHD children. Fractional anisotropy of the corpus callosum, as well as the bilateral corticospinal tracts, were lower in the IGHD group, while left corticospinal tract diffusivity was higher. There were no statistically significant differences in behavioral scales or in attention and memory tasks.
Looking only within the IGHD group, the authors found that several findings were significantly correlated when using appropriate statistical analyses. IQ and verbal performance were positively correlated with IGFBP-3 levels. IGF-1 levels also were correlated with verbal scores, but not with IQ. The volume of the splenium of the corpus callosum correlated with verbal scores was well as IGF-1 levels, while white matter integrity of the entire corpus callosum was correlated with IQ. Bilateral thalami and left pallidum volumes were correlated with IGFBP-3. Left and right corticospinal tract fractional anisotropy was correlated with an aiming and catching assessment, while the right corticospinal tract was also correlated with balance. Total movement scores were correlated with the volume of the splenium, left and right pallidum, and left thalamus.
Commentary
Although this study has a relatively small sample size, it is well-controlled with tightly defined inclusion criteria and controls. The authors find a clinically relevant reduction of 10 IQ points in children with IGHD. IQ and other cognitive measures were also related to decreased IGF-1 or IGFBP-3 levels as well as the volume of several brain regions. It is a novel finding that children with IGHD have decreased motor function, and that this decreased motor function is correlated to differences in the brain volume of deeper brain structures as well as white matter differences in the corticospinal tract. Children with GH deficiency commonly have other endocrinological abnormalities, which complicates the interpretation of some previous studies.
The GF/IGF-1 axis is involved in several intracellular signaling pathways, primarily stimulating cell growth and preventing apoptosis. IGH and IGF-1 receptors are expressed in the embryonic rodent brain, and IGF-1 pathways regulate prenatal and postnatal differentiation of inhibitory interneurons, which are critical for normal development. This study reinforces that GH treatment should not necessarily be reserved for short stature, but it remains to be seen whether early treatment with GH in deficient children can prevent cognitive and motor deficits.
Children with isolated growth hormone deficiency have lower IQ, worse motor skills, and several brain regions with smaller volumes than carefully selected controls.Subscribe Now for Access
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