BACKGROUND 22q11.2 Deletion Syndrome (22q11DS) confers strongly increased genetic risk for multiple psychiatric disorders. Similarly to the general population, rates of psychiatric comorbidity suggest that common disease mechanisms are shared across dimensions of psychopathology. Such pleiotropic disease mechanisms remain however currently unknown. We hypothesized that pituitary dysmaturation, indicative of HPA-axis dysregulation, could correlate to reduced tolerance to daily life stressors and reflect pleiotropic risk factor for psychopathology. Moreover HPA-axis dysregulation could affect atypical cortical and hippocampal development previously described in 22q11DS. METHODS Pituitary volume, hippocampal volume and cortical thickness measures were obtained from T1-weighted MRI images in a large longitudinal cohort of youth with 22q11DS (115 subjects, 260 scans, age-range = 5.4-31.6) and healthy controls (151 subjects, 280 scans, age-range = 5.1-32.3). We explored effects of pituitary dysmaturation on tolerance to stress, psychopathology and neurodevelopment employing mixed-models linear regression. Associations of pituitary and cortical development were correlated with the expression pattern of glucocorticoid receptor gene NR3C1 obtained from the Allen-Human-Brain-Atlas. RESULTS We observed aberrant pituitary developmental trajectories in 22q11DS, with volumetric reductions emerging by young-adulthood (P = 0.0006). Longitudinal pituitary decline was associated with to reduced tolerance to stress (P = 0.04), higher overall psychopathology (P = 0.0003) and increased risk of psychiatric comorbidity (P = 0.02). Moreover, pituitary decline correlated with blunted growth of the right hippocampus (P = 0.03) and to increased cortical thinning of mostly temporal and orbitofrontal regions mediated by NR3C1 gene expression. CONCLUSION Atypical pituitary development could reflect progressive extinction of HPAA due to chronic hyper-activation, in agreement with existing biochemical evidence in 22q11DS. HPAA dysregulation could represent and endophenotype that confers pleiotropic vulnerability to psychopathology and atypical neurodevelopment in 22q11DS.

中文翻译：

---

垂体不成熟影响 22q11.2 缺失综合征的精神病理学和神经发育

背景 22q11.2 缺失综合征 (22q11DS) 显着增加了多种精神疾病的遗传风险。与一般人群类似，精神病合并症的发生率表明，常见的疾病机制在精神病理学的各个维度上是相同的。然而，这种多效性疾病机制目前仍然未知。我们假设垂体不成熟，表明 HPA 轴失调，可能与对日常生活压力源的耐受性降低有关，并反映了精神病理学的多效性风险因素。此外，HPA 轴失调可能影响先前在 22q11DS 中描述的非典型皮质和海马发育。方法垂体体积，海马体积和皮质厚度测量值是从具有 22q11DS（115 名受试者，260 次扫描，年龄范围 = 5.4-31.6）和健康对照（151 名受试者，280 次扫描，年龄-范围 = 5.1-32.3）。我们使用混合模型线性回归探讨了垂体不成熟对压力耐受性、精神病理学和神经发育的影响。垂体和皮质发育的关联与从 Allen-Human-Brain-Atlas 获得的糖皮质激素受体基因 NR3C1 的表达模式相关。结果 我们在 22q11DS 中观察到了异常的垂体发育轨迹，在青年期出现体积减少（P = 0.0006）。纵向垂体下降与对压力的耐受性降低有关（P = 0.04），更高的整体精神病理学 (P = 0.0003) 和增加的精神病合并症风险 (P = 0.02)。此外，垂体下降与右侧海马体的迟钝生长（P = 0.03）以及由 NR3C1 基因表达介导的主要颞区和眶额区的皮质变薄增加相关。结论 非典型垂体发育可以反映由于慢性过度激活导致的 HPAA 逐渐消失，这与 22q11DS 中现有的生化证据一致。HPAA 失调可能代表和内表型赋予 22q11DS 中精神病理学和非典型神经发育的多效脆弱性。03) 并增加了由 NR3C1 基因表达介导的主要颞区和眶额区的皮质变薄。结论 非典型垂体发育可以反映由于慢性过度激活导致的 HPAA 逐渐消失，这与 22q11DS 中现有的生化证据一致。HPAA 失调可能代表和内表型赋予 22q11DS 中精神病理学和非典型神经发育的多效脆弱性。03) 并增加了由 NR3C1 基因表达介导的主要颞区和眶额区的皮质变薄。结论 非典型垂体发育可以反映由于慢性过度激活导致的 HPAA 逐渐消失，这与 22q11DS 中现有的生化证据一致。HPAA 失调可能代表和内表型赋予 22q11DS 中精神病理学和非典型神经发育的多效脆弱性。