BACKGROUND Apart from PRKAR1A mutations in a subset of cyclical Cushing's syndrome due to primary pigmented nodular adrenocortical disease, the molecular basis of cyclical Cushing's syndrome has not been investigated. We speculated that cyclical Cushing's syndrome may be due to mutations in the clock genes that govern circadian rhythms, including the hypothalamic-pituitary-adrenal axis. CASE PRESENTATION A 47-year-old man presented with mass effects from a sellar lesion. He was ultimately diagnosed with cyclical Cushing's disease due to a giant corticotrophinoma. We performed whole exome sequencing of germline and tumour DNA, SNP array of tumour DNA and tumour immunohistochemistry in order to detect variants in candidate circadian/pituitary-associated genes. We identified a rare germline missense variant in the aryl hydrocarbon receptor (AHR) gene, which has previously been indirectly linked to pituitary tumorigenesis and clock system disruption. The AHR variant was found in a highly conserved site involved in phosphorylation. It was predicted to be damaging by multiple in silico tools and AHR tumour immunohistochemistry demonstrated loss of the normal nuclear staining pattern, suggestive of an inactivating mutation. We also found a novel, damaging germline missense variant in the retinoid X receptor gamma (RXRG) gene, multiple somatic chromosomal gains (including AHR), and a somatic mutational signature consistent with oncogenesis that may have acted synergistically with the AHR variant. CONCLUSIONS This is the first report of an AHR variant with predicted pathogenicity in the pituitary adenoma setting. Our preliminary data suggest that the highly conserved AHR gene may represent a link between pituitary tumorigenesis, the hypothalamic-pituitary-adrenal axis and the clock system. Further research may indicate a role for the gene in the development of cyclical Cushing's disease.

中文翻译：

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在周期性库欣氏病患者中，芳烃受体（AHR）基因的推定作用。

背景技术除了由于原发性色素性结节性肾上腺皮质疾病引起的周期性库欣氏综合征子集中的PRKAR1A突变外，尚未研究周期性库欣氏综合征的分子基础。我们推测周期性库欣综合症可能是由于控制昼夜节律的时钟基因突变所致，包括下丘脑-垂体-肾上腺轴。病例介绍一名47岁的男子表现为来自足底病变的肿块。最终他被诊断出患有巨大的促肾上腺皮质激素瘤，患有周期性的库欣氏病。为了检测候选昼夜节律/垂体相关基因的变异，我们进行了种系和肿瘤DNA的全外显子组测序，肿瘤DNA的SNP阵列和肿瘤免疫组化。我们在芳烃受体（AHR）基因中鉴定出一种罕见的种系错义变体，该变体先前已与垂体肿瘤发生和时钟系统破坏间接相关。在与磷酸化有关的高度保守的位点中发现了AHR变异体。预测它会受到多种计算机工具的破坏，并且AHR肿瘤免疫组织化学证明正常核染色模式的丧失，提示失活突变。我们还发现了类视黄醇X受体gamma（RXRG）基因中的一种新颖的，有害的种系错义变体，多个体细胞染色体增益（包括AHR）以及与可能与AHR变体协同起作用的肿瘤发生相一致的体细胞突变特征。结论这是在垂体腺瘤环境中具有预期致病性的AHR变异的首次报道。我们的初步数据表明，高度保守的AHR基因可能代表了垂体肿瘤发生，下丘脑-垂体-肾上腺轴和时钟系统之间的联系。进一步的研究可能表明该基因在周期性库欣病发展中的作用。