偽副甲狀腺低下症Ib型的基因檢測與遺傳諮詢

Abstract

偽副甲狀腺低下症（Pseudohypoparathyroidism, PHP）是一種罕見的體染色體顯性遺傳代謝疾病的總稱，疾病機制複雜且臨床表現多樣化，但具有一個共通的特色就是對副甲狀腺素的阻抗性。主要的臨床表現為：低血鈣、高血磷、血中副甲狀腺素升高。 偽副甲狀腺低下症兩種最主要的分型是PHP Ia型及PHP Ib型，這兩種疾病分型的致病原因都是源於GNAS locus發生突變。PHP Ia是由於基因內部發生突變；而PHP Ib則是因為基因的甲基化調控出現了異常。 GNAS基因所表現的蛋白為Gsα，是異三元體（heterotrimer）Gs蛋白的其中一個次單元（α subunit），為內分泌訊息傳導途徑中一個很重要的蛋白質。 PHP Ia的病患在外觀上會有AHO (Albright hereditary osteodystrophy)的臨床表現，如：身高矮小、頸部短小、短指（特別是在第四及第五節掌骨）、肥胖、皮下組織鈣化及可能有心智障礙等特徵。因此在臨床診斷上除了透過實驗室生化檢查、影像學檢查、以及基因診斷之外，在門診時就可以透過臨床觀察以較快地速度推測出病患的疾病。 然而，本論文所研究的對象，PHP Ib病患其臨床表現則很少會出現外觀上AHO的特徵，疾病症狀主要為腎近端小管對副甲狀腺素的阻抗性，會有低血鈣、高血磷、血中副甲狀腺素升高的症狀。因此，期望透過基因檢測方式的建立提供未來在臨床上的分子診斷技術及遺傳諮詢服務平台，也希望未來在產前診斷上能夠帶給病患更多的幫助。

Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders characterized by hypocalcemia, hyperphosphatemia, increased serum concentration of parathyroid hormone (PTH), and insensitivity to the biological activity of PTH. The two main subtypes of pseudohypoparathyroidism (PHP), PHP Ia and PHP Ib, are caused by mutations in GNAS exons 1–13 and methylation defects in the imprinted GNAS cluster, respectively. PHP Ia patients show Albright hereditary osteodystrophy (AHO) and resistance toward multiple hormones (PTH/TSH/GHRH/gonadotropins), whereas PHP Ib patients classically display hormone resistance limited to PTH and TSH. GNAS, the gene mainly encoding α subunit of the heterotrimeric stimulatory G protein, called Gsα. Gsα protein plays an important part of the endocrine signal transduction pathway. Patients with PHP Ia present with a characteristic phenotype, collectively called AHO. The constellation of findings includes short stature, stocky habitus, obesity, developmental delay, round face, dental hypoplasia, brachymetacarpals, brachymetatarsals, and soft tissue calcification/ossification. Therefore, in addition to clinical diagnosis by laboratory biochemical tests, imaging and genetic diagnosis, patients can be diagnosis faster by the clinical characteristic observation. Patients with PHP Ib lack features of AHO, have normal expression of Gsα protein in accessible tissues, and manifest hormonal resistance limited to PTH target tissues. PTH resistance may be limited to the kidney, with PTH responsiveness preserved in the bone, as evidenced by the hyperparathyroid skeletal lesions observed in these patients. It is difficult to diagnosis by clinical characteristic observation. Therefore, the hope that through the establishment of genetic testing methods to provide future clinical molecular diagnostic techniques and genetic counseling services platform. Furthermore, we hope that the future of prenatal diagnosis on the patient can bring more help.