University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Hepatology. 2012 Apr;55(4):1139-45. doi: 10.1002/hep.24781. Epub 2012 Feb 8.
The most common inborn error of bile acid metabolism is 3β-hydroxy-Δ(5)-C(27)-steroid oxidoreductase (3β-HSD) deficiency, a disorder that usually presents in early childhood with hepatic dysfunction. Timely diagnosis of this disorder is crucial because it can be effectively treated with primary bile acid replacement. Here we describe a 24-year-old woman from Iran with cirrhosis of unknown etiology. Her sister and a first cousin died of cirrhosis (ages 19 and 6 years) and another 32-year-old first cousin had a self-limited liver disorder in childhood that resolved at age 9 years. The family history suggested that the affected family members were homozygous for a mutant allele inherited identical-by-descent. A genome-wide analysis of 2.4 million single nucleotide polymorphisms was performed to identify regions of homozygosity that were present in the proband and the 32-year-old first cousin, but not in a healthy relative. One of these regions contained the gene encoding 3β-HSD (HSD3B7). Sequence analysis of HSD3B7 revealed that the proband and her 32-year-old cousin were homozygous for a frameshift mutation (c.45_46del AG, p.T15Tfsx27) in exon 1. The diagnosis of 3β-HSD deficiency was confirmed by documenting high levels of 3β-hydroxy-Δ(5) bile acids in the serum of the proband and the 32-year-old first cousin using mass spectrometry. To our knowledge, the 32-year-old relative in this family represents the oldest asymptomatic patient with this disorder.
This study highlights the clinical utility of homozygosity mapping in diagnosing autosomal recessive metabolic disorders. This family illustrates the wide variation in expressivity that occurs in 3β-HSD deficiency and underscores the need to consider a bile acid synthetic defect as a possible cause of liver disease in adults.
胆汁酸代谢中最常见的先天性错误是 3β-羟-Δ(5)-C(27)-固醇氧化还原酶（3β-HSD）缺乏症，这种疾病通常在儿童早期表现为肝功能障碍。及时诊断这种疾病至关重要，因为它可以用初级胆汁酸替代疗法有效治疗。在这里，我们描述了一位来自伊朗的 24 岁女性，患有原因不明的肝硬化。她的姐姐和一个表亲死于肝硬化（年龄分别为 19 岁和 6 岁），另一个 32 岁的表亲在童年时有过自限性肝脏疾病，9 岁时痊愈。家族史表明，受影响的家庭成员是相同来源的突变等位基因纯合子。对 240 万个单核苷酸多态性进行了全基因组分析，以确定在先证者和 32 岁表亲中存在但在健康亲属中不存在的纯合区域。这些区域之一包含编码 3β-HSD（HSD3B7）的基因。HSD3B7 的序列分析显示，先证者及其 32 岁表亲在第 1 外显子中纯合发生移码突变（c.45_46del AG，p.T15Tfsx27）。通过使用质谱法在先证者和 32 岁表亲的血清中检测到高水平的 3β-羟-Δ(5)胆汁酸，证实了 3β-HSD 缺乏症的诊断。据我们所知，该家族中这位 32 岁的亲属是该疾病中年龄最大的无症状患者。
这项研究强调了同系基因映射在诊断常染色体隐性代谢疾病中的临床实用性。该家族说明了 3β-HSD 缺乏症的表达多样性很大，并强调了需要将胆汁酸合成缺陷视为成人肝脏疾病的可能原因。
