Balwani Manisha, Naik Hetanshi, Anderson Karl E, Bissell D Montgomery, Bloomer Joseph, Bonkovsky Herbert L, Phillips John D, Overbey Jessica R, Wang Bruce, Singal Ashwani K, Liu Lawrence U, Desnick Robert J
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York.
Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston.
JAMA Dermatol. 2017 Aug 1;153(8):789-796. doi: 10.1001/jamadermatol.2017.1557.
Autosomal recessive erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare photodermatoses presenting with variable degrees of painful phototoxicity that markedly affects quality of life. The clinical variability, determinants of severity, and genotype/phenotype correlations of these diseases are not well characterized.
To describe the baseline clinical characteristics, genotypes, and determinants of disease severity in a large patient cohort with EPP or XLP.
DESIGN, SETTING, AND PARTICIPANTS: A prospective observational study was conducted among patients with confirmed diagnoses of EPP or XLP from November 1, 2010, to December 6, 2015, at 6 academic medical centers of the Porphyrias Consortium of the National Institutes of Health Rare Diseases Clinical Research Network. Detailed medical histories, including history of phototoxicity and treatment, were collected on standardized case report forms. Patients underwent baseline laboratory testing, total erythrocyte protoporphyrin (ePPIX) testing, and molecular genetic testing. Data were entered into a centralized database.
Results of biochemical and genetic tests were explored for association with clinical phenotype in patients with EPP or XLP.
Of the 226 patients in the study (113 female and 113 male patients; mean [SD] age, 36.7 [17.0] years), 186 (82.3%) had EPP with a FECH (OMIM 612386) mutation and the common low-expression FECH allele IVS3-48T>C, and only 1 patient had 2 FECH mutations. Twenty-two patients had XLP (9.7%; 10 male and 12 female patients), and 9 patients (4.0%) had elevated ePPIX levels and symptoms consistent with protoporphyria but no detectable mutation in the FECH or ALAS2 (OMIM 301300) gene. Samples of DNA could not be obtained from 8 patients. Patients' mean (SD) age at symptom onset was 4.4 (4.4) years. Anemia (107 [47.3%]), history of liver dysfunction (62 [27.4%]), and gallstones (53 [23.5%]) were commonly reported. Higher ePPIX levels were associated with earlier age of symptom onset (median ePPIX levels for those who developed symptoms before vs after 1 year of age, 1744 vs 1567 µg/dL; P = .02), less sun tolerance (median ePPIX levels for those reporting symptoms before vs after 10 minutes of sun exposure, 2233 vs 1524 µg/dL; P ≤ .001), and increased risk of liver dysfunction (median ePPIX levels for those with liver dysfunction vs normal liver function, 2016 vs 1510 µg/dL; P = .003). Patients with EPP and FECH missense mutations had significantly lower ePPIX levels than those with other mutations (1462 vs 1702 µg/dL; P = .01). Male patients with XLP had significantly higher ePPIX levels, on average, than did patients with EPP (3574 vs 1669 µg/dL; P < .001). Marked clinical variability was seen in female patients with XLP owing to random X-chromosomal inactivation.
These data suggest that higher ePPIX levels are a major determinant of disease severity and risk of liver dysfunction in patients with EPP or XLP. These findings provide a framework for clinical monitoring and management of these disorders.
常染色体隐性遗传性红细胞生成性原卟啉病（EPP）和X连锁原卟啉病（XLP）是罕见的光皮肤病，表现出不同程度的疼痛性光毒性，显著影响生活质量。这些疾病的临床变异性、严重程度的决定因素以及基因型/表型相关性尚未得到充分描述。
描述一大群EPP或XLP患者的基线临床特征、基因型和疾病严重程度的决定因素。
设计、背景和参与者：2010年11月1日至2015年12月6日，在美国国立卫生研究院罕见病临床研究网络卟啉病联盟的6个学术医疗中心，对确诊为EPP或XLP的患者进行了一项前瞻性观察研究。通过标准化病例报告表收集详细的病史，包括光毒性和治疗史。患者接受了基线实验室检查、总红细胞原卟啉（ePPIX）检测和分子遗传学检测。数据录入中央数据库。
探讨EPP或XLP患者生化和基因检测结果与临床表型的关联。
研究中的226例患者（113例女性和113例男性患者；平均[标准差]年龄为36.7[17.0]岁），186例（82.3%）患有EPP且存在FECH（OMIM 612386）突变以及常见的低表达FECH等位基因IVS3 - 48T>C，仅有1例患者有2个FECH突变。22例患者患有XLP（9.7%；10例男性和12例女性患者），9例患者（4.0%）ePPIX水平升高且症状与原卟啉病一致，但FECH或ALAS2（OMIM 301300）基因未检测到突变。8例患者无法获取DNA样本。患者症状出现时的平均（标准差）年龄为4.4（4.4）岁。常见报告的情况有贫血（107例[47.3%]）、肝功能障碍史（62例[27.4%]）和胆结石（53例[23.5%]）。较高的ePPIX水平与症状出现年龄较早相关（1岁之前与1岁之后出现症状者的ePPIX中位数水平分别为1744 vs 1567 µg/dL；P = 0.02）、日光耐受性较差（暴露于阳光下10分钟之前与之后报告症状者的ePPIX中位数水平分别为2233 vs 1524 µg/dL；P≤0.001）以及肝功能障碍风险增加（有肝功能障碍与肝功能正常者的ePPIX中位数水平分别为2016 vs 1510 µg/dL；P = 0.003）。具有EPP和FECH错义突变的患者ePPIX水平显著低于其他突变患者（1462 vs 1702 µg/dL；P = 0.01）。平均而言，XLP男性患者的ePPIX水平显著高于EPP患者（3574 vs 1669 µg/dL；P < 0.001）。由于随机X染色体失活，XLP女性患者存在明显的临床变异性。
这些数据表明，较高的ePPIX水平是EPP或XLP患者疾病严重程度和肝功能障碍风险的主要决定因素。这些发现为这些疾病的临床监测和管理提供了一个框架。
