Cole Sarah, Giri Neelam, Alter Blanche P, Gianferante D Matthew
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States.
Walter Reed National Military Medical Center, Bethesda, MD, United States.
Front Genet. 2022 Jul 18;13:914141. doi: 10.3389/fgene.2022.914141. eCollection 2022.
Diamond Blackfan anemia (DBA) is an autosomal dominant ribosomopathy caused predominantly by pathogenic germline variants in ribosomal protein genes. It is characterized by failure of red blood cell production, and common features include congenital malformations and cancer predisposition. Mainstays of treatment are corticosteroids, red blood cell transfusions, and hematologic stem cell transplantation (HSCT). Despite a better understanding of the genotype of DBA, the biological mechanism resulting in the clinical phenotype remains poorly understood, and wide heterogeneity can be seen even within a single family as depicted here. Thirty family members enrolled in the National Cancer Institute inherited bone marrow failure syndromes study were evaluated with detailed medical questionnaires and physical examinations, including 22 in the family bloodline and eight unrelated partners. Eight participants had been previously told they had DBA by clinical criteria. Targeted germline testing was done on all family members. A pathogenic heterozygous missense mutation in (p.R62Q, c.185G > A) was detected in ten family members, including one person previously presumed unaffected. Eight family members presented with macrocytic anemia in infancy; all of whom were responsive to prednisone. Four family members became treatment independent; however, one individual became transfusion-dependent 36 years later following an episode of pneumonia. One prednisone responsive individual electively discontinued steroid treatment, and lives with severe anemia. One prednisone responsive individual died at age 28 from a stroke. Two family members developed colorectal cancer in their fifties; one had never required treatment for anemia. None had major congenital anomalies. This large family with DBA demonstrates the heterogeneity of phenotypes that can be seen within the same genotype. Most family members presented with steroid-responsive anemia in infancy and subtle congenital malformations, findings consistent with recent genotype-phenotype studies of DBA. However, two family members were relatively unaffected, underscoring the importance of further studies to assess modifier genes, and epigenetic and/or environmental factors which may result in normal erythropoiesis despite underlying ribosome dysfunction. This large, multigenerational family highlights the need for individualized treatment, the importance of early cancer surveillance even in individuals with clinically mild phenotypes, and the benefit of long-term follow-up to identify late complications.
钻石黑范贫血（DBA）是一种常染色体显性核糖体病，主要由核糖体蛋白基因中的致病种系变异引起。其特征是红细胞生成障碍，常见特征包括先天性畸形和癌症易感性。治疗的主要方法是使用皮质类固醇、红细胞输血和血液学干细胞移植（HSCT）。尽管对DBA的基因型有了更好的了解，但导致临床表型的生物学机制仍知之甚少，正如本文所描述的，即使在一个单一家庭中也能看到广泛的异质性。对参加美国国立癌症研究所遗传性骨髓衰竭综合征研究的30名家庭成员进行了详细的医学问卷调查和体格检查，其中包括22名家族血统成员和8名无血缘关系的配偶。8名参与者此前根据临床标准被告知患有DBA。对所有家庭成员进行了靶向种系检测。在10名家庭成员中检测到 （p.R62Q，c.185G > A） 致病性杂合错义突变, 其中包括一名此前被认为未受影响的人。8名家庭成员在婴儿期出现大细胞性贫血；他们所有人对泼尼松均有反应。4名家庭成员不再需要治疗；然而，有一人在肺炎发作36年后变得依赖输血。一名对泼尼松有反应的个体选择性地停止了类固醇治疗，患有严重贫血。一名对泼尼松有反应的个体在28岁时死于中风。两名家庭成员在五十多岁时患了结直肠癌；其中一人从未因贫血需要治疗。没有人有重大先天性异常。这个患有DBA的大家庭展示了同一基因型中可见的表型异质性。大多数家庭成员在婴儿期出现对类固醇有反应的贫血和细微的先天性畸形，这些发现与最近关于DBA的基因型-表型研究一致。然而，两名家庭成员受影响相对较小，这凸显了进一步研究以评估修饰基因以及可能导致尽管存在潜在核糖体功能障碍但仍能正常红细胞生成的表观遗传和/或环境因素的重要性。这个大型多代家庭凸显了个体化治疗的必要性、即使是临床表型较轻的个体进行早期癌症监测的重要性以及长期随访以识别晚期并发症的益处。
