DNMT3A Overgrowth Syndrome (DOS, also known as Tatton-Brown Rahman Syndrome/TBRS) is one of several overgrowth syndromes with complex phenotypes caused by constitutional mutations in genes encoding epigenetic regulators. The clinical features of DOS are variable but include overgrowth (tall stature and/or obesity) and intellectual disability. DNMT3A is essential for de novo DNA methylation and plays an important role in hematopoiesis. Somatic mutations in DNMT3A are among the most common initiating mutations in normal karyotype acute myeloid leukemia (AML) patients and in elderly people with clonal hematopoiesis. The natural history of DOS has not been fully explored since the first description of this rare condition in 2014. Because of the association of somatic DNMT3A mutations and leukemia development, we assessed information from the ~200 known DOS patients world-wide and were able to document eight with hematologic malignancies. Based on this prevalence, we suggest DOS is a cancer predisposition syndrome, especially for hematologic malignancies. Using recommendations from an expert panel, we suggest DOS patients should be prospectively monitored for hematologic malignancies, which may allow for early intervention and permit its natural history to be better defined.

中文翻译：

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DNMT3A 过度生长综合征与儿童和年轻人的造血系统恶性肿瘤的发生有关。


DNMT3A 过度生长综合征（DOS，也称为 Tatton-Brown Rahman 综合征/TBRS）是几种具有复杂表型的过度生长综合征之一，由编码表观遗传调节因子的基因的体质突变引起。 DOS 的临床特征多种多样，但包括过度生长（身材高大和/或肥胖）和智力障碍。 DNMT3A 对于 DNA 从头甲基化至关重要，在造血过程中发挥着重要作用。 DNMT3A 的体细胞突变是正常核型急性髓系白血病 (AML) 患者和克隆造血老年人中最常见的起始突变之一。自 2014 年首次描述这种罕见病症以来，DOS 的自然史尚未得到充分探索。由于体细胞 DNMT3A 突变与白血病发展之间的关联，我们评估了全球约 200 名已知 DOS 患者的信息，并能够文件八与血液系统恶性肿瘤有关。基于这种患病率，我们认为 DOS 是一种癌症易感综合征，尤其是血液系统恶性肿瘤。根据专家小组的建议，我们建议对 DOS 患者进行前瞻性血液恶性肿瘤监测，这样可以进行早期干预并更好地确定其自然史。