DNMT3Aovergrowth syndrome is associated with the development of hematopoietic malignancies in children and young adults

Abstract

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.

Melanoma in a patient with DNMT3A overgrowth syndrome

“…Most cases of DOS-associated malignancies have been described in the pediatric and young adult populations ( Hollink et al 2017 ; Tatton-Brown et al 2018 ; Ferris et al 2021 ). Melanoma is typically a disease diagnosed in later life, with a median age of 65 yr at diagnosis (SEER21).…”

“…DNMT3A overgrowth syndrome (MIM #615879) consists of a constellation of clinical manifestations with three principal features, including overgrowth (tall stature, increased head circumference, elevated body mass index), impaired intellectual development, and characteristic facial features, and is associated with de novo germline heterozygous mutations in the DNA methyltransferase gene DNMT3A ( Tatton-Brown et al 2014 ). Since its first description, the number of patients with documented DNMT3A overgrowth syndrome (DOS) has grown to more than 300 at present, whereas the repertoire of clinical manifestations has expanded to include obesity, cardiac defects, umbilical hernia, hypotonia, joint hypermobility, seizures, behavioral disorders, and other phenotypes ( Hollink et al 2017 ; Kosaki et al 2017 ; Shen et al 2017 ; Xin et al 2017 ; Tatton-Brown et al 2018 ; Jeffries et al 2019 ; Balci et al 2020 ; Ferris et al 2021 ; Smith et al 2021 ; Cecchi et al 2022 ).…”

A novel DNA methylation-related gene signature for the prediction of overall survival and immune characteristics of ovarian cancer patients

“…In recent years, the role of epigenetic modifications in the pathogenesis of diseases has been gradually clarified [37,38]. As an important type of epigenetic modification, DNA methylation has been reported to participate in the process of disease occurrence, diagnosis, prognosis evaluation and treatment [10,22,39,40]. In OC, DNA methylation also shows value in prognostic evaluation, but the prediction efficiency is not particularly accurate, and whether there are other values remains unclear [12,13].…”

Overgrowth syndromes, diagnosis and management

“…A compelling illustration of this emerging understanding can be found in the context of Tatton-Brown-Rahman syndrome, where an evolving risk of hematopoietic malignancies has been reported. Recent case reports highlight the occurrence of various hematopoietic malignancies within this syndrome, revealing a potential risk profile, particularly for acute myeloid leukemia (AML) [37 ▪ ]. Extrapolating from this data, an estimated risk of roughly 2% emerges within the Tatton–Brown–Rahman syndrome population.…”