CEBPA-associated familial acute myeloid leukemia mimicking Werner syndrome: a case report

Abstract

CEBPA-associated familial acute myeloid leukemia (AML) is an autosomal dominant leukemia predisposition syndrome associated with germline variants in the CEBPA gene. Werner syndrome (WS) is an autosomal recessive progeroid syndrome causing premature aging and malignancies (e.g., AML). We report a 41-year-old man referred for medical genetic evaluation because of 3 synchronous tumors (colon, kidney, and thyroid) and premature aging. He underwent hematopoietic stem cell transplantation (HSCT) at 12 years of age because of AML diagnosed 3 years earlier. His sister (donor for the HSCT) and his brother later developed AML, as did two of her sister's three children. The patient met the clinical criteria for a "probable" WS, but duo-based (urine and blood DNA) whole exome sequencing did not confirm this diagnosis. A heterozygous c.350del p.(Gly117Alafs*43) pathogenic variant in the CEBPA gene was found in the proband's urine and blood DNA, and in his affected relatives. We postulate that AML management led to adverse effects in the proband, mimicking a WS phenotype (phenocopy). To our knowledge, this is the first report of a leukemia predisposition syndrome mimicking a progeroid syndrome. The diagnosis allowed for personalized medicine (i.e., lifelong regular complete blood count check-up) in the proband and his affected relatives.

Keywords: case report; personalized medicine; phenocopy; tumor sequencing; whole exome sequencing.

FIGURE 1

AML segregated over two generations in the proband’s pedigree, with an age of onset comprised between 9 and 37 years of age. (A) Overview of the proband’s and his relatives’ medical journey. (B) Family tree presenting females (circles) and males (squares) affected (filled symbols) by AML. Arrow: proband, crossed symbol: deceased, horizontal double lines: infertility. (C) Proband’s face and profile photographs (taken at 41 years) highlighting premature aging and bilateral ptosis. AML: acute myeloid leukemia, HSCT: hematopoietic stem cell transplantation, WES: whole exome sequencing.

FIGURE 2

Next-generation sequencing results highlighted a germline familial c.350del CEBPA variant related to CEBPA-associated familial AML in (A) the proband’s urine (own DNA) and blood (sister’s DNA, due to HSCT) and (B) the proband’s (colon and kidney tumors) and relatives’ (bone marrow and blood) samples. In the bone marrow and blood samples, somatic variants (c.925_927dup and c.930_931insAAG, respectively) affecting the C-terminal extremity of the protein were detected (“second hit”) in addition to the germline variant. Integrative Genomics Viewer screenshots with black dash and purple rectangle representing deletion of one nucleotide and insertion of three nucleotides, respectively. Note that CEBPA is located on the minus strand of the chromosome. Thus the 5′ extremity is presented on the right side of the figure. AML: acute myeloid leukemia, HSCT: hematopoietic stem cell transplantation.