EZH2 mutation in an adolescent with Weaver syndrome developing acute myeloid leukemia and secondary hemophagocytic lymphohistiocytosis

Abstract

Weaver syndrome is an overgrowth syndrome characterized by pre- and postnatal overgrowth with distinctive craniofacial appearance. Mutations in the enhancer of zeste homolog 2 (EZH2) gene were found to cause Weaver syndrome, and have been associated with hematologic malignancies, including acute myeloid leukemia (AML). We present the first report of a patient with Weaver syndrome, who developed AML and harbored an EZH2 mutation. The clinical course of the 16-year-old female adolescent patient was complicated by a secondary hemophagocytic lymphohistiocytosis. Genomic DNA was isolated from bone marrow cells at AML diagnosis. Polymerase chain reactions were performed with primers covering all exons of the EZH2 gene. We found a novel heterozygous EZH2 mutation within exon 5 that caused an amino acid change from proline to leucine at position 132 (p.Pro132Leu) within the catalytic D1 domain. Analysis of a remission sample also showed this mutation, indicating a germline mutation. It remains to be elucidated whether EZH2 mutations contribute to disease severity in specific AML cases.

High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer

“…These patients showed a clinical phenotype compatible with the syndrome diagnosed. In five of these syndromes (Baraitser-Winter syndrome, Coffin-Siris syndrome, Rubinstein-Taybi syndrome, Weaver syndrome and APOB-based hypobetalipoproteinemia), malignancies have been described before (22,23,(34)(35)(36)(37), and the genes involved are also affected by somatic mutations in several cancer types (38)(39)(40). This suggests a role of these mutations in cancer development in these patients, but more studies are needed to firmly establish this relationship.…”

Novel SUZ12 mutations in Weaver‐like syndrome

“…Craniofacial features are present in patients with SUZ12 , EED and EZH2 mutations, but these appear differently; micrognathia/retrognathia is prominent in those with EED and EZH2 mutations but was not observed in our three patients with a SUZ12 mutation. EZH2 and EED mutation‐positive individuals generally exhibit specific facial phenotypes at birth or early childhood (<1 year) . In contrast, in the two SUZ12 ‐mutated individuals (2 and 3), facial features were noted later at the age of 5 years 5 months and 3 years, respectively.…”

“…EZH2 and EED mutationpositive individuals generally exhibit specific facial phenotypes at birth or early childhood (<1 year). [2][3][4][5][6][7][8]10,11,13,14 In contrast, in the two Therefore, pathogenic variants in SUZ12 likely cause a Weaver-like syndrome rather than WS, but further case reports are required.…”

“…In 2011, Khosravi et al proposed clinical criteria to support the diagnosis of WS . Pathogenic variants in the genes encoding enhancer of zeste homolog 2 ( EZH2 ) and embryonic ectoderm development ( EED ) have been identified in WS or Weaver‐like syndrome . In particular, EZH2 was previously established as the causative gene for WS; thus, a molecular diagnostic approach is crucial for overgrowth patients .…”

“…have been identified in WS or Weaver-like syndrome. [2][3][4][5][6][7][8][9][10][11][12][13][14] In particular, EZH2 was previously established as the causative gene for WS; thus, a molecular diagnostic approach is crucial for overgrowth patients. 11 Nevertheless, individuals with an EZH2 mutation do not always exhibit the classical manifestations of WS.…”