A rare PALB2 germline variant causing G2/M cell cycle arrest is associated with isolated myelosarcoma in infancy

Angelina Beer,Björn Lange,Maria Menzel,Anne Schedel,Ricardo Beck,Julia Hauer,Sebastian Brenner,Ralf Knöfler,Guido Fitze,Meinolf Suttorp,Malte Von Bonin,Jörn Meinel,Ulrike Anne Friedrich,Franziska Auer

doi:10.1002/mgg3.1746

Abstract

BackgroundIsolated myelosarcoma of infancy is a rare presentation of acute myelogenous leukaemia (AML). Because of its rarity and early onset in infancy underlying genetic predisposition is potentially relevant in disease initiation.Methods and ResultsWe report an oncologic emergency in an infant with thoracic and intraspinal aleukaemic myeloid sarcoma causing acute myelon compression and lower leg palsy. Whole‐exome sequencing of the patient's germline DNA identified a rare PALB2 (OMIM 610355) variant (p.A1079S), which is located in a domain critical for the gene's proper function within the homology‐directed repair pathway. In line with potential DNA damage repair defects mediated by the PALB2 deregulation, the patient's fibroblasts showed increased sensitivity towards radiation and DNA intercalating agents.ConclusionTherefore, we suggest PALB2 p.A1079S as a pathogenic variant potentially contributing to the here observed patient phenotype.

Highlights

PALB2 is a tumour suppressor that plays a critical role in homologous recombination repair (HR)
Consistent with a functional effect of the identified PALB2 variant, fibroblasts carrying p.A1079S showed a significantly higher percentage of cells arrested in G2/M phase compared to the healthy control (Figure 3a)
The diagnosis of a primarily extramedullary manifestation of an acute myelogenous leukaemia (AML) can be very complex and, dependent on the localization of the myeloid sarcoma, can even lead to an oncological emergency. This case is the first description of an infant with a vast isolated extramedullary medio-thoraco-spinal tumour infiltration as the first manifestation of an AML

Summary

| INTRODUCTION

PALB2 is a tumour suppressor that plays a critical role in homologous recombination repair (HR) It mediates the recruitment of BRCA2 and RAD51 to sites of DNA damage and functions downstream of BRCA1 (Hanenberg & Andreassen, 2018; Xia et al, 2006). Bi-allelic inactivating germline mutations in PALB2 that at least partly truncate the BRCA2-b inding C-terminal WD40 domain, result in the Fanconi anaemia (FA) subtype N. These patients display a severe FA phenotype with a high cancer incidence, including acute myeloid leukaemia (AML) before the age of 5 years (Reid et al, 2007; Xia et al, 2007). We report an infant with an extended atypic localization of myeloid sarcoma as isolated manifestation of an AML with a paternally inherited rare PALB2 germline variation

| RESULTS

| DISCUSSION

Findings

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