Received: 19 February 2020 Revised: 9 April 2020 Accepted: 11 April 2020 DOI: 10.1002/pbc.28368 Pediatric Blood & Cancer The American Society of Pediatric Hematology/Oncology LETTER TO THE EDITOR Juvenile myelomonocytic leukaemia presentation after preceding juvenile xanthogranuloma harbouring an identical somatic PTPN11 mutation To the Editor: The association of juvenile xanthogranuloma (JXG) and juvenile myelomonocytic leukaemia (JMML) has been described in approxi- mately 20 cases in the literature 1-3 ; however, the pathogenesis under- lying the concomitant presentation has never been elucidated in detail. We present the case of a child who developed JXG at the age of 3 months, and 23 months later he was diagnosed with JMML har- bouring a somatic PTPN11 p.E76K mutation. The same mutation was detected in his previous JXG specimen, suggesting a clonal relationship between the two diseases in this case. A 3-month-old male infant presented with yellowish maculopapular lesions on the skin of the chest, followed by the appearance of similar lesions on the head and extremities at 7 months (Figure 1). The skin biopsy revealed CD68 + , S100 - and CD1a - infiltrating tumour cells in the dermal layer confirming the diagnosis of JXG. The magnetic resonance imaging, bone scintigraphy, ultrasonography and laboratory evaluations revealed no evidence of extracutaneous disease. Subse- quently, no alteration was observed on follow-up physical, imaging and laboratory examinations. At month 23, he presented with pansinusitis, significant blood count alterations and minor splenomegaly, however histopathological examination of the bone marrow did not clearly indicate malignancy. As his blood count parameters had deteriorated further with an increased grade of anaemia and thrombocytopenia, a bone marrow biopsy was performed again at month 26. Performing cytogenetic and molecular diagnostics for JMML, a heterozygous, pathogenic c.226G>A PTPN11 mutation was detected resulting in p.E76K (Figure 1). The germline genetic analysis from hair follicle returned a negative result, and according to the standard treatment protocol the patient received allogeneic haemopoietic stem cell transplantation (HSCT). The cutaneous lesions resolved, and the child is in complete remission 18 months post-HSCT. Intriguingly, mutation analyses of PTPN11 in the skin biopsy spec- imen from month 7, and in the bone marrow biopsy from month 23 detected an identical p.E76K mutation (Figure 1). Next-generation sequencing of 52 genes (Table S1) recurrently harbouring mutations in childhood myeloid malignancies revealed solely the previously identi- fied PTPN11 mutation with a variant allelic frequency of 30.0% in the JXG sample and 34.0% in the JMML sample, respectively, confirming a common cell of origin for both JXG and JMML. The pathomechanism underlying the concomitant presentation of JXG and JMML has long been a subject of discussion. 2-7 PTPN11 harbours gain-of-function mutations in 35% of the patients with JMML, leading to an increased activation of the RAS-MAPK signalling pathway. 8,9 The p.E76K mutation was described exclusively in de novo, non- syndromic JMML conferring a great transforming potential. 9 Addition- ally, activating PTPN11 mutations also play an important role in the development of other haematological and solid malignancies, including acute myeloid leukaemia, lung cancer and melanoma. 10-12 Historically, JXG has been considered a reactive process. 13,14 Recently, Diamond et al identified somatic mutations targeting the RAS-MAPK pathway in 7/11 (63%) patients with JXG and in the case of a patient with dissemi- nated juvenile xanthogranuloma the activating mutation of MAPK1 has been described as well, however PTPN11 mutations were not investi- gated in these studies. 15,16 To date, only a single case has been reported, where clonal associa- tion of a haematological malignancy and JXG was described based on identical TCR- rearrangement in a 5-year-old child, who developed systemic JXG secondary to T-cell acute lymphoblastic leukaemia. 17 Presumably, in our patient the mutation arising in the haemopoietic stem cell compartment contributed to the aberrant development of the myelomonocytic lineage, first presenting as JXG, and retained the capacity to subsequently transform into JMML. 13,18 We report the first case of the sequential presentation of a clonally related JXG and JMML harbouring an identical somatic driver muta- tion. Further studies will be required to evaluate a possible clonal rela- tionship in similar cases. Informed consent was obtained from the family of the patient for the publication of pictures and data. CONFLICT OF INTEREST The authors declare that there is no conflict of interest. ACKNOWLEDGEMENTS This study was funded by the Hungarian National Research, Develop- ment and Innovation Office (NKFIH) (KH17-126718 and NVKP_16-1- 2016-0004 grants), the Momentum grant of the Hungarian Academy of Sciences (LP-95021), and the ERA PerMed 2018 grant co-founded by the European Commission (ERAPERMED2018-123). The study also received funding from the ÚNKP-19-2-I-SE-47 grant of the New Pediatr Blood Cancer. 2020;e28368. c ○ 2020 Wiley Periodicals, Inc. 1 of 3 wileyonlinelibrary.com/journal/pbc https://doi.org/10.1002/pbc.28368