{'fraction_non_alphanumeric': 0.025733634311512415, 'fraction_numerical': 0.02144469525959368, 'mean_word_length': 5.59375, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
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 approximately 20 cases in the literature1-3; however, the pathogenesis underlying 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 harbouring 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-oldmale infant presentedwith yellowishmaculopapular 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. Subsequently, no alterationwas 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 18months post-HSCT. Intriguingly, mutation analyses of PTPN11 in the skin biopsy specimen 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 harbouringmutations in childhood myeloid malignancies revealed solely the previously identified 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, nonsyndromic JMMLconferring a great transforming potential.9 Additionally, activating PTPN11 mutations also play an important role in the development of other haematological and solidmalignancies, including acute myeloid leukaemia, lung cancer andmelanoma.10-12 Historically, JXG has been considered a reactive process.13,14 Recently, Diamond et al identified somaticmutations targeting theRAS-MAPKpathway in 7/11 (63%) patients with JXG and in the case of a patient with disseminated juvenile xanthogranuloma the activatingmutation ofMAPK1has been described as well, however PTPN11 mutations were not investigated in these studies.15,16 To date, only a single case has been reported, where clonal association of a haematological malignancy and JXG was described based on identical TCR-γ 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 mutation. Further studies will be required to evaluate a possible clonal relationship in similar cases. Informed consent was obtained from the family of the patient for the publication of pictures and data.