Notable therapeutic response in a patient with systemic juvenile xanthogranuloma with KIF5B‐ALK fusion

Abstract

To the Editor, Juvenile xanthogranuloma (JXG) is classified as ahistiocytosis that is generally diagnosed on the basis of the presence of cutaneous nodules in infancy. It has been considered benign and can undergo spontaneous regression without therapy.1 However, some patients with systemic JXG, particularly those with central nervous system (CNS) involvement, have severe neurological sequelae. Conventional chemotherapy based on Langerhans cell histiocytosis (LCH) has been applied for severe cases,2 but the response rate remains unclear. Recently, BRAF V600E mutation and recurrent kinase fusions, including BRAF, NTRK, and anaplastic lymphoma kinase (ALK), including KIF5B-ALK fusion, have been identified in histiocytic neoplasms.3,4 We present the case of a patient with CNS lesions causing neurological disorders, in whom systemic JXGwith KIF5B-ALK fusion was detected by next-generation sequencing (NGS) panel-based comprehensive genomeprofiling (CGP). Thepatient, amale infant born to nonconsanguineous Japanese parents, presented at age 2 weeks with multiple subcutaneous tumours of up to 6.0 cm in diameter (Figure 1A). He showed lack of movement in his right arm with no other neurological abnormalities. An enhanced computed tomography (CT) scan demonstrated subpleural nodular shadows in both lung fields (Figure 1B) and multiple lowdensity areas in the liver (Figure 1C) and right kidney (Figure 1D). Brain and whole spine magnetic resonance imaging (MRI) revealed enlargement of the left side of themedulla, a tumour in the cerebellum, and an intra-axial massive tumour with contrast enhancement in the cervicothoracic spinal cord. Biopsy of a cutaneous lesion demonstrated spindle cells with circular unequal nuclei and light cytoplasm proliferating between the dermal collagen fibres (Figure S1A–C). Immunohistochemical staining showed that the cellswerepositive forALKD5F3and ALK1 (Figure S1D–F). Taken together, the diagnosis of JXGwasmade. The patient did not receive any anti-tumoural treatment at first, and his developmental disabilities progressed in his first year of life. He could not turn over and uttered only a few lallings. Severe foot clonus was evoked easily by touching his lower extremities, and the spasticity and muscle weakness of the lower extremities progressed. The patient needed tube feeding owing to dysphagia, and he experienced severebronchitis five times andageneralised convulsive seizure. At 12 months of age, CT revealed a new lesion in an ischial bone in