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Background Use of NGS in patients with unclassifiable disease lies a possible approach to the identification of novel disease causing genes. Objectives We report a patient with an early onset inflammatory bowel disease with granulomatous lesions and recurrent HLH episodes carrying a missense mutation in the WNT6 gene. Methods A trio based Whole Exome Sequencing (WES) approach was used. Cytokine levels were measured by multiplex assay and by specific ELISAs. Results Ten years old Caucasian boy affected by early onset pan-colitis from 9 months of age. Since the disease onset the patient is on glucocorticoid treatment with amino acidic enteral nutrition and oligo antigenic diet. Because of recurrent disease relapses at any attempt of glucocorticoid withdrawal, azathioprine and cyclosporine treatments were also added. At 2 years of age he received total colectomy with ileostomy. Because of insufficient disease control, treatment with a TNF-inhibitor (infliximab) was started with apparent improvement of intestinal symptoms. However, persistent granulomatous inflammatory disease of the distal portion of the ileus-rectal anastomosis persisted. Moreover, the patient presented recurrent HLH episodes that required high dose of glucocorticoid and cyclosporine-A treatment. Except one HLH episode related to a varicella zoster infection, the other HLH events were most likely triggered by his underlying inflammatory condition. During the HLH episodes levels of IL-18 were moderately elevated (10.880 pg/ml) the IFN-gamma induced chemokine CXCL9 was markedly high (21.871 pg/mL) and remained markedly elevated also during clinical and laboratory HLH remission (3.121 pg/ml and 9.929 pg/ml respectively). Considering the early disease onset, primary immunodeficiency and early intestinal bowel disease onset were genetically ruled out as well as chronic granulomatosis diseases through extensive NGS panels. WES revealed carriage of a private (MAF: 1/125568, TOPMED), predicted pathogenic (CADD: 31), homozygous variant of WNT6 (c.793G>C; p.(Asp265His); NM_006522.3). The patient is now partially controlled on low dose of oral glucocorticoid (0.1 mg/kg), cyclosporine-A (5mg/kg) and antimicrobic treatment. Conclusion WNT signalling has been primarily described as a regulatory pathway in ontogeny and homeostatic processes. Schaale at al. demonstrated that WNT6 is expressed in granulomatous lesions in the lung of Mycobacterium tuberculosis–infected mice. Moreover, they found that the transcription factor c-Myc is significantly induced in murine macrophages by WNT6. This identifies WNT6 as a novel factor driving macrophage polarization toward an M2-like phenotype, suggesting a role for WNT6 in macrophage differentiation. Our case suggests defective function of WNT6 might be involved in the development of a granulomatous disease. WNT6 role in macrophage differentiation and polarization might also be important in the activation of the IFN-gamma pathway and in recurrent HLH episodes. References [1] K. Schaale, et al. Wnt6 Is Expressed in Granulomatous Lesions of Mycobacterium tuberculosis–Infected Mice and Is Involved in Macrophage Differentiation and Proliferation. J Immunol2013; 191:5182-5195. Disclosure of Interests Claudia Bracaglia: None declared, Daniela Knafelz: None declared, Fiammetta Bracci: None declared, Antonella Insalaco: None declared, Giulia Marucci: None declared, Manuela Pardeo: None declared, Giusi Prencipe: None declared, Ivan Caiello: None declared, Antonia Pascarella: None declared, Marcello Niceta: None declared, Francesca Pantaleoni: None declared, Andrea Ciolfi: None declared, Bronislava Papadatou: None declared, Marco Tartaglia: None declared, Giuliano Torre: None declared, Fabrizio De Benedetti Grant/research support from: Abbvie, SOBI, Novimmune, Roche, Novartis, Sanofi, Pfizer |
