Spectrum of Atypical Clinical Presentations in Patients with Biallelic PRF1 Missense Mutations. Issue 12 (16th July 2015)

• Record Type: Journal Article
• Authors: Tesi, Bianca; Chiang, Samuel C. C.; El‐Ghoneimy, Dalia; Hussein, Ayad Ahmed; Langenskiöld, Cecilia; Wali, Rabia; Fadoo, Zehra; Silva, João Pinho; Lecumberri, Ramón; Unal, Sule; Nordenskjöld, Magnus; Bryceson, Yenan T.; Henter, Jan‐Inge; Meeths, Marie
• Is Part Of: Pediatric blood & cancer. Volume 62:Issue 12(2015:Dec.)
• Page Start: 2094
• Page End: 2100
• Publication Date: 2015-07-16
• Subjects: Tumors in children -- Periodicals; Blood -- Diseases -- Periodicals; Cancer in children -- Periodicals; 618.92
• DOI: 10.1002/pbc.25646
• Languages: English
• ISSNs: 1545-5009

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="pbc25646-sec-0001" sec-type="section"> <title>Background</title> <p>Perforin, encoded by <italic>PRF1</italic>, is a pore‐forming protein crucial for lymphocyte cytotoxicity. Biallelic <italic>PRF1</italic> nonsense mutations invariably result in early‐onset hemophagocytic lymphohistiocytosis (HLH), termed familial HLH type 2 (FHL2). In contrast, biallelic <italic>PRF1</italic> missense mutations may give rise to later‐onset disease and more variable manifestations.</p> </sec> <sec id="pbc25646-sec-0002" sec-type="section"> <title>Procedure</title> <p>We retrospectively searched our database for patients from families with siblings carrying biallelic <italic>PRF1</italic> missense mutations where at least one sibling did not develop HLH, and for patients with biallelic <italic>PRF1</italic> missense mutations and an atypical presentation of disease. We reviewed their clinical, genetic, and immunological characteristics.</p> </sec> <sec id="pbc25646-sec-0003" sec-type="section"> <title>Results</title> <p>In all, we identified 10 such patients, including three sibling pairs with discordant manifestations. Interestingly, in two families, siblings of late‐onset HLH patients developed Hodgkin lymphoma but no HLH. In a third family, one sibling presented with recurrent HLH episodes, whereas the other remains healthy. Of note, the affected sibling also suffered from systemic lupus erythematosus. Additional unrelated patients with biallelic <italic>PRF1</italic> missense mutations were affected by neurological disease without classical signs of HLH, gastrointestinal inflammation as initial presentation of disease, as well as a hematological malignancy. Compared to early‐onset FHL2 patients, the patients with an atypical presentation displayed a partial recovery of NK cell cytotoxicity upon IL‐2 stimulation in vitro.</p> </sec> <sec id="pbc25646-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Our findings substantiate and expand the spectrum of clinical presentations of perforin deficiency, linking <italic>PRF1</italic> missense mutations to lymphoma susceptibility and highlighting clinical variability within families. <italic>PRF1</italic> mutations should, therefore, be considered as a cause of several diseases disparate to HLH. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.</p> </sec> </abstract>