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Six novel mutations in the PRF1 gene in children with haemophagocytic lymphohistiocytosis
  1. Rita Clementia,
  2. Udo zur Stadtb,
  3. Gianfranco Savoldic,
  4. Stefania Varottod,
  5. Valentino Contere,
  6. Carmela De Fuscof,
  7. Luigi D Notarangeloc,
  8. Marion Schneiderg,
  9. Catherine Klersyh,
  10. Gritta Jankab,
  11. Cesare Danesinoa,
  12. Maurizio Aricòi
  1. aBiologia Generale e Genetica Medica, Università di Pavia, Italy, bDepartment of Paediatric Haematology and Oncology, University Children Hospital, Hamburg, Germany, cIstituto di Medicina Molecolare, “Angelo Nocivelli”, Clinica Pediatrica, Università di Brescia, Italy, dClinica Pediatrica, Università di Padova, Italy, eClinica Pediatrica, Università di Milano Bicocca, Ospedale San Gerardo, Monza, Italy, fOnco-Ematologia Pediatrica, Ospedale Pausilipon, Napoli, Italy, gSection of Experimental Anaesthesiology, University of Ulm, Germany, hBiometry and Clinical Epidemiology Service, IRCCS Policlinico San Matteo, Pavia, Italy, iClinica Pediatrica, IRCCS Policlinico San Matteo, Pavia, Italy
  1. Dr Danesino, CP 217, 27100 Pavia, Italycidi{at}

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Editor—The histiocytoses represent a heterogeneous group of disorders including both hereditary and sporadic forms. The familial form of haemophagocytic lymphohistiocytosis (HLH) was originally described by Farquhar and Claireaux1 in 1952. The main features of this disease are fever, hepatosplenomegaly, cytopenia, hypertriglyceridaemia, hypofibrinogenaemia, and central nervous system involvement.2 3 Haemophagocytosis is observed at presentation or later during the course of the disease in most patients. In 1991, the Histiocyte Society defined its diagnostic criteria4; however, the differential diagnosis of HLH from other disorders may remain problematical, especially in patients without familial recurrence. Linkage of the disease gene to an approximately 7.8 cM region between markers D9S1867 and D9S1790 at 9q21.3-22 was identified by homozygosity mapping in four inbred families with HLH of Pakistani descent.5 Also, linkage analysis of a group of 17 families with HLH indicated mapping of a locus linked to HLH to the proximal region of the long arm of chromosome 10 in the 10q21-22 region in 10 families but not in the remaining seven, providing evidence for genetic heterogeneity of this condition.6-9 While no further cases of HLH linked to the 9q21.3-22 locus have been reported, recently Steppet al 10 identified nine different mutations, three nonsense and six missense, in the two coding exons of the perforin 1 gene (PRF1) in a group of eight unrelated patients, providing the first evidence for a disease related to PRF1.10Perforin is an important mediator of lymphocyte cytotoxicity in a pathway independent from the Fas mediated apoptotic machinery. Thus,PRF1 mutations may affect cellular cytotoxicity, resulting in impaired antiviral defence and dysregulation of the apoptotic mechanisms involved in regulation of the immune response.11

We report six novel mutations and also confirm three additional mutations which had been previously reported. …

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