GENOTYPE-PHENOTYPE STUDY OF FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS TYPE 3

Elena Sieni (1) , Valentina Cetica (1) , Alessandra Santoro (2) , Karin Beutel (1) , Elena Mastrodicasa (3) , Marie Meeths (4) , Benedetta Ciambotti (1) , Francesca Brugnolo (1) , Udo Zur Stadt (5) , Daniela Pende (6) , Lorenzo Moretta (7) , Gillian M. Griffiths (8) , Jan-Inge Henter (9) , Gritta Janka (10) , Maurizio Arico (1)

1 Department Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer, Florence
2 U.O. Ematologia I, A.O. Ospedali Riuniti Villa Sofia-Cervello, Palermo
3 S.C. di Oncoematologia Pediatrica con Trapianto di CSE, O
4 Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karo
5 Research Institute Children's Cancer Center, Hamburg
6 Istituto Nazionale per la Ricerca sul Cancro, Genoa
7 IRCCS Istituto Giannina Gaslini, Genova
8 Addenbrooke's Hospital
9 Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institute
10 Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg

Background: Mutations of UNC13D are causative for FHL3 (OMIM 608898). We present a genotype-phenotype study of 845 FHL3 patients. Methods: A consortium of 3 countries planned to pool in a common database data on presenting features and mutations from individual patients with biallelic UNC13D mutations. Results: 845 FHL3 patients (median age: 4.1 months) were reported from Florence, Italy (n=54), Hamburg, Germany (n=18), Stockholm, Sweden (n=123). Their ethnic origin was: Caucasian, n=57, Turkish, n=10, Asian, n=7, Hispanic, n=4, African, n=3 (not reported, n=34). Thrombocytopenia was present in 96%, splenomegaly in 95%, fever in 89%. Central nervous system was involved in 49/812 (60%) patients versus 36% in FHL2 (p=0.001). The combination of fever, splenomegaly, thrombocytopenia and hyperferritinemia was present in 71%. CD107a expression, NK activity and Munc13-4 protein expression were absent or reduced in all but one of the evaluated patients. We observed 54 different mutations, including 15 novel ones: 19 missense, 14 deletions or insertions, 12 nonsense, 911 splice errors. None was specific for ethnic groups. Patients with two disruptive mutations were younger than patients with two missense mutations (p<0.001), but older than comparable FHL2 patients (p=0.001). Conclusion. UNC13D mutations are scattered over the gene. Ethnic-specific mutations were not identified. CNS involvement is more frequent than in FHL2; in patients with FHL3 and disruptive mutations, age at diagnosis is significantly higher than in FHL2. The combination of fever, splenomegaly, thrombocytopenia and hyperferritinemia appears to be the most easily and frequently recognized clinical pattern and their association with defective granule release assay may herald FHL3.

Mots clés: Haematology (incl Blood transfusion); Immunology (including allergy)

Elena Sieni, Valentina Cetica, Alessandra Santoro, Karin Beutel, Elena Mastrodicasa, et al.. GENOTYPE-PHENOTYPE STUDY OF FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS TYPE 3. Journal of Medical Genetics, 2011, 48 (5), pp.343. ⟨10.1136/jmg.2010.085456⟩. ⟨hal-00601562⟩