Characterization of PRF1, STX11 and UNC13D genotype-phenotype correlations in familial hemophagocytic lymphohistiocytosis

Authors: Horne, AnnaCarin; Ramme, Kim Göransdotter¹; Rudd, Eva; Zheng, Chengyun; Wali, Yasser²; al-Lamki, Zakia²; Gürgey, Aytemiz³; Yalman, Nevin⁴; Nordenskjöld, Magnus⁵; Henter, Jan-Inge¹

Source: British Journal of Haematology, Volume 143, Number 1, October 2008 , pp. 75-83(9)

Publisher: Wiley-Blackwell

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Abstract:

Summary

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive lethal condition characterized by fever, cytopenia, hepatosplenomegaly and hemophagocytosis. The hallmark of FHL is defect apoptosis triggering and lymphocyte cellular cytotoxicity. Thus far three disease-causing genes (PRF1, UNC13D, STX11) have been identified. We performed a genotype-phenotype study in a large, multi-ethnic cohort of 76 FHL patients originating from 65 unrelated families. Biallelic mutations in PRF1, UNC13D and STX11 were demonstrated in 13/74 (18%), 6/61 (10%) and 14/70 (20%) patients, respectively. In 27/60 (45%) patients analyzed for all three genes, no molecular diagnosis was established. STX11 mutations were most common in Turkish families (7/28, 25%), whereas in Middle East families, PRF1 mutations were most frequent (6/13, 46%). No biallelic mutation was identified in most families of Nordic origin (13/14, 93%). Patients carrying PRF1 mutations had higher risk of early onset (age <6 months) compared to patients carrying STX11 mutations [adjusted odds ratio 8·23 (95% confidence interval [CI] = 1·20-56·40), P = 0·032]. Moreover, patients without identified mutations had increased risk of pathological cerebrospinal fluid (CSF) at diagnosis compared to patients with STX11 mutations [adjusted odds ratio 26·37 (CI = 1·90-366·82), P = 0·015]. These results indicate that the disease-causing mutations in FHL have different phenotypes with regard to ethnic origin, age at onset, and pathological CSF at diagnosis.

Keywords: familial hemophagocytic lymphohistiocytosis; phenotype; PRF1; UNC13D; STX11

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1365-2141.2008.07315.x

Affiliations: 1: Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Karolinska University Hospital 2: Department of Child Health, College of Medicine, Sultan Qaboos University, Oman 3: Department of Paediatric Haematology, Hacettepe University, Ankara 4: Department of Medical Biology and Bone Marrow Bank, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey 5: Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

Publication date: 2008-10-01

Characterization of PRF1, STX11 and UNC13D genotype-phenotype correlations in familial hemophagocytic lymphohistiocytosis

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