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: Blackwell Publishing

Key:

- Free Content

- New Content

- Subscribed Content

- Free Trial Content

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: 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

The full text electronic article is available for purchase. You will be able to download the full text electronic article after payment.

$49.48 plus tax Refund Policy

Key:

- Free Content

- New Content

- Subscribed Content

- Free Trial Content

Share this item with others: These icons link to social bookmarking sites where readers can share and discover new web pages.