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J Med Genet 45:134-141 doi:10.1136/jmg.2007.054288
  • Original article

Spectrum, and clinical and functional implications of UNC13D mutations in familial haemophagocytic lymphohistiocytosis

  1. E Rudd1,2,
  2. Y T Bryceson3,4,
  3. C Zheng1,2,
  4. J Edner1,2,
  5. S M Wood4,
  6. K Ramme1,2,
  7. S Gavhed1,2,
  8. A Gürgey5,
  9. M Hellebostad6,
  10. A G Bechensteen7,
  11. H-G Ljunggren4,
  12. B Fadeel8,
  13. M Nordenskjöld2,
  14. J-I Henter1
  1. 1
    Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  2. 2
    Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  3. 3
    Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA
  4. 4
    Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
  5. 5
    Department of Pediatric Hematology, Hacettepe University, Ankara, Turkey
  6. 6
    Department of Pediatrics, Rikshospitalet University Hospital, Oslo, Norway
  7. 7
    Department of Pediatrics, Ullevål University Hospital, Oslo, Norway
  8. 8
    Division of Biochemical Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  1. E Rudd, CMM L8:02, Karolinska Hospital, SE-171 76 Stockholm, Sweden; Eva.Rudd{at}ki.se
  • Received 4 September 2007
  • Revised 13 October 2007
  • Accepted 15 October 2007
  • Published Online First 9 November 2007

Abstract

Objective: Familial haemophagocytic lymphohistiocytosis (FHL) is a fatal disorder of immune dysregulation with defective cytotoxic lymphocyte function. Disease-causing mutations have been identified in the genes encoding perforin (PRF1), syntaxin-11 (STX11), and Munc13-4 (UNC13D). We screened for UNC13D mutations and studied clinical and functional implications of such mutations in a well defined patient cohort.

Methods: Sequencing of UNC13D was performed in 38 FHL patients from 34 FHL families in which PRF1 and STX11 mutations had been excluded.

Results: We identified six different mutations affecting altogether 9/38 individuals (24%) in 6/34 (18%) unrelated PRF1/STX11-negative families. Four novel mutations were revealed; two homozygous nonsense mutations (R83X and W382X), one splice mutation (exon 28), and one missense mutation (R928P). In addition, two known mutations were identified (R214X and a deletion resulting in a frame-shift starting at codon 782). There was considerable variation in the age at diagnosis, ranging from time of birth to 14 years (median 69 days). Three of nine patients (33%) developed central nervous system (CNS) symptoms. Natural killer (NK) cell activity was impaired in all four patients studied. Defective cytotoxic lymphocyte degranulation was evident in the two patients investigated, more pronounced in the patient with onset during infancy than in the patient with adolescent onset.

Conclusions: Biallelic UNC13D mutations were found in 18% of the PRF1/STX11-negative FHL families. Impairment of NK cell degranulation was less pronounced in a patient with adolescent onset. FHL should be considered not only in infants but also in adolescents, and possibly young adults, presenting with fever, splenomegaly, cytopenia, hyperferritinaemia, and/or CNS symptoms.

Footnotes

  • Funding: Supported by the Swedish Children’s Cancer Foundation, the Swedish Cancer Foundation, the Swedish Research Council, the Cancer and Allergy Foundation of Sweden, the Histiocytosis Association of America, the Märta and Gunnar V Philipson Foundation, and the Stockholm County Council (ALF project).

  • Competing interests: None.

  • Ethics approval: The study was approved by Karolinska Institutet ethics committee