Abstract
We report the case of an autoimmune lymphoproliferative syndrome (ALPS) patient who developed a non-Hodgkin lymphoma, in whom we identified, in addition to a previously never described fas mutation, a mutation in the perforin (Prf1) gene. In this 27-yr old patient with multiple recurrent adenopathies a diagnosis of ALPS was made. ALPS is a rare disorder characterized by splenomegaly and early-onset massive lymphadenopathy, autoimmune manifestations, and increased incidence of solid and hematological malignancies, including Hodgkin and non-Hodgkin lymphomas. Fas mutations were previously reported as the genetic defect responsible for this syndrome. Fas gene sequencing demonstrated a novel point mutation in intron 7, affecting a canonical splicing site (IVS7nt1 G->A). This mutation produced skipping of exon 7 and a frameshift in exon 8. The frameshift revealed a stop codon in exon 8. Abnormally spliced products lacking exon 7 were demonstrated by cDNA analysis. The predicted protein would then lack the death domain, which is required for apoptosis induction. The same mutation was found in his father and brother, who were both healthy. Two years later, cervical adenopathy recurred; lymph node biopsy was diagnostic for a T-cell/histiocyte-rich large B-cell lymphoma. Disease staging demonstrated multiple sites of involvement (nodes, liver, bone marrow), and an elevated LDH. After four cycles of chemotherapy, worsening of liver function tests precluded further treatment, and the patient died shortly thereafter of disease progression. The mechanisms implicated in lymphomagenesis in ALPS are unclear. The particularly aggressive clinical course of lymphoma in this patient prompted us to investigate whether mutations in other genes might be associated to the identified Fas gene mutation. In this regard, the integrity of the perforin/granzyme pathway of cell-mediated killing appears to be critical. Perforin, a pore-forming molecule expressed in granules of cytotoxic effector lymphocytes, has been implicated in T and NK cell-mediated immune surveillance against viral infections and tumors. Indeed, increased lymphoma incidence has been associated with perforin deficiency in mice. We analyzed the sequence of the Prf1 gene in the patient and in his family. Prf1 gene sequencing in our patient demonstrated a point mutation in exon 3 (g755a) resulting in a change, at position 252, from a medium sized and polar aminoacid (asparagin) to a small sized and polar aminoacid (serin). This mutation occurs within the membrane-attack-complex, a region critically involved in the pore-forming activity of the molecule. The same mutation was found in his healthy mother. In conclusion, we propose that the family described in the present report represents a new genetic model that can explain the development of ALPS and lymphoma, due to a synergistic effect of the mutations in different genes: the family members who carry a heterozygous mutation in a single gene (either Fas or Prf1) are healthy, while the member with mutations in both genes developed ALPS and lymphoma. Perforin mutation may be one of the additional defects contributing to the development of lymphoma in ALPS patients, possibly in conjunction with other unknown factors.
Clinical Diagnosis of X-Linked Spondyloepiphyseal Dysplasia Tarda and a Novel Missense Mutation in the Sedlin Gene (SEDL)