Longitudinal decline in lung function in patients with primary immunoglobulin deficiencies.

within a given pedigree can only be explained by a ‘‘second signal.’’ In our patient the nature of this second signal was shown not to be one of the known genes involved in hemophagocytosis. Once intravenous immune globulin and prednisone were started, ferritin and sIL-2R levels did not completely normalize (ferritin, 600-750 mg/L [upper limit of normal, 350 mg/L]; sIL-2R, 4320 U/mL [upper limit of normal, 2400 U/mL]), even after almost 3 years of follow-up. Hemophagocytosis was detected in neither bone marrow smears nor in spleen and lymph node biopsy specimens. Clinically, the patient fulfilled the diagnosis of hemophagocytic lymphohistiocytosis but was not treated accordingly. The hemophagocytic lymphohistiocytosis parameters (ie, blood cell counts, ferritin, lactate dehydrogenase, sIL-2R, and triglycerides) were considered to be triggered by the pneumonia. The hypoimmunoglobulinemia and defective immunization responses were most compatible with CVID and highly unusual for ALPS. Increased susceptibility to malignancy, particularly hematological malignancy, is the most worrying consequence of ALPS. Lymphoma develops in about 10% of patients, and the relative risks of (non)Hodgkin lymphoma are 15to 50-fold, respectively. Also, patients who have CVID and granulomatous or lymphocytic interstitial lung disease are at high risk for early mortality and B-cell lymphomas. The absence of an increased risk among relatives suggests that the increased cancer morbidity in patients with CVID is related to the immunodeficiency per se rather than to specific genetic traits shared with their relatives. Whether the risk of lymphoproliferative malignancy in our family is increased remains uncertain. The grandfather has died from a mucosa-associated lymphoid tissue lymphoma but was healthy until he presented at old age. We do not know whether he carried the same FAS mutation. In conclusion, mutations in FAS (TNFRSF6) might not only result in clinical ALPS but also in hypogammaglobulinemia and reduced reactivity on immunization, which is defined as CVID. Similar phenotypic overlap was most recently suggested in a study including patients with ALPS and CVID, some of whom were carrying a FAS mutation. Our patient adds to this complex overlap syndrome, presenting with CVID and features of hemophagocytosis, whereas his FAS-mutated family members were without any clinical disease. Taco W. Kuijpers, MD, PhD Paul A. Baars, PhD Daan J. aan de Kerk, MD Machiel H. Jansen Natasja Dors, MD Rene A. W. van Lier, MD, PhD Steven T. Pals, MD, PhD