CLINICAL AND MOLECULAR FEATURES OF X-LINKED IMMUNODEFICIENCY WITH HYPER-IgM: A EUROPEAN SURVAY 5

X-linked immunodeficiency with hyper-IgM (XHIM) is a rare primary disorder of immunity that is caused by mutations affecting the expression of CD40 ligand (CD40L) on T lymphocytes. With the purpose of improving our knowledge on the biology of this disease, a European Registry of CD40L mutations(CD40Lbase) has been recently established that collects information on molecular, immunological and clinical aspects of XHIM. Fifty-six XHIM patients from 47 European families have been entered in the database. Analysis of collected data shows that mutations are widely scattered along the CD40L gene although not evenly distributed, most mutations being located in the TNF homology, extracellular domain. Missense mutations are more common than nonsense or frameshift aberrations. Clinically, most XHIM patients with defined mutation have a clinical history of multiple and often severe infections from bacterial opportunistic pathogens; upper and lower respiratory tract infections are particularly common, and 43% of patients with an early onset of the disease present with interstitial pneumonia by Pneumocystis carinii. One third of the patients experience chronic, watery diarrhoea that results in failure to thrive and may require total parenteral nutrition. Chronic inflammation and/or carcinomas of the liver, pancreas and biliary tree are observed in about 20% of the patients. The most commonly reported hematological abnormality in XHIM patients is chronic neutropenia that is typically associated to oral ulcers. Immunological findings include normal B and T cell counts, but markedly decreased serum levels of IgG, IgA, and IgE. IgM levels are normal in 50% of XHIM patients at the time of diagnosis; about 70% of patients, however, develop high levels of IgM later in life. In vitro proliferative responses to mitogens are usually normal, whereas impairment of responses to T-cell dependent stimuli (i.e. tetanus toxoid) is often observed. The inadequacy of XHIM patients' immunity accounts for the overall poor prognosis of this disease. Death usually occurs because of severe infections early in life, whereas, after the first decade, XHIM patients more often succumb to severe liver disease or cancer. Current survival rate for XHIM patients at 25 years is only 20%. For this reason allogeneic bone marrow (BMT) from HLA-identical siblings is now indicated and has proven successful applied. BMT from HLA-matched unrelated donors has also recently achieved positive results. For patients who lack HLA-identical bone marrow donors the recommended treatment is based on antibiotic prophylaxis with trimethoprimsulfamethoxazole, regular infusions of intravenous immunoglobulins and careful monitoring of liver complications and cancer.