Common Variable Immunodeficiency belongs to the group of rare diseases encompassing antibody deficiency syndromes of highly variable clinical presentation and outcome. The multicenter prospective study on a cohort of 224 patients with Common Variable Immunodeficiency provides an updated view of the spectrum of illnesses which occurred at the clinical onset and over a long period of follow-up (mean time: 11 years) and information on the effects of long-term immunoglobulin treatment. The mean age at the time of diagnosis was 26.6 years. Seventy-five patients were younger than 14 years of age. The mean age at the onset of symptoms was 16.9 years. This implicates with a mean diagnostic delay of 8.9 years. Respiratory tract infections were the most prominent clinical problem observed at diagnosis and during the follow-up. Intravenous immunoglobulin administration induced a significant reduction in the incidence of acute infections, mainly acute pneumonia and acute otitis. However, a progressive increase in the prevalence of patients with chronic diseases, mainly sinusitis and lung disease, was observed in all age groups, including the pediatric population. The morbidity of Common Variable Immunodeficiency due to all associated clinical conditions increased over time despite an adequate replacement with intravenous immunoglobulins. Our data stressed the need to develop international guidelines for the prevention and therapy of chronic lung disease, chronic sinusitis, chronic diarrhoea, and chronic granulomatosis in patients with humoral immunodeficiencies.

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The recent discovery of the human coun-terpart of the hairlessmousephenotype1has helped our understandingof the molecular genetics of hair growth.But there are no reports of a defect in thehuman homologue of the best known of the'bald' mouse phenotypes, the nudemouse2.This may be because affected individualsare so gravely ill from the accompanyingimmunodeficiency that their baldness goesunnoticed. We have carried out a geneticanalysis that reveals a human homologue ofthe nudemouse.The nudemouse is characterized by acongenital absence of hair and a severeimmunodeficiency2, resulting from muta-tions in the whn(winged-helix-nude;Hfh11nu) gene, which encodes a member ofthe forkhead/winged-helix transcriptionfactor family with restricted expression inthymus and skin3. The simultaneous occur-rence of severe functional T-cell immunodeficiency, congenital alopecia and nail dys-trophy (MIM database no. 601705) in twoaffected sisters led to the recognition thatthe clinical phenotype was reminiscent ofthe nudemouse4. We therefore investigatedwhether this syndrome represents thehuman counterpart of the nudemousephenotype.We obtained DNA samples from mem-bers of the sisters' family in a small villagein southern Italy. The affected sisters wereborn with a complete absence of scalp hair (Fig. 1a), eyebrows and eyelashes and haddystrophic nails, and no thymic shadow wasevident upon X-ray examination. The firstaffected child revealed a striking impair-ment of T-cell function shortly after birth,and died at the age of 12 months. Her sisterhad similar immunological abnormalities,but bonemarrow transplantation at fivemonths of age led to full immunologicalreconstitution, although the alopecia andnail dystrophy are still present4.We performed linkage analysis usingmicrosatellite markers near the humanWHNlocus on chromosome 17, and founda lod score of 1.32, suggestive of linkage. Wethen sequenced the human WHNgene5andfound a homozygous C-to-T transition atnucleotide position 792 of the WHNcDNA(GenBank accession no. Y11739) (Fig. 1b).This leads to a nonsense mutation atresidue 255 (R255X) in exon 5, and predictsthe complete absence of functional proteinas a result of nonsense-mediated decay ofmessenger RNA.Because the proband's bonemarrowtransplant was from her brother, we exam-ined her leukocyte DNA both before andafter the graft for the presence of chi-maerism. Genotyping the proband beforethe transplant showed that her leukocyteDNA was homozygous only for the mutantallele (Fig. 1c). Four years after the transplant, we detected the haplotype specific forthe wild-type paternal WHNallele receivedfrom the brother, as well as the mutantallele, indicative of chimaerism. Genderdetermination revealed that the proband'sleukocyte DNA was genotypically XXbefore the transplant, and the brother'sDNA was XY. Afterwards, the proband'sleukocyte DNA was found to be XY (Fig.1c), providing evidence of longtermengraftment and expansion of the bone-marrow graft.The WHNgene encodes a transcriptionfactor, which is developmentally regulatedand directs cel...

FOXN1 deficiency is a primary immunodeficiency characterized by athymia, alopecia totalis, and nail dystrophy. Two infants with FOXN1 deficiency were transplanted with cultured postnatal thymus tissue. Subject 1 presented with disseminated Bacillus Calmette-Guérin infection and oligoclonal T cells with no naive markers. Subject 2 had respiratory failure, human herpes virus 6 infection, cytopenias, and no circulating T cells. The subjects were given thymus transplants at 14 and 9 months of life, respectively. Subject 1 received immunosuppression before and for 10 months after transplantation. With follow up of 4.9 and 2.9 years, subjects 1 and 2 are well without infectious complications. The pretransplantation mycobacterial disease in subject 1 and cytopenias in subject 2 resolved. Subject 2 developed autoimmune thyroid disease 1.6 years after transplantation. Both subjects developed functional immunity. Subjects 1 and 2 have 1053/mm3 and 1232/mm3 CD3+ cells, 647/mm3 and 868/mm3 CD4+ T cells, 213/mm3 and 425/mm3 naive CD4+ T cells, and 10 200 and 5700 T-cell receptor rearrangement excision circles per 100 000 CD3+ cells, respectively. They have normal CD4 T-cell receptor β variable repertoires. Both subjects developed antigen-specific proliferative responses and have discon-tinued immunoglobulin replacement. In summary, thymus transplantation led to T-cell reconstitution and function in these FOXN1 deficient infants.

Hereditary hemolytic anemias are a group of disorders with a variety of causes, including red cell membrane defects, red blood cell enzyme disorders, congenital dyserythropoietic anemias, thalassemia syndromes and hemoglobinopathies. As damaged red blood cells passing through the red pulp of the spleen are removed by splenic macrophages, splenectomy is one possible therapeutic approach to the management of severely affected patients. However, except for hereditary spherocytosis for which the effectiveness of splenectomy has been well documented, the efficacy of splenectomy in other anemias within this group has yet to be determined and there are concerns regarding short- and long-term infectious and thrombotic complications. In light of the priorities identified by the European Hematology Association Roadmap we generated specific recommendations for each disorder, except thalassemia syndromes for which there are other, recent guidelines. Our recommendations are intended to enable clinicians to achieve better informed decisions on disease management by splenectomy, on the type of splenectomy and the possible consequences. As no randomized clinical trials, case control or cohort studies regarding splenectomy in these disorders were found in the literature, recommendations for each disease were based on expert opinion and were subsequently critically revised and modified by the Splenectomy in Rare Anemias Study Group, which includes hematologists caring for both adults and children.