Cognitive and behavioral abnormalities in children after hematopoietic stem cell transplantation for severe congenital immunodeficiencies.

Hematopoietic stem cell transplantation (HSCT) is a highly successful treatment for severe congenital immunodeficiencies. However, some studies have suggested that children may experience cognitive difficulties after HSCT. This large-scale study assessed cognitive and behavioral function for the cohort of children treated by HSCT at one center between 1979 and 2003 to determine the frequency and severity of problems and to identify risk factors. A total of 105 patients were assessed on standardized measures of cognitive and emotional and behavioral function together with a control group of unaffected siblings. The average IQ for the cohort was 85 (95% confidence interval, 81-90), significantly lower than both the population average of 100 (P < .001) and unaffected siblings. Multivariate analysis indicated that the underlying genetic defect, diagnosis of adenosine deaminase-deficient severe combined immunodeficiency, and consanguinity were associated with worse outcome but that age at transplantation and chemotherapy conditioning were not. Children treated by HSCT for severe immunodeficiency have an increased risk of long-term cognitive difficulties and associated emotional and behavioral difficulties. The specific genetic diagnosis, consanguinity, and severe clinical course are associated with poor outcome. Long-term follow-up of these patients should include screening to identify and manage these problems more effectively.

Severe combined immunodeficiency: a national surveillance study.

National immunodeficiency registers in several countries have reported prevalence but not incidence rates for severe combined immunodeficiency (SCID). The objective of this study was to document the incidence and type of SCID in Australia, the age and clinical features at presentation and short-term management. The Australian Paediatric Surveillance Unit conducts active, monthly, national surveillance of rare disorders with reporting by child-health specialists. Between May 1995 and December 2001, clinicians provided clinical and laboratory data on children newly diagnosed with SCID. Thirty-three incident cases of SCID were identified [incidence 1.8/10(5) live births per annum; 95% confidence interval (CI) 1.2-2.5]. Twenty-six children had classical SCID (1.45/10(5) live births; 95% CI, 0.9-2.0) and 20 (77%) of these were boys. Classical SCID was X-linked in 13 children, autosomal recessive (AR), not further classified in four, and attributed to adenosine deaminase deficiency (ADA) in four, interleukin-7 receptor alpha chain deficiency in one, Ommen syndrome in two, and Di George syndrome in two. Twenty-one (81%) received bone marrow/stem cell transplantation, three of whom died between 1 and 4 months after transplantation (two ADA deficient, one AR). Seven children had atypical SCID, five of whom died within 1-4 yr of diagnosis. Most children with SCID presented with failure to thrive and recurrent infections and there was no significant delay between presentation and diagnosis. The reported national incidence of classical SCID in Australia (1.45/10(5) or approximately 4 cases per year or 1/69,000 live births) is consistent with the rate (1.4/10(5)) previously reported in Victoria. Diagnosis is rarely delayed, and transplantation is associated with good short-term survival.

Severe combined immunodeficiency: a cohort of 40 patients.

Severe Combined Immunodeficiency (SCID) consists of a heterogeneous group of genetic disorders characterized by an arrest in T lymphocyte development which is variably associated with an abnormal differentiation of B and NK cells. In order to depict the clinical state of Iranian patients with SCID, records of forty patients were reviewed. Patients were classified based on the flow cytometry data in two groups of B- and B+. In thirty two families (80%) parents were consanguine and in 17 families (50%) there were affected members other than proband. We showed that autosomal forms of SCID might be more frequent due to higher rate of consanguineous marriages. Alongside several infective complications, complicated Bacillus Calmette-Guérin (BCG) vaccination was documented in 18 cases (45%) following the routine vaccination at birth. BCG immunization is still a part of standard vaccination for newborns in developing countries; whereas in communities with a better health condition it could be held for a few months and performed for kids whose immune system sounds intact. We discuss where consanguine mating is common, a test of screening should be run timely. A complete blood count of cord blood could reveal lymphocytopenia at birth; this helps early diagnosis. Genetic consultation would help the families with affected members preventing new SCID offspring.

Stem cell transplantation for congenital immunodeficiencies using reduced-intensity conditioning.

The optimal preparation for stem cell transplantation (SCT) in children with congenital immunodeficiencies is currently unknown. In all, 81 children with immunodeficiency underwent 82 SCTs using reduced-intensity conditioning (RIC). The incidence of significant GVHD was low; viral reactivation was prominent with an unexpected increase in EBV reactivation; immune reconstitution was similar between different donor groups and comparable to conventional SCT. Overall, 68/81 (84%) survive with no significant difference between donor types or between severe combined immunodeficiency (SCID) and non-SCID diseases. Findings suggest a significant survival advantage in the unrelated donor setting for RIC compared to conventional SCT.

Allogeneic stem cell transplantation for treatment of immunodeficiency.

Primary immunodeficiencies constitute a group of highly complex congenital disorders commonly characterized by an extremely poor prognosis. Allogeneic hematopoietic stem cell transplantation has the potential to establish a permanently functioning immune system and represents a curative approach in many of these disorders. In this review several aspects of stem cell transplantation are presented, with an emphasis on the mechanism of immune reconstitution in severe combined immunodeficiency diseases. In this disorder transplant modalities vary, and also include transplantation without cytoreductive conditioning. Clinical results are summarized based on recent analysis performed in large patient cohorts, which have shown steady improvements and have led to a marked change in the prognosis of patients with primary immunodeficiencies.

Ancestral founder mutation of the nude (FOXN1) gene in congenital severe combined immunodeficiency associated with alopecia in southern Italy population.

Genetic alterations of the FOXN1 transcription factor, selectively expressed in thymic epithelia and skin, are responsible in both mice and humans for the Nude/SCID phenotype. The first described human FOXN1 mutation was a C792T transition in exon 5 resulting in the nonsense mutation R255X, and was detected in two probands originated from a small community in southern Italy. In this community, four additional children affected with congenital alopecia died in early childhood because of severe infections. In this study, we report on the screening for this mutation in 30% of the village population. This analysis led us to identify 55 heterozygous carriers (6.52%) of the R255X mutation out of 843 inhabitants screened. A genealogical study revealed that these subjects, belonging to 39 families, were linked in an extended 7-generational pedigree comprising 483 individuals. Through the archival database a single ancestral couple, born at the beginning of the 19th century, was identified. To confirm the ancestral origin of the mutation we genotyped two microsatellite markers, D17S2187 and D17S1880, flanking the FOXN1 gene on chromosome 17. The three haplotypes identified, 3/R255X/3, 3/R255X/2 and 3/R255X/1, are consistent with a single ancestral origin for the mutation R255X.

A lesson for unraveling complex aspects of novel immunodeficiencies from the human equivalent of the nude/SCID phenotype.

The human equivalent form of the severe combined congenital immunodeficiency of the nude/SCID mouse has been recently described in 2 siblings originating from a small community in southern Italy. Similar to the mouse, the human phenotype is characterized by a profound T cell ontogenetic defect associated with congenital alopecia and nail dystrophy. The disease is related in either mice and humans to molecular alterations of the gene encoding a forkhead/winged helix transcription factor, which is selectively expressed in thymic epithelia. Remarkably, due to the selectivity of the tissue expressivity of the gene responsible for the syndrome, this is the first example of SCID not primarily related to an hematopoietic cell abnormality, but rather to thymic aplasia. The opportunity to study immunological reconstitution in the absence of a functioning thymus following a bone marrow transplantation from a related HLA-identical sibling gave us insight into the role of the thymus in in vivo T cell ontogeny and maintenance of T cell functionality. This model led us to address a few general issues that may have clinical implications.

Association of reticular dysgenesis (thymic alymphoplasia and congenital aleukocytosis) with bilateral sensorineural deafness.

Reticular dysgenesis is a rare congenital disorder characterized by severe combined immunodeficiency and profound neutropenia, curable to date, only by bone marrow transplantation. This report describes the association of bilateral sensorineural deafness with this disease.

In utero acute graft-versus-host disease in a neonate with severe combined immunodeficiency.

We describe a male neonate with severe combined immunodeficiency who at birth had acute graft-versus-host disease (GVHD) as a result of maternal-fetal transfusion during pregnancy. Several clinical signs helped establish this diagnosis. Findings of a skin biopsy specimen confirmed the diagnosis of acute GVHD. Immunologic evaluation disclosed an absence of T and B lymphocytes. Acute GVHD in severe combined immunodeficiency most often occurs during the first weeks of life; intrauterine occurrence is unusual.