Wiskott-Aldrich syndrome is an X-linked recessive immunodeficiency characterized by thrombocytopenia, eczema, and recurrent infections (Lemahieu et al., 1999).
The manifestations of Wiskott-Aldrich syndrome are eczema, thrombocytopenia, proneness to infection, and bloody diarrhea. Death usually occurs before age 10 years. The original American kindred reported by Aldrich et al. (1954) was of Dutch extraction; the 3 patients ... The manifestations of Wiskott-Aldrich syndrome are eczema, thrombocytopenia, proneness to infection, and bloody diarrhea. Death usually occurs before age 10 years. The original American kindred reported by Aldrich et al. (1954) was of Dutch extraction; the 3 patients of Wiskott (1937) were German. Wiskott, who worked in Munich, referred to the disorder in his patients as 'Werlhof's disease,' the eponymic designation for thrombocytopenic purpura. Van den Bosch and Drukker (1964) described several families in the Netherlands. In 3 of 5 female carriers, the platelet count was below the lower limit of normal. Perry et al. (1980) reported that median survival increased from 8 months for patients born before 1935 to 6.5 years for those born after 1964. One patient had survived to age 36 years at the time of the survey. Causes of death were mainly infections or bleeding, but 36 of the 301 patients (12%) developed malignancies: lymphoreticular tumors in 23 and leukemia in 7. Ten Bensel et al. (1966) called attention to the occurrence of malignancy of the reticuloendothelial system, which they saw in 2 of 4 sibs and found in 5 reported cases. Capsoni et al. (1986) described a 19-year-old man with WAS. Only 7 affected persons over age 18 had been described previously. Standen et al. (1986) reported a kindred with 13 males in 6 sibships, related through females, with inherited thrombocytopenia thought to be a variant of WAS because it was associated with elevated serum IgA and mild nephropathy. Five suffered from severe eczema since infancy but had no unusual susceptibility to infections. Platelet volume was reduced. Gutenberger et al. (1970) reported a similar family. Renal biopsy was performed in 3 patients. In the first, advanced membranoproliferative glomerulonephritis was found with deposition of complement and IgG on the basement membrane. In the second, mesangial glomerulonephritis with focal glomerulosclerosis and deposition of complement and IgA were found. The third showed minimal glomerulonephritis. Standen et al. (1986) concluded that despite the clinical similarities and the elevated IgA in both conditions, the disorder is distinct from Berger disease (161950). Spitler et al. (1980) found nephropathy in 5 of 32 patients with WAS who participated in a study of treatment with transfer factor, a dialyzable extract of leukocytes that enhances cellular immunity. Although nephropathy occurred without such treatment, the temporal relationships suggested that transfer factor aggravated the problem. McEnery and Nash (1973) described 2 unrelated males with the association of WAS and infantile cortical hyperostosis (Caffey disease; 114000), and Abinun et al. (1988) also described a case. Thus, an immunologic defect may play a role in the pathogenesis of infantile cortical hyperostosis. Meropol et al. (1992) reported the case of a 24-year-old man with WAS complicated by T-cell large cell lymphoma and Kaposi sarcoma (148000). Kaposi sarcoma is well known in connection with the immunosuppression used with allograft transplantation and in patients with HIV infection, but this was the first incidence of its occurrence in this form of immunodeficiency. Sullivan et al. (1994) reported on a multiinstitutional survey of WAS in the U.S. in which laboratory and clinical data were collected on 154 affected individuals. There was a family history of the disorder in the case of 74 of the patients. Thrombocytopenia was a prerequisite for entry into the study; however, only 27% of patients had the typical set of 3 symptoms described originally by Aldrich et al. (1954). The immunologic findings in particular varied considerably with the most distinctive finding: that 61% of the patients had a low CD8+ count. Eczema developed in 81% but was not always present at diagnosis. In those patients in whom platelet size was measured, Sullivan et al. (1994) found them to be small, although they did increase in size following splenectomy. The average age at diagnosis was 21 months; the average age at death was 8 years. There were 16 patients who lived beyond 18 years, and the prognosis for the disorder had improved considerably in recent years. Bone marrow transplantation had been carried out in 47 cases and a good outcome was reported in two-thirds of them. Autoimmune disorders occurred in 40% of patients; this group had a poor prognosis as they were more likely to develop a malignancy. Malignancies were seen in 13% of patients and were mainly of the lymphoreticular system. Du et al. (2006) described somatic mosaicism in a 15-year-old male WAS patient due to a second-hit mutation in the initiation codon. See 300392.0019-300392.0020. The patient had no clear family history. Thrombocytopenia was noticed at 1 month of age and thereafter eczema and recurrent infections were clinical features. At 8 years of age, he had persistent cough due to pulmonary hilar lymph node swelling. From the result of hilar lymph node biopsy, he was diagnosed with Hodgkin disease and received chemotherapy and local radiotherapy (Sasahara et al., 2001; Sasahara et al., 2002). The patient had remained in complete remission thereafter. His platelet count was in the range of 6,000-15,000/microliter. Episodes of respiratory infections occurred less frequently, although severe eczema and thrombocytopenia persisted.
Schindelhauer et al. (1996) found no genotype/phenotype correlation emerge after a comparison of the identified mutations with the resulting clinical picture for a classical WAS phenotype. A mild course, reminiscent of X-linked thrombocytopenia, or an attenuated phenotype was ... Schindelhauer et al. (1996) found no genotype/phenotype correlation emerge after a comparison of the identified mutations with the resulting clinical picture for a classical WAS phenotype. A mild course, reminiscent of X-linked thrombocytopenia, or an attenuated phenotype was more often associated with missense than with the other types of mutations. Greer et al. (1996) examined the genotypes and phenotypes of 24 patients with WAS and compared them with other known mutations of the WASP gene. They demonstrated clustering of WASP mutations within the 4 most N-terminal exons of the gene and identified arg86 as the most prominent hotspot for WASP mutations. They noted the prominence of missense mutations among patients with milder forms of WAS, while noting that missense mutations also comprise a substantial portion of mutations in patients with severe forms of the disease. Greer et al. (1996) concluded that phenotypes and genotypes of WAS are not well correlated; phenotypic outcome cannot be reliably predicted on the basis of WASP genotype. Lemahieu et al. (1999) identified 17 WASP gene mutations, 12 of which were novel. All missense mutations were located in exons 1 to 4. Most of the nonsense, frameshift, and splice site mutations were found in exons 6 to 11. Mutations that alter splice sites led to the synthesis of several types of mRNAs, a fraction of which represented the normally spliced product. The presence of normally spliced transcripts was correlated with a milder phenotype. When one such case was studied by Western blot analysis, reduced amounts of normal-sized WASP were present. In other cases as well, a correlation was found between the amount of normal or mutant WASP present and the phenotypes of the affected individuals. No protein was detected in 2 individuals with severe Wiskott-Aldrich syndrome. Reduced levels of a normal-sized WASP with a missense mutation were seen in 2 individuals with X-linked thrombocytopenia. Lemahieu et al. (1999) concluded that mutation analysis at the DNA level is not sufficient for predicting clinical course, and that studies at the transcript and protein levels are needed for a better assessment. Wada et al. (2001) provided evidence that in vivo reversion had occurred in the WAS gene in a patient with Wiskott-Aldrich syndrome, resulting in somatic mosaicism. The mutation was a 6-bp insertion (ACGAGG; 300392.0013) which abrogated expression of the WAS protein. Most of the patient's T lymphocytes expressed nearly normal levels of WAS protein. These lymphocytes were found to lack the deleterious mutation and showed a selective growth advantage in vivo. Analysis of the sequence surrounding the mutation site showed that the 6-bp insertion followed a tandem repeat of the same 6 nucleotides. These findings strongly suggested that DNA polymerase slippage was the cause of the original germline insertion mutation in this family and that the same mechanism was responsible for its deletion in one of the proband's T-cell progenitors, thus leading to reversion mosaicism. That some mutations in WASP result in X-linked thrombocytopenia without the associated features of the Wiskott-Aldrich syndrome is well established. Devriendt et al. (2001) demonstrated, furthermore, that a constitutively activating mutation in WASP can cause X-linked severe congenital neutropenia (SCNX; 300299). See 300392.0012 for the L270P mutation in WASP demonstrated by Devriendt et al. (2001). Wada et al. (2004) described 2 additional patients from the same family of the man with revertant T-cell lymphocytes reported by Wada et al. (2001). Somatic mosaicism was demonstrated in leukocytes from the first patient that were cryopreserved when he was 22 years old, 11 years before his death from kidney failure. The second patient, 16 years old at the time of report, had a moderate clinical phenotype and developed revertant cells after the age of 14 years. T lymphocytes showed selective in vivo advantage. These results supported DNA polymerase slippage as a common underlying mechanism and indicated that T-cell mosaicism may have different clinical effects in WAS. Wada et al. (2004) stated that sibs with revertant mosaicism had previously been reported (Wada et al., 2003; Waisfisz et al., 1999), but 3 patients with revertant disease in a single kindred was unprecedented. Boztug et al. (2008) reported 2 Ukrainian brothers, aged 3 and 4 years, respectively, with WAS due to somatic mosaicism for a truncation mutation and multiple different second-site mutations. Flow cytometric analysis of peripheral blood cells showed that each patient had WAS-negative cells resulting from the truncation mutation and a subset of WAS-positive cells that expressed second-site missense WAS mutations. The second-site mutations resulted in the production of altered, but possibly functional, protein. All second-site mutations in both patients occurred in the same nucleotide triplet in which the truncation mutation occurred. Over time, both boys had a decrease in bleeding diathesis and eczema, and normalization of platelet counts. Boztug et al. (2008) suggested that the second-site mutations may confer a proliferative advantage to the affected cells in these patients. - X-Inactivation Status Wengler et al. (1995) stated that obligate female carriers of the gene for X-linked agammaglobulinemia (300300) show nonrandom X-chromosome inactivation only in B lymphocytes, and obligate female carriers of the gene for X-linked severe combined immunodeficiency (XSCID) show nonrandom X-chromosome inactivation in both T and B lymphocytes, as well as natural killer cells. However, all formed elements of the blood appear to be affected, as a rule, in obligate carriers of WAS, as judged by the criteria of nonrandom X-chromosome inactivation and segregation of G6PD alleles in informative females. Wengler et al. (1995) demonstrated that CD34+ hematopoietic progenitor cells collected from obligate carriers of WAS by apheresis showed nonrandom inactivation. They used PCR analysis of a polymorphic VNTR within the X-linked androgen receptor gene (313700) to demonstrate nonrandom inactivation which clearly must occur early during hematopoietic differentiation. Parolini et al. (1998) reported X-linked WAS in an 8-year-old girl. She had a sporadic mutation, glu133 to lys, on the paternally derived X chromosome, but had nonrandom X inactivation of the maternal X chromosome in both blood and buccal mucosa. Her mother and maternal grandmother also had nonrandom X inactivation, which suggested to the authors the possibility of a defect in XIST (314670) or some other gene involved in the X-inactivation process. Puck and Willard (1998) commented on the subject of X inactivation in females with X-linked disease in reference to the paper by Parolini et al. (1998). Lutskiy et al. (2002) described a female heterozygote for a splice site mutation (300392.0017) who presented at 14 months of age with features of WAS (thrombocytopenia, small platelets, and immunologic dysfunction) and had random inactivation of the X chromosome. She appeared to have a defect in the mechanisms that, in disease-free WAS carriers, lead to preferential survival/proliferation of cells bearing the active wildtype X chromosome.
Derry et al. (1994) found that the WAS gene was not expressed in 2 unrelated patients with Wiskott-Aldrich syndrome, 1 of whom had a single base deletion that produced a frameshift and premature termination of translation (300392.0001). Two ... Derry et al. (1994) found that the WAS gene was not expressed in 2 unrelated patients with Wiskott-Aldrich syndrome, 1 of whom had a single base deletion that produced a frameshift and premature termination of translation (300392.0001). Two additional patients were identified with point mutations that changed the same arginine residue to either a histidine or a leucine (300392.0002-300392.0003). Villa et al. (1995) presented proof that mutations in the WAS gene can result in X-linked thrombocytopenia characterized by thrombocytopenia with small-sized platelets as an isolated finding (313900). Why some mutations impair only the megakaryocytic lineage and have no apparent effect on the lymphoid lineage was unclear. In a study of 16 WAS patients and 4 X-linked thrombocytopenia patients, Thompson et al. (1999) identified 14 distinct mutations, including 7 novel gene defects. In an affected grandson of a female first cousin of the 3 patients described originally by Wiskott (1937), Binder et al. (2006) found a 2-nucleotide deletion in exon 1 of the WAS gene (300392.0021). Dobbs et al. (2007) identified 2 different but contiguous single basepair deletions in maternal cousins with WAS (300392.0022 and 300392.0023, respectively). Their maternal grandmother was found to be a mosaic for the deletions, both of which occurred on the haplotype from the unaffected maternal great-grandfather, consistent with a bichromatid mutation in a male gamete.