Wiskott-Aldrich syndrome

INTRODUCTION — Wiskott-Aldrich syndrome (WAS; MIM #301000) is an X-linked disorder caused by mutations in the gene that encodes the Wiskott-Aldrich syndrome protein (WASP). The originally described features of WAS include susceptibility to infections (subsequently associated with adaptive and innate immunodeficiency), microthrombocytopenia, and eczema [1,2]. However, there is a wide spectrum of disease severity due to WAS gene mutations, ranging from a severe phenotype (classic form) of WAS associated with bacterial and viral infections, severe eczema, autoimmunity, and/or malignancy, to a milder form characterized by thrombocytopenia and less severe or sometimes absent infections and eczema, referred to as X-linked thrombocytopenia (XLT). A separate phenotypic entity associated with particular WAS gene variants is X-linked neutropenia (XLN).

This topic reviews the epidemiology, pathogenesis, clinical manifestations, diagnosis, treatment, and prognosis of WAS, XLT, and XLN.

EPIDEMIOLOGY — WAS is a rare syndrome with an estimated incidence of approximately 1:100,000 live births [3]. As an X-linked disorder, it is seen almost exclusively in males. Approximately 50 percent of patients with WAS gene mutations have the WAS phenotype, and nearly all others have the X-linked thrombocytopenia (XLT) phenotype (figure 1 and figure 2). WAS gene mutations causing X-linked neutropenia (XLN) are very rare, with <12 patients in four families reported to date. (See 'Clinical phenotypes' below.)

PATHOGENESIS — Wiskott-Aldrich syndrome protein (WASP) is a member of a distinct family of cytoplasmatic proteins that link signaling pathways to actin cytoskeleton reorganization by activating actin polymerization mediated by actin-related protein (Arp) 2/3. A small amount of WASP is located in the nucleus, where it regulates RNA polymerase II-dependent transcription in cells of the hematolymphoid lineage [4]. The WASP family of proteins is characterized by a C-terminal domain containing a common actin monomer-binding motif, a verprolin homology domain, a central acidic region that is capable of binding and activating the Arp-2/3 complex, and an N-terminal domain containing the pleckstrin homology/enabled VASP homology 1 (PH/EVH1) domain and the WASP interacting protein (WIP) binding region (figure 1) [5].

WASP is expressed exclusively in hematopoietic cells and plays a crucial role in actin cytoskeleton remodeling [6]. Its absence impacts the formation of the immunologic synapse, the site of interaction between T cells and antigen-presenting cells such as dendritic cells [7] that depends upon the generation of so-called lipid rafts, which provide a platform to recruit crucial molecules to ensure the stability of the immunologic synapse [8]. Thus, T cell function is defective due to abnormal cytoskeletal reorganization, leading to impaired migration and adhesion and insufficient interaction with other cells due to abnormal synapse formation. B cell homeostasis is perturbed due to the abnormalities in T cell function, resulting in the depletion of circulating mature B cells, splenic marginal zone precursors, and marginal zone B cells [9,10]. The phenomenon of lymphocyte numbers declining over time is possibly due to accelerated cell death [11].

Circulating natural killer (NK) cell numbers are normal or increased, but cytotoxicity of WASP-deficient natural killer (NK) cells is impaired as a result of defective immune synapse formation on the cell surface, a process requiring WASP [12,13]. Interleukin (IL) 2 can, at least in part, restore cytotoxicity in NK cells [13] by inducing expression of a functionally related protein, WASP family verprolin-homologous 2 (WAVE2) [14]. Invariant natural killer T (iNKT) cells are thought to play an important role in protection against autoimmunity and in cancer immunosurveillance. iNKT cells are completely absent in patients with WAS and reduced in patients with X-linked thrombocytopenia (XLT) [15]. In mice, WASP is required for late-stage thymic iNKT cell development and egress [16].

WASP-deficient humans and mice have regulatory T (Treg) cells that fail to suppress effector cells in vitro and that are incapable of controlling autoimmunity in several mouse models [17-20]. While WASP does not seem to be required for the thymic generation of natural Treg cells, it appears to play a crucial role in peripheral homeostasis of these cells [18]. The suppressive effect of Tregs on effector T cells requires direct cell-to-cell contact. The failure of WASP-deficient Tregs to form synapses with effector T cells may explain their decreased function.

WASP-deficient myeloid lineage cells exhibit impaired phagocytosis and chemotaxis [21,22]. In addition, monocytes, macrophages, and dendritic cells from WASP-deficient patients and mice demonstrate almost completely abrogated assembly of podosomes (actin-rich structures on the outer surface of cells) [23,24]; the formation of lamellipodia (sheet-like, actin-containing extensions) and filopodia (hairlike projects [micro-spikes] that extend beyond the leading edge of the lamellipodia) at the migrating edge of macrophages and dendritic cells is defective; and chemotaxis to specific chemoattractants is impaired [23,25,26]. Defective migration and homing of several cell lineages may be a significant pathogenic mechanism in WAS.

Thrombocytopenia has been explained by increased clearance of platelets, ineffective thrombocytopoiesis [22], reduced platelet survival due to intrinsic platelet abnormalities, and/or immune-mediated events [27,28].

Mechanisms for the high incidence of autoimmunity in WAS include inadequate Treg cell function [17-19], B cell-intrinsic loss of tolerance via positive selection of self-reactive transitional B cells [29], expansion of autoreactive B cells [30] and production of autoantibodies [31], impaired Fas-mediated apoptosis of self-reactive lymphocytes [32], and defective phagocytosis of apoptotic cells resulting in chronic inflammation [33].

Whereas "loss-of-function" mutations in the WAS gene cause either XLT or WAS, unique "gain-of-function" missense mutations in the guanosine triphosphate hydrolase (GTPase) cell division control protein 42 homolog (Cdc42)-binding domain of WASP impair the autoinhibitory conformation of the molecule and lead to increased actin polymerization, resulting in congenital neutropenia. (See 'Clinical phenotypes' below.)

GENETICS — Mutations of the WAS gene on the X chromosome (figure 1 and figure 2) are responsible not only for classic WAS, but also for X-linked thrombocytopenia (XLT) and, in rare instances, congenital X-linked neutropenia (XLN) [34-37]. Biallelic mutations of the WIPF1 gene on chromosome 2, which encodes WAS protein (WASP) interacting protein (WIP), a cytoplasmic protein required to stabilize WASP, can also cause a WAS phenotype [38,39].

WAS/XLT/XLN have in common mutations in the WAS gene, located on the short arm of the X chromosome (figure 1). The WAS gene consists of 12 exons spanning approximately 9 kb of genomic deoxyribonucleic acid (DNA) [34] and encodes a 502 amino acid protein, designated WASP. Many different WAS gene mutations can cause WAS, although several mutational hotspots have been identified (figure 1). Certain types of mutations at particular locations are more likely to cause XLT than classic WAS, and activating missense mutations in the cell division control protein 42 homolog (Cdc42)-binding domain (GTPase-binding domain, GBD) result in XLN (figure 1) [36].

The analysis of affected members of 270 unrelated WAS families from three large referral centers (United States, Italy, Japan) revealed a total of 158 unique WAS gene mutations [40,41]. Most common were missense mutations, followed by splice-site mutations, short deletions, and nonsense mutations. Insertions, complex mutations, and large deletions were less frequent. Most deletions and insertions involved fewer than 10 nucleotides, resulting in frame shift and early termination of transcription. Amino acid substitutions are typically located in exons 1 to 4.

Splice-site mutations occur predominantly in the downstream half of the WAS gene (introns 6 to 11) (figure 1 and figure 2). Mutations affecting variant splice sites may result in multiple splicing products, which often include close to normal amounts of WAS gene complementary DNA (cDNA; eg, c.559+5G>A).

Six mutational hotspots, defined as occurring in >2.5 percent of the WAS/XLT population, have been identified. Three of these hotspots represent point mutations (T45M; R86C/H/L/S; R211X) within the coding regions, whereas the other three involve splice sites (c.559+5G>A; c.777+1G>N; c.777+1_4 del) [42]. These six hotspot mutations accounted for 25.6 percent of the entire cohort [40,41].

Spontaneous somatic reversions of the causative mutations restore WASP expression in a fraction of the lymphocytes in up to 10 percent of patients with WAS. Somatic reversions and mosaicism observed in patients with classic WAS preferentially affect natural killer (NK) cells and differentiated T cell subsets, most often CD8⁺ T cells, but do not seem to influence the clinical phenotype [43-45]. Thus, the clinical benefit observed in association with reversion and expansion of reverted lymphocytes is minimal at best [46,47].

CLINICAL PHENOTYPES — Mutations in the WAS gene result in variable clinical phenotypes that correlate with the type of mutation and its effect on WAS protein (WASP) expression [40,41]. Affected patients are categorized into three major groups: classic WAS, X-linked thrombocytopenia (XLT), and X-linked neutropenia (XLN) (table 1).

While there is a considerable phenotype/genotype correlation, there are exceptions, making it difficult in individual cases to accurately predict the clinical course based solely on the type of mutations of the WAS gene. The most consistent phenotype/genotype correlation is observed when patients are divided into two categories: WASP⁺ for patients whose mutated, nonfunctional protein is expressed, although often in reduced quantities and of normal size, and WASP^- for patients whose mutated protein is absent or truncated [40,41]. Patients with mutations that allow the expression of normal-sized mutated protein develop, with few exceptions, the XLT phenotype (figure 2). In contrast, patients with lymphocytes that do not express WASP or express only truncated WASP are more likely to have the classic WAS phenotype (figure 1).

A WAS disease severity scoring system (table 1) facilitates the clinical categorization of patients and may be useful in predicting disease severity and outcome of hematopoietic cell transplantation (HCT) [48]. The clinical phenotype of the disease evolves over time and is often incomplete in males younger than two years of age. Thus, WAS scores should not be used to predict disease severity in infancy.

A score of 1 or 2 defines patients with XLT, a score of 3 to 4 identifies patients with classic WAS, and a score of 5 is reserved for patients with either XLT or WAS who develop autoimmunity and/or malignancies. A modified scoring system also assigns a score of 5 to patients with severe refractory thrombocytopenia since these patients are at increased risk for hemorrhage with associated morbidity and mortality [49]. However, progression of the disease can occur at a later age. Thus, some patients originally diagnosed with XLT (score of 1 to 2) may develop autoimmunity or cancer later in life (score of 5) [50].

The WAS score reflects the severity of the clinical phenotype without taking into account the type of mutation or whether WASP is expressed. However, most patients with missense mutations in exon 1, 2, and 3 of the WAS gene express mutated, nonfunctional WASP, often in decreased amounts, and tend to have a milder disease phenotype (figure 1 and figure 2) [40,41,50].

X-linked neutropenia — XLN is one of several distinct single gene defects presenting as severe, congenital neutropenia. Patients with XLN suffer from infections characteristic for neutropenia but may also develop infections associated with lymphocyte dysfunction [36,51-53]. These patients are also at increased risk for myelodysplasia. Severe congenital neutropenia is discussed in greater detail separately. (See "Congenital neutropenia", section on 'Severe congenital neutropenia'.)

X-linked thrombocytopenia — This less severe variant of WAS presents as congenital thrombocytopenia [35] that is sometimes intermittent (IXLT) [54-56]. Eczema, if present, is mild. These patients generally have a benign disease course compared with classic WAS and good long-term survival, although they still carry an increased risk (lower than that for WAS) for severe events such as life-threatening infections (especially post-splenectomy), serious hemorrhage, autoimmune complications, and cancer [50]. XLT must be differentiated from immune thrombocytopenia (ITP), which does not have an increased risk of malignancies. Any male with thrombocytopenia and small platelets should be evaluated for WASP expression and WAS gene mutations. (See 'Prognosis' below and 'Diagnosis' below.)

Classic (severe) Wiskott-Aldrich syndrome — The phenotype originally described by Wiskott is often referred to as classic WAS [1]. Affected males present in early childhood with hemorrhagic diathesis due to thrombocytopenia; recurrent bacterial, viral, and fungal infections; and extensive eczema. Lymphadenopathy is frequently present, especially in those patients with WAS who have chronic eczema, and hepatosplenomegaly is common. In contrast, adenoid tissue on lateral neck radiographs is often absent [57]. Patients with classic WAS tend to develop autoimmune complications and lymphoma or other malignancies, often leading to early death [58]. (See 'Prognosis' below.)

There are a few case reports of females with the WAS phenotype due to either a heterozygous WAS mutation with skewed X-chromosome inactivation [59-63] or a homozygous nonsense mutation in WIPF1 that encodes WASP-interacting protein (WIP), a protein that stabilizes WASP [38,39].

Specific clinical manifestations

Bleeding — Thrombocytopenia is present at birth, and almost 90 percent of patients have manifestations of thrombocytopenia at the time of diagnosis. Affected patients may present in the first days of life with petechiae and/or prolonged bleeding from the umbilical stump or after circumcision. Other manifestations may include purpura, hematemesis, melena, epistaxis, hematuria, and such life-threatening symptoms as oral, gastrointestinal, and intracranial bleeding. A subset of infants ≤2 years of age may present with "severe refractory thrombocytopenia," possibly due to antiplatelet autoantibody, a complication that is associated with poor prognosis [49]. Infants with WAS and an ITP-like complication invariably fail to increase thrombocyte counts following platelet transfusions and require early HCT. (See "Approach to the child with bleeding symptoms".)

Immunodeficiency — The severity of the immunodeficiency in patients with WAS depends largely upon the mutation and its effect on protein expression [40,41]. Patients with a severe WAS phenotype may have recurrent infections in early infancy, but, in most patients with classic WAS, the frequency of infections increases with age.

Patients are particularly susceptible to such organisms as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. Manifestations include otitis media, sinusitis, pneumonia, meningitis, sepsis, and colitis. Splenectomy, which is occasionally performed to decrease the risk of bleeding, further increases the risk of severe bacterial infections and sepsis [64].

Opportunistic infections with Pneumocystis jirovecii, Molluscum contagiosum, as well as systemic varicella and cytomegalovirus infection, are also common. Fungal infections are relatively rare (10 percent), consisting primarily of mucocutaneous infection due to Candida albicans [58].

Eczema — Eczema of varying severity, often with superinfection, develops in approximately one-half of patients with WAS during the first year of life and resembles classical atopic dermatitis (picture 1) [48,65]. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

Autoimmune manifestations — Autoimmune diseases have been reported in 26 to 70 percent of WAS patients [58,66,67] and include hemolytic anemia, neutropenia, vasculitis involving both small and large vessels, inflammatory bowel disease, and kidney diseases. One review has summarized the published data and presents a narrative list of autoimmune manifestations in WAS/XLT [68]. A broad spectrum of autoantibodies has been observed both in classic WAS and in XLT [31], supporting the hypothesis that altered B cell tolerance leads to positive selection of self-reactive transitional B cells [29].

Malignancies — Malignancies can occur during childhood but are most frequently observed in adolescent and young adult males with the classic WAS phenotype [41,58]. B cell lymphoma (often Epstein-Barr virus positive) and leukemia are common in classic WAS but do occur, although less frequently, in XLT [50].

Laboratory findings

Immunology — Abnormal immunologic findings in patients with WAS include [22,58,69]:

●Decreased number and function of T cells

●Abnormal immunoglobulin isotypes, notably low to normal immunoglobulin G (IgG) and immunoglobulin M (IgM) and high immunoglobulin A (IgA) and immunoglobulin E (IgE)

●Defective antibody responses to some vaccine antigens

●Normal to increased natural killer (NK) cell numbers, but reduced cytotoxicity [12,13]

●Decreased function of regulatory T (Treg) cells [17,18]

●Impaired chemotaxis of phagocytic cells [22]

Absolute lymphocyte counts are usually normal during infancy, but T and B cell numbers decrease later in life in patients with classic WAS [22]. Decreased lymphocyte proliferation in response to mitogens occurs in approximately 50 percent of patients. Delayed-type hypersensitivity skin testing is abnormal in 90 percent of affected individuals [58]. In vitro proliferation of T cells to specific antigens is also reduced.

●Morphologically, WAS lymphocytes are relatively devoid of microvillus projections (picture 2) [70]. Upon in vitro activation with an anti-CD3 antibody, patient lymphocytes proliferate poorly and fail to undergo normal cytoskeleton rearrangements, producing very long filopodial projections instead [71]. This reduced lymphocyte proliferation to anti-CD3 antibody has also been observed in patients with XLN.

●Variations in the levels of immunoglobulin have been described, including normal levels of serum IgG, decreased levels of IgM, and elevated levels of IgA and IgE [72,73]. Consistent findings in patients with WAS are low isohemagglutinin titers, decreased antibody responses to polysaccharide antigens (eg, unconjugated pneumococcal polysaccharide vaccine) and the T-dependent neoantigen bacteriophage phi X174, normal antibody responses to diphtheria and tetanus toxoid, and rapid IgG catabolism [22,74].

●The number and phagocytic activity of neutrophils are normal. However, chemotactic responses are defective [22].

Histopathology — Abnormal findings in lymphoreticular tissue are commonly observed:

●Most patients have varying degrees of T cell zone depletion in lymph nodes and the spleen, as well as decreased number of follicles and abnormal follicular formation devoid of marginal zone, and regressive or "burned out" germinal centers [75-77].

●Abnormalities observed in the thymus vary from a small-sized thymus with normal architecture and corticomedullary differentiation [78] to a completely atrophic thymus [79].

Thrombocytopenia and platelet abnormalities — Thrombocytopenia associated with small platelet volume is a consistent finding in patients with WAS gene mutations, except for those presenting with an XLN phenotype due to missense mutations within the Cdc42-binding domain [36]. Platelet counts are generally 20,000 to 50,000/mm³ but may drop below 10,000/mm³. The mean platelet volume is 3.8 to 5.0 femtoliter (fL) compared with 7.1 to 10.5 fL in normal subjects [22]. Normal platelet size or macrothrombocytopenia has been reported in rare cases of WAS [80-82]. Patients with a WAS phenotype due to WIP deficiency have thrombocytopenia with normal or reduced platelet volume [38,39,83].

DIAGNOSIS — The diagnosis of WAS or X-linked thrombocytopenia (XLT) should be considered in any male patient presenting with petechiae, bruises, and congenital or early-onset thrombocytopenia associated with small platelet size (table 2). To confirm the diagnosis, a deleterious mutation in the WAS gene (other than mutations in the cell division control protein 42 homolog [Cdc42] binding domain that cause X-linked neutropenia [XLN]) is required. Presence of mild or severe eczema supports the diagnosis. Infections and immunologic abnormalities may be absent, mild, or severe. Autoimmune diseases and malignancies develop more often in patients with classic WAS than in those with XLT.

Screening for presence/absence of WAS protein (WASP) can be performed in lymphocytes by flow cytometry using an anti-WASP antibody [84]. However, this testing may miss patients with WAS (including classic WAS) who have expression of mutated, nonfunctional, or hypofunctional WASP. Sequence analysis of the WAS gene with identification of a deleterious mutation is essential to confirm the diagnosis. A combination of these two methods may aid in estimating the severity of the disease and long-term outcome [40,41,50]. (See "Flow cytometry for the diagnosis of inborn errors of immunity", section on 'Wiskott-Aldrich syndrome'.)

WASP-interacting protein (WIP) deficiency should be suspected in patients with features of WAS in whom WASP is absent but WAS sequence and messenger RNA (mRNA) levels are normal. The diagnosis of WIP deficiency is confirmed by sequencing WIPF1 [38,39,83].

The diagnosis of XLN should be considered in any male patient presenting with severe congenital neutropenia [36,51-53]. Male infants with this form of severe, congenital neutropenia have missense mutations in the Cdc42-binding domain (exon 7 to 8). (See "Congenital neutropenia", section on 'Severe congenital neutropenia'.)

Wiskott-Aldrich syndrome/X-linked thrombocytopenia in females — A few symptomatic female patients have been identified who are heterozygous for mutations of the WAS gene. They presented with either a classic WAS phenotype [59,60] or an XLT phenotype [61-63,85-87]. In all cases, the symptomatic females were found to have markedly skewed X-chromosome inactivation in favor of the X chromosome with the WAS gene mutation. The WAS phenotype in a female may also be caused by WIP deficiency [38,83].

Carrier detection and prenatal diagnosis — Carrier females can be identified with certainty by mutation analysis if the WAS gene mutation is known. Prenatal diagnosis of a male fetus at risk for WAS or XLT can be performed by DNA analysis with chorionic villi sampling or cultured amniocytes as the source of genomic DNA [88].

DIFFERENTIAL DIAGNOSIS — Several syndromes presenting with eczema, elevated serum IgE, and susceptibility to infections may resemble WAS/X-linked thrombocytopenia (XLT) including:

●Omenn syndrome due to hypomorphic mutations in genes associated with severe combined immunodeficiency (SCID; eg, recombinase-activating genes 1 and 2 [RAG1/2], adenosine deaminase [ADA], interleukin [IL] 7 receptor [IL7R], Artemis, IL-2 receptor gamma [IL-2R-gamma]; RNA component of mitochondrial RNA processing endoribonuclease [RMRP]) (see "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Omenn syndrome phenotype')

●Immune dysregulation, polyendocrinopathy, X-linked (IPEX) due to mutations in forkhead box P3 (FOXP3) [89] (see "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked")

●Netherton syndrome due to mutations of serine peptidase inhibitor, Kazal type 5 (SPINK5) [90] (see "Overview and classification of the inherited ichthyoses", section on 'Netherton syndrome')

●Hyper-IgE syndrome due to heterozygous signal transducer and activator of transcription 3 (STAT3) mutations [91] (see "Autosomal dominant hyperimmunoglobulin E syndrome")

●Dedicator of cytokinesis 8 (DOCK8) deficiency [92] (see "Combined immunodeficiencies: Specific defects", section on 'DOCK8 deficiency')

●Atopic dermatitis (see "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis")

None of these molecularly defined syndromes present with thrombocytopenia (except some IPEX patients with immune thrombocytopenia [ITP]) or small platelets.

●ITP is a frequent misdiagnosis of patients with XLT [93]. The fact that WAS/XLT platelets are consistently, with few exceptions [80-82], small and ITP platelets are large is useful for differentiating these two conditions. Automated platelet counting, unfortunately, does not pick up very small platelets, and the platelet size difference determined by Colter counter is less impressive than when manual counts using blood smears are performed.

●WAS/XLT belong to a large group of disorders affecting actin polymerization/depolymerization, a process that controls actin cytoskeletal remodeling required for cell motility, synapse formation, and cell-cell interaction [94]. Several of these actinopathies are associated with thrombocytopenia [95]. Deficiency of WIP, a cytoplasmic protein that stabilizes WASP, results in a WAS/XLT phenotype with autosomal-recessive inheritance, including microthrombocytopenia, eczema, and recurrent viral and bacterial infections [39]. Biallelic mutations in the actin-related protein 2/3 complex subunit 1B gene (ARPC1B) are associated with early-onset bacterial and viral infections reflecting combined immunodeficiency, skin rashes due to small-vessel vasculitis, and microthrombocytopenia [96]; ARPC1B is a crucial component of the actin-related protein 2/3 complex (ARP2/3), which, following interaction with WASP, initiates actin polymerization. Biallelic mutations in WDR1, the gene encoding the actin-interacting-protein 1 (AIP1), which plays an important role in actin depolymerization, result in combined immunodeficiency, autoinflammation, and thrombocytopenia with normal-size or large platelets [97].

●The neutropenia associated with WAS gene mutations (X-linked neutropenia [XLN]) is congenital and has to be differentiated from cyclic neutropenia due to neutrophil elastase (ELANE, also known as ELA2) mutations; severe congenital neutropenia due to HCLS1 associated protein X-1 (HAX1) mutations (Kostmann disease), ELANE mutations, G6PC3 mutations, or VPSO5 mutations; warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome due to mutations in the C-X-C motif chemokine receptor 4 (CXCR4) gene; Hermansky-Pudlak syndrome due to mutations in AP3B1 [98]; or mutations in the granulocyte colony-stimulating factor (G-CSF) receptor [99]. (See "Cyclic neutropenia" and "Congenital neutropenia" and "Epidermodysplasia verruciformis", section on 'WHIM syndrome' and "Inherited platelet function disorders (IPFDs)".)

TREATMENT — Treatment of WAS and X-linked thrombocytopenia (XLT) is discussed below. Treatment of X-linked neutropenia (XLN) is discussed in detail separately. (See "Congenital neutropenia", section on 'Severe congenital neutropenia'.)

Conventional treatment and supportive care — Conventional treatment and supportive care for WAS/XLT patients include:

●Prophylactic antibiotics, such as trimethoprim-sulfamethoxazole, to prevent P. jirovecii pneumonia in infants and children less than three to four years of age with classic WAS.

●Prophylactic acyclovir in patients with recurrent herpes simplex virus (HSV) infections.

●Platelet transfusions to treat major bleeding episodes, such as acute central nervous system hemorrhage or gastrointestinal bleeding, or to prevent excessive blood loss during surgery (platelet transfusions are not recommended as routine prophylaxis or for minor hemorrhages).

●Blood products, such as red blood cell (RBC) and platelet preparations, should be irradiated and negative for cytomegalovirus.

Intravenous immune globulin therapy — Intravenous immune globulin (IVIG) therapy is indicated in WAS/XLT patients with significant antibody deficiency. The dose is usually higher than that used for other primary immunodeficiencies (400 to 600 mg/kg every three weeks) due to an increased catabolic rate observed in patients with WAS [74]. Immune globulin may also be given subcutaneously. However, this route of administration must be used with caution in this patient population because of bleeding tendency. (See "Immune globulin therapy in inborn errors of immunity".)

Thrombopoietin receptor agonist (TPO-RA) therapy — Eltrombopag, an oral TPO-RA approved for the treatment of ITP, may be useful in preventing bleeding in patients with WAS who are awaiting hematopoietic cell transplantation (HCT) [100], but it is less effective in raising the platelet count in WAS/XLT patients than in patients with ITP [101]. Romiplostim, another TPO-RA used once weekly by subcutaneous injection, resulted in complete (33 percent) or partial (27 percent) correction of the thrombocytopenia in a cohort of 67 children with WAS/XLT, preventing episodes of serious bleeding, while waiting for HCT [102].

Low-dose IL-2 therapy — Low-dose interleukin (IL) 2 therapy, explored in a phase-I trial conducted in a cohort of patients with WAS/XLT, achieved a modest increase in platelet counts and a trend toward higher T, B, and natural killer (NK) cell numbers and increased regulatory T (Treg) cell percentages [103].

Immunosuppressive treatment — Immunosuppressive treatment may be required for autoimmune manifestations. Autoimmune cytopenias often respond to a monoclonal antibody targeting the B cell–specific CD20 antigen (rituximab), which is relatively safe for those patients already being treated with IVIG.

Splenectomy — Elective splenectomy has been advocated in selected patients with WAS/XLT to reverse the thrombocytopenia and arrest the bleeding tendency by increasing the number of circulating platelets [64]. However, splenectomy markedly increases the risk of septicemia [50]. Thus, it is not routinely performed, especially not for those patients who might undergo HCT. Patients with WAS/XLT who undergo splenectomy require lifelong antibiotic prophylaxis.

Hematopoietic cell transplantation — HCT is the only readily available curative treatment, with excellent results for patients with human leukocyte antigen (HLA) matched family or unrelated donors (URDs) or partially matched cord-blood donors [104-113], achieving 100 percent overall survival in a 2018 report of 34 transplanted patients with WAS/XLT [114]. Outcomes have been less satisfactory for other donor types, although a retrospective study reports improved survival for recipients of mismatched-related-donor transplants and partially matched cord blood [109,110,113]. Haploidentical HCT using posttransplant cyclophosphamide [115] or T cell alpha beta receptor (TCR-alpha-beta) and CD19 depletion [116,117] can achieve sustained engraftment and early immune recovery with a low risk of graft-versus-host disease. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)

Reduced-intensity, nonmyeloablative conditioning, although associated with a reduction in adverse and chronic events, is not recommended in patients with WAS, because this approach may result in graft rejection or lead to mixed chimerism that is often associated with an increased incidence of autoimmune manifestations [107]. Mixed chimerism affecting the myeloid compartment may result in persistent thrombocytopenia. Thus, allogeneic HCT from an HLA genotypically identical sibling, a 9/10 or 10/10 allele-matched URD, or a 4 to 6/6 cord blood, following (reduced) myeloablative conditioning, is the standard of care for any patient with WAS who has clinically significant disease (score 3 to 5) or who has absent WAS protein (WASP) expression [118]. If no such donor is available, a haploidentical donor, usually a parent, is a viable alternative.

The decision to perform HCT in a patient with XLT is less urgent because these patients have a more favorable long-term outcome with only supportive treatment [50]. However, HCT is a reasonable treatment option if an HLA-identical sibling or a matched unrelated donor is available. The outcomes of 24 patients with XLT identified worldwide who have undergone HCT are similar to those of patients with classic WAS [111]. Of the four posttransplant deaths reported, two were attributed to sepsis in the setting of pretransplant splenectomy.

Gene therapy — Gene therapy is an alternative, potentially curative, investigational therapy for patients with WAS who do not have a suitable donor for HCT [118]. WAS is an ideal candidate for gene therapy because of the selective advantage conferred by expression of WASP in hematopoietic stem cells and their derivatives. Thus, gene-corrected cells have a proliferative advantage over the host WASP-negative cells. For this procedure, a normal WAS complementary DNA (cDNA) is introduced ex vivo into hematopoietic CD34+ stem cells isolated from a patient with WAS. These manipulated cells are then reinfused into the same patient after conditioning with submyeloablative doses of busulfan, thus ensuring engraftment without graft-versus-host disease (GVHD). Long-term follow-up is necessary to determine if this experimental therapy is safe and will result in long-term cure, as is the case for HCT. (See "Overview of gene therapy for inborn errors of immunity".)

The initial retroviral-based gene therapy trial involved two patients and resulted in sustained expression of WASP in hematopoietic stem cells (CD34+), lymphocytes, myeloid cells, and platelets and functional correction of T, B, monocytes and NK cells. Following treatment, both patients demonstrated marked clinical improvement and, 2.5 years after therapy, showed resolution of hemorrhagic diathesis (although platelets remained somewhat low), eczema, autoimmunity, and predisposition to severe infections [119]. Subsequently, eight additional patients underwent gene therapy using the same retroviral vector. One of these eight patients failed to engraft and was successfully treated with HCT. Within the entire trial cohort, seven of the nine remaining patients developed leukemia within 16 to 60 months following gene therapy [120]. Six of these patients were subsequently successfully treated with HCT.

Gene therapy trials with a lentiviral vector under the endogenous promoter were subsequently initiated in Italy, using autologous gene-corrected hematopoietic stem cells administered after reduced-intensity myeloablative conditioning and one dose of rituximab given on day -22 [121,122]. This therapy progressively restored immune function in all eight patients enrolled in the study and substantially increased, but did not normalize, platelet counts, thereby preventing serious bleeding. The treatment was associated with reduced autoimmunity and infections during a median follow-up period of 3.6 years. Similar results were reported by a British/French consortium that treated eight children and one adult [123-126]. Over a median follow-up of 7.6 years, all hematopoietic lineages progressively reconstituted and maintained engraftment, serum immunoglobulin levels normalized, severity and frequency of infections decreased, spontaneous severe bleeding episodes ceased, eczema resolved or markedly improved, and other inflammatory and autoimmune manifestation were reduced, although arthritis, nephrotic syndrome, vasculitis, and platelet autoantibodies were reported [126]. Most patients were able to discontinue antimicrobial prophylaxis (except for penicillin in those post-splenectomy) and immune globulin replacement therapy. No graft failure, treatment-related adverse events, or clonal expansion were reported. The splenectomized adult patient died four years after treatment from pneumococcal sepsis and H1N1 influenza infection.

The reduction in hemorrhagic episodes despite WASP-positive transduced platelet counts remaining low in most patients with WAS who have undergone lentiviral gene therapy (<100x10³) has been explained by the fact that gene therapy restores platelet size and function and reduces the hyperactive phenotype of platelets proportionally to WASP expression and length of follow-up [127].

PROGNOSIS — Life expectancy of patients with classic WAS not treated with hematopoietic cell transplantation (HCT) or gene therapy is reduced, with premature death resulting from infections, hemorrhage, autoimmune disease, and malignancies. Bleeding is the main cause of death [58]. Malignancies in patients with classic WAS are often fatal. In one study, only 1 of 21 patients who developed a malignancy was alive more than two years after diagnosis [58].

In contrast, in a resource-abundant country, life expectancy of patients with X-linked thrombocytopenia (XLT) is close to that of the normal male population [50], even though event-free survival is reduced (median 10.2, range 0.1 to 74 years) [50].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY

●Definition – Wiskott-Aldrich syndrome (WAS) is defined as an X-linked hereditary disorder associated with adaptive and innate immunodeficiency, microthrombocytopenia, eczema, and an increased risk of autoimmune disorders and malignancy. (See 'Introduction' above.)

●Genetics – WAS protein (WASP) is a member of a distinct family of proteins that link signaling pathways to actin cytoskeleton reorganization. "Loss-of-function" mutations of the WAS gene are responsible not only for classic WAS, but also for X-linked thrombocytopenia (XLT) (figure 1 and figure 2). More rarely, "gain-of-function" mutations result in congenital X-linked neutropenia (XLN). (See 'Genetics' above.)

●Classic WAS – The phenotype originally described by Wiskott is often referred to as classic WAS. Affected males present in early childhood with hemorrhagic diathesis due to thrombocytopenia; recurrent bacterial, viral, and fungal infections; and extensive eczema. Patients with classic WAS tend to develop autoimmune disorders and lymphoma or other malignancies, leading to early death. (See 'Classic (severe) Wiskott-Aldrich syndrome' above.)

●X-linked thrombocytopenia – XLT is a less severe variant of WAS that presents with congenital microthrombocytopenia, sometimes intermittently, and mild, if any, eczema. The disease course is generally benign, although these patients still carry an increased risk for severe events such as life-threatening infections (especially post-splenectomy), serious hemorrhage, autoimmunity, and cancer. (See 'X-linked thrombocytopenia' above.)

●X-linked neutropenia – Patients with XLN (congenital neutropenia) present with infections characteristic for neutropenia but may also develop infections associated with lymphocyte dysfunction and are at increased risk for myelodysplasia. (See 'X-linked neutropenia' above.)

●Diagnosis – The diagnosis of WAS/XLT should be considered in any male patient presenting with petechiae, bruises, and congenital or early-onset thrombocytopenia associated with small platelet size (table 2). Screening for WASP expression may be performed by flow cytometry using an anti-WASP antibody. However, this testing may miss patients with expression of mutated, nonfunctional WASP. Sequence analysis of the WAS gene is essential to confirm the diagnosis. (See 'Diagnosis' above.)

●Treatment – Conventional treatment and supportive care include the use of prophylactic antimicrobials and platelet transfusions to stop life-threatening hemorrhages. Intravenous immune globulin (IVIG) therapy is indicated in patients with significant antibody deficiency. Immunosuppressive treatment may be required for autoimmune manifestations. Hematopoietic cell transplantation (HCT) is the only available curative treatment for WAS, but gene therapy through a clinical trial may be an option for patients who do not have a suitable donor for HCT. (See 'Treatment' above.)

●Prognosis – Life expectancy of patients with classic WAS is reduced, with premature death resulting from infections, hemorrhage, autoimmune disease, and malignancies. In contrast, life expectancy of patients with XLT is near normal. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.