Pediatric Wiskott-Aldrich Syndrome Differential Diagnoses
- Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD more...
This disorder should be considered in male infants with persistent unexplained thrombocytopenia, especially if the platelet size is small, recognizing that the clinical presentation is variable. Physicians must distinguish between infants with bleeding and thrombocytopenia and infants with neonatal alloimmune thrombocytopenia. The presence of small platelets with mean platelet value (MPV) less than 6 fL characterizes Wiskott-Aldrich syndrome (WAS), whereas the other 2 disorders usually have large MPVs because of the young age of the platelets. However, the MPV is difficult to measure in the presence of profound thrombocytopenia (platelet count < 10,000/dL).
X-linked thrombocytopenia is a mild phenotype of Wiskott-Aldrich syndrome with mutations in WASP that confer thrombocytopenia, possibly eczema, but no significant immunologic deficit. Sites for the WASP mutations in X-linked thrombocytopenia are somewhat different; thus, mutational analysis as well as clinical and laboratory data contribute to the final diagnosis of X-linked thrombocytopenia versus Wiskott-Aldrich syndrome (WAS). Differentiating this phenotype is important because stem cell reconstitution is not appropriate therapy for this clinically mild nonfatal disease.
The differential diagnosis of generalized eczema in infants includes Wiskott-Aldrich syndrome, as well as atopic dermatitis, seborrheic dermatitis, severe combined immunodeficiency (SCID), Langerhans cell histiocytosis, seborrheic dermatitis, Omenn syndrome, and ataxia-telangiectasia (AT).
AT presents with symptoms of eczema and recurrent infections; however, in contrast to Wiskott-Aldrich syndrome, patients with AT have decreased levels of immunoglobulin A (IgA) and, often, immunoglobulin E (IgE), and cerebellar ataxia is an early feature.
Wiskott-Aldrich syndrome is sometimes confused with Bruton agammaglobulinemia (X-linked agammaglobulinemia [XLA]) when the infant presents with recurrent otitis media, and when quantitative immunoglobulin levels show low immunoglobulin G (IgG). Patients with XLA are unlikely to have bleeding related to thrombocytopenia. Typically, Wiskott-Aldrich syndrome is associated with low immunoglobulin M (IgM) levels and normal-to-high immunoglobulin A (IgA) levels, whereas all immunoglobulin levels are undetectable in XLA. T-cell and B-cell population patterns are also characteristically different (normal CD19+ B cells and high CD4:CD8 ratios in Wiskott-Aldrich syndrome compared with absent CD19+ B cells and normal-to-elevated T cells in XLA).
X-linked hyperimmunoglobulin M (XHIM) syndrome may clinically resemble Wiskott-Aldrich syndrome, although bleeding manifestations are absent. Laboratory study findings should distinguish between them. Wiskott-Aldrich syndrome is associated with low IgM, high IgA, and high immunoglobulin E (IgE) levels; XHIM has normal-to-high IgM, low IgA, and low IgE levels. The pattern of T-cell abnormalities also differs as follows: high CD4:CD8 because of low CD8 in Wiskott-Aldrich syndrome compared with a normal ratio with lymphopenia in XHIM.
Other T-cell disorders occur early in infancy but without bleeding manifestations. Wiskott-Aldrich syndrome and other T-cell disorders share an increased incidence of dermatitis. X-linked severe combined immunodeficiency (X-SCID) is usually clinically different because of the early presence of more significant opportunistic and viral infections. Fluorocytometric analysis of T-cell and B-cell populations is used to distinguish Wiskott-Aldrich syndrome from X-SCID and other forms of SCID, such as major histocompatibility (MHC) class II deficiency ("bare lymphocyte" syndrome).
See Table 1 in Severe Combined Immunodeficiency.
Severe Combined Immunodeficiency
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|Brand(Manufacturer)||Manufacturing Process||pH||Additives (IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors [eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs].)||Parenteral Form and Final Concentrations||IgA Content mcg/mL|
|Kistler-Nitschmann fractionation; pH 4 incubation, nanofiltration||6.4-6.8||6% solution: 10% sucrose, < 20 mg NaCl/g protein||Lyophilized powder 3%, 6%, 9%, 12%||Trace|
|Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization||5.1-6||Sucrose free, contains 5% D-sorbitol||Liquid 5%||< 50|
|Gammagard Liquid 10%
|Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation||4.6-5.1||0.25M glycine||Ready-for-use Liquid 10%||37|
|Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation||4-4.5||Contains no sugar, contains glycine||Liquid 10%||46|
|Solvent/detergent treatment targeted to enveloped viruses; virus filtration using Pall Ultipor to remove small viruses including nonenveloped viruses; low pH incubation||4.8-5.1||Contains sorbitol (40 mg/mL); do not administer if fructose intolerant||Ready-for-use solution 5%||< 10|
|Cohn-Oncley fraction II/III; ultrafiltration; pasteurization||6.4-7.2||5% solution: 5% glucose, 0.3% NaCl||Lyophilized powder 5%||< 10|
(Baxter Bioscience for the American Red Cross)
|Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated||6.4-7.2||5% solution: 0.3% albumin, 2.25% glycine, 2% glucose||Lyophilized powder 5%, 10%||< 1.6 (5% solution)|
9/24/10: Withdrawn from market because of unexplained reports of thromboembolic events
|Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization||5.1-6||10% maltose||Liquid 5%||200|
(Swiss Red Cross for the American Red Cross)
|Kistler-Nitschmann fractionation; pH 4, trace pepsin, nanofiltration||6.6||Per gram of IgG: 1.67 g sucrose, < 20 mg NaCl||Lyophilized powder 3%, 6%, 9%, 12%||720|
|Privigen Liquid 10%
|Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration||4.6-5||L-proline (~250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose)||Ready-for-use liquid 10%||≤ 25|