Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released - Under Revision 1.1.2
• GENE/GENE PANEL: WAS
• Condition: WAS-related disorders
• Mode(s) of Inheritance: X-linked

Actionability Assertion

• WAS ⇔ 0010294 (neutropenia, severe congenital, x-linked; scnx): Moderate Actionability
• WAS ⇔ 0010518 (wiskott-aldrich syndrome; was): Moderate Actionability
• WAS ⇔ 10743 (thrombocytopenia 1; thc1): Moderate Actionability

Actionability Rationale

All experts agreed with the assertion computed according to the rubric. This assertion only applies to males due to the X-linked nature of the condition.

Final Consensus Scores

Gene Condition Pairs: WAS ⇔ 0010294 (OMIM:300299) WAS ⇔ 0010518 (OMIM:301000) WAS ⇔ 10743 (OMIM:313900)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
WAS-related morbidity and mortality (males only) / Referral to hematology for clinical scoring of WAS-related conditions to determine treatment	2	3C	2C	2	9CC

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

WAS-related disorders include Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN). The estimated incidence of all WAS-related disorders is 1-4/1,000,000 live male births. The disorders occur worldwide with no racial or ethnic predilection. The incidence of WAS has been estimated as less than 1/100,000 live births, with a prevalence range of 1-9/1,000,000. Information on the prevalence of XLT was not available but assumed to be rare. XLN is rare, with prevalence estimated as <1/1,000,000. [1, 2, 3]

Clinical Features

WAS-related disorders are a spectrum of disorders resulting from deficiency of the WAS protein (WASP) that leads to a deficiency of hematopoietic cells, with predominant defects of platelets and lymphocytes.
WAS: Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura. Eczema and recurrent bacterial and viral infections, particularly of the ear, are also seen. Infections by opportunistic agents, such as Epstein Barr virus (EBV), are common. Roughly 25-40% of those who survive early complications develop one or more autoimmune conditions, including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis, and immune-mediated damage to the kidneys and liver. Individuals, particularly those who have been exposed to EBV, are at increased risk of developing lymphomas, which often occur in unusual, extranodal locations including the brain, lung, or gastrointestinal tract.
XLT: XLT is an attenuated form of WAS. Males have thrombocytopenia with small platelets that may be intermittent and a bleeding tendency. Other complications of WAS, including eczema, immune dysfunction, and risk of malignancy, are usually mild or absent.
XLN: Males have congenital neutropenia, myelodysplasia, increased myeloid cell apoptosis, and lymphoid cell abnormalities. Major bacterial infections are also recurrent. [1, 2, 3, 4, 5, 6]

Natural History

WAS-related disorders are usually present in infancy. The phenotypic spectrum ranges from severe to mild. However, because the clinical phenotype may worsen with age, it is particularly difficult to predict eventual disease severity in an infant. The prognosis of WAS-related disorders has improved in the last 20 years as a result of improved treatment.
WAS: Thrombocytopenia is usually present at birth, though cases of near-normal platelet counts in the newborn period followed by chronic thrombocytopenia have been reported. Intracranial bleeding is a potential early life-threatening complication. Life-threatening bleeding occurs in 30% of males prior to diagnosis. The risk of developing an autoimmune disorder increases with age, and the risk of developing lymphoma increases with age and in the presence of an autoimmune disorder. Approximately 13% of individuals develop lymphoma at an average age of 9.5 years. The reported median survival of children who do not undergo successful allogeneic hematopoietic cell transplantation (HCT) is 8-14.5 years. The causes of non-HCT-related deaths include infection (44%), malignancy (26%), and bleeding (23%).
XLT: Life expectancy may not be significantly affected in males as a group; however, severe disease-related events including life-threatening infections, bleeding, autoimmune diseases, and malignancies are common.
XLN: Several complications can occur with congenital neutropenia, including infectious complications. An estimated 20-30% of males are at risk of myelodysplastic syndrome or acute myeloid leukemia (AML). Some cases are only diagnosed in adulthood, implying that some patients have limited infectious complications.
WAS scores (0-5 range) facilitate clinical categorization and may predict disease severity. It is based on clinical parameters, such as the presence of thrombocytopenia, eczema, immunodeficiency, autoimmunity, and malignancy. As progression of the disease can occur at a later age, individuals may transition from a lower to a higher WAS score.
Female carriers of a WAS pathogenic variant are usually asymptomatic and have no immunologic or biochemical markers of the disorder, though mild thrombocytopenia has been noted in a small proportion. In rare cases, female carriers may be symptomatic; blood cell populations can vary depending on with either normal or abnormal WASP expression or skewed X-chromosome inactivation that favors expression of the mutated allele. [1, 3, 4, 5]

2. How effective are interventions for preventing harm?

Patient Management

The following evaluations following initial diagnosis are appropriate:
• Referral to immunologist for management
• Platelet count and size
• T-cell subsets
• Immunoglobulin levels. (Tier 4) [1]

HCT is the only curative treatment clinically available for WAS. Males with a WAS score 3-5, have markedly decreased WASP expression, and have a suitably matched donor are candidates for HCT. Five-year survival rates for HCT performed since 2000 are as high as 92%, with increased survival associated with HCT from a matched healthy sib or closely matched unrelated donor and earlier age of the procedure. Some symptoms (e.g., autoimmune disease) may take months to resolve following complete engraftment. (Tier 3) [1]

Given persistent morbidity, HCT may be considered in XLT if an HLA–identical donor can be identified. However, HCT in XLT (WAS score 1-2) is controversial and should be decided on an individual basis. (Tier 4) [1]

For XLN, HCT can permanently correct the neutropenia, though treatment is only recommended on a case by case basis when granulocyte colony-stimulating factor (G-CSF) therapy is not effective. (Tier 4) [5]

Treatment of XLN includes G-CSF to correct the neutropenia. No long-term randomized controlled trials have been published on effectiveness. However, a randomized study of 120 patients with severe neutropenia demonstrated a significantly increased proportion of maturing neutrophils and significantly decreased infection-related events, with an approximately 50% reduction in incidence and duration of infection-related events and almost 70% reduction in duration of antibiotic use. (Tier 4) [1]

For individuals with WAS with clinical signs or symptoms of infection, prompt evaluation and treatment is necessary. The initiation of empiric parenteral antibiotic treatment is necessary in the majority of individuals. The evaluation should be exhaustive until the source of the infection is uncovered. This may include invasive assessments, as cultures and isolation of the offending organism should be sought in order to guide therapy. (Tier 4) [1, 5]

Use of antibiotic prophylaxis to prevent infections depends on the individual risk, history, and severity. Antibiotic prophylaxis for pneumonia secondary to Pneumocystis jiroveci, formerly known as Pneumocystis carinii (PCP), is indicated for infants with WAS as they are at risk of developing PCP. (Tier 4) [1, 3, 5]

Immunoglobulin replacement therapy (IVIgG, a highly purified blood derivative) prevents infections. It is administered by age six months intravenously every three to four weeks or subcutaneously, usually on a weekly basis. (Tier 4) [1, 3]

Surveillance

Regular follow-up is indicated to monitor blood counts, adequacy of the IVIgG replacement therapy, and other potential complications. (Tier 4) [1]

Circumstances to Avoid

Live vaccines for routine childhood immunizations should be avoided. Other “non-live” vaccinations can be given safely to individuals with a WAS-related disorder but may not generate protective levels of antibody. (Tier 4) [1]

Circumcision of an at-risk newborn male should not be undertaken in the presence of thrombocytopenia. (Tier 4) [1]

The use of over-the-counter medications should be discussed with a physician as some medications can interfere with platelet function. (Tier 4) [1]

When possible, elective surgical procedures should be deferred until after HCT. (Tier 4) [1]

For patients with WAS, treatments that can weaken the immune system (steroids, splenectomy, immunosuppressive agents) should be used with the highest caution by trained medical staff. (Tier 4) [3]

3. What is the chance that this threat will materialize?

Mode of Inheritance

X-linked

Prevalence of Genetic Variants

Pathogenic variants in WAS account for all cases of WAS-associated disorders. (Tier 3) [1]

Penetrance

Penetrance is complete in males with a WAS pathogenic variant. (Tier 4) [1]

27% of children with WAS have the triad of (1) bloody diarrhea, mucosal bleeding and/or petechiae; (2) eczema; and (3) recurrent middle-ear infections and purulent drainage from the ears. (Tier 3) [1]

25-40% of males who survive the early complications of WAS develop one or more autoimmune conditions. (Tier 3) [1]

Eczema occurs in about 80% of males with WAS. (Tier 3) [1]

Approximately 13% of individuals with WAS develop lymphoma. (Tier 4) [1]

It is estimated that 20-30% of males with XLN are at risk of myelodysplastic syndrome or AML. (Tier 3) [1]

Relative Risk

Information on relative risk was not available for the Pediatric context.

Expressivity

The range of clinical complications experienced by affected males can vary widely, even in the same kindred. In some families, adult males in their 60s have mild manifestations such as chronic thrombocytopenia, whereas other affected male relatives succumb from complications of severe manifestations in infancy and childhood. (Tier 3) [1]

4. What is the Nature of the Intervention?

Nature of Intervention

Interventions include HCT, G-CSF, aggressive treatment of infections, prophylactic antibiotic use, IVIgG, and circumstances to avoid.
HCT is associated with significant risk of morbidity and mortality. In a study of 194 patients with WAS who received HCT, 45.9% of patients experienced complications within the first year, which included primary graft failure or graft rejection, autoimmune manifestations, infection requiring hospitalization, and neurological complications.
G-CSF is administered daily subcutaneously. Tolerability of G-CSF is good or excellent, with frequently reported adverse events frequently reported including bone pain, headache, and rash, which are generally mild and manageable. [1, 5]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Life-threatening bleeding occurs in 30% of males prior to a diagnosis of WAS. (Tier 3) [1]

Date of Search: 11.16.2018

Reference List

1. S Chandra, L Bronicki, CB Nagaraj, K Zhang. WAS-Related Disorders. 2004 Sep 30 [Updated 2016 Sep 22]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1178

2. X-linked severe congenital neutropenia. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=86788

3. Wiskott-Aldrich syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=906

4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. WISKOTT-ALDRICH SYNDROME; WAS. MIM: 301000: 2017 Nov 14. World Wide Web URL: http://omim.org.

5. Donadieu J, Fenneteau O, Beaupain B, Mahlaoui N, Chantelot CB. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis. (2011) 6:26.

6. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. COLORBLINDNESS, PARTIAL, PROTAN SERIES; CBP. MIM: 303900: 2010 Sep 13. World Wide Web URL: http://omim.org.