Wiskott - Aldrich Syndrome

 

Mrs. D. Babitha¹, Dr. Mrs. Santhi Appavu²

¹Asst. Prof, Christian College of Nursing, Neyyoor, The Tamilnadu Dr. M.G.R. Medical University, Chennai.

²Principal, Christian College of Nursing, Neyyoor. The Tamilnadu Dr. M.G.R. Medical University, Chennai.

 

ABSTRACT:

Background: Wiskott -Aldrich Syndrome (WAS) is an X_linked disorder characterized by clinical triad of micro thrombocytopenia, eczema and recurrent infections. It was first described by in 1937 by Dr. Alfred Wiskott, a German Pediatrician who identified three brothers with low platelet counts (thrombocytopenia), bloody diarrohea, skin rash (eczema) and recurrent ear infections. All three subsequently died at an early age from their sisters did not have symptoms. Seventeen years later, by studying a large six-generation Dutch family that the disease was passed down from generation to generation in an X- linked recessive manner.¹ The gene product, (WAS) is a 502 amino acid protein expressed within the cytoplasm of non- erythroid hematopoietic cells. More than 300 unique mutations in the WAS gene have been identified. Depending on the mutations within the WASP gene protein, there is wide variability of clinical disease. In one study of 154 patients with Wiskott- Aldrich Syndrome only 30% had the classic presentation with thrombocytopenia, small platelets, eczema and immuno deficiency. 80% had eczema, 20% had only hematologic abnormalities and 5% had only infectious manifestations. Auto immune disease is common and occurs in upto 40_ 70% of patients. There is also a significantly increased risk of lympho reticular malignancy (10_20%) such as lymphoma, leukemia and myelodysplasia.²

 

 

 

INTRODUCTION:

Case presentation:

3 months male infant was evaluated for poor feeding and oral ulceration blood work up showed anemia and thrombocytopenia. He was treated with intra venous immunoglobulin. At 11 months of age he presented with yellowish discoloration of eyes, poor feeding, irritability, vomiting, generalised purpuric rashes.  Blood investigation revealed anemia, thrombocytopenia. He relapsed in 1 month, 6 doses of rituximab were given. His hemoglobin and white blood cell counts improved after rituximab therapy.

 

Wiskott- Aldrich Syndrome (WAS) is unique among primary immune deficiency diseases because, in addition to being susceptible to infections, patients have problems with abnormal bleeding. The bleeding problems are the result of unusually small, dysfunctional platelets. For patients with WAS, this leads to unique health challenges that are not typically seen in other immuno deficiency disorders.³

 

Definition:

Wiskott- Aldrich Syndrome (WAS) is X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea. (Secondary to thrombocytopenia). It is also called as Eczema Thrombocytopenia Immuno deficiency syndrome.⁴

 

Incidence:

The estimated incidence of Wiskott- Aldrich syndrome is approximately 1:100,000 live births. As an X-linked disorder it is seen almost exclusively in males. Can occur in females only when X- chrosome containing the functional allele is inactive. Approximately 50 percent of patients with WAS gene mutations have Wiskott- Aldrich syndrome phenotype, and the other half have the X- linked thrombocytopenia phenotype. The estimated prevalence of WAS in the US is 1.2% of patients with identified primary immune defects.⁵

 

Causes:

WAS gene mutations that cause Wiskott- Aldrich syndrome lead to lack of functional protein. That signaling disrupts the function of actin cytoskeleton in developing blood cells. White blood cells that lack functional protein have decreased ability to respond to their environment and form immune synapses.⁶

 

Inheritance of Wiskott-Aldrich Syndrome:

 

 

It is caused by mutations in WAS gene which produce Wiskott-Aldrich Syndrome Protein. The WAS gene is located on the short arm of the x-chromosome so the disease is inherited is an X- linked recessive manner. ⁷

 

Target Organ:

·       WASP is a key regulator in hematopoietic cells.

·       All cells in the hematopoietic cell line are affected.

·       Primarily lymphocytes and platelets.

·       T cell defect in the activation and TCR engagement.

·       The spleen is a secondary target since it acts by to remove defective blood cells.

 

 

Pathogenesis:

 

Wiskott- Aldrich Syndrome protein is a member of a distinct family of cytoplasmic proteins that link signaling pathways to actin cyto skeleton reorganization by activating actin related protein. A small amount of wiskott aldrich syndrome protein in nucleus where it regulates RNA polymerase II dependent transcription in cells of the hematolymphoid lineage, WASP is expressed exclusively in the cytoplasm of hematopoietic cells and plays a crucial role in actin cytoskeleton remodeling. Its absence impacts the formation of the immunologic synapse, the site of interaction between T cells and antigen_presenting cells such as dentritic cells, that depends upon the generation 30 called lipid rafts, which provide a platform to recruit crucial molecules to ensure the stability of immunologic synapse.

 

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 hemostasis 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.

 

Wiskott- Aldrich Syndrome is also characterized by abnormal or non functional immune system cells known as white blood cells. Changes in white blood cells lead to an immune and inflammatory disorders in people with Wiskott-Aldrich Syndrome. These immune problems vary in severity and include an increased susceptibility to infection from bacteria, viruses and fungi.⁸

 

Symptoms:

·       Decreased number of platelets (Thrombocytopenia)

·       Bleeding inside the brain

·       Mucosal bleeding

·       Bloody diarrhea

·       Bruishing or purplish areas on the skin or mucous membranes

·       Pinpoint red spots on the skin (Petechiae)

·       Red patches of red and irritated skin (eczema)

·       Other skin Diseases such as Impetigo, Cellulitis, and abscess

·       Increased risk of infections especially to bacterial and viral infections

·       Increased risk of developing auto immune disorders that may include hemolytic anemia, immune thrombocytopenic purpura , rheumatoid arthritis, vasculitis

·       Increased risk of developing some types of cancer such as Lymphoma

·       Auto immune manifestations

·       Umbilical stump or following circumcision

·       Pneumonia- upper and lower respiratory⁹

 

Diagnostic findings:

·       Clinical history

·       Physical examination

·       Laboratory exam

·       Complete blood count it includes Anemia, Thrombocytopenia, microcytosis.

·       Platelet abnormalities including low numbers and small platelet size

·       Peripheral blood smear

·       Serum IgA and IgE levels are elevated and IgM levels are low.

·       T-Lymphocyte function is abnormal.

·       Bone marrow biopsy

·       DNA sequence analysis¹⁰

 

Medical care:

Promptly and aggressively treat infection and bleeding. General treatment strategies includes use of antibiotics, Intravenous immuno globulin (IVIG) therapy, splenectomy in special cases Gene therapy, and early hematopoietic stem cell transplantation, Immuno modulatory agents such as rituximab may serve a role in associated auto immunity.

 

Childhood Vaccinations:

Auto immune disease is common and occurs in upto 40_70% patients. Surveillance for malignancy is an important aspect of care. Killed vaccines may be given, however, responses may be insuffient due to underlying immune dysfunction. Live attenuated Vaccines are contra indicated.

 

Intravenous Immuno globulin (IVIG) therapy:

Patients with WAS mutations and lymphopenia are candidates for pneumocystis prophylaxis. Give Intra venous Immuno globulin (IVIG) or subcutaneous immunoglobulin (SQIg) (500mg/kg) every 3-4 weeks for patients with classic WAS. Gamma globulin replacement may be considered for patients with the milder variant of X-linked thrombocytopenia and those with recurrent infection. Acyclovir may be considered for chronic herpes virus infection. Post exposure to chicken pox may be treated with IVIG, which contains high anti- varicella antibody titers.

 

Antibiotics:

Additional prophylactic antibiotic therapy such as azithromycin (10mg/kg/ day three times a week) may be considered if infection continue despite immunoglobulin infusions.

 

Managing eczema:

Eczema may be severe. Manage eczema aggressively with careful attention to skin care, emollient use, and appropriate topical steroid therapy. Cutaneous infections are common and may require systemic antibiotics.

 

Patients with severe thrombocytopenia may require high dose Intra venous immunoglobulin (2gram/kg/day) and or cortico steroids (2mg/kg/day).

 

Guarding against bleeding:

Patients with severe bleeding may require platelet and or red blood cell transfusions. All blood products should be irradiated. Non irradiated blood contains T lymphocytes, which could lead to fatal- graft_versus host disease.

 

Hematopoietic stem cell and bone marrow transplantation:

Stem cells are a versatile type of cell found in bone marrow. In child with Wiskott aldrich syndrome, stem cells from a healthy donor are injected into the child's blood stream. They will then become healthy white blood cells and platelets that replenish blood and immune functions.

 

Gene therapy:

Gene therapy is an approach where by a normal copy of the WAS gene is delivered into the patient's own bone marrow cells using a virus so the blood cells coming from the bone marrow are then able to make normal WASP protein. Since the patient's own cells are being modified.

 

Immuno Suppressants:

It helps to prevent the patient abnormal immune cells from attacking body’s healthy cells.

 

Splenectomy¹¹

Prognosis:

Long-term survival after bone marrow transplant for children with Wiskott-Aldrich syndrome is over 80%. Children who are less than 2 years old at the time of the transplant have the best outcome with survival rates over 90%.

 

CONCLUSION:

Wiskott- aldrich syndrome is a disorder with wide clinical manifestations. In the mild Wiskott Aldrich Syndrome phenotype, which is classified as X-linked thrombocytopenia. A diagnosis of WAS should be considered in any male child with congenital thrombocytopenia regardless of platelet size, especially when there is a positive family history of early death in male infants.¹²

 

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Received on 07.10.2020          Modified on 15.12.2020

Accepted on 09.02.2021        © AandV Publications all right reserved