Indian Pediatr 2014;51:
Wiskott-Aldrich Syndrome with
Dejan Skoric, *Aleksandar Dimitrijevic,
From *University Children’s Hospital and #Faculty of
Medicine, University of Belgrade, Belgrade, Serbia.
Correspondence to: Dr Aleksandar Dimitrijevic,
Department of Neurology, University Children’s Hospital,
Received: April 24, 2014;
Initial review: June 10, 2014;
Accepted: October 01, 2014
syndrome is a rare X-linked immunodeficiency disorder with a variable
phenotype. Case Characteristics: 3.5-year-old boy diagnosed with
Wiskott-Aldrich syndrome. Observation: Unusual and persistent
thrombocytopenia with increased platelet volume (>10fL). He did not
exhibit characteristic clinical and laboratory finding for the syndrome.
Outcome: Maternally inherited causative mutation in the exon 2 of
the WAS gene was disclosed. Message: This is a need for
multidisciplinary assessment of patients with congenital or early
infantile thrombocytopenia, including testing for mutations of the
WAS gene in all unexplained cases even in the absence of
Keywords: Immunodeficiency, Platelet
iskott-Aldrich syndrome (WAS) is a rare X-linked
disorder characterized by microtrombocytopenia, eczema and reccurent
infections . WAS gene has been linked to the region Xp11.23, encoding
a 502-amino acids intracellular protein expressed exclusively in the
cytoplasm of hematopoetic cells . So far, a wide spectrum of the WAS
gene mutations have been identified causing a wide variety of clinical
phenotypes, ranging from isolated thrombocytopenia to severe WAS [3-5].
A 4-month-old patient was admitted to our hospital
together with his twin brother due to a persistent thrombocytopenia
complicated with muosal bleeding and skin petechiae. Both twins
presented with thrombocytopenia on 1st day of life with normal findings
on the initial physical examination.
Comprehensive clinical and laboratory evaluation was
performed aimed to exclude other possible diagnosis. Neonatal alloimune
thrombocytopenia was ruled out based on their age (5 months). The bone
marrow examination ruled out a myelodisplastic syndrome and malignant
infiltration as the cause of thrombocytopenia. Immunophenotyping of
lymphocytes from peripheral blood showed no "double negative" CD3+CD4-CD8-
T-lymphocytes with normal range of absolute and relative B-and
T-lymphocyte count for the age as well as CD4 to CD8 ratio. This finding
and abscence of lymphadenopathy and splenomegaly ruled out auto-immune
lymphoproliferative syndrome. Presence of persistent
macrothrombocytopenia and no skin changes initially ruled out WAS.
Abdominal ultrasound was normal. Comprehensive metabolic analysis ruled
out common metabolic conditions. Serology tests for viruses viz.
Epstein–Barr virus (EBV), Parvovirus B19, Herpes simplex virus 1 and
Human Immunodeficiency Virus (HIV) screening were all negative.
Initial assessment of humoral and cellular immunity of both twin
brothers at the age of 5 months were normal. Our patient’s twin brother
died suddenly at the age of 6 months due to acute and progressive
respiratory failure. Post-mortem examination confirmed that the cause of
the death was massive interstitial pneumonia.
At the age of 10 months, our patient developed a
severe neurological deterioration, characterized by pronounced hypotonia,
high-pitch cry, rapid visual and hearing decline and decreased level of
consciousness. MRI of the brain revealed confluent symetrical signal
changes of demyelinization and dysmyelination in the subcortical and
deep white mater of both hemispheres. These findings were suggested the
possibility of acute disseminated encephalomyelitis (ADEM) and further
investigation was performed. Blood analysis proved CMV infection, with
confirmed seroconversion at later time. During the following few months,
his neurological status gradually improved, with regaining of the head
and posture control. However, the right sided hemiparesis continued to
Analysis of serum immunoglobulins revealed increase
of IgE. Cellular imunodefficiency was found since our patient had
decreased lymphocyte proliferation on phytohaemaglutinine (PHA) while
proliferative response of cell cultures stimulated with concavaline A (conA)
remained negative. Further investigation showed Coombs positive tests in
several episodes of hemolytic anemia, with positive antinuclear
antibodies (ANA) and antineutrophil cytoplasmic antibodies (ANCA). He
also developed a chronic generalised molluscum contagiosum infection
starting from the age of 18 months.
Due to a cellular immuno-defficiency, increase of the
IgE antibodies, opportunistic infections as well as male gender and
autoimmune disease manifestations, we suspected WAS. Genetic analysis
for the detection of a mutation of WAS gene was performed in the
patient at the age of 2 years, and subsequently in the patient’s mother,
by polymerase chain reaction-single strand conformational polymorphism
analysis (PCR-SSCP) and direct sequencing of the PCR products. PCR-SSCP
analysis in the exon 2 of the WAS gene disclosed aberrantly
migrating bands in the patient and his mother. In the direct sequencing
analysis of the PCR products for SSCP, a nucleotide substitution 190 T>C
in the exon 2 was observed in the patient. Direct sequencing performed
in the patient’s mother confirmed that she is a heterozygous carrier of
the same mutation; thus, X-linked recessive inheritance was shown.
Genetic status of mother’s parents and relatives is unknown.
Our patient was referred for hematopoetic cell
Wiskott-Aldrich syndrome is an X-linked recessive
condition that exhibits a wide spectrum of clinical severity .
Patients may develop mild thrombo-cytopenia or suffer more severe
disorders from the spectrum. Autoimmune disorders are frequent, being
present in 40% of large cohort of families . In addition, malignant
tumors can occur during childhood, but are more frequent in adolescents
and young adults with the classic form of disorder . Thus, the
clinical diagnosis can be difficult and is usually supported by the
detection of WAS gene mutations . Our patient with mutation of
WAS gene did not exhibit characteristic microthrombo-cytopenia, but
increased platelet volume. Presence of macrothrombocytopenia in our
patient could be due to the presence of autoimmune disorder. Causes of
macrothrombocytopenia could also be immune trombocytopenic purpura (ITP)
usually due to infection, drugs, vaccination and other causes. Rare
hereditary causes of macrotrombocytopenia such as Bernard–Soulier
syndrome, DiGeorge/Velocardiofacial syndrome or Platelet-type von
Willebrand disease were ruled out based on clinical and laboratory
In addition, he did not develop eczema or
malignancies. Such clinical course was pointing out other possible
diagnoses, such as congenital CMV infection resulting in delayed
diagnosis. We stress the need for multidisciplinary assessment of
patients with congenital or early infantile thrombocytopenia, including
testing for mutations of the WAS gene in all unexplained cases
even in the absence of characteristic microthrombocytopenia.
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