Hunter syndrome with persistent thrombocytopenia

Abstract

A case of Hunter syndrome, 6½-year-old boy presented with persistent thrombocytopenia and bleeding diathesis. However, cytopenia is not a usual presentation in patients with mucopolysaccharidosis II. After ruling out other causes of severe thrombocytopenia, a clinical possibility of chronic Epstein-Barr virus (EBV) infection was considered. He was treated with intravenous immunoglobulin for refractory thrombocytopenia and intracranial bleed. This was followed by oral prednisolone. The EBV serology was found positive. Platelet counts gradually recovered and no recurrence of bleeds was observed. EBV infection usually causes haematological abnormalities, mainly atypical lymphocytosis, which is a feature of infectious mononucleosis, and uncomplicated cases often present with mild decreases in platelet counts. Severe thrombocytopenia is an extremely rare complication of acute or chronic EBV infection. In Asians, EBV infection should be considered in children presenting with thrombocytopenia, bleeding diathesis and anaemia along with organomegaly.

Background

Cytopenias are features of storage disorders especially Gaucher and Niemann-Pick diseases, but unlikely in mucopolysaccharidoses. A bleeding diathesis can also result from chronic Epstein-Barr virus (EBV) infection. It is well recognised that mild-to-moderate thrombocytopenia occurs in 25%–50% of uncomplicated cases of EBV infection.^{1 2} On the other hand, severe thrombocytopenia (platelet count<20×10⁹/L) is very rare.^{3 4} Here, we describe a case of severe thrombocytopenia associated with chronic EBV infection in a child with mucopolysaccharidosis (MPS) II or Hunter syndrome.

Case presentation

A 6½-year-old boy, suspected to have MPS, under genetic-metabolic unit follow-up, was admitted in the paediatric emergency for recurrent nasal bleed for 2 days and fever for 1 day. He also had melena for 2 days and progressive paleness of the body. There were no localising signs or symptoms. No other focus of bleeding was identified. He had a previous admission at 1½ years of age with pallor and hepatosplenomegaly, and bone marrow done then showed-foamy macrophages suggestive of storage disorder. IQ done earlier was 70. The child was mobile but activities, such as feeding himself, and outdoor activities were restricted.

On admission, he had respiratory difficulty and features of congestive cardiac failure along with severe anaemia. He had acute-on-chronic malnutrition with coarse facial features (figure 1), short stature, multiple joint contractures, thickened skin texture and loss of lumbar curvature. Systemic examination revealed distended abdomen with firm, massive splenohepatomegaly (around 10 cm below costal margins) and pansystolic murmur with normal respiratory and central nervous system examination.

Figure 1.

Child showing coarse facies and bleeding over the lower lip.

He received blood transfusion for severe anaemia at admission following which his respiratory distress improved. For hemophagocytosis, the points favouring were splenomegaly and bicytopenia; however, there was no persistent fever, triglycerides were mildly elevated 215 mg/dL (normal), plasma fibrinogen level was normal—2.75 g/L and serum ferritin level was normal—40 ng/mL (normal—24–336 ng/mL). So bone marrow examination was not done.

Viral infection associated thrombocytopenia was considered.

Investigations

His haemogram revealed anaemia (haemoglobin 47 g/L) and thrombocytopenia (lowest count—2000/µL) so possibility of sequestration crisis was less likely, as one would expect pancytopenia as compared with bicytopenia.

His blood indices revealed anisopoikilocytosis, elevated RDW 29.1 cv% (normal 11.5–14.5 cv%). Peripheral smear examination did not reveal features of haemolysis and DCT was weakly positive for cold immunoglobulins and negative for the warm antibodies along with normal G6PD levels. Initial lactate dehydrogenase level was also increased—773 units. There was no difficulty in blood cross match and no evidence of bacterial sepsis (CRP 3.79 mg/L and blood culture sterile). Blood smear for malarial parasite was also negative.

He did not have any other dysfunction (normal liver enzymes and coagulogram; and normal renal function). Investigations revealed parvovirus serology—negative, mycoplasma cold agglutinin antibody—negative, HBsAg antigen and anti-HCV IgM serology—negative, and HIV serology—non-reactive; however, EBV IgM serology was positive.

X-ray of dorsolumbar spine, hands and pelvis showed dysostosis multiplex. Echocardiography showed mitral valve prolapse with mitral regurgitation and severe left ventricular (LV) systolic dysfunction. Enzyme analysis report was collected and sulfatase enzyme level was 0 units (600–1616 nmol/4 hour/mL plasma). The MRI showed a focus of intracranial bleed and MR angiography showed bright signals as cribriform focal lesions in periventricular white matter in the brain consistent with MPS.

Differential diagnosis

In some cases of MPS I and MPS VI, there may not be clinically clouding of corneae, and can have features overlapping with MPS II or Hunter syndrome. Manifestations can be subtle and diagnosis requires a high index of suspicion. Detailed clinical evaluation and enzyme analysis confirm the diagnosis. EBV infection is a commoner cause of cytopenia especially in Asians and should be ruled out along with other viral causes; even in children presenting with thrombocytopenia or pancytopenia.

Treatment

The child received multiple platelet concentrates and packed red cell transfusions, along with 1 gm/kg dose of intravenous immunoglobulin (IVIG) anticipating a rapid response for intracranial bleed during the hospital stay. Thrombocytopenia was persistent and caused persistent mucosal bleed requiring frequent PRBC transfusions (total 6) and platelet concentrate (total 23 random donor platelet concentrates (PC) and 3 single donor PC).

Subsequently, he was started on oral prednisolone therapy. There was response noted within 2 days, attributed to effect of both the drugs, following which he did not require transfusions. He was subsequently discharged on day 20 of hospital stay and followed-up in OPD when platelet count normalised without any evidence of overt bleeding manifestations.

Outcome and follow-up

The platelet count gradually improved and remained stable at 2 years follow-up. The child had some contractures and genu varum. The younger sibling was also tested by enzyme analysis and also found to be affected. Genetic counselling was done and options for therapy and prenatal diagnosis by enzyme or DNA testing were discussed.

Discussion

EBV is a double-stranded DNA virus known for the infectious mononucleosis syndrome in >90% cases. In developing countries, such as India, infection occurs in early infancy and childhood with the course depending on the age of infection and immune status of the host. Other manifestations of the EBV are Hodgkin disease, hemophagocytosis, post-transplant lymphoproliferation, interstitial pneumonitis, oral hairy leukoplakia, nasopharyngeal carcinoma and Burkitt lymphoma. Severe thrombocytopenia is usually associated with severe mucosal or dermal bleed, which can be life-threatening. The various pathophysiological factors include antiplatelet antibodies, platelet dysfunction with increased consumption, hypersplenism and antibody formation. A positive direct Coombs test and cold agglutinins specific for red cell i-antigen occur in 3% of cases and severe pancytopenia or aplastic anaemia is rare.

The child, here, was a follow-up case of MPS. Common types of MPS seen in the genetic clinic include mainly MPS II and MPS IV. MPS II can have a variable presentation with early onset hepatosplenomegaly, coarse facies and claw hands, or may have later onset presentation with intellectual disability and skeletal deformities. Corneal clouding is not seen in this form of MPS. The initial presentation in some MPS can be in form of recurrent respiratory problems, and diagnosis requires a high index of suspicion.

Usually, in child presenting with organomegaly and cytopenia for prolonged duration, Gaucher and Niemann-Pick diseases are kept upfront in the differentials but MPS with organomegaly can also create a similar situation if complicated by infection, as highlighted by the present case.

Only case reported of MPS II with thrombocytopenia was a few years earlier, and this is not a frequent presentation.⁵ Severe thrombocytopenia is treated with platelet transfusions, corticosteroids, IVIG and immunomodulatory therapies. The clinical utility of acyclovir for thrombocytopenia is limited even at high doses as the outcome may remain unchanged.

Corticosteroids are recommended if thrombocytopenia leads to significant bleeding manifestations, and in presence of autoimmune haemolytic anaemia, or neurological complications, such as seizures, or in cases of suspected severe infection. IVIG may be tried in severe cases or cases that are refractory to steroid therapy.⁶ Splenectomy can be used as desperate measure in unusual non-responding situation. The definitive treatment for MPS II is enzyme replacement therapy and is available from 2006 and is associated with increased survival outcomes.⁷ One family with MPS II has been reported earlier with NK cell and B cell deficiencies.⁸ Further immunological studies are needed to check whether, actually, these MPS patients have selective immunodeficiencies making them predisposed to some viral infections.

Learning points.

• It is important to consider Epstein-Barr virus (EBV) infection as a possible cause of chronic thrombocytopenia with acute aggravation along with bleeding-related anaemia, especially in Asian patients.

• Severe thrombocytopenia in patients with EBV infection remains refractory to the transfusions so use of intravenous immunoglobulin and steroids have definitive role in the management, reducing the need for transfusions.

• Mucopolysaccharidosis patients may also present with thrombocytopenia or bleeding as a complication, and appropriate complete evaluation, especially in cases of severe thrombocytopenia, can aid in the diagnosis.