Treading an unsure path

Two case reports of ITP demonstrate how interpreting gene mutation tests can be challenging at times

Treading an unsure path

Immune thrombocytopenic purpura or idiopathic thrombocytopenic purpura or ITP is an autoimmune disorder where antibodies destroy platelets, resulting in a tendency to bleed. Common visible symptoms are purpura or bruising, petechiae or large patches of bluish discoloration of the skin and pinpoint dots of bleeding. Bleeding may occur in the nose or mouth, and in severe cases, in the gastrointestinal tract, resulting in blood in the stools, prolonged menstrual bleeding or blood in the urine. Life-threatening intracranial haemorrhage can also occur: This is extremely rare but dreaded. It is generally believed that the severity of bleeding depends on the platelet count – the lower the count, the greater the risk of bleeding. However, in ITP, it is seen that even very low platelet counts may not result in severe bleeding.

Acute ITP occurs primarily in children between the age of 2 and 6 years. Its onset is sudden, with the symptoms disappearing within 6 months and failing to recur. Chronic ITP, on the other hand, mostly occurs in adolescents and adults, but can also occur occasionally in children. Symptoms of chronic ITP can last for 6 months to several years and may recur often.

The cause of ITP is unknown. However, it is often associated with viral infections. While the body prepares to fight off the invading virus, the infection also triggers the immune system to attack its own platelets. Most children improve without treatment, and only require regular monitoring of platelet counts and the treatment of bleeding. Intravenous immunoglobulin or corticosteroids are the first line of treatment in children with severe bleeding. In case of life-threatening bleeding, platelet transfusions are required.

Tamanna (name changed), a 6-year old child, was referred to Dr Swati Kanakia, Kanakia Health Care, Mumbai, with purpura and low platelet counts. A complete blood count confirmed the low platelet count and revealed high mean platelet volume and high immature platelet fraction. These results pointed towards the destruction of platelets in the periphery. Several other tests, including liver function tests, creatinine, serum LDH, ANA, anti-dsDNA, HIV and hepatitis, were carried out to rule out different causes of solitary thrombocytopenia. A bone marrow test confirmed that there was adequate production of platelets. ITP was the working diagnosis and Tamanna was started on steroids. ITP typically responds to steroids, which are given for 21 days followed by one week of tapering. Tamanna responded very well to the steroids and the treatment was tapered and stopped. However, soon after, she developed purpura and her platelet counts dropped to 4,000. She had to be given steroids again. She continued to get episodes of purpura and petechiae every 2-3 months and required treatment. She was given intravenous immunoglobulin as well as dapsone as alternative treatment options. However, Tamanna’s platelet count remained low for more than a year.

Deepa (name changed), an 8-year-old girl, had also been suffering from purpura for the past 1.5 years and came to Dr Kanakia for treatment. Her symptoms and initial treatment plan were similar to that of Tamanna’s. However, Deepa was not as responsive to steroids. She was also given intravenous immunoglobulin, dapsone and mycophenolate mofetil, without effect.

Both the girls were diagnosed with chronic ITP, i.e. low platelet counts for more than a year.

ITP can also be seen in cases of primary immune deficiency diseases. So, clinical exome sequencing for thrombocytopenia was advised in both the patients. A dominant, heterozygous missense mutation in the ITGB3 gene was found for Tamanna, whereas a mutation in the ITGA2B gene was detected for Deepa. Both these genes encode for integrin proteins integrin beta 3 and alpha IIb in platelets. Mutations in these genes affect the function of platelets, resulting in bleeding. These mutations are rare and are known to cause Glanzmann›s thrombasthenia — a platelet function disorder where the platelet count is normal, but the function is defective and leading to bleeding. Thus, it is very likely that there are other secondary mutations in Tamanna and Deepa that may contribute to the low platelet counts.

‘Interestingly, both Tamanna and Deepa share the same last name. However, they are unrelated,’ says Dr. Kanakia. ‘While the secret to their illness lies in whole-exome sequencing and parental studies, these studies are expensive. Further, even if we are able to identify the mutant genes involved, it is unlikely to aid in treating the disorder. Thus, it has been challenging to determine a treatment path for these two girls. Prolonged steroid treatment can be harmful. Since it is acceptable to have low platelet counts, we have discussed the option of not treating these girls anymore. Rather, we will carefully monitor them and use steroids only in cases of bleeding episodes.’

With ample advances in medicine and the availability of extensive and expensive tests, one would like to believe that diagnosis and therapy will be possible in every child. However, these patients prove that genotype and phenotype may not always correlate and that there are many more mysteries of nature waiting to be unraveled. 

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