CASE REPORT

Upshaw-Schulman Syndrome Rabia Ahmad1, Muneeza Natiq1 and Mona Aziz2

ABSTRACT A 13 years girl presented with history of sudden onset fits, altered sensorium and anuria for 2 days. There was also history of right sided weakness of the whole body. Past history revealed repeated episodes of similar complaints since early childhood. On the basis of history, physical examination and extensive investigations, patient was diagnosed as Upshaw- Schulman syndrome, a rare case of congenital Thrombotic Thrombocytopenic Purpura (TTP). She is now in remission and being maintained on twice weekly transfusions of Fresh Frozen Plasma (FFP).

Key Words: Upshaw-Schulman syndrome (USS). Congenital thrombotic thrombocytopenic purpura (TTP). Plasmapharesis. Fresh frozen plasma (FFP). Microangiopathic hemolytic anemia (MAHA). Cerebrovascular accident. Anuria.

INTRODUCTION She had undergone splenectomy in another hospital 2 Upshaw-Schulman Syndrome (USS) is an extremely months back with the suspicion of immune-mediated rare hereditary disorder in which there is a severe platelet destruction. deficiency of A Disintegrin And Metalloprotease with At the time of admission in Emergency her hemoglobin Thrombospondin repeats 13 (ADAMTS13) resulting in (Hb) was 4.8 g/dl, Total Leucocyte Count (TLC) was congenital Thrombotic Thrombocytopenic Purpura 28.4 x 109/l, with 90% neutrophils and platelets were (TTP).1,2 It is a form of microangiopathic hemolytic 40 x 109/L; PT was 12/12 seconds and APTT was 31/30 anaemia characterized by pentad of neurological seconds. Peripheral smear revealed numerous symptoms including renal abnormalities, thrombo- fragmented RBCs and few nucleated red cells. Bilirubin cytopenia, fever and Microangiopathic Hemolytic was raised (4.5 mg/dl) with unconjugated hyper- Anaemia (MAHA).2 The clinical signs are usually mild bilirubinemia. Blood Urea Nitrogen (BUN) (104 mg/dl), during childhood in patients with Upshaw-Schulman and creatinine (2 mg/dl) levels were also elevated. LDH syndrome but may be associated with and aggravated in level was 2230 U/L (normal = 225 - 450U/L). Direct severe phenotype, often presenting with isolated and Coomb's test was negative. Blood cultures revealed no recurrent thrombocytopenia. Many times their symptoms growth. She was diagnosed as a suspected case of are first noticed when they have infections or get microangiopathic hemolytic anaemia on the basis of pregnant.3 history, physical examination findings and peripheral This report describes a teen age girl presenting with smear examination which revealed schistocytes on renal and neurologic symptoms finally diagnosed USS. repeated occasions. She was treated with plasma infusions and later with CASE REPORT plasmapharesis followed by immunosuppression in the A 13 years girl presented in the Emergency of Jinnah form of inj Solumedrol 1g intravenously X OD for 3 days. Hospital with complaint of sudden onset of fits for 2 Her CT scan of brain was done in order to find out the hours. There was history of right sided weakness as cause of her right sided weakness. It revealed an old well. Patient had a history of similar episodes in the past, infarct in right parietal region and hemorrhagic infarcts in but the present episode was more severe. Past history right frontoparietal region. There were hemorrhagic also included repeated admissions in hospitals with infarcts in left frontoparietal region as well with mild complaint of altered sensorium, jaundice and anuria. Her cerebral atrophy. Her Hb improved to 8.7 g/dl and 9 parents were first cousins. She had 3 siblings and none platelet count increased to 170 x 10 /L after one week. of them ever had such complaints and all were healthy. LDH reduced to 900 U/L. Neurological symptoms recovered partially. 1 Department of Pathology, Allama Iqbal Medical College, Due to her history of such repeated episodes since Lahore. childhood her ADAMTS13 levels were done, which were 2 Department of Haematology, Sheikh Zayed Hospital/FPGMI, markedly low 300 ng/ml (630 - 850 ng/ml). Patient was Lahore. finally diagnosed as a confirmed case of Upshaw- Correspondence: Dr. Rabia Ahmad, 487-M Block, Model Schulman syndrome. As these patients do not benefit Town Extension, Lahore. from immunosuppressant therapy, thus immuno- E-mail: [email protected] suppressive agents were discontinued. Plasmapharesis Received: January 20, 2014; Accepted: August 17, 2015. was also discontinued as it is not required in this

Journal of the College of Physicians and Surgeons Pakistan 2015, Vol. 25 (Special Supplement 2 of Case Reports): S97-S99 S97 Rabia Ahmad, Muneeza Natiq and Mona Aziz

usually have mild thrombocytopenia during childhood unless they are exposed to provoking stimului, such as a cytokine storm during influenza virus infection.7,10 However, after adolescence the gender disparity apparently determines the ultimate outcome of these USS-patients, as adult females have more episodes of TTP than males.7 Although gene analysis was not done in this case but phenotypically she had a severe presentation. Pregnancy undoubtedly is a strong inducer of overt TTP in female USS-patients, although the pathogenesis is not fully known.9 However, it is now well established that plasma Von Willebrand Factor (VWF) levels remarkably Figure 1: Peripheral smear showing schistocytes, polychromasia, macrocytes and nucleated RBCs. increase as gestation progresses, alongwith the appearance of ultra large Von Willebrand factor syndrome becaue there is no autoantibody against multimers (UL-VWFMs), which are accompanied by ADAMTS13. Her condition improved and now she is reduced ADAMTS13 activity due to consumption, even being maintained on fresh frozen plasma infusion twice in normal pregnant women.10 Thus, in pregnant USS weekly. She is now on follow-up with CBC and LDH. women, an enormous excess of the substrate (larger VWFM) relative to the ADAMTS13 enzyme is the most DISCUSSION plausible pathogenic mechanism.10 Along with it, aging, The diagnosis of this rare disorder is extremely interferon therapy and heavily drinking alcohol are also important as these children are often misdiagnosed as considered to be additional disease aggravating factors ITP and treated with immunosuppression which is of no for USS patients.10 benefit and may even result in serious consequences. An assay for ADAMTS13 activity should be done as a This patient was also initially misdiagnosed and routine test to make and/or exclude a diagnosis of USS, managed as a case of immune thrombocytopenia, when physicians come across the patients with repeatedly, had received immunosuppression and had thrombocytopenia of unknown etiology, especially during even undergone splenectomy. The classical hallmarks of childhood.1,2 USS are severe neonatal jaundice with a negative direct Coomb's test. There are repeated childhood episodes The distinction between congenital and acquired TTP is of thrombocytopenia and MAHA that are reversed by important as it helps us to provide information to patients infusions of Fresh Frozen Plasma (FFP).4,5 Often regarding their diagnosis (i.e; Upshaw-Schulman only an isolated thrombocytopenia occurs, causing syndrome versus acquired immune mediated disease) physicians to sometimes overlook this important and its specific consequences. Secondly, it provides disease. Although this patient did not present with correct information for the future management of female neonatal jaundice but recurrent episodes of MAHA and patients during pregnancy or other health related issues neurological symptoms were present since early which can precipitate an episode of MAHA. Moreover, it childhood. USS is an extremely rare disease, and to also helps in family screening of asymptomatic members date, it is estimated that there have been only about 100 of family as disease may be precipitated in those patients worldwide.6-9 Nara Medical University has individuals during pregnancy or an episode of functioned as a TMA referral centre in Japan since 1998 infection.12 and collected a large dataset of 919 patients with TMA The most important aspect of this case report is the 10 between 1998 and 2008. In this registry, only 41 USS mode of presentation. Equally important is the patients in 36 different families were identified who neurological aspect of this case. These features point ranged in age from early childhood to 79 years of age.10 towards importance of genetic mutational analysis in Only one case report is published in Pakistan recently.11 such patients which may predict severity of congenital ADAMTS13 deficiency is prothrombotic, but this alone is TTP. Gene mutation in such cases is not available in unable to precipitate acute symptoms. Thus, second hits Pakistan up till now. To some extent we can emphasize or triggering factors should exist.5 In this patient recent multicentre study on rare families with Upshaw- episode of MAHA was precipitated by upper respiratory Schulman syndrome for possible genetic mutations tract infection. There are two clinical phenotypes of USS, which can predict severity and possible neurological and termed as the early-onset and the late onset renal damage if not treated aggressively with FFPs. 5,6 phenotypes. Possibly in near future recombinant ADAMTS13 will The phenotype of the homozygous p.R193W/p.R193W become available and patients with severe phenotypes mutation is mild and the patients carrying this mutation can be benefitted with this product.

S98 Journal of the College of Physicians and Surgeons Pakistan 2015, Vol. 25 (Special Supplement 2 of Case Reports): S97-S99 Upshaw-Schulman syndrome

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