A NOVEL ADAMTS13 MUTATION IN A PEDIATRIC PATIENT WITH CONGENITAL AND ACQUIRED ADAMTS13 DEFICIENCY
(Abstract release date: 05/19/16)
EHA Library. Yalcin K. 06/09/16; 133110; E1561
Dr. Koray Yalcin
Contributions
Contributions
Abstract
Abstract: E1561
Type: Eposter Presentation
Background
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening disorder caused by the deficiency of von Willebrand factor (VWF) cleaving protease, ADAMTS13. Severe ADAMTS13 deficiency (activity levels <10% of normal) can be due either to anti-ADAMTS13 autoantibodies (acquired TTP) or to ADAMTS13 gene mutations (congenital TTP).
Aims
In this report, we describe the novel mutation and clinical history of a pediatric patient with both congenital and acquired ADAMTS13 deficiency.
Methods
A 8 years old girl presented with easy bruising and thrombocytopenia. She was diagnosed with immune thrombocytopenic purpura (ITP) when she was 8 months old and followed with mild thrombocytopenia. Family history was unremarkable. At admission, blood work-up exhibited anemia, thrombocytopenia, fragmented erythrocytes, and schistocytes. Elevated serum LDH was detected. Renal function tests were impaired. TTP was diagnosed and started double volume plasma exchange (PEX) immediately. She was unresponsive to plasma exchange therapy. We used high dose methylprednisolone, acetylcysteine, cyclosporin, rituximab, vincristine and cyclophosphamide therapies unfortunately, there was no response. In spite of splenectomy, clinical status was deteriorated. We continued PEX beside all these therapies. During the treatment she had serious complications related to TTP as partial retina detachment, convulsion, renal failure and myocardial hypertrophy. During the treatment she had to be transfused with 118 units erythrocyte and despite of all efforts she died at the nineth month of TTP attack.
Results
The patient had undetectable ADAMTS13 activity (measured by FRETS-VWF73 assay) and antigen (measured by Technozym ADAMTS13 Antigen assay) and a high titer of anti-ADAMTS13 IgG. ADAMTS13 activity of the patient’s mother was 60%. According to these results congenital and acquired ADAMTS13 deficiency seemed to be together in one patient. The genetic analysis identified the presence of a nonsense mutation in homozygous state on the ADAMTS13 gene, a C to T substitution at nucleotide589 in the exon 6 (c.589C>T) leading to the substitution of the Glutamine 197 with a premature stop codon (p.Gln197X) in the metalloprotease domain in homozygous state. The mutation was also confirmed in heterozygous state in the patient’s mother (her father died in an accident years ago).
Conclusion
This patient is unique with complex phenotype (congenital and acquired ADAMTS13 deficiency together) and novel mutation in ADAMTS13 gene.Similar complex phenotype is reported before and in that case ticlodipine is the trigger factor for acquired TTP. We could not detect any trigger factor for acquired TTP as drugs or infections. We also measure a high titer of anti-ADAMTS13 IgG at admission before the first plasma exchange. The novel mutation has not been previously reported in the literature and there aren’t any data from in vitro expression studies. However, due to its location within the metalloprotease domain, it is most probably responsible for the deficiency of protein product and its activity.This phenotipic complexity and mutation could be a novel type of TTP with severe clinical status and unresponsive to treatment.
Session topic: E-poster
Keyword(s): ADAMTS13, Pediatric, Thrombotic thrombocytopenic purpura (TTP)
Type: Eposter Presentation
Background
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening disorder caused by the deficiency of von Willebrand factor (VWF) cleaving protease, ADAMTS13. Severe ADAMTS13 deficiency (activity levels <10% of normal) can be due either to anti-ADAMTS13 autoantibodies (acquired TTP) or to ADAMTS13 gene mutations (congenital TTP).
Aims
In this report, we describe the novel mutation and clinical history of a pediatric patient with both congenital and acquired ADAMTS13 deficiency.
Methods
A 8 years old girl presented with easy bruising and thrombocytopenia. She was diagnosed with immune thrombocytopenic purpura (ITP) when she was 8 months old and followed with mild thrombocytopenia. Family history was unremarkable. At admission, blood work-up exhibited anemia, thrombocytopenia, fragmented erythrocytes, and schistocytes. Elevated serum LDH was detected. Renal function tests were impaired. TTP was diagnosed and started double volume plasma exchange (PEX) immediately. She was unresponsive to plasma exchange therapy. We used high dose methylprednisolone, acetylcysteine, cyclosporin, rituximab, vincristine and cyclophosphamide therapies unfortunately, there was no response. In spite of splenectomy, clinical status was deteriorated. We continued PEX beside all these therapies. During the treatment she had serious complications related to TTP as partial retina detachment, convulsion, renal failure and myocardial hypertrophy. During the treatment she had to be transfused with 118 units erythrocyte and despite of all efforts she died at the nineth month of TTP attack.
Results
The patient had undetectable ADAMTS13 activity (measured by FRETS-VWF73 assay) and antigen (measured by Technozym ADAMTS13 Antigen assay) and a high titer of anti-ADAMTS13 IgG. ADAMTS13 activity of the patient’s mother was 60%. According to these results congenital and acquired ADAMTS13 deficiency seemed to be together in one patient. The genetic analysis identified the presence of a nonsense mutation in homozygous state on the ADAMTS13 gene, a C to T substitution at nucleotide589 in the exon 6 (c.589C>T) leading to the substitution of the Glutamine 197 with a premature stop codon (p.Gln197X) in the metalloprotease domain in homozygous state. The mutation was also confirmed in heterozygous state in the patient’s mother (her father died in an accident years ago).
Conclusion
This patient is unique with complex phenotype (congenital and acquired ADAMTS13 deficiency together) and novel mutation in ADAMTS13 gene.Similar complex phenotype is reported before and in that case ticlodipine is the trigger factor for acquired TTP. We could not detect any trigger factor for acquired TTP as drugs or infections. We also measure a high titer of anti-ADAMTS13 IgG at admission before the first plasma exchange. The novel mutation has not been previously reported in the literature and there aren’t any data from in vitro expression studies. However, due to its location within the metalloprotease domain, it is most probably responsible for the deficiency of protein product and its activity.This phenotipic complexity and mutation could be a novel type of TTP with severe clinical status and unresponsive to treatment.
Session topic: E-poster
Keyword(s): ADAMTS13, Pediatric, Thrombotic thrombocytopenic purpura (TTP)
Abstract: E1561
Type: Eposter Presentation
Background
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening disorder caused by the deficiency of von Willebrand factor (VWF) cleaving protease, ADAMTS13. Severe ADAMTS13 deficiency (activity levels <10% of normal) can be due either to anti-ADAMTS13 autoantibodies (acquired TTP) or to ADAMTS13 gene mutations (congenital TTP).
Aims
In this report, we describe the novel mutation and clinical history of a pediatric patient with both congenital and acquired ADAMTS13 deficiency.
Methods
A 8 years old girl presented with easy bruising and thrombocytopenia. She was diagnosed with immune thrombocytopenic purpura (ITP) when she was 8 months old and followed with mild thrombocytopenia. Family history was unremarkable. At admission, blood work-up exhibited anemia, thrombocytopenia, fragmented erythrocytes, and schistocytes. Elevated serum LDH was detected. Renal function tests were impaired. TTP was diagnosed and started double volume plasma exchange (PEX) immediately. She was unresponsive to plasma exchange therapy. We used high dose methylprednisolone, acetylcysteine, cyclosporin, rituximab, vincristine and cyclophosphamide therapies unfortunately, there was no response. In spite of splenectomy, clinical status was deteriorated. We continued PEX beside all these therapies. During the treatment she had serious complications related to TTP as partial retina detachment, convulsion, renal failure and myocardial hypertrophy. During the treatment she had to be transfused with 118 units erythrocyte and despite of all efforts she died at the nineth month of TTP attack.
Results
The patient had undetectable ADAMTS13 activity (measured by FRETS-VWF73 assay) and antigen (measured by Technozym ADAMTS13 Antigen assay) and a high titer of anti-ADAMTS13 IgG. ADAMTS13 activity of the patient’s mother was 60%. According to these results congenital and acquired ADAMTS13 deficiency seemed to be together in one patient. The genetic analysis identified the presence of a nonsense mutation in homozygous state on the ADAMTS13 gene, a C to T substitution at nucleotide589 in the exon 6 (c.589C>T) leading to the substitution of the Glutamine 197 with a premature stop codon (p.Gln197X) in the metalloprotease domain in homozygous state. The mutation was also confirmed in heterozygous state in the patient’s mother (her father died in an accident years ago).
Conclusion
This patient is unique with complex phenotype (congenital and acquired ADAMTS13 deficiency together) and novel mutation in ADAMTS13 gene.Similar complex phenotype is reported before and in that case ticlodipine is the trigger factor for acquired TTP. We could not detect any trigger factor for acquired TTP as drugs or infections. We also measure a high titer of anti-ADAMTS13 IgG at admission before the first plasma exchange. The novel mutation has not been previously reported in the literature and there aren’t any data from in vitro expression studies. However, due to its location within the metalloprotease domain, it is most probably responsible for the deficiency of protein product and its activity.This phenotipic complexity and mutation could be a novel type of TTP with severe clinical status and unresponsive to treatment.
Session topic: E-poster
Keyword(s): ADAMTS13, Pediatric, Thrombotic thrombocytopenic purpura (TTP)
Type: Eposter Presentation
Background
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening disorder caused by the deficiency of von Willebrand factor (VWF) cleaving protease, ADAMTS13. Severe ADAMTS13 deficiency (activity levels <10% of normal) can be due either to anti-ADAMTS13 autoantibodies (acquired TTP) or to ADAMTS13 gene mutations (congenital TTP).
Aims
In this report, we describe the novel mutation and clinical history of a pediatric patient with both congenital and acquired ADAMTS13 deficiency.
Methods
A 8 years old girl presented with easy bruising and thrombocytopenia. She was diagnosed with immune thrombocytopenic purpura (ITP) when she was 8 months old and followed with mild thrombocytopenia. Family history was unremarkable. At admission, blood work-up exhibited anemia, thrombocytopenia, fragmented erythrocytes, and schistocytes. Elevated serum LDH was detected. Renal function tests were impaired. TTP was diagnosed and started double volume plasma exchange (PEX) immediately. She was unresponsive to plasma exchange therapy. We used high dose methylprednisolone, acetylcysteine, cyclosporin, rituximab, vincristine and cyclophosphamide therapies unfortunately, there was no response. In spite of splenectomy, clinical status was deteriorated. We continued PEX beside all these therapies. During the treatment she had serious complications related to TTP as partial retina detachment, convulsion, renal failure and myocardial hypertrophy. During the treatment she had to be transfused with 118 units erythrocyte and despite of all efforts she died at the nineth month of TTP attack.
Results
The patient had undetectable ADAMTS13 activity (measured by FRETS-VWF73 assay) and antigen (measured by Technozym ADAMTS13 Antigen assay) and a high titer of anti-ADAMTS13 IgG. ADAMTS13 activity of the patient’s mother was 60%. According to these results congenital and acquired ADAMTS13 deficiency seemed to be together in one patient. The genetic analysis identified the presence of a nonsense mutation in homozygous state on the ADAMTS13 gene, a C to T substitution at nucleotide589 in the exon 6 (c.589C>T) leading to the substitution of the Glutamine 197 with a premature stop codon (p.Gln197X) in the metalloprotease domain in homozygous state. The mutation was also confirmed in heterozygous state in the patient’s mother (her father died in an accident years ago).
Conclusion
This patient is unique with complex phenotype (congenital and acquired ADAMTS13 deficiency together) and novel mutation in ADAMTS13 gene.Similar complex phenotype is reported before and in that case ticlodipine is the trigger factor for acquired TTP. We could not detect any trigger factor for acquired TTP as drugs or infections. We also measure a high titer of anti-ADAMTS13 IgG at admission before the first plasma exchange. The novel mutation has not been previously reported in the literature and there aren’t any data from in vitro expression studies. However, due to its location within the metalloprotease domain, it is most probably responsible for the deficiency of protein product and its activity.This phenotipic complexity and mutation could be a novel type of TTP with severe clinical status and unresponsive to treatment.
Session topic: E-poster
Keyword(s): ADAMTS13, Pediatric, Thrombotic thrombocytopenic purpura (TTP)
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