|Year : 2018 | Volume
| Issue : 3 | Page : 104-107
A rare sporadic case of C3 gene mutation in 5-month-old baby girl with atypical hemolytic uremic syndrome, with good prognosis
Abdullah A Baothman1, Hani Almalki2, Mohammed Almaghrabi1
1 King Abdullah International Medical Research Center; College of Medicine, King Saud Bin Abdulaziz University for Health Sciences; Department of Pediatrics, King Abdulaziz Medical City, Ministry of the National Guard – Health Affairs, Jeddah, Saudi Arabia
2 King Abdullah International Medical Research Center; College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Jeddah, Saudi Arabia
|Date of Web Publication||31-Oct-2018|
Dr. Hani Almalki
King Abdullah International Medical Research Center, King Abdulaziz Medical City, Western Region, Jeddah; King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Western Region, Jeddah
Source of Support: None, Conflict of Interest: None
Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy representing <10% of HUS cases, characterized by hemolytic anemia, thrombocytopenia, and renal failure. A 5-month-old baby girl, the daughter of Saudi nonconsanguineous parents, presented with fever, vomiting, and watery diarrhea when she was admitted as a case of gastroenteritis. The laboratory results showed high urea (10.2 mmol/L) and creatinine (134 μmol/L) as well as low hemoglobin (4.5 g/dL) and a low platelet count (81 × 109/L) with a normal coagulation profile. Blood, urine, and stool cultures were all negative for bacterial growth. Despite the lack of strong indicators of aHUS, the patient received 4 weekly cycles of eculizumab in the induction phase (300 mg/m2/dose intravenously over 2 h) based on the clinical emergence diagnosis. She showed dramatic improvements in clinical and laboratory parameters and was taken off peritoneal dialysis. Molecular tests confirmed our clinical diagnosis and revealed a rare heterozygous missense variant of the C3 gene, c.3343G>A, p.(Asp1115Asn). The early recognition and administration of eculizumab are a lifesaving measure. C3 gene mutations are an autosomal dominant inherited pattern, with 50% risk of inheriting this mutation. Therefore, genetic counseling and family member testing are recommended.
Keywords: Atypical hemolytic uremic syndrome, eculizumab, microangiopathy
|How to cite this article:|
Baothman AA, Almalki H, Almaghrabi M. A rare sporadic case of C3 gene mutation in 5-month-old baby girl with atypical hemolytic uremic syndrome, with good prognosis. J Appl Hematol 2018;9:104-7
|How to cite this URL:|
Baothman AA, Almalki H, Almaghrabi M. A rare sporadic case of C3 gene mutation in 5-month-old baby girl with atypical hemolytic uremic syndrome, with good prognosis. J Appl Hematol [serial online] 2018 [cited 2020 Jul 2];9:104-7. Available from: http://www.jahjournal.org/text.asp?2018/9/3/104/244537
| Introduction|| |
Thrombotic microangiopathy (TMA) comprises two distinct disorders (thrombotic thrombocytopenic purpura [TTP] and hemolytic uremic syndrome [HUS]) characterized by epithelial injury of microvessels, including small capillaries and arterioles, resulting in thrombus formation and organ damage. TTP can be caused by Upshaw–Shulman syndrome, which is an autosomal recessive disorder associated with a mutation in ADAMTS13 or more commonly by the formation of autoantibodies targeting ADAMTS13 resulting in <10% activity. HUS, which is characterized by nonimmune-mediated hemolytic anemia, thrombocytopenia, and acute renal failure, can be further classified as Shiga toxin Escherichia More Details coli (STEC) and atypical HUS. STEC-HUS is commonly associated with the Shiga toxin-producing bacteria, E. coli O157:H7, resulting in typical symptoms of diarrhea containing blood. It rarely results in long-term renal impairment. Atypical HUS is a rare form of TMA representing <10% of HUS cases, with estimated prevalence of 3.3 cases/million among the pediatric age group., Compared to the typical form (STEC-HUS), the overall prognosis of atypical HUS is poor. It is estimated that more than 25% of patients with atypical HUS die in the early phase, with a further 50% going on to develop the end-stage renal disease. Atypical HUS is characteristically not associated with E. coli O157:H7 or a history of diarrhea containing blood but is associated with long-term renal failure. Approximately 70% of atypical HUS cases are induced by dysregulation of the complement system either due to a mutation or formation of autoantibodies against complement factor H (CFH)., These phenomena abolish the ability of cells to control the complement system, leading to overactivation and formation of the membrane activation complex. This process causes endothelial injury and promotes a continuous activation of the coagulation cascade and formation of microthrombi that commonly target microvessels of the kidney. Although the kidney is the most commonly affected organ in this process, it has been reported that 20% of atypical HUS patients have involvement in the heart, intestine, pancreas, lungs, and brain.
Here, we report a case of atypical HUS in a 5-month-old Saudi baby girl who presented with atypical HUS due to a rare sporadic mutation in the C3 gene.
| Case Report|| |
A 5-month-old baby girl, the daughter of Saudi nonconsanguineous parents, was delivered normally at full term. The baby was well until 5 days before her presentation with fever, vomiting, and watery diarrhea when she was admitted as a case of gastroenteritis. She received intravenous fluids and was treated with intravenous empirical antibiotics and blood transfusion due to severe anemia. However, the child was becoming hypoactive and exhibited generalized body swelling. The laboratory results showed high urea (10.2 mmol/L) and creatinine (134 μmol/L) as well as low hemoglobin (4.5 g/dL) and a low platelet count (81 × 109/L) with a normal coagulation profile. Blood smear tests showed the presence of schistocytes and nucleated red cells as well as thrombocytopenia. Blood, urine, and stool cultures were all negative for bacterial growth. Chest X-rays were obtained due to the presence of progressive dyspnea. The images showed a bilateral peribronchial thickening with the intermittent progression of the diffuse lung contusion and suspicion of right pulmonary effusion in addition to mild cardiomegaly. The patient had diarrhea, which was watery, but not associated with blood or mucus. The child had a fever, reaching 39°C, without abnormal movements or rashes. Her blood pressure was 113/88 mmHg, with a heart rate of 163 beats per minute, respiratory rate of 52 breaths per minute, and oxygen saturation of 97%. Periorbital edema was noticed bilaterally with generalized edema. Later, the patient was admitted to the pediatric intensive care unit as case of acute kidney injury. She was treated with Lasix and nifedipine, with intravenous NAHCO3 administered to manage high blood pressure with metabolic acidosis. Initially, the patient improved, but then, she exhibited irritability, tachypnea, tachycardia, and reduced oxygen saturation, which necessitated the administration of oxygen.
The patient was intubated for 10 days and underwent peritoneal dialysis for renal failure. Due to the critical condition of the patient, the biochemical complement profile was not done, and a preliminary diagnosis of atypical HUS was made. Furthermore, despite the lack of strong indicators of atypical HUS, and importantly, normal activity of ADAMST13 (0.89), which ruled out TTP, the patient received 4 weekly cycles of eculizumab in the induction phase (300 mg/m2/dose intravenously over 2 h) based on the clinical emergence diagnosis and negative stool culture. She showed dramatic improvements in clinical and laboratory parameters and was taken off peritoneal dialysis. Subsequently, she received the same dose of eculizumab in maintenance cycles every 3 weeks [Figure 1] and [Figure 2]. She also received a meningococcal vaccine and ciprofloxacin for 14 days to protect her from encapsulated organisms that may be associated with the administration of eculizumab. Subsequently, molecular tests confirmed our clinical diagnosis and revealed a heterozygous missense variant of the C3 gene, c.3343G>A, p.(Asp1115Asn), which is pathogenic for complement 3 deficiency in atypical HUS.
|Figure 1: Hemoglobin and platelet levels following eculizumab administration|
Click here to view
|Figure 2: Creatinine and lactate dehydrogenase levels following eculizumab administration|
Click here to view
| Discussion|| |
HUS was first described in 1955 in children with a classical triad of hemolytic anemia, thrombocytopenia, and acute renal failure. However, atypical HUS diverges from the typical type by a negative culture of Shiga toxin-producing bacteria E. coli O157:H7, O111:H8, O103:H2, O123, and O26 infection and the presence of complement system mutations. This form is rare, representing <10% of all HUS cases and with an estimated prevalence of 3.3 cases/million in the pediatric population.,
Atypical HUS can be either familial or sporadic. The familial type was first described in 1965 in monozygous twins presenting with hemolytic anemia and azotemia. Approximately 20% of cases are familial exhibiting an autosomal dominant or recessive inheritance pattern and with poor prognosis and end-stage renal disease or death occurring in 50% to 90% of patients., Patients without a family history of atypical HUS are classified as sporadic cases, which can be idiopathic (50%) or triggered by secondary causes. Triggers commonly seen in adult atypical HUS cases include pregnancy, human immunodeficiency virus, acute lymphoblastic leukemia, and organ and bone marrow transplant.,
All complement system pathways require the formation of the C3 convertase that is essential for the propagation of complement activation. In contrast to the classical and lectin pathways that require the recognition of an antigen by antibody or mannose-binding lectin for activation, the alternative pathway is part of the innate immune system and does not require specific antigen recognition. Regulation of complement system is mediated by soluble CFH and factor I and a membrane-anchored protein.
Most patients with atypical HUS (50%–60%) have a mutation in one of the regulatory complement proteins, factor H, I, or the membrane-anchored protein. In addition, 2%–8% comprise gain-of-function mutations in complement factor B or C3.
In the index patient reported here, a rare heterozygous missense variant (c.3343G>4, p,[Asp1115Asn]) in the C3 gene was identified by sequence analysis. This variant has previously been reported in two previous studies., In 2008, the same variant mutation was identified in a sporadic case of a 24-year-old woman. Her C3 levels were 0.54 g/L, factor H was 0.67 g/L, and factor I was 61 mg/L. The patient had the end-stage renal disease and had received two kidney transplants. This variant was found to decrease the binding of C3b to membrane cofactor protein to 17% of that associated with the wild-type allele. In another study in 2015, the interactions between complement C3 and regulators were investigated in the same patient described in the previous report in addition to another pediatric patient who recovered. This variant was found to lead to C3 consumption and low C3 levels in the patients. Factor H binding of the membrane cofactor protein and membrane cofactor protein cofactor activity was also found to be decreased compared to that associated with the wild-type allele.
For a long time, the standard treatment of atypical HUS involved plasma infusions containing the functional complement inhibitors without removing defective complement inhibitors, or plasma exchange, replacing defective complement inhibitors with functional complement inhibitors. However, this approach can only be used to support the patient and does not prevent the TMA episodes. In 2011, the Food and Drug Administration approved the first medication to treat atypical HUS and the humanized monoclonal antibody eculizumab that blocks the final pathway of the complement cascade by inhibiting the C5 protein. The approval was based on two prospective studies in adults and one retrospective pediatric study. In 2016, another prospective study evaluated the efficacy of eculizumab in the pediatric age group (aged 5 months to 17 years) using the complete TMA response at 26 weeks as the primary endpoint. Eculizumab was well tolerated in 22 patients with atypical HUS, without incidence of death or meningococcal infection. In the same study, 14 patients had a complete TMA response, 18 patients had hematologic normalization, and 16 patients had more than 25% improvement in serum creatinine. The index patient showed a significant improvement after four cycles in the induction phase of eculizumab (300 mg/m2/dose intravenously over 2 h). She is now off peritoneal dialysis, and her renal and hematological indices have improved as follows: serum creatinine (by 48%), lactate dehydrogenase (by 85%), hemoglobin (by 37%), and platelet count (by 76%).
| Conclusion|| |
Atypical HUS is an extremely rare TMA disorder in the pediatric age group although this could be due to misdiagnosis at initial presentation. Atypical HUS is distinguished by complement mutation and negative culture for Shiga toxin-producing bacteria and importantly, negative for the thrombotic thrombocytic purpura marker, ADAMTS13. The early recognition and administration of eculizumab are an essential and lifesaving measure to avoid devastating organ damage, especially renal complications, and death.
C3 gene mutations are an autosomal dominant inherited pattern, with 50% risk of inheriting this mutation. Therefore, genetic counseling and family member testing are recommended. Additional information is still needed to confirm the pathogenicity of this variant, which could allow independent risk stratification based on this mutation.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Blueprint Genetics performed the molecular study and sequence analysis of the index patient's DNA sample.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Noris M, Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol 2005;16:1035-50.
Loirat C, Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis 2011;6:60.
Zimmerhackl LB, Besbas N, Jungraithmayr T, van de Kar N, Karch H, Karpman D, et al.
Epidemiology, clinical presentation, and pathophysiology of atypical and recurrent hemolytic uremic syndrome. Semin Thromb Hemost 2006;32:113-20.
Kavanagh D, Goodship TH, Richards A. Atypical haemolytic uraemic syndrome. Br Med Bull 2006;77-78:5-22.
Bresin E, Rurali E, Caprioli J, Sanchez-Corral P, Fremeaux-Bacchi V, Rodriguez de Cordoba S, et al.
Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. J Am Soc Nephrol 2013;24:475-86.
Picard C, Burtey S, Bornet C, Curti C, Montana M, Vanelle P, et al.
Pathophysiology and treatment of typical and atypical hemolytic uremic syndrome. Pathol Biol (Paris) 2015;63:136-43.
Schramm EC, Roumenina LT, Rybkine T, Chauvet S, Vieira-Martins P, Hue C, et al.
Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome. Blood 2015;125:2359-69.
Noris M, Remuzzi G. Glomerular diseases dependent on complement activation, including atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, and C3 glomerulopathy: Core curriculum 2015. Am J Kidney Dis 2015;66:359-75.
Gasser C, Gautier E, Steck A, Siebenmann RE, Oechslin R. Hemolytic-uremic syndrome: Bilateral necrosis of the renal cortex in acute acquired hemolytic anemia. Schweiz Med Wochenschr 1955;85:905-9.
Campbell S, Carré IJ. Fatal haemolytic uraemic syndrome and idiopathic hyperlipaemia in monozygotic twins. Arch Dis Child 1965;40:654-8.
Kaplan BS, Chesney RW, Drummond KN. Hemolytic uremic syndrome in families. N Engl J Med 1975;292:1090-3.
Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med 2009;361:1676-87.
Han D, Baek H, Cho Y, Kim C, Shin M, Kook H, et al
. Z leukemia. Korean J Pediatr 2010;53:253.
Afshar-Kharghan V. Atypical hemolytic uremic syndrome. Hematology Am Soc Hematol Educ Program 2016;2016:217-25.
Lee MD, Tzen CY, Lin CC, Huang FY, Liu HC, Tsai JD, et al.
Hemolytic uremic syndrome caused by enteroviral infection. Pediatr Neonatol 2013;54:207-10.
Frémeaux-Bacchi V, Miller EC, Liszewski MK, Strain L, Blouin J, Brown AL, et al.
Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 2008;112:4948-52.
Christmann M, Hansen M, Bergmann C, Schwabe D, Brand J, Schneider W, et al.
Eculizumab as first-line therapy for atypical hemolytic uremic syndrome. Pediatrics 2014;133:e1759-63.
Soliris® [Package Insert]. Cheshire, CT: Alexion Pharmaceuticals, Inc.; 2014.
Greenbaum LA, Fila M, Ardissino G, Al-Akash SI, Evans J, Henning P, et al.
Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int 2016;89:701-11.
[Figure 1], [Figure 2]