Clinical caseSuccessful treatment of neonatal atypical hemolytic uremic syndrome with C5 monoclonal antibodyEfficacité du traitement d’un syndrome hémolytique et urémique atypique néonatal par anticorps monoclonal C5
Introduction
Hemolytic uremic syndrome (HUS), defined by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment, is uncommon in the neonatal period [1]. HUS is divided into typical HUS (90% of cases), where a shiga-toxin producing Escherichia coli (STEC) triggers the disease, and atypical HUS (aHUS) (5–10% of pediatric cases and a majority of adults HUS) [2]. aHUS is defined as a HUS without coexisting disease. The diagnosis requires the exclusion of inborn errors of cobalamin absorption and metabolism, von Willebrand factor-cleaving protease (ADAMTS 13) deficiency, and Streptococcus pneumonia-associated HUS, in which Thomsen-Friedenreich antigen is implicated [3]. aHUS has a worse prognosis than typical HUS with a higher mortality rate, end-stage renal disease (ESRD), and recurrence. In 56% of cases, onset of the disease occurs before 2 years of age [4]. In French and Italian cohorts, the mortality rate for children during the acute phase was 4.5% (7.8% mortality rate in children at the end of follow-up) and 11.4%, respectively, with 22.3% of survivors developing ESRD after the first episode and 43% of children with a relapse in the French cohort [4]. After 5 years of follow-up, ESRD affected 36% of patients with childhood-onset [4]. Extrarenal manifestations occurred most frequently in the central nervous system (16%). Neurological lesions were related either to reversible posterior leukoencephalopathy syndrome or to microangiopathy [4]. Currently, aHUS could be due to abnormalities of either the alternative complement pathway (64.7%) or the complement-independent pathway (7.9%) [4]. Alternative complement pathway disorders include anti-complement factor H (CFH) antibodies preventing the binding of CFH to C3b on the cell surface, accounting for 11% of aHUS in children, or mutations in genes implicated in the alternative complement pathway. CFH mutations were the most frequent genetic abnormalities (21.3%) found in children and carried the worst prognosis [4]. Mutations of CD46 encoding for the membrane cofactor protein (MCP) [4] and mutations of complement factor I, C3, complement factor B, and thrombomodulin have been also described [5]. A normal C3 level does not exclude a complement mutation [3]. In children less than 2 years old, mutations of diacylglycerol kinase epsilon (DGKE) cause aHUS by upregulation of prothrombotic factors and platelet activation and are very frequent (7.9% of aHUS and 27% of children less than 2 years old with aHUS) [3], [6], [7], [8]. In 30% of cases, no mutations are found. Absence of a family history does not preclude a genetic transmission [2]. In children, once shiga-toxin, S. pneumonia, and cobalamin C defect are ruled out and the complement assay is carried out, the diagnosis of aHUS can be made even if no mutation is identified [3]. Since 2009, anti-C5 monoclonal antibody (eculizumab) appears to be increasingly used to treat aHUS. However, to our knowledge, there are currently no guidelines on the dosage, frequency, and duration of treatment, especially for neonates.
We report herein on a neonate with aHUS, who was successfully treated with eculizumab.
Section snippets
Case report
At 14 days of life this previously healthy Caucasian newborn presented non-bloody diarrhea with vomiting but no fever. A diagnosis of acute gastroenteritis was retained and she did not receive any antibiotics. The mother had had loose stools a few days before, which spontaneously resolved. The baby was born after an unremarkable pregnancy, without risk of infection and with good neonatal adaptation. The family history was disease-free and the parents were not consanguineous. She was breastfeed.
Discussion
aHUS is a rare disease, especially in the neonatal period, related to mutations in genes encoding for proteins of the alternative pathway of the complement system with overactivation, for which eculizumab offers promising therapeutic perspectives [3], [9]. Bacteriological evidence of infection with E. coli is made in only 66% of patients with post-diarrheal HUS [1]. However, infectious gastrointestinal disease appears to trigger the onset of the disease in 39% of aHUS cases [4]. In our patient,
Conclusion
Although no mutation of the alternative complement pathway or DGKE mutations were found, we report the case of a newborn with a neurological presentation of aHUS successfully treated with eculizumab every 3 weeks with complete recovery of neurological symptoms and renal function at 24 months of follow-up.
Author contribution
K. Anastaze Stelle participated in patient care, drafted the initial manuscript, and accepted the final manuscript as submitted.
E. Gonzalez participated in patient care, helped draft the manuscript, and corrected/approved the final manuscript as submitted.
A. Wilhelm-Bals participated in patient treatment and corrected/approved the final manuscript as submitted.
P-R. Michelet participated in patient treatment and approved the final manuscript as submitted.
C.M. Korff participated in patient care
Disclosure of interest
The authors declare that they have no competing interest.
Funding source: no external funding was secured for this study.
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