Elsevier

Archives de Pédiatrie

Volume 23, Issue 3, March 2016, Pages 283-286
Archives de Pédiatrie

Clinical case
Successful 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

https://doi.org/10.1016/j.arcped.2015.11.020Get rights and content

Summary

Hemolytic uremic syndrome (HUS) is rare in neonates. We report the case of atypical HUS (aHUS) revealed by neonatal seizures. This 18-day-old baby presented with repeated clonus of the left arm and eye deviation. Four days earlier, she had suffered from gastroenteritis (non-bloody diarrhea and vomiting without fever). Her work-up revealed hemolytic anemia (120 g/L), thrombocytopenia (78 g/L), and impaired renal function (serum creatinine = 102 μmol/L) compatible with the diagnosis of HUS. Levels of C3 and C4 in the serum were normal. Shiga-toxin in the stools as well as the IgM and IgG against Escherichia coli O157 were negative. ADAMTS 13 deficiency, inborn error of the cobalamin pathway, deficiency in the H and I protein, and factor H antibodies were excluded and we concluded in aHUS. Genetic screening of the alternative complement pathway was normal. Cerebral magnetic resonance imaging performed after 24 h and 1 week showed restricted diffusion areas with periventricular white matter ischemic-hemorrhagic lesions. Extensive infectious work-up was negative. Upon admission the baby received antiepileptic drugs and 2 days later C5 monoclonal antibody (eculizumab) and two transfusions of packed erythrocytes because the hemoglobin value had dropped to 55 g/L. The platelet value was minimal at 30 g/L. Renal function normalized in 48 h without dialysis and neurological examination was normal in 1 week. She was discharged from the hospital at day 10 with eculizumab perfusions (300 mg) planned every 3 weeks. After 24 months, she was relapse-free and seizure-free, with a normal neurological examination.

Résumé

Le syndrome hémolytique et urémique (SHU) est rare en période néonatale. Nous rapportons le cas d’un nouveau-né de 18 jours ayant présenté un SHU atypique (aSHU) diagnostiqué dans un contexte de convulsions néonatales. Ce nouveau-né de 18 jours, en bonne santé, a été hospitalisé à la suite d’épisodes répétés de clonies du bras gauche associées à une déviation du regard de l’œil droit vers la gauche. Quatre jours avant, elle avait présenté une gastro-entérite avec diarrhée non sanglante et vomissements. Le bilan a mis en évidence une anémie hémolytique, une thrombopénie et une insuffisance rénale compatibles avec un SHU. Les taux de compléments C3 et C4 étaient normaux. La recherche de shiga-toxines s’est avérée négative, excluant le diagnostic d’un SHU typique. L’absence de déficit en ADAMTS 13 et d’une anomalie du métabolisme des cobalamines a fait poser le diagnostic de SHU atypique. Il n’y avait pas de déficit des protéines H et I ni d’anticorps anti-facteur H. L’analyse génétique de la voie alterne du complément s’est avérée normale. L’imagerie par résonance magnétique (IRM) cérébrale après 24 h a montré une restriction de la diffusion avec de multiples lésions ischémo-hémorragiques de la substance blanche périventriculaire. Dès son arrivée, l’enfant avait reçu un traitement par phénobarbital et au bout de 48 h un traitement par anticorps monoclonal anti-complément C5 (eculizumab) a été instauré. La fonction rénale s’est normalisée en 48 h et l’examen neurologique en 1 semaine. L’enfant a quitté l’hôpital après 10 jours sous eculizumab, administré par la suite toutes les 3 semaines.

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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