Publications by authors named "Pauline Krug"

18 Publications

  • Page 1 of 1

Long-term kidney and liver outcome in 50 children with autosomal recessive polycystic kidney disease.

Pediatr Nephrol 2020 Nov 9. Epub 2020 Nov 9.

Department of Gastroenterology-Hepatology-Nutrition, Reference Center for Biliary Atresia and Cholestatic Genetic Diseases, Hôpital Universitaire Necker-Enfants Malades, AP-HP, Paris, France.

Background: Autosomal recessive polycystic kidney disease (ARPKD) is a rare ciliopathy characterized by congenital hepatic fibrosis and cystic kidney disease. Lack of data about long-term follow-up makes it difficult to discuss timing and type of organ transplantation. Our objectives were to evaluate long-term evolution and indications for transplantation, from birth to adulthood.

Methods: Neonatal survivors and patients diagnosed in postnatal period with ARPKD between 1985 January and 2017 December from 3 French pediatric centers were retrospectively enrolled in the study.

Results: Fifty patients with mean follow-up 12.5 ± 1 years were enrolled. ARPKD was diagnosed before birth in 24%, and at mean age 1.8 years in others. Thirty-three patients were < 1 year of age at first symptoms, which were mostly kidney-related. These most often presented high blood pressure during follow-up. Portal hypertension was diagnosed in 29 patients (58%), 4 of them with bleeding from esophageal varices. Eight patients presented cholangitis (> 3 episodes in three children). Liver function was normal in all patients. Nine children received a kidney transplant without liver complications. A 20-year-old patient received a combined liver-kidney transplant (CLKT) for recurrent cholangitis, and a 15-year-old boy an isolated liver transplant for uncontrollable variceal bleeding despite portosystemic shunt.

Conclusions: Long-term outcome in patients with ARPKD is heterogeneous, and in this cohort did not depend on age at diagnosis except for blood pressure. Few patients required liver transplantation. Indications for liver or combined liver-kidney transplantation were limited to recurrent cholangitis or uncontrollable portal hypertension. Liver complications after kidney transplantation were not significant.
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http://dx.doi.org/10.1007/s00467-020-04808-9DOI Listing
November 2020

Donor-targeted serotherapy as a rescue therapy for steroid-resistant acute GVHD after HLA-mismatched kidney transplantation.

Am J Transplant 2020 08 10;20(8):2243-2253. Epub 2020 Mar 10.

Paris University, Paris, France.

Acute graft-versus-host disease (GVHD) is a rare but frequently lethal complication after solid organ transplantation. GVHD occurs in unduly immunocompromised hosts but requires the escalation of immunosuppression, which does not discriminate between host and donor cells. In contrast, donor-targeted therapy would ideally mitigate graft-versus-host reactivity while sparing recipient immune functions. We report two children with end-stage renal disease and severe primary immune deficiency (Schimke syndrome) who developed severe steroid-resistant acute GVHD along with full and sustained donor T cell chimerism after isolated kidney transplantation. Facing a therapeutic dead end, we used a novel strategy based on the adoptive transfer of anti-HLA donor-specific antibodies (DSAs) through the transfusion of highly selected plasma. After approval by the appropriate regulatory authority, an urgent nationwide search was launched among more than 3800 registered blood donors with known anti-HLA sensitization. Adoptively transferred DSAs bound to and selectively depleted circulating donor T cells. The administration of DSA-rich plasma was well tolerated and notably did not induce antibody-mediated rejection of the renal allografts. Acute GVHD symptoms promptly resolved in one child. This report provides a proof of concept for a highly targeted novel therapeutic approach for solid organ transplantation-associated GVHD.
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http://dx.doi.org/10.1111/ajt.15827DOI Listing
August 2020

Long-term outcome of methylmalonic aciduria after kidney, liver, or combined liver-kidney transplantation: The French experience.

J Inherit Metab Dis 2020 03 11;43(2):234-243. Epub 2020 Feb 11.

Reference Center of Inherited Metabolic Diseases, Hôpital Universitaire Necker-Enfants Malades, APHP, Imagine Institute, Filière G2M, MetabERN, INEM, University Paris Descartes, Paris, France.

Organ transplantation is discussed in methylmalonic aciduria (MMA) for renal failure, and poor quality of life and neurological outcome. We retrospectively evaluated 23 French MMA patients after kidney (KT), liver-kidney (LKT), and liver transplantation (LT). Two patients died, one after LKT, one of hepatoblastoma after KT. One graft was lost early after KT. Of 18 evaluable patients, 12 previously on dialysis, 8 underwent KT (mean 12.5 years), 8 LKT (mean 7 years), and 2 LT (7 and 2.5 years). At a median follow-up of 7.3 (KT), 2.3 (LKT), and 1.0 years (LT), no metabolic decompensation occurred except in 1 KT. Plasma and urine MMA levels dramatically decreased, more after LKT. Protein intake was increased more significantly after LKT than KT. Enteral nutrition was stopped in 7/8 LKT, 1/8 KT. Early complications were frequent after LKT. Neurological disorders occurred in four LKT, reversible in one. Five years after KT, four patients had renal failure. The metabolic outcomes were much better after LKT than KT. LKT in MMA is difficult but improves the quality of life. KT will be rarely indicated. We need more long-term data to indicate early LT, in the hope to delay renal failure and prevent neurodevelopmental complications.
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http://dx.doi.org/10.1002/jimd.12174DOI Listing
March 2020

Influenza vaccination among children with idiopathic nephrotic syndrome: an investigation of practices.

BMC Nephrol 2019 02 25;20(1):65. Epub 2019 Feb 25.

Néphrologie Pédiatrique, Centre de Référence du Syndrome Néphrotique Idiopathique de l'enfant et l'adulte, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Université Paris Descartes, Sorbonne paris Cité, 149 rue de Sèvres, 75015, Paris, France.

Background: Annual influenza vaccination is recommended for all children with idiopathic nephrotic syndrome (INS) in France. Consequently, the Social Security automatically sends prescriptions to all patients suffering from a chronic disease. The aim of this study was to evaluate the follow-up to these recommendations.

Methods: We conducted a monocentric retrospective investigation of practices. We included all children with steroid-sensitive INS in remission who attended our clinics from January 1st 2015 to January 1st 2017, resided in France and had a valid phone number. Data were collected from May 2017 to June 2017 through a phone interview and review of clinical charts.

Results: 75 patients met the inclusion criteria. The parents of 57 children could be reached by phone and agreed to participate to the survey. 35/57 (61.4%) declared having received a prescription during the 2016-2017 campaign. Only 14 children (24.6%) were vaccinated. 17/43 (39.5%) parents of unvaccinated children had concerns about the safety of the vaccine, 16/43 (37.2%) were not aware of the recommendations, 5/43 (11.6%) had been recommended by their physician not to vaccinate their child, 3/43 (7%) forgot to have them vaccinated and 2/43 (4.6%) reported no reason. 13/43 (30%) unvaccinated children presented a relapse during the flu season - 2/13 during an influenza-like illness - whereas 1/14 (7%) immunized children presented a relapse during the six months of post-vaccination follow-up. Relapse rates were not increased in vaccinated children compared to unvaccinated children (p = 0.15), nor in the 6 months following vaccination compared to the 6 months prior (1/14 vs 5/14, p = 0.20).

Conclusions: 1) < 2/3 patients were properly prescribed the recommended yearly influenza vaccination at our center 2) only 1/4 were vaccinated and most of their parents were misinformed. Physicians must be aware of this and should make every effort to better inform their patients on the risks of flu illness and the benefits and safety of the vaccination.
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http://dx.doi.org/10.1186/s12882-019-1240-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388483PMC
February 2019

Pharmacokinetics of Enoxaparin After Renal Transplantation in Pediatric Patients.

J Clin Pharmacol 2018 12 26;58(12):1597-1603. Epub 2018 Sep 26.

Néphrologie pédiatrique, Centre de référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Institut Imagine, Université Paris Descartes, Hôpital Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.

Enoxaparin is commonly used in the prevention of renal allograft vascular thrombosis but off-label in children, and no consensus exists regarding the optimal dosing and dose adjustment. In this retrospective study, 444 anti-Xa levels were obtained from 30 pediatric renal transplant recipients in order to investigate enoxaparin population pharmacokinetics. The main results were (1) 25% of children achieved the target anti-Xa activity 36 hours after initiation of treatment, (2) anti-Xa time courses were best described by a 1-compartment open model with first-order absorption, (3) body weight but not renal function was the sole covariate influencing clearance and volume of distribution, and (4) large between-subject and between-occasion variabilities in anti-Xa activity were observed. However, creatinine-based estimated glomerular filtration rate in the first post-renal transplantation hours may not reliably reflect the actual renal function of the children. Based on the final population model, a Bayesian-based program was developed in order to estimate the individual pharmacokinetic parameters on a single anti-Xa measurement, allowing determination of the next enoxaparin dose that will quickly achieve an appropriate anti-Xa activity (targeting 0.3-0.5 IU/mL) and anticoagulation. Finally, these results should help standardize practices that remain to date largely heterogeneous in pediatric intensive care units.
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http://dx.doi.org/10.1002/jcph.1289DOI Listing
December 2018

Clinical and Genetic Spectrum of Bartter Syndrome Type 3.

J Am Soc Nephrol 2017 Aug 5;28(8):2540-2552. Epub 2017 Apr 5.

Department of Genetics and.

Bartter syndrome type 3 is a clinically heterogeneous hereditary salt-losing tubulopathy caused by mutations of the chloride voltage-gated channel Kb gene (), which encodes the ClC-Kb chloride channel involved in NaCl reabsorption in the renal tubule. To study phenotype/genotype correlations, we performed genetic analyses by direct sequencing and multiplex ligation-dependent probe amplification and retrospectively analyzed medical charts for 115 patients with mutations. Functional analyses were performed in oocytes for eight missense and two nonsense mutations. We detected 60 mutations, including 27 previously unreported mutations. Among patients, 29.5% had a phenotype of ante/neonatal Bartter syndrome (polyhydramnios or diagnosis in the first month of life), 44.5% had classic Bartter syndrome (diagnosis during childhood, hypercalciuria, and/or polyuria), and 26.0% had Gitelman-like syndrome (fortuitous discovery of hypokalemia with hypomagnesemia and/or hypocalciuria in childhood or adulthood). Nine of the ten mutations expressed decreased or abolished chloride conductance. Severe (large deletions, frameshift, nonsense, and essential splicing) and missense mutations resulting in poor residual conductance were associated with younger age at diagnosis. Electrolyte supplements and indomethacin were used frequently to induce catch-up growth, with few adverse effects. After a median follow-up of 8 (range, 1-41) years in 77 patients, chronic renal failure was detected in 19 patients (25%): one required hemodialysis and four underwent renal transplant. In summary, we report a genotype/phenotype correlation for Bartter syndrome type 3: complete loss-of-function mutations associated with younger age at diagnosis, and CKD was observed in all phenotypes.
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http://dx.doi.org/10.1681/ASN.2016101057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533235PMC
August 2017

Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis.

Am J Hum Genet 2017 02 12;100(2):323-333. Epub 2017 Jan 12.

INSERM, UMR-1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.

Nephronophthisis (NPH), an autosomal-recessive tubulointerstitial nephritis, is the most common cause of hereditary end-stage renal disease in the first three decades of life. Since most NPH gene products (NPHP) function at the primary cilium, NPH is classified as a ciliopathy. We identified mutations in a candidate gene in eight individuals from five families presenting late-onset NPH with massive renal fibrosis. This gene encodes MAPKBP1, a poorly characterized scaffolding protein for JNK signaling. Immunofluorescence analyses showed that MAPKBP1 is not present at the primary cilium and that fibroblasts from affected individuals did not display ciliogenesis defects, indicating that MAPKBP1 may represent a new family of NPHP not involved in cilia-associated functions. Instead, MAPKBP1 is recruited to mitotic spindle poles (MSPs) during the early phases of mitosis where it colocalizes with its paralog WDR62, which plays a key role at MSP. Detected mutations compromise recruitment of MAPKBP1 to the MSP and/or its interaction with JNK2 or WDR62. Additionally, we show increased DNA damage response signaling in fibroblasts from affected individuals and upon knockdown of Mapkbp1 in murine cell lines, a phenotype previously associated with NPH. In conclusion, we identified mutations in MAPKBP1 as a genetic cause of juvenile or late-onset and cilia-independent NPH.
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http://dx.doi.org/10.1016/j.ajhg.2016.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294754PMC
February 2017

Renal involvement in lysinuric protein intolerance: contribution of pathology to assessment of heterogeneity of renal lesions.

Hum Pathol 2017 Apr 11;62:160-169. Epub 2017 Jan 11.

Pathology Department Hôpital Necker-Enfants Malades, Assistance Publique, Hôpitaux de Paris, Université Sorbonne Paris Cité, 75015, Paris, France. Electronic address:

Lysinuric protein intolerance (LPI) is a rare autosomal recessive disease caused by mutations in the SLC7A7 gene encoding the light subunit of a cationic amino acid transporter. Symptoms mimic primary urea cycle defects but dysimmune symptoms are also described. Renal involvement in LPI was first described in the 1980s. In 2007, it appeared that it could concern as much as 75% of LPI patients and could lead to end-stage renal disease. The most common feature is proximal tubular dysfunction and nephrocalcinosis but glomerular lesions are also reported. However, very little is known regarding histological lesions associated with LPI. We gathered every kidney biopsy of LPI-proven patients in our highly specialized pediatric and adult institution. Clinical, biological, and histological information was analyzed. Five LPI patients underwent kidney biopsy in our institution between 1986 and 2015. Clinically, 4/5 presented with proximal tubular dysfunction and 3/5 with nephrotic range proteinuria. Histology showed unspecific tubulointerstitial lesions and nephrocalcinosis in 3/5 biopsies and marked peritubular capillaritis in one child. Glomerular lesions were heterogeneous: lupus-like-full house membranoproliferative glomerulonephritis (MPGN) in one child evolved towards monotypic IgG1κ MPGN sensitive to immunomodulators. One patient presented with glomerular non-AA non-AL amyloidosis. Renal biopsy is particularly relevant in LPI presenting with glomerular symptoms for which variable histological lesions can be responsible, implying specific treatment and follow-up.
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http://dx.doi.org/10.1016/j.humpath.2016.12.021DOI Listing
April 2017

Update on Lysinuric Protein Intolerance, a Multi-faceted Disease Retrospective cohort analysis from birth to adulthood.

Orphanet J Rare Dis 2017 01 5;12(1). Epub 2017 Jan 5.

Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.

Background: Lysinuric protein intolerance (LPI) is a rare metabolic disease resulting from recessive-inherited mutations in the SLC7A7 gene encoding the cationic amino-acids transporter subunit yLAT1. The disease is characterised by protein-rich food intolerance with secondary urea cycle disorder, but symptoms are heterogeneous ranging from infiltrative lung disease, kidney failure to auto-immune complications. This retrospective study of all cases treated at Necker Hospital (Paris, France) since 1977 describes LPI in both children and adults in order to improve therapeutic management.

Results: Sixteen patients diagnosed with LPI (12 males, 4 females, from 9 families) were followed for a mean of 11.4 years (min-max: 0.4-37.0 years). Presenting signs were failure to thrive (n = 9), gastrointestinal disorders (n = 2), cytopenia (n = 6), hyperammonemia (n = 10) with acute encephalopathy (n = 4) or developmental disability (n = 3), and proteinuria (n = 1). During follow-up, 5 patients presented with acute hyperammonemia, and 8 presented with developmental disability. Kidney disease was observed in all patients: tubulopathy (11/11), proteinuria (4/16) and kidney failure (7/16), which was more common in older patients (mean age of onset 17.7 years, standard deviation 5.33 years), with heterogeneous patterns including a lupus nephritis. We noticed a case of myocardial infarction in a 34-year-old adult. Failure to thrive and signs of haemophagocytic-lymphohistiocytosis were almost constant. Recurrent acute pancreatitis occurred in 2 patients. Ten patients developed an early lung disease. Six died at the mean age of 4 years from pulmonary alveolar proteinosis. This pulmonary involvement was significantly associated with death. Age-adjusted plasma lysine concentrations at diagnosis showed a trend toward increased values in patients with a severe disease course and premature death (Wilcoxon p = 0.08; logrank, p = 0.17). Age at diagnosis was a borderline predictor of overall survival (logrank, p = 0.16).

Conclusions: As expected, early pulmonary involvement with alveolar proteinosis is frequent and severe, being associated with an increased risk of death. Kidney disease frequently occurs in older patients. Cardiovascular and pancreatic involvement has expanded the scope of complications. A borderline association between increased levels of plasma lysine and poorer outome is suggested. Greater efforts at prevention are warranted to optimise the long-term management in these patients.
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http://dx.doi.org/10.1186/s13023-016-0550-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217205PMC
January 2017

Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization.

Nat Commun 2015 Oct 21;6:8666. Epub 2015 Oct 21.

Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, 75015 Paris, France.

Ciliopathies are a large group of clinically and genetically heterogeneous disorders caused by defects in primary cilia. Here we identified mutations in TRAF3IP1 (TNF Receptor-Associated Factor Interacting Protein 1) in eight patients from five families with nephronophthisis (NPH) and retinal degeneration, two of the most common manifestations of ciliopathies. TRAF3IP1 encodes IFT54, a subunit of the IFT-B complex required for ciliogenesis. The identified mutations result in mild ciliary defects in patients but also reveal an unexpected role of IFT54 as a negative regulator of microtubule stability via MAP4 (microtubule-associated protein 4). Microtubule defects are associated with altered epithelialization/polarity in renal cells and with pronephric cysts and microphthalmia in zebrafish embryos. Our findings highlight the regulation of cytoplasmic microtubule dynamics as a role of the IFT54 protein beyond the cilium, contributing to the development of NPH-related ciliopathies.
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http://dx.doi.org/10.1038/ncomms9666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617596PMC
October 2015

Mutations of CEP83 cause infantile nephronophthisis and intellectual disability.

Am J Hum Genet 2014 Jun 29;94(6):905-14. Epub 2014 May 29.

INSERM, UMR 1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France. Electronic address:

Ciliopathies are a group of hereditary disorders associated with defects in cilia structure and function. The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis. The molecular composition of DAPs was recently elucidated and mutations in two genes encoding DAPs components (CEP164/NPHP15, SCLT1) have been associated with human ciliopathies, namely nephronophthisis and orofaciodigital syndrome. To identify additional DAP components defective in ciliopathies, we independently performed targeted exon sequencing of 1,221 genes associated with cilia and 5 known DAP protein-encoding genes in 1,255 individuals with a nephronophthisis-related ciliopathy. We thereby detected biallelic mutations in a key component of DAP-encoding gene, CEP83, in seven families. All affected individuals had early-onset nephronophthisis and four out of eight displayed learning disability and/or hydrocephalus. Fibroblasts and tubular renal cells from affected individuals showed an altered DAP composition and ciliary defects. In summary, we have identified mutations in CEP83, another DAP-component-encoding gene, as a cause of infantile nephronophthisis associated with central nervous system abnormalities in half of the individuals.
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http://dx.doi.org/10.1016/j.ajhg.2014.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121475PMC
June 2014

Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans.

Am J Hum Genet 2013 Nov 17;93(5):915-25. Epub 2013 Oct 17.

Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease. To identify additional IFT-B components defective in ciliopathies, we independently performed different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes in 1,467 individuals with a nephronophthisis-related ciliopathy or whole-exome resequencing in 63 individuals with ATD. We thereby detected biallelic mutations in the IFT-B-encoding gene IFT172 in 12 families. All affected individuals displayed abnormalities of the thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts from affected individuals showed disturbed ciliary composition, suggesting alteration of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated the human phenotype and demonstrated a genetic interaction between ift172 and ift80. In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS. Our findings link the group of skeletal ciliopathies to an additional IFT-B component, IFT172, similar to what has been shown for IFT-A.
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http://dx.doi.org/10.1016/j.ajhg.2013.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824130PMC
November 2013

Brain magnetic resonance imaging pattern and outcome in children with haemolytic-uraemic syndrome and neurological impairment treated with eculizumab.

Dev Med Child Neurol 2013 Aug 10;55(8):758-65. Epub 2013 May 10.

Pediatric Neurology Department, Necker-Enfants Malades Hospital, APHP, Paris, France.

Aim: The aim of this study was to describe the magnetic resonance imaging (MRI) findings and the neurological and neuropsychological outcomes in paediatric, diarrhoea-associated haemolytic-uraemic syndrome (D+HUS) with central nervous system impairment treated with eculizumab, a monoclonal antibody.

Method: The 14-month single-centre prospective study included seven children (three males, four females; age range 16 mo-7 y 8 mo; median age 3 y 7 mo) with typical D+HUS and acute neurological impairment. In the acute phase of the disease, neurological assessment and brain magnetic resonance imaging (MRI), including measurement of the apparent diffusion coefficient (ADC), were performed, and neuropsychological evaluation and brain MRI were also carried out 6 months after disease onset.

Results: In the acute phase, basal ganglia and white matter abnormalities with ADC restriction were a common and reversible MRI finding. In all the surviving patients (5/7), follow-up MRI after 6 months was normal, indicating reversible lesions. Clinical and neuropsychological evaluations after 6 months were also normal.

Interpretation: This specific brain MRI pattern consisting of an ADC decrease in basal ganglia and white matter without major T2/fluid-attenuated inversion recovery (FLAIR) injury may be a key finding in the acute phase of the disease in favour of a vasculitis hypothesis. These reversible lesions were associated with a good neurological outcome. These results call for further evaluation of the potential role of eculizumab in the choice of treatment for severe D+HUS, particularly in the case of early neurological signs.
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http://dx.doi.org/10.1111/dmcn.12161DOI Listing
August 2013

Nephrotic syndrome in Kawasaki disease: a report of three cases.

Pediatr Nephrol 2012 Sep 24;27(9):1547-50. Epub 2012 Apr 24.

Pediatric Nephrology, Necker Hospital, Paris, France.

Background: Renal manifestations are rare in Kawasaki disease (KD). Acute renal failure with tubular necrosis, tubulointerstitial nephritis and renovascular hypertension have been reported in KD, but only one case of a patient with KD associated with nephrotic syndrome (NS) has been reported to date, with the patient improving on steroid therapy but dying from coronary aneurysm.

Methods: We report the cases of three children, aged 4, 4.5 and 8 years, respectively, who presented with typical KD symptoms (high fever, diffuse maculopapular rash, conjunctivitis, peripheral oedema, cervical adenopathies and high C reactive protein levels) and developed NS.

Results: Patient 1 had a haemodynamic shock due to cardiac dysfunction and transient renal failure. Ten days later, he developed a NS which spontaneously disappeared 1 week later. Patient 2 had a NS on admission with normal plasma creatinine and no haematuria. Proteinuria disappeared within 10 days. Patient 3 developed NS 5 days after onset with a moderate increase in plasma creatinine. Proteinuria disappeared within 2 weeks. All three patients were treated with intravenous immunoglobulins, antibiotic therapy and aspirin, but none of them received steroid therapy. To date, all three patients have maintained long-term remission.

Conclusions: In conclusion, proteinuria with NS may develop during the acute phase of KD with persistent remission occurring without steroid therapy.
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http://dx.doi.org/10.1007/s00467-012-2172-2DOI Listing
September 2012

Mutation screening of the EYA1, SIX1, and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations.

Hum Mutat 2011 Feb;32(2):183-90

AP-HP, Service de Néphrologie Pédiatrique, Hôpital Necker-Enfants Malades, Paris, France.

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial, ear, and renal anomalies. Over 80 mutations in EYA1 have been reported in BOR. Mutations in SIX1, a DNA binding protein that associates with EYA1, have been reported less frequently. One group has recently described four missense mutations in SIX5 in five unrelated patients with BOR. Here, we report a screening of these three genes in a cohort of 140 patients from 124 families with BOR. We identified 36 EYA1 mutations in 42 unrelated patients, 2 mutations, and 1 change of unknown significance in SIX1 in 3 unrelated patients, but no mutation in SIX5. We did not find correlation between genotype and phenotype, and observed a high phenotypic variability between and within BOR families. We show the difficulty in establishing a molecular diagnosis strategy in BOR syndrome: the screening focusing on patients with typical BOR would detect a mutation rate of 76%, but would also miss mutations in 9% of patients with atypical BOR. We detected a deletion removing three EYA1 exons in a patient who was previously reported to carry the SIX5 Thr552Met mutation. This led us to reconsider the role of SIX5 in the development of BOR.
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http://dx.doi.org/10.1002/humu.21402DOI Listing
February 2011

Spinal imaging contributes to the diagnosis of Marfan syndrome.

Joint Bone Spine 2010 Oct 8;77(5):445-50. Epub 2010 May 8.

Service de pédiatrie, hôpital Ambroise-Paré, AP-HP, 9, avenue Charles-de-Gaulle, 92100 Boulogne, France.

Unlabelled: The diagnosis of Marfan syndrome (MFS) is defined by a combination of major and minor criteria, related to the different systems involved, according to the Ghent nosology of the spine. Spinal imaging can detect both skeletal (including scoliosis and spondylolisthesis) and neurological involvement (i.e. dural ectasia). The aim of the present study was to assess the interest of screening the rachis by conventional radiography CR and complementary imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) in patients suspected of MFS, and to modelise the most relevant imaging procedure to diagnose MFS.

Methods: Evaluation of the sensitivity and specificity of CR of the lumbosacral spine versus sectional imaging for the detection of dural ectasia (DE) in a subgroup of 92 patients suspected of MFS. Retrospective analysis of the contribution of CR to the diagnosis of MFS in 1992 patients referred to our clinic.

Results: DE was detected by CR in 12 of the 92 patients (13%) and was always confirmed by CT or MRI. Complementary imaging alone detected 33 DE (35.9%). All patients with DE detected by CR were diagnosed with MFS. Among the 1992 patients, 591 were confirmed MFS; 117 patients had DE detected by CR (19,8%) while 12 (2,0%) were detected by complementary imaging. In MFS patients, 98 (16.6%) had significant scoliosis and 14 (2.4%) had spondylolisthesis. The positive predictive value of DE detected by CR for the diagnosis of MFS was 92.9% (95% IC: 86.8-96.4), and the negative predictive value was 74.6% (95% IC: 72.6-76.5). We conclude that spinal imaging is useful for the diagnosis of MFS.
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http://dx.doi.org/10.1016/j.jbspin.2010.02.031DOI Listing
October 2010

Opsoclonus-myoclonus in children associated or not with neuroblastoma.

Eur J Paediatr Neurol 2010 Sep 27;14(5):400-9. Epub 2010 Jan 27.

Pediatric Oncology, Institut Curie, 26 rue d'Ulm, 75248 Paris, France.

Objective: To compare the clinical data at diagnosis, treatment and neurological outcome in 34 children with opsoclonus-myoclonus syndrome (OMS) associated with a detected neuroblastoma or not.

Study Design: This is a multicentric retrospective study of 34 children presenting with OMS from four pediatric centers diagnosed between 1988 and 2008.

Results: Twenty-two patients had OMS associated with a neuroblastoma. These patients all had neuroblastomas with favourable prognostic features; all underwent surgery, six received chemotherapy. Twelve children had OMS without a detected neuroblastoma. For OMS, the main treatment in all children was corticotherapy (n=33), but immunoglobulins (n=13), cyclophosphamide (n=4) and rituximab (n=4) were also given. In the 27 OMS patients with or without neuroblastoma whose follow up was greater than two years, the neurological outcome was evaluated: 59.3% had neurological sequelae, including motor, praxic and/or language sequelae (n=9), persistent ataxia (n=6) and moderate motor deficit (n=3). No significant difference in neurological outcome was noted between the two patient groups.

Conclusion: Our retrospective study provides further evidence that OMS with or without a detected neuroblastoma is the same disease, whose major challenges are the neurological sequelae. An international collaboration is required to improve the knowledge about OMS, the treatment and the outcome in this rare disorder.
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http://dx.doi.org/10.1016/j.ejpn.2009.12.005DOI Listing
September 2010