Identification of the first homozygous intragenic deletion in the YY1AP1 gene in a consanguineous family: New insights into the phenotypic variability associated with Grange syndrome.

Grange syndrome (GRNG-MIM#135580) is a rare recessive disorder associating variable features including diffuse vascular stenosis, brachysyndactyly, osteopenia with increased bone fragility, cardiac malformations, and variable developmental delay. Since its first description in 1998, only 15 individuals from 10 families have been reported, carrying homozygous or compound heterozygous frameshift or nonsense variants in YY1AP1. In a patient with cutaneous and bone syndactyly and a hemorrhagic stroke at the age of 16 months, consistent with a clinical diagnosis of GRNG, we performed exome sequencing after negative array-CGH and congenital limb malformation panel results. Copy number variant analysis from exome data identified a homozygous intragenic out-of-frame deletion of 1.84 kb encompassing exons seven and eight of YY1AP1, confirming a molecular diagnosis of GRNG. Genetic counseling led to the identification of additional family members compatible with GRNG. Here, we provide new insights into the phenotypic variability associated with GRNG and highlight the utility of the detection of small copy number variants to identify the molecular causes of heterogeneous malformative genetic disorders.

Age-specific characteristics of neutrophilic dermatoses and neutrophilic diseases in children.

BACKGROUND: Our suggested 'modern' concepts of 'neutrophilic dermatoses' (ND) and 'neutrophilic disease' were based on observations in adult patients and have not been studied in paediatric patients. Only a minority of ND occurs in children, and little is known about age-specific characteristics. OBJECTIVES: To describe age-specific characteristics of ND in children and to study whether our suggested 'modern' classification of ND may be applied to children. METHODS: We conducted a retrospective multicentre study in a French cohort of 27 paediatric patients diagnosed with pyoderma gangrenosum (PG) or Sweet's syndrome (SS). RESULTS: Demographics and distribution of typical/atypical forms were similar in patients diagnosed with PG and SS. Atypical ND were more frequent in infants (90%), when compared to young children (60%) and adolescents (33%). Neutrophilic disease was observed in 17/27 patients and was most frequent in infants. Neutrophilic disease of the upper respiratory tract, as well as cardiac neutrophilic disease, was only observed in infants, whereas other locations were similarly found in infants, young children and adolescents. In infants and young children, ND were associated with a large spectrum of general diseases, whereas in adolescents associations were limited to inflammatory bowel disease and Behçet's disease. CONCLUSIONS: Our study describes the concept of ND in paediatric patients and shows that they have some characteristics different from ND occurring in adults. ND occurring in infants can be associated with a large spectrum of general diseases. Occurrence of neutrophilic disease is frequent in children. Thus, ND occurring in young paediatric patients should incite clinicians to schedule complementary explorations in order to search for involvement of other organs and to rule out monogenetic autoinflammatory syndromes.

[Significance of the urine strip test in case of stunted growth]. / Intérêt de l'examen des urines à la bandelette en cas de retard de croissance.

Observation of stunted growth in children usually leads the general practitioner to refer the patient to endocrinologists or gastroenterologists. In most cases, after a complementary check-up, the diagnosis is made and treatment is initiated. However, certain cases remain undiagnosed, particularly renal etiologies, such as proximal tubulopathy. The urine strip test at the initial check-up would be an easy and inexpensive test to avoid delayed diagnosis. The aim of the present paper is to increase general physicians' and pediatricians' awareness of the significance of questioning the parents and using the urine strip test for any child presenting stunted growth. We report a patient case of a 20-month-old child admitted to the emergency department for severe dehydration. He had displayed stunted growth since the age of 5 months and showed a negative etiologic check-up at 9 months of age. Clinical examination at admission confirmed stunted growth with loss of 2 standard deviations and signs of dehydration with persistent diuresis. Skin paleness, ash-blond hair, and signs of rickets were also observed and the urine strip test showed positive pads for glycosuria and proteinuria. Polyuria and polydipsia were also revealed following parents' questioning, suggesting proximal tubulopathy (Fanconi syndrome). Association of stunted growth, rickets, polyuria and polydipsia, glycosuria (without ketonuria and normal glycemia), and proteinuria suggest nephropathic cystinosis. Ophthalmic examination showed cystine deposits in the cornea. The semiotic diagnosis of nephropathic cystinosis was confirmed by leukocyte cystine concentrations and genetic investigations. This case report clearly illustrates the significance of the urine strip test to easily and quickly concentrate the diagnosis of stunted growth on a renal etiology (glycosuria, proteinuria), especially on proximal tubulopathy for which the most frequent cause is nephropathic cystinosis. Specificity of nephropathic cystinosis treatment is that the age of treatment initiation is crucial and determinant for the prognosis of the disease and the onset of final stage renal failure. Therefore, the urine strip test should be included in the systematic check-up of stunted growth to identify any renal etiology.

[Lowe syndrome revealed by prenatal diagnosis of congenital cataract with brain abnormalities]. / Syndrome de Lowe révélé par une cataracte congénitale avec anomalies cérébrales de diagnostic anténatal: à propos d'un cas.

Congenital cataract is a rare disease whose incidence is estimated to 0.5% of birth in France. A study of the literature shows that congenital cataract is idiopathic in 50% of cases, hereditary forms representing 25% of cases. Other causes of congenital cataract are represented by viral embryofoetopathies acquired during pregnancy, metabolic disorders and chromosomal aberrations within the scope of malformative syndromes. The authors report the case of a neonatal diagnosis of Lowe syndrome suspected by the discovery of bilateral cataract initially isolated. The morphological exploration was completed by secondary brain abnormalities (periventricular lesions). The etiological prenatal exploration was negative. Lowe syndrome is a rare cause of antenatal cataract, which so far only one case has been reported.

[Is there an outcome difference between posterior urethral valves diagnosed prenatally and postnatally at the time of antenatal screening?]. / Impact de l'âge au diagnostic sur le devenir à long terme des patients opérés de valves de l'urètre postérieur.

PURPOSE: Posterior urethral valves (PUV) diagnosed during childhood have classically been associated with a better outcome than antenatally diagnosed PUV. The aim of our study was to compare long-term outcome of these two patients' groups. MATERIAL AND METHODS: We retrospectively reviewed the medical records of boys with PUV managed between 1990 and 2010. Patient demographics, clinical background, radiographic data (including prenatal ultrasonography data when available), renal and bladder functional outcomes, surgical procedures and urinary tract infections (UTI) were abstracted. Impaired renal function (IRF) was defined as glomerular filtration rate less than 90 mL/min/1.73 m(2) at last follow-up. RESULTS: We identified 69 patients with confirmed PUV. Thirty-eight were diagnosed prenatally (group 1) at 30.5 weeks of gestation and 31 had a delayed diagnosis (group 2) at a median age of 6.31 years. At diagnosis, 20 patients in group 1 had renal insufficiency versus two in group 2 (P<0.05). At the end of mean follow-up of 7.2 ± 0.5 years, in group 1, 26.3% developed IRF versus 6.3% in group 2 (mean follow-up 2.3 years). Mean age at last follow-up was 7.3 years in group 1 versus 8.3 in group 2 (P>0.05). In group 1, 27% had voiding dysfunction versus 30% in group 2 (NS). In group 1, 35% had UTI during follow-up versus 10% (P=0.01). CONCLUSION: During the follow-up, the patients with delayed diagnosis VUP have developed fewer complications related to the initial obstruction than the population who was detected antenatally and managed from the early hours of life. However, the rate of IRF and voiding disorders in our study, associated with the data of the literature, highlights the potential persistence and worsening of these conditions. That is why, whatever the age at diagnosis, VUP patients require a close monitoring.

[Atypical onset of Churg and Strauss syndrome in a child]. / Révélation atypique d'un syndrome de Churg et Strauss chez l'enfant.

We report the case of a 13-year-old boy who had been treated since the age of 6 for moderate asthma. Except asthma, his past medical history was uneventful. The patient was referred for the sudden onset of bilateral leg edemas with peripheral purpuric lesions. Blood tests showed increased blood eosinophilia (9000/mm(3)) with no fever. The antineutrophil cytoplasmic antibodies (ANCA) were negative. The skin biopsy showed extensive ischemic subcutaneous necrosis related to necrotizing vasculitis. The general secondary symptoms occurred with multiorgan involvement (pulmonary infiltrates, peripheral neuropathy, gastrointestinal tract symptoms, and arthralgia). Genital infiltration was also noted. The child's general health was preserved. Neither cardiac nor renal involvement were found. The patient showed favorable clinical progression after oral prednisone therapy.

Development of a Bayesian estimator for the therapeutic drug monitoring of mycophenolate mofetil in children with idiopathic nephrotic syndrome.

The use of mycophenolate mofetil (MMF) in children with idiopathic nephrotic syndrome (INS) is increasing. However, the clinical benefit of its monitoring has been scarcely studied, and little is known about its pharmacokinetics in this context. The objectives of the present study were: (i) to study and model the pharmacokinetics of mycophenolic acid (MPA; the active moiety of MMF) in paediatric patients with INS given MMF, at all stages of the disease; (ii) to develop a Bayesian estimator (MAP-BE) for individual inter-dose area under the concentration-time curve (AUC) prediction in this population, using a limited blood sampling strategy (LSS). Full-pharmacokinetic (PK) profiles of MPA collected in paediatric inpatients with INS already treated with a maintenance immunosuppressive therapy based on MMF (with no calcineurin inhibitors; CNI) were studied. A classical iterative two-stage (ITS) method was applied to model the data and develop MAP-BEs using a one-compartment open model where the absorption is described by a double gamma law allowing the description of a potential enterohepatic recirculation. The performance of the MAP-BE developed for individual exposure assessment was evaluated by the bias and precision of predicted AUCs with respect to measured, trapezoidal AUCs (reference value), and by the proportion of predicted AUCs with absolute error >20%. These PK tools were tested in an independent group of patients. Sixty PK profiles of MPA from children receiving MMF in association to corticosteroids or given alone were included in the study. Forty-five of these PK profiles were used to develop a PK model and a MAP-BE, and 15 for their validation. In the building group, the PK model fitted accurately the PK profiles of MPA: mean residual error of modelled vs. reference AUC was m±SD=-0.015±0.092 (range: -0.153 to 0.204). The MAP-BE which allowed the estimation of MPA AUC on the basis of a 20 min-60 min-180 min LSS was then developed. In the independent group of patients, its mean residual error vs. reference AUCs was m±SD=-0.036±0.145 (range: -0.205 to 0.189). Thus, a PK model and its derived MAP-BE for MMF (without any associated CNI) when given to children with INS have been developed. Clinical trials using these PK tools could test the potential impact of the therapeutic drug monitoring of MMF based on the AUC on the clinical evolution of INS.

[E.coli from urinary tract infections and acute pyelonephritis of children: 1% of strains are resistant to a subset of third generation cephalosporins]. / Escherichia coli des infections urinaires et pyélonéphrites aiguës en pédiatrie : 1% des souches sont résistantes à certaines céphalosporines de 3e génération.

E. coli remains the most often isolated pathogen in community urinary tract infections in children. We reported a retrospective study of antibiotic susceptibility of 506 E. coli strains isolated from urine. We found that 53% of the strains were resistant to amoxicilline and 22% to cotrimoxazole. The frequency of resistance to amoxicillin-clavulanic acid was of 7%, 40% of the strains were just intermediary and 53% were sensitive. Only five strains (1%) were resistant to ceftazidime: two mechanisms of resistance, hyperproduction of TEM betalactamase (3 cases) and cephalosporinase (2 cases), were suggested. This study illustrates the necessity of constant monitoring of bacterial resistance to adapt antibiotherapeutic guidelines to local evolution.

Renal outcome of children exposed to cyclosporine in utero.

The number of pregnancies in immunosuppressed women has increased during the recent years and this has become a major part of the rehabilitation and quality of life of treated patients. Most of them are organ transplant recipients and large series from the literature have shown that children born to such women may present with intrauterine growth retardation, a condition which may be associated with significant reduction in nephron number and oligomeganephronia. On the other hand, experimental data in animals have demonstrated that in utero exposure to CsA may alter nephrogenesis and further alter renal function. Therefore offspring of organ transplant women treated with CsA exhibit a theoretical risk of renal impairment, due to both IUGR and fetal nephrotoxicity. However, despite the limited experience of long term studies in children, there is no evidence of any significant deleterious adverse effect of in utero exposure to CsA. However further studies based on large series are required in order to demonstrate that renal fetal effects have limited clinical consequences.

[Revised prevalence of afa+ Escherichia coli strains in acute pyelonephritis of children]. / Révision de la prévalence des souches afa+ dans les Escherichia coli responsables de pyélonéphrites aiguës de l'enfant.

Two hundred E. coli strains isolated from children with pyelonephritis were investigated for the presence of six virulence factors. The used primers amplified adhesin pap and sfa, toxin haemolysin (hly) and cytotoxic necrotizing factor 1 (cnf1) and aerobactin (aer). For afimbrial adhesin, the previously used set of primers could not allow to detect the newly reported afa operons (Le Bouguenec et al., 2001). With a new set of primers specific for the afa operon family the prevalence of afa+ strains increased from 3.5% to 13.5%. Combinations of three or more factors in a same strain were found in 48.5%. Thirty two different urovirulent genotypes were observed; two strains contained the six studied factors.

[Berger's disease in childhood]. / La maladie de Berger chez l'enfant.

Berger's disease or IgA nephropathy (NIgA) is the most common form of glomerulonephritis in the world. In children macroscopic haematuria is the first sign in about 80% of the patients. Renal failure appears in 20% of cases after twenty years of follow-up. The most important prognosis indicators are a nephrotic syndrome at the onset, a proteinuria > 1 g/24 hours, diffuse tubulo-interstitial lesions and extracapillary proliferation with crescents in more than 50% of the glomeruli. The pathogenic mechanisms are just emerging and involve a disrupted process of the systemic tolerance to mucosal antigen with abnormal mucosal gamma delta T cell repertoire, abnormally glycosylated IgA1 molecules and a down-regulation of Fc alpha receptors on blood cells. After IgA deposition, the mechanisms of mesangial cell damage and activation involve vascular factors as endothelin/nitric oxide system, cytokines and growth factors such as interleukine-6, platelet derived growth factor and transforming growth factor beta. There is no curative treatment but steroids are useful in diffuse proliferative extracapillary forms, when histological activity score is high with a short delay between diagnosis and treatment, or for moderately severe NIgA with normal renal function.

In utero exposure to immunosuppressive drugs: experimental and clinical studies.

Over the last few decades, the number of pregnant women under immunosuppressive (IS) therapy following transplantation or autoimmune diseases has increased. At first, IS drugs, including prednisone, azathioprine, and cyclosporine A were used, but now new molecules such as tacrolimus and mycophenolate mofetil have appeared. These IS drugs cross the placental barrier and enter into the fetal circulation, which poses a risk for fetal development. Experimental data have shown that IS drugs often have deleterious effects on fetuses, while human data have reported an increased rate of abortion, prematurity, intrauterine growth retardation (IUGR), and low birth weight, without significant increases in malformation rates. However, only limited information is available about the newly used molecules. Although fetal and neonatal data are reassuring, long-term effects of IS drugs on fertility, immune response and renal function, as well as the consequences of prematurity and IUGR, should be monitored.