NR4A2 haploinsufficiency is associated with intellectual disability and autism spectrum disorder.

NR4A2, a member of the nuclear receptor superfamily, is involved in modulation of target gene transcription, regulating several developmental processes such as regulation of cellular homeostasis, neuronal development, inflammation and carcinogenesis. 2q24.1 deletions are extremely rare, and only 1 patient with a de novo deletion encompassing only NR4A2 gene was reported so far. We report 3 additional patients with a de novo deletion encompassing NR4A2: 2 patients have deletions encompassing only NR4A2 gene and 1 patient has a deletion including NR4A2 and the first exon of GPD2. Our patients presented a neurodevelopmental disorder including language impairment, developmental delay, intellectual disability and/or autism spectrum disorder. We suggest that NR4A2 haploinsufficiency is implicated in neurodevelopmental disorder with high penetrance.

[Impact of sex and age on the clinical and epidemiological aspects of childhood psoriasis: Data from a French cross-sectional multicentre study]. / Impact de l'âge et du sexe sur les aspects cliniques et épidémiologiques du psoriasis de l'enfant. Données d'une étude transversale multicentrique française.

BACKGROUND: The prevalence of childhood psoriasis is estimated at between 0.4% and 0.7%. Clinical aspects of the diseases depend on age. The aim of this study was to investigate the clinical aspects of psoriasis according to age and sex. PATIENTS AND METHODS: A cross-sectional, multicentre study of children with psoriasis was performed by investigators belonging to the Research Group of the French Society of Paediatric Dermatology. The study was conducted from April 2012 to March 2013. Inclusion criteria were age less than 18 years and clinical diagnosis of psoriasis. The children were classified into 3 groups by age: infants: <2 years; children: ≥2 years and <13 years; adolescents≥13 years. The information collected included demographic data, clinical, epidemiological, and therapeutic aspects of the psoriasis, as well as analysis of comorbidities. RESULTS: Three hundred and thirteen children were included: 27 (8.6%) infants, 207 (66.1%) children, and 79 (25.2%) adolescents. Plaque psoriasis was the most frequent clinical type of psoriasis seen in children and adolescents (>41%), but it accounted for only 25.9% of psoriasis of infants (P<0.0001). Napkin psoriasis (37.0%) and inverse psoriasis (22.2%) were the most common forms of psoriasis seen in infants and were described significantly more frequently in this group than in the two other groups (P<0.003). Nail involvement was more common in adolescents (37.2%, P=0.03) and children (32.9%) than in infants (14.8%) and affected boys more than girls (43.6% vs 22.0%, P<0.0001). Girls presented scalp psoriasis more frequently (17.7% vs 8.7%, P=0.02). Local vitamin-D treatment and systemic therapies were used more frequently in children and adolescents than in infants. There was no significant difference for treatment use, including for acitretin, according to gender. DISCUSSION: Plaque psoriasis was the most common clinical type of psoriasis in children but affected less than 50% of the children. Age had a significant impact on extra-cutaneous skin disorders and on treatment used, while sex had little incidence. The frequency of comorbidities was not affected by age. CONCLUSION: Childhood psoriasis thus presents specific characteristics dependent on the age of the child. The results of studies exclusively dealing with adults cannot be extrapolated to children.

A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome.

Cornelia de Lange syndrome is a multisystemic developmental disorder mainly related to de novo heterozygous NIPBL mutation. Recently, NIPBL somatic mosaicism has been highlighted through buccal cell DNA study in some patients with a negative molecular analysis on leukocyte DNA. Here, we present a series of 38 patients with a Cornelia de Lange syndrome related to a heterozygous NIPBL mutation identified by Sanger sequencing. The diagnosis was based on the following criteria: (i) intrauterine growth retardation and postnatal short stature, (ii) feeding difficulties and/or gastro-oesophageal reflux, (iii) microcephaly, (iv) intellectual disability, and (v) characteristic facial features. We identified 37 novel NIPBL mutations including 34 in leukocytes and 3 in buccal cells only. All mutations shown to have arisen de novo when parent blood samples were available. The present series confirms the difficulty in predicting the phenotype according to the NIPBL mutation. Until now, somatic mosaicism has been observed for 20 cases which do not seem to be consistently associated with a milder phenotype. Besides, several reports support a postzygotic event for those cases. Considering these elements, we recommend a first-line buccal cell DNA analysis in order to improve gene testing sensitivity in Cornelia de Lange syndrome and genetic counselling.

[Wells Syndrome in children and atopy: Retrospective study of 11 cases and review of the literature]. / Syndrome de Wells de l'enfant et atopie : étude rétrospective de 11 cas et revue de la littérature.

BACKGROUND: Well's syndrome, or eosinophilic cellulitis, is rare in childhood, with fewer than 40 pediatric cases being reported since 1979. The physiopathology is unknown. PATIENTS AND METHODS: In February 2012, members of the research group of the Department of Pediatric Dermatology Society submitted their case of Wells' syndrome in children aged 0-15 years. Details of clinical, biological and histological features and of therapeutic strategies were collected by physicians using a standardized questionnaire. Pictures were reviewed by the authors. RESULTS: Eleven patients were included (average age: 6 years), with a strong prevalence of atopy (63%). Two types of clinical manifestation were noted: single or multiple cellulitis associated or not with vesiculobullous lesions and fixed urticaria. Eighty-two percent of patients had pruritus and 73% had eosinophilia. For all patients, histological examination of skin biopsies showed an eosinophilic infiltrate extending in the dermis with associated Sweet-like neutrophilic infiltrate being seen in 2 patients. The course of the disease was protracted (mean duration: 8 months) with flare-ups. Treatment varied depending on the doctors (topical or systemic steroids, tacrolimus and dapsone). DISCUSSION: Our study confirms some of the data in the literature concerning the clinical, histological features and course of Well's syndrome in children. The key information is the high prevalence of atopic children hitherto unreported. In a setting of insect bites, vaccination, infection or traumatism, this unusual background could explain the onset of inflammatory reaction with eosinophils. Oral or topical steroids appear to be the first-line treatment in children when necessary. CONCLUSION: Well's syndrome in children is rare and characterized by its polymorphism. We report for the first time in a series of patients a high prevalence of atopy, which raises new perspectives in understanding these rare diseases. We propose topical steroids as first-line therapy in children with superficial lesions, with oral steroids being given for cellulitic lesions or where topical therapy fails.

[Blueberry Muffin Baby and Langerhans' congenital cell histiocytosis]. / Histiocytose langerhansienne congénitale et « Blueberry Muffin Baby ¼

BACKGROUND: Blueberry Muffin Baby is a rare neonatal cutaneous syndrome for purpuric lesions reflective of extramedullary hematopoiesis. Many causes are known, examples are congenital infections, malignancy and hematologic disorders. Langerhans' cell histiocytosis is a clonal proliferation of dendritic histiocytes. This has very rarely been associated with a Blueberry Muffin Baby presentation. CASE REPORT: We report the case of a newborn presenting with Blueberry Muffin Baby syndrome related to congenital Langherans' cell histiocytosis. At birth, he had multiple purpuric lesions on the trunk, limbs and face. Skin biopsy showed a dermal proliferation of histiocytes staining positive for S100 and CD1a. Chest and bone radiographs, and abdominal ultrasound were normal. Skin lesions have resolved in 8 weeks, the patient is in complete remission at 18 months of follow-up. DISCUSSION: A Blueberry Muffin Baby syndrome may reveal neonatal Langerhans' histiocytosis.

[Allergic contact dermatitis due to methoxy PEG-22 dodecyl glycol present in a cosmetic cold cream]. / Eczéma de contact aigu au méthoxy PEG-22 dodécyl glycol contenu dans un cold cream cosmétique.

BACKGROUND: We report the case of a girl presenting acute allergic contact dermatitis due to methoxy PEG 22 dodecyl glycol contained in Mustela Cold Cream Nutriprotecteur®. PATIENTS AND METHODS: A 6-year-old girl was referred with acute eczema of the face occurring within 12h of applying a new moisturizing cream, Mustela Cold Cream Nutriprotecteur®. Patch tests were performed on the upper back using the Finn Chamber technique with the European standard series and the patient's own cream. Readings were performed after 2 days and the sole positive ++ reaction was associated with Mustela Cold Cream®. Additional patch testing was carried out with the ingredients of the cream, with the sole positive ++ reaction again being to methoxy PEG 22 dodecyl glycol copolymer. The other ingredients were negative. DISCUSSION: Methoxy PEG 22 dodecyl glycol is a copolymer used in cosmetics as an emulsion stabilizer and viscosity-increasing agent. It is found in 20 cosmetics currently on the market, most of which are prescribed for children. CONCLUSION: Although it is rare, doctors must be aware of allergic contact dermatitis due to methoxy PEG 22 dodecyl glycol because of the extent of clinical reactions and because it chiefly affects the paediatric population.

[Multiple familial trichoepithelioma: a new CYLD gene mutation]. / Trichoépithéliomes multiples familiaux : nouvelle mutation du gène CYLD.

BACKGROUND: Multiple familial trichoepithelioma (MFT) is an autosomal dominant disease characterized by the development of numerous skin-coloured papules on the central area of the face. It is associated with various CYLD gene mutations that are also responsible for familial cylindromatosis and Brooke-Spiegler syndrome. PATIENTS AND METHODS: We report a novel mutation in the CYLD gene in a family with MFT and discuss new developments in therapeutic options. DISCUSSION: Recent studies indicate that CYLD is a tumour-suppressor gene.

[Cutaneous polymorph manifestations of familial Mediterranean fever in a child]. / Atteinte cutanée polymorphe de la fièvre méditerranéenne familiale chez un enfant.

We describe the case of a 4-year-old child with Mediterranean fever characterized by cutaneous features. Familial Mediterranean fever is an autosomal recessive disorder characterized by recurrent attacks of fever and polyserositis including peritonitis, pleuritis, and arthritis. Skin involvement is less common. In our case, the successively patient presented erysipelas-like erythema, edemas of the palmar and plantar regions, and purpuric lesions. From these clinical observations, several diagnoses were raised: infectious erysipelas, Kawasaki disease, Henoch-Schönlein purpura, and familial Mediterranean fever. Only the latter diagnosis was confirmed after exploration and then confirmed with genetic analysis, which found a M694V homozygous mutation. Erysipelas-like erythema is the most frequent cutaneous sign reported in the literature and the only one to be associated with the M694V homozygous mutation. The originality of this case is the dominancy and polymorphism of the skin lesions.

Prospective multicenter evaluation of colon capsule examination indicated by colonoscopy failure or anesthesia contraindication.

BACKGROUND AND STUDY AIMS: In France, in about 5% of cases colonoscopies are incomplete or temporarily contraindicated.We tested the diagnostic yield of colon capsule endoscopy (CCE) in these patients. PATIENTS AND METHODS: In a prospective study, in 17 French centers, inclusion criteria were colonoscopy failure or general disease that excluded colonoscopy with anesthesia. Patients underwent CCE using the first-generation PillCam Colon capsule. The main end point was CCE diagnostic yield, defined as identification of a colorectal lesion that directly explained symptoms or necessitated a diagnostic or therapeutic examination. A secondary objective was to test a simplified Movi-Prep colon cleansing. Follow-up to identify missed symptomatic cancer was scheduled. RESULTS: CCE showed positive findings in 36 patients (diagnostic yield 33.6 %), among whom 23 subsequently underwent therapeutic intervention. Among 64 patients with negative capsule findings, 9 had a complementary procedure showing adenomas in only 1 case. CCE was incomplete in 7/107 patients. Colonoscopy was done in one patient to retrieve a capsule retained in the left colon, and sigmoidoscopy in 11 because the rectum was not reached. No colorectal cancer was diagnosed during the follow-up period. Colon cleansing with MoviPrep was rated good or excellent in 75.9% of cases. CONCLUSION: This study shows the feasibility and the usefulness of CCE in the situation of colonoscopy failure or contraindication. The colon capsule modality should be tested against other available approaches, such as virtual colonoscopy or repeat colonoscopy by an expert.

Somatic mosaicism in Cornelia de Lange syndrome: a further contributor to the wide clinical expressivity?

Cornelia de Lange syndrome (CdLS) is a rare, congenital syndrome characterized by growth retardation, dysmorphic face, mental retardation and limb reduction defects. Clinical manifestations of CdLS can be extremely variable. Mutations in NIPBL, SMC1A and SMC3 genes, encoding for a regulator and two subunits of the cohesin complex, respectively, are found in 60-65% of CdLS patients. We report on a male with CdLS who is mosaic for the c.2827delA mutation in the NIPBL gene. Allele quantitation by pyrosequencing showed the presence of the mutation in about 10% and 33% of DNA samples from peripheral blood and buccal smears, respectively. The patient shows a complex phenotype: growth and psychomotor retardation are characteristic of the severe forms of CdLS, while the absence of severe limb reduction defects and major malformations are typical of the mild phenotype. He also has depigmentation areas following Blashko lines, an unusual finding in CdLS, which has been associated with mosaicism in other genetic conditions. This case represents the first evidence of somatic mosaicism in CdLS and explains the mild phenotype in the patient as compared to that predicted by a truncating mutation. Besides confirming the clinical and genetic heterogeneity of CdLS, this case also raises the likely underestimated mutation rate of known genes and points to the complexity of addressing genotype-phenotype correlations.

Study of Helicobacter pullorum proinflammatory properties on human epithelial cells in vitro.

BACKGROUND AND AIMS: Helicobacter pullorum is an enterohepatic Helicobacter species of avian origin detected in patients with acute diarrhoea and inflammatory bowel disease. The aim of the present study was to determine whether H pullorum exerts a direct effect on human intestinal epithelial cells in vitro and to characterise the bacterial mechanisms and the signalling pathways involved. MATERIALS AND METHODS: The proinflammatory properties of H pullorum from human and avian origins were measured on human gastric (AGS) and intestinal (CaCo-2 and HT-29) epithelial cell lines after co-culture with different H pullorum strains, and the extent of nuclear factor-kappaB (NF-kappaB) involvement was determined. RESULTS: All of the H pullorum strains tested stimulated interleukin 8 (IL8) secretion by the three cell lines. Similar results were obtained with heat-killed H pullorum. Incubation of cells with filtered H pullorum culture supernatants did not stimulate IL8 secretion. The same observation was made when bacterial adherence was inhibited by Transwell inserts. H pullorum induced NF-kappaB activation and rapid nuclear translocation as demonstrated by immunofluorescent staining and cellular fractionation. NF-kappaB involvement was confirmed by using the specific inhibitor SN50 and small interfering RNA (siRNA) which abolished H pullorum-induced IL8 production. CONCLUSIONS: H pullorum strains stimulate IL8 secretion by human gastric and intestinal epithelial cell lines. This effect requires bacterial adherence and probably lipopolysaccharides, and is mediated by NF-kappaB signalling. The present study strengthens the argument that H pullorum is a potent human pathogen and highlights its putative role in acute and chronic digestive diseases such as inflammatory bowel disease.

[Atypical staphylococcal scalded skin syndrome: it could be battered child syndrome]. / Syndrome d'ébouillantement staphylococcique atypique: penser à une maltraitance.

A case of pseudo staphylococcal scalded skin syndrome is presented and discussed within the clinical spectrum of the battered child syndrome. The authors underline the behavior of the parents in this setting, which can mislead the physician in charge. Dermatologic symptoms are important to make a diagnosis of the battered child syndrome.

[Chronic exanthema in a child with congenital rubella]. / Exanthème chronique chez un enfant atteint de rubéole congénitale.

BACKGROUND: Since congenital rubella has become extremely uncommon following the introduction of rubella vaccination, cutaneous signs are currently rarely reported. PATIENTS AND METHODS: An infant, presenting congenital rubella (seroconversion of the mother for rubella at 11 weeks' amenorrhoea), presented diffuse exanthema between the ages of seven and 24 months. In a setting of congenital rubella syndrome, the infant presented psychomotor retardation, deafness, hypoplasia of the pulmonary artery and under-nourishment. Humoral and cell-mediated immunodeficiency was also noted. DISCUSSION: The cutaneous signs of congenital rubella were first described in the 1960s and 1970s; they are rare and appear after a symptom-free period before resolving spontaneously several months later. Standard findings include chronic exanthema of the face and extremities associating reticulated erythema and pigmented macular papules. Exanthema indicates chronic and persistent viral infection, a common situation in newborn babies and infants following maternal-foetal infection. The persistence of viral infection in infants is attributed to immature cellular immunity, which would otherwise either eradicate the virus or ensure passage to the latency phase. In the present case, there was also relative humoral immunodeficiency resulting from foetal rubella infection. The symptom-free interval before the onset of rash and other clinical signs may be due to the relative transient protection afforded by the presence of maternal immunoglobulines G.

Determinants of gastro-oesophageal reflux perception in patients with persistent symptoms despite proton pump inhibitors.

BACKGROUND AND AIMS: Approximately 20% of patients have persistent symptoms of gastro-oesophageal reflux despite proton pump inhibitor (PPI) therapy. The aim of this study was to assess the determinants of reflux perception in patients on PPI therapy. PATIENTS AND METHODS: 20 patients with typical gastro-oesophageal reflux symptoms (heartburn and/or regurgitation) despite double-dose PPIs (twice daily) were included in this study. Ambulatory 24 h pH-impedance studies were performed in all patients. The characteristics of symptomatic and asymptomatic reflux episodes were compared. Symptoms were considered globally and separately for heartburn and regurgitation. RESULTS: A total of 1273 reflux episodes were detected including 243 (19.1%) acidic, 1018 (80.0%) weakly acidic and 12 (0.9%) weakly alkaline reflux episodes. Overall, 312 (24.5%) reflux episodes were symptomatic. The only factor associated with reflux perception was high proximal extent (p = 0.037). Compared with regurgitation, reflux episodes associated with heartburn were more frequently pure liquid (p = 0.009) and acidic (p = 0.027), had a lower nadir pH (p<0.001), were more frequently preceded by acid reflux episodes (p<0.001) and had a longer reflux bolus clearance time (p<0.001). CONCLUSIONS: High proximal extent of the refluxate is the only factor associated with reflux perception in patients on double-dose PPI. However, compared with regurgitation, composition of the refluxate, sensitisation of the oesophagus by preceding acid exposure and delayed bolus clearance appear to play a role in heartburn perception.