Lymphomatoid papulosis in children: a series of 25 cases.

BACKGROUND: Lymphomatoid papulosis (LyP) is an uncommon cutaneous T-cell lymphoproliferative disorder (CTLPD) rarely encountered in children. OBJECTIVES: To specify characteristics of paediatric LyP and to describe both diagnostic difficulties and the course of the disease with the experience of 10 years' follow-up. METHODS: This was a retrospective, single-centre study of 25 children diagnosed with LyP according to the 2008 World Health Organization guidelines, and a clinical and pathological correlation by two experts. RESULTS: The mean age at onset was 7·5 years. The lesions were mostly papulonodular with frequent pruritus (40%). Mucosal involvement was sometimes observed. A single ulcerative nodule was initially suggestive of a primary cutaneous anaplastic large-cell lymphoma (C-ALCL). Pityriasis lichenoides was associated in 36% of cases, atopic dermatitis in 28% and nonspecific infections in 28%. Complete remission was observed in 44% of cases. Through the mean follow-up of 10 years, none of our patients have experienced lymphoma occurrence. Histopathological subtype A clearly predominated (82%). A marked eosinophilic infiltrate was present in 44% of cases and a cutaneous T-gamma clone in 40%. No correlation was observed between histopathological subtype, cutaneous clone or LyP clinical course. CONCLUSIONS: Paediatric LyP belongs to the group of CD30-positive CTLPDs including C-ALCL. Children have to be carefully followed up lifelong, even if the prognosis appears good. The high frequencies of an associated viral infection, atopic dermatitis, marked eosinophilic infiltrate and a good outcome suggest that paediatric LyP could be considered a reactional disease rather than a malignant disorder.

Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome.

We describe here eleven different mutations in SPINK5, encoding the serine protease inhibitor LEKTI, in 13 families with Netherton syndrome (NS, MIM256500). Most of these mutations predict premature termination codons. These results disclose a critical role of SPINK5 in epidermal barrier function and immunity, and suggest a new pathway for high serum IgE levels and atopic manifestations.

Nutritional outcome in children with severe generalized recessive dystrophic epidermolysis bullosa: a short- and long-term evaluation of gastrostomy and enteral feeding.

BACKGROUND: Generalized recessive dystrophic epidermolysis bullosa (RDEB) is often complicated by high nutritional difficulties with risks of malnutrition. OBJECTIVES: To provide information regarding the benefits of enteral feeding by gastrostomy (GTF), energy and protein requirements, tolerance, growth and pubertal development in children with RDEB. METHODS: Twenty-four patients were referred over a 7-year period in a retrospective study. Gastrostomy placement was decided in patients unable to feed orally and/or presenting loss in weight and height of at least 1 SD compared with their best growth level, despite regular nutritional advice. Weight and height were expressed as Z-scores. Catch-up growth following GTF onset was studied. RESULTS: Gastrostomies were performed in 11 children (aged 9·0±5·8years), and one young man aged 18years. The body weight Z-score was -2·3±1·0, height Z-score 1·1±1·1, weight-for-height was 81±11% and height-for-age 95± 4%. At onset, GTF provided 74±21% and 180±81% of the recommended dietary allowance (RDA) for energy and proteins, respectively. At study update (53±20months), GTF provided 91±29% and 205±100% of RDA for energy and proteins, respectively. Weight-for-height reached 92±15% and height-for-age 98±5%. A normal puberty was obtained when GT was performed before the age of 10years. Skin was not improved. CONCLUSION: Malnutrition was observed in 50% of the children with generalized RDEB. Protein and energy needs are particularly high. GTF is well tolerated and helps with catch-up growth and puberty. It must be considered before malnutrition onset, and, if necessary, before puberty.

Germline mosaicism in keratitis-ichthyosis-deafness syndrome: pre-natal diagnosis in a familial lethal form.

Keratitis-ichthyosis-deafness (KID) syndrome is an autosomal dominant congenital ectodermal defect characterized by the association of skin lesions, hearing loss and keratitis. Most of the cases appear to be sporadic. KID syndrome is mostly related to mutations of GJB2 gene encoding connexin-26. Recently, a lethal form of the disease during the first year of life has been reported in two unrelated Caucasian patients. This rare lethal form is caused by the G45E mutation of GJB2 gene. We here report the first pre-natal molecular genetic diagnosis of the lethal form of KID syndrome relating to a G45E mutation. In the same family, the occurrence of this condition in three other siblings born to African non-consanguineous healthy parents lead to perform pre-natal diagnosis for this last pregnancy. Molecular analysis confirms the diagnosis of the lethal form of KID for the fetus. These results establish the role of germline mosaicism in KID syndrome and warrant careful genetic counseling. Furthermore, analysis of our cases and the literature allowed us to define a characteristic severe neonatal phenotype including facial dysmorphy, severe cornification with massive focal hyperkeratosis of the skin with erythroderma, dystrophic nails, complete atrichia and absence of foreskin.

Efficacy of tacrolimus 0.03% ointment as second-line treatment for children with moderate-to-severe atopic dermatitis: evidence from a randomized, double-blind non-inferiority trial vs. fluticasone 0.005% ointment.

Tacrolimus 0.03% ointment is licensed for second-line treatment of children with atopic dermatitis (AD). Although data are available from clinical trials, no study has enrolled only second-line patients. This double-blind, non-inferiority study compared tacrolimus 0.03% and fluticasone 0.005% ointments in children with moderate-to-severe AD, who had responded insufficiently to conventional therapies. Children (aged 2-15 yr) were randomized to tacrolimus ointment (n = 240) or fluticasone ointment (n = 239), twice daily until clearance or for a maximum of 3 wk and, if lesions remained, once daily for up to 3 wk further. Primary end-point was week 3 response rate (improvement of >or=60% in modified Eczema Area and Severity Index and not withdrawn for lack of efficacy). Secondary end-points included pruritus and sleep quality, global assessment of clinical response, incidence of new flares and safety. Response rates were 86.3% with tacrolimus ointment and 91.5% with fluticasone. Lower limit of the 95% confidence interval was -11.8%, exceeding the non-inferiority limit of -15% and meeting the primary end-point. Moderate or better improvement on the physicians' global assessment occurred in 93.6% and 92.4% of patients in the tacrolimus ointment and fluticasone arms, respectively, while median pruritus scores improved by 84.0% and 91.5%. Sleep quality improved by approximately 92% in both treatment arms. After day 21, new flare-up occurred in 5.5% and 11.3% of patients receiving tacrolimus ointment and fluticasone, respectively; mean times to new flares were 6.5 +/- 5.0 and 8.6 +/- 5.2 days. Adverse events were similar between the two arms, with the exception of application-site skin burning sensation in the tacrolimus ointment group. In conclusion, efficacy of tacrolimus 0.03% ointment as second-line treatment was not inferior to that of fluticasone 0.005% ointment, with similar benefits on global disease improvement and quality of sleep.

Cutaneous manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome.

BACKGROUND: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder characterized by neonatal autoimmune enteropathy, diabetes and thyroiditis, food allergies and skin rash. IPEX syndrome is caused by mutations in FOXP3, a master control gene of regulatory T cells (Tregs), resulting in absent or dysfunctional Tregs. Data in the literature are scarce and the cutaneous manifestations are rarely depicted. OBJECTIVES: To evaluate the frequency and characteristics of cutaneous manifestations found in IPEX. METHODS: Retrospective single-centre study of a case series of IPEX. Patients' data were retrieved from medical files and numerous parameters concerning general and cutaneous characteristics of the disease were recorded. RESULTS: Ten children with IPEX were studied. Cutaneous involvement was present in seven of 10 children; age at onset was 0-4 months, median 1.5. All patients presented with atopic dermatitis (AD). Three presented more psoriasiform lesions. Eczema was severe; most affected areas were lower limbs, trunk and face. Pruritus was present in four of seven, and painful fissurary cheilitis in four of seven. Hyper-IgE was found in seven of 10 and hypereosinophilia in five of 10. Skin biopsies showed eczematiform or psoriasiform features. Affected patients were improved by dermocorticoids; no clear improvement was obtained with immunosuppressive regimens. Other features were urticaria secondary to food allergies and staphylococcal sepsis, mostly Staphylococcus aureus and catheter related. CONCLUSIONS: AD seems to be a frequent finding in IPEX syndrome, which is characterized by Treg anomalies. This hints to a possible role of Tregs in AD, which is then discussed in this study.

[Sirolimus-induced onychopathy in renal transplant recipients]. / Onychopathie associée au sirolimus chez les transplantés rénaux.

INTRODUCTION: A large number of drugs may be responsible for the development of nail changes. Sirolimus is an immunosuppressive drug recently developed in organ transplantation. Herein, we evaluate sirolimus-induced nail abnormalities in renal transplant recipients. PATIENTS AND METHODS: The nails of 80 consecutive renal transplant recipients receiving sirolimus have been evaluated in a systematic dermatological study in 2003. The patients were mainly men (60%) with a mean age of 48 years. The mean duration of the graft was 6 years and of sirolimus treatment 18 months. Mycophenolate mofetil and steroids were combined with sirolimus in 86% of patients. RESULTS: Fifty-seven patients (74%) complained for nail alterations. The most frequent anomalies (88%) were matrix alterations including slow growth, onychomalacia, onychorrexis, and leukonychia. Nail bed alterations (onycholysis), vascular phenomenon (erythema, splinter hemorrhages), and periungual anomalies (mainly pyogenic granulomas) were observed in 42, 42 and 19% of cases respectively. One observation of type 1 photo-onycholysis was described. DISCUSSION: This study reports a new drug-induced onychopathy. Responsibility of sirolimus is highly suggested. The main pathogenesis hypothesis to explain these nail alterations is inhibition of EGF (epidermal growth factor) pathway by sirolimus.

[The value of topical immunosuppressors in the treatment of atopic dermatitis in children]. / Place des immunosuppresseurs topiques dans le traitement de la dermatite atopique de l'enfant.

The use of topical immunosuppressors during treatment of atopic dermatitis is an important innovation that reinforces the therapeutic arsenal in this chronic disease in children. Two products have been studied in depth: tacrolimus, which exists in pomade form at a concentration of 0.1 and 0.03% under the trademark Protopic. It is the 0.03% concentration that has been studied in children and obtained official indication in children aged over 2. Pimecrolimus marketed under the trademark Elidel in the form of a 1% cream has also been studied in depth and obtained European marketing authorisation for prescription in children aged over 2. Unfortunately it is not yet available in France, although it is marketed in nearly all countries worldwide. These products decrease the production of cytokines by the T-cell lymphocytes when stimulated by the antigen. This effect is produced by the inhibition of calcineurine. The clinical efficacy of these two products has been demonstrated in many studies in the United States and in Europe. Short term efficacy has been demonstrated in comparisons versus a placebo or versus grade 2 or 3 corticosteroids. Longer term studies (6 months to one year) have confirmed the efficacy. Short-term tolerance to these new treatments has been shown, although, as with any new product, the long-term results are unknown. Nevertheless, tolerance studies after more than 4 years' use exist. The side effects most often reported are local, erythema-like at the start of treatment with burning and pruritus. There has been no significant increase in the number of bacterial and viral infections compared with control groups. Doubt remains regarding viral infections of herpetic origin, notably Kaposi-Juliusberg's disease, although no significant difference has been observed compared with the placebo-treated. No systemic impact has been reported with these two products or inhibition of the effect of vaccinations made in infants or children. However, care should be taken: not to use the products in patients with a history of Kaposi-Juliusberg's disease and any contact with a patient exhibiting herpes should be avoided; the photoprotection measures should be respected as instructed in the patient insert for the use of tacrolimus.

Role of cytotoxic T cells in chronic alopecia areata.

Cytokines play a role in alopecia areata. We used immunohistochemical and in situ hybridization studies to demonstrate the persistence of pro-inflammatory as well as apoptotic mechanisms in skin biopsies from patients with chronic alopecia areata. In situ hybridization allows the visualization of the distribution of immunocompetent cells in vivo. We studied skin biopsies from 11 untreated alopecia areata patients and two normal controls. In situ hybridization was performed on frozen sections using 35S-radio-labeled riboprobes, specific for IL-1beta, IL-2, IL-6, INFgamma, and granzyme B mRNA. Immunohistochemistry was carried out using an anti-IL-1beta monoclonal antibody, and a monoclonal antibody directed against the human Fas protein. We demonstrated the presence of cells labeled with IL-1beta, IL-6, INFgamma, and granzyme B antisense probes. Similarly, cells labeled with anti-IL-1beta were found in 10 of 11 cases. The labeled cells were located in the mononuclear peri- and intrafollicular infiltrate. Cells expressing granzyme B were found in close contact with the follicle. Fas positivity was demonstrated in four of four cases at the level of the cytoplasmic membrane of the hair follicle keratinocytes. These results, based on visualizing the labeled cells, demonstrate that pro-inflammatory cytokines are produced by the mononuclear cell infiltrate in close contact with follicles in alopecia areata. Furthermore, they demonstrate for the first time that apoptotic mechanisms involving granzyme B and Fas-Fas ligand pathways may play a major role in the persistence of chronic alopecia areata.

Reversal effects of topical retinoic acid on the skin of kidney transplant recipients under systemic corticotherapy.

The systemic long-term corticosteroid treatment administered to kidney graft recipients (KGR) within the framework of the required immunosuppressive therapy induces an atrophy of the skin, from the sixth month onwards. We studied the effect of topical all-trans retinoic acid (0.05%; Galderma Labs.) applied to the forearms of 27 KGR (14 men, 13 women) over a 6-month period. Twenty-four subjects completed the trial. The following results were obtained in the treated forearm versus the untreated forearm (excipient alone): clinically, an increase in skin thickness; by noninvasive techniques, an increase in skin thickness, skin elasticity, skin conductance, and TEWL, and a reduction in the size of the corneocytes. No change in stratum corneum lipid content was observed. A sex-related difference was noted in the response to treatment under our experimental conditions, the female patients responding better. A punch biopsy (4 mm) was performed on both forearms of four patients after the 6-month period. Histologic and ultrastructural examination revealed epidermal and dermal changes evoking increased cellular metabolism in the retinoic acid-treated forearms.

DNA-based prenatal diagnosis of generalized recessive dystrophic epidermolysis bullosa in six pregnancies at risk for recurrence.

Linkage analyses in generalized recessive dystrophic epidermolysis bullosa (RDEB) have implicated the type VII collagen gene (COL7A1), which encodes the major component of anchoring fibrils, and recent identification of COL7A1 mutations has provided direct evidence for COL7A1 defects underlying RDEB. In this study, COL7A1 gene analysis was used to successfully perform first-trimester prenatal diagnosis in six families at risk for recurrence of the disease. In four families, three affected with the most severe variant of RDEB (the Hallopeau-Siemens form, HS-RDEB) and one with generalized nonmutilating RDEB, prenatal diagnosis was established by linkage analysis using polymerase chain reaction-based detection of PvuII and AluI intragenic restriction fragment length polymorphism. In two other HS-RDEB families, prenatal diagnosis was carried out by direct detection of mutations in COL7A1, using denaturing gradient gel electrophoresis analysis of polymerase chain reaction-amplified genomic fragments. Analysis of fetal DNA from chorionic villus biopsy or from amniotic fluid cells showed that the fetus had inherited at least one normal COL7A1 allele in all cases. Therefore, the fetus was predicted to be unaffected in the six pregnancies, and this has been confirmed in the newborn infants. Genotype analysis with COL7A1 polymorphic markers, or direct COL7A1 mutation detection in families at risk for the disease, represent early and rapid diagnostic alternatives to second-trimester evaluation of fetal skin samples, and thus offer a major advance in prenatal diagnosis of this life-threatening form of epidermolysis bullosa.

Linkage of Marie-Unna hypotrichosis locus to chromosome 8p21 and exclusion of 10 genes including the hairless gene by mutation analysis.

Marie-Unna hypotrichosis (MU) is a rare autosomal dominant congenital alopecia characterised by progressive hair loss starting in early childhood, often aggravated at puberty and leading to scarring alopecia of variable severity. We have studied three multigeneration families of Belgian, British and French descent. The human genome was screened with microsatellite markers spaced at 10-cM intervals and significant evidence for linkage to the disease was observed on chromosome 8p21, with a maximum two-point lod score of 8.26 for D8S1786 at a recombination fraction of 0. Recombinants narrowed the region of interest to a genetic interval of about 12 cM flanked by markers D8S280 and D8S1839. This interval contains the hairless gene which is mutated in autosomal recessive congenital atrichia. Sequencing of the entire coding region and intronic splice sites of the hairless gene in these three families and in two unrelated familial cases revealed several polymorphic changes but failed to identify causative mutations. Nine other genes located within this region and expressed in skin were also excluded by mutation analysis. Together with a recent linkage study performed in a Dutch and a British family by van Steensel et al these results provide evidence for the presence of a gene distinct from hairless in chromosomal region 8p21 playing an important role in hair follicle biology.

Three novel point mutations in the keratinocyte transglutaminase (TGK) gene in lamellar ichthyosis: significance for mutant transcript level, TGK immunodetection and activity.

We have investigated 8 patients from 7 unrelated families with lamellar ichthyosis (LI) for defects in the keratinocyte transglutaminase (TGK) gene. We have characterized three novel homozygous mutations and a previously reported splice acceptor site mutation. One patient showed a C-to-T change in the binding site for the transcription factor Sp1 within the promoter region. Another patient had a Gly 143-to-Glu mutation in exon 3 and a third patient, affected with a particular form of LI sparing the four limbs, demonstrated a Val382-to-Met mutation within exon 7. These three patients exhibited drastically reduced transglutaminase activity and an absence of detectable TGK polypeptide, as assessed by immunofluorescence and immunoblotting. Northern blot analysis showed that the Sp1 site mutation was associated with profound reduction of TGK transcript levels whereas normal transcript levels were observed for the two missense mutations. We hypothesize that the Sp1 site mutation impairs transcription of the TGK gene, whereas the two missense mutations induce structural changes leading to protein instability. Linkage to TGK was excluded in another family and no evidence for TGK defect was found in 3 other patients. These results further support the involvement of TGK in some patients with LI. They identify a TGK mutation as a cause for non-generalized LI and further delineate the molecular mechanisms underlying TGK deficiency in LI.

Skin elastic fibers in Williams syndrome.

The elastin gene is consistently deleted in Williams syndrome and as this protein represents the major component of the elastic fibers of the dermis, we sought to investigate skin elastic fibers in Williams syndrome as a key to unraveling extracellular matrix disorganization in this condition. Both morphometric parameters analyzed by using automated image analysis and immunofluorescence labeling with monoclonal antibodies against elastin and fibrillin 1 showed a disorganized pre-elastic (oxytalan and elaunin) and mature elastic fibers in the dermis of 10 Williams syndrome patients compared with five healthy children and one patient with isolated supravalvular aortic stenosis. Skin biopsies in Williams syndrome patients provide a simple mean to elucidate extracellular matrix anomalies. Hopefully, this method could give clues to the understanding of the elastic network anomalies in this condition and even to the consequences of these latter on elasticity and resilience of other tissues such as the arterial tree.

Dinitrochlorobenzene treatment of alopecia areata.

Forty-two patients with alopecia areata were treated with local applications of dinitrochlorobenzene (DNCB); We used DNCB in two forms, an acetone solution applied weekly or a cream used every day, employing a wide range of DNCB concentrations. The concentration used was varied at the time of each application to produce a contact dermatitis. Seven patients experienced complete and lasting hair regrowth, 17 had poor results, and in 18 patients the treatment was a failure. Acquired tolerance to DNCB was observed in six patients; in five it was abolished by the administration of cimetidine. Certain factors such as the delay in appearance and the intensity of the sensitization reaction influence the hair regrowth. Poor prognostic criteria for treatment effect included a history of previous systemic corticosteroid therapy, atopy, and the presence of alopecia areata in close relatives.

Neonatal and infantile erythrodermas: a retrospective study of 51 patients.

OBJECTIVE: To determine the frequency of the various underlying causes of erythroderma in newborns or infants, as well as which clinical or laboratory findings were relevant for the etiological diagnosis. PATIENTS: Fifty-one patients who presented with exfoliative erythroderma during their first year of life were included in this retrospective study. SETTING: Department of Pediatric Dermatology at a university hospital. RESULTS: On average, the etiological diagnosis was established 11 months after the onset of erythroderma. The underlying causes observed included immunodeficiency (30%), simple or complex ichthyosis (24%), Netherton syndrome (18%), and eczematous or papulosquamous dermatitis (20%). Five patients (10%) had erythroderma of unknown origin. The following parameters were of value in determining the underlying cause of erythroderma: congenital onset, skin induration and the presence of large scaling plaques, alopecia with or without hair dysplasia, evolution, response to topical corticosteroid therapy, presence of infections, and failure to thrive. Histological analysis confirmed the diagnosis in only 19 (45%) of 42 cases. However, it proved of great value for the detection of significant lymphocyte infiltration or keratinocyte necrosis indicating a diagnosis of Omenn syndrome or immunodeficiency. The prognosis was poor in this series: the mortality rate was 16%, and severe dermatosis persisted in 29 (67%) of the survivors. CONCLUSIONS: The etiological diagnosis of neonatal erythroderma is difficult to make; some clinical features may be helpful, but no one feature is characteristic of a cause. An immunodeficiency must be suspected in cases of severe erythroderma with skin induration, severe alopecia, failure to thrive, infectious complications, or evocative histological findings. The prognosis is poor, with a high rate of mortality in immunodeficiency disorders and severe chronic disease in Netherton syndrome and psoriasis.

Epidermolysis bullosa acquisita in childhood.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is an autoimmune bullous disease characterized by the presence of antitype VII collagen antibodies, leading to the formation of bullae in the dermoepidermal junction. This disease is rare in childhood. OBSERVATIONS: We report 3 new cases of EBA in children. The 3 patients were similar; all 3 children were black, with a clinical phenotype resembling linear IgA bullous disease in children and typical histologic and immunologic features of EBA. In the 3 patients, diagnosis was proven using immune electron microscopy and Western blot analysis, where antitype VII collagen antibodies were demonstrated. Patients 1 and 2 were successfully treated with a combination of prednisone and dapsone. In patient 3, the lesions healed without specific therapy. We found 11 other pediatric cases of EBA in the literature and studied those cases in addition to the cases presented herein to describe the characteristics of EBA in childhood. CONCLUSIONS: Epidermolysis bullosa acquisita is a rare disease in childhood. Mucosal involvement is frequent and severe. Because the clinical features are misleading, the use of immune electron microscopy and Western blot analysis is essential to making a diagnosis. Treatment with a combination of prednisone and dapsone is often effective. The prognosis in children is better than it is in adult patients.

Bullous dermatosis associated with dysglobulinemia (two cases). Relationships with epidermolysis bullosa acquisita.

Two cases of bullous dermatosis with dysglobulinemia are described. The first one was associated with renal and neuromuscular amyloidosis and production of a monoclonal lambda IgG. Optical and electron microscopy showed amyloid deposits beneath basal lamina of the dermis. Results for direct and indirect immunofluorescence (IF) were negative. This bullous dermatosis is not an epidermolysis bullosa acquisita (EBA), in the strict sense, because the amorphous material deposited is amyloid. In the second case, associated with Waldenström's disease, there was no cutaneous or systemic amyloidosis. Direct IF was positive; linear IgM deposits were seen along the basal membrane of the bulla and the healthy skin. Indirect IF showed the presence of circulating antibodies against basal membrane zone. This bullous dermatosis is probably an EBA, despite the absence of IgG deposits. The absence of electron microscopy does not permit the confirmation of this diagnosis.