Kaposiform Haemangioendothelioma-spectrum Lesions with Kasabach-Merritt Phenomenon: Retrospective Analysis and Long-term Outcome.

Kasabach-Merritt phenomenon (KMP) is a rare life-threatening vascular condition of infancy. Prognosis factors and long-term follow-up data are lacking. We retrospectively analysed the records of 24 infants (10 females, 14 males) treated for KMP in the Department of Dermatology of Necker-Enfants Malades Hospital, Paris, France, from 1984 to 2012. Mean duration of thrombocytopaenia (2,000-38,000 platelets/mm3, mean 10,500/µl) was 8.8 months (range 3 days-84 months), which correlated with tumour infiltration depth on imaging. D-dimer levels were always elevated, even before KMP onset. Each patient received a mean of 4.8 different treatments (range 1-10). Median follow-up was 6.5 years (range 2 months-22 years). All infants had residual cutaneous lesions, along with inflammatory manifestations (n = 9), elevated D-dimer (n = 5) and orthopaedic sequelae (n = 5). The permanent coagulopathy (elevated D-dimer) even after resolution of KMP suggests the presence of chronic low-grade platelet trapping, with possible sudden worsening, and raises the possibility of prophylactic anti-platelet therapy.

Cutaneous hematologic disorders in children.

BACKGROUND: To determine and list the clinical and pathological features of cutaneous hematologic diseases in childhood. PROCEDURE: We retrospectively analyzed the data for 51 patients up to 15 years of age, who presented with primary cutaneous hematologic disorders according to the WHO-EORTC classification, at Necker-Enfants Malades Hospital, Paris, France, over a 17-year period. The cases were classified into the following diagnostic categories: CD30+ T-cell lymphoproliferative disorders (24) all consisting of lymphomatoid papulosis (LyP, 24), lymphoblastic lymphoma (LL, 7), acute leukemias (AL, 7), mycosis fungoides (MF, 5), Epstein-Barr virus-related lymphoproliferative disorders (EBV-related LPD, 5), T/NK-cell lymphoma, nasal type (1), γ/δ T-cell lymphoma (1), and panniculitis-like T-cell lymphoma (1). RESULTS: We encountered a majority of LyP. No secondary lymphoma was found in LyP patients with a median follow-up of 8 years. 29% and 80% of LyP and MF patients, respectively, presented with pityriasis lichenoides chronica (PLC) before onset of disease. Owing to a frequently misleading clinicopathological presentation, MF patients were first underdiagnosed. Clinicopathological features of LL and AL were highly stereotypical, leading to the diagnosis being suspected and confirmed more promptly. In the latter patients and in EBV-related LPD patients, skin lesions usually led to the discovery of systemic disease. CONCLUSION: Distribution of cutaneous hematologic diseases seems to be different in adults and in children aged <15-year old. PLC was strongly correlated with MF and LyP. Physicians must be made aware of the stereotypical clinical presentations of LL and AL to allow prompt diagnosis and treatment.

Connective tissue nevi: an entity revisited.

BACKGROUND: Connective tissue nevi (CTN) may be isolated, either sporadic or hereditary, or syndromic as in the Buschke-Ollendorff syndrome. Few publications have addressed the variable clinical and histopathologic expression of these benign hamartomas. OBJECTIVE: We sought to characterize the clinical and histopathologic features of CTN and to highlight a spectrum of clinical disease. METHODS: We carried out a retrospective study of cases selected after strict clinical and histopathologic confirmation of the diagnosis. RESULTS: A total of 33 patients with CTN were included. The average age of onset was 2 years. Three clinical forms were distinguished: type A with lesions at a single site, with one case presenting as an ulcerated infiltrated plaque; type B with two or more sites of involvement; and type C with unusually severe infiltration with functional impairment of a limb. Histopathologic examination of lesional biopsy specimens showed 10 collagenomas, one elastoma, 18 mixed CTN, and an increased number of fibroblasts in 4 cases. No correlation between clinical type and histopathologic findings was observed. LIMITATION: This was a descriptive case series. CONCLUSIONS: CTN comprise a clinical spectrum ranging from isolated papules to unusually severe aggressive plaques with monomelic involvement. The histopathologic features are heterogeneous and include a newly described variant, which we name "cellular CTN" because of the increased number of fibroblasts.

Cutaneous B-cell lymphoblastic lymphoma in children: a rare diagnosis.

BACKGROUND: Lymphoblastic lymphoma (LBL) is a rare malignant neoplasm usually occurring in the mediastinum of children and adolescents. The B-cell immunophenotype of LBL (B-LBL) accounts for less than 20% of all cases and may involve extramediastinal areas, such as the skin. Although highly aggressive, LBL is potentially curable if diagnosed early. OBJECTIVE: We sought to describe the clinical and histopathologic features of B-LBL in children presenting with cutaneous lesions, and to highlight the specific features of this rare and serious disease. METHODS: Seven children with a confirmed diagnosis of cutaneous B-LBL were identified by retrospective chart review. The clinical and histopathologic features were documented, analyzed, and compared with cases previously published in the literature. RESULTS: Six children developed nodules on the head, and one child presented with lesions on the back and abdomen. Histopathology showed a diffuse dermal and subcutaneous monomorphous infiltrate made up of atypical cells with an immature B-cell phenotype. The average duration of the lesions before diagnosis was 3.2 months. A staging workup revealed extracutaneous disease in 5 patients, including bone-marrow involvement in 4 children. LIMITATIONS: This was a retrospective study with a small number of patients. CONCLUSION: The cutaneous lesions of B-LBL typically manifest as rapidly growing erythematous firm nodules located on the head. Awareness of these clinical features is important for the diagnosis to be reached rapidly and treatment started without delay.

[Place of immunosuppressors in atopic dermatitis]. / Place des traitements immunosuppresseurs au cours de la prise en charge de la dermatite atopique.

Use of immunosuppressors in the treatment of atopic dermatitis is an important innovation that reinforces the therapeutic arsenal in this chronic disease. Two such drugs are used topically for the treatment of atopic dermatitis. Tacrolimus exists in pommade form at a concentration of 0.1% for adults and 0.03% for children. Pimecrolimus, another calcineurine inhibitor with similar efficacy and tolerability, is not marketed in France. These products inhibit cytokine production by antigen-stimulated T lymphocytes. Their clinical efficacy has been demonstrated in many studies in the United States and Europe. They are particularly valuable for patients whose clinical course is marked by disease persistence and frequent flares, which would otherwise require almost continuous topical corticosteroid treatment. Topical calcineurine inhibitors may also have a significant benefit in patients with involvement of sensitive skin areas, such as around the eyes, face, neck and genital area, where systemic absorption and the risk of skin atrophy are particular concerns. The most frequent adverse effects are a local erythema-like reaction with burning and pruritus at the outset of treatment. No significant increase in bacterial or viral infections has been noted by comparison with control groups, and no systemic impact has been reported. However, these drugs should not be used in patients with a history of Kaposi-Juliusberg disease or in patients with herpes. Photoprotection measures must be respected. New trials with tacrolimus show that atopic lesions can be controlled by treating subclinical inflammation twice weekly between flares, thereby preventing flares and prolonging the flare-free interval. This new therapeutic approach is called proactive treatment. The efficacy of oral cyclosporine at 4-5 mg/kg/day in severe forms of atopic dermatitis is now well demonstrated. There is consistent evidence that oral cyclosporin is beneficial in patients whose disease is not adequately controlled by conventional topical therapies, leading to a significant improvement in health-related quality of life. Other immunosuppressors like methotrexate and some biologics (omalizumab, retuximab, etc.) show good efficacy during flares of severe forms, but larger comparative studies are needed before recommending these new treatments in severe atopic dermatitis.

Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases.

Hypohidrotic and anhidrotic ectodermal dysplasia (HED/EDA) is a rare genodermatosis characterized by abnormal development of sweat glands, teeth, and hair. Three disease-causing genes have been hitherto identified, namely, (1) EDA1 accounting for X-linked forms, (2) EDAR, and (3) EDARADD, causing both autosomal dominant and recessive forms. Recently, WNT10A gene was identified as responsible for various autosomal recessive forms of ectodermal dysplasias, including onycho-odonto-dermal dysplasia (OODD) and Schöpf-Schulz-Passarge syndrome. We systematically studied EDA1, EDAR, EDARADD, and WNT10A genes in a large cohort of 65 unrelated patients, of which 61 presented with HED/EDA. A total of 50 mutations (including 32 novel mutations) accounted for 60/65 cases in our series. These four genes accounted for 92% (56/61 patients) of HED/EDA cases: (1) the EDA1 gene was the most common disease-causing gene (58% of cases), (2)WNT10A and EDAR were each responsible for 16% of cases. Moreover, a novel disease locus for dominant HED/EDA mapped to chromosome 14q12-q13.1. Although no clinical differences between patients carrying EDA1, EDAR, or EDARADD mutations could be identified, patients harboring WNT10A mutations displayed distinctive clinical features (marked dental phenotype, no facial dysmorphism), helping to decide which gene should be first investigated in HED/EDA.

Scalp nodules as a presenting sign of fibrodysplasia ossificans progressiva: a register-based study.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by progressive ossification of soft tissues. Clinical diagnosis is important because trauma from lesional biopsies can exacerbate the disease. OBJECTIVE: We sought to evaluate the frequency of scalp nodules as the presenting manifestation of FOP. METHODS: We describe 3 infants with FOP who presented with multiple neonatal scalp nodules. We reviewed all 43 cases of this disorder in the French FOP registry. RESULTS: Scalp nodules were found in 40% of cases and usually represented the first manifestation of the disease. All 43 patients had characteristic skeletal malformations involving the great toes (n = 43), fingers (n = 12), and vertebrae (n = 3). Other abnormalities were cerebral malformations (n = 1) and alopecia (n = 2). Histopathologic analysis did not contribute to the differential diagnosis and was interpreted as cranial fasciitis in two patients. LIMITATIONS: Our study was retrospective, and the presence or absence of scalp nodules was not always recorded. CONCLUSION: Neonatal scalp nodules associated with a characteristic malformation of the great toes are a common presentation of FOP. Physicians should be aware that lesional biopsies can exacerbate the disease and must therefore be avoided. A diagnosis of classic FOP can be confirmed by molecular genetic studies.

Cutaneous findings in sporadic and familial autosomal dominant hyper-IgE syndrome: a retrospective, single-center study of 21 patients diagnosed using molecular analysis.

BACKGROUND: Recent identification of STAT3 mutations in autosomal dominant (AD) hyper-IgE syndrome (HIES) has improved the clinical, genetic, and molecular classification of the HIES. OBJECTIVE: We sought to characterize the cutaneous signs observed in molecularly diagnosed AD-HIES. METHODS: We conducted a retrospective study of 21 patients with AD-HIES and confirmed STAT3 mutations, treated at Necker-Enfants Malades Hospital, Paris, France. RESULTS: A papulopustular rash on the face and scalp before the age of 2 months was observed in 67% of patients. This "early rash" was distinguished from other neonatal pustular eruptions by crusted papules and pustules, rash intensity, and a continuum with chronic dermatitis. An eczematous dermatitis was almost always present before the age of 18 months (95% of patients) and was mainly confined to the face, scalp, chest, and buttocks. All patients presented with infected dermatitis (Staphylococcus aureus) and 59% had chronic candidiasis of the oral mucosa and nails. Cutaneous herpes virus infections were not unusually severe. Coarse facial skin at puberty, and sometimes at a younger age, with prominent follicular ostia resembling atrophoderma vermiculatum was not related to severe acne or facial abscesses. LIMITATIONS: This was a retrospective study with a small number of patients. CONCLUSION: When associated with serum IgE levels 10 times the age-appropriate level, a neonatal papulopustular rash progressing to a chronic impetiginized eczematous dermatitis that differs from classic atopic dermatitis is highly suggestive of AD-HIES. Early recognition is important for initiation of prophylactic antistaphylococcal and antifungal treatment.

Clinical and histologic features of incontinentia pigmenti in adults with nuclear factor-κB essential modulator gene mutations.

BACKGROUND: Incontinentia pigmenti (IP) is a multisystem disorder, in which cutaneous symptoms can be accompanied by dental, ocular, and central nervous system defects. In adults, the clinical diagnosis of IP is based principally on the late onset of stage 4 lesions and their association with dental, nail, ocular, or central nervous system anomalies. Nevertheless, these lesions are often unrecognized. OBJECTIVES: Our aim was assessment of IP manifestations in adults to clarify diagnostic criteria for mild forms of the disease, to help physicians detect adult IP in the presence of subtle lesions and avoid misdiagnosis. METHOD: We conducted clinical and histologic examination of 25 adults with IP and nuclear factor-κB essential modulator gene rearrangement or mutations. RESULTS: Linear atrophic, hypopigmented, and hairless lesions (stage 4) are constant in adults. Apoptotic keratinocytes in the epidermis or dermis and atrophic hair follicles, with absence of arrector pili muscles, are frequently observed. In contrast, nipple anomalies are rare. LIMITATIONS: We were unable to determine the age of the onset of IP stage 4 lesions. CONCLUSION: Skin manifestations are constant in adult patients with IP. Histology is characteristic and could be considered as a minor diagnostic criterion of IP. Nipple anomalies also may be considered as a minor criterion. Detection of such subtle manifestations can evoke IP in patients with repeated miscarriages or unexplained neurologic manifestations.

Neonatal rhabdomyosarcoma misdiagnosed as a congenital hemangioma.

Highly vascularized malignant soft-tissue tumors can clinically and radiologically mimic deep hemangiomas. We present a case of congenital rhabdomyosarcoma of the neck, which was initially identified as congenital hemangioma.

Skin biopsy is helpful for the diagnosis of incontinentia pigmenti at late stage (IV): a series of 26 cutaneous biopsies.

BACKGROUND: Hypochromic streaks can be the only cutaneous sign of incontinentia pigmenti (IP) in adulthood (stage IV). Discovery of such lesions in an adult female with no family history of IP is essential for appropriate genetic counselling. OBJECTIVE: To describe and to validate the histological features of residual skin lesions in adult IP. METHODS: The analysis and comparison of skin biopsies of 26 women affected with molecularly confirmed IP. RESULTS: Most biopsies showed slight atrophy and some scattered apoptotic cells in the epidermis, epidermal hypopigmentation and reduced melanocyte number. The dermis appeared thickened and homogeneous and revealed a complete absence of hair follicles (23/26) and sweat glands (22/26). There was no melanin incontinence or inflammatory cells, and the elastic network was normal. CONCLUSION: These features lead unequivocally to the diagnosis of a stage IV IP skin lesion. Consequently, histology is a major confirmatory criterion for diagnoses of these mild clinical forms of IP. It is therefore a useful tool in genetic counselling and prenatal diagnosis. Moreover, the observations described here may contribute to understanding the physiopathology of the late stages of IP.

Clinical demonstration of skin mildness and suitability for sensitive infant skin of a new baby wipe.

BACKGROUND: A cleansing baby wipe with sufficient pH buffering capacity may help to restore the pH balance of skin following exposure to urine and feces in the diaper environment and maintain skin health. OBJECTIVE: To evaluate the skin effects of a novel baby wipe formulation with increased pH buffering. SUBJECTS AND METHODS: A series of clinical studies was designed and conducted to evaluate the skin effects of the new baby wipe, including a 21-day cumulative skin irritation patch study in adults (n = 31), a 4-week study in babies with medically confirmed atopic dermatitis (n = 32), a 2-week study comparing skin pH of babies (n = 15) following use of wipes compared with water and wash cloth, a series of clinical skin pH measurements following fecal exposure and subsequent cleaning with different products (n = 50) and a study evaluating comfort of product application on irritated skin (n = 31). RESULTS: The wipes formulation was well-tolerated, even in babies with atopic dermatitis, and was more comfortable versus water and washcloth. Increased buffering capacity of a wet wipes lotion helps to maintain a physiologically balanced skin pH value in the diaper region.

Identification of new RECQL4 mutations in Caucasian Rothmund-Thomson patients and analysis of sensitivity to a wide range of genotoxic agents.

Rothmund-Thomson syndrome (RTS), a rare recessive autosomal disorder, presents genome instability and clinical heterogeneity with growth deficiency, skin and bone defects, premature aging symptoms and cancer susceptibility. A subset of RTS patients presents mutations of the RECQL4 gene, member of the RecQ family of DNA helicases, including the RECQL2 (BLM) and RECQL3 (WRN) genes, defective in the cancer prone Bloom and Werner syndromes, respectively. Analysis of the RECQL4 gene in six clinically diagnosed RTS patients shows five patients, including two siblings, with eight mutations mainly located in the helicase domain, three patients presenting two mutations. The alterations include four missense mutations, one nonsense mutation and the same frameshift deletion, g.2881delG in exon 9 found in three patients. Seven RECQL4 polymorphisms, two being new, have also been identified. Primary RTS fibroblasts from these RTS patients show no sensitivity to a wide variety of genotoxic agents including ionizing or ultraviolet irradiation, nitrogen mustard, 4NQO, 8-MOP, Cis-Pt, MMC, H2O2, HU, or UV plus caffeine which could be related to the RECQL4 alterations identified here. This is in contrast with the DNA damage sensitive Bloom and Werner cells and highlights the complexity of the numerous RecQ protein functions implicated in the different cellular pathways required for maintaining genomic integrity.

A clinical, histologic, and molecular study of 9 cases of congenital dermatofibrosarcoma protuberans.

BACKGROUND: The diagnosis of dermatofibrosarcoma protuberans (DFSP) in childhood is often difficult because of the deceptive appearance of the lesions. Little is known about congenital DFSP, the frequency of which is probably underestimated because the initial lesion may pass unnoticed. OBSERVATIONS: We studied 9 DFSP congenital cases (8 plaques and 1 nodule) initially suspected to be benign lesions. The first biopsies or excisions were performed after a delay of 5(1/2) months to 15 years. All cases were CD34+. Histologic patterns were similar to the DFSP adult classic pattern in 4 cases. One case was a Bednar tumor. The histologic diagnosis of the 4 remaining cases was difficult. The collagen, type I, alpha 1-platelet-derived growth factor beta fusion gene (COL1A1-PDGFB) was detected by means of reverse transcriptase-polymerase chain reaction or fluorescence in situ hybridization. CONCLUSIONS: All cases of congenital DFSP were difficult to identify clinically. The diagnosis was suspected by means of histologic and immunohistochemical evaluation and was confirmed using molecular analyses. This study illustrates the difficulties and pitfalls of the recognition of congenital DFSP and emphasizes the value of immunohistochemical study with anti-CD34 and complementary molecular analysis for all cutaneous spindle cell tumors and plaques in neonates and infants.

Clinical management of atopic eczema with pimecrolimus cream 1% (Elidel) in paediatric patients.

Atopic eczema is predominantly a disease of children and infants, and is often a significant burden for both the sufferer and the family. Pimecrolimus cream 1% (Elidel) is a topical calcineurin inhibitor that has been developed for the treatment of inflammatory skin diseases. When applied twice daily, pimecrolimus has been shown to be effective and well tolerated in paediatric patients with mild to moderate atopic eczema, and appears to be particularly suitable for use on the face, the neck and skin folds. Reduction of pruritus or erythema can be seen within 48 hours of initiating treatment, and when used at the first signs or symptoms of recurrence, pimecrolimus can significantly reduce the incidence of flares and the amount of topical corticosteroid used. Long-term pimecrolimus therapy shows that the initial reduction of disease severity (Eczema Area and Severity Index) is sustained and that most patients have minimal residual disease at 2 years. The most common application-site reaction is a mild to moderate, transient, warm/burning sensation occurring in approximately 10% of patients. Blood concentrations of pimecrolimus following topical administration remain low in all patients. Currently there is no evidence for systemic adverse events, immune suppression or alterations in the vaccine response, after short-term or prolonged treatment. In conclusion, pimecrolimus is an effective treatment option for the short-term treatment and long-term control of atopic eczema in paediatric patients.

Adjuvant treatment with the bacterial lysate (OM-85) improves management of atopic dermatitis: A randomized study.

BACKGROUND: Environmental factors play a major role on atopic dermatitis (AD) which shows a constant rise in prevalence in western countries over the last decades. The Hygiene Hypothesis suggesting an inverse relationship between incidence of infections and the increase in atopic diseases in these countries, is one of the working hypothesis proposed to explain this trend. OBJECTIVE: This study tested the efficacy and safety of oral administration of the bacterial lysate OM-85 (Broncho-Vaxom®, Broncho-Munal®, Ommunal®, Paxoral®, Vaxoral®), in the treatment of established AD in children. METHODS: Children aged 6 months to 7 years, with confirmed AD diagnosis, were randomized in a double-blind, placebo-controlled trial to receive, in addition to conventional treatment with emollients and topical corticosteroids, 3.5mg of the bacterial extract OM-85 or placebo daily for 9 months. The primary end-point was the difference between groups in the occurrence of new flares (NF) during the study period, evaluated by Hazard Ratio (HR) derived from conditional Cox proportional hazard regression models accounting for repeated events. RESULTS: Among the 179 randomized children, 170 were analysed, 88 in the OM-85 and 82 in the placebo group. As expected most children in both treatment groups experienced at least 1 NF during the study period (75 (85%) patients in the OM-85 group and 72 (88%) in the placebo group). Patients treated with OM-85 as adjuvant therapy had significantly fewer and delayed NFs (HR of repeated flares = 0.80; 95% confidence interval (CI): 0.67-0.96), also when potential confounding factors, as family history of atopy and corticosteroids use, were taken into account (HR = 0.82; 95% CI: 0.69-0.98). No major side effect was reported, with comparable and good tolerability for OM-85 and placebo. CONCLUSIONS: Results show an adjuvant therapeutic effect of a well standardized bacterial lysate OM-85 on established AD.

Presence of chimeric maternally derived keratinocytes in cutaneous inflammatory diseases of children: the example of pityriasis lichenoides.

During pregnancy, maternal cells may enter the fetal circulation and persist until adulthood. The fate of these cells remains unknown. As unexplained T-cell-mediated conditions such as pityriasis lichenoides (PL) may occur in children, we aimed at identifying maternal cells in lesional skin of PL and controls. Archived skin biopsy specimens from young males with PL, atopic dermatitis, or normal skin were scanned for the presence of female (presumably maternal) cells using fluorescence in situ hybridization (FISH) with X and Y chromosome-specific probes. Phenotyping of maternal cells relied on FISH combined with anti-CD45, anti-CD1a, or anti-cytokeratin labelling, identifying leukocytes, Langerhans cells, and keratinocytes, respectively. Maternal cells were found in PL (11/12) and controls (4/7), but their average frequency was higher in PL: 99 per million cells as compared to 5 per million cells in controls (P = 0.005). In the epidermis, the maternal microchimeric cells were labelled by anti-cytokeratin in all cases. We identified maternally derived keratinocytes in the skin of male children with inflammatory skin disorders. These cells may either help repair the damaged skin or home initially in the skin and trigger a host (child) versus graft (mother) disease.

Three severe cases of EBS Dowling-Meara caused by missense and frameshift mutations in the keratin 14 gene.

We report three unrelated patients affected at birth with an unusually severe form of epidermolysis bullosa simplex Dowling-Meara type (EBS-DM) because of mutations in KRT14 encoding keratin 14. Two patients were heterozygous for the previously described p.M119T mutation. The third patient was heterozygous for a novel c.1246delC mutation predicting the replacement of the helix termination peptide and the tail domain by a 25 amino-acid aberrant carboxyterminal sequence. At age 2 years, patients carrying the p.M119T mutation still suffered from severe EBS-DM, whereas the patient harboring the c.1246delC mutation has improved over time. These cases illustrate genotype-phenotype correlations and have implications for genetic counselling of EBS.

Acne in recipients of renal transplantation treated with sirolimus: clinical, microbiologic, histologic, therapeutic, and pathogenic aspects.

We evaluated the clinical characteristics of sirolimus-induced acne in 80 recipients of renal transplantation. It developed in 36 of 48 (75%) men and 2 of 32 (6%) women. Lesion locations and clinical, bacteriologic, and histologic features differentiated sirolimus-induced acne from acne vulgaris, but therapeutic management was similar. The main limitation for this study was the absence of a control group without sirolimus. Epidermal growth factor inhibition by sirolimus is a plausible explanation for this acne.