Discrepancy between the clinical and histopathologic diagnosis of soft tissue vascular malformations.

BACKGROUND: Soft tissue vascular malformations are generally diagnosed clinically, according to the International Society for the Study of Vascular Anomalies (ISSVA) classification. Diagnostic histopathologic examination is rarely performed. OBJECTIVE: We sought to evaluate the validity of the current diagnostic workup without routinely performed diagnostic histopathology. METHODS: We retrospectively determined whether there were discrepancies between clinical and histopathologic diagnoses of patients with clinically diagnosed vascular malformations undergoing therapeutic surgical resections in our center (2000-2015). Beforehand, a pathologist revised the histopathologic diagnoses according to the ISSVA classification. RESULTS: Clinical and histopathologic diagnoses were discrepant in 57% of 142 cases. In these cases, the pathologist indicated the diagnosis was not at all a vascular malformation (n = 24; 17%), a completely different type of vascular malformation (n = 26; 18%), or a partially different type with regard to the combination of vessel-types involved (n = 31; 22%). Possible factors associated with the discrepancies were both clinician-related (eg, diagnostic uncertainty) and pathology-related (eg, lack of immunostaining). LIMITATIONS: Retrospective analysis of a subgroup of patients undergoing surgery. CONCLUSION: The large discrepancy between clinical and histopathologic diagnoses raises doubt about the validity of the current diagnostic workup for vascular malformations. Clear clinical and histopathologic diagnostic criteria might be essential for a uniform diagnosis.

No detectable beneficial systemic immunomodulatory effects of a specific synbiotic mixture in infants with atopic dermatitis.

BACKGROUND: In a murine model of allergic inflammation, Bifidobacterium breve M-16V has been shown to reduce IL-4 and IgE by inducing IL-10 and IFN-γ. However, it remains unknown whether this strain has the same effect in humans with allergic disease. OBJECTIVE: To determine the effects of Bifidobacterium breve M-16V combined with a prebiotic oligosaccharide mixture (synbiotic) on atopic markers, ex vivo cytokine production by peripheral blood mononuclear cells (PBMCs) and circulating regulatory T cell percentage in infants with atopic dermatitis. METHODS: In a double-blind, placebo-controlled multi-centre trial, 90 infants with atopic dermatitis, age <7 months, were randomized to receive an infant formula with Bifidobacterium breve M-16V and a mixture of short chain galactooligosaccharides and long chain fructooligosaccharides (Immunofortis(®) ), or the same formula without synbiotics during 12 weeks. At week 0 and 12, plasma levels of IL-5, IgG1, IgG4, CTACK and TARC, ex vivo cytokine responses by PBMCs and percentage of regulatory T cells, were determined. RESULTS: There were no significant differences between the synbiotic and the placebo group in IL-5, IgG1, IgG4, CTACK and TARC levels and ex vivo cytokine production by anti-CD3/anti-CD28-stimulated PBMCs. With allergen-specific stimuli, we found a decreased IL-12p40/70 and IL-12p70 production in response to egg allergen (P = 0.04 and P = 0.01, respectively) and decreased IL-12p70 production in response to peanut allergen (P = 0.003) in the synbiotic compared with the placebo group. Circulating regulatory T cell percentage did not significantly differ between the groups. CONCLUSIONS AND CLINICAL RELEVANCE: This synbiotic mixture has no detectable effect on plasma levels of the analysed atopic disease markers, ex vivo cytokine production and circulating regulatory T cell percentage in infants with atopic dermatitis, besides down-regulation of IL-12 production in egg- and peanut-stimulated PBMCs. These results do not support the use of this synbiotic in clinical practice.

Effect of a new synbiotic mixture on atopic dermatitis in infants: a randomized-controlled trial.

BACKGROUND: Clinical trials investigating the therapeutic effect of probiotics on atopic dermatitis (AD) show inconsistent results. Better results can possibly be achieved by combining probiotics with prebiotics, i.e. synbiotics. OBJECTIVE: To investigate the therapeutic effect of a synbiotic mixture on the severity of AD in infants. METHODS: In a double-blind, placebo-controlled multi-centre trial, 90 infants with AD [SCORing Atopic Dermatitis (SCORAD) score > or =15], aged < 7 months and exclusively formula fed, were randomly assigned to receive either an extensively hydrolysed formula with Bifidobacterium breve M-16V and a galacto-/fructooligosaccharide mixture (Immunofortis), or the same formula without synbiotics for 12 weeks. The primary outcome was severity of AD, assessed using the SCORAD index. A secondary outcome measure was intestinal microbiota composition. RESULTS: There was no difference in SCORAD score improvement between the synbiotic and the placebo group. The synbiotic group did have a significantly higher percentage of bifidobacteria (54.7% vs. 30.1%, P<0.001) and significantly lower percentages of Clostridium lituseburense/Clostridium histolyticum (0.5 vs. 1.8, P=0.02) and Eubacterium rectale/Clostridium coccoides (7.5 vs. 38.1, P<0.001) after intervention than the placebo group. In the subgroup of infants with IgE-associated AD (n=48), SCORAD score improvement was significantly greater in the synbiotic than in the placebo group at week 12 (-18.1 vs. -13.5 points, P=0.04). CONCLUSIONS: This synbiotic mixture does not have a beneficial effect on AD severity in infants, although it does successfully modulate their intestinal microbiota. Further randomized-controlled trials should explore a possible beneficial effect in IgE-associated AD.

[Doctors and their sins--doctor, why did you do that?]. / De dokter en zijn zonden--dokter, waarom doet u dat nou?

A medical doctor and a lawyer searched for the seven deadly sins in medical case law, the media and stories from daily practice. It appears that the temptations of the seven sins hide behind many of the minor and major malpractice incidents in medical care. These sins are considered worse when not conceded. Patients, but also colleagues, the judiciary and society are more forgiving if medical doctors recognize and admit to their sins.

[The practice guideline 'atopic dermatitis']. / Richtlijn 'Constitutioneel eczeem'.

Since clear evidence is lacking that avoidance of exposure to inhalation or food allergens will have a favourable effect on the course of atopic dermatitis, allergological screening should be restricted to patients having acute allergic symptoms. Topical corticosteroids are the treatment of choice. The working group recommends starting with a class 2-3 corticosteroid daily followed by intermittent maintenance therapy with a corticosteroid of the same class or daily administration of a class 1 corticosteroid. When used in this way, corticosteroids are safe as far as local and systemic side effects are concerned; patients with severe atopic dermatitis have decreased serum-cortisol levels but this is due to the illness and not the corticosteroid. Serum-cortisol levels will usually return to normal following topical steroid therapy. Topical calcineurin inhibitors are a good second-line alternative for patients in whom corticosteroids are insufficiently effective or produce side effects. During such treatment, the skin should be protected against ultraviolet light. Non-sedating antihistamines have no place in the treatment of atopic dermatitis. Cyclosporin is the agent of choice for the systemic treatment of severe atopic dermatitis. The attending physician should also pay attention to psychosocial factors, since severe eczema in children, their parents and adults has a serious impact on the quality of life. Patients with severe atopic dermatitis should be discouraged from working in a wet environment. Patients with moderately active atopic dermatitis without eczema of the hands should avoid exposure to water and other irritating factors.

Classification of congenital melanocytic naevi and malignant transformation: a review of the literature.

INTRODUCTION: Congenital naevi (CN) vary greatly in size, macroscopic appearance and histology. There is a practical need to subdivide CN according to size, since size differences have a direct bearing on cosmetic and resultant psychological problems, and on therapeutic options, and probably on the chance of malignant transformation. In this review, we summarise the literature on size subgroupings of CN, with special focus on giant congenital naevi and their risk of malignant transformation. MATERIALS AND METHODS: A Medline literature search from 1966 to October 2002 was performed. Only English-language studies focusing on CN in association with melanoma were included. The final strategy consisted of textwords and medical subject heading (MeSH) terms on small, medium, large and giant congenital naevi combined with the textwords classification, histology and melanoma. Additional manual cross-referencing was performed. We excluded articles that dealt only with aspects of treatments. RESULTS: A wide variety of criteria for size subgrouping of CN has been put forward in the literature and precludes a direct comparison of reported data (Table 1). We identified 35 such articles in the world literature in which no less than seven different definitions of minimum size of a giant CN were employed. Histologically, it is difficult or even impossible to conclude that a naevus is congenital or acquired, especially in case of a small lesion, since the differences are not absolute (Table 2). Giant CN have an increased risk for malignant transformation, but the reported incidence rates have differed widely from one to 31% (Table 3). Reported melanoma incidence rates have derived from retro- and prospective studies, reviews and case reports, and compared with each other using different definitions. On top of this, patients in different age groups were reported, who were registered in different referral centers. CONCLUSION: To allow comparison of study results from different centers, it is essential that the size subclassification of CN is based on standard and generally accepted criteria. We recommend defining GCN as a CN covering one percent body surface area in face and neck and two percent elsewhere on the body. Based on a review of the world literature, we recommend prophylactic excision of all CN, in close communication with patient and family and individualising treatment accordingly.

[Constitutional eczema; the possibilities of local treatment]. / Constitutioneel eczeem; de mogelijkheden van lokale therapie.

Atopic dermatitis is a common skin disease with a major impact on the quality of life. The cause of this disease is unknown and the diagnosis is made using a set of diagnostic features. In very moderate cases topical treatment of the dry skin may be sufficient. In more severe cases topical treatment with corticosteroids is recommended. Dependent on the steroid used and the severity of the eczema, different application schemes and treatment methods may be used. In exceptional cases, tar derivatives, topical antibacterial compounds and non-steroidal anti-inflammatory drugs may be applied. In the near future, the limited therapeutic arsenal of topically effective substances will almost certainly be extended to include drugs such as tacrolimus and pimecrolimus with an inhibiting effect on inflammatory cytokines.

The millennium criteria for the diagnosis of atopic dermatitis.

Atopic dermatitis forms an active area of basic and clinical research, where important new knowledge about genetics and immunopathogenesis has surfaced over the past years, and where simultaneous development of new and innovative therapies is under way. However, the inclusion of any patient in an atopic dermatitis study, whether it is on its genetics, pathogenesis or therapy, requires a diagnosis which is irrefutable. Since there is no simple and also no complicated laboratory procedure to reach a diagnosis of atopic dermatitis, different sets of clinical criteria have been developed for the purpose of making the diagnosis uniformly in different studies as well as in different study centers. The most commonly used are Hanifin and Rajka's set of diagnostic features, which have major and minor clinical criteria to be fulfilled in order to establish a diagnosis of atopic dermatitis. Recent developments in the immunology of atopy have clearly established the major abnormality in this syndrome, the preferential production of allergen-specific IgE. In this contribution, it is suggested that the presence of such antibodies in a given patient should be a mandatory criterium for the diagnosis of atopic dermatitis. Such a diagnostic test however establishes a diagnosis of atopic syndrome, not atopic dermatitis. Thus, for atopic dermatitis we have to rely, for the time being, on additional clinical criteria. The clinical features described in the literature are critically evaluated, and it is suggested that in addition to the mandatory presence of allergen-specific IgE, 2 of 3 principal criteria (pruritus, typical morphology and distribution, chronic or chronically relapsing) should be present for such a diagnosis. Finally, the minor features originally described by Hanifin and Rajka and later evaluated by others are revised and divided over 4 subcategories; a) related to subclinical eczema; b) related to dry skin; c) extra skin folds; and d) ophthalmological pathology. They are suggested to be used as additional criteria only, needed when clinical suspicion is high but the new mandatory and principal diagnostic criteria described here are inconclusive. For study purposes, we suggest that the mandatory and principal criteria are sufficient. They are now evaluated and validated in ongoing atopic dermatitis treatment studies.

Keratin 17 mutations cause either steatocystoma multiplex or pachyonychia congenita type 2.

Pachyonychia congenita type 2 (PC-2; Jackson-Lawler syndrome) is an autosomal dominant disorder characterized by hypertrophic nail dystrophy, mild focal keratoderma, multiple pilosebaceous cysts and other features of ectodermal dysplasia. Keratin 17 (K17) is a differentiation-specific keratin expressed in the nail bed, hair follicle, sebaceous gland and other epidermal appendages. Previously, we have demonstrated that PC-2 is caused by mutations in K17 and that similar mutations in this gene can present as steatocystoma multiplex with little or no nail dystrophy. Here, we describe three unrelated kindreds carrying K17 mutations. Two of these families have identical missense mutations (R94C) in the 1A domain of K17. However, while affected members of one kindred have the classical features of PC-2, affected persons in the other family have the steatocystoma multiplex phenotype. In a third family with PC-2, mutation N92S was detected, bringing the total number of distinct mutations reported in K17 thus far to 11. These results demonstrate that K17 mutations commonly underlie both PC-2 and steatocystoma multiplex and that the alternate phenotypes which arise from these genetic lesions in K17 are independent of the specific mutation involved.

Iatrogenic isolated isoleucine deficiency as the cause of an acrodermatitis enteropathica-like syndrome.

We present two patients with a suspected inborn error of metabolism. A female newborn presented with dysmorphic features and convulsions. Metabolic screening suggested a defect in isoleucine degradation. Within 2 weeks after the introduction of an isoleucine-restricted diet, she developed a severe acrodermatitis enteropathica-like syndrome. The plasma level of isoleucine was low with a normal leucine/isoleucine ratio. The second patient, a female infant deficient in leucine as a result of a leucine-restricted diet, did not develop a dermatosis. Isoleucine is essential for normal growth and differentiation of keratinocytes and enterocytes. Deficiency of isoleucine, and not leucine or an imbalance in the leucine/isoleucine ratio, may result in an acrodermatitis enteropathica-like syndrome.

Chronic bullous disease of childhood and a paecilomyces lung infection in chronic granulomatous disease.

A 12 year old boy suffering from p67-phox deficient chronic granulomatous disease presented with a bullous skin disease and a lung infection with paecilomyces species. The histopathology of a bullous lesion showed subepidermal blister formation and microabcesses containing eosinophils in the dermal papillae. By direct immunofluorescence, linear staining of IgA at the dermal-epidermal junction was detected which confirmed the clinical diagnosis of chronic bullous disease of childhood (linear IgA dermatosis).

[Neurofibromatosis type 1: a survey of 195 patients]. / Neurofibromatosis type 1: een overzicht van 196 patiënten.

OBJECTIVE: To analyse symptoms and complications in patients with neurofibromatosis type 1 (NF1). All patients were examined in a multidisciplinary outpatient neurofibromatosis clinic during a period of 10 years. DESIGN: Retrospective. SETTING: Academic Medical Center, University Hospital Amsterdam, the Netherlands. METHOD: All data on 450 persons visiting the neurofibromatosis clinic were stored in a database. Data were collected on the results of dermatological, neurological, ophthalmological and general examinations and on family history. For this study the follow-up data of 196 patients with a definite diagnosis of 'NF1' were analysed. RESULTS: In childhood diagnosis NF1 is predominantly based on specific dermatological symptoms such as > 6 café-au-lait (CAL) spots and freckling and on the presence of characteristic ophthalmological signs as two or more Lisch nodules. In this study the frequencies of these symptoms were 98% (CAL). 92% (freckles), and 93% (Lisch nodules) respectively. The frequencies of well-known complications of this disorder are comparable with the literature findings. In this study we found optic pathway glioma (OPG) in 10%, macrocephaly in 36%, hydrocephalus in 5%, retardation in 14%, brain tumours in 5%, kyphoscoliosis in 13%. renal artery stenosis in 0.5% and neurofibrosarcoma in 0.5% of NF1 patients. In children the degree of severity of this disorder is less than in adults, demonstrating the progressive character of the disease. CONCLUSION: The diagnosis of 'NF1' can usually be made by dermatological and ophthalmological examination. In case of a definite diagnosis in childhood regular follow-up is recommended since severe complications, such as OPG and kyphoscoliosis, may occur specifically in childhood and adolescence. For adult patients determination of the degree of severity is essential for the decision whether or not they need regular follow-up; they should have their blood pressure measured annually.

Immune dysregulation in atopic eczema.

BACKGROUND: In this review, present knowledge of atopic eczema immunopathogenesis is summarized, emphasizing recent new findings. Systemic abnormalities in cell-mediated immunity have not been demonstrated firmly in patients with atopic eczema. Within the skin itself, there is evidence for decreased cell-mediated immunity, which is partially correlated with the severity of skin disease. Atopic eczema, however, cannot be regarded as a direct result of decreased cutaneous cell-mediated immunity, since immunophenotyping studies have revealed activated T cells as well as dendritic cells within involved skin. In addition, disease marker studies in peripheral blood indicate vigorous T-cell activation in atopic dermatitis. OBSERVATIONS: The original observation of IgE molecules on the membranes of Langerhans cells may indicate trapping of IgE allergen complexes, their processing, and subsequent presentation to allergen-specific T cells within involved skin. Recent findings as to the abnormal regulation of IgE synthesis in atopy point to a preferential expansion of interleukin 4 and interleukin 5 producing allergen-specific T cells, leading to increased production of interleukin 4 and thus increased levels of allergen-specific IgE. We have prepared atopic skin as well as peripheral blood-derived T-cell clones and determined their specificity and cytokine production profile. Results indicate in situ production of interleukin 4 and interleukin 5 within involved skin in response to environmental antigens. CONCLUSIONS: These new findings as to the basis of IgE dysregulation in atopy, as well as to the identification of an abnormal cytokine secretion pattern by T cells presumed to be central in immunopathogenesis of atopy-related disorders, suggest a distorted and cytokine-mediated self-perpetuating response of the skin immune system to environmental allergen(s) in the pathogenesis of skin disease in atopy. These observations may have important implications for the development of new therapies for atopic eczema.

The skin in severe combined immunodeficiency: a case with transient cutaneous presence of gamma/delta (TRC1+) T cells.

We report the case of a boy with severe combined immunodeficiency (SCID) and serious skin problems. The level of purine 5'-nucleotidase was greatly reduced in the lymphocytes of this patient. To our knowledge, no patients with SCID and this enzyme deficiency have been described previously. The relationship between reduced levels of this enzyme and the immunodeficiency is unclear. This case is also unusual because of the presence of large numbers of T lymphocytes expressing TCR1 (gamma/delta) in the skin. Moreover, the presence of so many TCR1-positive cells was not consistent with the low numbers of these cells in the peripheral blood. These cells were not present in skin biopsies taken at a later stage during the course of the disease. An oligoclonal lymphocytosis developed during follow-up, and a monoclonal antibody reactive with these clones was found, indicating that these lymphocytes were present in the skin. This case report illustrates the benefit of the use of monoclonal antibodies in identifying the cells involved in the cutaneous inflammation in SCID, in order to gain a better insight into the characteristics of these cells.