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.

[Oral and maxillofacial surgery in The Netherlands: from Esser until today]. / Mondziekten, kaak- en aangezichtschirurgie in Nederland: van Esser tot heden.

In 2006, it was 50 years ago that the oral and maxillofacial surgery was officially recognized as a dental speciality in The Netherlands. During those five decades, oral and maxillofacial surgery significantly evolved, which is nicely reflected by the changes in the name of the scientific society supporting the speciality. Originally its name was The Netherlands Society for Oral Surgery and Surgical Prosthodontics, but in 1975 its name was changed into The Netherlands Society for Oral Medicine and Oral Surgery, and in 2006 into The Netherlands Society for Oral Medicine and Oral and Maxillofacial Surgery. Esser is considered to be the first oral and maxillofacial surgeon in The Netherlands. In The Netherlands, 2 schools of oral and maxillofacial surgery are recognized: the Utrecht School with Tjebbes as its founder and the Groningen School with Hut as its founder. Because of the 50th anniversary of the speciality, a thematic issue of the Dutch Journal of Dentistry offers a review of the current status of and expected future developments in oral medicine, head and neck oncology, maxillofacial traumatology, growth and development disorders of the maxillofacial skeleton, temporomandibular joint disorders and reconstructive surgery in The Netherlands.

[Diagnosis image (251). A man with a tongue ulcer]. / Diagnose in beeld (251). Een man met een tongulcus.

A 23-year-old man presented with a left-sided tongue ulcer caused by a squamous cell carcinoma.

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.

Novel types of mutation responsible for the dermatosparactic type of Ehlers-Danlos syndrome (Type VIIC) and common polymorphisms in the ADAMTS2 gene.

Ehlers-Danlos syndrome (EDS) type VIIC, or dermatosparactic type, is a recessively inherited connective tissue disorder characterized, among other symptoms, by an extreme skin fragility resulting from mutations inactivating ADAMTS-2, an enzyme excising the aminopropeptide of procollagens type I, II, and III. All previously described mutations create premature stop codons leading to a marked reduction in the level of mRNA. In this study, we analyzed the ADAMTS2 cDNA sequences from five patients displaying clinical and/or biochemical features consistent with a diagnosis of either typical or potentially mild form of EDS type VIIC. Three different alterations were detected in the two patients with typical EDS type VIIC. The first patient was homozygous for a genomic deletion causing an in-frame skipping of exons 3-5 in the transcript. In the second patient, the allele inherited from the mother lacks exon 3, generating a premature stop codon, whereas the paternal allele has a genomic deletion resulting in an in-frame skipping of exons 14-16 at the mRNA level. Although the exons 3-5 or 14-16 encode protein domains that have not been previously recognized as crucial for ADAMTS-2 activity, the aminoprocollagen processing was strongly impaired in vitro and in vivo, providing evidence for the requirement of these domains for proper enzyme function. The three other patients with a phenotype with some resemblance to EDS type VIIC only had silent and functionally neutral variations also frequently found in a normal population.

Features of epidermolysis bullosa simplex due to mutations in the ectodomain of type XVII collagen.

BACKGROUND: Mutations in COL17A1, coding for type XVII collagen, cause junctional epidermolysis bullosa with an ultrastructural plane of cleavage through the lamina lucida of the epidermal basement membrane. OBJECTIVES: To identify the COL17A1 mutations in a child with reduced type XVII collagen expression and intraepidermal blister formation. PATIENT AND METHODS: Protein expression and level of tissue separation were studied by immunofluorescence and electron microscopy. The mutations were identified by analysing the patient's DNA and mRNA. RESULTS: Immunofluorescence microscopy performed on nonlesional skin demonstrated absence of the type XVII collagen endodomain and presence, although reduced, of the shed ectodomain. Electron microscopy showed that the plane of cleavage was through the basal cells, not through the lamina lucida. Two heterozygous mutations were identified in COL17A1: a new 3'-acceptor splice-site mutation in intron 21 (1877-2A-->C), and a deletion in exon 48 (3432delT). The splice-site mutation in intron 21 results in alternative transcripts of which two are in-frame, with deletions of the first nine codons of exon 22 and the entire exon 22, respectively. By Western blot analysis, a type XVII collagen molecule was detected that was slightly smaller than normal. CONCLUSIONS: Occasionally mutations in the COL17A1 gene may result in split levels suggesting epidermolysis bullosa simplex rather than junctional epidermolysis bullosa.

Acquired arteriovenous malformation induced by pressure: a case report.

Arteriovenous malformations may be congenital or acquired. In the latter case, usually a traumatic injury to the arteries precedes the arteriovenous anastomoses. Two elderly patients presented with large, purple-colored verrucous tumors on the buttocks. Both patients were obese and immobile, and reported repeated bleeding from the lesions after minor trauma. The tumors were soft and could be emptied by applying pressure. Doppler examination revealed arterial pulsations over the lesions. Both cases were diagnosed as pressure-induced arteriovenous malformations. The lesions are assumed to have been caused by tissue damage in the deep subcutis induced by decubitus.

[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.

[Two neonates with vesicular skin lesions due to incontinentia pigmenti]. / Twee pasgeborenen met blaasjes door incontinentia pigmenti.

In two neonate girls with vesicular skin lesions, incontinentia pigmenti (Bloch-Sulzberger syndrome) was diagnosed. This rare X-linked dominant ectodermal disease can cause abnormalities in several organ systems. Most prominent are the dermatological abnormalities, developing in 4 stages: the vesicular stage, the verrucous stage, the hyperpigmentation phase, and the atrophic phase. In addition to the cutaneous manifestations, many patients have anomalies of nails, hair and teeth. Serious related abnormalities of the eyes (intraocular vasculopathy) and central nervous system (convulsions, mental retardation) may occur. In 1989 the locus for the incontinentia pigmenti mutation was shown to be present on Xq28. Recently it was shown that the causative mutation is located on the NEMO ('NF-kappa B essential modulator') gene. A NEMO knock-out mouse model shows a dermatopathy of a transient nature, resembling the skin lesions in patients with incontinentia pigmenti.

[Acute hemorrhagic edema of childhood and its differentiation from Schoenlein-Henoch purpura]. / Acuut hemorragisch oedeem van de kinderleeftijd en het onderscheid met Henoch-Schönlein-purpura.

In two young patients with an elevated temperature, a girl aged 6 months and a boy aged 10 months, purpura and oedema were noticed on the face, ears, arms and legs. On one occasion the boy lost blood anally. A histopathological examination revealed leucocytoclastic vasculitis with fibrin deposits. The diagnosis was 'acute haemorrhagic oedema of infancy' (AHOI), a relatively unknown variant of palpable purpura due to leucocytoclastic vasculitis affecting infants and young children (up to two years of age). AHOI is characterised clinically by marked oedema and fever as well as large palpable purpuric and ecchymotic skin lesions in a target-like pattern mainly on the face, ears and extremities. The skin lesions heal spontaneously within one to three weeks and internal organs are rarely affected. This is in contrast to Henoch-Schönlein purpura, which was observed in a 5-year old boy suffering from similar skin lesions on the legs as well as painful joints, in whom IgA deposits were found in the vasculitis. Henoch-Schönlein purpura is clinically characterised by palpable purpura on the extensor surfaces of the legs and on the buttocks, whereas in AHOI larger purpura and ecchymoses are found on the face, ankles and wrists, with far more extensive oedema. There are also histological differences: in AHOI there is more extensive vasculitis with fibrin deposits and IgA deposits are seen in a minority of cases. Awareness of this relatively unknown form of leucocytoclastic vasculitis will assist in making an early diagnosis possible, thereby avoiding unnecessary treatment and concern.

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.