Rarities in rare: illuminating the microvascular and dermal status in juvenile localised scleroderma. A case series.

OBJECTIVES: To assess the (structural and functional) characteristics of the microvascular and dermal status in juvenile localised scleroderma (jLoS), using novel non-invasive standardised research tools commonly used in adult systemic sclerosis (SSc). METHODS: Ten consecutive patients with a confirmed jLoS diagnosis were studied cross-sectionally in this two-centre case series. For each patient, the most prominent lesion (i.e., "target lesion") was chosen for further examination of the centre, edge and contralateral unaffected site. High-frequency ultrasonography was used to determine dermal thickness, durometer for skin hardness, and laser speckle contrast analysis (LASCA) for a dynamical evaluation of the microcirculation. The structure of the microcirculation was evaluated at the nailfolds of the 2nd-5th finger bilaterally, using nailfold videocapillaroscopy (NVC). RESULTS: 6 linear and 4 plaque subtype jLoS lesions were included. Dermal thickness was thinner at the centre of the "target lesions" vs. the edges (p<0.001) and control sites (p<0.001). Skin hardness was harder at the centre of the "target lesions" vs. the edges (p=0.012) and control sites (p=0.003). A higher perfusion was found in the centre of the "target lesion" (124.87±66.40 PU) vs. the edges (87.27±46.40 PU; p<0.001) and control sites (67.85±37.49; p<0.001). Of note, all patients had a "non-scleroderma" pattern on NVC. CONCLUSIONS: This case series suggests the supportive value of both microcirculatory and dermal assessments of skin lesions using novel non-invasive research tools, adopted from adult SSc, for (j)LoS.

Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis.

Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1ß secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1ß at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation.

Identification of Codon 146 KRAS Variants in Isolated Epidermal Nevus and Multiple Lesions in Oculoectodermal Syndrome: Confirmation of the Phenotypic Continuum of Mosaic RASopathies.

Mosaic RASopathies are a molecularly heterogeneous group of (neuro)cutaneous syndromes with high phenotypical variability. Postzygotic variants in KRAS have been described in oculoectodermal syndrome (OES), encephalocraniocutaneous lipomatosis (ECCL) and epidermal nevus syndrome (ENS). This study confirms the continuum of mosaic neurocutaneous RASopathies showing codon 146 KRAS variants in an individual with OES and, for the first time, in an individual with (isolated) epidermal nevus. The presence of a nevus psiloliparus in individuals with OES indicates that this finding is not specific for ECCL and highlights the phenotypical overlap between ECCL and OES. The presence of the somatic KRAS variant in the nevus psiloliparus resolves the underlying molecular etiology of this fatty-tissue nevus. In addition, this finding refutes the theory of non-allelic twin-spotting as an underlying hypothesis to explain the concurrent presence of two different mosaicisms in one individual. The identification of codon 146 KRAS variants in isolated epidermal nevus introduces a new hot spot for this condition, which is useful for increasing molecular genetic testing using targeted gene sequencing panels.

Coexistence of systemic and localized scleroderma: a systematic literature review and observational cohort study.

OBJECTIVE: SSc and localized sclerosis (LoS) are considered clinically distinct entities. We describe herein the coexistence of SSc and LoS by both a systematic literature review and an observational cohort study of unselected SSc patients. METHODS: Original studies documenting the coexistence of SSc and LoS were identified in three electronic databases by means of a systematic literature search according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Additionally, the coexistence of SSc and LoS was studied in a prospective cohort of SSc patients visiting the Ghent University Scleroderma Unit for their yearly follow-up visit between January 2018 and January 2019. RESULTS: Five studies were finally included for quality appraisal and data extraction. The coexistence of SSc and LoS ranged between 2.4 and 7.4%. RP, scleroderma pattern on nailfold videocapillaroscopy (NVC) and the presence of SSc-specific antibodies were commonly observed in coexistent cases. Additionally, coexistence of SSc and LoS was found in 8/296 (2.7%) consecutive SSc patients of the Ghent University Scleroderma Unit. RP was present in 6/8 coexistent cases; a scleroderma pattern on NVC was observed in all coexistent cases, and SSc-specific antibodies (i.e. cenp-B) were found in 4/8 coexistent cases. CONCLUSION: This is the first systematic literature review with additional cohort evaluation investigating the coexistence of SSc and LoS. A relatively high overlap of SSc and LoS was revealed, which is peculiar because both are rare diseases.

Pitfalls in the detection of myositis specific antibodies by lineblot in clinically suspected idiopathic inflammatory myopathy.

OBJECTIVES: Today, the contribution of myositis-specific autoantibodies (MSA) in the diagnostic workup of idiopathic inflammatory myopathies (IIM) is on the rise. The aim of this study was to document MSA frequency as detected by lineblot in a set of consecutive MSA requests and to correlate the results with clinical diagnosis, IIM subtype and indirect immunofluorescence (IIF) findings. Additionally, a comparison between two lineblots was performed. METHODS: A total of 118 consecutive samples of patients with suspicion of IIM were analysed on IIF and two lineblots. A total of 107 patients with autoimmune rheumatic diseases served as controls. RESULTS: MSA were detected in 55% of IIM patients (n=31) and 7.9% (n=12) of patients without clinical diagnosis of IIM or myositis overlap syndrome. All the IIM patients had a MSA-compatible clinical subtype. There was no to fair agreement between both lineblots for the individual antibodies, with most discrepancies observed for anti-TIF1γ (κ=-0.021), anti-SRP (κ=-0.006) and anti-SAE (κ=0.395). Differences between both assays were mostly observed in the non-IIM patients, also showing signi cantly lower blot signal intensities compared to IIM patients (p=0.0013). MSA in the non-IIM patients frequently showed an incompatible IIF pattern. CONCLUSIONS: Lineblot seems to be an interesting tool for MSA detection in a clinical context, allowing the identification of clinical subtypes. However, considerable caution must be exercised in interpreting the results in case of low positive MSA signal intensity, discordant lineblot results and/or an incompatible IIF pattern.

Correction: Arterial tortuosity syndrome: 40 new families and literature review.

In the published version of this paper the author Neus Baena's name was incorrectly given as Neus Baena Diez. This has now been corrected in both the HTML and PDF versions of the paper.

Care for children with severe chronic skin diseases.

In this study, the care for children with a severe chronic skin disease in our national expert center of pediatric dermatology was evaluated. Patients and their parents were questioned by using existing questionnaires: 50 pediatric patients completed the modified "my positive health" questionnaire of Huber and 51 parents completed Pelentsov parental needs scale. Nineteen involved professionals answered a questionnaire with open boxes. Parents of children with a variety of chronic skin diseases and young adult patients were interviewed to find out what an optimal approach would look like according to them. Children with a severe chronic and/or congenital skin disorder score high on the "my positive health" questionnaire, indicating they are able to adapt and self-manage. Their highest median score was measured for the dimension "quality of life." Their parents expect improvement of "working with health care professionals," more specifically they want them to adopt a more holistic approach throughout the patient's life. Structured interviews showed they expect that a multidisciplinary team of care providers determine together with the patient and its family-in advance-which care is needed, at what time and by whom. The interviewed professionals indicated adoption of a holistic multidisciplinary approach as the single largest improvement to achieve better care.Conclusion: Although these children with a severe chronic and/or congenital skin disease were able to adapt and self-manage, they need a more personalized integrative multidisciplinary and systematic transmural approach covering all aspects of life during their lifetime. What is Known: • Severe skin disorders affect the child and its family in several ways. In our expert center, we try to optimize the care for these children through a multidisciplinary approach. What is New: • To our knowledge, no English publication describes the requirements for good care for pediatric patients with severe chronic skin disorders and how to optimize this care. We evaluated the health status of children with severe chronic skin disorders and the strengths and weaknesses of past and current care by questioning these children, their parents, adult patients, and involved professionals.

Arterial tortuosity syndrome: 40 new families and literature review.

PURPOSE: We delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10. METHODS: We retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-ß signaling with immunohistochemistry for pSMAD2 and CTGF. RESULTS: Stenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-ß signaling. CONCLUSION: Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities.

Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype.

We report germline loss-of-function mutations in SPRED1 in a newly identified autosomal dominant human disorder. SPRED1 is a member of the SPROUTY/SPRED family of proteins that act as negative regulators of RAS->RAF interaction and mitogen-activated protein kinase (MAPK) signaling. The clinical features of the reported disorder resemble those of neurofibromatosis type 1 and consist of multiple café-au-lait spots, axillary freckling and macrocephaly. Melanocytes from a café-au-lait spot showed, in addition to the germline SPRED1 mutation, an acquired somatic mutation in the wild-type SPRED1 allele, indicating that complete SPRED1 inactivation is needed to generate a café-au-lait spot in this syndrome. This disorder is yet another member of the recently characterized group of phenotypically overlapping syndromes caused by mutations in the genes encoding key components of the RAS-MAPK pathway. To our knowledge, this is the first report of mutations in the SPRY (SPROUTY)/SPRED family of genes in human disease.

Clinicopathologically Defined Naevus Subtypes and Melanoma Risk.

Early detection of melanoma is a major determinant in disease outcome and drives the number of (over)excised naevi in clinical practice. This study aimed to evaluate demographic features and melanoma risk of clinically suspicious, mainly flat naevus subtypes. Based on the methodology of ex vivo dermoscopy and derm dotting, the 12 most prevalent naevus subtypes were identified in a collection of over 7000 naevi excised for medical reason. Dermoscopical, histopathological and clinical features of these subtypes were described. In addition, the association with melanoma history, histopathological atypia and melanoma occurrence within naevi was compared. Nearly half of the naevi removed for medical reasons were of the hypermelanotic subtype with no or mild histopathological atypia and low melanoma association, suggesting overtreatment in daily practice. Contrarily, the subtypes atypical lentiginous naevus and orange pulverocytic flat naevus were associated with higher proportions of (severe) atypia and melanoma (history). We believe these subtypes may reflect different tumoural and/or (germline) genetic entities with different melanoma risk. The data from this study may direct further prospective research on specific naevus subtypes in order to obtain better insights in associated clinical/genetic factors and melanoma risk.

Exploring the Severity Strata of Disease Activity and Repigmentation in Vitiligo Based on Validated Physician Global Assessment (PGA) Scores.

Background/Objectives: There is currently no guidance on how to interpret the global degrees of activity (worsening) and repigmentation (improvement) in vitiligo. Stratification into global degrees can be completed for static evaluations (e.g., visible disease activity signs) and dynamic assessments (e.g., evolution over time). For the latter, the Vitiligo Disease Activity Score (VDAS15&60) and Vitiligo Disease Improvement Score (VDIS15&60) were recently validated. Methods: In the current study, a Physician Global Assessment (PGA) for disease activity (worsening) and repigmentation (improvement) was evaluated for validity (construct) and reliability (inter- and intrarater) based on a photo set of 66 patients. Subsequently, the PGA activity (worsening) and repigmentation (improvement) were used to stratify the Vitiligo Extent Score plus (VESplus), VDAS15&60 or VDIS15&60 into three global categories (slightly, moderately and much worse/improved), based on ROC analysis. Results: For the VESplus, cut-off values for the categories 'slightly, moderately and much worse' were >0.3%, >27.71% and >128.75% BSA (relative changes in the affected total BSA), respectively. For the categories 'slightly, moderately and much improved', they were >0%, >4.87% and >36.88% BSA (relative changes in the affected total BSA), respectively. The optimal cut-off values of the number of active (VDAS15) body areas were >0 areas for slightly worse, >2 areas for moderately worse and >7 for much worse. For VDIS15, the cut-off values for slightly improved and moderately improved were >0 and >1. For VDAS60 and VDIS60, the cut-off points were >0.5, >3, >9.5 and >0.5 and >1.5, respectively. The results should be interpreted with caution in patients with extensive vitiligo due to the rather limited disease extent of the included patient population (VESplus (median: 3.2%)). Conclusions: This research will aid in the development of more detailed international definitions.

A single-stage bilayered skin reconstruction using Glyaderm® as an acellular dermal regeneration template results in improved scar quality: an intra-individual randomized controlled trial.

Background: Absence of almost the entire reticular dermal layer is inherent to the use of autologous split-thickness skin grafting (STSG) to close full-thickness wounds, often resulting in hypertrophic scars and contractures. Many dermal substitutes have been developed, but unfortunately most have varying results in terms of cosmetic and/or functional improvement as well as patient satisfaction, in addition to high costs. Bilayered skin reconstruction using the human-derived glycerolized acellular dermis (Glyaderm®) has been reported to result in significantly improved scar quality using a two-step procedure. Unlike the necessary two-step procedure for most commercially available dermal substitutes, in this study we aimed to investigate the use of Glyaderm® in a more cost-effective single-stage engrafting. This is a method which, if autografts are available, is preferred by the majority of surgeons given the reduction in costs, hospitalization time and infection rate. Methods: A prospective, randomized, controlled, intra-individual, single-blinded study was performed, investigating the simultaneous application of Glyaderm® and STSG vs. STSG alone in full-thickness burns or comparable deep skin defects. During the acute phase, bacterial load, graft take and time to wound closure were assessed and were the primary outcomes. Aesthetic and functional results (secondary outcomes) were evaluated at 3, 6, 9 and 12 months follow-up using subjective and objective scar measurement tools. Biopsies for histological analysis were taken at 3 and 12 months. Results: A total of 66 patients representing 82 wound comparisons were included. Graft take (>95%), pain management and healing time were comparable in both groups. At 1 year follow-up, the overall Patient and Observer Scar Assessment Scale assessed by the patient was significantly in favour of sites where Glyaderm® was used. Not infrequently, patients attributed this difference to improved skin sensation. Histological analysis showed the presence of a well-formed neodermis, with donor elastin present for up to 12 months. Conclusions: A single-stage bilayered reconstruction with Glyaderm® and STSG results in optimal graft take without loss of Glyaderm® nor the overlaying autografts due to infection. The presence of elastin in the neodermis was demonstrated during long-term follow-up in all but one patient, which is a crucial factor contributing to the significantly improved overall scar quality as evaluated by the blinded patients. Trial registration: The trial was registered on clinicaltrials.gov and received the following registration code: NCT01033604.

Cutaneous Manifestations in Biological-Treated Inflammatory Bowel Disease Patients: A Narrative Review.

The biologic era has greatly improved the treatment of Crohn's disease and ulcerative colitis. Biologics can however induce a wide variety of skin eruptions, especially those targeting the TNF-α and Th17 pathway. These include infusion reactions, eczema, psoriasis, lupus, alopecia areata, vitiligo, lichenoid reactions, granulomatous disorders, vasculitis, skin cancer, and cutaneous infections. It is important to recognize these conditions as treatment-induced adverse reactions and adapt the treatment strategy accordingly. Some conditions can be treated topically while others require cessation or switch of the biological therapy. TNF-α antagonists have the highest rate adverse skin eruptions followed by ustekinumab and anti-integrin receptor blockers. In this review, we provide an overview of the most common skin eruptions which can be encountered in clinical practice when treating IBD (Inflammatory bowel disease) patients and propose a therapeutic approach for each condition.

Biologicals for moderate-to-severe plaque type psoriasis in pediatric patients.

INTRODUCTION: Psoriasis affects around 2% of children in Europe. The majority of cases is readily managed with topical treatments using corticosteroids without or with calcipotriol. More resistant and extensive moderate-to-severe cases require UVA or UVB phototherapies or conventional systemic treatment including ciclosporin, acitretin and methotrexate. However, these therapies are associated with a low tolerability and potential cumulative long-term adverse effects and toxicities. AREAS COVERED: About 15 years ago, the first biological appeared for the treatment of moderate-to-severe plaque type psoriasis in adult patients. Several years later, the first biologic treatment to be approved in children was etanercept, a soluble receptor that binds both tumor necrosis factor (TNF)-α and ß followed by adalimumab, a monoclonal antibody against TNF-α, and currently by ustekinumab, a monoclonal IL12/23 p40 antagonist and, very recently, secukinumab and ixekizumab, both IL17 antagonists. All these biologic treatments brought significantly improved treatment results compared to light-based therapies and conventional treatments and present very good tolerance and safety profiles. EXPERT OPINION: Due to their excellent efficacy and safety profiles ustekinumab, secukinumab and ixekizumab could currently be considered as a first-line treatment options for moderate-to-severe childhood and adolescent psoriasis requiring a systemic treatment.

Vaccinations in Patients Receiving Systemic Drugs for Skin Disorders: What Can We Learn for SARS-Cov-2 Vaccination Strategies?

Large-scale vaccination strategies are currently being deployed against severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2). Whether systemic medication for skin diseases affects the efficacy of vaccination and whether temporary interruption or extension of the dosing interval is necessary is under debate. Most immunomodulating/immunosuppressive drugs only affect vaccine-induced immune responses to a limited or moderate extent, preserving sufficient immunity in most patients. Mycophenolate mofetil, Janus kinase inhibitors, and rituximab require a more cautious approach, and judicious timing of vaccination might be appropriate in patients receiving these treatments. It should be noted that, for most drugs except methotrexate, data on the length of the interruption period to restore vaccine-induced immune responses to normal levels are either very limited or absent. In these cases, only the drug half-life can be used as a practical guideline. In most patients, systemic medication can be continued through the vaccination process, although case-by-case decisions can be considered.

Defining the Clinical, Molecular and Ultrastructural Characteristics in Occipital Horn Syndrome: Two New Cases and Review of the Literature.

Occipital horn syndrome (OHS) is a rare connective tissue disorder caused by pathogenic variants in ATP7A, encoding a copper transporter. The main clinical features, including cutis laxa, bony exostoses, and bladder diverticula are attributed to a decreased activity of lysyl oxidase (LOX), a cupro-enzyme involved in collagen crosslinking. The absence of large case series and natural history studies precludes efficient diagnosis and management of OHS patients. This study describes the clinical and molecular characteristics of two new patients and 32 patients previously reported in the literature. We report on the need for long-term specialized care and follow-up, in which MR angiography, echocardiography and spirometry should be incorporated into standard follow-up guidelines for OHS patients, next to neurodevelopmental, orthopedic and urological follow-up. Furthermore, we report on ultrastructural abnormalities including increased collagen diameter, mild elastic fiber abnormalities and multiple autophagolysosomes reflecting the role of lysyl oxidase and defective ATP7A trafficking as pathomechanisms of OHS.

Facial Lichen Planopilaris: A Separate Entity or Not? A Case Series.

Lichen planopilaris (LPP) is an inflammatory hair disorder that is characterized by scarring hair loss, mostly affecting the vertex and parietal areas of the scalp. Frontal fibrosing alopecia (FFA) is considered a particular form of LPP, primarily affecting the hair follicles in the frontotemporal area of the scalp, with the hairline recession and eyebrow loss. There are case reports of FFA with concomitant involvement of facial vellus, characterized by roughening of the facial skin. We report five cases of facial vellus hair involvement in LPP, in the absence of other sites of disease activity. To the best of our knowledge, ours is the first report of LPP affecting the facial vellus hairs in the absence of FFA.