Cross-sectional study on autosomal recessive congenital ichthyoses: association of genotype with disease severity, phenotypic and ultrastructural features in 74 Italian patients.

BACKGROUND: Autosomal recessive congenital ichthyoses (ARCI) are a clinically heterogeneous group of keratinization disorders characterized by generalized skin scaling due to mutations in at least 12 genes. The aim of our study was to assess disease severity, phenotypic and ultrastructural features and to evaluate their association with genetic findings in ARCI patients. METHODS: Clinical signs and symptoms, and disease severity were scored in a single-center series of patients with a genetic diagnosis of ARCI. Skin ultrastructural findings were reviewed. RESULTS: Seventy-four consecutive patients (mean age 11.0 years, range 0.1-48.8) affected with lamellar ichthyosis (50/74, 67.5%), congenital ichthyosiform erythroderma (18/74, 24.3%), harlequin ichthyosis (two/74, 2.7%), and other minor ARCI subtypes (four/74, 5.4%) were enrolled. Mutated genes were: TGM1 in 18/74 (24.3%) patients, ALOX12B in 18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%), ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1 and SDR9C7 in one patient each (1.4%). Twenty-five previously undescribed mutations in the different ARCI causative genes, as well as two microduplications in TGM1, and two microdeletions in CYP4F22 and NIPAL4 were identified. The mean ichthyosis severity score in TGM1 and ABCA12-mutated patients was significantly higher than in all other mutated genes, while the lowest score was observed in CYP4F22-mutated patients. Alopecia, ectropion, and eclabium were significantly associated with TGM1 and ABCA12 mutations, and large, thick and brownish scales with TGM1 mutations. Among specific phenotypic features, psoriasis-like lesions as well as a trunk reticulate scale pattern and striated keratoderma were present in NIPAL4-mutated patients. Ultrastructural data available for 56 patients showed a 100% specificity of cholesterol clefts for TGM1-mutated cases, and revealed abnormal lamellar bodies in SDR9C7 and CERS3 patients. CONCLUSION: Our study expands the phenotypic and genetic characterization of ARCI by the description of statistically significant associations between disease severity, specific clinical signs, and different mutated genes. Finally, we highlighted the presence of psoriasis-like lesions in NIPAL4-ARCI patients as a novel phenotypic feature with diagnostic and possible therapeutic implications.

Gamma-Secretase Inhibitors Downregulate the Profibrotic NOTCH Signaling Pathway in Recessive Dystrophic Epidermolysis Bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare skin fragility disorder caused by mutations in COL7A1. RDEB is hallmarked by trauma-induced unremitting blistering, chronic wounds with inflammation, and progressive fibrosis, leading to severe disease complications. There is currently no cure for RDEB-associated fibrosis. Our previous studies and increasing evidence highlighted the profibrotic role of NOTCH pathway in different skin disorders, including RDEB. In this study, we further investigated the role of NOTCH signaling in RDEB pathogenesis and explored the effects of its inhibition by γ-secretase inhibitors DAPT and PF-03084014 (nirogacestat). Our analyses demonstrated that JAG1 and cleaved NOTCH1 are upregulated in primary RDEB fibroblasts (ie, RDEB-derived fibroblasts) compared with controls, and their protein levels are further increased by TGF-ß1 stimulation. Functional assays unveiled the involvement of JAG1/NOTCH1 axis in RDEB fibrosis and demonstrated that its blockade counteracts a variety of fibrotic traits. In particular, RDEB-derived fibroblasts treated with PF-03084014 showed (i) a significant reduction of contractility, (ii) a diminished secretion of TGF-ß1 and collagens, and (iii) the downregulation of several fibrotic proteins. Although less marked than PF-03084014-treated cells, RDEB-derived fibroblasts exhibited a reduction of fibrotic traits also upon DAPT treatment. This study provides potential therapeutic strategies to antagonize RDEB fibrosis onset and progression.

The VASCERN-VASCA Working Group Diagnostic and Management Pathways for Venous Malformations.

To elaborate expert consensus patient pathways to guide patients and physicians toward efficient diagnostics and management of patients with venous malformations. Methods: VASCERN-VASCA (https://vascern.eu/) is a European network of multidisciplinary centers for Vascular Anomalies. The Nominal Group Technique was used to establish the pathways. Two facilitators were identified: one to propose initial discussion points and draw the pathways, and another to chair the discussion. A dermatologist (AD) was chosen as first facilitator due to her specific clinical and research experience. The draft was subsequently discussed within VASCERN-VASCA monthly virtual meetings and annual face-to-face meetings. Results: The Pathway starts from the clinical suspicion of a venous type malformation (VM) and lists the clinical characteristics to look for to support this suspicion. Strategies for subsequent imaging and histopathology are suggested. These aim to inform on the diagnosis and to separate the patients into 4 subtypes: (1) sporadic single VMs or (2) multifocal, (3) familial, multifocal, and (4) combined and/or syndromic VMs. The management of each type is detailed in subsequent pages of the pathway, which are color coded to identify sections on (1) clinical evaluations, (2) investigations, (3) treatments, and (4) associated genes. Actions relevant to all types are marked in separate boxes, including when imaging is recommended. When definite diagnoses have been reached, the pathway also points toward disease-specific additional investigations and recommendations for follow up. Options for management are discussed for each subtype, including conservative and invasive treatments, as well as novel molecular therapies. Conclusion: The collaborative efforts of VASCERN-VASCA, a network of the 9 Expert Centers, has led to a consensus Diagnostic and Management Pathways for VMs to assist clinicians and patients. It also emphasizes the role of multidisciplinary expert centers in the management of VM patients. This pathway will become available on the VASCERN website (http://vascern.eu/).

COVID 19-associated chilblain-like acral lesions among children and adolescents: an Italian retrospective, multicenter study.

BACKGROUND: Since the COVID-19 pandemic started, great interest has been given to this disease, especially to its possible clinical presentations. Besides classical respiratory symptoms, dermatological manifestations occur quite often among infected and non-infected patients, particularly in children. A prominent IFN-I response, that is generally higher in children compared to adults, may not only cause chilblain lesions, but it could also prevent infection and viral replication, thus justifying the negative swab results, as well as the absence of relevant systemic symptoms in positive cases. Indeed, reports have emerged describing chilblain-like acral lesions in children and adolescents with either proven or suspected infection. METHODS: Patients aged from 1 to 18 years old were enrolled in this study from 23 Italian dermatological units and were observed for an overall period of 6 months. Clinical pictures were collected along with data on the location and duration of skin lesions, their association with concomitant local and systemic symptoms, presence of nail and/or mucosal involvement, as well as histological, laboratory and imaging findings. RESULTS: One hundred thirty-seven patients were included, of whom 56.9% were females. Mean age was 11.97±3.66 years. The most commonly affected sites were the feet (77 patients, 56.2%). Lesions (48.5%) featured cyanosis, chilblains, blisters, ecchymosis, bullae, erythema, edema, and papules. Concomitant skin manifestations included maculo-papular rashes (30%), unspecified rashes (25%), vesicular rashes (20%), erythema multiforme (10%), urticaria (10%) and erythema with desquamation (5%). Forty-one patients (29.9%) reported pruritus as the main symptom associated with chilblains, and 56 out of 137 patients also reported systemic symptoms such as respiratory symptoms (33.9%), fever (28%), intestinal (27%), headache (5.5%), asthenia (3.5%), and joint pain (2%). Associated comorbid conditions were observed in 9 patients presenting with skin lesions. Nasopharyngeal swabs turned out positive in 11 patients (8%), whereas the remainder were either negative (101, 73%) or unspecified (25, 18%). CONCLUSIONS: COVID-19 has been credited as the etiology of the recent increase in acro-ischemic lesions. The present study provides a description of pediatric cutaneous manifestations deemed to be potentially associated with COVID-19, revealing a possible association between acral cyanosis and nasopharyngeal swab positivity in children and teenagers. The identification and characterization of newly recognized patterns of skin involvement may aid physicians in diagnosing cases of asymptomatic or pauci-symptomatic COVID patients.

Real-World Experience of Methotrexate in the Treatment of Skin Diseases: an Italian Delphi Consensus.

BACKGROUND: After decades of use, methotrexate displays an established safety and efficacy profile in both in-hospital and outpatient settings. Despite its widespread use, there is surprisingly little clinical evidence to guide daily practice with methotrexate in dermatology. OBJECTIVES: To provide guidance for clinicians in daily practice for areas in which there is limited guidance. METHODS: A Delphi consensus exercise on 23 statements was carried out on the use of methotrexate in dermatological routine settings. RESULTS: Consensus was reached on statements that cover six main areas: (1) pre-screening exams and monitoring of therapy; (2) dosing and administration in patients naïve to methotrexate; (3) optimal strategy for patients in remission; (4) use of folic acid; (5) safety; and (6) predictors of toxicity and efficacy. Specific recommendations are provided for all 23 statements. CONCLUSIONS: In order to optimize methotrexate efficacy, it is essential to optimize treatment using appropriate dosages, carrying out a rapid drug-based step-up on a treat-to-target strategy and preferably using the subcutaneous formulation. To manage safety aspects appropriately, it is essential to evaluate patients' risk factors and carry out proper monitoring during the course of treatment.

Staphylococcal Infections and Neonatal Skin: Data from Literature and Suggestions for the Clinical Management from Four Challenging Patients.

Staphylococcal infections in neonates might be associated with skin blistering since early antibiotic therapy has been shown to limit infection spread and positively influence outcomes; therefore, neonatologists should be aware of these conditions. This review examines the recent literature on the management of Staphylococcal infections that involve neonatal skin, discussing the most appropriate clinical approach to four cases of neonatal blistering diseases with Staphylococcal infections: a case of Staphylococcal bullous impetigo, a case of Staphylococcal scalded skin syndrome (SSSS), a case of epidermolysis bullosa with overlapping Staphylococcal infection, and a case of burns with overlapping Staphylococcal infection. In treating Staphylococcal infections involving skin in neonates, the presence or absence of systemic symptoms should be considered. In the lack of evidence-based guidelines in this age category, treatment should be individualized according to several factors including the extension of the disease or further skin comorbidities (such as skin fragility), with a multidisciplinary approach.

Tailored treatments in inborn errors of immunity associated with atopy (IEIs-A) with skin involvement.

Inborn errors of immunity associated with atopy (IEIs-A) are a group of inherited monogenic disorders that occur with immune dysregulation and frequent skin involvement. Several pathways are involved in the pathogenesis of these conditions, including immune system defects, alterations of skin barrier and metabolism perturbations. Current technological improvements and the higher accessibility to genetic testing, recently allowed the identification of novel molecular pathways involved in IEIs-A, also informing on potential tailored therapeutic strategies. Compared to other systemic therapy for skin diseases, biologics have the less toxic and the best tolerated profile in the setting of immune dysregulation. Here, we review IEIs-A with skin involvement focusing on the tailored therapeutic approach according to their pathogenetic mechanism.

Vascular lesions of the pediatric orbit: A radiological walkthrough.

Vascular anomalies of the pediatric orbit represent a heterogeneous group that include both vascular tumors and vascular malformations. The disorder may initially be silent and then associated with symptoms and/or function damage, depending on the type of vascular anomaly and its extension. Vascular tumors include benign, locally aggressive (or borderline) and malignant forms while vascular malformations are divided into "simple", "combined" and syndromic, or "low flow" or "high flow". Both entities can arise in isolation or as part of syndromes. In this review, we describe the imaging findings of the vascular lesions of the orbit in the pediatric population, which are key to obtain a correct diagnosis and to guide the appropriate treatment in the light of the new genetic and molecular discoveries, and the role of the radiologist in their multidisciplinary management. We will also touch upon the main syndromes associated with orbital vascular abnormalities.

The VASCERN-VASCA working group diagnostic and management pathways for lymphatic malformations.

Lymphatic malformations (LMs) are developmental defects of lymphatic vessels. LMs are histologically benign lesions, however, due to localization, size, and unexpected swelling, they may cause serious complications that threaten vital functions such as compression of the airways. A large swelling of the face or neck may also be disfiguring and thus constitute a psychological strain for patients and their families. LMs are also highly immunologically reactive, and are prone to recurrent infections and inflammation causing pain as well as chronic oozing wounds. The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) is dedicated to gathering the best expertise in Europe. There are only few available guidelines on management and follow up of LMs, which commonly focus on very specific situations, such as head and neck LM (Zhou et al., 2011). It is still unclear, what constitutes an indication for treatment of LMs and how to follow up the patients. The Vascular Anomalies Working Group (VASCA-WG) of VASCERN decided to develop a diagnostic and management pathway for the management of LMs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following 2 face-to-face meetings and multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with lymphatic malformations in a practical manner; we present an algorithmic view of the results of our work.

Update on the Management of Pediatric Psoriasis: An Italian Consensus.

INTRODUCTION: Psoriasis affects children with a considerable burden in early life. Treating pediatric psoriasis is challenging also because of the lack of updated specific guidelines. With the recent approval of several biologics for pediatric psoriasis and the ongoing COVID-19 pandemic, the management of young psoriatic patients is facing major changes. A revision of treatment recommendations is therefore needed. METHODS: In September 2021, a board of six Italian dermatologists convened to update treatment recommendations. The board issued evidence- and consensus-based statements covering relevant areas of pediatric psoriasis, namely: assessment of psoriasis severity, management of children with psoriasis, and treatment of pediatric psoriasis. To reach consensus, the statements were submitted to a panel of 24 experts in a Delphi process performed entirely via videoconference. A treatment algorithm was produced. RESULTS: There was full consensus that psoriasis severity is determined by the extension/severity of skin lesions, site of lesions, and impact on patient quality of life. Agreement was reached on the need for a multidisciplinary approach to pediatric psoriasis and the importance of patient/parents education. The relevance of vaccinations, including COVID-19 vaccination, for psoriatic children was acknowledged by all participants. Management issues that initially failed to reach consensus included the screening for psoriasis comorbidities and early treatment with biologics to prevent them and the use of telemedicine to facilitate patient follow-up. There was full consensus that topical corticosteroids are the first choice for the treatment of mild pediatric psoriasis, while phototherapy and systemic therapy are used in children with moderate-severe psoriasis. According to the proposed treatment algorithm, biologics are the first line of systemic therapy. CONCLUSIONS: Targeted systemic therapies are changing the treatment of moderate-severe pediatric psoriasis, while topical corticosteroids continue to be the first choice for mild disease. Children-centered research is needed to further improve the treatment of pediatric psoriasis.

Clinical and Molecular Spectrum of Sporadic Vascular Malformations: A Single-Center Study.

Sporadic vascular malformations (VMs) are a large group of disorders of the blood and lymphatic vessels caused by somatic mutations in several genes-mainly regulating the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways. We performed a cross-sectional study of 43 patients affected with sporadic VMs, who had received molecular diagnosis by high-depth targeted next-generation sequencing in our center. Clinical and imaging features were correlated with the sequence variants identified in lesional tissues. Six of nine patients with capillary malformation and overgrowth (CMO) carried the recurrent GNAQ somatic mutation p.Arg183Gln, while two had PIK3CA mutations. Unexpectedly, 8 of 11 cases of diffuse CM with overgrowth (DCMO) carried known PIK3CA mutations, and the remaining 3 had pathogenic GNA11 variants. Recurrent PIK3CA mutations were identified in the patients with megalencephaly-CM-polymicrogyria (MCAP), CLOVES, and Klippel-Trenaunay syndrome. Interestingly, PIK3CA somatic mutations were associated with hand/foot anomalies not only in MCAP and CLOVES, but also in CMO and DCMO. Two patients with blue rubber bleb nevus syndrome carried double somatic TEK mutations, two of which were previously undescribed. In addition, a novel sporadic case of Parkes Weber syndrome (PWS) due to an RASA1 mosaic pathogenic variant was described. Finally, a girl with a mild PWS and another diagnosed with CMO carried pathogenic KRAS somatic variants, showing the variability of phenotypic features associated with KRAS mutations. Overall, our findings expand the clinical and molecular spectrum of sporadic VMs, and show the relevance of genetic testing for accurate diagnosis and emerging targeted therapies.

Auricular leishmaniasis in a child successfully treated with intralesional amphotericin B.

Cutaneous leishmaniasis (CL) is the most frequent form of leishmaniasis. The auricle is an extremely rare site for CL in the Old World. Auricular CL may be mistaken for other entities, such as relapsing polychondritis (RP). Here we report a pediatric case of Old World auricular CL mimicking RP in a child successfully treated with intralesional liposomal amphotericin B.

PIK3CA-related overgrowth with an uncommon phenotype: case report.

BACKGROUND: Megalencephaly-capillary malformation syndrome is a rare multiple-malformation syndrome secondary to somatic activating mutations in the PI3K-AKT-MTOR pathway. This is included in a heterogeneous group of disorders, now defined "PIK3CA-related overgrowth spectrum". CASE PRESENTATION: We report a 22-months-old female presenting an uncommon phenotype associated with a genetic mosaicism in the PIK3CA gene, detected on DNA extracted from blood peripheral and tissue biopsy. CONCLUSIONS: NGS is the preferred method for molecular diagnosis of PROS on affected skin and overgrown tissues as primary samples. The wide phenotypic variability is based on the distribution of mosaicism, in fact the same mutation can cause different PIK3CA related disorders. Continuous understanding of the clinical spectrum and of molecular basis of PROS and their overlap will lead to improve diagnosis, management and new treatment strategies.

Prominent Follicular Keratosis in Multiple Intestinal Atresia with Combined Immune Deficiency Caused by a TTC7A Homozygous Mutation.

Multiple intestinal atresia with combined immune deficiency (MIA-CID) is an autosomal recessive syndrome due to mutations in the TTC7A gene implicated in the polarization of intestinal and thymic epithelial cells. MIA-CID is lethal in the first year of life in the majority of patients. Dermatological manifestations have been reported in a few cases. We describe a child affected with MIA-CID due to a previously unreported TTC7A homozygous missense mutation. Surgery for bowel occlusion was performed in the first days of life. The patient was totally dependent on parenteral nutrition since birth and presented severe diarrhea and recurrent infections. He underwent hematopoietic stem cell transplantation at 17 months with complete donor engraftment and partial immunity improvement. In the second year of life, he progressively developed diffuse papular follicular keratoses on ichthyosiform skin, nail clubbing, and subungual hyperkeratosis. Histopathology showed hyperkeratosis with follicular plugging and scattered apoptotic keratinocytes, visualized at an ultrastructural examination. Our findings expand the spectrum of dermatological manifestations which can develop in MIA-CID patients. Examination of further patients will allow defining whether keratinocyte apoptosis is also a disease feature.

The VASCERN-VASCA working group diagnostic and management pathways for severe and/or rare infantile hemangiomas.

The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN), is dedicated to gathering the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. Infantile Hemangiomas (IH) are benign vascular tumors of infancy that rapidly growth in the first weeks of life, followed by stabilization and spontaneous regression. In rare cases the extent, the localization or the number of lesions may cause severe complications that need specific and careful management. Severe IH may be life-threatening due to airway obstruction, liver or cardiac failure or may harbor a risk of functional impairment, severe pain, and/or significant and permanent disfigurement. Rare IHs include syndromic variants associated with extracutaneous abnormalities (PHACE and LUMBAR syndromes), and large segmental hemangiomas. There are publications that focus on evidence-based medicine on propranolol treatment for IH and consensus statements on the management of rare infantile hemangiomas mostly focused on PHACES syndrome. The Vascular Anomalies Working Group (VASCA-WG) decided to develop a diagnostic and management pathway for severe and rare IHs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following two face-to-face meetings and in multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with severe and rare IH in a practical manner; we present an algorithmic view of the results of our work.

Cardiomyopathies in Children and Systemic Disorders When Is It Useful to Look beyond the Heart?

Cardiomyopathy (CMP) is a rare disease in the pediatric population, with a high risk of morbidity and mortality. The genetic etiology of CMPs in children is extremely heterogenous. These two factors play a major role in the difficulties of establishing standard diagnostic and therapeutic protocols. Isolated CMP in children is a frequent finding, mainly caused by sarcomeric gene variants with a detection rate that can reach up to 50% of analyzed cohorts. Complex multisystemic forms of pediatric CMP are even more heterogenous. Few studies in literature take into consideration this topic as the main core since it represents a rarity (systemic CMP) within a rarity (pediatric population CMP). Identifying etiology in this cohort is essential for understanding prognosis, risk stratification, eligibility to heart transplantation and/or mechanical-assisted procedures, preventing multiorgan complications, and relatives' recurrence risk calculation. The previous points represent a cornerstone in patients' empowerment and personalized medical care approach. The aim of this work is to propose a new approach for an algorithm in the setting of the diagnostic framework of systemic pediatric CMP. On the other hand, during the literature review, we noticed a relatively common etiologic pattern in some forms of complex/multisystem CMP. In other words, certain syndromes such as Danon, Vici, Alström, Barth, and Myhre syndrome share a common pathway of directly or indirectly defective "autophagy" process, which appears to be a possible initiating/triggering factor for CMPs. This conjoint aspect could be important for possible prognostic/therapeutic implications in this category of patients. However, multicentric studies detailed functional and experimental models are needed prior to deriving conclusions.