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.

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.

Management of Upper Airway Infantile Hemangiomas: Experience of One Italian Multidisciplinary Center.

Airway infantile hemangiomas (IHs) can represent a life-threatening condition since the first months of life. They may be isolated or associated to cutaneous IHs, and/or part of PHACES syndrome. Diagnosis, staging, and indication to treatment are not standardized yet despite the presence in the literature of previous case series and reviews. The diagnosis might be misleading, especially in the absence of cutaneous lesions. Airway endoscopy is the gold standard both for diagnosis and follow-up since it allows evaluation of precise localization and entity of obstruction and/or stricture. Proliferation of IH in the infant airways manifests frequently with stridor and treatment is required as soon as possible to prevent further complications. The first line of therapy is oral propranolol, but duration of treatment is not yet well-defined. All considered, we report the experience of our multidisciplinary center from 2009 to date, on 36 patients affected by airway IHs, and successfully treated with oral propranolol. Thus, the authors propose their experience for the management of airway IHs, specifically early diagnosis, when to perform endoscopy, how to interpret its findings, and when to stop the treatment.

A multicenter study on quality of life of the "greater patient" in congenital ichthyoses.

BACKGROUND: Autosomal recessive congenital ichthyoses (ARCI) are a genetically heterogeneous group of rare and chronic disorders characterized by generalized skin scaling and hyperkeratosis, erythroderma, and palmoplantar keratoderma. Additional features include ectropion, eclabium, ear deformities, foul-smell, joints contractures and walking problems, recurrent infections, as well as pruritus and pain. No curative therapy is available and disease care mainly relies on daily application of topical emollients and keratolytics to the whole-body surface. Altogether, disease signs and symptoms and treatment modalities have a major impact on quality of life of patients and their caregivers. However, very few studies have evaluated the family disease burden in ARCI. METHODS: We have performed an Italian multicenter cross-sectional study to assess the secondary disease impact on family members of pediatric and adult patients with ARCI, using a validated dermatology-specific questionnaire, the family dermatology life quality index (FDLQI). Disease severity was assessed by the dermatologist in each center. RESULTS: Seventy-eight out of 82 patients who were accompanied by at least one family member filled the FDLQI. Forty-eight (61.5%) patients were aged less than 18 years. The mean FDLQI score was 10.3 (median 10), and the most affected dimensions were (1) time needed for care, (2) extra-housework, and (3) household expenditure. Higher total FDLQI score significantly correlated with more severe disease score (P = 0.003). Features associated with greater family burden included recurrent infections (P = 0.004), foul-smell (P = 0.009), palmoplantar keratoderma (P = 0.041), but also presence of scales on the face (P = 0.039) and ear deformities (P = 0.016). CONCLUSIONS: Our findings highlight the major socio-economic and psychological burden imposed by ARCI on the QoL of family caregivers. In addition, they show that global evaluation of disease impact also on family members is an essential part of patient-reported outcomes. Finally, our data underline the need to develop specific measures for family support.

Ectodermal Dysplasia-Syndactyly Syndrome with Toe-Only Minimal Syndactyly Due to a Novel Mutation in NECTIN4: A Case Report and Literature Review.

Ectodermal dysplasia-syndactyly syndrome 1 (EDSS1) is characterized by cutaneous syndactyly of the toes and fingers and abnormalities of the hair and teeth, variably associated with nail dystrophy and palmoplantar keratoderma (PPK). EDSS1 is caused by biallelic mutations in the NECTIN4 gene, encoding the adherens junction component nectin-4. Nine EDSS1 cases have been described to date. We report a 5.5-year-old female child affected with EDSS1 due to the novel homozygous frameshift mutation c.1150delC (p.Gln384ArgfsTer7) in the NECTIN4 gene. The patient presents brittle scalp hair, sparse eyebrows and eyelashes, widely spaced conical teeth and dental agenesis, as well as toenail dystrophy and mild PPK. She has minimal proximal syndactyly limited to toes 2-3, which makes the phenotype of our patient peculiar as the overt involvement of both fingers and toes is typical of EDSS1. All previously described mutations are located in the nectin-4 extracellular portion, whereas p.Gln384ArgfsTer7 occurs within the cytoplasmic domain of the protein. This mutation is predicted to affect the interaction with afadin, suggesting that impaired afadin activation is sufficient to determine EDSS1. Our case, which represents the first report of a NECTIN4 mutation with toe-only minimal syndactyly, expands the phenotypic and molecular spectrum of EDSS1.

The Burden of Autosomal Recessive Congenital Ichthyoses on Patients and their Families: An Italian Multicentre Study.

Autosomal recessive congenital ichthyoses (ARCI) are characterized by generalized skin scaling, hyperkeratosis, erythroderma, and disabling features affecting the skin (palmoplantar keratoderma, fissures, pain, itch), eyes, ears, and joints. Disease severity and chronicity, patient disfigurement, and time and costs required for care impose a major burden on quality of life. This multicentre cross-sectional study investigated the impact of ARCI on quality of life of patients and families, using the Dermatology Life Quality Index (DLQI), the Children DLQI (CDLQI) and Family Burden of Ichthyosis (FBI) questionnaires. Disease severity was assessed by a dermatologist. A total of 94 patients were recruited, of whom 52 (55.3%) children. Mean age was 20.1 (median 13.5) years. The mean CDLQI/DLQI score was 7.8, and 21 patients scored >10, indicating a major impairment in quality of life: symptoms, feelings and treatment problems were the most affected domains of quality of life. FBI showed a major repercussion on psychological factors and work. The results of this study highlight the impact of ARCI on specific aspects of patient and family life, underlining the need for psychological support.

Cutaneous venous malformations as a clue for possible gastrointestinal tract involvement: Diagnosis and treatment of six cases.

Venous malformation (VM) is the most common type among vascular malformations classified by the International Society for the Study of Vascular Anomalies. Most VMs are sporadic (94%), caused in 40% of cases by somatic mutation of TEK gene. VMs can be cutaneous, visceral, or combined. Visceral involvement is rare, and gastrointestinal (GI) tract is the most common localization. Visceral VMs, usually asymptomatic, may manifest with bleeding, anemia, and consumptive coagulopathy, which sometimes require an emergency treatment. Our aim is to study the possible GI involvement in patients with only one cutaneous VM. We analyzed a series of six patients who presented with a single cutaneous VM and have subsequently manifested intestinal involvement at our reference center for vascular anomalies since 2010. In our patients, cutaneous VMs were located on lower or upper limbs, and GI involvement manifested from 3 to 10 years after skin diagnosis. Our experience urges to early diagnose a GI involvement also in patients with only one skin VM and to prevent severe complications. A multidisciplinary approach is mandatory for the diagnosis and treatment of these patients.

First Case of KRT2 Epidermolytic Nevus and Novel Clinical and Genetic Findings in 26 Italian Patients with Keratinopathic Ichthyoses.

Keratinopathic ichthyoses (KI) are a clinically heterogeneous group of keratinization disorders due to mutations in KRT1, KTR10, or KRT2 genes encoding keratins of suprabasal epidermis. Characteristic clinical features include superficial blisters and erosions in infancy and progressive development of hyperkeratosis. Histopathology shows epidermolytic hyperkeratosis. We describe the clinical, histopathological, and molecular findings of a series of 26 Italian patients from 19 unrelated families affected with (i) epidermolytic ichthyosis due to KRT1 or KRT10 mutations (7 and 9 cases, respectively); (ii) KTR10-mutated ichthyosis with confetti (2 cases); (iii) KRT2-mutated superficial epidermolytic ichthyosis (5 cases); and (iv) KRT10-mutated epidermolytic nevus (2 cases). Of note, molecular genetic testing in a third case of extensive epidermolytic nevus revealed a somatic missense mutation (p.Asn186Asp) in the KRT2 gene, detected in DNA from lesional skin at an allelic frequency of 25% and, at very low frequency (1.5%), also in blood. Finally, we report three novel dominant mutations, including a frameshift mutation altering the C-terminal V2 domain of keratin 1 in three familiar cases presenting a mild phenotype. Overall, our findings expand the phenotypic and molecular spectrum of KI and show for the first time that epidermolytic nevus can be due to somatic KRT2 mutation.

Cutaneous Infantile Haemangiomas with Intracranial and Intraspinal Involvement: A European Multicentre Experience and Review.

Infantile haemangiomas are very common benign tumours in the first months of life. They are mostly cutaneous; however, extracutaneous lesions are possible, and occur in very rare cases in the central nervous system. A European multicentre observational retrospective study was conducted in the last 5 years. Seven patients with intracranial or intraspinal infantile haemangiomas were selected and treated with oral propranolol. Propranolol was interrupted after complete or almost complete resolution of infantile haemangiomas. All patients tolerated the treatment well without side-effects. Central nervous system infantile haemangiomas are probably underestimated due to the frequent absence of symptoms and their spontaneous involution. However, they should be investigated in case of segmental cutaneous infantile haemangiomas, particularly on the head, neck, upper trunk, lumbar or sacral area in order to diagnosis intra-central nervous system involvement at an early stage.

Successful topical treatment of anal giant condylomata acuminata in an infant.

Anogenital condylomata acuminata are induced by human papillomavirus (HPV) and they rarely manifest in immunocompetent children. Therapeutic options depend on patient's age and general conditions and extension of the lesions. However, management is still a challenge and recurrences are frequent. Cryotherapy, laser, and surgical treatments in children are painful and frequently require general anesthesia. Imiquimod is a topical immune response modifier and constitutes a noninvasive alternative for the treatment of anogenital condylomata acuminata. Here, we report an infant admitted to our hospital with a giant vegetative papillomatous lesion on the perianal region surrounded by small satellites papules. PCR for HPV confirmed the clinical diagnosis of giant condylomata acuminata due to HPV type 6. The child has been successfully treated with topical 5% imiquimod cream without side effects. Although topical imiquimod is not licensed for pediatric age, this report highlights the potential benefits of its use in selected pediatric cases.

Juvenile idiopathic arthritis in infants with Harlequin Ichthyosis: two cases report and literature review.

BACKGROUND: Harlequin Ichthyosis is the most severe variant of congenital autosomal recessive ichthyosis, associated with severe morbidity and potentially lethal in early life. At birth, patients present thick and plaque-like scales all over the body, with consequent cutaneous and extra-cutaneous complications, such as poor thermoregulation, recurrent infections, pain, electrolytes imbalance and joint contractures. Juvenile Idiopathic Arthritis usually manifests before the age of 16 years and persists for more than 6 weeks. The association between these two pathologies has been described in the literature as a very rare event, which creates diagnostic and therapeutic challenge. CASE PRESENTATION: We describe two patients affected by Harlequin Ichthyosis who early developed Juvenile Idiopathic Arthritis. Both patients were treated with retinoids, ibuprofen and long-acting intra-articular glucocorticoids; due to polyarticular involvement, one child was also treated with weekly oral methotrexate. CONCLUSIONS: The association between Harlequin Ichthyosis and Juvenile Idiopathic Arthritis is rare and the pathophysiological mechanism that binds them is still unknown. Nonetheless caregivers should be aware of the possible occurrence of Juvenile Idiopathic Arthritis at very early ages in children affected by Harlequin Ichthyosis.

Correction to: Italian translation, cultural adaptation, and pilot testing of a questionnaire to assess family burden in inherited ichthyoses.

The original article contains a misspelling of co-author, Christine Bodemer's name which is presented correctly in this Correction article.

Pruritus in pediatric patients with atopic dermatitis: a multidisciplinary approach - summary document from an Italian expert group.

Given the inadequate overall awareness of the main disease features and treatment modalities of pruritus in pediatric patients with atopic dermatitis, a multidisciplinary Italian expert group met with the major aim of increasing knowledge of the condition for improved diagnosis and better management among specialists involved in disease management. Herein, the overall features of the condition are reviewed, along with its etiopathogenesis and symptoms. Likewise, management options are summarized, emphasizing the need for a multidisciplinary approach, minimally composed of a management team that includes a pediatrician, dermatologist, psychologist, play assistant, and dedicated nurse. In addition to more traditional therapies such as emollients as highlighted by European guidelines, therapeutic patient education in a group or individually is highly encouraged as it helps patients and their parents to better understand the disease and provide practical guidance for dressing and bandaging. It can also aid in outlining coping strategies for itching and sleep disturbance. The utility of distraction techniques should also be stressed as such educational interventions involving the child and their parents can substantially improve the overall quality of life. All approaches should be tailored according to patient age and clinical features and requires individualized strategy to ensure good adherence by both children and their parents. Thus, a holistic approach embracing systemic, topical and psychological interventions is advocated in order to provide patients and their caregivers the best possible care.

Fibrolipomatous hamartomas not only on the soles.

Fibrolipomatous hamartomas are asymptomatic, subcutaneous lumps usually located on the infant's heels. There is wide heterogeneity in the naming of and management of this condition. Ultrasound examination permits a clear distinction from other disorders. We report herein a case of palmoplantar fibrolipomatous hamartomas.

Angioma serpiginosum: a case report and review of the literature.

BACKGROUND: Angioma serpiginosum is a rare vascular anomaly whose pathogenesis is still unknown. It is characterized by the onset of vascular reddish macules and papules during childhood, lesions are usually monolateral with a linear serpiginous pattern. It is rarely associated with extracutaneous findings. This entity has not yet been included in the classification of the International Society for the Study of Vascular Anomalies. CASE PRESENTATION: We describe the first Italian report of angioma serpiginosum with a congenital symmetrical presentation. The patient had a further extension of macules during puberty involving both of the soles. No extracutaneous manifestations were present. Diagnosis was confirmed with dermoscopy and light microscopy that revealed the typical clusters of dilated, thickened and PAS+ capillaries in the upper dermis. Moreover, Immunohistochemistry showed positive WT-1 staining. Genetic analysis with next generation sequencing did not detected any mutation. CONCLUSIONS: Our patient presented a peculiar symmetrical and planar extension with a serpiginous linear pattern. The proliferative nature of this condition has been widely discussed in literature. In our case immunohistochemistry was positive for Wilms tumor-1, a new endothelial marker expressed during angiogenesis in reparative processes and endothelial tumors. Clinical evolution, histological and immunohistochemical findings suggest that angioma serpiginosum should be considered as a vascular proliferation. For these reasons we think it should be included in the international classification as a tumor.

Italian translation, cultural adaptation, and pilot testing of a questionnaire to assess family burden in inherited ichthyoses.

BACKGROUND: Inherited ichthyoses are rare disorders characterized by generalized skin scaling. Among them, autosomal recessive congenital ichthyoses (ARCI) form a major subgroup presenting lifelong and severely disabling cutaneous and extracutaneous features and symptoms for which no curative treatment is available. Management relies on daily time-consuming and distressing topical medications. Disease manifestations, symptoms, and daily care affect not only the patient self-perception, but also different dimensions of patient and family life. To date, there is only a French validated ichthyosis-specific questionnaire, "Family Burden in Ichthyosis" (FBI), for the evaluation of family disease burden. It addresses economical aspects, daily life, familial and personal relationships, work, and psychological impact. The aim of our study was to develop an Italian translation of the French FBI questionnaire and to pilot-test it in ARCI patients. METHODS: The guidelines for cross-cultural adaptation of health-related quality of life measures were followed. Specifically, two independent forward translations were produced, followed by a reconciliation step by a multidisciplinary expert committee and back-translation. Revision of the original text and all translations was performed by the expert committee leading to a final version, which was pilot-tested by cognitive debriefing on 10 caregivers whose comments were evaluated by the committee. RESULTS: The translation and reconciliation process led to minor changes in five items in order to clarify the questions in relation to the possible answers or to obtain semantic/idiomatic/cultural equivalence of the Italian version with the French one. The cognitive debriefing process resulted into further minor wording modifications in four items to describe more precisely the disease impact according to parents' comments. The FBI developer approved the final Italian FBI version. CONCLUSIONS: The Italian version of the FBI generated in the present study is a useful instrument to measure the impact of ichthyosis on family daily life, education and working activities, psychological implications, and the disease economic load. The questionnaire will be further validated through a multicenter Italian study on burden of ARCI. A validated Italian questionnaire is a valuable tool for future clinical trials. In addition, it can be used to rapidly identify family distressing situations, which require attention and prompt intervention.

Electrochemotherapy for Breast Cancer-Results From the INSPECT Database.

BACKGROUND: Cutaneous recurrence from breast cancer can pose a clinical challenge. It might be the only disease site, or could be part of disseminated disease, and often profoundly affects quality of life. Electrochemotherapy is a palliative treatment using electric pulses to locally permeabilize tumor cells and thereby significantly increase bleomycin cytotoxicity. Collaborating with the International Network for Sharing Practice on ElectroChemoTherapy (INSPECT), we consecutively and prospectively accrued data on patients treated with electrochemotherapy for cutaneous metastases from breast cancer. PATIENTS AND METHODS: Patients were treated with electrochemotherapy at 10 European centers. Under either local or general anaesthesia patients were treated with either local injection (1000 IU/mL intratumoral) or systemic infusion (15,000 IU/m2) of bleomycin. RESULTS: One hundred nineteen patients were included at 10 institutions in the INSPECT network. The primary location was the chest (89%), the median diameter of the cutaneous metastases was 25 mm. Ninety patients were available for response evaluation after 2 months. Complete response was observed in 45 patients (50%), partial response in 19 (21%), stable disease in 16 (18%), and progressive disease in 7 (8%). Three patients were not evaluable. Common side effects were ulceration, long-lasting hyperpigmentation, and low-grade pain. No serious adverse events were observed. CONCLUSION: Electrochemotherapy showed high response rates after a single treatment. Electrochemotherapy has few side effects and can be used as an adjunct to systemic therapies or as a solo treatment. We therefore recommend considering electrochemotherapy for patients with cutaneous metastases.

Predictive factors in non-melanoma skin cancers treated with electrochemotherapy.

BACKGROUND: The management of non-melanoma skin cancers may benefit from alternative treatments and in this spectrum electrochemotherapy plays a pivotal role. The aim was to describe the predictive features of patients with cutaneous carcinomas treated with electrochemotherapy, with regard to clinical, pathological and instrumental predictors. METHODS: We analyzed disease free survival (DFS), and overall survival (OS) for each patient. Assuming that the effects of the predictor variables are constant over time, the independent predictive factors were assessed by Cox-proportional hazards regression in both univariate and multivariate analyses. RESULTS: We can assess that in the brief-term (DFS), the patients' age, tumor-site, tumor size, photo-type and the dose of the cytotoxic drug showed a statistical significant better behavior. However, in the multivariate, only the variables tumor's site (P=0.01) and tumor appearance (P=0.03) reached the statistical significance. In the long-term, female patients, patients with a median age ≤70 years, with III-IV photo types and patients, which received a dosage of bleomycin, ≤14 mg/m2 presented a significant better behavior. However in the multivariate analysis a significance was maintained for the variables tumor's appearance (HR: 11.6; 95% CI: 11.56 to 27.5; P=0.01), infiltration (HR:0.11; 95% CI: 0.012 to 0.9; P=0.04), electrode type (HR:0.19; 95% CI:0.04 to 0.8; P=0.03) and photo type (HR:5.7; 95% CI:1.3 to 24.3; P=0.01). CONCLUSIONS: According to our results, in electrochemotherapy different individual variables can have an important influence, which shows how this treatment could improve. The refinement of the technique and the optimization of patients' selection has the aim to improve the therapeutic response.