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.

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.

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.

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.

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.

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.

Color Doppler Evaluation of Arterial Resistive Index in Infantile Hemangioma: A Useful Parameter to Monitor the Response to Oral Propranolol?

Infantile hemangioma (IH) is the most common benign vascular tumor in childhood. In more than 85% of all cases, IHs undergo spontaneous involution, but nearly 10-12% of IHs develop complications and require immediate therapy. Oral propranolol is currently the first-line treatment for IHs. Color Doppler ultrasound is the gold standard in the diagnosis of deep IH, and it is used to evaluate the morphological change and the modification of vascularization that occur during its evolution and treatment. To date, only few data in the literature described the changes of intralesional arterial resistive index (RI) during treatment with propranolol; particularly, some authors have shown an increase of intralesional arterial RI in IHs with clinical regression during treatment with propranolol. The objective of this paper is to evaluate the changes of RI of the intralesional arteries of the IHs during the treatment with oral propranolol. We retrospectively analyzed a total of 64 IHs in 60 patients treated with oral propranolol with a good clinical response. Gray-scale ultrasonography and color Doppler imaging were performed before and during the therapy. The intralesional RIs were measured before and during the treatment. For each lesion, we recorded the RI values, and then we calculated the mean RI value for any single lesion. We compared the mean RI value observed at the baseline with the mean RI value of the last detectable sampling at color Doppler. We also compared between them the mean RI values observed during intermediate ultrasound. The RI values were compared in 44 lesions, with at least two significant samplings of RI. In the 44 lesions compared, we did not find statistically significant variations in the mean RI values between the baseline control and the values recorded at the last post-treatment control. The time trend of mean RI values of the intermediate color Doppler analysis performed between the first pre-treatment control and the last measurable control did not show any statistically significant variation in the trend of mean RI values. Contrarily to what has been described by some authors, in our experience, we have not observed an increase of RI in IHs treated with oral propranolol.

Vascular Birthmarks as a Clue for Complex and Syndromic Vascular Anomalies.

Vascular birthmarks are common in neonates (prevalence: 20-30%) and mostly incidental findings sometimes with spontaneous regression (salmon patch and nevus simplex). Capillary malformations are found in about 1% and infantile hemangiomas are found in 4% of mature newborns. Vascular malformations are classified according to their most prominent vessel type. The term "capillary malformation" (port wine stain) includes a wide range of vascular lesions with different characteristics; they may be isolated or part of specific syndromic conditions. Part of the infantile hemangiomas and of the vascular malformations may require treatment for functional or cosmetic reasons, and in rare cases, investigations are also necessary as they represent a clue for the diagnosis of complex vascular malformation or tumors associated with extracutaneous abnormalities. Complex vascular malformations are mostly mosaicism due to early somatic mutations. Genetic advances have led to identify the main pathogenic pathways involved in this disease group. Diffuse capillary malformation with overgrowth, Klippel-Trenaunay syndrome, CLAPO syndrome, CLOVES syndrome, and megalencephaly-capillary malformation belong to the PIK3CA-related overgrowth. Capillary malformation-arteriovenous malformation underlies a fast-flow vascular malformation, sometimes manifesting as Parkes-Weber syndrome. Recognition of these different types of capillary vascular stains is sometimes difficult; however, associated findings may orient the clinicians while genetic testing may confirm the diagnosis. Lymphatic malformation frequently manifests as large masses that compress and/or infiltrate the surrounding tissues, representing a neonatal emergency when airways are involved. Infantile hemangiomas may cause functional and/or permanent esthetical damage, depending on their localization (such as periorbital area, lip, nose); large (more than 5 cm) infantile hemangiomas with a segmental distribution can be associated with obstruction or malformations of the underneath organs with complications: PHACE syndrome, LUMBAR/SACRAL syndrome, and beard infantile hemangioma. In our review, we discuss controversies regarding the international classification and emerging concepts in the field of vascular anomalies. Finally, we discuss potential developments of new, non-invasive diagnostic techniques and repurposing of target therapies from oncology. Complex and/or life-threatening vascular tumors and malformations are extremely rare events and they represent a considerable therapeutic challenge. Early recognition of clinical signs suggestive for a specific disease may improve therapeutic outcomes and avoid severe complications.

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.

Clinical trial of ABCB5+ mesenchymal stem cells for recessive dystrophic epidermolysis bullosa.

BACKGROUNDRecessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating, and life-threatening inherited skin fragility disorder that comes about due to a lack of functional type VII collagen, for which no effective therapy exists. ABCB5+ dermal mesenchymal stem cells (ABCB5+ MSCs) possess immunomodulatory, inflammation-dampening, and tissue-healing capacities. In a Col7a1-/- mouse model of RDEB, treatment with ABCB5+ MSCs markedly extended the animals' lifespans.METHODSIn this international, multicentric, single-arm, phase I/IIa clinical trial, 16 patients (aged 4-36 years) enrolled into 4 age cohorts received 3 i.v. infusions of 2 × 106 ABCB5+ MSCs/kg on days 0, 17, and 35. Patients were followed up for 12 weeks regarding efficacy and 12 months regarding safety.RESULTSAt 12 weeks, statistically significant median (IQR) reductions in the Epidermolysis Bullosa Disease Activity and Scarring Index activity (EBDASI activity) score of 13.0% (2.9%-30%; P = 0.049) and the Instrument for Scoring Clinical Outcome of Research for Epidermolysis Bullosa clinician (iscorEB­c) score of 18.2% (1.9%-39.8%; P = 0.037) were observed. Reductions in itch and pain numerical rating scale scores were greatest on day 35, amounting to 37.5% (0.0%-42.9%; P = 0.033) and 25.0% (-8.4% to 46.4%; P = 0.168), respectively. Three adverse events were considered related to the cell product: 1 mild lymphadenopathy and 2 hypersensitivity reactions. The latter 2 were serious but resolved without sequelae shortly after withdrawal of treatment.CONCLUSIONThis trial demonstrates good tolerability, manageable safety, and potential efficacy of i.v. ABCB5+ MSCs as a readily available disease-modifying therapy for RDEB and provides a rationale for further clinical evaluation.TRIAL REGISTRATIONClinicaltrials.gov NCT03529877; EudraCT 2018-001009-98.FUNDINGThe trial was sponsored by RHEACELL GmbH & Co. KG. Contributions by NYF and MHF to this work were supported by the NIH/National Eye Institute (NEI) grants RO1EY025794 and R24EY028767.

Operative Management of Neonatal Lymphatic Malformations: Lesson Learned From 57 Consecutive Cases.

Aim of the study: Lymphatic malformations (LMs) are rare entities, sometimes difficult to treat, that may be life-threatening when intricately connected to airway structures. Invasive treatments are occasionally required, with sclerotherapy considered the treatment of choice and surgery as a second-line approach. The aim of the present study was to evaluate our multidisciplinary team experience in treating newborns affected by LMs requiring operative management, while defining early outcomes. Methods: Retrospective review of all consecutive patients admitted for LMs requiring operative management between January 2000 and January 2019. Patients were mainly characterized based on anatomical district of the LM (and further stratified based on the development of respiratory distress), need for tracheostomy, number of sclerotherapies, indication for surgery, and residual disease beyond the 1st year. Morbidity and mortality were also evaluated. Fisher exact test and Mann-Whitney test were used as appropriate. Statistical significance was set at p < 0.05. Results: Fifty-seven patients were included in the study, 36 with cervicofacial and/or mediastinal LMs and 21 with LMs of other anatomical districts. Due to the risk of developing respiratory distress at birth, patients with cervicofacial and/or mediastinal LMs were divided into two groups (8/36 group A vs. 28/36 group B). Group A patients are at higher risk for tracheostomy (7/8 group A vs. 1/28 group B, p = 0.0001) and more often require surgical reduction of the residual lymphatic abnormality (5/8 group A vs. 4/28 group B, p = 0.013). They also require sclerotherapies more often, but the difference is not statistically significant (8/8 group A vs. 19/28 group B, p = 0.15). Patients with cervicofacial/mediastinal LMs frequently suffer from persistent residual disease beyond the 1st year of life, significantly more often in group A (7/8 group A vs. 12/28 group B, p = 0.043). Conclusion: LMs are rare conditions with potential life-threatening behavior. Their intrinsic clinical complexity requires a multidisciplinary approach to the affected patients. Planning a long-term follow-up is essential because of the late-term problems those patients may experience.

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.

Congenital self-healing reticulohistiocytosis in a newborn: unusual oral and cutaneous manifestations.

BACKGROUND: Congenital self-healing reticulohistiocytosis (CSHRH), also called Hashimoto-Pritzker disease, is a rare and benign variant of Langerhans cell histiocytosis, characterized by cutaneous lesions without extracutaneous involvement. CASE PRESENTATION: We present a case of CSHRH with diffuse skin lesions and erosions in the oral mucosa, present since birth and lasting for 2 months, and we perform a review of the literature on Pubmed in the last 10 years. CONCLUSIONS: Our case confirm that lesions on oral mucosa, actually underestimated, may be present in patients with CSHRH. Patients affected by CSHRH require a close follow-up until the first years of life, due to the unpredictable course of Langerhans cell histiocytosis, in order to avoid missing diagnosis of more aggressive types of this disorder.

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.

Sequelae following infantile haemangiomas treated with propranolol.

BACKGROUND: Oral propranolol accelerates the involution of infantile haemangiomas (IHs). However, it is not clear whether IHs treated with oral propranolol are associated with fewer sequelae than when left untreated. OBJECTIVES: To quantify and describe sequelae associated with IHs treated with oral propranolol, and to explore whether treated IHs are associated with fewer sequelae than untreated IHs. MATERIALS & METHODS: This multicentre, retrospective, cohort study included patients with IH treated with oral propranolol ≥2 mg/kg for at least six months, with photographic images available at baseline and at age 4-5 years. A historical comparison cohort comprised 185 patients with untreated IHs. Main outcomes/measures were: IH features, treatment characteristics and type/degree of sequelae. RESULTS: Oral propranolol, most commonly at 2 mg/kg/day (mean duration: nine months), was initiated in 171 patients (mean age: 6.02 months). After treatment, 125 of 171 (73.1%) IHs were associated with no/minimal sequelae. The most common sequelae were telangiectasia (78%), fibrofatty tissue (37%) and anetodermic skin (28%). Deep IHs were associated with significantly fewer sequelae than other subtypes. Ulceration appeared to increase the likelihood of severe sequelae. IHs with a stepped border was associated with more severe sequelae than those with a progressive border (44% versus 27%, p < 0.05). Treated IHs resolved without sequelae or were associated with a sequela that did not need correction in 27.7% more cases than untreated IHs (RR: 1.61; p < 0.001). CONCLUSION: Among IHs treated with oral propranolol, 73% resolved without, or were associated with minimal sequelae. Deep IHs were associated fewer sequelae than other subtypes. Oral propranolol decreased the likelihood of IH sequelae requiring correction.

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.