Genes and phenotypes in vascular malformations.

Vascular malformations (VMs) are caused by localized defects of vascular development. Most VMs are due to sporadic, postzygotic mutations, while some are the result of autosomal dominant germline mutations. Genotype-phenotype correlation is influenced by many factors. Individual genes can induce different phenotypes (pleiotropy), and similar phenotypes can be due to different genes/mutations (redundancy). The phenotypic spectrum of somatic mutations is wide, and depends on variant allele frequency, timing during embryogenesis, cell type(s) involved and type of mutation. The phenotype of germline mutations is determined by penetrance and expressivity, and is influenced by epigenetic factors (DNA methylation, histone modification) or 'second-hit' somatic mutations. Except for disorders with pathognomonic phenotypes such as Proteus syndrome or a characteristic constellation of symptoms such as CLOVES [congenital lipomatous (fatty) overgrowth, vascular malformations, epidermal naevi and scoliosis/skeletal/spinal anomalies] or PIK3CA-related overgrowth spectrum syndrome, differential diagnosis of VM is therefore difficult. It will be greatly facilitated with increasing analytic sensitivity of sequencing techniques such as next-generation sequencing. High-sensitivity molecular techniques are a prerequisite for targeted pharmacotherapy, i.e. selective therapeutic inhibition of activating mutations underlying VM, which has shown promising results in preliminary studies.

Sustained long-term efficacy and safety of adalimumab in paediatric patients with severe chronic plaque psoriasis from a randomized, double-blind, phase III study.

BACKGROUND: Adalimumab (ADA) (Humira® , AbbVie Inc., U.S.A.) is approved by the European Medicines Agency for children aged ≥ 4 years with severe plaque psoriasis. OBJECTIVES: To evaluate the long-term efficacy and safety of ADA in children with severe plaque psoriasis. METHODS: Results are presented from the 52-week long-term extension (LTE) of the randomized, double-blind, double-dummy, phase III trial, in children with severe plaque psoriasis (results from prior periods have been published). Patients aged ≥ 4 and < 18 years were randomized 1 : 1 : 1 to ADA 0·8 mg kg-1 (40 mg maximum) or 0·4 mg kg-1 (20 mg maximum) every other week or to methotrexate (MTX) 0·1-0·4 mg kg-1 (25 mg maximum) weekly. The 16-week initial treatment (IT) period was followed by a 36-week withdrawal period and a 16-week retreatment period. Patients could enter the LTE at prespecified time points to receive ADA 0·8 mg kg-1 (blinded or open label) or ADA 0·4 mg kg-1 (blinded), or to remain off treatment. Efficacy is reported for patient groups according to doses received in the IT and LTE periods. RESULTS: Of the 114 patients randomized in the IT period, 108 entered the LTE (n = 36 in each group); 93 received ADA 0·8 mg kg-1 . Efficacy (≥ 75% improvement from baseline in Psoriasis Area and Severity Index) was maintained or improved from entry to the end of the LTE: MTX(IT)/ADA 0·8(LTE) 31-86% of patients; ADA 0·4(IT)/0·4 or 0·8(LTE) 28-47%; ADA 0·8(IT)/0·8(LTE) 50-72%. No serious infections occurred in the LTE. CONCLUSIONS: After 52 weeks of long-term ADA treatment in children aged 4-18 years with severe plaque psoriasis, disease severity was reduced and maintained or further improved, as demonstrated by efficacy outcomes. No new safety risks were identified. What's already known about this topic? The results from the first three periods of this phase III trial in children aged 4-18 years with severe plaque psoriasis suggest that adalimumab is a safe and efficacious treatment option in this population. What does this study add? This is the first study to evaluate long-term treatment of adalimumab in children with severe psoriasis, and the first to evaluate switching from methotrexate to adalimumab in this population.

Febrile ulceronecrotic Mucha-Habermann disease following suspected hemorrhagic chickenpox infection in a 20-month-old boy.

We present the youngest pediatric patient so far with febrile ulcerative Mucha-Haberman disease (FUMHD) after an admitting clinical picture of hemorrhagic varicella infection. With a time to diagnosis of 25 days, the 20-month-old boy responded to low dose cyclosporine and prednisolone given for 3 months and is free of disease after 4 years of follow up. We describe a polyclonal CD8+ T cell response with elevated pro-inflammatory cytokines and a fivefold upregulation of the high-affinity Fc receptor type I (CD64) on granulocytes. Early consideration of FUMHD in the differential diagnosis of a systemic inflammatory disease combined with a generalized necrotizing rash is important for early and adequate management of children with this rare and challenging disease.

Vascular tumours in infants. Part II: vascular tumours of intermediate malignancy [corrected] and malignant tumours.

Malignant cutaneous vascular tumours are very uncommon in children. As in adults, they are aggressive neoplasms with metastatic potential and a high mortality rate. Some nonmalignant vascular tumours may exhibit a locally aggressive behaviour and some of them can be associated with life-threatening systemic complications such as Kasabach-Merritt syndrome. Early diagnosis of these aggressive neoplasms in children is very important in order to start appropriate therapy as soon as possible, as this can have a significant impact on the prognosis of these patients. This review focuses on cutaneous vascular tumours of intermediate dignity (tufted angioma, kaposiform haemangioendothelioma, multifocal lymphangioendotheliomatosis with thrombocytopenia, papillary intralymphatic angioendothelioma, retiform haemangioendothelioma, adult-type haemangioendotheliomas) and malignant vascular tumours in young children (Kaposi sarcoma, angiosarcoma).

Vascular tumours in infants. Part I: benign vascular tumours other than infantile haemangioma.

Vascular anomalies can be subdivided into vascular tumours and vascular malformations (VMs). While most VMs are present at birth and do not exhibit significant postnatal growth, vascular tumours are characterized by their dynamics of growth and (sometimes) spontaneous regression. This review focuses on benign vascular tumours other than infantile haemangiomas (IHs), namely pyogenic granuloma, eruptive pseudoangiomatosis, glomangioma, rapidly involuting and noninvoluting congenital haemangioma, verrucous haemangioma and spindle cell haemangioma. While some of them bear clinical resemblance to IH, they can be separated by age of appearance, growth characteristics and/or negative staining for glucose transporter 1. Separation of these tumours from IH is necessary because their outcome and therapeutic options are different. Semimalignant and malignant vascular tumours will be addressed in a separate review.

Linear skin atrophy preceding calcinosis cutis in pseudo-pseudohypoparathyroidism.

Albright hereditary osteodystrophy (AHO) is a syndrome caused by inactivating mutations in the GNAS (guanine nucleotide-binding protein, alpha-stimulating) gene. Patients with AHO have short stature, obesity, brachydactyly and subcutaneous calcifications. AHO can be associated with pseudohypoparathyroidism type IA (PHP-IA) with upregulation of parathyroid hormone, whereas in pseudo-pseudohypoparathyroidism (PPHP), an endocrinopathy is not present. We report the case of a 5-month-old male infant who presented with slowly progressive linear atrophic skin lesions. The histological findings showed evidence of dermal hypoplasia. The child's father had PHP-IA. Four months after presentation, the infant developed calcifications within the pre-existent atrophic lesions. No alterations in calcium metabolism were noted. Analysis of the GNAS gene identified a short duplication leading to a frameshift mutation. We conclude that linear atrophic skin lesions may be an early sign of imminent cutaneous calcifications in AHO.

Efficacy and safety of two different antifungal pastes in infants with diaper dermatitis: a randomized, controlled study.

BACKGROUND: Diaper dermatitis (DD) is the most common type of irritative dermatitis in infancy. It is frequently complicated by Candida superinfection. OBJECTIVE: Comparison of efficacy and safety of two antifungal pastes (Imazol = 1% clotrimazole; Multilind = 100,000 IU nystatin/g + 20% zinc oxide) in infants with DD. METHODS: A total of 96 infants were included in this multi-centre, controlled, randomized, evaluator-blinded phase IV trial and treated with pastes containing either clotrimazole (n = 45) or nystatin (n = 46) twice daily for 14 days. In all, 91 children (age 12.1 +/- 5.3 months; 48 females) with DD were evaluable. Total symptom score after 7 days (TSS7) was assessed as primary parameter. Secondary efficacy parameters were TSS at 14 days (TSS14), clinical and microbiological cure rates and global assessment (GA) of clinical response. RESULTS: TSS improved markedly with both pastes. Decreases in symptom score were 4.5 +/- 2.1 (day 7) and 6.1 +/- 1.9 (day 14) with clotrimazole compared with 4.2 +/- 2.3 and 5.4 +/- 2.4 with nystatin (P < 0.0001). With respect to TSS14, clotrimazole was superior to nystatin (P = 0.0434). Clinical cure rate was higher with clotrimazole [36.2% (day 7) and 68.1% (day 14)] compared with 28.6% and 46.9% (nystatin). GA was very good in 26 (55.3%) clotrimazole-treated children (nystatin: 16 [32.7%], P = 0.0257). Frequency of adverse events was comparable in both treatment groups. CONCLUSION: Clotrimazole was superior to nystatin with respect to reduction in symptom score and GA. Microbiological cure rate was 100% for both agents. Both treatments were safe and well-tolerated.

Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action.

Infantile haemangiomas (IH) are the most common benign tumours of infancy. Although most IH are innocuous and 85-90% regress spontaneously, some may become life- or function-threatening and require immediate treatment. Previous standard therapeutic options include physical measures (laser surgery, cryosurgery) and systemic corticosteroids, in severe cases also vincristine, alpha-interferon or cyclophosphamide, all bearing the risk of serious side-effects. Oral propranolol is a very recent therapeutic option for complicated IH with impressive efficacy and generally good tolerance. The effects of propranolol on IH were discovered by chance, and very little is known about its mechanisms of action in IH. Here we present a summary of current knowledge of how propranolol interferes with endothelial cells, vascular tone, angiogenesis and apoptosis. Early, intermediate and long-term effects of propranolol on IH can be attributed to three different pharmacological targets. Early effects (brightening of the haemangioma surface within 1-3 days after start of therapy) are attributable to vasoconstriction due to decreased release of nitric oxide. Intermediate effects are due to the blocking of proangiogenic signals (vascular endothelial growth factor, basic fibroblast growth factor, matrix metalloproteinase 2/9) and result in growth arrest. Long-term effects of propranolol are characterized by induction of apoptosis in proliferating endothelial cells, and result in tumour regression.

Atopic dermatitis in children: what to do when nothing works.

Atopic eczema in children usually responds to a management programme involving the regular use of emollients and the topical use of anti-inflammatory agents combined with patient education and the avoidance of environmental irritants or allergens (where necessary). If treatment fails, non-compliance should be considered first. Parents need to be reassured; a standardized educational program how to handle the disease with all its implications seems helpful. Persistent allergens or irritative triggers should be identified and eliminated. Systemic immunosuppression with either ciclosporin or azathioprine, mycophenolate mofetil or others should only be considered when parental compliance is warranted and all efforts have been made to eliminate external triggers. This article gives a short review on possible causes of treatment failures and ways to cope with them.

Neonatal haemangiomatosis associated with placental chorioangiomas: report of three cases and review of the literature.

We report three cases of neonatal haemangiomatosis associated with large placental chorioangioma. Pregnancies were complicated by polyhydramnios, and all mothers underwent amniocentesis to drain the liquid. Steroid treatment was required for two children. Although the theory has been largely disproved in normal haemangiomas, embolization of precursor endothelial cells derived from placental vessels is a likely explanation for the pathogenesis of haemangiomatosis associated with large placental chorioangiomas.

Cutis marmorata telangiectatica congenita: a prospective study of 27 cases and review of the literature with proposal of diagnostic criteria.

BACKGROUND: Cutis marmorata telangiectatica congenita (CMTC) is a congenital vascular anomaly of unknown aetiology. About 300 cases have been reported in the literature. The rate of associated anomalies varies between 20% and 70%. METHODS: We report a series of 27 children with CMTC, 18 of whom were followed-up prospectively for a median of 22 months (range 2 months-5.3 years). RESULTS: Both genders were equally affected (13 male/14 female). The legs were involved in 20 cases (74%), the arms in 10 (37%), the face in 4 (15%) and the trunk in 18 (67%). There were 20 (74%) patients who presented with involvement of both trunk and limbs, a further 20 patients had lesions affecting the limb on only one side of the body, and 7 children (26%) had bilateral lesions; 1 child had generalized CMTC lesions. The involved areas covered a mean of 18% of body surface area (range 3-90). Associated anomalies were found in 15 patients (56%), with some exhibiting more than one. There was body asymmetry (hypertropy or hypotrophy of the affected limb) in nine patients (33%), seven patients had a variety of other malformations (congenital glaucoma, syndactyly, lipoma, macrocephaly, renal hypoplasia, Kartagener's syndrome), and other vascular lesions were present in four patients (15%). There was no correlation between the extent of skin lesions and likelihood of associated anomalies. On follow-up, fading of skin lesions was noted in 67% of our patients. CONCLUSION: Body asymmetry is the most common anomaly associated with CMTC; other associations might be pure chance. In order to separate CMTC from other vascular malformations, notably Klippel-Trénaunay syndrome, we suggest diagnostic criteria for their differentiation.

The treatment of facial atopic dermatitis in children who are intolerant of, or dependent on, topical corticosteroids: a randomized, controlled clinical trial.

BACKGROUND: Atopic dermatitis (AD) is most prevalent in areas of reduced skin barrier reserve, like face and neck, especially in children. Treatment with topical corticosteroids (TCS) is limited due to heightened risk of treatment-associated side-effects, thus necessitating alternative AD therapies. OBJECTIVES: The primary study objective was to determine the efficacy of pimecrolimus cream 1% in children with mild-moderate facial AD dependent on/intolerant of TCS. Secondary objectives included effects on overall Eczema Area and Severity Index (EASI), head/neck EASI, pruritus severity and time to clearance of facial AD. METHODS: A multicentre, double-blind (DB) study of < or = 6 weeks, followed by a 6-week, open-label (OL) phase was conducted. Two hundred patients (aged 2-11 years) were randomized 1:1 to pimecrolimus cream 1% (n = 99) or vehicle (n = 101) twice daily until clearance of facial AD or for a maximum of 6 weeks (DB phase). Sixteen patients receiving vehicle were allowed to switch to the OL phase at day 22. RESULTS: Significantly more pimecrolimus-treated vs. vehicle-treated patients were cleared/almost cleared of facial AD (Investigators' Global Assessment 0/1): 74.5% vs. 51.0%, P < 0.001 (day 43) [57.1% vs. 36.0%, P = 0.004 (day 22)]. Median time to clearance was 22.0 vs. 43.0 days (pimecrolimus vs. vehicle, respectively). Statistically significant differences for pimecrolimus vs. vehicle were also seen on head/neck EASI, overall EASI, and head/neck pruritus scores. Adverse events were mainly mild-moderate, occurring with similar frequency in both treatment groups. CONCLUSIONS: In children with facial dermatitis intolerant of/dependent on TCS, pimecrolimus cream 1% effectively controls eczema and pruritus and is well tolerated.