Response to sirolimus in capillary lymphatic venous malformations and associated syndromes: Impact on symptomatology, quality of life, and radiographic response.

BACKGROUND: Capillary lymphatic venous malformations (CLVM) and associated syndromes, including Klippel-Trenaunay syndrome (KTS) and congenital lipomatous overgrowth, vascular malformation, epidermal nevi, skeletal, and spinal syndrome (CLOVES), are underrecognized disorders associated with high morbidity from chronic pain, recurrent infections, bleeding, and clotting complications. The rarity of these disorders and heterogeneity of clinical presentations make large-scale randomized clinical drug trials challenging. Identification of PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [gene]) mutations in CLVM has made targeted medications, such as sirolimus, attractive treatment options. The aim of this study was to investigate the safety and efficacy of sirolimus therapy in CLVM. PROCEDURE: A combined prospective and retrospective cohort of pediatric and young adult patients with CLVM treated with sirolimus was evaluated for disease response, including symptom improvement, quality of life (QOL), and radiologic response. Sirolimus dosing regimens and toxicities were also assessed. RESULTS: Twenty-nine patients with CLVM, including KTS and CLOVES, were included. Ninety-three percent of patients reported improved QOL, and 86% had improvement in at least one symptom. Most significantly, improvement was noted in 100% of patients with bleeding and 89% with thrombotic complications with corresponding decreases in mean D-dimer (p = .008) and increases in mean fibrinogen (p = .016). No patients had progressive disease on sirolimus. Most common side effects included neutropenia, lymphopenia, infection, and aphthous ulcers/stomatitis. No toxicities were life-threatening, and none required long-term discontinuation of sirolimus. CONCLUSION: Sirolimus appears to be effective at reducing complications and improving QOL in patients with CLVM and associated syndromes. In this patient cohort, sirolimus was well tolerated and resulted in few treatment-related toxicities.

Late growth of infantile hemangiomas in children >3 years of age: A retrospective study.

BACKGROUND: The proliferative phase of infantile hemangiomas (IHs) is usually complete by 9 months of life. Late growth beyond age 3 years is rarely reported. OBJECTIVE: To describe the demographic and clinic characteristics of a cohort of patients with late growth of IH, defined as growth in a patient >3 years of age. METHODS: A multicenter, retrospective cohort study. RESULTS: In total, 59 patients, 85% of which were female, met the inclusion criteria. The mean first episode of late growth was 4.3 (range 3-8.5) years. Head and neck location (55/59; 93%) and presence of deep hemangioma (52/59; 88%) were common characteristics. Posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects, eye abnormalities (PHACE) syndrome was noted in 20 of 38 (53%) children with segmental facial IH. Systemic therapy (corticosteroid or ß-blocker) was given during infancy in 58 of 59 (98%) and 24 of 59 (41%) received systemic therapy (ß-blockers) for late IH growth. LIMITATIONS: The retrospective nature and ascertainment by investigator recall are limitations of the study. CONCLUSION: Late IH growth can occur in children after 3 years of age. Risk factors include head and neck location, segmental morphology, and involvement of deep dermal/subcutaneous tissues.

Wound management of ulcerated haemangioma of infancy - an audit.

Haemangioma of infancy, a benign tumour of blood vessels, is the most common tumour of infancy. Ulceration, the most common complication, presents a unique wound care challenge. A retrospective audit of medical records of children with haemangioma of infancy who presented to the Royal Children's Hospital, Melbourne, Australia, between January 2000 and December 2014 was undertaken with an aim to examine wound management of ulcerated haemangioma of infancy. In total, 535 hospital medical records were identified as suitable, of which 352 were randomly selected and audited, of which 84 patients had ulcerated haemangioma of infancy, and 62 were subject to wound management. Of these, 35 were successfully managed by wound dressings, 9 were not fully healed at the time of last review, and 18 were referred for surgical excision. Patients attended an average of five outpatient visits, and the average time from presentation to documented healing was 105 days. There were a total of 225 episodes of wound dressing, for which there was a documented follow-up appointment at which healing could be assessed. Although a wide range of dressings were used, there was no clear pattern of benefit of one dressing over another. Wounds were less likely to be healed after the use of a silver-impregnated dressing. Pain was poorly documented. Clinical assessment of whether wounds were infected was of no help in planning treatment. There is considerable variability in the management of this difficult wound group, and further prospective studies are required.

Adverse effects of topical corticosteroids in paediatric eczema: Australasian consensus statement.

Atopic eczema is a chronic inflammatory disease affecting about 30% of Australian and New Zealand children. Severe eczema costs over AUD 6000/year per child in direct medical, hospital and treatment costs as well as time off work for caregivers and untold distress for the family unit. In addition, it has a negative impact on a child's sleep, education, development and self-esteem. The treatment of atopic eczema is complex and multifaceted but a core component of therapy is to manage the inflammation with topical corticosteroids (TCS). Despite this, TCS are often underutilised by many parents due to corticosteroid phobia and unfounded concerns about their adverse effects. This has led to extended and unnecessary exacerbations of eczema for children. Contrary to popular perceptions, (TCS) use in paediatric eczema does not cause atrophy, hypopigmentation, hypertrichosis, osteoporosis, purpura or telangiectasia when used appropriately as per guidelines. In rare cases, prolonged and excessive use of potent TCS has contributed to striae, short-term hypothalamic-pituitary-adrenal axis alteration and ophthalmological disease. TCS use can also exacerbate periorificial rosacea. TCS are very effective treatments for eczema. When they are used to treat active eczema and stopped once the active inflammation has resolved, adverse effects are minimal. TCS should be the cornerstone treatment of atopic eczema in children.

A randomized, controlled trial of oral propranolol in infantile hemangioma.

BACKGROUND: Oral propranolol has been used to treat complicated infantile hemangiomas, although data from randomized, controlled trials to inform its use are limited. METHODS: We performed a multicenter, randomized, double-blind, adaptive, phase 2-3 trial assessing the efficacy and safety of a pediatric-specific oral propranolol solution in infants 1 to 5 months of age with proliferating infantile hemangioma requiring systemic therapy. Infants were randomly assigned to receive placebo or one of four propranolol regimens (1 or 3 mg of propranolol base per kilogram of body weight per day for 3 or 6 months). A preplanned interim analysis was conducted to identify the regimen to study for the final efficacy analysis. The primary end point was success (complete or nearly complete resolution of the target hemangioma) or failure of trial treatment at week 24, as assessed by independent, centralized, blinded evaluations of standardized photographs. RESULTS: Of 460 infants who underwent randomization, 456 received treatment. On the basis of an interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg of propranolol per kilogram per day for 6 months was selected for the final efficacy analysis. The frequency of successful treatment was higher with this regimen than with placebo (60% vs. 4%, P<0.001). A total of 88% of patients who received the selected propranolol regimen showed improvement by week 5, versus 5% of patients who received placebo. A total of 10% of patients in whom treatment with propranolol was successful required systemic retreatment during follow-up. Known adverse events associated with propranolol (hypoglycemia, hypotension, bradycardia, and bronchospasm) occurred infrequently, with no significant difference in frequency between the placebo group and the groups receiving propranolol. CONCLUSIONS: This trial showed that propranolol was effective at a dose of 3 mg per kilogram per day for 6 months in the treatment of infantile hemangioma. (Funded by Pierre Fabre Dermatologie; ClinicalTrials.gov number, NCT01056341.).

Infantile haemangiomas that failed treatment with propranolol: clinical and histopathological features.

AIM: To describe the clinical and histopathological characteristics of infantile haemangiomas that failed treatment with oral propranolol . DESIGN: This study is a case series from the vascular birthmarks clinic at Royal Children's Hospital, Melbourne. PATIENTS: The patients for this study were infants who commenced treatment with oral propranolol before 6 months of age and who were treated for at least 4 months without a satisfactory result. For histology and immunohistochemistry, tissue from the four non-responding patients who subsequently underwent surgical excision was matched with four historical controls. OUTCOME MEASURES: Based on medical record review and photographic assessments, infants were defined as having failed treatment with oral propranolol if the infantile haemangioma either continued to grow or showed 20% improvement or less. Tissue sections were examined for tissue structure, mast cells, sympathetic innervations and beta-2 adrenergic receptor expression, and the number of mast cells and beta-2 adrenergic positive cells. RESULTS: From a group of 135 infants who met the inclusion criteria, 14 infants failed propranolol treatment. Eleven of these infants had focal facial haemangiomas. No difference was seen in tissue morphology, tissue innervations, beta-2 adrenergic receptor expression, cell number or mast cell distribution, and number between non-responding and control haemangiomas. CONCLUSION: We report a treatment failure rate of 10%, which is higher than previously reported. Focal facial lesions failed to respond twice as frequently as other types of haemangioma. No histopathological reason was identified to indicate why some haemangiomas failed to respond.

Headache after lumbar puncture: randomised crossover trial of 22-gauge versus 25-gauge needles.

OBJECTIVES: To compare the frequency of headache and the procedure time following lumbar puncture (LP) using a 25-gauge needle compared to a 22-gauge needle. DESIGN: 4-period crossover blinded randomised controlled trial. SETTING: Oncology unit, Royal Children's Hospital, Melbourne. PATIENTS: Children aged 4-15 years at enrolment having LPs as part of their treatment for leukaemia. INTERVENTIONS: Each child was allocated a random sequence of four LPs, two with a 22-gauge and two with a 25-gauge needle. OUTCOME MEASURES: The presence of post-LP headache. Secondary outcomes included the presence of any headache, procedure time and impact of headache on the family. RESULTS: Data on 341 procedures in 93 randomised children were analysed. There was little difference in the incidence of post-LP headache between the two needle sizes (22-gauge 7.2%, 95% CI 3.8 to 12.2; 25-gauge 4.6%, 95% CI 2.0 to 8.9, p=0.3) or in the incidence of any headache (22-gauge 18% 95% CI 12.5 to 24.6; 25-gauge 15%, 95% CI 10.0 to 21.1, p=0.4). Use of the 25-gauge needle was associated with longer procedure times. The incidence of post-LP headache showed little evidence of an age effect (OR =1.1, 95% CI 0.98 to 1.3) and was higher in girls than in boys (11% vs 3%, respectively, OR=3.3, 95% CI 1.3 to 8.4, p=0.014). Fifty-five per cent of families with a child with a post-LP headache assessed the overall functional impact as moderate or severe. CONCLUSIONS: There was little difference in the occurrence of post-LP headache or any headache between procedures carried out using the 22-gauge or 25-gauge needles. Depending on the circumstances of the procedure and the experience of the operator, either gauge may be appropriate for an LP in a child.

Use of propranolol for treatment of infantile haemangiomas in an outpatient setting.

INTRODUCTION: Propranolol has recently emerged as an effective drug treatment for infantile haemangiomas. The side effect profile of the drug and the safety of administering propranolol in outpatient settings in this age group remain uncertain. We report our experience with 200 infants and children prescribed propranolol to treat infantile haemangiomas, including 37 patients considered to have a poor response to treatment. METHOD: Patients were prescribed propranolol (1 mg/kg/dose bd) as outpatients at the Vascular Anomalies Service at the Royal Children's Hospital, Melbourne. RESULTS: The median age at commencement was 4 months (range 5 days-7 years). Twenty patients were older than 12 months at commencement. The median duration of treatment was 8 months. About 80% of treated haemangiomas were on the face. Approximately 50% of patients were considered to have an excellent response, 30% to have a good response and 20% to have a poor response. All segmental facial haemangiomas responded well. In contrast, 25% of focal facial haemangiomas responded poorly. Sleep disturbance was the most common side effect. Gross motor abnormalities including delayed walking were observed in 13 patients. CONCLUSION: Propranolol appears to be an effective treatment for infantile haemangiomas, particularly large segmental facial lesions. A poor response was seen in 20% of patients. Treatment has been provided in an outpatient setting without major complications and with excellent parental compliance. The side effect profile appears to be favourable, but further follow-up is required to identify unexpected long-term side effects.

Erosive pustular dermatosis of the scalp after perinatal scalp injury.

We report four infants born with necrotic caput succedaneum that led to a scarring alopecia with ongoing inflammation and persistent scale-crust. These lesions did not significantly improve with topical or oral antibiotics, but did respond somewhat to topical corticosteroids. Alopecia with chronic erosive scale-crust and a moderate response to topical corticosteroids are findings consistent with a diagnosis of erosive pustular dermatosis of the scalp.

Keratosis pilaris rubra: a common but underrecognized condition.

BACKGROUND: Keratosis pilaris is a common skin disorder of childhood that often improves with age. Less common variants of keratosis pilaris include keratosis pilaris atrophicans and atrophodermia vermiculata. OBSERVATIONS: In this case series from dermatology practices in the United States, Canada, Israel, and Australia, the clinical characteristics of 27 patients with keratosis pilaris rubra are described. Marked erythema with follicular prominence was noted in all patients, most commonly affecting the lateral aspects of the cheeks and the proximal arms and legs, with both more marked erythema and widespread extent of disease than in keratosis pilaris. The mean age at onset was 5 years (range, birth to 12 years). Sixty-three percent of patients were male. No patients had atrophy or scarring from their lesions. Various treatments were used, with minimal or no improvement in most cases. CONCLUSIONS: Keratosis pilaris rubra is a variant of keratosis pilaris, with more prominent erythema and with more widespread areas of skin involvement in some cases, but without the atrophy or hyperpigmentation noted in certain keratosis pilaris variants. It seems to be a relatively common but uncommonly reported condition.

An unusual N-terminal deletion of the laminin alpha3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome.

Laryngo-onycho-cutaneous (LOC or Shabbir) syndrome (OMIM 245660) is an autosomal recessive epithelial disorder confined to the Punjabi Muslim population. The condition is characterized by cutaneous erosions, nail dystrophy and exuberant vascular granulation tissue in certain epithelia, especially conjunctiva and larynx. Genome-wide homozygosity mapping localized the gene to a 2 Mb region on chromosome 18q11.2 with an LOD score of 19.8 at theta=0. This region includes the laminin alpha3 gene (LAMA3), in which loss-of-expression mutations cause the lethal skin blistering disorder Herlitz junctional epidermolysis bullosa. Detailed investigation showed that this gene possesses a further 38 exons (76 exons in total) spanning 318 kb of genomic DNA, and encodes three distinct proteins, designated laminin alpha3a, alpha3b1 and alpha3b2. The causative mutation in 15 families was a frameshift mutation 151insG predicting a stop codon 7 bp downstream in an exon that is specific to laminin alpha3a. This protein is secreted only by the basal keratinocytes of stratified epithelia, implying that LOC is caused by dysfunction of keratinocyte-mesenchymal communication. Surprisingly, the 151insG mutation does not result in nonsense-mediated mRNA decay due to rescue of the transcript by an alternative translation start site 6 exons downstream. The resultant N-terminal deletion of laminin alpha3a was confirmed by immunoprecipitation of secreted proteins from LOC keratinocytes. These studies show that the laminin alpha3a N-terminal domain is a key regulator of the granulation tissue response, with important implications not only in LOC but in a range of other clinical conditions associated with abnormal wound healing.