Propranolol Treatment for Hemangioma of Infancy: Risks and Recommendations

Abstract:  Hemangioma of infancy is a condition that may be associated with significant morbidity. While evidence most supports the use of corticosteroids, there is no well-defined or Federal Drug Administration (FDA)-approved systemic therapy for hemangioma of infancy. All currently used treatments have significant risks. Dramatic improvement of complicated hemangioma of infancy to propranolol was recently reported, but details for initiating therapy, monitoring, and potential risks were not included. We present two infants treated with propranolol, who suffered complications and propose a treatment protocol to minimize potential adverse events.     

Acropustulosis of infancy.

Acropustulosis of infancy (Al) is a syndrome consisting of pruritic pustules that are found primarily on the extremities of infants. It is uncommon, but not rare, and persists about two years. In two infants in whom Al began at birth, there was a striking response to sulfones. There was no response to other therapy. Laboratory findings are not diagnostic for Al. Similar histopathologic changes (subcorneal pustules) can be found in other eruptions of infancy.     

Hemangiomas of infancy

Hemangiomas of infancy are unique, benign, pediatric tumors of endothelial cells characterized by an initial phase of rapid proliferation, followed by slow involution, often leading to complete regression. Although most of these tumors are small and innocuous, some may be may be life- or function-threatening, or have associated structural congenital anomalies. Uncertainties regarding their diagnosis or management often prompt referral to a dermatologist. The pathogenesis of hemangiomas of infancy is not well understood, but recent findings suggest a unique vascular phenotype with dysregulated vascular homeostasis. This article reviews new information regarding the pathogenesis of these tumors and highlights the more worrisome presentations, including syndromic hemangiomas, that are likely to be problematic. In addition, management strategies and treatment options are discussed. (J Am Acad Dermatol 2003;48:477-93.) Learning objective: At the completion of this learning activity, participants should be able to describe the clinical features of hemangiomas of infancy and potential complications as well as to understand the strengths and limitations of various treatment options.     

婴儿血管瘤的细胞起源

婴儿血管瘤是婴儿时期常见的良性肿瘤,其发病机制尚不清楚.婴儿血管瘤的发生可能是几种机制联合作用的病理生理过程.回顾近年来有关婴儿血管瘤细胞起源的文献,包括胎盘源性理论、内皮祖细胞源性理论,转移性生态位理论,以增进临床工作者对婴儿血管瘤的认识.目前,对婴儿血管瘤的研究仍存在众多令人困惑的问题,解决婴儿血管瘤的起源问题,将有助于发现更有效的治疗方法.

Abstract：

Infantile hemangiomas are common benign tumor of infancy. Their etiology remains unknown. The initiation of infantile hemangiomas is reported to be a complex pathophysiological process with the involvement of several mechanisms. The authors review recent studies and new hypotheses on the cell origin of infantile hemangiomas, including placental origin theory, endothelial progenitor cell theory and metastatic niche theory, in hope to enhance clinician recognition of infantile hemangiomas. At present, there are numerous problems remaining unanswered. To clarify the cell origin of infantile hemangiomas will help to develop more effective treatment strategies for this entity.     

The differential diagnosis of atopic dermatitis in childhood

Atopic is the most common of the dermatitides seen in infancy and childhood, but there are numerous other diseases that can mimic the skin findings. These include seborrheic dermatitis, immunodeficiency, and psoriasis in infancy; scabies, tinea corporis infection, perioral, nummular, contact, and molluscum dermatitis in childhood. It is sometimes extremely difficult to differentiate between ichthyosis and AD, and it is also important to differentiate AD from erythrodermic conditions including acrodermatitis enteropathica, biotin deficiency, and Netherton syndrome. A rare condition in children that may mimic AD is mycosis fungoides.     

Fibrous hamartoma of infancy manifesting as multiple nodules with hypertrichosis

Fibrous hamartoma of infancy is a rare benign tumor, which usually occurs within the first year of life. Most cases present as a solitary, painless, skin-colored subcutaneous nodule; multiple lesions are rarely reported. There have also been a few cases which have showed overlying skin changes, including hypertrichosis and alterations in pigmentation. We report a rare case of fibrous hamartoma of infancy in a 6-month-old female who presented as multiple nodules with overlying hypertrichosis on the left buttock. To the best of our knowledge, there have been only two reported cases in the dermatological published work that showed these unusual findings simultaneously.     

Clinical pharmacology of intravenous paracetamol in perinatal medicine

Clinical pharmacology aims to predict drug-related effects based on compound and population specific pharmacokinetics (PK, concentration-time), and pharmacodynamics (PD, concentration-effect). Consequently, dosing needs to be based on the physiological characteristics of the individual patient. Pregnancy and early infancy hereby warrant focused assessment. The specific characteristics of both subpopulations will be illustrated based on observations on intravenous (iv) paracetamol PK and PD collected in these specific populations. At delivery, there is a significant higher paracetamol clearance (+ 45%, L/h) when compared to non-pregnant observations. This higher clearance is in part explained by a proportional increase in oxidative metabolite production, but mainly an increase in glucuronidation. When focusing on PD, an association between maternal paracetamol exposure and atopy in infancy and fetal gastroshizis has been reported. In early infancy, paracetamol clearance is significantly lower and mainly depends on size (weight 0.75), while also the distribution volume is higher (L/kg). Reports on hepatic tolerance, haemodynamic stability and impact of body temperature have been published while the concentration effect profile for analgesia seems to be similar between neonates and children. Similar to maternal exposure, there are reports on the association with atopy. Studies on the use of paracetamol to close the patent ductus arteriosus are ongoing. At least, these observations provide evidence on the need to study commonly administered anesthetics in such specific subpopulations with specific focus on both population specific PK and PD to further improve patient tailored pharmacotherapy.     

Atenolol as an alternative to propranolol for the management of sleep disturbances in the treatment of infantile hemangiomas

Infantile hemangiomas are the most common tumors of infancy and are often managed with oral beta‐blockers to address or prevent associated complications. However, treatment with propranolol can occasionally be associated with sleep disturbances, which in some cases are severe enough to warrant discontinuation or replacement with another agent. We herein report four cases in which treatment with propranolol resulted in significant sleep disturbances prompting substitution with atenolol, which in some cases resolved these issues.     

Interferon α 2B for treatment of complex cutaneous haemangiomas of infancy

Summary Interferon alpha 2b for the treatment of complex haemangiomas of infancy (HI) and childhood. Background Recombinant interferon α has been used with success in the treatment of complex haemangiomas of infancy. Materials and methods Eleven infants and children (10 females and 1 male) with complex haemangiomas (age 3–14 months) were treated with interferon α 2b by subcutaneous infection of up to 1 million UI/m²/day three times a week for 2 weeks: then the dosage was increased to 3 million Ul/m²/day three times a week. The duration of treatment ranged from 6 to 14 months. A decrease of 50% or more in the dimension of haemangiomas that was maintained for at least 6 months during the treatment or after the withdrawal of the medication was considered a consequence of therapy. Results In 1 case regression of HI was of 20%; in the other 10 cases, regression ranged from 60% to 90%. The side effects of interferon therapy were mild and transient. Our treatment schedule shows that the administration of interferon α 2b three times a week is as effective as the daily administration of the drug. In our opinion interferon α 2b is a safe agent in the treatment of complex haemangiomas of infancy and therefore should he considered a first line therapeutic option.     

Surgical excision of pedunculated supernumerary digits prevents traumatic amputation neuromas

Nine patients divided into two groups were treated for pedunculated supernumerary digits or their sequelae. The first group consisted of three patients who had among them five traumatic amputation neuromas. In each case these lesions resulted from primary suture ligation of accessory digits in infancy. Secondary surgical excision of the vestigial digit with high ligation and retraction of the accompanying nerve tissue was required in all cases. The second group consisted of six patients who had 12 pedunculated supernumerary digits. Primary surgical excision of these digits was performed with high transection and retraction of the accompanying accessory digital nerve. All patients in this group had excellent cosmetic results with no postoperative neuroma formation. Adult family members who had undergone suture ligation of similar supernumerary digits in infancy accompanied seven of the nine patients in this series. On careful examination, each of these family members had signs and symptoms attributable to traumatic amputation neuromas. We feel identification and high transection of the accessory digital nerve is essential in the treatment of pedunculated supernumerary digits. This treatment prevents traumatic amputation neuromas and yields a better cosmetic result than the traditional method of suture ligation in infancy.     

Eosinophilic pustular folliculitis in infancy: not a distinctive inflammatory disease of the skin

In the standard literature of dermatology and dermatopathology "eosinophilic pustular folliculitis in infancy" is presented as a distinctive inflammatory disease of the skin, to wit, a variant of "Ofuji's eosinophilic folliculitis". Assessment critically of the first publication devoted to the subject revealed a potpourri of findings clinical and histopathologic, with no clear criteria being set forth by the authors to enable diagnosis, with precision. Our review of all articles dedicated to the matter of "eosinophilic pustular folliculitis in infancy" shows that criteria for diagnosis are found with great difficulty. The majority of patients reported on had neither "eosinophilic folliculitis," nor did they present themselves clinically in any way similar to what was originally described by Ofuji. The findings histopathologic told of most commonly were dense and diffuse infiltrates in the dermis that contained many eosinophils, sometimes with periadnexal distribution. We think that the findings reported on in several articles suggest that the patients more likely had a variety of different diseases, among them scabies, insect bites, impetigenized nummular dermatitis, and linear IgA-dermatosis. For clarification of terminology, we suggest that "eosinophilic folliculitis" is better defined as a pattern histopathologic than as a distinctive disease entity. It may be encountered in a variety of conditions (eg, Ofuji's disease, arthropod bites, scabies, or dermatophytosis). In sum, no clear criteria have been established for diagnosis of "eosinophilic pustular folliculitis of infancy" and there is no convincing evidence, at present, that "eosinophilic pustular folliculitis of infancy" qualifies as a distinctive inflammatory disease of the skin.     

Periocular hemangiomas: what every physician should know

Hemangiomas are the most common benign tumor of infancy. Most hemangiomas remain asymptomatic and can be managed by close observation; however, immediate treatment is indicated for hemangiomas that may cause significant complications. Periocular hemangiomas warrant close evaluation and early, active treatment of those with the potential to threaten or permanently compromise vision. Herein we review the clinical features of periocular hemangiomas, differential diagnosis, possible ophthalmologic complications and sequelae, and therapeutic modalities.     

Pruritus and dermographism due to intrahepatic cholestasis of infancy

A case report of intrahepatic cholestasis of infancy presenting with chronic severe pruritus is described. This presentation is compared with similar cases attending this unit. Intrahepatic cholestasis of infancy and the pathogenesis of puritus associated with cholestasis are briefly discussed.     

Juvenile xanthogranuloma with lichenoid appearance

Juvenile xanthogranulomas are benign histiocytic cell tumors that develop mainly in infancy and early childhood and then spontaneously regress. We report a 2-year-old boy who presented with generalized eruption of a mixture of micronodular and macronodular juvenile xanthogranuloma with a large number of widely distributed lichenoid papules. Light microscopic and immunocytochemical analyses of the lesion were consistent with juvenile xanthogranuloma. Abdominal ultrasonography did not detect any visceral lesions, and brain magnetic resonance imaging did not detect any mass lesions. We decided to observe the course without treatment in this case because there are no internal masses of juvenile xanthogranuloma. Regular follow up has therefore been scheduled. To our knowledge, this is the third report of a case demonstrating juvenile xanthogranuloma with lichenoid appearance. Future analyses of various cytokines such as granulocyte-macrophage colony-stimulating factor and/or tumor necrosis factor-α in juvenile xanthogranuloma lesions should be of great help in elucidating the pathogenesis of this disease.     

Management of naevus sebaceous: a national survey of UK dermatologists and plastic surgeons

Naevus sebaceous (NS) is a congenital cutaneous hamartoma, which typically occurs on the head and neck. Historically, the treatment of choice was excision in infancy because of the potential for malignant transformation; however, recent studies suggest that this risk is < 1% and unlikely in childhood. We sent a questionnaire to UK dermatologists and plastic surgeons to investigate current management practice of NS. We found that almost a third of dermatologists still recommend excision for malignancy prevention, while over 90% of plastic surgeons consider excision, with 64% citing malignancy prevention as the reason. Plastic surgeons most commonly recommended excision in childhood, whereas dermatologists waited until adulthood. We have shown there is significant variation in practice across the UK in the management of naevus NS. It is important that patients across the UK receive the same standard of care, and therefore we advocate the development of evidence‐based guidance for treatment of naevus NS.     

Pharmacologic blockade of angiopoietin-2 is efficacious against model hemangiomas in mice

Hemangioma of infancy is the most common neoplasm of childhood. While hemangiomas are classic examples of angiogenesis, the angiogenic factors responsible for hemangiomas are not fully understood. Previously, we demonstrated that malignant endothelial tumors arise in the setting of autocrine loops involving vascular endothelial growth factor (VEGF) and its major mitogenic receptor vascular endothelial growth factor receptor 2. Hemangiomas of infancy differ from malignant endothelial tumors in that they usually regress, or can be induced to regress by pharmacologic means, suggesting that angiogenesis in hemangiomas differs fundamentally from that of malignant endothelial tumors. Here, we demonstrate constitutive activation of the endothelial tie-2 receptor in human hemangioma of infancy and, using a murine model of hemangioma, bEnd.3 cells; we show that bEnd.3 hemangiomas produce both angiopoietin-2 (ang-2) and its receptor, tie-2, in vivo. We also demonstrate that inhibition of tie-2 signaling with a soluble tie-2 receptor decreases bEnd.3 hemangioma growth in vivo. The efficacy of tie-2 blockade suggests that either tie-2 activation or ang-2 may be required for in vivo growth. To address this issue, we used tie-2-deficient bEnd.3 hemangioma cells, which, surprisingly, were fully proficient in in vivo growth. Previous studies from our laboratory and others have implicated reactive oxygen-generating nox enzymes in the angiogenic switch, so we examined the effect of nox inhibitors on ang-2 production in vitro and on bEnd.3 tumor growth in vivo. We then inhibited ang-2 production pharmacologically using novel inhibitors of nox enzymes and found that this treatment nearly abolished bEnd.3 hemangioma growth in vivo. Signal-transduction blockade targeting ang-2 production may be useful in the treatment of human hemangiomas in vivo.     

Eosinophilic Pustular Folliculitis In Infancy

Abstract: Five infants under 1 year of age were reported with a syndrome of recurrent crops of pruritic papulopustules of the scalp. In three children there were also intermittent outbreaks on the trunk and extremities. Cultures showed the pustules to be sterile. Biopsies of scalp and skin tissues showed eosinophilic folliculitis. Some patients had eosinophilia during outbreaks of pustules. These cases are similar to the eosinophilic pustular folliculitis reported in a few adult patients with the exception that there was predominant scalp involvement in the children. We propose that eosinophilic pustular folliculitis of infancy is a distinct pustular dermatosis.     

Eosinophilic pustular folliculitis: A published work‐based comprehensive analysis of therapeutic responsiveness

Eosinophilic pustular folliculitis (EPF) is a non‐infectious inflammatory dermatosis of unknown etiology that principally affects the hair follicles. There are three variants of EPF: (i) classic EPF; (ii) immunosuppression‐associated EPF, which is subdivided into HIV‐associated (IS/HIV) and non‐HIV‐associated (IS/non‐HIV); and (iii) infancy‐associated EPF. Oral indomethacin is efficacious, especially for classic EPF. No comprehensive information on the efficacies of other medical management regimens is currently available. In this study, we surveyed regimens for EPF that were described in articles published between 1965 and 2013. In total, there were 1171 regimens; 874, 137, 45 and 115 of which were applied to classic, IS/HIV, IS/non‐HIV and infancy‐associated EPF, respectively. Classic EPF was preferentially treated with oral indomethacin with efficacy of 84% whereas topical steroids were preferred for IS/HIV, IS/non‐HIV and infancy‐associated EPF with efficacy of 47%, 73% and 82%, respectively. Other regimens such as oral Sairei‐to (a Chinese–Japanese herbal medicine), diaminodiphenyl sulfone, cyclosporin and topical tacrolimus were effective for indomethacin‐resistant cases. Although the preclusion of direct comparison among cases was one limitation, this study provides a dataset that is applicable to the construction of therapeutic algorithms for EPF.     

Successful treatment of a large hemangioma with propranolol

Hemangiomas are the most common vascular tumors in children. They occur in 8–12% of all infants and in 22% of premature infants (female: male = 3: 1). Hemangiomas are usually sporadic; their etiology is unknown [ 1 ]. A premature female infant, born at 28 weeks of gestation, presented with a large hemangioma of the right thoracic wall. Within the first few weeks, the hemangioma showed rapid horizontal and vertical growth as well as ulceration, which led us to initiate systemic therapy. The effectiveness of propranolol (non‐selective ß‐blocker) in the management of severe cases of hemangioma has been shown in a recent series of cases [ 2 ]. We began oral propranolol treatment, in close interdisciplinary cooperation. After a few days of therapy, the tumor had stopped expanding. After 18 weeks, there has been marked regression but the therapy is still being continued. We propose that propranolol may be an effective and relatively well tolerable alternative in the management of selected cases of severe hemangiomas in infancy, providing interdisciplinary cooperation between dermatologists and pediatricians is available.