Ilona J. Frieden

Infantile Hemangiomas: Current Knowledge, Future Directions. Proceedings of a Research Workshop on Infantile Hemangiomas

Ilona J. Frieden, M.D.,* Anita N. Haggstrom, M.D.,† Beth A. Drolet, M.D.,‡ Anthony J. Mancini, M.D.,§ Sheila Fallon Friedlander, M.D.,¶ Laurence Boon, M.D., Ph.D.,** Sarah L. Chamlin, M.D.,§ Eulalia Baselga, M.D.,†† Maria C. Garzon, M.D.,‡‡ Amy J. Nopper, M.D.,§§ Dawn H. Siegel, M.D.,* Erin W. Mathes, M.D.,* Deborah S. Goddard, M.D.,¶¶ Joyce Bischoff, Ph.D.,¶¶ Paula E. North, M.D., Ph.D.,*** and Nancy B. Esterly, M.D.†††

Infantile hemangiomas: how common are they? A systematic review of the medical literature.

Abstract:  No published prospective studies have been published for several decades examining the incidence of hemangiomas. Older studies were performed before the delineation of “hemangiomas” from other vascular birthmarks was well‐established. The objective of our study is to critically re‐examine the literature reporting the incidence of infantile hemangiomas to determine if the true incidence is actually known. We performed both an electronic database search and hand search of the medical literature on the natural history of hemangiomas in full‐term newborns and infants. A total of seven articles were found comprising two study populations: newborns <2 weeks of age and infants over the age of 2 weeks. All studies included samples sizes >500 patients including both hospital‐based and primary care settings. Study designs ranged from retrospective chart reviews to cross‐sectional cohort studies. Descriptive nomenclature was not uniform between studies, and all had methodologic limitations including problems of definition and study design. Studies estimating the true incidence of infantile hemangiomas are all many decades old and have significant methodologic issues limiting their ability to determine hemangioma incidence. Future studies in primary care settings using the currently accepted classification schema of vascular birthmarks may more accurately define the incidence and potential impact of this common vascular tumor of infancy.

Propranolol and infantile hemangiomas four years later: a systematic review.

To systematically review the literature evaluating efficacy and adverse events of propranolol treatment for infantile hemangiomas, we searched the MEDLINE and Cochrane databases for all studies examining the response of infantile hemangiomas (IHs) to propranolol published between June 12, 2008, and June 15, 2012. Forty‐one studies with 1,264 patients were included; 74% of patients were female and approximately 30% had received other treatments before propranolol. Propranolol was initiated at a mean age of 6.6 months at a mean dose of 2.1 mg/kg/day and for a mean treatment duration of 6.4 months. The response rate for patients with IHs treated with propranolol was 98% (range 82%–100%), with response rate defined as any improvement with propranolol. Treatment response rates were comparable for studies evaluating IHs at specific sites, such as periorbital IHs. Studies that followed patients after treatment completion reported IH rebound growth in 17% of patients. There were 371 adverse events reported in 1,189 patients. The most common adverse events were changes in sleep (n = 136) and acrocyanosis (n = 61). Serious adverse events were rare, with reports of symptomatic hypotension in five patients, hypoglycemia in four, and symptomatic bradycardia in one. This systematic review of 1,264 patients treated with propranolol for IHs showed a high rate of efficacy and a low rate of serious adverse events.

Propranolol for Infantile Hemangiomas: Promise, Peril, Pathogenesis

To the Editor: The recent reports of propranolol as a treatment for infantile hemangiomas (IH) have been met with great interest and enthusiasm. Two small published case series show impressive results and our own experience and anecdotal reports from many other physicians support the apparent efficacy of this medication for IH (1).While many IH are innocuous, requiring no treatment, a significant minority do require therapeutic intervention (2). Systemic corticosteroids, which are the mainstay of treatment for more severe IH have many potential sideeffects. Moreover, they work best at stopping further growth, but actual shrinkage, rather than cessation of growth, only occurs in approximately one-third of patients (3). Preliminary reports, mirrored by our own experience, suggest that propranolol is effective not only in stopping hemangioma growth, but that it causes decreased tumor volume with more regularity than corticosteroids. It should be emphasized that these observations are based on relatively small numbers of patients (1,4). Adding a safe and effective therapy to our therapeutic armamentarium for those IH needing treatment would be an important advance, but many questions remain about both efficacy and safety. Lawley and Siegfried’s report (5) of adverse effects underscores both the need for caution with current off-label use and the need for large, formal clinical trials before widespread adoption of propranolol as a treatment for IH should be considered. One of us (IJF) has also had a patient develop bradycardia and hypoglycemia, while receiving propranolol, 2 mg ⁄kg ⁄day for an eyelid IH (I.J. Frieden, unpublished data). These cautionary notes recall the initial enthusiasm which greeted reports of alfa-interferon as an effective treatment for IH to treat hemangiomas (6), an enthusiasm which was dampened considerably a few years later when it was found that neurotoxicity, specifically spastic diplegia, was a serious potential adverse effect (7). Propranolol is a non-selective beta-blocker which has previously been used in young infants for a variety of indications, primarily for hypertension, supraventricular tachycardia, long Q-T syndrome, congestive heart failure, and thyrotoxicosis, conditions where infants are often being treated in an inpatient hospital setting (8– 14). In many studies, a dosage of 1 mg ⁄kg ⁄day has been used, but higher doses were used in some studies. Most patients in the initial reports treating IH received 2 mg ⁄kg ⁄day, but an ideal dose or dose range has not been established. Among the known potential adverse effects of propranolol in infants are bradycardia, hypotension, hypoglycemia, and bronchospasm (wheezing), side-effects which are relatively easy to monitor for and treat in an inpatient setting. Virtually, all children with IH are outpatients, however, and protocols and dosing regimens such as the one proposed by Lawley and Siegfried are among many being considered or tried by clinicians who are now beginning to use propranolol for IH. An additional reason for caution is that the evidence to date is based on observations of small groups of patients who were not treated in a prospective, controlled fashion, and thus not subjected to the stringency of phases II or III clinical trials. Many variables such as

Topical timolol for infantile hemangiomas: putting a note of caution in "cautiously optimistic".

Recent reports regarding the utility of topical betablocker therapy, specifically timolol maleate, in treating infantile hemangiomas represent a new and potentially exciting treatment option. Since the first case report in February 2010 byGuo et al (1) severalmore case reports (2–4) have appeared in the medical literature. The recent multicenter study by Pope et al (5) is the largest study to date, providing 73 additional cases with results that are encouraging. Being informed about timolol is important as physicians caring for infants with infantile hemangiomas consider its use for this newfound indication. This commentary discusses what is and is not known about the potential side effects of topical timolol to help physicians decide which patients are appropriate candidates for this form of therapy and which are not.

Propranolol Use in PHACE Syndrome with Cervical and Intracranial Arterial Anomalies: Collective Experience in 32 Infants

The objective of this retrospective study of patients evaluated between July 2008 and October 2011 in seven pediatric dermatology centers was to combine collective clinical experience using oral propranolol therapy in 32 infants with PHACE syndrome (Posterior fossa [brain malformations present at birth], Hemangioma [usually covering a large area of the skin of the head or neck >5 cm]; Arterial lesions [abnormalities of the blood vessels in the neck or head]; Cardiac abnormalities or aortic coarctation [abnormalities of the heart or blood vessels that are attached to the heart]; Eye abnormalities) with cervical or intracranial arterial anomalies. Patients were given an average daily dose of oral propranolol of 1.8 mg/kg divided two or three times per day for an average duration of 12.3 months. The main outcome measure was adverse neurologic events. Seven (22%) patients were categorized as being at higher risk for stroke, defined on magnetic resonance imaging as severe, long‐segment narrowing or nonvisualization of major cerebral or cervical vessels without anatomic evidence of collateral circulation, often in the presence of concomitant cardiovascular comorbidities. Only one patient developed a change in neurologic status during propranolol treatment: mild right hemiparesis that remained static and improved while propranolol was continued. An additional three patients had worsening hemangioma ulceration or tissue necrosis during therapy. This is the largest report thus far of patients with PHACE syndrome treated with propranolol. Although no catastrophic neurologic events occurred, serious complications, particularly severe ulcerations, were seen in a minority of patients, and given the sample size, we cannot exclude the possibility that propranolol could augment the risk of stroke in this population. We propose radiologic criteria that may prove useful in defining PHACE patients as being at high or standard risk for stroke. We continue to advise caution in using systemic beta‐blockers, particularly for children with vascular anomalies at higher risk for stroke. Use of the lowest possible dosage, slow dosage titration, three times per day dosing to minimize abrupt changes in blood pressure, and close follow‐up, including neurologic consultation as needed, are recommended.

Annular pustular psoriasis--most common form of pustular psoriasis in children: report of three cases and review of the literature.

Annular pustular psoriasis (APP) is a rare form of pustular psoriasis with a chronic recurrent course and good prognosis. We report three cases of APP in children, two of whom were siblings. Review of the medical literature reveals that a disproportionately high percentage of cases of APP occur in children. In some cases topical therapy can clear the condition, although in severe or recalcitrant disease, systemic therapy may be necessary.

PHACE Syndrome: Current Knowledge, Future Directions

Abstract:  On November 7–8, 2008, physicians gathered in Houston Texas for the first‐ever workshop on PHACE syndrome, an important and recently described neurocutaneous syndrome. This article represents a summary of the discussions held at that workshop, which was attended by a broad range of medical specialists.

Infantile Acropustulosis Revisited: History of Scabies and Response to Topical Corticosteroids

Abstract: Infantile acropustulosis (IA) is a condition of young children characterized by recurrent episodes of pruritic vesicles and pustules in an acral distribution. Several reports describe patients with scabies infestation prior to the diagnosis of IA, although the relationship between the two remains unclear. Furthermore, optimal therapy is controversial. We reviewed the history of scabies and response to therapy in 21 patients diagnosed with IA at two institutions between 1983 and 1997. A history of prior treatment for scabies was noted in 14 patients, although only two had mites, feces, or ova detected on microscopic examination for diagnostic verification. All patients were treated with topical corticosteroids (4 with class I, 12 with class II, 3 with class III, 1 with class IV, and 1 with class VI). All 18 patients who returned for follow‐up experienced significant improvement or cleared completely with treatment. There were no observed cutaneous or systemic side effects from corticosteroid therapy. We conclude that a history of preceding scabies is common in patients with IA, but often this diagnosis is made without microscopic confirmation. We also demonstrate that mid‐ to high‐potency topical corticosteroids are a safe and effective first‐line therapy for patients with IA.

Virginal Breast Hypertrophy

Abstract: Macromastia is the massive enlargement of the breast, unilateral or bilateral, disproportional to growth in the remainder of the body. Most patients seen with macromastia have breasts that develop normally at puberty but simply reach excessive size. Virginal breast hypertrophy is a rare and distinct disorder with the rapid onset of macromastia at the onset of puberty. Although the disorder has been reported in the surgical, pediatric, and gynecologic literature, virginal breast hypertrophy has not been reported in dermatologic journals. We report two cases of virginal breast hypertrophy. Patient 1 is a 14‐year‐old girl who developed macromastia 6 months after a liver transplant for α 1‐antitrypsin deficiency. She had intense erythema as well as verrucous hyperplasia overlying the breasts. Patient 2 was a 12‐year‐old girl who experienced severe bilateral breast enlargement 4 months after beginning treatment for thyrotoxicosis. She had extreme tenderness, erythema, and edema of the breasts and was treated with tamoxifen citrate, with improvement of her symptoms. Although virginal breast hypertrophy is a rare disorder, the dermatologist may be asked to consult on the associated skin changes in these cases and should be aware of its existence. The definitive therapy is surgical, but until breast growth is stabilized, cutaneous manifestations need to be managed.