Beth A. Drolet

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.†††

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develop bradycardia and hypoglycemia, while receiving propranolol, 2 mg ⁄kg ⁄day for an eyelid IH (I.J. Frieden, unpublished data).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

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.

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.

Childhood Lichen Planus: Demographics of a U.S. Population

Abstract:  Lichen planus is an inflammatory dermatosis of unknown origin that is relatively uncommon in children. Demographic data for lichen planus of children in the United States are lacking, with most large case reports originating from India, Kuwait, Mexico, and the United Kingdom. We hypothesized that a greater proportion of our pediatric lichen planus patients were African American, an observation not previously documented. A retrospective chart review was performed to investigate characteristics of our pediatric lichen planus patients. The ethnicity of the lichen planus patients was compared with the data for our general patient population. The proportion of African American patients in each group was compared using the chi‐squared test. We report 36 children (female to male ratio 2:1) who presented with lichen planus to the pediatric dermatology clinic at Children’s Hospital of Wisconsin. Twenty‐six (72%) of these patients were African American (OR 9.63, p < 0.0001). A personal or family history of autoimmune disease was present in six (17%) patients. Although there has been no reported racial predominance of lichen planus, we observed lichen planus to occur more commonly in African American children. Interestingly, the incidence of autoimmune disease was higher than has previously been reported. Future studies will confirm or refute these observations and advance our understanding of potential genetic or environmental risk factors for the development of lichen planus.

Familial nonmembranous aplasia cutis of the scalp.

Abstract:  Aplasia cutis of the scalp is often a sporadic condition, but familial occurrences with an autosomal dominant inheritance have been documented. Aplasia cutis of the scalp may be seen in two main clinical variants: oval‐shaped membranous aplasia cutis and irregular, larger defects. We report six families in whom more than one member has aplasia cutis of the scalp, all of them with large irregular defects located over the vertex or anterior to the vertex along the sagittal suture. We review previous reports of this entity with clinical pictures and note that in most instances, the defects are of the nonmembranous variant.

Erosive Pustular Dermatosis of the Scalp after Perinatal Scalp Injury

Abstract:  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.

Propranolol Treatment of Infantile Hemangiomas: Anticipatory Guidance for Parents and Caretakers

Infantile hemangiomas (IH) are benign tumors of endothelial‐like cells. Occurring in 4.5% of children, they are the most common tumor of childhood. The great majority of patients with IH will not need treatment, but 10% require systemic treatment. Many treatments have been described for the treatment of IH, but the Food and Drug Administration has not approved any. Over the last decade, numerous reports of successful treatment of IH with propranolol have been published. Despite its widespread use, little is known regarding the proper dosing, safety monitoring, and during of treatment or long‐term outcomes for propranolol treatment of IH. Given its potential side effects, detailed education regarding proper administration of the medication as well as warning signs to watch for is necessary for parents and caretakers. Herein, we provide a parental handout that practitioners can individually tailor for use in their clinics when educating parents and caretakers about the use of propranolol for IH. Updates will also need to be made as more is learned regarding the optimal dosing and safety monitoring when using propranolol for this indication.

Inverse Gottron’s Papules: An Unusual Cutaneous Manifestation of Juvenile Dermatomyositis

Abstract:  Dermatomyositis is an autoimmune inflammatory myopathy characterized by unique cutaneous features. Gottron’s papules are pathognomonic, lichenoid papules that can be found overlying the joints of the dorsal hand. Papules on the palms of the hand are less commonly seen, especially in the pediatric age group. Recognition of these inverse Gottron’s papules as a sign of dermatomyositis is important as they may be the only cutaneous feature and may be a clue of underlying interstitial lung disease.

Risk of Dysphagia and Speech and Language Delay in PHACE Syndrome

PHACE (posterior fossa, hemangioma, arterial lesions, cardiac, and eye) syndrome consists of infantile hemangiomas of the head and neck along with a spectrum of noncutaneous anomalies. Neurodevelopmental abnormalities have also been noted. Here we describe the association between PHACE syndrome and abnormalities in oropharyngeal development and coordination manifesting as dysphagia or speech and language delay. A retrospective chart review was conducted of 34 patients with PHACE syndrome. Data were collected from prior clinical notes and radiographic studies and the results of a comprehensive questionnaire that those who attended the July 2012 PHACE Syndrome Family Conference completed. Seventeen of 34 patients with PHACE syndrome and signs or symptoms of dysphagia or speech or language problems were included for analysis. Nine had dysphagia, seven had a history of cardiac surgery, four had a posterior fossa malformation, and seven had lip or oropharynx hemangiomas. Speech or language delay was noted in 16; posterior fossa abnormalities and lip or oropharynx hemangiomas were the most commonly seen associated finding in this group. There was considerable overlap between subset populations with dysphagia, speech delay, and language delay. A subset of individuals with PHACE syndrome experience dysphagia, speech delay, or language delay. This risk seems to be greater in certain subsets of patients, including those with posterior fossa malformations or lip or oropharynx hemangiomas and those with a history of cardiac surgery. Although this descriptive study was not comprehensive enough to examine prevalence, the high incidence of dysphagia and speech and language delay seen in our cohort warrants future prospective studies to further investigate the association.