Denise W. Metry

Prospective study of infantile hemangiomas: Clinical characteristics predicting complications and treatment

OBJECTIVES. Infantile hemangiomas are the most common tumor of infancy. Risk factors for complications and need for treatment have not been studied previously in a large prospective study. This study aims to identify clinical characteristics associated with complications and the need for therapeutic intervention. PATIENTS AND METHODS. We conducted a prospective cohort study at 7 US pediatric dermatology clinics with a consecutive sample of 1058 children, aged ≤12 years, with infantile hemangiomas enrolled between September 2002 and October 2003. A standardized questionnaire was used to collect data on each patient and each hemangioma, including clinical characteristics, complications, and treatment. RESULTS. Twenty-four percent of patients experienced complications related to their hemangioma(s), and 38% of our patients received some form of treatment during the study period. Hemangiomas that had complications and required treatment were larger and more likely to be located on the face. Segmental hemangiomas were 11 times more likely to experience complications and 8 times more likely to receive treatment than localized hemangiomas, even when controlled for size. CONCLUSIONS. Large size, facial location, and/or segmental morphology are the most important predictors of poor short-term outcomes as measured by complication and treatment rates.

Growth characteristics of infantile hemangiomas: implications for management.

OBJECTIVES. Infantile hemangiomas often are inapparent at birth and have a period of rapid growth during early infancy followed by gradual involution. More precise information on growth could help predict short-term outcomes and make decisions about when referral or intervention, if needed, should be initiated. The objective of this study was to describe growth characteristics of infantile hemangioma and compare growth with infantile hemangioma referral patterns. METHODS. A prospective cohort study involving 7 tertiary care pediatric dermatology practices was conducted. Growth data were available for a subset of 526 infantile hemangiomas in 433 patients from a cohort study of 1096 children. Inclusion criteria were age younger than 18 months at time of enrollment and presence of at least 1 infantile hemangioma. Growth stage and rate were compared with clinical characteristics and timing of referrals. RESULTS. Eighty percent of hemangioma size was reached during the early proliferative stage at a mean age of 3 months. Differences in growth between hemangioma subtypes included that deep hemangiomas tend to grow later and longer than superficial hemangiomas and that segmental hemangiomas tended to exhibit more continued growth after 3 months of age. The mean age of first visit was 5 months. Factors that predicted need for follow-up included ongoing proliferation, larger size, deep component, and segmental and indeterminate morphologic subtypes. CONCLUSIONS. Most infantile hemangioma growth occurs before 5 months, yet 5 months was also the mean age at first visit to a specialist. Recognition of growth characteristics and factors that predict the need for follow-up could help aid in clinical decision-making. The first few weeks to months of life are a critical time in hemangioma growth. Infants with hemangiomas need close observation during this period, and those who need specialty care should be referred and seen as early as possible within this critical growth period.

Initiation and Use of Propranolol for Infantile Hemangioma: Report of a Consensus Conference

Infantile hemangiomas (IHs) are common neoplasms composed of proliferating endothelial-like cells. Despite the relative frequency of IH and the potential severity of complications, there are currently no uniform guidelines for treatment. Although propranolol has rapidly been adopted, there is significant uncertainty and divergence of opinion regarding safety monitoring, dose escalation, and its use in PHACE syndrome (PHACE = posterior fossa, hemangioma, arterial lesions, cardiac abnormalities, eye abnormalities; a cutaneous neurovascular syndrome characterized by large, segmental hemangiomas of the head and neck along with congenital anomalies of the brain, heart, eyes and/or chest wall). A consensus conference was held on December 9, 2011. The multidisciplinary team reviewed existing data on the pharmacologic properties of propranolol and all published reports pertaining to the use of propranolol in pediatric patients. Workgroups were assigned specific topics to propose protocols on the following subjects: contraindications, special populations, pretreatment evaluation, dose escalation, and monitoring. Consensus protocols were recorded during the meeting and refined after the meeting. When appropriate, protocol clarifications and revision were made and agreed upon by the group via teleconference. Because of the absence of high-quality clinical research data, evidence-based recommendations are not possible at present. However, the team agreed on a number of recommendations that arose from a review of existing evidence, including when to treat complicated IH; contraindications and pretreatment evaluation protocols; propranolol use in PHACE syndrome; formulation, target dose, and frequency of propranolol; initiation of propranolol in infants; cardiovascular monitoring; ongoing monitoring; and prevention of hypoglycemia. Where there was considerable controversy, the more conservative approach was selected. We acknowledge that the recommendations are conservative in nature and anticipate that they will be revised as more data are made available.

Consensus Statement on Diagnostic Criteria for PHACE Syndrome

OBJECTIVES: A subgroup of patients with infantile hemangiomas have associated structural anomalies of the brain, cerebral vasculature, eyes, sternum, and/or aorta in the neurocutaneous disorder known as PHACE syndrome. The diagnosis has been broadly inclusive by using a case definition of a facial hemangioma plus ≥1 extracutaneous features, leading to numerous reports of potential associated disease features, many of uncertain significance. This consensus statement was thus developed to establish diagnostic criteria for PHACE syndrome. METHODS: A multidisciplinary group of specialists with expertise in PHACE syndrome drafted initial diagnostic criteria on the basis of review of published, peer-reviewed medical literature and clinical experience. The group then convened in both executive and general sessions during the PHACE Syndrome Research Conference held in November 2008 for discussion and used a consensus method. All conflicting recommendations were subsequently reconciled via electronic communication and teleconferencing. RESULTS: These criteria were stratified into 2 categories: (1) PHACE syndrome or (2) possible PHACE syndrome. Major and minor criteria were determined for the following organ systems: cerebrovascular, structural brain, cardiovascular, ocular, and ventral/midline. Definite PHACE requires the presence of a characteristic segmental hemangioma or hemangioma >5 cm on the face or scalp plus 1 major criterion or 2 minor criteria. Possible PHACE requires the presence of a hemangioma >5 cm on the face or scalp plus 1 minor criterion. The group recognized that it may be possible to have PHACE syndrome with a hemangioma affecting the neck, chest, or arm only or no cutaneous hemangioma at all. In such cases, fulfillment of additional required criteria would also lead to a possible PHACE diagnosis. CONCLUSIONS: These criteria represent current knowledge and are expected to enhance future assessments of PHACE syndrome. It is understood that modifications are to be expected over time to incorporate new research findings.

A prospective study of PHACE syndrome in infantile hemangiomas: demographic features, clinical findings, and complications.

PHACE (OMIM no. 606519) is a neurocutaneous syndrome that refers to the association of large, plaque‐like, “segmental” hemangiomas of the face, with one or more of the following anomalies: posterior fossa brain malformations, arterial cerebrovascular anomalies, cardiovascular anomalies, eye anomalies, and ventral developmental defects, specifically sternal defects and/or supraumbilical raphe. The etiology and pathogenesis of PHACE is unknown, and potential risk factors for the syndrome have not been systematically studied. The purpose of this study was thus to determine (1) the incidence of PHACE and associated anomalies among a large cohort of hemangioma patients, (2) whether certain demographic, prenatal or perinatal risk factors predispose infants to this syndrome, and (3) whether the cutaneous distribution of the hemangioma can be correlated to the types of anomalies present. We undertook a prospective, cohort study of 1,096 children with hemangiomas, 25 of whom met criteria for PHACE. These 25 patients represented 20% of infants with segmental facial hemangiomas. Compared to previous reports, our PHACE patients had a higher incidence of cerebrovascular and cardiovascular anomalies. Two developed acute arterial ischemic stroke during infancy, while two with cardiovascular anomalies showed documented evidence of normalization, suggesting that both progressive and regressive vascular phenomena may occur in this syndrome. Correlation to the anatomic location of the hemangioma appears to be helpful in determining which structural abnormalities might be present. A comparison of demographic and perinatal data between our PHACE cases and the hemangioma cohort overall showed no major differences, except a trend for PHACE infants to be of slighter higher gestational age and born to slightly older mothers. Eighty‐eight percent were female, a finding which has been noted in multiple other reports. Further research is needed to determine possible etiologies, optimal evaluation, and outcomes.

Risk for PHACE Syndrome in Infants With Large Facial Hemangiomas

OBJECTIVES: This study was conducted to determine the prevalence of posterior fossae of the brain, arterial anomalies, cardiac anomalies, and eye anomalies (PHACE) in infants with large facial hemangiomas. The extracutaneous manifestations of PHACE may be associated with significant morbidity, and the prevalence of PHACE in patients with facial hemangiomas has not previously been reported. METHODS: A multicenter prospective study was conducted with 108 infants who had large facial hemangiomas and were systematically evaluated for manifestations of PHACE. The prevalence of PHACE and its extracutaneous manifestations in this cohort was calculated. The relationship between hemangioma distribution and the manifestations of PHACE was analyzed. RESULTS: Thirty-three (31%) of 108 had PHACE. Thirty of the 33 patients with PHACE had >1 extracutaneous finding. The risk for PHACE syndrome was higher in infants with larger hemangiomas and in those with hemangiomas that encompassed >1 facial segment. The most common extracutaneous anomalies observed in infants with PHACE were of the arteries of the cerebrovasculature (91%) and cardiac anomalies (67%). Upper face (frontotemporal and frontonasal) hemangiomas were commonly observed in infants with PHACE; isolated maxillary hemangiomas were rarely associated with PHACE. CONCLUSIONS: In infants with large facial hemangiomas, one-third have extracutaneous manifestations consistent with the diagnosis of PHACE syndrome, most commonly cerebrovascular and cardiovascular anomalies. The high prevalence of arterial anomalies in this cohort has implications for clinical management and future research regarding the pathophysiology of PHACE.

Cervical and Intracranial Arterial Anomalies in 70 Patients with PHACE Syndrome

BACKGROUND AND PURPOSE: Cerebral and cervical arterial abnormalities are the most common non-cutaneous anomaly in PHACE syndrome, but the location and type of arterial lesions that occur have not been systematically assessed in a large cohort. Our aim was to characterize the phenotypic spectrum of arteriopathy, assess the frequency with which different arteries are involved, and evaluate spatial relationships between arteriopathy, brain structural lesions, and hemangiomas in PHACE syndrome. MATERIALS AND METHODS: Intracranial MRA and/or CTA images from 70 children and accompanying brain MR images in 59 patients with arteriopathy and PHACE syndrome were reviewed to identify the type and location of arterial lesions and brain abnormalities. Five categories of arteriopathy were identified and used for classification: dysgenesis, narrowing, nonvisualization, primitive embryonic carotid-vertebrobasilar connections, and anomalous arterial course or origin. Univariate logistic regression analyses were performed to test for associations between arteriopathy location, hemangiomas, and brain abnormalities. RESULTS: By study design, all patients had arterial abnormalities, and 57% had >1 form of arteriopathy. Dysgenesis was the most common abnormality (56%), followed by anomalous course and/or origin (47%), narrowing (39%), and nonvisualization (20%). Primitive embryonic carotid-vertebrobasilar connections were present in 20% of children. Hemangiomas were ipsilateral to arteriopathy in all but 1 case. The frontotemporal and/or mandibular facial segments were involved in 97% of cases, but no other specific associations between arteriopathy location and hemangioma sites were detected. All cases with posterior fossa anomalies had either ICA anomalies or persistent embryonic carotid-basilar connections. CONCLUSIONS: The arteriopathy of PHACE syndrome commonly involves the ICA and its embryonic branches, ipsilateral to the cutaneous hemangioma, with dysgenesis and abnormal arterial course the most commonly noted abnormalities. Brain abnormalities are also typically ipsilateral.

Variable response to propranolol treatment of kaposiform hemangioendothelioma, tufted angioma, and Kasabach-Merritt phenomenon

Propranolol is a non‐selective beta‐adrenergic antagonist successfully used in a case of kaposiform hemangioendothelioma (KHE) associated with Kasabach–Merritt phenomenon (KMP). We report 11 patients treated with propranolol for KHE and the related variant tufted angioma (TA), six of whom also had KMP. The varied responses to treatment, with only 36% responding in our series, demonstrate the need for further study of this medication before routine use for these indications. Pediatr Blood Cancer 2012; 59: 934–938.

Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis.

Infantile myofibromatosis (IM) is a disorder of mesenchymal proliferation characterized by the development of nonmetastasizing tumors in the skin, muscle, bone, and viscera. Occurrence within families across multiple generations is suggestive of an autosomal-dominant (AD) inheritance pattern, but autosomal-recessive (AR) modes of inheritance have also been proposed. We performed whole-exome sequencing (WES) in members of nine unrelated families clinically diagnosed with AD IM to identify the genetic origin of the disorder. In eight of the families, we identified one of two disease-causing mutations, c.1978C>A (p.Pro660Thr) and c.1681C>T (p.Arg561Cys), in PDGFRB. Intriguingly, one family did not have either of these PDGFRB mutations but all affected individuals had a c.4556T>C (p.Leu1519Pro) mutation in NOTCH3. Our studies suggest that mutations in PDGFRB are a cause of IM and highlight NOTCH3 as a candidate gene. Further studies of the crosstalk between PDGFRB and NOTCH pathways may offer new opportunities to identify mutations in other genes that result in IM and is a necessary first step toward understanding the mechanisms of both tumor growth and regression and its targeted treatment.

Infantile hemangiomas with unusually prolonged growth phase: a case series.

BACKGROUND Most infantile hemangiomas (IHs) complete their proliferative growth phase before 9 months of age, but those with unusually prolonged growth create unique clinical challenges. We performed a retrospective case series of IHs with prolonged growth to further characterize these lesions and their treatment. OBSERVATIONS We identified 23 patients as having IHs with prolonged growth after 9 months of age, with growth to a mean age of 17 months. All of the IHs had a deep dermal to subcutaneous component, all had either segmental or indeterminate morphologic characteristics, and 39% involved the parotid gland. A total of 20 of 23 received prolonged treatment with systemic corticosteroids (mean duration of treatment, 11 months), and 9 of 20 received additional systemic therapies (vincristine sulfate and/or interferon alfa-2a or alfa-2b). CONCLUSIONS Prolonged growth was observed primarily in IHs with a deep component and segmental morphologic characteristics. Recognition of this subset of hemangiomas is important for clinicians, and further study of IHs may provide clues to their pathogenesis.