Delphi Consensus on Diagnostic Criteria for LUMBAR Syndrome.

OBJECTIVE: To develop consensus on diagnostic criteria for LUMBAR syndrome, the association of segmental infantile hemangiomas that affect the Lower body with Urogenital anomalies, Ulceration, spinal cord Malformations, Bony defects, Anorectal malformations, Arterial anomalies and/or Renal anomalies. STUDY DESIGN: These diagnostic criteria were developed by an expert multidisciplinary and multi-institutional team based on analysis of peer-reviewed data, followed by electronic-Delphi consensus of a panel of 61 international pediatric specialists. RESULTS: After 2 Delphi rounds, a 92% or higher level of agreement was reached for each Delphi statement. 98% of panelists agreed with the diagnostic criteria, and 100% agreed the criteria would be useful in clinical practice. The diagnosis of LUMBAR requires the presence of a segmental, or patterned, infantile hemangioma of the lumbosacral, sacrococcygeal, or pelvic cutaneous regions plus one additional criterion of the urogenital, spinal, bony, anorectal, arterial, or renal organ systems. CONCLUSIONS: These diagnostic criteria will enhance clinical care by improving screening, detection, and overall awareness of this poorly understood neurocutaneous disorder. The criteria can be utilized by a wide variety of pediatric subspecialists. In addition, formal criteria will improve phenotypic uniformity among LUMBAR syndrome cohorts and a patient registry, allowing investigators to assess clinical features, long-term outcomes, and results of genetic sequencing in a standardized manner. Finally, these criteria will serve as a starting point for prospective studies to establish formal screening and management guidelines.

Multicenter Study of Long-Term Outcomes and Quality of Life in PHACE Syndrome after Age 10.

OBJECTIVE: To characterize long-term outcomes of PHACE syndrome. STUDY DESIGN: Multicenter study with cross-sectional interviews and chart review of individuals with definite PHACE syndrome ≥10 years of age. Data from charts were collected across multiple PHACE-related topics. Data not available in charts were collected from patients directly. Likert scales were used to assess the impact of specific findings. Patient-Reported Outcomes Measurement Information System (PROMIS) scales were used to assess quality of life domains. RESULTS: A total of 104/153 (68%) individuals contacted participated in the study at a median of 14 years of age (range 10-77 years). There were infantile hemangioma (IH) residua in 94.1%. Approximately one-half had received laser treatment for residual IH, and the majority (89.5%) of participants were satisfied or very satisfied with the appearance. Neurocognitive manifestations were common including headaches/migraines (72.1%), participant-reported learning differences (45.1%), and need for individualized education plans (39.4%). Cerebrovascular arteriopathy was present in 91.3%, with progression identified in 20/68 (29.4%) of those with available follow-up imaging reports. Among these, 6/68 (8.8%) developed moyamoya vasculopathy or progressive stenoocclusion, leading to isolated circulation at or above the level of the circle of Willis. Despite the prevalence of cerebrovascular arteriopathy, the proportion of those with ischemic stroke was low (2/104; 1.9%). PROMIS global health scores were lower than population norms by at least 1 SD. CONCLUSIONS: PHACE syndrome is associated with long-term, mild to severe morbidities including IH residua, headaches, learning differences, and progressive arteriopathy. Primary and specialty follow-up care is critical for PHACE patients into adulthood.

Prenatal Risk Factors for PHACE Syndrome: A Study Using the PHACE Syndrome International Clinical Registry and Genetic Repository.

The cause of PHACE syndrome is unknown. In a study of 218 patients, we examined potential prenatal risk factors for PHACE syndrome. Rates of pre-eclampsia and placenta previa in affected individuals were significantly greater than in the general population. No significant risk factor differences were detected between male and female subjects.

Infantile Hemangiomas in Twins: A Prospective Cohort Study.

BACKGROUND: Twins have a higher-than-expected risk of infantile hemangiomas (IHs), but the exact reasons for this association are not clear. Comparing concordant and discordant twin pairs might help elucidate these factors and yield more information about IH risk factors. METHODS: A prospective cohort study of twin pairs from 12 pediatric dermatology centers in the United States, Canada, Argentina, and Spain was conducted. Information regarding maternal pregnancy history, family history of vascular birthmarks, zygosity (if known), and pregnancy-related information was collected. Information regarding twins (N = 202 sets) included birthweight, gestational age (GA), presence or absence of IHs, numbers and subtypes of IHs, presence of other birthmarks, and other medical morbidities. RESULTS: Two hundred two sets of twins were enrolled. Concordance for IH was present in 37% of twin pairs. Concordance for IH was inversely related to gestational age (GA), present in 42% of GA of 32 weeks or less, 36% of GA of 33 to 36 weeks, and 32% of GA of 37 weeks or more. Twins of GA of 34 weeks or less were more than two and a half times as likely to be concordant as those of GA of 35 weeks or more (odds ratio (OR) = 2.66, 95% confidence interval (CI) = 1.42-4.99; p < 0.01). In discordant twins, lower birthweight conferred a high risk of IH; of the 64 sets of twins with 10% or greater difference in weight, the smaller twin had IH in 62.5% (n = 40) of cases, versus 37.5% (n = 24) of cases in which the higher-birthweight twin was affected. Zygosity was reported in 188 twin sets (93%). Of these, 78% were dizygotic and 22% monozygotic. There was no statistically significant difference in rates of concordance between monozygotic twins (43%, 18/42) and dizygotic twins (36%, 52/146) (p = 0.50). In multivariate analysis comparing monozygotic and dizygotic twins, adjusting for effects of birthweight and sex, the likelihood of concordance for monozygotic was not appreciably higher than that for dizygotic twins (OR = 1.14, 95% CI = 0.52-2.49). Female sex also influenced concordance, confirming the effects of female sex on IH risk. The female-to-male ratio was 1.7:1 in the entire cohort and 1.9:1 in those with IH. Of the 61 concordant twin sets with known sex of both twins, 41% were female/female, 43% were female/male, and 16% were male/male. CONCLUSIONS: These findings suggest that the origin of IHs is multifactorial and that predisposing factors such as birthweight, sex, and GA may interact with one another such that a threshold is reached for clinical expression.

Gastrointestinal bleeding in infantile hemangioma: a complication of segmental, rather than multifocal, infantile hemangiomas.

OBJECTIVE: To highlight an association of facial segmental hemangiomas with gastrointestinal bleeding in infants with infantile hemangiomas. STUDY DESIGN: We conducted a multicenter retrospective case series study. RESULTS: Ten female patients met study inclusion criteria; 8 were Caucasian, 9 had a facial segmental hemangioma, and 9 cases met the diagnostic criteria for definitive posterior fossa malformations, hemangioma, arterial lesions, cardiac anomalies/coarctation of the aorta and eye abnormalities syndrome with abnormalities of the aorta and cerebral arteriopathy. Severe gastrointestinal bleeding requiring blood transfusion occurred in 9 cases, with age at presentation of gastrointestinal bleeding ranging from 8 days to 6 months. When detected, the location of the hemangioma in the small intestine was in the distribution of the superior mesenteric artery. More than one agent was required to control the gastrointestinal bleeding, including oral or intravenous steroids, vincristine, oral propranolol, interferon, and resection of the small intestine. All cases needed ongoing support care with red blood cell transfusions. CONCLUSIONS: Gastrointestinal bleeding is a rare complication of true infantile hemangioma. The segmental pattern of the cutaneous hemangioma associated with gastrointestinal bleeding should suggest a segmental infantile hemangioma of the lower gastrointestinal tract.

Prospective study of spinal anomalies in children with infantile hemangiomas of the lumbosacral skin.

OBJECTIVE: To prospectively evaluate a cohort of patients with infantile hemangioma in the midline lumbosacral region for spinal anomalies to determine the positive predictive value of infantile hemangioma for occult spinal anomalies and to make evidence-based recommendations for screening. STUDY DESIGN: A multicenter prospective cohort study was performed at 9 Hemangioma Investigator Group sites. RESULTS: Intraspinal abnormalities were detected in 21 of 41 study participants with a lumbosacral infantile hemangioma who underwent a magnetic resonance imaging evaluation. The relative risk for all patients with lumbosacral infantile hemangiomas for spinal anomalies was 640 (95% confidence interval [CI], 404-954), and the positive predictive value of infantile hemangioma for spinal dysraphism was 51.2%. Ulceration of the hemangioma was associated with a higher risk of having spinal anomalies. The presence of additional cutaneous anomalies also was associated with a higher likelihood of finding spinal anomalies; however, 35% of the infants with isolated lumbosacral infantile hemangiomas had spinal anomalies, with a relative risk of 438 (95% CI, 188-846). The sensitivity for ultrasound scanning to detect spinal anomalies in this high-risk group was poor at 50% (95% CI, 18.7%-81.3%), with a specificity rate of 77.8% (95% CI, 40%-97.2%). CONCLUSIONS: Infants and children with midline lumbosacral infantile hemangiomas are at increased risk for spinal anomalies. Screening magnetic resonance imaging is recommended for children with these lesions.

LUMBAR: association between cutaneous infantile hemangiomas of the lower body and regional congenital anomalies.

OBJECTIVE: To define the clinical spectrum of regional congenital anomalies associated with large cutaneous hemangiomas of the lower half of the body, clarify risk for underlying anomalies on the basis of hemangioma location, and provide imaging guidelines for evaluation. STUDY DESIGN: We conducted a multi-institutional, retrospective case analysis of 24 new patients and review of 29 published cases. RESULTS: Hemangiomas in our series tended to be "segmental" and often "minimal growth" in morphology. Such lesions were often extensive, covering the entire leg. Extensive limb hemangiomas also showed potential for extracutaneous anomalies, including underlying arterial anomalies, limb underdevelopment, and ulceration. The cutaneous hemangioma and underlying anomalies demonstrated regional correlation. Myelopathies were the most common category of associated anomalies. CONCLUSIONS: We propose the acronym "LUMBAR" to describe the association of Lower body hemangioma and other cutaneous defects, Urogenital anomalies, Ulceration, Myelopathy, Bony deformities, Anorectal malformations, Arterial anomalies, and Renal anomalies. There are many similarities between LUMBAR and PHACE syndrome, which might be considered regional variations of the same. Although guidelines for imaging are suggested, prospective studies will lead to precise imaging recommendations and help determine true incidence, risk and long-term outcomes.

Infantile hemangiomas: an emerging health issue linked to an increased rate of low birth weight infants.

A total of 420 children with infantile hemangioma (IH) were compared with 353 age-matched controls. Using multivariate logistic regression, low birth weight was the most significant risk factor; for every 500-g decrease in birth weight, the risk of IH increased by 40%. A positive family history also increased the risk of IH (33% vs 15% of controls; P < .001).

Multicenter prospective study of ulcerated hemangiomas.

OBJECTIVE: To identify clinical features of infants with ulcerated infantile hemangiomas. STUDY DESIGN: Cross-sectional analysis was conducted within a prospective cohort study of children with infantile hemangiomas. Children younger than 12 years of age were recruited. Demographic and prenatal/perinatal information was collected. Hemangioma size, location, subtype, course, complications, and treatments were recorded. RESULTS: One thousand ninety-six patients were enrolled, and 173 (15.8%) patients experienced ulceration. Ulceration occurred in 192 (9.8%) of 1960 [corrected] total hemangiomas. Hemangiomas with ulcerations were more likely large, mixed clinical type, segmental morphologic type, and located on the lower lip, neck, or anogenital region. Ulceration occurred at a median age of 4 months, most often during the proliferative phase. Children with ulcerated hemangiomas were more likely to present to a pediatric dermatologist at a younger age and to require treatment. Bleeding occurred in 41% of ulcerated lesions but was rarely of clinical significance. Infection occurred in 16%. CONCLUSIONS: Ulceration occurs in nearly 16% of patients with infantile hemangiomas, most often by 4 months of age, during the proliferative phase. Location, size, and clinical and morphologic type are associated with an increased risk for development of ulceration.

Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics.

OBJECTIVES: To characterize demographic, prenatal, and perinatal features of patients with infantile hemangiomas and to determine the importance of these factors in predicting rates of complication and treatment. STUDY DESIGN: We conducted a prospective study at 7 U.S. pediatric dermatology clinics. A consecutive sample of 1058 children, aged 12 years and younger, with infantile hemangiomas was enrolled between September 2002 and October 2003. A standardized questionnaire was used to collect demographic, prenatal, perinatal, and hemangioma-specific data. National Vital Statistic System Data (NVSS) was used to compare demographic variables and relevant rates of prenatal events. RESULTS: In comparison with the 2002 United States National Vital Statistics System birth data, we found that infants with hemangiomas were more likely to be female, white non-Hispanic, premature (P < .0001) and the product of a multiple gestation (10.6% versus 3.1%; P < .001). Maternal age was significantly higher (P < .0001), and placenta previa (3.1%) and pre-eclampsia (11.8%) were more common. CONCLUSIONS: Infants with hemangiomas are more likely to be female, white non-Hispanic, premature, and products of multiple gestations. Prenatal associations include older maternal age, placenta previa, and pre-eclampsia. No demographic, prenatal, and perinatal factors predicted higher rates of complications or need for treatment.

Kindler syndrome in native Americans from Panama: report of 26 cases.

OBJECTIVE: To investigate the clinical, genetic, and laboratory features of 26 patients with Kindler syndrome. DESIGN: Case series of patients recruited when they were seen at outpatient consultations in the Department of Dermatology at the Changuinola Hospital in Bocas del Toro, Panama, between May 1986 and December 1990. SETTING: Clinical history, physical examination, and laboratory studies were done at a community hospital in Panama. Twelve of the patients had further studies performed at a children's hospital in Costa Rica. PATIENTS: A total of 26 patients were entered into the study. They were members of the Ngöbe-Buglé tribe and resided in isolated villages in rural Panama. RESULTS: The major findings were skin fragility with blistering (100%), poikiloderma (96%), photosensitivity (92%), severe cutaneous atrophy (89%), hyperkeratosis of the palms and soles (81%), congenital acral blisters (81%), severe periodontal disease (81%), and phimosis (80% of male subjects). In 1 large family with 10 patients, inheritance of Kindler syndrome followed that of an autosomal recessive disease. Karyotypes in 3 patients and 1 unaffected father were normal. Findings from ultrastructural studies showed replication of lamina densa in 10 patients. CONCLUSIONS: To our knowledge, this study represents the largest series to date of patients with Kindler syndrome. The clinical features confirm previously reported cases, and segregation analysis confirms its autosomal recessive inheritance. We also report severe phimosis as a complication, which has not been previously described in this syndrome.

Nephrogenic fibrosing dermopathy: two pediatric cases.

We report two pediatric cases of nephrogenic fibrosing dermopathy (NFD), first described in 2000. NFD is a condition in which individuals with renal dysfunction have development of extensive skin hardening and histopathologic evidence of a scleromyxedema-like condition.

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.

Cutaneous manifestations of hyper-IgE syndrome in infants and children.

We describe 8 children with hyper-IgE syndrome who had papulopustular eruption on the face and scalp in the first year of life. Seven of the 8 patients had persistent peripheral eosinophilia and 3 had leukocytosis noted before diagnosis. Skin biopsy specimens in 6 patients revealed spongiosis and perivascular dermatitis and/or folliculitis with a predominance of eosinophils. Two patients had bone fractures and osteopenia. Recurrent pneumonia occurred in 6 children and pneumatoceles in 5. The diagnosis of hyper-IgE syndrome was made an average of 18 months after the onset of the initial papulopustular eruption. These findings may lead to earlier recognition of the disease and institution of appropriate treatment.