John B Mulliken

Boston Children's Hospital, Boston, Massachusetts, United States

Are you John B Mulliken?

Claim your profile

Publications (496)1987.63 Total impact

  • Plastic and Reconstructive Surgery 05/2015; 135(5S Suppl):56. DOI:10.1097/01.prs.0000465520.85176.40 · 3.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To document the clinical presentation, diagnostic studies, and therapy of gastrointestinal infantile hemangiomas. This is a retrospective analysis of children with gastrointestinal hemangiomas culled from our Vascular Anomalies Center database. We detailed the location of visceral and cutaneous tumors, as well as radiologic and procedural methods used for diagnosis and treatment. Nine of 16 children (14 female: 2 male) with hollow visceral hemangiomas also had cutaneous lesions. The most common extra-visceral sites were: regional facial (n = 6), multifocal lesions (n = 2) and a solitary chest lesion (n = 1). Presenting symptoms were melena and hematochezia in the first 4 months of life (n = 14); several infants required multiple blood transfusions. The most frequent locations were small bowel and mesentery. One-half of patients (n = 8) were diagnosed by laparotomy; the majority (n = 12) had suspicious radiologic findings. Corticosteroid and/or propranolol were the most common therapies. Melena and hematochezia, sometimes with profound anemia, in the first 4 months of life, suggest the possibility of intestinal infantile hemangioma even in the absence of cutaneous tumor. Intestinal bleeding, particularly in association with a regional facial lesion, should initiate workup: ultrasonography, CT, and MRI display diagnostic features. First line treatment is medical management; bowel resection may be necessary, particularly for perforation.
    Journal of pediatric gastroenterology and nutrition 04/2015; DOI:10.1097/MPG.0000000000000812 · 2.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Verrucous venous malformation (VVM), also called "verrucous hemangioma," is a non-hereditary, congenital, vascular anomaly comprised of aberrant clusters of malformed dermal venule-like channels underlying hyperkeratotic skin. We tested the hypothesis that VVM lesions arise as a consequence of a somatic mutation. We performed whole-exome sequencing (WES) on VVM tissue from six unrelated individuals and looked for somatic mutations affecting the same gene in specimens from multiple persons. We observed mosaicism for a missense mutation (NM_002401.3, c.1323C>G; NP_002392, p.Iso441Met) in mitogen-activated protein kinase kinase kinase 3 (MAP3K3) in three of six individuals. We confirmed the presence of this mutation via droplet digital PCR (ddPCR) in the three subjects and found the mutation in three additional specimens from another four participants. Mutant allele frequencies ranged from 6% to 19% in affected tissue. We did not observe this mutant allele in unaffected tissue or in affected tissue from individuals with other types of vascular anomalies. Studies using global and conditional Map3k3 knockout mice have previously implicated MAP3K3 in vascular development. MAP3K3 dysfunction probably causes VVM in humans. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 02/2015; 135(5S Suppl). DOI:10.1016/j.ajhg.2015.01.007 · 10.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To test the hypothesis that somatic phosphatidylinositol-4,5-bisphospate 3-kinase, catalytic subunit alpha (PIK3CA) mutations would be found in patients with more common disorders including isolated lymphatic malformation (LM) and Klippel-Trenaunay syndrome (KTS). We used next generation sequencing, droplet digital polymerase chain reaction, and single molecule molecular inversion probes to search for somatic PIK3CA mutations in affected tissue from patients seen at Boston Children's Hospital who had an isolated LM (n = 17), KTS (n = 21), fibro-adipose vascular anomaly (n = 8), or congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (n = 33), the disorder for which we first identified somatic PIK3CA mutations. We also screened 5 of the more common PIK3CA mutations in a second cohort of patients with LM (n = 31) from Seattle Children's Hospital. Most individuals from Boston Children's Hospital who had isolated LM (16/17) or LM as part of a syndrome, such as KTS (19/21), fibro-adipose vascular anomaly (5/8), and congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (31/33) were somatic mosaic for PIK3CA mutations, with 5 specific PIK3CA mutations accounting for ∼80% of cases. Seventy-four percent of patients with LM from Seattle Children's Hospital also were somatic mosaic for 1 of 5 specific PIK3CA mutations. Many affected tissue specimens from both cohorts contained fewer than 10% mutant cells. Somatic PIK3CA mutations are the most common cause of isolated LMs and disorders in which LM is a component feature. Five PIK3CA mutations account for most cases. The search for causal mutations requires sampling of affected tissues and techniques that are capable of detecting low-level somatic mosaicism because the abundance of mutant cells in a malformed tissue can be low. Copyright © 2015 Elsevier Inc. All rights reserved.
    Journal of Pediatrics 02/2015; DOI:10.1016/j.jpeds.2014.12.069 · 3.74 Impact Factor
  • Lymphatic Research and Biology 02/2015; DOI:10.1089/lrb.2014.0045 · 1.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Capillary malformation (CM) can be a “red flag” for several syndromic vascular anomalies. We identified a subset of patients with diffuse CM and fetal pleural effusion and documented the type of CM, the etiology of the pleural effusion, the potential syndromic diagnosis, and outcome. Patients with a history of CM and fetal pleural effusion were identified by searching the database of patients evaluated at the Vascular Anomalies Center at Boston Children's Hospital. Standardized patient interviews and a retrospective review of records, photographs, and imaging studies were conducted. Five patients had diffuse CM and fetal pleural effusion. Two patients had macrocephaly-CM (M-CM), one had features of M-CM and CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and spinal/skeletal anomalies and/or scoliosis), and one had diffuse CM with overgrowth. The pleural fluid was chylous in four patients. One patient had thoracic lymphatic malformation. Recurrent effusion occurred in one patient coincident with pneumonia at age 11 years. Four patients had a history of reactive airway disease and episodic pulmonary infections. The diagnosis of vascular anomaly–overgrowth syndromes, particularly M-CM, should be considered in neonates with fetal pleural effusion.
    Pediatric Dermatology 01/2015; 32(1). DOI:10.1111/pde.12401 · 1.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Endothelial glucose transporter 1 (GLUT1) is a definitive and diagnostic marker for infantile hemangioma (IH), a vascular tumor of infancy. To date, GLUT1-positive endothelial cells in IH have not been quantified nor directly isolated and studied. We isolated GLUT1-positive and GLUT1-negative endothelial cells from IH specimens and characterized their proliferation, differentiation and response to propranolol, a first-line therapy for IH, and to rapamycin, an mTOR pathway inhibitor used to treat an increasingly wide array of proliferative disorders. Although freshly isolated GLUT1-positive cells, selected using anti-GLUT1 magnetic beads, expressed endothelial markers CD31, VE-Cadherin and VEGFR2, they converted to a mesenchymal phenotype after three weeks in culture. In contrast, GLUT1-negative endothelial cells exhibited a stable endothelial phenotype in vitro. GLUT1-selected cells were clonogenic when plated as single cells and could be induced to re-differentiate into endothelial cells, or into pericyte/smooth muscle cells or into adipocytes, indicating a stem cell-like phenotype. These data demonstrate that, although they appear and function in the tumor as bona fide endothelial cells, the GLUT1-positive endothelial cells display properties of facultative stem cells. Pretreatment with rapamycin for 4 days significantly slowed proliferation of GLUT1-selected cells, whereas propranolol pretreatment had no effect. These results reveal for the first time the facultative nature of GLUT1-positive endothelial cells in infantile hemangioma. Stem Cells 2014
    Stem Cells 01/2015; 33(1). DOI:10.1002/stem.1841 · 7.70 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Uncommon congenital hemangiomas differ from common infantile hemangiomas in their appearance, postnatal behavior, histopathology, and immunohistologic staining. Two types are well described in the literature: noninvoluting congenital hemangioma (NICH) and rapidly involuting congenital hemangioma (RICH). We report a series of infants with another presentation of congenital hemangioma that arises prenatally and is nearly regressed at birth. This was a retrospective case series. We describe six infants with unusual congenital vascular tumors. Each lesion presented at birth as a violaceous, atrophic plaque with a surrounding pale halo. The lesions involuted in infancy, fading in color and becoming atrophic, with prominent central veins, similar to RICH in the final stage of regression. The distinctive morphology and behavior suggests that these tumors undergo a life cycle of proliferation and involution during fetal life. We describe a new variant of congenital hemangioma that we refer to as rapidly involuting congenital hemangioma with fetal involution.
    Pediatric Dermatology 12/2014; DOI:10.1111/pde.12356 · 1.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Maffucci syndrome (MS) is a rare congenital disorder characterized by multiple central cartilaginous tumors (enchondromas) in association with cutaneous spindle cell hemangiomas. These patients have a high incidence of malignant transformation. No familial case is known and the etiopathogenic cause remains unknown. In enchondromatosis (Ollier disease, OD), which is comprised of enchondromas only, 4 mutations in the PTHR1 gene have been identified in 4 patients; 3 were somatic and 1 was germline. No PTHR1 mutations have been detected in MS, whereas somatic IDH1 and, more rarely, IDH2 mutations have been observed in 77% of patients with MS and 81% of patients with OD. These genetic alterations are shared with other tumors, including glioma, leukemia and carcinoma. To search for underlying somatic genomic causes, we screened MS tissues using Affymetrix SNP-chips. We looked for CNVs, LOH and uniparental isodisomy (UPID) by performing pairwise analyses between allelic intensities in tumoral DNA versus the corresponding blood-extracted DNA. While common chromosomal anomalies were absent in constitutional DNA, several shared CNVs were identified in MS-associated tumors. The most frequently encountered somatic alterations were localized in 2p22.3, 2q24.3 and 14q11.2, implicating these chromosomal rearrangements in the formation of enchondromas and spindle cell hemangiomas in MS. In one chondrosarcoma specimen, large amplifications and/or deletions were observed in chromosomes 3, 6, 9, 10, 12, 13, and 19. Some of these genetic changes have been reported in other chondrosarcomas suggesting an etiopathogenic role. No LOH/UPID was observed in any Maffucci tissue. Our findings identify frequent somatic chromosomal rearrangements on 2p22.3, 2q24.3 and 14q11.2, which may unmask mutations leading to the lesions pathognomonic of MS.
    Molecular syndromology 12/2014; 5(6):259-67. DOI:10.1159/000365898
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective : To describe the subtle clinical features, genetic considerations, and management of progressive postnatal pansynostosis, a rare form of multisutural craniosynostosis that insidiously occurs after birth and causes inconspicuous cranial changes. Design, Participants, Setting : The study is a retrospective chart review of all patients diagnosed with progressive postnatal pansynostosis at a major craniofacial center between 2000 and 2009. Patients with kleebattschädel were excluded. Results : Nineteen patients fit our inclusion criteria. Fifteen patients had a syndromic diagnosis: Crouzon syndrome (n = 8), Saethre-Chotzen syndrome (n = 5), and Pfeiffer syndrome (n = 2). With the exception of one patient with moderate turricephaly, all patients had a relatively normal head shape with cranial indices ranging from 0.72 to 0.93 (mean, 0.81). Patients were diagnosed at an average of 32.4 months; craniosynostosis was suspected based on declining percentile head circumference (n = 14), detection of an apical prominence (n = 12), papilledema (n = 7), and worsening exorbitism (n = 3). Nearly all patients had evidence of increased intracranial pressure. Conclusion : Progressive postnatal pansynostosis is insidious; diagnosis is typically delayed because the clinical signs are subtle and appear gradually. All infants or children with known or suspected craniosynostotic disorder and a normal head shape should be carefully monitored; computed tomography is indicated if there is any decrease in percentile head circumference or symptoms of intracranial pressure.
    The Cleft Palate-Craniofacial Journal 10/2014; DOI:10.1597/14-092 · 1.24 Impact Factor
  • Kamlesh B Patel, John B Mulliken
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: After repair of cleft lip and nasal deformity, a lateral vestibular web is often evident on submental view. The authors describe the five components of this web (i.e., piriform rim, upper lateral cartilage, lower lateral cartilage, vestibular lining, and alar base) and present their technique for primary nasal correction and prevention. Methods: Labial repair follows the Millard rotation-advancement principle. Nasal correction addresses the vestibular web: (1) centralization of deviated anterocaudal septum; (2) elevation of inferiorly positioned medial crus in the C-flap; (3) endonasal advancement and fixation of displaced alar base; (4) excision of excess vestibular lining; (5) release of tethered lateral crus from the piriform ligament; and (6) anatomical fixation of dislocated lower lateral cartilage to the contralateral middle crus and ipsilateral upper lateral cartilage. Results: Intraoperative dissection exposes the framework of the vestibular web as the lower (caudal) edge of the displaced lateral crus lying beneath expanded vestibular lining. Sixty-two consecutive patients had primary cleft nasal repair focused on the architectural components of the vestibular web. Nostril stenting was not used; the nostril rim scar was hidden and no patients had nostril stenosis. Conclusion: The vestibular web seen after repair of a cleft lip has bony, cartilaginous, and soft-tissue elements and can be prevented during primary correction of the cleft nasal deformity.
    Plastic &amp Reconstructive Surgery 10/2014; 134(4):600e-7e. DOI:10.1097/PRS.0000000000000549 · 3.33 Impact Factor
  • Leonard B Kaban, Bonnie Padwa, John B Mulliken
    Plastic &amp Reconstructive Surgery 10/2014; 134(4):657e-8e. DOI:10.1097/PRS.0000000000000547 · 3.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Inlay cranioplasty in children is challenging because autologous bone is limited. Cranial particulate bone graft effectively closes defects when placed over normal dura. The purpose of this study was to determine if particulate bone graft will ossify when used for secondary cranioplasty over scarred dura. Methods: A 17 x 17-mm critical-sized defect was made in the parietal bone of 16 rabbits. Four animals had no implant (group 1). Twelve animals had the defect remade 16 weeks postoperatively, which was managed in 2 ways: group 2 (no implant; n = 6) and group 4 (particulate bone graft; n = 6). Particulate graft was obtained using a brace and bit from the frontal bone. Computed tomography was used to determine the area of ossification and thickness of the healed graft. Eight animals previously managed with particulate bone graft over normal dura were used as an additional control (group 3). Results: Critical-sized defects filled with particulate bone graft over scarred dura (group 4) exhibited superior healing of the area (83.8%; range, 73.0%-90.6%) compared to control defects over normal dura (group 1: 62.9%; range, 56.5%-73.4%) or scarred dura (group 2: 56.9%; range, 40.0%-68.3%) (P = 0.0004). Particulate bone on scarred dura exhibited less ossified area (P = 0.002), and thinner bone (0.95 mm, range, 0.71-1.32 mm) compared to defects in which graft was placed over normal dura (group 3: area, 99.2%; range, 96.8%-100%; thickness, 1.9 mm, range; 1.1-3.1 mm) (P = 0.04). Conclusions: Particulate bone graft ossifies inlay cranial defects over scarred dura although inferior to placement over normal dura. Clinically, particulate bone graft may be used for secondary inlay cranioplasty.
    Plastic &amp Reconstructive Surgery 10/2014; 134(4S-1 Suppl):18. DOI:10.1097/01.prs.0000455337.85782.24 · 3.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective : To summarize the clinical characteristics and surgical and speech outcomes for patients with Van der Woude/popliteal pterygium syndromes (VWS/PPS) and to compare them with a historic cohort of patients with nonsyndromic cleft lip/cleft palate (CL/P). Design : Retrospective chart review. Setting : Tertiary care center. Patients : All patients with VWS/PPS seen at Boston Children's Hospital from 1979 to 2012: 28 patients with VWS (n = 21)/PPS (n = 7) whose mean age was 17.3 ± 10.4 years, including 18 females (64%) and 10 males (36%); 18 patients (64%) had a family history of VWS/PPS. Main Outcome Measures : Cleft type, operative procedures, speech, and midfacial growth. Data were compared with historic cohorts of patients with nonsyndromic CL/P treated at one tertiary care center. Results : There were 24 patients (86%) with CP±L, Veau types I (n = 4, 17%), II (n = 4, 17%), III (n = 5, 21%), and IV (n = 11, 46%). Nine patients (38%) had palatal fistula after palatoplasty. Fourteen of 23 (61%) patients with CL/P age 5 years or older had midfacial retrusion, and 10 (43%) required a pharyngeal flap for velopharyngeal insufficiency. Fisher's exact test demonstrated higher frequencies of Veau type IV CP±L (P = .0016), bilateral CL±P (P = .0001), and complete CL±P (P < .0001) in VWS/PPS compared with nonsyndromic patients. Incidences of midfacial retrusion (P = .0001), palatal fistula (P < .0001), and need for pharyngeal flap (P = .0014) were significantly greater in patients with VWS/PPS. Conclusions : Patients with VWS/PPS have more severe forms of labiopalatal clefting and higher incidences of midfacial retrusion, palatal fistula, and velopharyngeal insufficiency following primary repair as compared with nonsyndromic CL/P.
    The Cleft Palate-Craniofacial Journal 09/2014; DOI:10.1597/14-132 · 1.24 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: "Habsburg Jaw" is a frequently used eponymous designation for patients with mandibular prognathism, hyperplasia, or overgrowth. The purpose of this study was to evaluate portraits of the Spanish Habsburgs to determine the relative contributions of maxillary deficiency and mandibular prognathism to overall facial appearance. Representative portraits of the Spanish Habsburgs were assessed by 4 investigators for the presence of 11 anatomic features of maxillary deficiency and 7 of mandibular prognathism. Each characteristic was given a binary score of 1 if present and 0 if absent. Thus, the maximum score would be 11 for maxillary deficiency and 7 for mandibular prognathism. A semi-quantitative scale was established to determine the likelihood of each diagnosis: Maxillary deficiency: 0-4.99 (unlikely), 5-7.99 (likely), 8-11 (very likely); mandibular prognathism: 0-2.99 (unlikely), 3-5.99 (likely), 6-7 (very likely). Six of 7 Habsburg rulers were considered either likely or very likely to have maxillary deficiency, whereas 3/7 were assessed as likely and 4 unlikely to have mandibular prognathism. The results of this study suggest that the primary deformity of the "Habsburg Jaw" is maxillary deficiency rather than absolute mandibular prognathism. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2014; 164A(9). DOI:10.1002/ajmg.a.36639 · 2.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect of complex etiology. Several genes have been implicated in the etiology of NSCL/P, although only a few have been replicated across datasets.MethodsARHGAP29 was suggested as a candidate gene for NSCL/P as it is located in close proximity to ABCA4 (1p22), a gene previously identified in a genome-wide association study of NSCL/P.ResultsRare, potentially damaging, coding variants in ARHGAP29 were found in NSCL/P cases, and its expression was detected during murine craniofacial development. In this study, we investigated whether variations in ARHGAP29 were associated with NSCL/P in our family based dataset. Five single-nucleotide polymorphisms (SNPs) flanking and within ARHGAP29 were genotyped in our NSCL/P datasets consisting of simplex and multiplex families of non-Hispanic white (NHW, primarily European) and Hispanic ethnicities. Results showed strong association of three ARHGAP29 SNPs with NSCL/P in the NHW families. Two intronic SNPs (rs1541098 and rs3789688) showed strong association with NSCL/P in all NHW families (p = 0.0005 and p = 0.0002, respectively), and simplex NHW families (p = 0.003 for both SNPs). A SNP in the 3′ untranslated region (rs1576593) also showed strong association with NSCL/P in all NHW families (p = 0.002), and the multiplex subset (p = 0.002). ARHGAP29 SNP haplotypes were also associated with NSCL/P. Evidence of gene–gene interaction was found between ARHGAP29 and additional cleft susceptibility genes.Conclusion This study further supports ARHGAP29 as a candidate gene for human NSCL/P in families of Caucasian descent. Birth Defects Research (Part A), 2014 © 2014 Wiley Periodicals, Inc.
    Birth Defects Research Part A Clinical and Molecular Teratology 09/2014; 100(9). DOI:10.1002/bdra.23286 · 2.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sclerotherapy is the mainstay of treatment of macrocystic lymphatic malformation (LM), but the response using traditional sclerosants is much less beneficial in microcystic lesions. Intralesional bleomycin has been reported to be effective in microcystic LM; however, its use is limited by concerns about pulmonary fibrosis. The purpose of this study was to evaluate the safety and efficacy of bleomycin sclerotherapy in microcystic LM. The medical records and imaging studies of all patients with microcystic or combined LM who underwent percutaneous image-guided sclerotherapy using bleomycin were retrospectively reviewed. Only patients with pre- and postprocedure imaging were included. Thirty-one patients with a mean age of 13.4 years (range 3 months-31 years) were treated. Response was graded as complete (> 90 % size reduction), partial (25-90 %), or minimal/no response (< 25 %). Pulmonary function tests (PFT) and chest X-rays were performed before the procedure. PFT were repeated at 6 months and 1 year postprocedure. Annual postprocedure chest X-rays were also performed. The malformations were located in the head and neck (n = 27) and trunk (n = 4). The number of procedures ranged from 1 to 4 (mean 1.7). Up to 1 U/kg of bleomycin was injected per session, with a maximum of 15 U. The mean follow-up period was 3.2 years (range 1.5-5 years). There was complete response in 38 % (n = 12), partial response in 58 % (n = 18), and no response in 3 % (n = 1). No complications were identified. Preliminary indicate that sclerotherapy of microcystic LMs using bleomycin is effective and safe.
    CardioVascular and Interventional Radiology 06/2014; 37(6). DOI:10.1007/s00270-014-0932-z · 1.97 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Large numbers of international children with cleft lip and palate are, adopted in the United States; many had their first operation before arrival. Methods: We reviewed records of internationally adopted children with cleft lip/palate, treated by one surgeon over 25 years. Our study focused on anatomic types, frequency/methods of initial repair and also documented correction of unrepaired deformities and secondary procedures in this country. Results: Of 105 internationally adopted children with cleft lip/ palate, 91% were from Asia; 75% had either labial or labiopalatal closure in their native country. Of repaired unilateral cleft lips, 43% required complete revision; 49% had minor revisions; 8% had no revision. All repaired bilateral cleft lips were revised, 90% complete and 10% minor revisions. 'Delayed' primary nasal correction was always necessary in both unilateral/bilateral forms. Labial closure was scheduled first in young infants with an unrepaired unilateral defect, whereas, palatal closure took precedence in older children. Premaxillary setback and palatoplasty were scheduled first in older children with unrepaired bilateral cleft lip/palate. Of children who arrived with a repaired palate, 43% required a pharyngeal flap. Conclusions: Whenever initial repair of cleft lip/palate is done in another country, revision rates are high for both unilateral and bilateral types. Nevertheless, primary nasolabial repair in the native country increases the likelihood for adoption, domestic or international. Traditional surgical protocols often are altered for an adoptee with an unrepaired cleft lip/palate, in particular, the sequence of labial and palatal closure, depending on the child's age and type of defect. (C)2015American Society of Plastic Surgeons
    Plastic &amp Reconstructive Surgery 06/2014; 133(6):1445-52. DOI:10.1097/PRS.0000000000000224 · 3.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Propranolol, a β-adrenergic receptor (AR) antagonist, was discovered serendipitously to be an effective treatment for endangering infantile hemangioma (IH). Dramatic fading of cutaneous color is often seen a short time after initiating propranolol therapy, with accelerated regression of IH blood vessels discerned after weeks to months. Here we focus on hemangioma-derived pericytes (HemPericytes) isolated from proliferating and involuting phase tumors to assess a possible role for these cells in the apparent propranolol-induced vasoconstriction. HemPericytes express high levels of β2 AR mRNA, compared to positive control bladder smooth muscle cells. In addition, β2 AR mRNA levels were relatively high in IH specimens (n=15) compared to β1 AR, β3 AR and α1bAR. HemPericytes were assayed for contractility on a deformable silicone substrate: propranolol (10μM) restored basal contractile levels in HemPericytes that were relaxed with the AR agonist epinephrine. siRNA knockdown β2 AR blunted this response. Normal human retinal and placental pericytes were not affected by epinephrine or propranolol in this assay. Propranolol (10μM) inhibited proliferation of HemPericytes in vitro, as well as normal pericytes, indicating a non-selective effect in this assay. HemPericytes and HemEC were co-implanted subcutaneously in nude mice to form blood vessels, and at day 7 after injection, mice were randomized into vehicle and propranolol treated groups. Contrast-enhanced micro-ultrasonography of the implants after 7 days of treatment showed significantly decreased vascular volume in propranolol-treated animals, but no reduction in vehicle-treated animals. These findings suggest that the mechanism of propranolol's effect on proliferating IH involves increased pericytic contractility.This article is protected by copyright. All rights reserved.
    British Journal of Dermatology 04/2014; 171(5). DOI:10.1111/bjd.13048 · 4.10 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The mechanism for the growth of infantile hemangioma and vascular malformations is unknown. Follicle-stimulating hormone secretion mirrors the life cycle of infantile hemangioma and increases during adolescence, when vascular malformations often progress. The purpose of this study was to determine whether vascular anomalies express the receptor for follicle-stimulating hormone. Human vascular tumors (i.e., infantile hemangioma, congenital hemangioma, kaposiform hemangioendothelioma, and pyogenic granuloma) and vascular malformations (i.e., capillary, lymphatic, venous, and arteriovenous) were subjected to immunofluorescence for follicle-stimulating hormone receptor. Control specimens included normal skin/subcutis, mucosa, liver, spleen, Crohn disease, granulation, pancreatitis, rheumatoid arthritis, and synovitis. Receptor and microvessel density were quantified using imaging software. Follicle-stimulating hormone receptor was found in the endothelium of all vascular anomalies but was not present in control specimens. Expression was greater in proliferating infantile hemangioma (6.0 percent) compared with other vascular tumors (congenital hemangioma, 0.61 percent; kaposiform hemangioendothelioma, 0.55 percent; pyogenic granuloma, 0.56 percent; p < 0.0001), despite similar microvessel density (p = 0.1). Follicle-stimulating hormone receptor was elevated in arteriovenous malformations (2.65 percent) compared with other types of vascular malformations (capillary, 1.02 percent; lymphatic, 0.38 percent; venous, 0.76 percent; p < 0.0001). Vascular anomalies express follicle-stimulating hormone receptor on their endothelium, in contrast to vascular control tissues. Vascular anomalies are the only benign, pathologic tissue known to express this receptor. Because the secretion of follicle-stimulating hormone correlates with the growth pattern of infantile hemangioma and vascular malformations, follicle-stimulating hormone might be involved in the pathogenesis of these lesions.
    Plastic and Reconstructive Surgery 03/2014; 133(3):344e-51e. DOI:10.1097/01.prs.0000438458.60474.fc · 3.33 Impact Factor

Publication Stats

21k Citations
1,987.63 Total Impact Points

Institutions

  • 1987–2015
    • Boston Children's Hospital
      • • Department of Radiology
      • • Plastic and Oral Surgery Research Laboratory
      • • Department of Neurosurgery
      Boston, Massachusetts, United States
  • 2014
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 1984–2014
    • Harvard University
      • Department of Oral and Maxillofacial Surgery
      Cambridge, Massachusetts, United States
  • 1981–2014
    • Harvard Medical School
      • • Department of Cell Biology
      • • Department of Surgery
      Boston, Massachusetts, United States
  • 2013
    • Center for Human Genetics, Inc.
      Cambridge, Massachusetts, United States
  • 2004–2013
    • Catholic University of Louvain
      • Duve Institute
      Walloon Region, Belgium
    • The Children's Hospital of Philadelphia
      Filadelfia, Pennsylvania, United States
  • 2012
    • University of Michigan
      • Department of Orthodontics and Pediatric Dentistry
      Ann Arbor, MI, United States
  • 2010
    • University of British Columbia - Vancouver
      Vancouver, British Columbia, Canada
  • 2004–2010
    • Boston University
      • • Slone Epidemiology Center
      • • Center for Human Genetics
      Boston, MA, United States
  • 2009
    • Johns Hopkins Medicine
      • Department of Plastic and Reconstructive Surgery
      Baltimore, MD, United States
    • Hospital Roosevelt
      Guatemala la Nueva, Guatemala, Guatemala
  • 2005
    • Beth Israel Deaconess Medical Center
      • Department of Radiology
      Boston, MA, United States
  • 2001
    • University of Toronto
      Toronto, Ontario, Canada
  • 1979–2000
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 1984–1998
    • Brigham and Women's Hospital
      • Division of Plastic Surgery
      Boston, Massachusetts, United States
  • 1997
    • Johannes Gutenberg-Universität Mainz
      Mayence, Rheinland-Pfalz, Germany
  • 1996
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States
  • 1994
    • Dalhousie University
      Halifax, Nova Scotia, Canada
  • 1993
    • Johns Hopkins University
      • Department of Pediatrics
      Baltimore, MD, United States
  • 1991
    • Alpert Medical School - Brown University
      Providence, Rhode Island, United States