John B Mulliken

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

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Publications (521)2090.16 Total impact

  • Plastic and Reconstructive Surgery 09/2015; 136(4S Suppl):72-73. DOI:10.1097/01.prs.0000472371.96995.e5 · 2.99 Impact Factor
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    ABSTRACT: Background: A somatic mutation in GNAQ (c.548G>A;p.R183Q), encoding Gαq, has been found in syndromic and sporadic capillary malformation tissue. However, the specific cell type(s) containing the mutation is unknown. The purpose of this study was to determine which cell(s) in capillary malformations have the GNAQ mutation. Methods: Human capillary malformation tissue was obtained from 13 patients during a clinically-indicated procedure. Droplet digital PCR (ddPCR), capable of detecting mutant allelic frequencies as low as 0.1%, was used to quantify the abundance of GNAQ mutant cells in capillary malformation tissue. Six specimens were fractionated by fluorescence activated cell sorting (FACS) into hematopoietic, endothelial, perivascular, and stromal cells. The frequency of GNAQ mutant cells in these populations was quantified by ddPCR. Results: Eight capillary malformations contained GNAQ p.R183Q mutant cells, 2 lesions had novel GNAQ mutations (p.R183L; p.R183G), and 3 capillary malformations did not have a detectable GNAQ p.R183 mutation. Mutant allelic frequencies ranged from 2% to 11%. Following FACS, the GNAQ mutation was found in the endothelial but not the platelet-derived growth factor receptor-β-positive (PDGFRβ) cell population; mutant allelic frequencies were 3% to 43%. Conculsions: Endothelial cells in capillary malformations are enriched for GNAQ mutations and are likely responsible for the pathophysiology underlying capillary malformation.
    Plastic and Reconstructive Surgery 09/2015; DOI:10.1097/PRS.0000000000001868 · 2.99 Impact Factor
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    ABSTRACT: Cleft lip and/or palate (CL/P) is phenotypically diverse, making classification difficult. This article explores the evolution of ideas regarding CL/P classification and includes the schemes described by Davis and Ritchie (1922), Brophy (1923), Veau (1931), Fogh-Andersen (1943), Kernahan and Stark (1958), Harkins et al. (1962), Broadbent et al. (1968), Spina (1973), and others. Based on these systems, a longhand structured form is proposed for describing CL/P in a way that is clear, comprehensive, and consistent. A complementary shorthand notation is also described to improve the utility and convenience of this structured form.
    The Cleft Palate-Craniofacial Journal 09/2015; DOI:10.1597/14-080 · 1.20 Impact Factor
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    ABSTRACT: Objective: Tongue-lip adhesion (TLA) is commonly used to relieve obstructive sleep apnea (OSA) in infants with Robin sequence (RS), but few studies have evaluated its efficacy with objective measures. The purpose of this study was to measure TLA outcomes using polysomnography. Our hypothesis was that TLA relieves OSA in most infants. Methods: This is a retrospective study of infants with RS who underwent TLA from 2011 to 2014 and had at least a postoperative polysomnogram. Predictor variables included demographic and birth characteristics, surgeon, syndromic diagnosis, GILLS score, preoperative OSA severity, and clinical course. A successful outcome was defined as minimal OSA (apnea-hypopnea index score < 5) on postoperative polysomnogram and no need for additional airway intervention. Descriptive, bivariate, and regression statistics were computed, and statistical significance was set at P < .05. Results: Eighteen subjects who had TLA at a mean age of 28 + 4.7 days were included. Thirteen (72.2%) had a confirmed or suspected syndrome, and the mean GILLS score was 3 ± 0.3. All parameters trended toward improvement from the preoperative to postoperative polysomnograms, and improvement in OSA severity, oxygen saturation nadir, and arousals per hour was statistically significant (P< .02). This effect was significant across categories of surgeon, syndrome, and GILLS score. Nine subjects (50%) met the criteria for a successful outcome. Bivariate and regression analyses did not demonstrate a significant relationship between success and any predictor variable. Conclusions: TLA improved airway obstruction in all infants with RS but resolved OSA in only nine patients, and success was unpredictable.
    The Cleft Palate-Craniofacial Journal 07/2015; DOI:10.1597/15-058 · 1.20 Impact Factor
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    ABSTRACT: To examine the impact of dentofacial infant orthopedic treatment (DFIO) on facial growth in preadolescent children with unilateral complete cleft lip and palate (UCCLP) and bilateral complete cleft lip and palate (BCCLP). This is a retrospective study of patients with UCCLP and BCCLP treated at a single center. The treatment group had DFIO, and the control group did not have DFIO. Regression models were used to compare outcomes between the study and control groups. The study sample comprised 81 patients (54 had DFIO and 27 did not have DFIO). Among those with UCCLP, those who had DFIO had a shorter maxillary length (-2.12 mm; P = .04) and shorter lower anterior facial height (-2.77 mm; P = .04) compared with controls. Among those with BCCLP, there were no significant differences between the treatment and control groups. DFIO treatment could result in shorter maxillary length and lower anterior facial height in those with UCCLP. Copyright © 2015 Elsevier Inc. All rights reserved.
    06/2015; 120(3). DOI:10.1016/j.oooo.2015.04.016
  • Plastic and Reconstructive Surgery 05/2015; 135(5S Suppl):56. DOI:10.1097/01.prs.0000465520.85176.40 · 2.99 Impact Factor
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    ABSTRACT: Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect affecting 135,000 newborns worldwide each year. While a multifactorial etiology has been suggested as the cause, despite decades of research, the genetic underpinnings of NSCLP remain largely unexplained. In our previous genome-wide linkage study of a large NSCLP African-American family, we identified a candidate locus at 8q21.3-24.12 (LOD = 2.98). This region contained four genes, Frizzled-6 (FZD6), Matrilin-2 (MATN2), Odd-skipped related 2 (OSR2) and Solute Carrier Family 25, Member 32 (SLC25A32). FZD6 was located under the maximum linkage peak. In this study, we sequenced the coding and noncoding regions of these genes in two affected family members, and identified a rare variant in intron 1 of FZD6 (rs138557689; c.-153 + 432A>C). The variant C allele segregated with NSCLP in this family, through affected and unaffected individuals, and was found in one other NSCLP African-American family. Functional assays showed that this allele creates an allele-specific protein-binding site and decreases promoter activity. We also observed that loss and gain of fzd6 in zebrafish contributes to craniofacial anomalies. FZD6 regulates the WNT signaling pathway, which is involved in craniofacial development, including midfacial formation and upper labial fusion. We hypothesize, therefore, that alteration in FZD6 expression contributes to NSCLP in this family by perturbing the WNT signaling pathway.
    05/2015; DOI:10.1002/mgg3.155
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    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; Publish Ahead of Print. DOI:10.1097/MPG.0000000000000812 · 2.63 Impact Factor
  • Article: Abstract 52
    Plastic &amp Reconstructive Surgery 04/2015; 135(4):1204. DOI:10.1097/01.prs.0000463958.68172.47 · 2.99 Impact Factor
  • Article: Abstract 52
    Plastic &amp Reconstructive Surgery 04/2015; 135:1204. DOI:10.1097/01.prs.0000463309.02861.2d · 2.99 Impact Factor
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    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 · 10.93 Impact Factor
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    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; 166(4). DOI:10.1016/j.jpeds.2014.12.069 · 3.79 Impact Factor
  • Lymphatic Research and Biology 02/2015; 13(3). DOI:10.1089/lrb.2014.0045 · 1.71 Impact Factor
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    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 02/2015; 32(1). DOI:10.1111/pde.12401 · 1.02 Impact Factor
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    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 · 6.52 Impact Factor
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    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; 32(3). DOI:10.1111/pde.12356 · 1.02 Impact Factor
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    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
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    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 · 1.20 Impact Factor
  • Kamlesh B Patel · John B Mulliken
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    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 · 2.99 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 · 2.99 Impact Factor

Publication Stats

23k Citations
2,090.16 Total Impact Points


  • 1985–2015
    • Boston Children's Hospital
      • • Department of Radiology
      • • Plastic and Oral Surgery Research Laboratory
      • • Department of Neurosurgery
      Boston, Massachusetts, United States
  • 1984–2015
    • Harvard University
      • Department of Oral and Maxillofacial Surgery
      Cambridge, Massachusetts, United States
  • 2014
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 1978–2014
    • Harvard Medical School
      • • Department of Surgery
      • • Department of Cell Biology
      Boston, Massachusetts, United States
  • 2012
    • University of Michigan
      • Department of Orthodontics and Pediatric Dentistry
      Ann Arbor, MI, United States
  • 2009
    • Johns Hopkins Medicine
      • Department of Plastic and Reconstructive Surgery
      Baltimore, MD, United States
    • Hospital Roosevelt
      Guatemala la Nueva, Guatemala, Guatemala
  • 2004–2005
    • Catholic University of Louvain
      • Duve Institute
      Walloon Region, Belgium
    • The Children's Hospital of Philadelphia
      Filadelfia, Pennsylvania, United States
    • Boston University
      • Slone Epidemiology Center
      Boston, MA, United States
  • 2001
    • University of Toronto
      Toronto, Ontario, Canada
  • 1979–2000
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 1998
    • Riley Hospital for Children
      Indianapolis, Indiana, United States
  • 1984–1998
    • Brigham and Women's Hospital
      • Division of Plastic Surgery
      Boston, Massachusetts, United States
  • 1996
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States
  • 1995
    • University of Texas Medical School
      • Department of Pediatrics
      Houston, Texas, United States
    • Duke University Medical Center
      Durham, North Carolina, United States
  • 1994
    • Dalhousie University
      Halifax, Nova Scotia, Canada
  • 1991
    • Alpert Medical School - Brown University
      Providence, Rhode Island, United States
  • 1987
    • University of North Carolina at Chapel Hill
      • Department of Surgery
      North Carolina, United States
    • University of California, San Francisco
      • Department of Oral and Maxillofacial Surgery
      San Francisco, California, United States