John B Mulliken

Harvard Medical School, Boston, Massachusetts, United States

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Publications (543)2149.49 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Patients with repaired cleft lip and/or palate (CL/P) can develop velopharyngeal insufficiency after Le Fort I maxillary advancement. The aim of this study was to evaluate speech outcomes in patients who required a pharyngeal flap after Le Fort I maxillary advancement.
    No preview · Article · Jan 2016
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    ABSTRACT: Purpose: Midfacial hypoplasia is a characteristic feature of the syndromic craniosynostoses and predisposes these patients to developing obstructive sleep apnea (OSA). The purpose of this study was to identify anatomic factors associated with airway obstruction in patients with syndromic craniosynostoses. Materials and Methods: This was a retrospective cohort study. The authors enrolled a study sample composed of patients with syndromic craniosynostoses. The predictor variables were age, gender, body mass index (BMI), syndromic diagnosis, and parameters of upper airway length and size measured on lateral cephalograms. To control for age, upper airway length was corrected for differences in patient height. The outcome variable was OSA status (present or absent). Descriptive, bivariate, and regression statistics were computed. For all analyses, a P value less than or equal to.05 was considered statistically significant. Results: The sample was composed of 50 patients with a mean age of 10.3 +/- 0.6 years, 50% were boys, and 24 (48%) had OSA. Patients with and without OSA did not differ statistically in age, gender, BMI, or syndromic diagnosis. Those with OSA had increased upper airway length (P =.016), decreased posterior airway space (P =.001), and more severe midfacial retrusion (P = .022) compared to patients without OSA. After adjusting for covariates, the odds ratio for OSA was 32.9 in patients with an upper airway longer than 45.3 mm per meter of height (P =.018), and for every 1-mm decrease in posterior airway space, the risk of OSA increased by 30% (P = .022). Conclusions: Patients with syndromic craniosynostosis and OSA have a longer upper airway, smaller posterior airway space, and more severe midfacial retrusion than those without OSA. (C) 2015 American Association of Oral and Maxillofacial Surgeons
    No preview · Article · Dec 2015 · Journal of Oral and Maxillofacial Surgery
  • Raj M. Vyas · David C. Kim · Bonnie L. Padwa · John B. Mulliken
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    ABSTRACT: Objective: To analyze indications and outcomes for primary premaxillary setback. Design: Retrospective. Setting: Academic children's hospital. Patients: All children with bilateral complete cleft lip age ≤2 years of age who had premaxillary setback by one surgeon (1992 to 2011). Results: Twenty-five patients with bilateral complete cleft lip underwent primary premaxillary setback at an average age of 9 months; the mean follow-up was 47 months. There were three indications: failed dentofacial orthopedics (n = 9), delayed referral precluding manipulation (n = 10), and intact secondary alate (n = 6). Of 19 patients with bilateral complete cleft lip/palate, primary setback was combined with nasolabial repair (n = 11), adhesions (n = 2), or palatoplasty (n = 6). Patients who had nasolabial closure and setback were significantly younger than those who had combined palatal closure and setback (6.5 versus 16 months, P = .01). No patient exhibited postoperative premaxillary instability. Serial anthropometry showed similar growth of nasolabial features after both primary setback (n = 9) and active dentofacial orthopedics (n = 35). Conclusions: Primary premaxillary ostectomy and setback permits synchronous bilateral nasolabial-alveolar closure or alveolar-palatal repair in a child with intact secondary palate. This procedure should be considered whenever dentofacial orthopedics cannot be accomplished. Speech is paramount in an older child; setback with palatal closure is scheduled before nasolabial repair. Disturbance of midfacial growth is likely following primary premaxillary ostectomy and setback in patients with bilateral complete cleft lip/palate; however, most already need maxillary advancement. Furthermore, premaxillary setback permits proper primary nasolabial design and construction in appreciation of expected changes with growth.
    No preview · Article · Nov 2015 · The Cleft Palate-Craniofacial Journal
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    ABSTRACT: On or after October 1, 2015, the United States will require use of the Clinical Modification of the International Classification of Diseases, 10th Revision (ICD-10-CM) for diagnostic coding. This primer was written to assist the cleft care community with understanding and use of ICD-10-CM for diagnostic coding related to cleft lip and/or palate (CL/P).
    No preview · Article · Nov 2015 · The Cleft Palate-Craniofacial Journal
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    Stephen R Sullivan · Young-Soo Jung · John B Mulliken

    Full-text · Dataset · Oct 2015

  • No preview · Article · Sep 2015 · Plastic and Reconstructive Surgery
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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.
    No preview · Article · Sep 2015 · Plastic and Reconstructive Surgery
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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.
    No preview · Article · Sep 2015 · The Cleft Palate-Craniofacial Journal
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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.
    No preview · Article · Jul 2015 · The Cleft Palate-Craniofacial Journal
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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.
    Full-text · Article · Jun 2015

  • No preview · Article · May 2015 · Plastic and Reconstructive Surgery
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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.
    Full-text · Article · May 2015
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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.
    No preview · Article · Apr 2015 · Journal of pediatric gastroenterology and nutrition
  • Article: Abstract 52

    No preview · Article · Apr 2015 · Plastic & Reconstructive Surgery
  • Article: Abstract 52

    No preview · Article · Apr 2015 · Plastic & Reconstructive Surgery
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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.
    No preview · Article · Feb 2015 · The American Journal of Human Genetics
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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.
    No preview · Article · Feb 2015 · Journal of Pediatrics

  • No preview · Article · Feb 2015 · Lymphatic Research and Biology
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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.
    No preview · Article · Feb 2015 · Pediatric Dermatology
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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
    No preview · Article · Jan 2015 · Stem Cells

Publication Stats

28k Citations
2,149.49 Total Impact Points


  • 1978-2016
    • Harvard Medical School
      • • Department of Cell Biology
      • • Department of Surgery
      Boston, Massachusetts, United States
  • 1985-2015
    • Boston Children's Hospital
      • • Vascular Anomalies Center
      • • Department of Radiology
      Boston, Massachusetts, United States
  • 1978-2015
    • Harvard University
      • Department of Oral and Maxillofacial Surgery
      Cambridge, Massachusetts, United States
  • 2014
    • Massachusetts General Hospital
      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
  • 1987-2008
    • 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
  • 2004-2005
    • Catholic University of Louvain
      • Duve Institute
      Walloon Region, Belgium
  • 2002
    • Valley Children's Hospital
      Мадера, California, United States
  • 1998-2001
    • Riley Hospital for Children
      Indianapolis, Indiana, United States
  • 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
  • 1995-1996
    • 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
  • 1993
    • Wolfson Childrens Hospital
      Jacksonville, Florida, United States
  • 1991
    • Alpert Medical School - Brown University
      Providence, Rhode Island, United States
  • 1980
    • Beverly Hospital, Boston MA
      BVY, Massachusetts, United States
  • 1978-1980
    • Children's Hospital & Medical Center
      Omaha, Nebraska, United States