John B Mulliken

Harvard Medical School, Boston, Massachusetts, United States

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Publications (274)980.6 Total impact

  • [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; · 1.04 Impact Factor
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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 : official publication of the American Cleft Palate-Craniofacial Association. 10/2014;
  • Leonard B Kaban, Bonnie Padwa, John B Mulliken
    Plastic and reconstructive surgery. 10/2014; 134(4):657e-8e.
  • Kamlesh B Patel, John B Mulliken
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    ABSTRACT: 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.
    Plastic and reconstructive surgery. 10/2014; 134(4):600e-7e.
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    ABSTRACT: Background: Inlay cranioplasty in children is difficult because autologous bone is limited. Cranial particulate bone graft (PBG) effectively closes defects when placed over normal dura. The purpose of this study was to determine if PBG will ossify when used for secondary cranioplasty over scarred dura. Methods: A 17mm x 17mm critical-sized defect was made in the parietal bone of 16 rabbits. Four animals received no implant (Group I). Twelve animals had the defect recreated 16 weeks postoperatively which was managed in two ways: Group II (no implant) (n=6) and Group III (PBG) (n=6). PBG was obtained using a brace and bit from the frontal bone. Computed tomography was performed 32 weeks following the craniectomy to determine the area of ossification and thickness of the healed graft. Eight animals previously managed with PBG over normal dura were used as an additional control (Group IV). Results: Critical-sized defects treated with PBG over scarred dura exhibited superior healing of the area (83.8%; range, 73.0-90.6%) compared to control defects over normal dura (Group I: 62.9%; range, 56.5-73.4%) or scarred dura (Group II: 56.9%; range, 40.0-68.3%) (p=0.0004). PBG on scarred dura had less ossification area (p=0.002), and thinner bone (0.95 mm, range, 0.71-1.32), compared to when it was placed over normal dura (area 99.2%; range, 96.8%-100%; thickness 1.9 mm, range, 1.1 to 3.1) (p=0.04). Conclusions: PBG ossifies inlay cranial defects over scarred dura, although its efficacy is inferior compared to placement over normal dura. Clinically, PBG may be used for secondary inlay cranioplasty. Figure legend: Histological evaluation of particulate bone grafted cranial defects. (Left) Graft ossified over normal dura shows trabecular bone osseointigrated with the adjacent lamellar cranium. (Right) Graft healed over scarred dura shows rudimentary trabeculation and osseointegration. Grafted scarred and unscarred dura both show islands of lamellar particulate graft surrounded by areas of new woven bone (hematoxylin and eosin; original magnification, x400X).
    Plastic and reconstructive surgery. 10/2014; 134(4S-1 Suppl):18.
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    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 : official publication of the American Cleft Palate-Craniofacial Association. 09/2014;
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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 09/2014; · 7.70 Impact Factor
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    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 08/2014; · 2.27 Impact Factor
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    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.
    CardioVascular and Interventional Radiology 06/2014; · 2.14 Impact Factor
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    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 06/2014; · 2.30 Impact Factor
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    ABSTRACT: Families in the United States adopted approximately 230,000 foreign-born children over the past two decades. Age at adoption and the presence of a cleft palate impact speech and language development. The authors' purpose is to document speech outcome after palatal closure in internationally adopted children.
    Plastic and reconstructive surgery. 06/2014; 133(6):1445-52.
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    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; · 3.76 Impact Factor
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    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. · 3.33 Impact Factor
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    ABSTRACT: Glomuvenous malformation (GVM) is an inherited autosomal dominant trait. The lesions, which appear as bluish nodules or plaque-like cutaneous elevations, are usually tender and more firm than sporadic venous malformations. Conventionally, the lesions are thought to be limited to the cutaneous and subcutaneous tissue planes. The objective was to characterize the depth of involvement of GVM lesions. Magnetic resonance imaging (MRI) findings in GVM were retrospectively evaluated by two radiologists. The signal characteristics, tissue distribution, pattern of contrast enhancement of the lesions in GVM were documented. Thirty patients (19 female) aged 1-35 years (mean 18 years) were diagnosed with GVM based on clinical features (n = 20) and/or histopathological findings (n = 10). The lesions were present in the lower extremity (n = 15), upper extremity (n = 6), cervico-facial region (n = 6), pelvis (n = 2), and chest wall (n = 1). All patients had skin and subcutaneous lesions. Fifty percent of the patients (n = 15) demonstrated subfascial intramuscular (n = 15), intra-osseous (n = 1), and intra-articular involvement (n = 1). Contrary to the conventional belief that GVMs are generally limited to the skin and subcutaneous tissue, deep subfascial extension of the lesions is common.
    Skeletal Radiology 02/2014; · 1.74 Impact Factor
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    ABSTRACT: Infantile hemangiomas demonstrate a pattern of proliferative growth in infancy followed by a slow phase of involution. In contrast a rare type of vascular tumor, intramuscular capillary-type hemangioma, usually presents beyond the period of infancy with nonspecific symptoms and no evidence of involution. The purpose of this study was to characterize the clinical, imaging, histopathological characteristics and management of intramuscular capillary-type hemangioma. We performed a retrospective review of a 20-year period to identify children diagnosed with intramuscular capillary-type hemangioma. Patient demographics, imaging and histopathological findings were recorded. We included 18 children (10 boys, 8 girls) with histologically proven intramuscular capillary-type hemangioma - and adequate imaging. The mean age at presentation was 8.1 years (range 1 day to 19 years). Twelve lesions involved muscles of the extremities, 4 were located in the trunk and 2 were in the head and neck. MRI had been performed in all children and demonstrated a soft-tissue mass with flow voids, consistent with fast flow. The lesion was well-circumscribed in 16 children and intralesional fat was seen in 14. Doppler US demonstrated a heterogeneous lesion, predominantly isoechoic to surrounding muscle, with enlarged arterial feeders. Enlarged feeding arteries, inhomogeneous blush and lack of arteriovenous shunting were noted on angiography (n = 5). The most common histopathological findings were lobules of capillaries with plump endothelium and at least some adipose tissue. The lesions were excised in six children. Two children were lost to follow-up. In the remaining 10, follow-up MRI studies ranging from 3 months to 10 years showed that the lesion enlarged in proportion to the child (n = 7), demonstrated slow growth (n = 2) or remained stable (n = 1). There was no change in imaging characteristics on follow-up. Intramuscular capillary-type hemangioma is a rare benign vascular tumor of skeletal muscle. The most typical imaging features show a heterogeneous intramuscular mass with fast flow, and intralesional fat. Although the lesion is relatively stable in appearance over time, imaging does not obviate the need for a biopsy to rule out sarcoma. The diagnosis can usually be established by typical findings on histopathology.
    Pediatric Radiology 02/2014; · 1.57 Impact Factor
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    ABSTRACT: Most types of craniosynostosis cause predictable changes in cranial shape. However, the phenotype of combined metopic and unilateral coronal synostoses is anomalous. The purpose of this observational study was to better clarify the clinical and radiographic features of this rare entity. A retrospective review of a craniofacial database was performed. Patients with combined metopic and unilateral coronal synostoses were included in this study. Data collected included demographic information, physical and radiographic findings, genetic evaluation, treatment, and operative outcomes. Of 687 patients treated between 1989 and 2010, only 3 patients had combined metopic and unilateral coronal synostoses. All patients were diagnosed through computed tomography on the first day of life. Phenotypic features included the following: (1) narrowed forehead with a prominent midline ridge, (2) severe bilateral brow retrusion with an acute indentation on the side of the patient coronal suture, (3) facial and nasal angulation similar to isolated unilateral coronal synostosis, and (4) anterior displacement of the ear on the fused side. In addition, the cranial vertex was deviated toward the side of the open coronal suture. Two patients had a head circumference below the 25th percentile; 2 of the 3 had a TWIST gene mutation consistent with Saethre-Chotzen syndrome. One patient was managed through fronto-orbital advancement and required a revision. The other 2 patients had early endoscopic release, followed by postoperative helmet therapy; one improved but still required open cranial remodeling. The other has near-normal phenotype, and no further surgery is planned. Combined metopic and unilateral coronal synostoses present a rare and unusual phenotype. Although early intervention improves the deformity, revisional procedures are usually required.
    The Journal of craniofacial surgery 01/2014; · 0.81 Impact Factor
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    ABSTRACT: Facial infiltrating lipomatosis is a nonheritable disorder characterized by hemifacial soft-tissue and skeletal overgrowth, precocious dental development, macrodontia, hemimacroglossia, and mucosal neuromas. The authors tested the hypothesis that this condition is caused by a somatic mutation in the phosphatidylinositide-3 kinase (PI3K) signaling pathway, which has been indicted in other anomalies with overgrowth. The authors extracted DNA from abnormal tissue in six individuals, generated sequencing libraries, enriched the libraries for 26 genes involved in the PI3K pathway, and designed and applied a sequential filtering strategy to analyze the sequence data for mosaic mutations. Unfiltered sequence data contained variant reads affecting ~12 percent of basepairs in the targeted genes. Filtering reduced the fraction of targeted basepairs containing variant reads to ~0.008 percent, allowing the authors to identify causal missense mutations in PIK3CA (p.E453K, p.E542K, p.H1047R, or p.H1047L) in each affected tissue sample. Affected tissue from individuals with facial infiltrating lipomatosis contains PIK3CA mutations that have previously been reported in cancers and in affected tissue from other nonheritable, overgrowth disorders, including congenital lipomatous overgrowth, vascular, epidermal, and skeletal anomalies syndrome, Klippel-Trenaunay syndrome, hemimegalencephaly, fibroadipose overgrowth, and macrodactyly. Because PIK3CA encodes a catalytic subunit of PI3K, and in vitro studies have shown that the overgrowth-associated mutations increase this enzyme's activity, PI3K inhibitors currently in clinical trials for patients with cancer may have a therapeutic role in patients with facial infiltrating lipomatosis. The strategy used to identify somatic mutations in patients with facial infiltrating lipomatosis is applicable to other somatic mosaic disorders that have allelic heterogeneity.
    Plastic and Reconstructive Surgery 01/2014; 133(1):12e-9e. · 3.33 Impact Factor
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    ABSTRACT: Almost three times as many board-certified female plastic surgeons are unmarried compared with male colleagues. The purpose of this study was to determine why women in plastic surgery are less likely to be married. A 52-question survey was sent to all female members of the American Society of Plastic Surgeons. Questions focused on type of training and practice; marital status; age at marriage; spousal education, financial, and professional status; relational goals, values, and satisfaction. A total of 729 questionnaires were sent via e-mail; responses were anonymous. Response rate was 34 percent (n = 250). Respondents were either married (64 percent), engaged (2 percent), in a "serious" relationship (11 percent), or not in a committed relationship (23 percent). Of unmarried respondents, 56 percent wanted to marry, 44 percent did not wish marriage at the time of the survey, and 42 percent had deliberatively postponed marriage. The most frequently cited reasons for being single were perceived lack of desirable partners (45 percent), job constraints (14 percent), and personality differences (13 percent). Female plastic surgeons who married later than 36 years of age were more likely to choose a spouse with a lower income, less education, and lower financial success compared with female plastic surgeons who married at a younger age. Women in surgical practice who marry later are less likely to find a partner with equal educational level, financial resources, and professional success. Hence, a shift occurs from hypergamy toward hypogamy. These findings are not unique to plastic surgery.
    Plastic and Reconstructive Surgery 01/2014; 133(1):187-94. · 3.33 Impact Factor
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    ABSTRACT: The diagnosis and management of vascular anomalies of the extremities can be challenging as these disorders are uncommon and may clinically overlap. The aim of this paper is to describe the clinical, radiologic, and histopathologic features of fibro-adipose vascular anomaly (FAVA), a previously unrecognized disorder of the limb. The clinical, imaging, operative, and histopathologic data from patients with a unique intramuscular lesion of the extremities comprising dense fibrofatty tissue and slow-flow vascular malformations were retrospectively reviewed. Sixteen patients diagnosed with FAVA of the extremity (3 male and 13 female individuals) met the clinical, radiologic, and histopathologic inclusion criteria. The age at presentation ranged from the time of birth to 28 years. The locations of the lesions were: calf (n=10), forearm/wrist (n=3), and thigh (n=3). Fourteen patients presented with severe pain. Seven of the patients with calf lesions had limited ankle dorsiflexion. On imaging, the complex intramuscular lesions replaced muscle fibers with fibrofatty overgrowth and phlebectasia (dilation of the veins). The extrafascial component comprised fatty overgrowth, phlebectasia, and an occasional lymphatic malformation. The histopathologic features comprised dense fibrous tissue, fat, and lymphoplasmacytic aggregates within atrophied skeletal muscle. Adipose tissue also infiltrated skeletal muscle at the periphery of the lesion. There were large, irregular, and sometimes excessively muscularized venous channels and smaller, clustered channels. Other findings include organizing thrombi, a lymphatic component, and dense fibrous tissue-encircled nerves. The constellation of clinical, radiologic, and histopathologic features constitutes a distinct entity comprising fibrofatty infiltration of muscle, unusual phlebectasia with pain, and contracture of the affected extremity. The clinical and radiologic findings permit the diagnosis of FAVA with major therapeutic implications. Level III.
    Journal of pediatric orthopedics 01/2014; 34(1):109-17. · 1.23 Impact Factor
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    ABSTRACT: To describe the clinical and imaging characteristics of a new lymphatic disorder with a unique histological pattern and poor prognosis. An observational, retrospective study identified and characterized 20 patients with distinct lymphatic histopathology referred to the Vascular Anomalies Center at Boston Children's Hospital between 1995 and 2011. The median age at onset was 6.5 years (range, birth to 44 years). Clinical and radiologic findings suggested a generalized process. The most common presentations were respiratory symptoms (50%), hemostatic abnormalities (50%), and an enlarging, palpable mass (35%). All patients had mediastinal involvement; 19 patients developed pericardial (70%) and/or pleural effusions (85%). Extrathoracic disease manifested in bone and spleen and less frequently in abdominal viscera, peritoneum, integument, and extremities. Despite aggressive procedural and medical therapies, the 5-year survival was 51% and the overall survival was 34%. Mean interval between diagnosis and death was 2.75 years (range, 1-6.5 years). We describe a clinicopathologically distinct lymphatic anomaly. We propose the term kaposiform lymphangiomatosis (KLA) because of characteristic clusters or sheets of spindled lymphatic endothelial cells accompanying malformed lymphatic channels. The intrathoracic component is most commonly implicated in morbidity and mortality; however, extrathoracic disease is frequent, indicating that KLA is not restricted to pulmonary lymphatics. The mortality rate of KLA is high despite aggressive multimodal therapy.
    The Journal of pediatrics 11/2013; · 4.02 Impact Factor

Publication Stats

6k Citations
980.60 Total Impact Points


  • 1996–2014
    • Harvard Medical School
      • • Department of Surgery
      • • Department of Cell Biology
      • • Department of Anesthesia
      Boston, Massachusetts, United States
  • 2013
    • Michigan State University
      • Department of Pediatrics and Human Development
      East Lansing, MI, United States
    • Good Samaritan Medical Center
      West Palm Beach, Florida, United States
  • 2012–2013
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
    • University of Michigan
      • Department of Orthodontics and Pediatric Dentistry
      Ann Arbor, MI, United States
  • 2001–2013
    • Catholic University of Louvain
      • Institut de Duve
      Walloon Region, Belgium
  • 1995–2013
    • Boston Children's Hospital
      • Department of Radiology
      Boston, Massachusetts, United States
  • 2011
    • University of California, Los Angeles
      Los Angeles, California, United States
  • 2010–2011
    • University of Miami Miller School of Medicine
      Miami, Florida, United States
    • Tufts University
      • Department of Otolaryngology/Head and Neck Surgery
      Boston, GA, United States
    • University of British Columbia - Okanagan
      Kelowna, British Columbia, Canada
  • 2007–2011
    • University of Texas Medical School
      • Department of Pediatrics
      Houston, TX, United States
  • 2004–2011
    • Boston University
      • • Center for Human Genetics
      • • Slone Epidemiology Center
      Boston, MA, United States
    • Institut de Pathologie et de Génétique
      Charleroi, Walloon Region, Belgium
    • Cliniques Universitaires Saint-Luc
      • Division of Plastic Surgery
      Brussels, BRU, Belgium
  • 2009
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
    • Johns Hopkins Medicine
      • Department of Plastic and Reconstructive Surgery
      Baltimore, MD, United States
    • Hospital Roosevelt
      Guatemala la Nueva, Guatemala, Guatemala
    • Harvard University
      Cambridge, Massachusetts, United States
    • Baylor College of Medicine
      • Division of Plastic Surgery
      Houston, TX, United States
  • 2006–2009
    • Massachusetts General Hospital
      • • Center for Immunology and Inflammatory Diseases
      • • Center for Human Genetic Research
      Boston, MA, United States
    • Sheffield Children's NHS Foundation Trust
      Sheffield, England, United Kingdom
    • University of Oxford
      • Weatherall Institute of Molecular Medicine
      Oxford, ENG, United Kingdom
  • 2008
    • University of North Carolina at Chapel Hill
      North Carolina, United States
  • 2005
    • Cincinnati Children's Hospital Medical Center
      • Division of Plastic Surgery
      Cincinnati, OH, United States
    • Beth Israel Deaconess Medical Center
      • Department of Radiology
      Boston, MA, United States
  • 2004–2005
    • University of Virginia
      Charlottesville, Virginia, United States
  • 2003
    • Vascular and Interventional Radiology
      Chicago, Illinois, United States
  • 1993
    • Johns Hopkins University
      • Department of Pediatrics
      Baltimore, MD, United States