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    John Mulliken

    Congenital auricular anomalies can be categorized as either malformed or deformational. Auricular deformations most commonly affect the helix and antehelix. Surgical correction involves sutural modeling, wedge excision, reshaping and... more
    Congenital auricular anomalies can be categorized as either malformed or deformational. Auricular deformations most commonly affect the helix and antehelix. Surgical correction involves sutural modeling, wedge excision, reshaping and reversing cartilage segments, and morselization. Since neonatal auricular cartilage is extremely pliable, we used early splinting to correct deformational ear anomalies. Splints were constructed of leadfree, soft soldering wire threaded into polyethylene tubing and held in place with Steri-Strips. From August 1995 through February 1996 we treated 19 infants with 32 deformed auricles: 10 infants were male and 9 were female, ranging in age from 1 day to 10 weeks. Thirteen infants had both ears affected. There were 8 prominent ears, 23 lop ears, 2 Stahl's ears, and 1 infant with an inverted concha. For prominent ears, the helical-mastoid distance decreased from an average of 16.8 to 12.2 mm, after an average of 13 weeks of splinting. Fourteen corrected lop ears had a normal appearance, and 9 were improved with minor residual deformity. There was only one complication: skin irritation requiring adjustment of the prosthesis. Five children had molding started after 3 months of age and all had no significant improvement. In addition, the parents of 5 children refused therapy and 12 children had either poor compliance to therapy or were lost to follow-up. Our experience with auricular molding confirmed that it is easy, effective, and inexpensive. If molded sufficiently early, most auricular deformations should not need surgical correction in childhood.
    Congenital fenestration of the secondary palate is the rarest type of facial cleft. Of the 26 putative cases in the literature, only 5 had confirmation of the cleft during the neonatal period. This report documents such a cleft in an... more
    Congenital fenestration of the secondary palate is the rarest type of facial cleft. Of the 26 putative cases in the literature, only 5 had confirmation of the cleft during the neonatal period. This report documents such a cleft in an infant and presents the likely pathogenesis.
    ABSTRACT PURPOSE: Capillary malformations are associated with soft-tissue hypertrophy. The purpose of this study was to determine if angiogenesis or vasculogenesis is upregulated in this overgrowth condition. METHODS: Capillary... more
    ABSTRACT PURPOSE: Capillary malformations are associated with soft-tissue hypertrophy. The purpose of this study was to determine if angiogenesis or vasculogenesis is upregulated in this overgrowth condition. METHODS: Capillary malformation specimens were collected prospectively from nine patients after resection: lip (n=6), lower extremity (n=3). The average age of the cohort was 30.3 years (range 10-49 years). Neovascularization was compared to normal control tissue. Specimens were analyzed by immunohistochemistry for CD31 (microvascular density), CD31/H3 (proliferating endothelial cells), and CD34/CD133 (endothelial progenitor cells). Quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR) was used to determine mRNA expression of progenitor cells (CD133) and factors that recruit them: vascular endothelial growth factor (VEGF-A), hypoxia-inducible factor-1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), and stromal cell–derived factor-1α (SDF-1α). Angiopoetin-1,-2 (ANG-1,-2) and VEGF receptors (VEGFR1,2 and neuropilin1,2) also were quantified using qRT-PCR. RESULTS: Microvascular density (6.2%) was greater in capillary malformations compared to normal specimens (2.8%) (p = 0.03). Endothelial proliferation was noted in capillary malformations (5.1/field), but not in normal tissue (p = 0.01). Endothelial progenitor cells were absent in both study and control tissues. ANG-2 (2.7-fold), neuropilin 1 (2.0-fold), and neuropilin 2 (3.3-fold) were increased in capillary malformations (p = 0.005), whereas VEGF-A (0.5-fold), VEGFR1 (0.8-fold), VEGFR2 (1.7-fold), ANG-1 (1.1-fold), HIF-1α (0.7-fold), MMP-9 (1.7-fold), SDF-1α (1.6-fold), and CD133 (0.4-fold) were not elevated (p = 0.6). CONCLUSIONS: Capillary malformations exhibit elevated vasculature and proliferating endothelial cells; progenitor cells are not present. Neovascularization by angiogenesis may be involved in the evolution of capillary malformations. Further investigation may enable the prevention of soft-tissue overgrowth using pharmacotherapy.
    We describe a 4-year-old boy with Crouzon syndrome, with associated acanthosis nigricans and Chiari-I malformation, who developed increased intracranial pressure necessitating posterior cranial expansion. Postoperatively, an arteriovenous... more
    We describe a 4-year-old boy with Crouzon syndrome, with associated acanthosis nigricans and Chiari-I malformation, who developed increased intracranial pressure necessitating posterior cranial expansion. Postoperatively, an arteriovenous fistula appeared over the mastoid region. Cerebral angiography demonstrated bilateral atresia of the jugular veins and occlusion of the left sigmoid and right transverse sinuses. We propose that increased intracranial venous pressure, secondary to bilateral jugular foraminal stenosis, caused hydrocephaly and venous dilation in the scalp vasculature. The latter set the stage for a traumatic arteriovenous fistula of the scalp, probably resulting from laceration of an adjacent artery and vein. Jugular atresia is a basilar malformation common to achondroplasia and certain eponymous syndromic craniosynostoses. Our patient has a mutation in fibroblast growth factor receptor 3, a different locus in the same gene mutated in achondroplasia.
    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... more
    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.
    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... more
    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 palat...
    Jugular foraminal stenosis (JFS) or atresia (JFA) with collateral emissary veins (EV) has been documented in syndromic craniosynostosis. Disruption of EV during surgery can produce massive hemorrhage. Our purpose was to describe the... more
    Jugular foraminal stenosis (JFS) or atresia (JFA) with collateral emissary veins (EV) has been documented in syndromic craniosynostosis. Disruption of EV during surgery can produce massive hemorrhage. Our purpose was to describe the prevalence of prominent basal emissary foramina (EF), which transmit enlarged EV, in syndromic craniosynostosis. Our findings were correlated with phenotypic and molecular diagnoses. We reviewed the medical records and imaging examinations of 33 patients with syndromic craniosynostosis and known fibroblast growth factor receptor (FGFR) mutations. All patients underwent CT and 14 MR imaging. The cranial base was assessed for size of occipitomastoid EF and jugular foramina (JF). Vascular imaging studies were available from 12 patients. A control group (n = 76) was used to establish normal size criteria for JF and EF. Phenotypic classification included Crouzon syndrome (n = 10), crouzonoid features with acanthosis nigricans (n = 3), Apert syndrome (n = 10),...
    In 1983, we evaluated the stability of midface position after Le Fort III advancement for midface hypoplasia secondary to Crouzon's or Apert's syndromes. The patients were operated upon from 1972 to 1980, and mean follow-up was... more
    In 1983, we evaluated the stability of midface position after Le Fort III advancement for midface hypoplasia secondary to Crouzon's or Apert's syndromes. The patients were operated upon from 1972 to 1980, and mean follow-up was 5.8 years (Kaban et al, 1984). In this study, we present an additional 3 1/2 year follow-up of these patients to look at what happens to midface position after Le Fort III osteotomy in growing and nongrowing patients.
    Verrucous venous malformation (VVM), also called "verrucous... more
    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.
    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... more
    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…
    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... more
    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...
    Hemangioma, the most common tumor of infancy, is characterized by rapid growth and slow regression. Increased mRNA expression of insulin-like growth factor 2 (IGF2) has been detected in the proliferating phase by cDNA microarray analysis,... more
    Hemangioma, the most common tumor of infancy, is characterized by rapid growth and slow regression. Increased mRNA expression of insulin-like growth factor 2 (IGF2) has been detected in the proliferating phase by cDNA microarray analysis, but the underlying mechanism causing the increase remains unknown. Here, using quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry, we show that IGF2 is highly expressed in both proliferating and involuting phase hemangioma, but is not detectable in other vascular lesions such as pyogenic granuloma, venous malformation, lymphatic malformation, or in normal infant skin. Loss of imprinting of the Igf2 gene has been associated with IGF2 overexpression in a variety of childhood tumors. To determine if loss of imprinting and consequent bi-allelic expression might contribute to the increased expression of IGF2, we examined the genomic imprinting status of Igf2 in 48 individual hemangiomas. We determined allele-specific Igf2 ex...
    Hemangioma is a benign tumor of infancy whose hallmark is rapid growth during the first year of life followed by slow regression during early childhood. The proliferating phase is characterized by abundant immature endothelial cells, the... more
    Hemangioma is a benign tumor of infancy whose hallmark is rapid growth during the first year of life followed by slow regression during early childhood. The proliferating phase is characterized by abundant immature endothelial cells, the involuting phase by prominent endothelial-lined vascular channels and endothelial apoptosis, and the involuted phase by few remaining capillary-like vessels surrounded by loose fibrofatty tissue. Nothing is known about the mechanisms that contribute to the adipogenesis during this spontaneous regression. We postulated that mesenchymal stem cells (MSCs) reside in the tumor and preferentially differentiate into adipocytes. To test this hypothesis, we isolated MSCs from 14 proliferating and five involuting hemangiomas by taking advantage of the well known selective adhesion of MSCs to bacteriologic dishes. These hemangioma-derived MSCs (Hem-MSCs) are similar to MSCs obtained from human bone marrow, expressing the cell surface markers SH2 (CD105), SH3, ...
    ABSTRACT This work presents an efficient and stable methodology for the coupling of Finite Element Methods (FEM) and Boundary Element Methods (BEM) that is independent of the particular solver and allows for independent temporal... more
    ABSTRACT This work presents an efficient and stable methodology for the coupling of Finite Element Methods (FEM) and Boundary Element Methods (BEM) that is independent of the particular solver and allows for independent temporal discretizations among solvers. The approach satisfies explicitly compatibility conditions and equilibrium of forces at the contact interfaces. Although the proposed approach has been developed in view of the soil–rail–vehicle dynamic interaction problem in High Speed Rail applications, it is expressed in a general form applicable to any multi-domain, multi-phase transient problem. The method development and formulations are presented in detail. Verification and application studies demonstrate the accuracy, efficiency and versatility of the method for the direct time domain solution of dynamic problems including structure–structure interaction and soil–structure interaction. The proposed approach demonstrates high accuracy and efficiency to that of direct coupling solutions and more rigorous methods.
    Intramuscular venous malformations are often mistaken for tumors because of a similar presentation and improper nomenclature. This is a review of 176 patients with venous malformations localized to skeletal muscle compiled from the... more
    Intramuscular venous malformations are often mistaken for tumors because of a similar presentation and improper nomenclature. This is a review of 176 patients with venous malformations localized to skeletal muscle compiled from the Vascular Anomalies Center at Children's Hospital from 1980 through 1999. The female-to-male ratio was 2:1. Two-thirds of skeletal muscle venous malformations were noted at birth; the remainder manifested in childhood and adolescence. Venous malformations occurred in every muscle group, most often in the head and neck and extremities. Pain and swelling were the usual presenting complaints. Skeletal problems, such as fracture, deformation, or growth abnormalities, were rare. Hormonal exacerbation and intralesional bleeding were infrequent. Magnetic resonance imaging showed the lesions to be isointense to surrounding muscle on T1-weighted sequences and hyperintense on T2-weighted images. Characteristic tubular or serpentine components were oriented along the muscular long axis. Thrombi were hyperintense on T1-weighted and hypointense on T2-weighted sequences; phleboliths were seen as signal voids on all sequences. Gross examination of resected specimens revealed multicolored tissue with dilated vascular channels, frequently containing phleboliths. Light microscopy showed aggregates of primarily medium-sized, thin-walled vascular channels with flat endothelium and variable smooth muscle, most closely resembling dysplastic veins. Three lesions had a different histologic appearance consisting predominantly of small vessels with capillary structure and proliferative activity admixed with large feeding and draining vessels, similar to a lesion called intramuscular capillary hemangioma in the literature. The endothelium in these three lesions was negative for glucose transporter-1 by immunostaining. Eight percent of the patients, who had minor or no symptoms, were not treated. Twenty-four percent of the patients were managed conservatively (with aspirin and compressive garments); for 17 of these patients (10 percent of 176), noninvasive therapy was not successful, and they proceeded to sclerotherapy, excision, or both. A total of 31 percent of the patients had sclerotherapy, 20 percent had excision, and 27 percent had combined sclerotherapy and excision. Sclerotherapy was used for diffuse lesions, except for those with multiple intralesional thromboses, neurologic impairment, or compressive signs and symptoms. Resection was preferred for venous malformations well localized to a single muscle or muscle group, particularly if the muscles are expendable. Therapeutic outcomes were recorded in the charts or obtained by telephone interview in 122 of the patients (69 percent). Of these, compression garment and aspirin, resection, sclerotherapy, or combined excision and sclerotherapy improved symptoms in 121 patients (92 percent); no change was noted in 10 patients (8 percent). Only one patient was worse (self-reported) after intervention.
    Vascular malformations frequently enlarge during adolescence, suggesting that hormones may be involved. The purpose of this study was to determine whether pubertal hormone receptors are present in vascular malformations and whether they... more
    Vascular malformations frequently enlarge during adolescence, suggesting that hormones may be involved. The purpose of this study was to determine whether pubertal hormone receptors are present in vascular malformations and whether they differ from normal tissue. Tissue specimens (arteriovenous malformation, lymphatic malformation, and venous malformation) were prospectively collected from patients undergoing resection. Immunohistochemistry was used to determine the presence of androgen, estrogen, progesterone, and growth hormone receptors. The effects of age, sex, location, and malformation type on receptor expression were analyzed. Age-, sex-, and location-matched normal tissues served as controls. Forty-five vascular malformation specimens were collected: arteriovenous malformation (n = 11), lymphatic malformation (n = 20), and venous malformation (n = 14). Growth hormone receptor expression was increased in arteriovenous malformation (72.7 percent), lymphatic malformation (65.0 percent), and venous malformation (57.1 percent) tissues compared with controls (25.8 percent) (p < 0.05). Growth hormone receptor was present primarily in the endothelium/perivasculature of malformations (93.1 percent), whereas in normal tissue growth hormone receptor was located only in the stroma (p < 0.0001). Neither age, nor sex, nor location influenced receptor expression (p = 0.9). No differences in androgen receptor, estrogen receptor, and progesterone receptor staining were found between malformations and control samples (p = 0.7). Growth hormone receptor is overexpressed and principally located in the vessels of vascular malformations. Growth hormone might contribute to the expansion of vascular malformations.
    Lymphedema results from maldevelopment of the lymphatic system (primary) or injury to lymphatic vasculature (secondary). Primary lymphedema is far less common than the secondary condition. The purpose of this study was to determine the... more
    Lymphedema results from maldevelopment of the lymphatic system (primary) or injury to lymphatic vasculature (secondary). Primary lymphedema is far less common than the secondary condition. The purpose of this study was to determine the clinical features of primary lymphedema in the pediatric age group. The authors' Vascular Anomalies Center database was reviewed for patients evaluated between 1999 and 2010 with onset of lymphedema before 21 years of age. Cause, sex, age of onset, location, and familial/syndromic association were determined. Morbidity, progression, and treatment were analyzed. Lymphedema was confirmed in 142 children: 138 cases (97.2 percent) were primary and four (2.8 percent) were secondary. Analysis of the primary cohort showed that 58.7 percent of the patients were female. Age of onset was infancy, 49.2 percent; childhood, 9.5 percent; or adolescence, 41.3 percent. Boys most commonly presented in infancy (68.0 percent), whereas girls usually developed swelling in adolescence (55.3 percent). Lymphedema involved an extremity (81.9 percent), genitalia (4.3 percent), or both (13.8 percent). The lower limb was most commonly affected (91.7 percent), and 52.9 percent had bilateral lower extremity disease. Eleven percent of patients had familial or syndromic lymphedema. Cellulitis occurred in 18.8 percent of children; 13.0 percent required hospitalization. The majority of patients (57.9 percent) had progression of their disease. Treatment was compression garments alone (75.4 percent) or in combination with pneumatic compression (19.6 percent); 13.0 percent had operative intervention. Pediatric primary lymphedema usually involves the lower extremities. Boys typically are affected at birth, and girls most often present during adolescence. Most patients do not have major morbidity, are successfully managed by compression, and do not require surgical treatment.
    The purpose of this study was to examine the effects of intralesional bare fiber photocoagulation with the KTP and Nd:YAG lasers on periorbital hemangiomas of infancy. Initial reports by Apfelberg and Gregory suggest that intralesional... more
    The purpose of this study was to examine the effects of intralesional bare fiber photocoagulation with the KTP and Nd:YAG lasers on periorbital hemangiomas of infancy. Initial reports by Apfelberg and Gregory suggest that intralesional laser therapy may have a role in the treatment of hemangiomas. Intralesional photocoagulation may be preferred to superficial laser treatment for several reasons. It may decrease cutaneous skin damage and more effectively reduce bulky, deep lesions. Twenty-three patients with periorbital hemangiomas were treated (KTP, n = 7; Nd:YAG, n = 16). An 18-g Angiocath was placed into the lesion to pass the fiber through. Laser energy was delivered by means of a 0.6-mm bare fiber at 10 to 15 J (KTP) or 7 J (Nd:YAG). Treatments were done under general anesthesia. Patients were followed closely for 1 month and then monthly to assess results and complications. Results are as follows: 61 percent demonstrated 50-percent or more reduction at 3 months; 22 percent demonstrated 50-percent or more reduction in 3 to 8 months, i.e., 83 percent of patients had 50-percent or more reduction within 8 months. To achieve these results, two patients required two treatments. The remaining 17 percent had 10- to 14-percent reduction at 1 to 3 months. Two of these patients had two treatments. A subgroup of patients had a very dramatic response. Thirty-five percent (8 of 23) had 50- to 90-percent reduction in 1 month. It is unclear why these patients responded so dramatically. We expected some ulceration during the healing phase. Seventeen percent developed ulceration. Complications were limited (4 percent) to one wound infection. Intralesional photocoagulation treatment with the KTP and Nd:YAG lasers is effective and safe for the treatment of periorbital hemangiomas in the majority of patients with minimal complications. Further study is necessary to identify factors that result in dramatic or limited responses.
    The... more
    The authors' purpose was to document speech outcome after cleft palate repair in patients with syndromic versus nonsyndromic Robin sequence. Results of secondary correction of velopharyngeal insufficiency using a superiorly based pharyngeal flap or double-opposing Z-palatoplasty are also reported. Charts of patients with Robin sequence and cleft palate between 1980 and 2007 were reviewed. Data collected included date of birth, sex, syndrome/association, cleft palatal type (Veau I or II), age at palatoplasty, incidence of palatal fistula, postoperative speech assessment, videofluoroscopic results, need for secondary operation for velopharyngeal insufficiency, and type of secondary operation (pharyngeal flap or double-opposing Z-palatoplasty). The authors identified 140 patients with Robin sequence who had palatal closure. Postoperative speech evaluation was available for 96 patients (69 percent). A syndrome or association was identified in 42 patients (30 percent). Primary palatoplasty was successful in 74 patients (77 percent); speech was characterized as competent and competent to borderline competent. The authors found a significantly higher incidence of velopharyngeal insufficiency following palatal repair for syndromic (38 percent) than nonsyndromic Robin sequence (16 percent). (p = 0.039). In patients with velopharyngeal insufficiency, competent or borderline competent speech was determined after double-opposing Z-palatoplasty (two of five patients) or pharyngeal flap (eight of 10 patients). The rate of velopharyngeal insufficiency in syndromic Robin sequence is significantly greater than in nonsyndromic Robin sequence. The authors prefer pharyngeal flap for velopharyngeal insufficiency in patients with Robin sequence, whether syndromic or nonsyndromic, without retrognathism or signs/symptoms of obstructive sleep apnea.
    Morbidity following 104 bone graft harvesting operations (60 iliac, 44 rib) in 72 patients is documented. Early morbidity of iliac donor sites was found, as expected, to be far greater than that of rib donor sites. However, long-term... more
    Morbidity following 104 bone graft harvesting operations (60 iliac, 44 rib) in 72 patients is documented. Early morbidity of iliac donor sites was found, as expected, to be far greater than that of rib donor sites. However, long-term follow-up reveals that while hip symptoms largely resolve, a significant number of chest-wall sites cause persistent, unpleasant pain. Technical ways of minimizing problems are also discussed. When procuring an iliac graft, a lateral skin incision and a medial bony approach are used if possible. If full-thickness ilium is required, the crest should be left intact or raised and replaced as a trapdoor .
    A case is presented in which congestive heart failure and thrombocytopenia were complications of an inoperable hemangioma in a neonate. Selective embolization of the hemangioma in the patient achieved significant diminution in the... more
    A case is presented in which congestive heart failure and thrombocytopenia were complications of an inoperable hemangioma in a neonate. Selective embolization of the hemangioma in the patient achieved significant diminution in the congestive failure and tided this infant through the first few days of life while awaiting positive effects from the steroids and external compression. The combined treatment modalities of selective embolization, external compression, and short course of low-dose systemic steroids resulted in a rapid and complete resolution of this life-threatening problem.
    This is a retrospective review of our experience with microvascular transfer of scapular and parascapular flaps for the correction of lateral facial contour deficiencies. Twenty-eight patients with congenital (n = 8) and acquired (n = 20)... more
    This is a retrospective review of our experience with microvascular transfer of scapular and parascapular flaps for the correction of lateral facial contour deficiencies. Twenty-eight patients with congenital (n = 8) and acquired (n = 20) defects were treated with 30 flaps; two patients had bilateral flaps. The etiology of the defects included hemifacial microsomia (n = 2), oblique facial cleft (n = 1), Romberg's hemifacial atrophy (n = 5), neoplasm (n = 4), irradiation (n = 8), trauma (n = 4), tumor excision (n = 4), facial lipodystrophy (n = 2), and silicone granuloma (n = 2). The follow-up evaluation was from 2 to 13 years, with an average of 6 years. Fabrication of a facial moulage was part of the preoperative planning for each patient. These were compound flaps, including skin, deepithelialized skin, fat, fascia, and bone, if necessary. All flaps were constructed with an intact skin paddle for postoperative monitoring. Based on dissections and anatomic findings at operation, several variations in the level of emergence of the circumflex scapular artery from the triangular space and its branching patterns were noted. All flaps survived; changes in the patients' weights were reflected in the flaps. Twelve patients required secondary procedures: excision of skin monitor islands, scar revisions, debulking, or flap resuspension to the malar region. Bone grafts or alloplastic implants were necessary in four patients in whom the malar eminence could not be adequately corrected by transfer of a flap. The deepithelialized scapular/parascapular flap is preferred for correction of large lateral facial defects.
    Five hundred and eighty birthmarks were reviewed; 356 were hemangiomas and 224 were malformations. Bony alterations occurred in association with only 1 percent of hemangiomas, in contrast with 34 percent of patients with vascular... more
    Five hundred and eighty birthmarks were reviewed; 356 were hemangiomas and 224 were malformations. Bony alterations occurred in association with only 1 percent of hemangiomas, in contrast with 34 percent of patients with vascular malformations. These alterations in bone development were classified according to size, shape, and density changes. Hypertrophy and distortion were typical of lymphatic malformations. Hypoplasia and demineralization were characteristic findings in the extremity venous malformations. Destructive and intraosseous changes were more commonly noted in the arterial or high-flow lesions. Possible mechanisms of altered skeletal growth include mechanical, physiological, and developmental processes.
    Matrix metalloproteinases (MMPs) and the angiogenic proteins basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have been implicated in mechanisms of human cancer and metastasis. Assays were conducted on... more
    Matrix metalloproteinases (MMPs) and the angiogenic proteins basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have been implicated in mechanisms of human cancer and metastasis. Assays were conducted on the urine of patients with vascular anomalies (tumors and malformations), relatively common and occasionally life-threatening disorders for which few therapies exist. We sought to determine whether these angiogenesis modulators are present in the urine and whether their expression is associated with the extent and clinical course of the vascular lesion. A total of 217 patients with vascular anomalies and 74 age-matched control subjects participated. Urinary MMP expression was determined by substrate gel electrophoresis. Urinary bFGF and VEGF levels were measured by enzyme-linked immunosorbent assay. Each patient was assigned to 1 of 2 categories (tumor or malformation) and 1 of 9 specific groups. Extent of the vascular lesion and activity were scored by a blinded clinician. Urinary high molecular weight (hMW) MMPs and bFGF were significantly increased in patients with vascular tumors (53%) and vascular malformations (41%), compared with control subjects (22%). These percentages increased as a function of extent of the lesion and disease activity. hMW MMPs were increased in 4 groups: infantile hemangioma, other vascular neoplasms, lymphatic malformation and capillary-lymphaticovenous malformations, and extensive and unremitting capillary malformation and arteriovenous malformation. No significant differences among the groups were detected for low molecular weight MMPs or VEGF. Expression patterns of hMW MMPs and bFGF in the urine of patients with tumors and malformations are consistent with their different clinical behavior. These data represent the first evidence that MMPs are elevated in the urine of children with vascular anomalies. These data also suggest that the increased expression of urinary MMPs parallels the extent and activity of vascular anomalies in children. In addition to tumors, vascular malformations are angiogenesis dependent, suggesting that progression of a vascular malformation might be suppressed by angiogenic inhibitors, which would target bFGF and MMPs.
    We describe a 4-year-old boy with Crouzon syndrome, with associated acanthosis nigricans and Chiari-I malformation, who developed increased intracranial pressure necessitating posterior cranial expansion. Postoperatively, an arteriovenous... more
    We describe a 4-year-old boy with Crouzon syndrome, with associated acanthosis nigricans and Chiari-I malformation, who developed increased intracranial pressure necessitating posterior cranial expansion. Postoperatively, an arteriovenous fistula appeared over the mastoid region. Cerebral angiography demonstrated bilateral atresia of the jugular veins and occlusion of the left sigmoid and right transverse sinuses. We propose that increased intracranial venous pressure, secondary to bilateral jugular foraminal stenosis, caused hydrocephaly and venous dilation in the scalp vasculature. The latter set the stage for a traumatic arteriovenous fistula of the scalp, probably resulting from laceration of an adjacent artery and vein. Jugular atresia is a basilar malformation common to achondroplasia and certain eponymous syndromic craniosynostoses. Our patient has a mutation in fibroblast growth factor receptor 3, a different locus in the same gene mutated in achondroplasia.
    Lymphatic malformations (LMs) can be effectively treated by percutaneous intralesional injection of a variety of sclerosant drugs. This study aims to evaluate the efficacy of doxycycline in the treatment of LMs. We reviewed the medical... more
    Lymphatic malformations (LMs) can be effectively treated by percutaneous intralesional injection of a variety of sclerosant drugs. This study aims to evaluate the efficacy of doxycycline in the treatment of LMs. We reviewed the medical records of all patients with LMs who underwent sclerotherapy with doxycycline between January 1, 2003 and September 1, 2004 at Children's Hospital Boston. Follow-up imaging was performed to assess for change in lesion size. Surveys were sent to all study patients, to assess perceived improvements in symptoms and satisfaction with the results. Sixty sclerotherapy procedures were performed on 41 patients in the 20-month study period. The median age was 6.9 years (3 mo-31 y). The most common location was cervicofacial (66%), followed by truncal (19%) and extremity (15%). The most common lesion type was macrocystic (49%), followed by combined (44%) and microcystic (7%). The major and minor complication rates were 2% and 10%, respectively. The mean outcome score by imaging was 4.41/5 with a 95% CI of [4.13-4.68] corresponding to about an 83% reduction in lesion size, and by patient survey was 4.47/5 with a 95% CI of [4.15-4.79] corresponding to between a good to complete response. Higher complication rates were associated with microcystic and combined lesions (p = 0.03), and greater doxycycline dose (p = 0.05). Doxycycline is a safe and effective sclerosant for LMs. Greater follow-up is necessary to quantify long-term outcomes and assess the risks of lesion recurrence.
    A 5-day-old male neonate was referred to our vascular anomalies center with a large cystic submandibular mass. History and physical examination and ultrasonographic results indicated the diagnosis to be macrocystic lymphatic malformation.... more
    A 5-day-old male neonate was referred to our vascular anomalies center with a large cystic submandibular mass. History and physical examination and ultrasonographic results indicated the diagnosis to be macrocystic lymphatic malformation. Consequently, the child was treated with sclerotherapy and subtotal excision. The histopathological examination result showed that the lesion was infantile myofibroma. This diagnostic error was attributed to atypical features of infantile myofibroma in this child: unusually large cysts, rapid enlargement, and coagulopathy. This report expands the clinical spectrum of infantile myofibromatosis and suggests its consideration in the differential diagnosis of neonatal cystic cervicofacial lesions.
    Particulate bone graft (PBG) heals calvarial critical-size defects and is procured from the cranium with a hand-driven bit and brace. The donor sites ossify, and thus PBG potentially could be reharvested from the original areas. The... more
    Particulate bone graft (PBG) heals calvarial critical-size defects and is procured from the cranium with a hand-driven bit and brace. The donor sites ossify, and thus PBG potentially could be reharvested from the original areas. The purpose of this study was to determine if PBG obtained from a healed donor site is effective for inlay cranioplasty. A 17 × 17-mm critical-size defect was created in the parietal bones of 8 rabbits and treated with either no implant (group 1) or PBG harvested from the frontal bone (group 2). In 4 animals (group 3), a parietal defect was not created initially; PBG was harvested from the frontal bone and then discarded. Sixteen weeks later after the PBG donor sites had healed, a 17 × 17-mm parietal defect was made and filled with PBG reharvested from the previous donor area. Animals underwent micro-computed tomography 16 weeks after inlay cranioplasty. Critical-size defects in controls (group 1) exhibited partial ossification (35.1% ± 10.5%) compared with those treated with PBG (group 2) (99.1% ± 1.5%) or reharvested PBG (group 3) (99.3% ± 1.5%) (P = 0.02). No difference was found between groups 2 and 3 (P = 0.69). Bony thickness was similar in defects implanted with PBG (1.8 mm ± 1.1 mm) or reharvested PBG (2.1 mm ± 0.5 mm) (P = 0.68). Particulate bone graft reharvested from healed donor sites ossifies inlay cranial defects. Because the donor area for PBG is of partial thickness and less than critical size, reparative osteogenesis theoretically allows an unlimited supply of autologous bone for inlay cranioplasty using PBG.
    Frontoorbital advancement (FOA) improves forehead and superior orbital asymmetry associated with unilateral coronal synostosis but has little effect on facial asymmetry. This study compares frontofacial symmetry after FOA and... more
    Frontoorbital advancement (FOA) improves forehead and superior orbital asymmetry associated with unilateral coronal synostosis but has little effect on facial asymmetry. This study compares frontofacial symmetry after FOA and endoscopically assisted suturectomy (ESC) and postoperative helmet therapy.A retrospective review of 2 cohorts of patients with nonsyndromic unilateral coronal synostosis who had either FOA or ESC was undertaken. Choice of procedure was determined by age of patient at referral (younger than 4 months, FOA or ESC; older than 4 months, only FOA). Vectra 3D imaging system (Canfield Imaging Systems, Fairfield, NJ) was used to capture and analyze three-dimensional digital images. Comparative anthropometric measurements were made and statistically analyzed.Twenty-two patients met the inclusion criteria; 11 underwent ESC at mean age of 2 months (range, 1-4 months) and 11 underwent FOA at mean age of 12 months (range, 8-25 months). Mean age at three-dimensional digital imaging was 45.9 months (range, 18-64 months) for the FOA group and 34.5 months (range, 20-66 months) for the ESC group (P = 0.054).There was no difference between the 2 groups with regard to supraorbital symmetry (P = 0.54). The ESC group exhibited better facial symmetry in midline deviation (3.6° vs 1.4°; P = 0.018), nasal tip deviation (5.6° vs 2.3°; P = 0.006), and middle facial depth (6.9 vs 4.4 mm; P = 0.042). Lower facial depth was similar (3.8 vs 2.3 mm; P = 0.54).Early ESC and helmet therapy results in comparable brow symmetry and better overall facial symmetry than FOA done in late infancy.
    Infantile hemangioma is a benign endothelial tumor composed of disorganized blood vessels. It exhibits a unique life cycle of rapid postnatal growth followed by slow regression to a fibrofatty residuum. Here, we have reported the... more
    Infantile hemangioma is a benign endothelial tumor composed of disorganized blood vessels. It exhibits a unique life cycle of rapid postnatal growth followed by slow regression to a fibrofatty residuum. Here, we have reported the isolation of multipotential stem cells from hemangioma tissue that give rise to hemangioma-like lesions in immunodeficient mice. Cells were isolated based on expression of the stem cell marker CD133 and expanded from single cells as clonal populations. The CD133-selected cells generated human blood vessels 7 days after implantation in immunodeficient mice. Cell retrieval experiments showed the cells could again form vessels when transplanted into secondary recipients. The human vessels expressed GLUT-1 and merosin, immunodiagnostic markers for infantile hemangioma. Two months after implantation, the number of blood vessels diminished and human adipocytes became evident. Lentiviral expression of GFP was used to confirm that the hemangioma-derived cells formed the blood vessels and adipocytes in the immunodeficient mice. Thus, when transplanted into immunodeficient mice, hemangioma-derived cells recapitulated the unique evolution of infantile hemangioma--the formation of blood vessels followed by involution to fatty tissue. In summary, this study identifies a stem cell as the cellular origin of infantile hemangioma and describes for what we believe is the first time an animal model for this common tumor of infancy.
    Children with unoperated cleft lip/palate have nearly normal facial growth, whereas patients who have had labiopalatal repair often exhibit midfacial retrusion. The aim of this study was to compare cephalometric data in patients with... more
    Children with unoperated cleft lip/palate have nearly normal facial growth, whereas patients who have had labiopalatal repair often exhibit midfacial retrusion. The aim of this study was to compare cephalometric data in patients with repaired unilateral or bilateral complete cleft lip/alveolus (UCCLA or BCCLA) with patients with repaired unilateral or bilateral complete cleft lip/palate (UCCLP or BCCLP). This study might provide insight into the etiology of impaired facial growth in patients with repaired cleft lip/palate.

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