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Biomedical subjects

John B Mulliken

Publications and source records attributed to John B Mulliken.

At least 19 recordsLinked to original sources
PubMed2007

Hepatic hemangiomas: subtype classification and development of a clinical practice algorithm and registry.

PURPOSE: Hepatic hemangiomas, though histologically benign, may be associated with significant morbidity and mortality in afflicted infants. The literature presents much confusion regarding the natural history and treatment options for hepatic hemangiomas. Clinical manifestations range from asymptomatic self-limiting lesions to congestive heart failure associated with high-volume vascular shunting to fulminant hepatic failure with hypothyroidism, abdominal compartment syndrome, and death. There has been little rationale to choose among observation, corticosteroid, other pharmacologic agents, arterial embolization, hepatic artery ligation, resection, or liver transplantation for any given patient. METHODS: We analyzed several recent retrospective radiologic analyses and pathologic studies to determine whether hepatic hemangiomas could be categorized, allowing prediction of their natural history and rational choice of therapies based upon their clinical presentation and radiographic appearance. RESULTS: We propose that hepatic hemangiomas do not represent a single entity but, rather, 3 principle categories of lesions: focal, multifocal, and diffuse. Because these 2 categories represent different anatomical and physiologic variants, so, too, may they respond differently to previously anecdotally applied treatment regimens. With input from international multidisciplinary authorities on hemangiomas, we developed and proposed a clinical practice algorithm for the evaluation and management of hepatic hemangiomas. Toward that end, we propose a plan to institute a web-based international hepatic hemangioma registry. Participants in the registry could obtain no-cost centralized review of imaging studies (and histology if available) and guidance regarding the management algorithm from an established multidisciplinary team. In exchange, the registry will facilitate the acquisition of systematic clinical and imaging information. CONCLUSION: Longitudinal observation of response to more directed treatment protocols may contribute greatly to the understanding of these potentially fatal tumors.

Algorithms↗
PubMed2007

Zygomaticotemporal synostosis: a rare cause of progressive facial asymmetry.

Cranial synostosis is relatively common; however, premature closure of a facial suture is remarkably rare. We describe an adolescent male with zygomaticotemporal synostosis that manifested as progressive midfacial and orbital asymmetry, angulation of the cranial base, and nasal deviation. To our knowledge, this is the first description of this anomaly in the literature.

Child↗
PubMed2006

Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin.

Infantile hemangiomas are composed of endothelial cells (ECs), endothelial progenitor cells (EPCs), as well as perivascular and hematopoietic cells. Our hypothesis is that hemangioma-derived EPCs (HemEPCs) differentiate into the mature ECs that comprise the major compartment of the tumor. To test this, we isolated EPCs (CD133(+)/Ulex europeus- I(+)) and mature ECs (CD133(-)/Ulex europeus-I(+)) from proliferating hemangiomas and used a previously described property of hemangioma-derived ECs (HemECs), enhanced migratory activity in response to the angiogenesis inhibitor endostatin, to determine if HemEPCs share this abnormal behavior. Umbilical cord blood-derived EPCs (cbEPCs) were analyzed in parallel as a normal control. Our results show that HemEPCs, HemECs, and cbEPCs exhibit increased adhesion, migration, and proliferation in response to endostatin. This angiogenic response to endostatin was consistently expressed by HemEPCs over several weeks in culture, whereas HemECs and cbEPCs shifted toward the mature endothelial response to endostatin. Similar mRNA-expression patterns among HemEPCs, HemECs, and cbEPCs, revealed by microarray analyses, provided further indication of an EPC phenotype. This is the first demonstration that human EPCs, isolated from blood or from a proliferating hemangioma, are stimulated by an angiogenesis inhibitor. These findings suggest that EPCs respond differently from mature ECs when exposed to angiogenic or antiangiogenic signals.

Angiogenesis Inhibitors↗
PubMed2006

The origin of EFNB1 mutations in craniofrontonasal syndrome: frequent somatic mosaicism and explanation of the paucity of carrier males.

Craniofrontonasal syndrome (CFNS) is an X-linked disorder that exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis, and additional minor malformations, but males are usually mildly affected with hypertelorism only. Despite this, males appear underrepresented in CFNS pedigrees, with carrier males encountered infrequently compared with affected females. To investigate these unusual genetic features of CFNS, we exploited the recent discovery of causative mutations in the EFNB1 gene, which encodes ephrin-B1, to survey the molecular alterations in 59 families (39 newly investigated and 20 published elsewhere). We identified the first complete deletions of EFNB1, catalogued 27 novel intragenic mutations, and used Pyrosequencing and analysis of nearby polymorphic alleles to quantify mosaic cases and to determine the parental origin of verified germline mutations. Somatic mosaicism was demonstrated in 6 of 53 informative families, and, of 17 germline mutations in individuals for whom the parental origin of mutation could be demonstrated, 15 arose from the father. We conclude that the major factor accounting for the relative scarcity of carrier males is the bias toward mutations in the paternal germline (which present as affected female offspring) combined with reduced reproductive fitness in affected females. Postzygotic mutations also contribute to the female preponderance, whereas true nonpenetrance in males who are hemizygous for an EFNB1 mutation appears unusual. These results highlight the importance of considering possible origins of mutation in the counseling of families with CFNS and provide a generally applicable approach to the combined analysis of mosaic and germline mutations.

Craniofacial Abnormalities↗
PubMed2006

Expanding the phenotype of craniofrontonasal syndrome: two unrelated boys with EFNB1 mutations and congenital diaphragmatic hernia.

Craniofrontonasal syndrome (CFNS, MIM 304110) is an X-linked craniofacial disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Mutations have been identified in the EFNB1 gene that encodes a member of the ephrin-B family of transmembrane ligands for Eph receptor tyrosine kinases. Here, we describe two unrelated families, in both of which a mother and her son have proven mutations in EFNB1. The mothers have classical features of CFNS; although the sons have no major craniofacial features other than telecanthus, both had a congenital diaphragmatic hernia (CDH). Our cases represent the first in which CDH has been confirmed in males with mutations in EFNB1, highlighting an important role for signalling by ephrin-B1 in the development of the diaphragm.

Abnormalities, Multiple↗
PubMed2006

Mesenchymal stem cells and adipogenesis in hemangioma involution.

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, SH4, CD90, CD29, smooth muscle alpha-actin, and CD133 but not the hematopoietic markers CD45 and CD14 or the hematopoietic/endothelial markers CD34, CD31, and kinase insert domain receptor (KDR). Hem-MSCs exhibited multilineage differentiation with robust adipogenic potential that correlated with the proliferating phase. The numbers of adipogenic Hem-MSCs were higher in proliferating-phase than in involuting-phase tumors and higher than in normal infantile skin. Furthermore, Hem-MSCs exhibited a random pattern of X-chromosomal inactivation, indicating that these cells are not clonally derived. In summary, we have identified MSCs as a novel cellular constituent in infantile hemangioma. These MSCs may contribute to the adipogenesis during hemangioma involution.

Adipogenesis↗
PubMed2006

Robin sequence: a retrospective review of 115 patients.

OBJECTIVES: Review a large series of patients with Robin sequence to document the incidence of (1) associated syndromic diagnoses; (2) co-morbid conditions; (3) frequency and type of operative management for airway compromise and feeding difficulties; and (4) possible differences in treatment between syndromic and nonsyndromic infants. METHODS: Retrospective case-review of 115 patients with Robin sequence managed between 1962 and 2002 at two tertiary-care teaching hospitals for evaluation of demographic information, clinical findings, and treatment interventions. RESULTS: Fifty-four percent (N=63) of patients were nonsyndromic. Syndromic patients included: Stickler syndrome (18%), velocardiofacial syndrome (7%), Treacher-Collins (5%), facial and hemifacial microsomia (3%), and other defined (3.5%) and undefined (9%) disorders. There was no statistical difference between the syndromic and nonsyndromic patients with regard to need for operative airway management (Fisher's exact test, p=0.264). Forty-two percent of patients required a feeding gastrostomy tube to correct feeding difficulties. Patients with a syndromic diagnosis were more likely to be developmentally delayed. Fifty-one (44%) patients underwent operative airway management: 61% underwent tongue-lip adhesion and 39% underwent tracheotomy. Fifteen percent of patients initially had tongue-lip adhesion subsequently required tracheotomy. While the preferred treatment for respiratory compromise differed between the two institutions, the percentage of patients requiring operative intervention was similar. CONCLUSIONS: The pathogenesis of Robin sequence is multifactorial and syndromic in nearly half of the patients. Operative treatment of respiratory failure was required in 44% of infants; the rate was similar in both hospitals. The operative approach differed significantly between the institutions, however, based on the philosophy and training of the managing surgical specialty. Co-morbid factors such as baseline cardiopulmonary and neurologic status did not play a significant role in surgical decision making.

Airway Obstruction↗
PubMed2006

Radiofrequency ablation of microcystic lymphatic malformation in the oral cavity.

OBJECTIVE: To determine the efficacy and safety of radiofrequency (RF) ablation of vesicles and the resulting symptomatic control of microcystic lymphatic malformation (LM) in the oral cavity. DESIGN: An institutional review board-approved retrospective study with follow-up telephone interview. SETTING: Tertiary pediatric medical center. Patients Eleven children (6 girls and 5 boys), aged 4 to 16 years, presenting between August 1, 2002, and December 1, 2004. Intervention Radiofrequency ablation of LM in the oral cavity. MAIN OUTCOME MEASURES: Symptoms related to LM, postoperative oral intake, and postoperative antibiotic requirements. RESULTS: Eleven patients presented with microcystic LM involving the lips, tongue, floor of the mouth, or buccal mucosa. Complaints included bleeding, infection, swelling, vesicle formation, and malocclusion. Patients underwent RF ablation (coblation) of oral cavity lesions. Seven (64%) of the 11 patients were able to tolerate oral intake in the recovery room. The need for antibiotics was reduced after RF ablation. All patients related diminished bleeding, pain, infection, or vesicle formation, with more than half reporting a significant improvement (6 patients) or complete resolution (1 patient). Five (62%) of 8 parents stated that the improvement after RF ablation was superior to that following previous procedures. CONCLUSIONS: Subtotal RF ablation of LM appears to be safe, with early postoperative oral intake and minimal postoperative pain. Further studies are needed to determine long-term control of LM.

Adolescent↗
PubMed2006

Apert syndrome: what prenatal radiographic findings should prompt its consideration?

Apert syndrome was diagnosed in a newborn with typical facial and digital features whose only detected prenatal abnormality had been agenesis of the corpus callosum. This prompted a review of the central nervous system findings in all cases of Apert syndrome treated at the Craniofacial Center Boston Children's Hospital between 1978 and 2004. Two of 30 patients with Apert syndrome had prenatal identification of mild dilatation of the lateral cerebral ventricles and complete agenesis of the corpus callosum (ACC) documented with both ultrasound and MRI. Both had the common S252W mutation of FGFR2. Though cranial and orbital malformations typical of Apert were eventually seen in these fetuses in the third-trimester, even in retrospect, these were not detectable at mid second-trimester, ultrasound screening for congenital malformations. Hand malformations also went undetected in the second-trimester despite extensive imaging by experienced radiologists. We conclude that prenatal ultrasonographic identification of mild ventriculomegaly or ACC should stimulate a careful search for features of Apert syndrome and prompt follow-up imaging to look for bony abnormalities that have later onset. Prenatal molecular testing for Apert mutations should be considered in cases of mild ventriculomegaly and ACC.

Acrocephalosyndactylia↗
PubMed2006

Combined push-pull distraction for correction of syndromic midfacial hypoplasia.

PURPOSE: Gradual midfacial advancement, applying the principle of distraction osteogenesis, reduces the restriction of the soft tissues and results in bony consolidation without need for grafting. The midface can be distracted by either pushing it forward, using semiburied devices, or pulling it forward by a rigid external device. For each method there are inherent technical problems, such as controlling the vector of movement, symmetry of advancement, and differential movement of the upper/lower face. We have used a combination of the 2 methods, called "push-pull," in an effort to control the distraction process. The purpose of this paper is to describe our push-pull distraction technique and summarize our early experience. MATERIALS AND METHODS: Ten patients (5 males and 5 females) with a mean age of 11 years 2 months underwent midfacial advancement using push-pull distraction. Two orthodontists, blinded for landmark identification, traced preoperative and postoperative cephalograms and determined linear and angular measurements of midfacial position. A Student t test was used to assess differences between the cephalometric measures on the 2 radiographs. Interexaminer reliability was calculated by an intraclass correlation coefficient. RESULTS: Postdistraction cephalograms were taken a mean of 10 months (range, 3 to 20 months) after removal of the devices. Patients exhibited improvement at all levels of the midface after distraction. There was a statistically significant sagittal advancement from the infraorbital rim to dentoalveolus. The central midface was sufficiently advanced as shown by an improved convexity, nasolabial angle, and upper labial protrusion. There were no significant differences between examiners for any of the measurements in this study. CONCLUSIONS: Push-pull distraction permits 1) equal movement at both the upper and lower facial levels, 2) advancement of the central midface, and 3) symmetric movement of the zygomaticomaxillary complexes. This method also provides a backup, in case one device malfunctions. In combination, the advantages of each device are additive; whereas the weaknesses are not. The push-pull technique is a practical method for midfacial distraction until a better single device is fabricated.

Acrocephalosyndactylia↗
PubMed2006

Prevention of temporal depression that follows fronto-orbital advancement for craniosynostosis.

Contour abnormalities presenting after fronto-orbital advancement for craniosynostosis are common. Often there is bilateral temporal depression, the result of leaving a coronal bony gap posterior to the advanced segments. The authors present techniques to prevent this temporal depression by utilizing full-thickness bone grafts for structural support in the inferior coronal defects, and cortico-cancellous graft in the remaining superior coronal and parietal donor defects. Prior to contouring and repositioning the frontal elements, a hand-driven Hudson brace and D'Ericco bit is used to harvest cortico-cancellous bone "mush" from the endo- and ectocortical surfaces. The bandeau and frontal elements are advanced and secured, and the resultant coronal gap is measured. Full-thickness cranial bone grafts are harvested from the parietal regions (near the vertex) and secured in the coronal defect behind the frontal elements. The temporalis muscle is rotated, advanced, and secured to the bandeau. Bone mush is used to fill the remaining superior coronal and donor site defects. Representative case examples are presented.

Bone Transplantation↗
PubMed2006

Mutational screening of FGFR1, CER1, and CDON in a large cohort of trigonocephalic patients.

OBJECTIVE: Screen the known craniosynostotic related gene, FGFR1 (exon 7), and two new identified potential candidates, CER1 and CDON, in patients with syndromic and nonsyndromic metopic craniosynostosis to determine if they might be causative genes. DESIGN: Using single-strand conformational polymorphisms (SSCPs), denaturing high-performance liquid chromatography, and/or direct sequencing, we analyzed a total of 81 patients for FGFR1 (exon 7), 70 for CER1, and 44 for CDON. PATIENTS: Patients were ascertained in the Centro de Estudos do Genoma Humano in São Paulo, Brazil (n = 39), the Craniofacial Unit, Oxford, U.K. (n = 23), and the Johns Hopkins University, Baltimore, Maryland (n = 31). Clinical inclusion criteria included a triangular head and/or forehead, with or without a metopic ridge, and a radiographic documentation of metopic synostosis. Both syndromic and nonsyndromic patients were studied. RESULTS: No sequence alterations were found for FGFR1 (exon 7). Different patterns of SSCP migration for CER1 compatible with the segregation of single nucleotide polymorphisms reported in the region were identified. Seventeen sequence alterations were detected in the coding region of CDON, seven of which are new, but segregation analysis in parents and homology studies did not indicate a pathological role. CONCLUSIONS: FGFR1 (exon 7), CER1, and CDON are not related to trigonocephaly in our sample and should not be considered as causative genes for metopic synostosis. Screening of FGFR1 (exon 7) for diagnostic purposes should not be performed in trigonocephalic patients.

Cell Adhesion Molecules↗
PubMed2006

Congenital fenestration of the palate: A case of embryologic syzygy.

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.

Cleft Palate↗
PubMed2005

Evidence by molecular profiling for a placental origin of infantile hemangioma.

The origin of the pathogenic endothelial cells in common infantile hemangioma is unknown. We show here that the transcriptomes of human placenta and infantile hemangioma are sufficiently similar to suggest a placental origin for this tumor, expanding on recent immunophenotypical studies that have suggested this possibility [North, P. E., et al. (2001) Arch. Dermatol. 137, 559-570]. The transcriptomes of placenta, hemangioma, and eight normal and diseased tissues were compared by hierarchical and nonhierarchical clustering analysis of >7,800 genes. We found that the level of transcriptome similarity between placenta and hemangioma exceeded that of any other tissue compared and paralleled that observed between a given tissue and its derived tumor, such as normal and cancerous lung. The degree of similarity was even greater when a subset of endothelial cell-specific genes was analyzed. Genes preferentially expressed in both placenta and hemangiomas were identified, including 17-beta hydroxysteroid dehydrogenase type 2 and tissue factor pathway inhibitor 2. These data demonstrate the value of global molecular profiling of tissues as a tool for hypothesis-driven research. Furthermore, it suggests that the unique self-limited growth of infantile hemangioma may, in fact, mirror the lifetime of placental endothelium.

17-Hydroxysteroid Dehydrogenases↗
PubMed2005

Variation in IRF6 contributes to nonsyndromic cleft lip and palate.

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common craniofacial birth defect which results in lifelong medical and social consequences. While there have been a number of attempts to identify the genes responsible for this disorder, the results have not been consistent among populations and no single gene has been identified as playing a major susceptibility role. Van der Woude syndrome, a disorder characterized by lower-lip pits with or without cleft lip/palate, results in many cases from mutations in the interferon regulatory factor 6 (IRF6) gene. Recently, Zucchero et al. [2004: N Engl J Med 351:769-780] detected an association between SNPs in IRF6 and NSCLP in a number of different populations. A subsequent study by Scapoli et al. [2005: Am J Hum Genet 76:180-183] confirmed this association in an Italian population. We examined the same SNPs as Scapoli et al. [2005] in our large, well-characterized sample of NSCLP families and trios, and also detected an altered transmission of IRF6 alleles. This additional confirmation further strengthens the IRF6 association and suggests that IRF6 plays a role in NSCLP susceptibility.

Alleles↗
PubMed2005

Cutaneovisceral angiomatosis with thrombocytopenia.

We describe 10 children with multiple vascular lesions of the skin and gastrointestinal tract associated with sustained, minor thrombocytopenia. In some children, there was involvement of the lung (n = 5), bone (n = 2), liver (n = 1), spleen (n = 1), and muscle (n = 1). The cutaneous lesions were congenital, multifocal, discrete, red-brown and variably blue macules and papules; in 3 children, a large dominant plaque was also present. All children developed hematemesis and/or melena and endoscopic evaluation revealed several to numerous small mucosal lesions that involved all levels of the gastrointestinal tract. Three of 5 children with pulmonary nodules had cough and 1 also had hemoptysis. Biopsies of cutaneous, gastrointestinal, and pulmonary lesions showed thin-walled, blood-filled vascular channels and variable endothelial hyperplasia. The endothelial nuclei were elongated, round, crescentic, or hobnailed. Cytoplasmic and extracellular periodic acid-Schiff positive deposits were often present in the zones of endothelial hyperplasia. The platelets were small in some children, suggesting a primary defect, possibly accounting for the thrombocytopenia. Gastrointestinal hemorrhage and hemoptysis required antiangiogenic therapy. The constellation of findings defines a congenital proliferative disorder of blood vessels with a distinctive microscopic appearance. We have termed this relatively indolent or slowly progressive disorder cutaneovisceral angiomatosis with thrombocytopenia because this designation incorporates its major clinical and histopathologic features.

Angiogenesis Inhibitors↗
PubMed2005

Expression of Wilms tumor 1 gene distinguishes vascular malformations from proliferative endothelial lesions.

BACKGROUND: Vascular malformations and hemangiomas, which are endothelial lesions of childhood, may result in considerable morbidity because they can cause discomfort and functional impairment and have a negative affect on the patient's appearance. Although vascular malformations may initially appear very similar to hemangiomas, they have distinct clinical courses. Infantile hemangiomas progress through 3 stages: proliferative, involuting, and involuted. The proliferative phase is characterized by clinical growth. Once hemangiomas reach their maximum size, they begin to regress or involute. Histologically, this stage is characterized by endothelial apoptosis. Finally, the involuted stage of the hemangioma occurs when the original lesion is replaced by a connective tissue remnant. In contrast to hemangiomas, vascular malformations do not involute but continue to enlarge as the patient grows. OBSERVATIONS: The biochemical differences between hemangiomas, which involute, and vascular malformations, which do not involute, are not well understood. We found that the transcription factor encoded by the Wilms tumor 1 (WT1) gene is expressed in the endothelium of hemangiomas but not in vascular malformations. CONCLUSIONS: Defects in WT1 signaling may underlie the inability of malformation endothelial cells to undergo physiologic apoptosis and remodeling. The availability of WT1 staining in hospital laboratories may allow the clinician to distinguish hemangiomas from vascular malformations and thus to give appropriate therapy to the patient.

Apoptosis↗