Propranolol targets the contractility of infantile haemangioma-derived pericytes.

BACKGROUND: Propranolol, a ß-adrenergic receptor (AR) antagonist, is an effective treatment for endangering infantile haemangioma (IH). Dramatic fading of cutaneous colour is often seen a short time after initiating propranolol therapy, with accelerated regression of IH blood vessels discerned after weeks to months. OBJECTIVES: To assess a possible role for haemangioma-derived pericytes (HemPericytes) isolated from proliferating and involuting phase tumours in apparent propranolol-induced vasoconstriction. METHODS: HemPericytes were assayed for contractility on a deformable silicone substrate: propranolol (10 µmol L(-1)) restored basal contractile levels in HemPericytes that were relaxed with the AR agonist epinephrine. Small interfering RNA knockdown of ß2-AR blunted this response. HemPericytes and haemangioma-derived endothelial cells were co-implanted subcutaneously in nude mice to form blood vessels; at day 7 after injection, mice were randomized into vehicle and propranolol-treated groups. RESULTS: HemPericytes expressed high levels of ß2-AR mRNA compared with positive control bladder smooth muscle cells. In addition, ß2-AR mRNA levels were relatively high in IH specimens (n = 15) compared with ß1-AR, ß3-AR and α1b-AR. Normal human retinal and placental pericytes were not affected by epinephrine or propranolol in this assay. Propranolol (10 µmol L(-1)) inhibited the proliferation of HemPericytes in vitro, as well as normal pericytes, indicating a nonselective effect in this assay. Contrast-enhanced microultrasonography of the implants after 7 days of treatment showed significantly decreased vascular volume in propranolol-treated animals, but no reduction in vehicle-treated animals. CONCLUSIONS: These findings suggest that the mechanism of propranolol's effect on proliferating IH involves increased pericytic contractility.

Hermann Friedberg's case report: an early description of CLOVES syndrome.

CLOVES syndrome is a recently described overgrowth disorder with complex vascular anomalies. Careful analysis of the case report by the German physician Hermann Friedberg "gigantism of the right lower limb" published in 1867 revealed that the report probably represents one of the first written accounts of CLOVES syndrome.

Recessive primary congenital lymphoedema caused by a VEGFR3 mutation.

BACKGROUND: Heterozygous mutations in VEGFR3 have been identified in some familial cases with dominantly inherited primary congenital lymphoedema, known as Nonne-Milroy disease. Recessive cases of primary lymphoedema with a genetic cause are not known, except for two families with syndromic hypotrichosis-lymphoedema-telangiectasia, with a SOX18 mutation. METHODS AND RESULTS: In this study, we present the first case of isolated primary congenital lymphoedema with recessive inheritance, caused by a homozygous mutation in VEGFR3. The novel mutation is a transition from alanine-to-threonine in amino acid 855, located in the ATP binding domain of the VEGFR3 receptor. Assessment of receptor function showed impaired ligand induced internalisation and ERK1/2 activity. Moreover, receptor phosphorylation was reduced, although less so than for a kinase-dead VEGFR3 mutation, which causes Nonne-Milroy disease. CONCLUSION: A hypomorphic VEGFR3 mutation, with moderate effect on receptor function, in a homozygous state can result in insufficient lymphatic functioning. Thus, in addition to Nonne-Milroy disease with dominant inheritance, VEGFR3 alterations can cause isolated recessive primary congenital lymphoedema. These data expand our understanding of the aetiology of congenital lymphoedema and suggest that large scale screening of VEGFR3 in all primary lymphoedema patients is necessary.

Techniques and results of palate fistula repair following palatoplasty: a 234-case multicenter study. / Técnicas y resultados de reparación de fístulas palatinas pospalatoplastia: estudio multicéntrico de 234 casos.

INTRODUCTION: Palate fistula is the most frequent complication following palatoplasty. The objectives of this study were: to describe the most widely used repair techniques; to study results and recurrence rate; to analyze potentially predictive recurrence variables; and to assess whether a specific technique is superior according to fistula size and location. MATERIALS AND METHODS: Retrospective study of patients undergoing palate fistula repair in 7 healthcare facilities from 2008 to 2018. All facilities had at least 20 new cases of cleft lift and palate annually (range: 20-80), with a fistula incidence of 14% (range: 1.5-20%). Minimum follow-up was 1 year. 8 variables were collected for statistical analysis purposes. RESULTS: 234 fistula patients underwent surgery. Most fistulas occurred in complete bilateral cleft lift and palate (Veau type IV). The most frequent location was the hard palate (Pittsburgh types IV and V (63.2%)), and fistulas were mostly large (42.1%) and medium (39.5%). The most frequent repair technique was re-palatoplasty (34.2%). Recurrence rate was 22%. The multivariate analysis demonstrated more recurrences in re-palatoplasty repaired type III fistulas in patients over 3 years old. CONCLUSION: A tendency towards using flap repair in large hard palate fistulas, re-palatoplasty in medium hard palate and soft and hard palate junction fistulas, and local flaps or re-palatoplasty in small fistulas at any location was observed. However, it could not be statistically demonstrated whether a specific repair technique was superior in different clinical situations.

INTRODUCCION: La fístula palatina es la complicación más frecuente tras una palatoplastia. Los objetivos de este estudio fueron: describir las técnicas de reparación más frecuentemente empleadas; estudiar los resultados y la tasa de recidiva; analizar posibles variables predictivas de recidiva y valorar la posible superioridad de una determinada técnica según el tamaño y la localización de la fístula. MATERIAL Y METODO: Estudio retrospectivo de pacientes operados de fístulas palatinas desde 2008 hasta 2018 en 7 centros. Todos operaban al menos 20 casos nuevos de fisuras labiopalatinas al año (rango 20-80) con una incidencia de fístulas de 14% (rango: 1,5-20%). El seguimiento mínimo fue de 1 año. Se recogieron 8 variables para el análisis estadístico. RESULTADOS: Se operaron 234 pacientes con fístulas. La mayoría ocurrieron en fisuras labiopalatinas bilateral completa (tipo IV de Veau). La localización más frecuente fue el paladar duro (tipos IV y V de Pittsburgh (63,2%) y la mayoría fueron grandes (42,1%) y medianas (39,5%). La técnica de reparación más frecuente fue la repalatoplastia (34,2%). La tasa de recidiva fue del 22%. El análisis multivariante mostró más recidivas en fístulas tipo III reparadas con repalatoplastia, en mayores de 3 años. CONCLUSION: Se observó una tendencia a utilizar más reparación con colgajo en fístulas grandes del paladar duro, repalatoplastia en fístulas medianas de paladar duro y de la unión, y colgajos locales o repalatoplastia en fístulas pequeñas en cualquier localización, pero no se pudo demostrar estadísticamente la superioridad de una técnica reparadora concreta en diferentes situaciones clínicas.

Cellular markers that distinguish the phases of hemangioma during infancy and childhood.

Hemangiomas, localized tumors of blood vessels, appear in approximately 10-12% of Caucasian infants. These lesions are characterized by a rapid proliferation of capillaries for the first year (proliferating phase), followed by slow, inevitable, regression of the tumor over the ensuing 1-5 yr (involuting phase), and continual improvement until 6-12 yr of age (involuted phase). To delineate the clinically observed growth phases of hemangiomas at a cellular level, we undertook an immunohistochemical analysis using nine independent markers. The proliferating phase was defined by high expression of proliferating cell nuclear antigen, type IV collagenase, and vascular endothelial growth factor. Elevated expression of the tissue inhibitor of metalloproteinase, TIMP 1, an inhibitor of new blood vessel formation, was observed exclusively in the involuting phase. High expression of basic fibroblast growth factor (bFGF) and urokinase was present in the proliferating and involuting phases. There was coexpression of bFGF and endothelial phenotypic markers CD31 and von Willebrand factor in the proliferating phase. These results provide an objective basis for staging hemangiomas and may be used to evaluate pharmacological agents, such as corticosteroids and interferon alfa-2a, which accelerate regression of hemangiomas. By contrast, vascular malformations do not express proliferating cell nuclear antigen, vascular endothelial growth factor, bFGF, type IV collagenase, and urokinase. These data demonstrate immunohistochemical differences between proliferating hemangiomas and vascular malformations which reflect the biological distinctions between these vascular lesions.

Clonality and altered behavior of endothelial cells from hemangiomas.

Hemangioma, the most common tumor of infancy, is a benign vascular neoplasm of unknown etiology. We show, for the first time to our knowledge, that endothelial cells from proliferating hemangioma are clonal, and we demonstrate that these hemangioma-derived cells differ from normal endothelial cells in their rates of proliferation and migration in vitro. Furthermore, migration of hemangioma endothelial cells is stimulated by the angiogenesis inhibitor endostatin, unlike the inhibition seen with normal endothelial cells. We conclude that hemangiomas constitute clonal expansions of endothelial cells. This is consistent with the possibility that these tumors are caused by somatic mutations in one or more genes regulating endothelial cell proliferation.

Multifocal rapidly involuting congenital hemangioma: a link to chorangioma.

Common infantile hemangioma is intriguing because of its variable presentation, rapid postnatal growth and slow regression in childhood. Interest in this tumor has increased with the recognition that it can be associated with structural anomalies in the craniofacial and ventral-caudal regions. The phenotype has expanded by characterization of rare vascular tumors that arise in the fetus and manifest at birth as rapidly involuting congenital hemangioma (RICH) or non-involuting congenital hemangioma (NICH). We describe a boy born with three RICH on the abdominal wall; one extended into the base of the umbilical cord. Two weeks later a small, infantile hemangioma arose on his neck. This patient stimulated a review of what is known about placental vascular tumors and their possible relationship to fetal and infantile hemangiomas. We suggest that chorangioma and umbilical cord hemangioma are clinically and histopathologically similar to cutaneous and hepatic RICH. These placental vascular tumors can also occur in conjunction with solitary and multiple infantile hemangiomas.

Intracranial vascular anomalies in patients with periorbital lymphatic and lymphaticovenous malformations.

BACKGROUND AND PURPOSE: The purpose of this study was to determine the nature, incidence, and radiologic appearance of intracranial vascular anomalies that occur in association with periorbital lymphatic malformation (LM) and lymphaticovenous malformation (LVM). MATERIALS AND METHODS: We retrospectively reviewed clinical records and imaging studies of 33 patients ranging in age from the neonatal period to 39 years (mean age, 5.1 years; median age, 1.0 year) who were evaluated for orbital LM or LVM at our institution between 1953 and 2002. Imaging studies, including CT, MR imaging, and cerebral angiograms, were evaluated by 2 radiologists to determine morphologic features of orbital LM and to identify associated noncontiguous intracranial vascular and parenchymal anomalies, including arteriovenous malformations (AVM), cerebral cavernous malformations (CCM), developmental venous anomalies (DVA), dural arteriovenous malformations (DAVM), and sinus pericranii (SP). RESULTS: The malformation was left-sided in 70% of patients. Twenty-two patients (70%) had intracranial vascular anomalies: DVA (n = 20; 61%), CCM (n = 2; 6%), DAVM (n = 4; 12%), pial AVM (n = 1; 3%), and SP (n = 1; 3%). Arterial shunts were present in the soft tissues in 2 patients (6%). Three patients had jugular venous anomalies. Three patients (9%) had cerebral hemiatrophy, 2 (6%) had focal cerebral atrophy, and 2 had Chiari I malformation. CONCLUSIONS: Intracranial vascular anomalies, some of which are potentially symptomatic and require treatment, are present in more than two thirds of patients with periorbital LM. Initial imaging of patients with orbital LM should include the brain as well as the orbit.

Four common glomulin mutations cause two thirds of glomuvenous malformations ("familial glomangiomas"): evidence for a founder effect.

BACKGROUND: Glomuvenous malformation (GVM) ("familial glomangioma") is a localised cutaneous vascular lesion histologically characterised by abnormal smooth muscle-like "glomus cells" in the walls of distended endothelium lined channels. Inheritable GVM has been linked to chromosome 1p21-22 and is caused by truncating mutations in glomulin. A double hit mutation was identified in one lesion. This finding suggests that GVM results from complete localised loss of function and explains the paradominant mode of inheritance. OBJECTIVE: To report on the identification of a mutation in glomulin in 23 additional families with GVM. RESULTS: Three mutations are new; the others have been described previously. Among the 17 different inherited mutations in glomulin known up to now in 43 families, the 157delAAGAA mutation is the most common and was present in 21 families (48.8%). Mutation 108C-->A was found in five families (11.8%), and the mutations 554delA+556delCCT and 1179delCAA were present together in two families (4.7% each). Polymorphic markers suggested a founder effect for all four mutations. CONCLUSIONS: Screening for these mutations should lead to a genetic diagnosis in about 70% of patients with inherited GVM. So far, a mutation in glomulin has been found in all GVM families tested, thus demonstrating locus homogeneity.

Molecular basis of vascular anomalies.

Vascular anomalies comprise a heterogeneous group of disorders that are divided into tumors (hemangiomas) and malformations. Recent advances in biomedical research provide insights into the molecular basis of these disorders and a deeper understanding of vascular morphogenesis. In the future, this emerging knowledge will contribute to novel ways to treat vascular anomalies and to regulate pathologic angiogenesis.

Human NELL-1 expressed in unilateral coronal synostosis.

Surgical correction of unilateral coronal synostosis offers a unique opportunity to examine the molecular differences between an abnormal and a normal cranial suture. We isolated and identified a cDNA fragment whose expression was up-regulated in the premature fusing and fused coronal sutures, as compared with normal coronal sutures. The nucleotide sequence of the full-length cDNA of this gene, human NELL-1, has approximately 61% homology with the chicken Nel gene. Both chicken Nel and human NELL-1 are comprised of six epidermal growth factor-like repeats. The human NELL-1 messages were localized primarily in the mesenchymal cells and osteoblasts at the osteogenic front, along the parasutural bone margins, and within the condensing mesenchymal cells of newly formed bone in sites of premature sutural fusion. Human multiorgan tissue mRNA blot showed that NELL-1 was specifically expressed in fetal brain but not in fetal kidney, liver, or lung. We also showed that Nell-1 was expressed in rat calvarial osteoprogenitor cells and was largely absent in rat tibiae and fibroblast cell cultures. In conclusion, our data suggest that the NELL-1 gene is preferentially expressed in cranial intramembranous bone and neural tissue (both of neural crest cell origin) and is up-regulated during unilateral premature closure of the coronal suture. The precise role of this gene is unknown.

Molecular genetics of vascular malformations.

Vascular malformations are localized errors of angiogenic development. Most are cutaneous and are called vascular 'birthmarks'. These anomalies are usually obvious in the newborn, grow commensurately with the child, and gradually expand in adulthood (Mulliken and Glowacki, 1982). Vascular malformations also occur in visceral organs, such as the respiratory and gastrointestinal tract, but are more common in the brain (Mulliken and Young, 1988). These anomalies are composed of tortuous vascular channels of varying size and shape, lined by a continuous endothelium and surrounded by abnormal complement of mural cells. Vascular malformation can be life threatening due to obstruction, bleeding or congestive heart failure. Most anomalies occur sporadically, but there are families exhibiting autosomal dominant inheritance. Genetic studies of such families have resulted in the identification of mutated genes, directly giving proof of their important role in the regulation of angiogenesis.

Linkage disequilibrium narrows locus for venous malformation with glomus cells (VMGLOM) to a single 1.48 Mbp YAC.

Venous malformations with glomus cells are localised cutaneous lesions of vascular dysmorphogenesis. They are usually sporadic, but sometimes familial. Using five families, we mapped the locus, VMGLOM, to chromosome 1p21-p22. In order to refine this locus, spanning 4-6 Mbp, we then studied seven additional families. They exhibited linkage to VMGLOM and the combined lod score for all 12 families was 18.41 at theta = 0.0 for marker D1S188. We found a distinct haplotype shared by seven families, comprising seven alleles which are rare in the general population (P < 0.01). This indicates that the haplotype is identical by descent in all seven families, and hence the locus can be refined by inferring ancestral crossovers. Using this approach, we position the causative gene between two markers on the same non-chimeric YAC of 1.48 Mbp, a feasible size for positional cloning. As there is no known gene involved in vasculogenesis and/or angiogenesis in this YAC, the identification of the causative gene is likely to reveal a novel regulator or vascular development.

Cosmetic surgery as an antecedent of life change.

Of 42 patients who underwent cosmetic surgery, 4 patients, who gave no indication of an impending life change before surgery, obtained a legal separation or divorce 3-6 months later. These 4 patients had had strong parental domination and hostile relationships with younger siblings; they had a need for success on their own terms and for the rapid closure of potential conflict. The authors suggest that such patients are undergoing significant identity changes that become conscious only after cosmetic surgery, which tests out their shift from passivity and withdrawal to activity and participation.

Mast cells in hemangiomas and vascular malformations.

Common pediatric vascular birthmarks, classified as hemangiomas or malformations, were analyzed for the presence of mast cells. Hemangiomas in the proliferative phase contained large numbers of mast cells (27 +/- 15 cells/high-power field [HPF]) in comparison with hemangiomas in the involuting phase (2.6 +/- 2.9), vascular malformations (1.7 +/- 3.2), and normal skin (5.0 +/- 1.0). Inasmuch as hemangiomas are characterized by endothelial proliferation and increased numbers of mast cells, these data raise the possibility that mast cells may have an important role in the formation and/or maintenance of these lesions.

Is there an association between hemangioma and syndromes with dysmorphic features?

Most vascular birthmarks can be categorized, based on clinical and cellular criteria, as either (1) a hemangioma, or (2) a malformation, or (3) a macular stain. Macular stains are commonly seen in newborns, and they consist of faint vascular stains of the glabella, eyelids, and nuchal region called "nevus flammeus," "stork bite," "salmon patch," etc. Unfortunately, the term "hemangioma" is frequently applied to all three types of cutaneous vascular lesions. Usually, these disparate vascular anomalies are listed in association with various malformative syndromes and are generically labeled "hemangioma." This study attempts to define accurately the specific vascular anomalies seen in children born with syndromes with dysmorphic features. This review of five standard textbooks of genetics showed that the majority of vascular anomalies reported in syndromic newborns are not hemangiomas. Rather, they are macular stains, and the vast majority of these fade with time. Congenital telangiectasias and other vascular malformations (capillary, lymphatic, venous, arterial, and combinations thereof) also occur in association with dysmorphic syndromes. In contrast, hemangioma, the most common neonatal tumor, is seen only incidentally with rare dysmorphic conditions. Specifically, hemangioma was found to occur only in association with midline (sternal, abdominal) clefting, right-sided aortic arch coarctation, and with a constellation of sacral and genitourinary defects.

Antiangiogenic therapy of a recurrent giant cell tumor of the mandible with interferon alfa-2a.

We report a 5-year-old girl with a large rapidly growing giant cell tumor of the mandible that recurred 2 months after the first surgical excision and 3 months after a second resection. An angiogenic protein, (bFGF), was abnormally elevated in her urine. The patient was treated with interferon alfa-2a for 1 year because this agent inhibits angiogenesis by suppressing bFGF overexpression in infantile hemangiomas and in other human tumors. During this time the bone tumor regressed and disappeared, the urinary bFGF fell to normal levels, and the mandible regenerated. She has remained tumor-free and has been off therapy for 3 years at this writing. This first successful use of interferon alfa-2a to treat a mandibular tumor in a child demonstrates: 1) low grade tumors that overexpress bFGF may respond to interferon alfa-2a, in a manner similar to life-threatening infantile hemangiomas; 2) antiangiogenic therapy, given without interruption for 1 year, was safe and effective in this patient; and 3) treatment may be continued for 1 year without the development of drug resistance.

Association between "plagiocephaly" and hemifacial microsomia.

Fifteen of 155 patients with hemifacial microsomia were noted to have frontal plagiocephaly. These patients were examined to determine whether the frontal flattening was either secondary to deformation, the result of unilateral coronal synostosis, or part of the spectrum of hemifacial microsomia. The patients were categorized as having deformational versus synostotic frontal plagiocephaly by documenting position of the supraorbital rims, nasal root, ears, malar eminences, chin point, and the palpebral fissure height. Other extracraniofacial anomalies were also noted. Fourteen of 15 (93%) patients had characteristic deformational abnormalities. Only 1/15 (7%) had an elevated orbit, suggestive of unilateral coronal synostosis, but this diagnosis was not radiographically confirmed. Frontal deformational plagiocephaly was ipsilateral to the side predominantly affected by hemifacial microsomia in all but one patient. Patients with hemifacial microsomia-deformational frontal plagiocephaly often had ipsilateral torticollis, cervical spine abnormalities, and anomalies outside the craniofacial region. This was in contrast to patients with deformational frontal plagiocephaly, in the absence of hemifacial microsomia, who frequently had ipsilateral torticollis but no other anomalies. This study also underscores possible confusion in differentiating hemifacial microsomia from deformational hemifacial hypoplasia on physical examination. The association of deformational frontal plagiocephaly and hemifacial microsomia belies a rigid etiologic label of deformational versus malformative anomaly.

Newly recognized autosomal dominant disorder with craniosynostosis.

We report a family with a newly recognized form of autosomal dominant craniosynostosis. The disorder has high penetrance and variable expression with respect to sutural involvement and cranial abnormalities, ranging from fronto-orbital recession to clover-leaf skull deformity. Associated problems included headache, poor vision, and seizures; intelligence, however, is normal. Assignment of a well-described syndromic designation, e.g., Crouzon, Pfeiffer, Saethre-Chotzen, or Jackson-Weiss, is precluded based upon the absence of characteristic changes, i.e., midfacial hypoplasia, orbital hypertelorism, blepharoptosis, hand anomalies, or foot anomalies. The large size of this family and high penetrance of the disorder suggests that this may be an excellent candidate for positional cloning of a locus important in craniofacial development.

Marked female predilection in some syndromes associated with facial hemangiomas.

Analysis of the literature yielded 42 examples of the combination of sternal non-union and supraumbilical raphé without evidence of sex predilection. However, among an additional 31 cases in which the triad included facial hemangioma, there was almost exclusive female occurrence. Another condition involves extensive unilateral hemangioma of the face, absence of ipsilateral carotid and vertebral vessels, mental retardation, and Dandy-Walker malformation. Still another disorder has been proposed which includes facial hemangioma and dilatation of the carotid syphon. Both of these conditions exhibit marked female predilection. Examples of overlap of all three "disorders" cause the authors to question the independence of these disorders, hypothesizing instead that they represent a spectrum.