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Isolated vascular anomalies and syndromes associated with vascular anomalies

Cutrupi MC, Manti S, Dipasquale V, Impollonia D, Stroscio G, Piraino B, Arrigo T, Salpietro C, Cuppari C

Pediatric Unit, University of  Messina, Messina, Italy


Isolated vascular anomalies and syndromes associated with vascular anomalies   vary in location, type, and clinical severity of the phenotype. In recent years, the identification of the genetic factors contributing to these anomalies have been elucidated.
Vascular anomalies have an incidence estimated around 1/10 000. (Boon, L.M., 1994) and subdivided into vascular tumors (mainly the hemangiomas, of unknown etiology) and vascular malformations (CVM) are thought to be due to defects in these pathways (Mulliken, J.B. et al., 1982). The two entities are diseases completely different, even though both are grouped under the common classification of vascular abnormalities. The CVM constitute errors of morphogenesis, as well as structural abnormalities, while hemangiomas are vascular tumors. Most malformations are present at birth and grow proportionately with the child.The etiopathological genetic defects have been elucidated for some of these, and they are discussed here with relevant functional data and development of small animal models. The clinical history allows to differentiate in most cases between cancer and the CVM, although not always be available history clear and appropriate.

Keywords: Klippel-Trenaunay syndrome; Weber syndrome; Sturge-Weber syndrome; capillary malformation-arteriovenous malformation; hereditary haemorrhagic telangiectasia; venous malformations

Childhood hemangiomas and congenital hemangiomas 
The childhood hemangiomas (HOI)  are the most common form of pediatric vascular proliferative tumors usually not present at birth, appearing at a later stage in childhood. These tumors have a two-step process of proliferation and regression: grow rapidly and disproportionately compared to the growth of the child, then reach a phase of maximum growth to pass then to a phase of involution. The majority of HOI reaches a stage of atrophy by the age of 10 years. It is likely that the HOI will originate from placental tissue. From the histological point of view, these lesions have a positive staining for glucose transporter-1 (GLUT-1) during all stages of growth and involution. (North PE et al., 2001)
The diagnosis of HOI is usually clinical, but ultrasound is necessary. Most hemangiomas are hypoechoic, although according to studies up to 18% of hemangiomas is hyperechoic. It is important to differentiate between HOI and congenital hemangiomas, with the latter constituting a small group of pediatric vascular tumors. The congenital hemangiomas grow completely utero, they are present at birth and therefore do not go through a phase of postnatal proliferation, as it occurs in the HOI. Histologically sight congenital hemangiomas do not stain with GLUT-1.
Normally it is possible to identify two subtypes of congenital hemangiomas: hemangiomas RICH (Rapidly involuting congenital hemangioma - fast congenital hemangiomas involution) and hemangiomas NICH (non-involuting congenital hemangioma - congenital hemangiomas not regressive).
The first pass through a phase of spontaneous involution in the first year of life, while the latter persist for a lifetime. Calcifications have not reported in infantile hemangioma but have been identified in a subset of congenital hemangiomas. (Gorincour G et al., 2005).


Table 1. Hemangiomas versus Vascular Malformations. (From Mulliken, J.B. and Glowacki, J. 1982)

Congenital vascular malformations (CVM)
The CVM are structural abnormalities of the vascular system and are NOT cancer. These injuries are result of an interruption of development in different stages of embryogenesis. They are always present from birth and constantly growing in line with the systemic growth of the child. In contrast, the HOI grow disproportionately compared to the growth of the child. The CVM does not regress spontaneously and remain throughout the course of the patient's life, such as residues of embryological tissue.
The CVM can affect vessels of any type and in general can be classified as follows (Table 1- Figure 2):
• arteriovenous malformations (AVM)
• venous malformations (VM)
• lymphatic malformations (LM)
• capillary malformations (CM)


Table 2. Classification of vascular anomalies (from Blei F et al., 2016)

Fig. 2. Mechanism of development of vascular malformations from fetal capillary plexus. (From Blei F et al., 2016)


Arteriovenous malformations (AVM)
The AVM are structural abnormalities involving a high flow interfacial communication abnormal between the arterial system and venous system and its full maturity can manifest itself in the form of mass extended button and hot. The increase in size is due the increase in abnormal vessels, in addition to hypertrophy associated soft tissue. The presence of hemorrhage can be a typical element of the presentation of an occult AVM. In infants the AVM may manifest in the form of pale pink skin color and can be difficult to differentiate with respect to a CM. The bone hypertrophy and / or of the normally associated soft tissue may entail an increase of the dimensions (length and width) of the involved side.
Venous malformations (VM)
Venous malformations (VM) are the most common abnormality of development dependent on the venous system. It is a fault caused by an interruption of the development of the venous system in different stages of embryogenesis.
VMs can be classified as follows:
1) VM extratronculari: lesions detectable in most tissues that may arise in the form of lumps of dilated veins or venous injury.
2) VM truncal: lesions in the form of aplasia, hypoplasia, obstruction, dilation, duplication or aneurysm.
Lymphatic malformations (LM)
The nomenclature for LM is still confusing and still are widely used obsolete terms like lymphangiomatosis, lymphangiectasia or lymphatic dysplasia to describe several related diseases.  When LM only involving the skin and subcutaneous tissue, the prognosis is usually favorable. When the lesions involving the upper airways, viscera or bone, the prognosis is generally poor, with a significant mortality rate.
Capillary malformation (CM)
The CM represent the most common type of VCM. Descriptive terminology used in past with reference to the CM was that of "Port wine stain" or "nevus flammeus". As congenital malformations of superficial blood vessels of the dermis, the CM are present at birth and grow in size in line with the child's development. The lesions persist for life and do not have any tendency to involution. The clinical progress of the CM. It varies depending on the anatomical location of the lesion. A significant number of dysmorphic syndromes was associated with CM.

Syndromic vascular malformations
Syndromic vascular malformations (Wassef M et al., 2015)include Klippel-Trenaunay (Capillary malformations, lymphatic or venous with hypertrophy of the limbs), Parkes-Weber syndrome (Similar to Klippel-Trenaunay with arterio-venous shunt), the Sturge-Weber syndrome (Malformation of the facial capillaries in triplets distribution, leptomeningeal angiomatosis, glaucoma and seizures), the Blue-Rubber-Bleb-Nevus (BRBNS syndrome, characterized by small generalized venous malformations), the Proteus syndrome (vascular malformations, lipoipoplasia trunk, scoliosis, cerebriform plantar surfaces, snow, partial gigantism and abnormalities of the fingers), the disease Ollier / Maffucci syndrome (hemangioendothelioma, enchondromatosis), the HHT (AVM multifocal), Gorham's syndrome (with lymphangiomatosis osteolysis), as well as several anomalies and syndromes or lymphatic linfedematose. Syndromes related to PTEN vascular anomalies include Cowden syndrome and syndrome Bannayan-Riley-Ruvalcaba; these syndromes have clinical features and radiological specifications. Patients with PTEN syndromes are at greater risk of malignant lesions (For example, thyroid, breast, colon, brain, genitourinary tract), which may occur earlier than normal in the general population. About 30% of patients with facial segmental hemangiomas may be suffering from syndrome PHACES (MIM 606519) [Injury to the posterior fossa or other structural lesions SNC, segmental hemangiomas, arterial anomalies, cardiac abnormalities, eye abnormalities or dependent deformation of the sternum or the median line]. The assessment provides: Cerebral magnetic resonance imaging with or without contrast and MRA brain, neck and upper chest, ophthalmologic examination, heart and chest, as well as thyroid function tests.

Table 3: Vascular malformation syndromes

Hereditary hemorrhagic telangiectasia
Ereditary hemorrhagic telangiectasia (HHT) (MIM 187300 and 600376) also known as Osler-Weber-Rendu syndrome, is an autosomal dominant disorder with an incidence around 1/10 000 (Abdalla, S.A.2006)  that is characterized by multiple arteriovenous malformations (AVMs) involving the skin, mucosal surfaces, and internal organs. HHT has an age-dependent penetrance and usually initially presents with recurrent epistaxis followed by the characteristic telangiectasias of the face, oropharynx, and hands over time. Patients often have vascular malformations that involve their lungs, brain, spinal cord, and gastrointestinal tract as well, which are the main causes of morbidity in patients with HHT (Guttmacher Ar et al., 1995). The sequelae of visceral organ involvement include ischemic stroke, cerebral bacterial abscesses, intracranial hemorrhage, chronic hypoxia, dyspnea with exertion, pulmonary hypertension, high output heart failure, gastrointestinal bleeds and liver failure.
At least four loci have been associated with HHT: HHT1 on 9q33–34, with mutations in endoglin (ENG) (McAllister, K.A., 1994 ), HHT2 on 12q11–14, with mutations in the activin receptor-like kinase 1 (ALK1) (Johnson, D.W., 1996), HHT3 on 5q (Cole et al., 2005) and HHT4 on 7p14 (Bayrak-Toydemir, 2006).Several genetic mutations (most commonly affecting one of two genes in the transforming growth factor-beta/bone morphogenetic protein [BMP] signaling family: endoglin or activin receptor-like kinase-1 [ACVRL1], or less commonly SMAD4 [Mothers Against Decapentaplegic, Drosophila Homolog of 4] or growth/differentiation factor [GDF2]; BMP9]) have been identified in this disorder, which has been recently reviewed by McDonald et al (McDonald et al., 2015).

Sturge–Weber syndrome
Sturge–Weber syndrome is a rare sporadic neurocutaneous syndrome the hallmark of which is a facial port-wine stain involving the first division of the trigeminal nerve, ipsilateral leptomeningeal angiomata and angioma involving the ipsilateral eye. The incidence of SWS is ~1:50, 000 infants, with no significant difference between males and females. (Di Rocco et al., 2006).The characteristic facial port-wine stain, involving the first branch of the trigeminal nerve and the embryonic vasculature distribution in this area, leads to several ocular complications of the anterior segment and can involve the eyelids and conjunctiva. The posterior segment of the eyes is also affected with diffuse choroidal hemangiomas. Our understanding of the disease process has vastly improved since it was first described in 1879, with recent identification of an activating somatic mutation in the GNAQ gene. A somatic mutation in the GNAQ gene in port-wine stains of patients with and without SWS has been identified. (Shirley MD et al., 2013).Sturge–Weber syndrome is marked by a variable but usually progressive course in early childhood characterised by seizures, stroke-like episodes, headaches, neurological and cognitive deterioration, hemiparesis, glaucoma and visual field defects. More recently, the increased prevalance of otolaryngological, endocrine and emotional–behavioural issues have been established. According to the clinical manifestation, SWS is classified into four types: 1) presence of brain and facial angioma, with or without glaucoma, 2) PWS without brain involvement, with or without glaucoma, 3) isolated brain angioma, usually without glaucoma, and 4) type 1 associated with systemic manifestation such as tuberous sclerosis (Table 2).Roach ES., 1992)
Neurophysiology and neuroimaging studies provide information regarding the evolution of changes in Sturge–Weber syndrome over time. Early recognition and aggressive management of symptoms remains cornerstone in the management of this syndrome. Two recent studies have challenged the previously accepted notion that CMs over the distribution of the trigeminal nerve places patients at highest risk of SWS (Dutkiewicz AS et al 2015, Waelchli R et al., 2014)

Table 4  Classification of Sturge–Weber syndrome

Maffucci syndrome
Maffucci syndrome, a rare sporadic form of enchondromatosis, is characterized by hemangiomas and multiple enchondromas, benign cartilaginous tumors that arise near growth plates. First described by Angelo Maffucci in 1881, Maffucci syndrome is an exceedingly rare disease with less than 250 cases reported. (Gao H et al., 2013) Maffucci syndrome affects both sexes and has no geographical or ethnic predisposition. The disease usually begins between the 1st and the 5th year of life. In 25% of cases, the clinical symptoms are present at birth or appear in the first year.  Considered a subtype of enchondromatosis, Maffuccisyndrome presents with multiple enchondromas that are associated with soft tissue hemangiomas. (Fanburg JC et al., 1995) Enchondromas are benign growths commonly in the small bones of the fingers and toes, long tubular bones, and flat bones such as the pelvis. They grow in close proximity to the growth plate cartilages and are therefore thought to result from abnormal regulation of proliferation and terminal differentiation of chondrocytes. (Hopyan S, et al 2002) Patients with enchondromatoses have an increased risk of chondrosarcomatous transformation, seen in up to 15%–30% of cases. ( Lewis et al., 1973, Kaplan et al., 1993)
The capillary malformations usually present on the distal end in the form of subcutaneous nodules prominent blue-dark, irregularly shaped, but can also be located elsewhere. They may be associated lymphatic and venous malformations. The skeletal and vascular lesions are usually asymmetrical and may be progressive. About 30-40% of enchondromas evolves into chondrosarcoma. The syndrome is associated with other benign or malignant tumors (goiter, parathyroid adenoma, pituitary adenoma, adrenal cancer, ovarian cancer, breast cancer, or astrocytoma; see these terms). The etiology of Maffucci syndrome is not completely known. The disease appears to be associated with mesodermal dysplasia early in life. No family transmission was observed. The diagnosis is based on clinical and radiographic findings. The main differential diagnosis with Ollier disease

Klippel-Trénaunay Syndrome and Parkes Weber Syndrome    
Klippel-Trénaunay syndrome is a congenital disorder classically characterized by three findings: a port-wine stain (nevus flammeus), abnormal venous structures (such as varicosities and venous malformations), and osseous and soft-tissue hypertrophy. This syndrome was initially described in 1900 by Klippel and Trénaunay (Klippel M, Trénaunay P 1900) and was originally called naevus vasculosus osteohypertrophicus. In 1907, Frederick Parkes Weber (Weber FP.1907) noted similar findings in association with arteriovenous malformations. This entity is referred to as Parkes Weber or Klippel-Trénaunay-Weber syndrome.
The affected limb can grow excessively, compared to the contralateral and the extent of the discrepancy in length between the limbs (LLD) can be mild to reach or exceed 10 centimeters. The effects of the pathological growth can only be evident at the level of a single bone (in particular the femur or tibia) or, in some cases, can affect an entire limb. (Jacob AG et al., 1998)The LLD may become evident in infancy, childhood or adolescence and is clearly diagnosable by comparing the folds of the buttocks or the back folds of the knees. The side signs are skin nevus, dilated superficial veins, limb enlargement, skin hyperthermia, dermatitis, ulcers and bleeding. These signs are not always present. Although the AOH syndrome is usually sporadic, in a few families it was noted autosomal dominant inheritance.

The evaluation, diagnosis, and management of vascular anomalies is a multidisciplinary process.  Some congenital vascular anomalies require no or minimal intervention, while others require a cohesive multidisciplinary approach.  It is important to recognize the clinical presentation and to establish an appropriate diagnosis to most appropriately evaluate and manage the patients. The rate of discovery continues to increase, expanding our understanding of the underlying interconnected molecular pathways.

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