Reticulate eruptions. Part 1: Vascular networks and physiology

Reticulate pattern is one of the most important dermatological signs of a pathological process involving the superficial vascular networks. Vascular malformations, such as cutis marmorata congenita telangiectasia and benign forms of livedo reticularis, and sinister conditions, such as meningococcal meningitis or Sneddon's syndrome, can all present with a reticulate pattern. The clinical presentation and morphology is determined by the nature and extent of the underlying pathology and the involvement of a particular vascular network. This review has been divided into four instalments. In the present paper, we discuss the anatomy and physiology of the complex network of vascular structures that support the function of the skin and subcutis.

Pentalogy or hexalogy of Cantrell?

Pentalogy of Cantrell (PC) is a rare congenital syndrome involving the abdominal wall, sternum, diaphragm, pericardium, and heart. The embryonic period in which PC develops coincides with that of umbilical cord (UC) formation. The aim of the following study was to address the question of whether PC is associated with UC pathologies. Four cases, prenatally identified between 2002 and 2008, were enrolled in this study. Umbilical cord pathologies defined as single umbilical artery, short cord, or UC with atypical coiling pattern were retrospectively assessed on stored ultrasound images and from autopsy reports. The literature regarding PC and UC pathologies was reviewed. Three singleton pregnancies and 1 monoamniotic twin pregnancy with twin reversed arterial perfusion sequence were reviewed. All had a normal karyotype. Three showed the classical PC stigmata, with ectopia cordis. One fetus had no ectopia cordis; this case had a normal UC, whereas all others fetuses showed a short UC with atypical coiling pattern. Of 26 publications dealing with PC, the UC was described in only 8 cases, 7 of which were abnormal. There seems to be a strong correlation between the PC and UC abnormalities, in particular in cases with ectopia cordis. We speculate that the insult leading to the classical malformations of PC and UC abnormalities is the same or the sequence of malformations itself may alter the early fetoplacental blood flow and therefore the normal development of the UC angioarchitecture.

Putative functions of extracellular matrix glycoproteins in secondary palate morphogenesis

Cleft palate is a common birth defect in humans. Elevation and fusion of paired palatal shelves are coordinated by growth and transcription factors, and mutations in these can cause malformations. Among the effector genes for growth factor signaling are extracellular matrix (ECM) glycoproteins. These provide substrates for cell adhesion (e.g., fibronectin, tenascins), but also regulate growth factor availability (e.g., fibrillins). Cleft palate in Bmp7 null mouse embryos is caused by a delay in palatal shelf elevation. In contrast, palatal shelves of Tgf-β3 knockout mice elevate normally, but a cleft develops due to their failure to fuse. However, nothing is known about a possible functional interaction between specific ECM proteins and Tgf-β/Bmp family members in palatogenesis. To start addressing this question, we studied the mRNA and protein distribution of relevant ECM components during secondary palate development, and compared it to growth factor expression in wildtypewild type and mutant mice. We found that fibrillin-2 (but not fibrillin-1) mRNA appeared in the mesenchyme of elevated palatal shelves adjacent to the midline epithelial cells, which were positive for Tgf-β3 mRNA. Moreover, midline epithelial cells started expressing fibronectin upon contact of the two palatal shelves. These findings support the hypothesis that fibrillin-2 and fibronectin are involved in regulating the activity of Tgf-β3 at the fusing midline. In addition, we observed that tenascin-W (but not tenascin-C) was misexpressed in palatal shelves of Bmp7-deficient mouse embryos. In contrast to tenascin-C, tenascin-W secretion was strongly induced by Bmp7 in embryonic cranial fibroblasts in vitro. These results are consistent with a putative function for tenascin-W as a target of Bmp7 signaling during palate elevation. Our results indicate that distinct ECM proteins are important for morphogenesis of the secondary palate, both as downstream effectors and as regulators of Tgf-β/Bmp activity.

Consensus Document of the International Union of Angiology (IUA)-2013. Current concept on the management of arterio-venous management

Arterio-venous malformations (AVMs) are congenital vascular malformations (CVMs) that result from birth defects involving the vessels of both arterial and venous origins, resulting in direct communications between the different size vessels or a meshwork of primitive reticular networks of dysplastic minute vessels which have failed to mature to become 'capillary' vessels termed "nidus". These lesions are defined by shunting of high velocity, low resistance flow from the arterial vasculature into the venous system in a variety of fistulous conditions. A systematic classification system developed by various groups of experts (Hamburg classification, ISSVA classification, Schobinger classification, angiographic classification of AVMs,) has resulted in a better understanding of the biology and natural history of these lesions and improved management of CVMs and AVMs. The Hamburg classification, based on the embryological differentiation between extratruncular and truncular type of lesions, allows the determination of the potential of progression and recurrence of these lesions. The majority of all AVMs are extra-truncular lesions with persistent proliferative potential, whereas truncular AVM lesions are exceedingly rare. Regardless of the type, AV shunting may ultimately result in significant anatomical, pathophysiological and hemodynamic consequences. Therefore, despite their relative rarity (10-20% of all CVMs), AVMs remain the most challenging and potentially limb or life-threatening form of vascular anomalies. The initial diagnosis and assessment may be facilitated by non- to minimally invasive investigations such as duplex ultrasound, magnetic resonance imaging (MRI), MR angiography (MRA), computerized tomography (CT) and CT angiography (CTA). Arteriography remains the diagnostic gold standard, and is required for planning subsequent treatment. A multidisciplinary team approach should be utilized to integrate surgical and non-surgical interventions for optimum care. Currently available treatments are associated with significant risk of complications and morbidity. However, an early aggressive approach to elimiate the nidus (if present) may be undertaken if the benefits exceed the risks. Trans-arterial coil embolization or ligation of feeding arteries where the nidus is left intact, are incorrect approaches and may result in proliferation of the lesion. Furthermore, such procedures would prevent future endovascular access to the lesions via the arterial route. Surgically inaccessible, infiltrating, extra-truncular AVMs can be treated with endovascular therapy as an independent modality. Among various embolo-sclerotherapy agents, ethanol sclerotherapy produces the best long term outcomes with minimum recurrence. However, this procedure requires extensive training and sufficient experience to minimize complications and associated morbidity. For the surgically accessible lesions, surgical resection may be the treatment of choice with a chance of optimal control. Preoperative sclerotherapy or embolization may supplement the subsequent surgical excision by reducing the morbidity (e.g. operative bleeding) and defining the lesion borders. Such a combined approach may provide an excellent potential for a curative result. Conclusion. AVMs are high flow congenital vascular malformations that may occur in any part of the body. The clinical presentation depends on the extent and size of the lesion and can range from an asymptomatic birthmark to congestive heart failure. Detailed investigations including duplex ultrasound, MRI/MRA and CT/CTA are required to develop an appropriate treatment plan. Appropriate management is best achieved via a multi-disciplinary approach and interventions should be undertaken by appropriately trained physicians.

Phase contrast and time-of-flight magnetic resonance angiography of the intracerebral arteries at 1.5, 3 and 7 T

Time-of-flight (ToF) and phase contrast (PC) magnetic resonance angiographies (MRAs) are noninvasive applications to depict the cerebral arteries. Both approaches can image the cerebral vasculature without the administration of intravenous contrast. Therefore, it is used in routine clinical evaluation of cerebrovascular diseases, e.g., aneurysm and arteriovenous malformations. However, subtle microvascular disease usually cannot be resolved with standard, clinical-field-strength MRA. The purpose of this study was to compare the ability of ToF and PC MRA to visualize the cerebral arteries at increasing field strengths.

Novel approach to complex pulmonary arteriovenous malformation embolization using detachable coils and Amplatzer vascular plugs

We evaluated the feasibility of a modified embolization technique of pulmonary arteriovenous malformations (PAVM) using venous sac embolization with detachable coils combined with the feeding artery embolization with the Amplatzer vascular plug (AVP).

A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

BACKGROUND: The recurrent ~600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. OBJECTIVE: To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. METHODS: We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. RESULTS: When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. CONCLUSIONS: The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Vascular endothelial cell-specific phosphotyrosine phosphatase (VE-PTP) activity is required for blood vessel development

VE-PTP, a receptor-type phosphotyrosine phosphatase, associates with the tyrosine kinase receptor Tie-2 and VE-cadherin and enhances the adhesive function of the latter. Here, VE-PTP was found to be restricted to endothelial cells, with a preference for arterial endothelium. Mutant mice expressing a truncated, secreted form of VE-PTP lacking the cytoplasmic and transmembrane domains and the most membrane-proximal extracellular fibronectin type III repeat, showed severe vascular malformations causing lethality at 10 days of gestation. Although blood vessels were initially formed, the intraembryonic vascular system soon deteriorated. Blood vessels in the yolk sac developed into dramatically enlarged cavities. In explant cultures of mutant allantoides, endothelial cells were found next to vessel structures growing as cell layers. No signs for enhanced endothelial apoptosis or proliferation were observed. Thus, the activity of VE-PTP is not required for the initial formation of blood vessels, yet it is essential for their maintenance and remodeling.

Estimation of pelvic tilt on anteroposterior X-rays--a comparison of six parameters

OBJECTIVE: To compare six different parameters described in literature for estimation of pelvic tilt on an anteroposterior pelvic radiograph and to create a simple nomogram for tilt correction of prosthetic cup version in total hip arthroplasty. DESIGN: Simultaneous anteroposterior and lateral pelvic radiographs are taken routinely in our institution and were analyzed prospectively. The different parameters (including three distances and three ratios) were measured and compared to the actual pelvic tilt on the lateral radiograph using simple linear regression analysis. PATIENTS: One hundred and four consecutive patients (41 men, 63 women with a mean age of 31.7 years, SD 9.2 years, range 15.7-59.1 years) were studied. RESULTS: The strongest correlation between pelvic tilt and one of the six parameters for both men and women was the distance between the upper border of the symphysis and the sacrococcygeal joint. The correlation coefficient was 0.68 for men (P<0.001) and 0.61 for women (P<0.001). Based on this linear correlation, a nomogram was created that enables fast, tilt-corrected cup version measurements in clinical routine use. CONCLUSION: This simple method for correcting variations in pelvic tilt on plain radiographs can potentially improve the radiologist's ability to diagnose and interpret malformations of the acetabulum (particularly acetabular retroversion and excessive acetabular overcoverage) and post-operative orientation of the prosthetic acetabulum.

Small omphalocele with umbilical evagination. A distinct entity?

A neonatal case of umbilical evagination of the bladder combined with a small omphalocele is presented. This rare congenital malformation has previously been described in only three cases. Umbilical evagination can be understood as a disturbance of development of both the vitelline and allantoic ducts, resulting in a non-descended but otherwise normal bladder opening to the inferior margin of a small omphalocele. Diagnosis is made by clinical inspection and ultrasound. Since other malformations are not present, this entity may be regarded as a minor form of a lower midline defect with excellent prognosis.

Functional interaction of vascular endothelial-protein-tyrosine phosphatase with the angiopoietin receptor Tie-2

During development of the vertebrate vascular system essential signals are transduced via protein-tyrosine phosphorylation. Null-mutations of receptor-tyrosine kinase (RTK) genes expressed in endothelial cells (ECs) display early lethal vascular phenotypes. We aimed to identify endothelial protein-tyrosine phosphatases (PTPs), which should have similar importance in EC-biology. A murine receptor-type PTP was identified by a degenerated PCR cloning approach from endothelial cells (VE-PTP). By in situ hybridization this phosphatase was found to be specifically expressed in vascular ECs throughout mouse development. In experiments using GST-fusion proteins, as well as in transient transfections, trapping mutants of VE-PTP co-precipitated with the Angiopoietin receptor Tie-2, but not with the Vascular Endothelial Growth Factor receptor 2 (VEGFR-2/Flk-1). In addition, VE-PTP dephosphorylates Tie-2 but not VEGFR-2. We conclude that VE-PTP is a Tie-2 specific phosphatase expressed in ECs, and VE-PTP phosphatase activity serves to specifically modulate Angiopoietin/Tie-2 function. Based on its potential role as a regulator of blood vessel morphogenesis and maintainance, VE-PTP is a candidate gene for inherited vascular malformations similar to the Tie-2 gene.

Prevalence of heart disease in symptomatic cats: an overview from 1998 to 2005

A total of 408 cats with various cardiovascular problems has been presented to two investigational clinics during the last 8 years. The number of yearly examinations has steadily increased during this period. Definitive cardiovascular disease was diagnosed in 287 cats, whereby hypertrophic cardiomyopathy (HCM) was the most common diagnosis with 67.6%. Congenital cardiovascular malformations were found in 11.8% of the cases. Ventricular septal defect (VSD) was the most frequent anomaly, in contrast to previously published studies. The ECG was found to be relatively non-specific and insensitive for the diagnosis of heart disease: Its usefulness lies in the recognition and diagnosis of cardiac arrhythmias. The radiographically recognized changes were also non-specific for certain heart diseases. Radiographs of the thorax are especially useful in the evaluation of cardiomegaly, and secondary signs of congestion.

Unilateral focal polymicrogyria in a patient with classical Aarskog-Scott syndrome due to a novel missense mutation in an evolutionary conserved RhoGEF domain of the faciogenital dysplasia gene FGD1

Faciogenital dysplasia or Aarskog-Scott syndrome (AAS) is an X-linked disorder characterized by craniofacial, skeletal, and urogenital malformations and short stature. Mutations in the only known causative gene FGD1 are found in about one-fifth of the cases with the clinical diagnosis of AAS. FGD1 is a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase Cdc42 via its RhoGEF domain. The Cdc42 pathway is involved in skeletal formation and multiple aspects of neuronal development. We describe a boy with typical AAS and, in addition, unilateral focal polymicrogyria (PMG), a feature hitherto unreported in AAS. Sequencing of the FGD1 gene in the index case and his mother revealed the presence of a novel mutation (1396A>G; M466V), located in the evolutionary conserved alpha-helix 4 of the RhoGEF domain. M466V was not found in healthy family members, in >300 healthy controls and AAS patients, and has not been reported in the literature or mutation databases to date, indicating that this novel missense mutation causes AAS, and possibly PMG. Brain cortex malformations such as PMG could be initiated by mutations in the evolutionary conserved RhoGEF domain of FGD1, by perturbing the signaling via Rho GTPases such as Cdc42 known to cause brain malformation.

[Acute headache in a case of cerebral cavernomas]

We report a case of a 52-year-old female patient with known cerebral cavernomas and acute headache. A cranial CT scan excluded an intracranial bleeding. Cavernomas are rare vascular malformations of the venous blood system (synon. cavernous angiomas) with a slow blood flow. Clinical manifestation is presented between an age of 30-50 years with mostly unspecific neurological symptoms like headache, nausea, vomiting and dizziness, but also epileptic seizures and bleedings may occur. In general, therapy is symptomatic. In cases of seizures, however, anticonvulsive treatment is indicated. Operation can be discussed for peripheral localized cavernomas with bleeding or for refractory seizures. If antiplatelet or anticoagulation therapy is necessary due to other diseases (coronary heart disease, atrial fibrillation, thrombosis, pulmonary embolism), cerebral cavernomas are not considered as an absolute contraindication. The risk for an ischemic stroke under atrial fibrillation (5-20%), for example, is higher than the risk for bleeding of a cerebral cavernoma under anticoagulation therapy.

Vascular birthmarks

Vascular birthmarks can be classified into hemangioma and vascular malformations. Hemangioma are frequent tumours of early infancy demonstrating endothelial hyperplasia, a history of rapid neonatal growth and slow involution during later childhood. Treatment of hemangioma is dependent of stage and type of the lesion. Given the current availability of drugs, lasers, and other techniques to treat hemangioma safely, philosophy of "benign neglect" should not be considered anymore. Vascular malformations show a normal endothelial turnover, being present at birth and growing commensurately with the child. Exact diagnosis by employing modern diagnostic means,which are able to differentiate low-flow from high flow lesions is important for further therapeutic management. Beside conservative treatment strategies, use of laser, sclerotherapy, interventional embolization and surgical treatment are possible management options. Patients should receive multidisciplinary care in qualified vascular centres.