RASA1 mutations may cause hereditary capillary malformations without arteriovenous malformations

BACKGROUND: Capillary malformation (CM), a common vascular abnormality, is often present among family members. Recently a rare form of hereditary vascular malformation termed capillary malformation-arteriovenous malformation (CM-AVM) was shown to be caused by heterozygous mutations in RASA1, encoding RAS p21 protein activator 1. CM-AVM is characterized by multiple, small CMs associated with either AVM or arteriovenous fistula (AVF) in affected individuals or at least one of their family members. OBJECTIVES: The purpose of the study was to find out whether CMs in the absence of AVM/AVF are associated with RASA1 mutations. PATIENTS/METHODS: We assessed three families comprising 14 affected individuals with CMs. Linkage to the RASA1 locus was evaluated using microsatellite markers. The RASA1 gene was scrutinized for pathogenic mutations using denaturing high-performance liquid chromatography screening and direct sequencing. RESULTS: AVM/AVF was identified in one of three affected families. CM without AVM/AVF was found to map in one large kindred to the RASA1 locus. Direct sequencing revealed novel heterozygous mutations segregating with CM in all three families. The mutations are predicted to result in premature termination of translation and RASA1 haplo-insufficiency. CONCLUSIONS: We have demonstrated that the spectrum of clinical manifestations due to mutations in RASA1 is wider than previously thought and also includes typical CMs not associated with AVM/AVF.     

Histopathologic and Ultrasound Characteristics of Cutaneous Capillary Malformations in a Patient with Capillary Malformation–Arteriovenous Malformation Syndrome

Capillary malformation–arteriovenous malformation (CM‐AVM) syndrome is an autosomal dominant disorder caused by mutations in RASA1. Multifocal, small, round‐to‐oval, pinkish‐to‐red cutaneous capillary malformations are seen in more than 90% of people with RASA1 mutations. These RASA1‐associated cutaneous capillary malformations (CMs) can accompany internal or cutaneous arteriovenous malformation (AVM) or arteriovenous fistula to constitute CM‐AVM syndrome. The cutaneous capillary malformations in CM‐AVM syndrome are unusual in that some lesions have high‐flow characteristics (according to Doppler or a white halo). We describe the histopathologic and corresponding ultrasound and Doppler findings in a CM from a patient with clinical CM‐AVM syndrome and show that an arterial component is not present in the dermis or the most superficial portions of the subcutaneous fat but that there is ultrasound evidence that an AVM resides in the underlying adipose tissue.     

Multifocal capillary malformations in an older,asymptomatic child with a novel RASA1 mutation

Multifocal capillary malformation (CM) is the cardinal feature of patients with RASA1 mutations. These CMs are ‘red flags’, signalling the possible association with an arteriovenous malformation (AVM) or an arteriovenous fistula (AVF). We report an 8‐year‐old boy who presented with > 20 CMs, who was found to have a novel mutation in the RASA1 gene. Radiological screening of children with RASA1 mutations is not standardized, and we elected to carry out baseline magnetic resonance imaging of the brain and spine in our case, which gave normal results. We discuss the recent literature and our approach in the management of such a case.     

EPHB4 Mutation Implicated in Capillary Malformation–Arteriovenous Malformation Syndrome: A Case Report

Capillary malformation–arteriovenous malformation (CM‐AVM) syndrome, due to inactivating mutations in RASA1 in 68% of cases, is characterized by the development of cutaneous capillary malformations and arteriovenous malformations or fistulas; no known genetic etiology has been identified in patients with CM‐AVM syndrome without RASA1 mutations. We present the case of a child with RASA1‐negative CM‐AVM syndrome with a de novo missense mutation in EPHB4, a transmembrane tyrosine kinase receptor essential for vasculogenesis. Inactivating the mutation in EPHB4 has been shown to upregulate the mitogen‐activated protein kinase pathway and the mammalian target of rapamycin complex 1, possibly contributing to the development of vascular malformations.     

A novel mutation in <Emphasis Type="Italic">RASA1</Emphasis> causes capillary malformation and limb enlargement

Capillary malformations are common vascular malformations. Several syndromes have been described in which CMs are present in association with limb enlargement, among these are Klippel-Trenaunay syndrome (KTS) and Parkes Weber syndrome (PWS). Mutations in the RASA1 gene have been shown to underlie the capillary malformation-arterio-venous malformation (CM-AVM) syndrome, sometimes presenting with PWS. We identified a family comprising a patient with CMs and limb enlargement and a number of family members with CM/CM-AVM. A novel mutation in RASA1 was found to underlie the disease in this case. The present results illustrate the extensive degree of phenotypic heterogeneity associated with deleterious mutations in RASA1.     

Heredity of port-wine stains: Investigation of families without a RASA1 mutation

Background: The prevalence of capillary malformations, also known as port-wine stains (PWS), is 0.3%. Familial segregation can occur. The capillary malformation–arteriovenous malformation (CM-AVM) phenotype is caused by mutations in the RASA1 gene. In PWS familial cases, the inheritance is considered to be autosomal dominant with variable penetrance. Objective: Investigation of the heredity of PWS among patients who attended the vascular anomaly section at the Department of Dermatology in Malmoe, Southern Sweden, between 1993 and 2004 and to study the involvement of the RASA1 gene in patients with a positive family history of PWS. Subjects and methods: A total of 254 patients were examined and given a questionnaire regarding family history of PWS. The first group of 175 patients (109 females and 66 males) reported a negative family history. The other group of 65 patients (46 females and 19 males) reported a positive family history (50% parents or brothers and sisters). Results: The heredity of PWS was 27% (65/240). Twenty-one patients with a positive family history and relatives had no CM-AVM phenotype for mutations in the RASA1 gene. Conclusion: PWS may have a stronger heredity component than it was reported earlier and inheritance should be considered when counseling a patient. RASA1 mutations do not explain the PWS in our patients.     

Good response to pulsed dye laser in patients with capillary malformation-arteriovenous malformation syndrome (CM-AVM)

Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is an autosomal dominant disorder caused by heterozygous mutations in RASA1 and EPHB4. Capillary stains in CM-AVM are compatible with Schöbinger's phase I AVMs. Vascular laser has been classically contraindicated for the treatment of AVMs, as there is a fear of accelerating their progression. In this study, we have treated capillary stains in five CM-AVM patients with pulsed dye laser, with improvement and without worsening or recurrence of the lesions after 1 year of clinical and ultrasound follow-up.     

Capillary Malformation—Arteriovenous Malformation Syndrome: Review of the Literature,Proposed Diagnostic Criteria,and Recommendations for Management

Capillary malformation–arteriovenous malformation syndrome is an autosomal dominant disorder caused by mutations in the RASA1 gene and characterized by multiple small, round to oval capillary malformations with or without arteriovenous malformations. Ateriovenous malformations occur in up to one‐third of patients and may involve the brain and spine. Although making the diagnosis is straightforward in some patients, there are other patients for whom diagnostic criteria may be helpful in their evaluation. Here we review the literature regarding capillary malformation?arteriovenous malformation syndrome, propose diagnostic criteria, and discuss the care of patients with this condition.     

Capillary Malformation–Arteriovenous Malformation Syndrome with Spinal Involvement

Capillary malformation–arteriovenous malformation (CM‐AVM) is a recently identified autosomal dominant disorder. Arteriovenous lesions have been reported in the brain, limbs, and face. We report a 7‐year‐old patient with CM‐AVM with spinal AVM, which is a rarely reported association.     

Atypical capillary malformations with subsequent diplegia: A difficult case of capillary malformation-arteriovenous malformation syndrome

Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is a rare condition associated with mutations in the genes RASA1 and EPHB4. We present a challenging case of CM-AVM in a 17-month-old boy with permanent diplegia from an undiagnosed arteriovenous malformation underlying a large atypical capillary malformation over the lower thoracic spine. This case demonstrates that clinicians should have a low threshold for neuroimaging in the context of new neurologic symptoms in patients with atypical capillary malformations.     

RASA1 mutation in a family with capillary malformation–arteriovenous malformation syndrome: A discussion of the differential diagnosis

We describe a family who presented with several scattered, vascular, cutaneous lesions and was found to have a novel mutation in RASA1, diagnostic of capillary malformation–arteriovenous malformation syndrome. Our patient was initially given a presumptive clinical diagnosis of hereditary hemorrhagic telangiectasia. Capillary malformation–arteriovenous malformation syndrome shares several features with hereditary hemorrhagic telangiectasia and hereditary benign telangiectasia, but it can be distinguished clinically according to its morphologic appearance and distribution of cutaneous vascular lesions, the presence of internal fast‐flow lesions, and genetic analysis.     

Síndrome malformaciones capilares-malformaciones arteriovenosas: presentación de 2 casos,claves diagnósticas y manejo

Capillary malformation-arteriovenous malformation syndrome is a rare type of vascular malformation first described in 2003. It is an autosomal dominant inherited disorder that has been reported in association with heterozygous mutations in the RASA1 gene, which encodes the protein RASp21. The clinical picture is characterized by multiple small capillary malformations which are associated with either arteriovenous malformations or arteriovenous fistulas in both the affected individual and other members of their family. We describe 2 new familial cases of this syndrome that were clinically and genetically diagnosed and studied in our hospital.     

Role of colour-Doppler high-frequency ultrasonography in capillary malformation-arteriovenous malformation syndrome: a case series

High-frequency ultrasonography (HFUS) represents a useful adjunct for dermatologists in the diagnosis of capillary malformation-arteriovenous malformation (CM-AVM) syndrome. We present a paediatric case series of 6 patients with confirmed RASA1 gene mutation in whom HFUS demonstrated AVM beneath cutaneous CM-like lesions greater than 1.5 cm.     

A Typical Vascular and Pigmentary Dermoscopic Pattern of Capillary Malformations in Capillary Malformation–Arteriovenous Malformation Syndrome: Report of Four Cases

We report dermoscopic characteristics of cutaneous capillary malformations in four patients with capillary malformation–arteriovenous malformation (CM‐AVM) syndrome. We observed a mixed vascular and pigmentary pattern with branched linear vessels and an underlying homogeneous brown background. Disappearance of the vascular pattern on pressure revealed an underlying faint pigmentary reticular pattern. Our results suggest that this typical biphasic pattern on dermoscopy may be useful for the diagnosis of CM‐AVM syndrome.     

Diffuse Capillary Malformation in Association with Fetal Pleural Effusion: Report of Five Patients

Capillary malformation (CM) can be a “red flag” for several syndromic vascular anomalies. We identified a subset of patients with diffuse CM and fetal pleural effusion and documented the type of CM, the etiology of the pleural effusion, the potential syndromic diagnosis, and outcome. Patients with a history of CM and fetal pleural effusion were identified by searching the database of patients evaluated at the Vascular Anomalies Center at Boston Children's Hospital. Standardized patient interviews and a retrospective review of records, photographs, and imaging studies were conducted. Five patients had diffuse CM and fetal pleural effusion. Two patients had macrocephaly‐CM (M‐CM), one had features of M‐CM and CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and spinal/skeletal anomalies and/or scoliosis), and one had diffuse CM with overgrowth. The pleural fluid was chylous in four patients. One patient had thoracic lymphatic malformation. Recurrent effusion occurred in one patient coincident with pneumonia at age 11 years. Four patients had a history of reactive airway disease and episodic pulmonary infections. The diagnosis of vascular anomaly–overgrowth syndromes, particularly M‐CM, should be considered in neonates with fetal pleural effusion.     

Vascular Stains: Proposal for a Clinical Classification to Improve Diagnosis and Management

Vascular stains are a common reason for consultation in pediatric dermatology clinics. Although vascular stains include all vascular malformations, the term is most often used to refer to capillary malformations, but capillary malformations include a wide range of vascular stains with different clinical features, prognoses, and associated findings. The discovery of several mutations in various capillary malformations and associated syndromes has reinforced these differences, but clinical recognition of these different types of capillary vascular stains is sometimes difficult, and the multitude of classifications and confusing nomenclature often hamper the correct diagnosis and management. From our own experience and a review of the most relevant literature on this topic, we propose categorizing patients with capillary vascular stains into seven major clinical patterns: nevus simplex, port‐wine stain, reticulated capillary malformation, geographic capillary malformation, capillary malformation–arteriovenous malformation (CM‐AVM), cutis marmorata telangiectatica congenita, and telangiectasia. We also discuss the differential diagnosis of vascular stains as well as other conditions that can closely resemble capillary malformations and thus may potentially be misdiagnosed.     

Cutaneous melanoma in a desert climate zone: a retrospective study of 125 cases

Background With increasing incidence over the last few decades, cutaneous malignant melanoma (CM) represents 3% of all skin tumors, and accounts for 75% of all deaths because of cutaneous malignancies. Little is known about the nature and epidemiology of CM in individuals with pigmented skin. Method Data were collected from the records of four public and private histopathology laboratories of Kerman city from March 20, 1994 to March 20, 2004. Skin biopsies with a diagnosis of CM were reevaluated to confirm the diagnosis of CM. The medical records of the patients were also taken into consideration. Results A total of 125 CMs were found. The male‐to‐female ratio was 1.08 : 1. The mean age at the time of diagnosis was 58.9 years; with a peak in the seventh decade of life. Acral‐lentiginous melanoma (ALM) represented 28.8% and; nodular melanoma occurred in 20% of cases. Limbs were the site of occurrence in 44% of tumors; whereas 36% of tumors occurred in head and neck region. There was a significant correlation between age and ALM (P = 0.007) and also between gender and melanoma types (P = 0.024). Conclusions This study indicates that some demographic and histopathologic features of CM in this population differ from those in the literature. More studies including cohort studies are needed to fully describe the nature and survival rate of CM in this area.     

Genotype and phenotype analysis of patients with pediatric cutaneous mastocytosis,especially wild-type KIT patients

Pediatric cutaneous mastocytosis (CM) is mainly attributed to gain-of-function mutations in KIT in mast cells. On the other hand, growing evidence suggests that CM patients exist without KIT mutations. To date, the association between the KIT mutation status and clinical phenotype has not been elucidated in pediatric CM, especially in patients with wild-type KIT. Nevertheless, genetic analysis has yet to be performed with whole KIT sequence of mast cells in Japanese patients with pediatric CM. In the present study, 11 Japanese patients with pediatric CM were analyzed to determine whether they had KIT mutations in their skin, and their clinical phenotypes were observed. The approximate frequency of patients with KIT mutation and that of wild-type KIT was almost consistent with the European analysis. The distribution of overall macules was similar between the patients with and without KIT mutations.     

Numerous intertriginous xanthomas in infant: A diagnostic clue for sitosterolemia

Sitosterolemia is a very rare autosomal recessive lipoprotein metabolic disorder caused by homozygous or compound heterozygous mutations in one of the two adenosine triphosphate‐binding cassette transporter genes, ABCG5 and ABCG8. Sitosterolemia is clinically characterized by xanthomas and atherosclerosis, arthritis, fever, hemolysis and macrothrombocytopenia even in early childhood. We described a 16‐month‐old girl, who had numerous yellowish‐brown intertriginous xanthomas along the skin creases on the extremities with severe hypercholesterolemia and elevated plant sterol levels. Histopathologically, xanthoma showed aggregation of foam cells in the dermis with a zone of mucin deposits in the dermal papilla. Electron microscopy showed numerous membrane‐bound lipid droplets and multivesicular lipid bodies in the foam cells, a round cell containing lipid droplets in the basal cell layer and abundant mucin deposits just beneath the basal lamina. Diagnosis of sitosterolemia was confirmed by DNA sequencing showing compound heterozygosity for previously reported missense mutations in exon 9 of ABCG5. Infants presenting with multiple xanthomas should be investigated for sitosterolemia, if there is no family history of dyslipidemia.     

Clinical characteristics and treatment of 52 cases of phakomatosis pigmentovascularis

Phakomatosis pigmentovascularis is a rare syndrome characterized by widespread capillary malformation and pigmented nevus. The objective of this study was to evaluate its characteristics and treatment. Fifty‐two patients presenting between 2003 and 2017 were retrospectively reviewed. Type IIa (port‐wine stain and dermal melanocytosis with oculocutaneous involvement) was most common. Systemic involvement was observed in 17.3% and it was not significantly correlated to extent of capillary malformation or pigmented nevus. However, systemic involvement was significantly frequent in patients with nevus of Ota and in patients with pigmented nevus located on the head and neck (P = 0.004 and 0.035, respectively). Capillary malformation was almost cleared in 28.6% of patients using pulsed dye laser, whereas pigmented nevus was almost cleared in 23.7% and completely cleared in 42.1% of patients using Q‐switched neodymium:yttrium–aluminum–garnet laser. Treatment outcome score showed significant inverse correlation with the extent of port‐wine stain or pigmented nevus (P = 0.047, ρ = ?0.308 and P = 0.011, ρ = ?0.410, respectively). Pigmented nevus demonstrated better treatment response to lasers than did capillary malformation. Smaller lesions tended to show better treatment outcomes for both capillary malformation and pigmented nevus.