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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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RASA1-Related Disorders

, MD, PhD, FACMG and , MD.

Author Information
, MD, PhD, FACMG
Department of Pathology
University of Utah
ARUP Laboratories
Salt Lake City, Utah
, MD
University of Utah
Salt Lake City, Utah

Initial Posting: ; Last Update: December 19, 2013.

Summary

Disease characteristics. RASA1-related disorders are characterized by the presence of multiple, small (1-2 cm in diameter) capillary malformations mostly localized on the face and limbs. About 30% of affected individuals also have associated arteriovenous malformations (AVMs) and/or arteriovenous fistulas (AFVs), fast-flow vascular anomalies that typically arise in the skin, muscle, bone, spine, and brain; life-threatening complications of these lesions can include bleeding, congestive heart failure, and/or neurologic consequences. Symptoms from intracranial AVMs/AVFs seem to occur early in life. Several individuals with a RASA1 mutation have the clinical diagnosis of Parkes Weber syndrome (multiple micro-AVFs associated with a cutaneous capillary stain and excessive soft tissue and skeletal growth of an affected limb).

Diagnosis/testing. The diagnosis is based on clinical findings and molecular genetic testing of RASA1, the only gene in which mutations are associated with RASA1-related disorders.

Management. Treatment of manifestations: For capillary malformations that are of cosmetic concern, referral to a dermatologist. For AVMs and AVFs, the risks and benefits of intervention (embolization vs. surgery) must be considered, usually with input from a multidisciplinary team (e.g., specialists in interventional radiology, neurosurgery, surgery, cardiology, and dermatology). For cardiac overload, referral to a cardiologist. For hemihyperplasia and/or leg-length discrepancy, referral to an orthopedist. Lymphangiography to evaluate for lymphatic malformations may be considered; compression stockings for those with evidence of lymphedema.

Surveillance: Repeat imaging studies if clinical signs/symptoms of AVMs/AVFs become evident.

Evaluation of relatives at risk: If the family-specific mutation is known, molecular genetic testing of at-risk relatives allows early diagnosis and, thus, prompt treatment of AVMs/AVFs in order to reduce/avoid secondary adverse outcomes. At-risk infants are candidates for prompt diagnosis given the early presentation of neurologic complications from intracranial AVMs/AVFs.

Genetic counseling. RASA1-related disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with a RASA1-related disorder have an affected parent; 30% of cases are caused by a de novo mutation. Each child of an individual with a RASA1-related disorder has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation of an affected family member is known.

GeneReview Scope

RASA1-Related Disorders: Included Disorders 
  • Capillary malformation-arteriovenous malformation syndrome
  • RASA1-related Parkes Weber syndrome

For synonyms and outdated names see Nomenclature.

Diagnosis

Clinical Diagnosis

The diagnosis of RASA1-related disorders may be suspected in individuals who have either of the following:

  • Multiple capillary malformations (CMs) with or without arteriovenous malformation (AVM) and/or arterio-venous fistula (AFV). CMs are the hallmark of a RASA1-related disorder; individuals with an identified RASA1 mutation typically have multifocal CMs.
  • Parkes Weber syndrome (PKWS)

Limb hemihyperplasia has been observed in several individuals with multifocal CMs with the clinical diagnosis of PKWS in whom mutations in RASA1 were identified [Revencu et al 2008].

Primary manifestations

  • Capillary malformations. The CMs associated with RASA1 mutations generally are atypical pink-to-reddish brown, multiple, small (1-2 cm in diameter), round-to-oval lesions sometimes with a white halo. The CMs are composed of dilated capillaries in the papillary dermis [Hershkovitz et al 2008b]. They are mostly localized on the face and limbs. Although AVMs or arteriovenous fistulas (AVF) can be observed, CMs may be the only finding in some affected individuals [Hershkovitz et al 2008a, Revencu et al 2008, Revencu et al 2013a].
  • Arteriovenous malformations/fistulas. AVMs and AVFs, which may be associated with overgrowth, have been observed in soft tissue, bone, and brain [Eerola et al 2003].

Molecular Genetic Testing

Gene. Mutations in RASA1 are responsible for capillary malformation-arteriovenous malformation syndrome (CM-AVM) and, in some cases, Parkes Weber syndrome.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in RASA1-Related Disorders

Gene 1 Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
RASA1Sequence analysis 4Sequence variantsAbout 70% 5
Deletion/duplication analysis 6Exon(s)or the entire geneUnknown 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Extrapolated from data obtained from two large studies that used denaturing high-performance liquid chromatography (DHPLC) mutation scanning [Revencu et al 2008, Revencu et al 2013a]. A RASA1 mutation was identified in 44 (78%) of 56 probands and 68 (68%) of 100 probands with multifocal CMs with or without additional vascular malformations [Revencu et al 2008]. A RASA1 mutation was identified in 13 (81%) of 16 probands with PKWS with multifocal CMs [Revencu et al 2008]. Note: (1) Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used. (2) Mutation detection frequency is lower in clinical cases when compared to well-characterized research study groups because patient selection criteria are not likely to be as strict in clinical settings. One study found mutation in 10 (39%) of 26 probands with CMs [Wooderchak-Donahue et al 2012].

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. A patient with a large AVM on the face was found to carry a deletion of exons 21-25 [unpublished data]. One patient with 3.1-Mb microdeletion on the 5q14.3q15 region including RASA1 and four other genes has been reported [Carr et al 2011]. This patient has multifocal CMs and severe developmental delay associated with MEF2C haploinsufficiency. Carr et al [2011] reviewed four other individuals previously reported with simultaneous deletions of RASA1 and MEF2C, but capillary malformations were not reported in these individuals.

Testing Strategy

To confirm/establish the diagnosis in a proband. Sequence analysis of RASA1 should be considered in a person with either of the following:

  • Characteristic multifocal capillary malformations with or without arteriovenous malformations;
  • The clinical diagnosis of Parkes Weber syndrome (see Differential Diagnosis), particularly when multifocal CMs are present.

If no mutation is identified through sequence analysis in an individual with the above finding(s), deletion/duplication analysis of RASA1 can be considered.

Clinical Description

Natural History

The natural history of RASA1-related disorders is primarily based on three publications with large cohorts (>20 cases) by Eerola et al [2003] (n=39), Revencu et al [2008] (n=101), and Revencu et al [2013a] (n=138), with insights from a number of other case series and case reports [Hershkovitz et al 2008a, Hershkovitz et al 2008b, Thiex et al 2010, Carr et al 2011, Buhl et al 2012, de Wijn et al 2012, Wooderchak-Donahue et al 2012, Burrows et al 2013, Català et al 2013, Durrington et al 2013, Kim et al 2013]. Over 320 individuals with RASA1 mutations have been reported, and it is clear that CMs, AVMs, AVFs, and a Parkes Weber phenotype are common manifestations.

According to data from the series of individuals reported by Revencu et al [2013a] and their review of previously published cases, the percentage of individuals with RASA1 mutations with common phenotypic findings are as follows:

  • CMs (~97%)
  • AVMs/AVFs (~24%; 10% intra-central nervous system, 13% extra-central nervous system)
  • Parkes Weber phenotype (8%)

CM

The CMs can be present at birth and tend to increase in number over time. In some affected individuals, the presence of numerous white pale halos (~1 cm in diameter) with a central red punctate spot have been reported [Revencu et al 2013a] in addition to typical CMs. Arterial flow with Doppler ultrasound has been reported over the CMs [Kim et al 2013] and is hypothesized to be a manifestation of an underlying AVM. It is unclear if arterial flow abnormalities associated with the CMs can increase or develop over time.

There have been multiple families described with significant variable expressivity. The intrafamilial variability, multifocal location, and increase in number over time suggest modifying factors and somatic events. In one individual with Parkes-Weber syndrome with a germline RASA1 mutation, Revencu et al [2013a] documented loss of the wild-type RASA1 allele in tissue taken from a neurofibroma from the affected limb, providing evidence that second hits may be involved.

AVM/AVF

Intracranial. Symptoms from intracranial AVMs/AVFs can occur early in life [Revencu et al 2008, Revencu et al 2013a]. Vein of Galen aneurismal malformation and other intracranial AVMs have led to seizures, hydrocephalus, migraine headaches, and cardiac failure [Eerola et al 2003, Revencu et al 2008]. Revencu et al [2008] reported that most of the intracranial lesions were macrofistulas causing symptoms in infancy. However, this finding may be biased given that the identification of the AVMs/AVFs may be secondary to associated symptoms and that asymptomatic individuals may not have had the imaging studies needed to detect the lesions.

Extracranial AVMs and AVFs are also prevalent and typically reported in skin, muscle, and spine; however, AVMs/AVFs have not been commonly reported in viscera [Revencu et al 2008], a distinguishing difference from hereditary hemorrhagic telangiectasia (HHT). Symptomatic intraspinal AVMs have been reported, and MRI identified treatable intraspinous lesions requiring endovascular/surgical treatment [Thiex et al 2010]. Intraspinal AVMs have resulted in neurologic insult [Thiex et al 2010].

Approximately 50% of AVMs/AVFs are located in the head/neck region [Revencu et al 2013a], but imaging is likely preferentially performed in this region. Prospective studies to determine if individuals become symptomatic over time have not been performed. In addition, given that all individuals with mutations in RASA1 are not likely to have had comprehensive imaging studies, it is difficult to determine how commonly AVMs/AVFs occur in the RASA1-related disorders.

Cardiac overload/failure is a potential complication in individuals with significant fast flow lesions. In particular, one third of individuals with PKWS with a RASA1 mutation were reported to require cardiac follow up [Revencu et al 2008]. One of the original persons reported in infancy by Eerola et al [2003] had an AVF between the left carotid artery and jugular vein which caused cardiac overload requiring treatment. Another affected individual with CM-AVM developed findings suggestive of high-output cardiac failure during pregnancy [Durrington et al 2013].

Congenital heart defects have been reported in four individuals with RASA1 mutations; this finding may be coincidental [Revencu et al 2008].

Lymphatic malformations have been reported in several individuals with RASA1 mutations [de Wijn et al 2012, Burrows et al 2013]. A study by Burrows et al [2013] supports the presence of lymphatic abnormalities in both Rasa1 knockout mice and in one individual with Parkes-Weber syndrome with a RASA1 mutation. Lymphangiography and near-infrared fluorescence lymphatic imaging in this person [Burrows et al 2013] showed abnormally dilated collecting lymphatics with sluggish flow in the unaffected limb, and tortuous lymphatics of the affected limb with lymphocele-like vesicles on the groin. Whether the lymphatic abnormalities in individuals with RASA1 mutations are progressive is not yet known.

Tumors. Individuals with a RASA1 mutation may theoretically be at increased risk for tumor development, but current review of the reported cases does not confirm this. Revencu et al [2008] reported in their 44 families with a RASA1 mutation several different types of tumors (e.g., optic glioma, lipoma, superficial basal cell carcinoma, angiolipoma, non-small-cell lung cancer, and vestibular schwannoma). However, in their larger series of 138 individuals in 2013, the only tumors reported were two common basal cell carcinomas in two affected individuals from the same family [Revencu et al 2013a]. The finding is interesting given that somatic mutations in RASA1 have been reported in basal cell carcinoma [Friedman et al 1993]. Revencu et al studied neurofibroma tissue from one individual with the RASA1 mutation c.2603+5G>T and found loss of the wild-type RASA1 allele in addition to two somatic NF2 mutations [Revencu et al 2013a]; hence, the contribution of RASA1 to the tumor development is not clear. Whether or not the rate of tumors is increased compared to the general population is still unknown, but it is likely not dramatically increased.

Limb overgrowth has been reported in both the upper and lower extremities. The overgrowth is typically noticeable in infancy and can range in severity. Most individuals with RASA1 mutations with limb overgrowth fulfill the findings of Parkes-Weber syndrome. Revencu et al [2013a] defined Parkes-Weber syndrome in their series as the presence of a capillary stain, bony and soft tissue hyperplasia, and multiple arteriolovenular microfistulas throughout an upper or lower extremity.

Other findings observed in a small number (but >1) of individuals with RASA1 mutations include seizures, headaches, hydrocephalus, neurogenic bladder, varicosities, and hemangiomas. It is not clear if these findings are truly associated with RASA1 mutations, or to what extent they represent secondary complications of AVMs/AVFs.

Developmental delay and severe neurologic findings were reported in individuals with microdeletions encompassing RASA1 and MEF2C [Carr et al 2011], but it is thought that these findings are not secondary to deletion of RASA1.

Little prospective data are available to truly delineate the natural history of RASA1-related conditions. As more individuals with RASA1 mutations are identified, the understanding of the natural history will likely evolve.

Genotype-Phenotype Correlations

Studies to date are insufficient to identify genotype-phenotype correlations.

Penetrance

Penetrance is 90%-99% based on the following studies:

Nomenclature

Eerola et al [2003] named the phenotype caused by RASA1 mutations 'capillary malformation-arteriovenous malformation' (CM-AVM).

Prevalence

Prevalence of RASA1-related disorders is estimated at 1:100,000 in Northern Europeans [Revencu et al 2008].

Differential Diagnosis

Parkes Weber syndrome (PKWS) (OMIM 608355) is characterized by a cutaneous capillary malformation associated with underlying multiple micro-AVFs and soft tissue and skeletal hypertrophy of the affected limb [Mulliken & Young 1988]. Most affected individuals are simplex cases (i.e., a single occurrence in a family); however, some persons with PKWS and multiple CMs have been found to have a RASA1 mutation [Eerola et al 2003, Revencu et al 2008]. Conversely, individuals with PKWS who do not have multifocal CMs are unlikely to have a RASA1 mutation. Thus, PKWS is likely a heterogeneous condition.

Hereditary benign telangiectasia (HBT) (OMIM 187260) is associated with widespread telangiectasias. The areas affected are predominantly the face, upper limbs, and upper trunk. The telangiectasias are venular and associated with atrophy of the upper dermis. Wells & Dowling [1971] reported three families in which HBT appeared to have an autosomal dominant pattern of inheritance. The telangiectasias observed in affected family members varied in size (1x1 cm to 6x4 cm) and number (1 to >10). Lesions invariably became paler with increasing age. Histologic examination showed normal epidermis and dilatation of the smallest blood vessels of the upper part of the dermis. The cause of HBT is currently unknown.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. Although HHT is a developmental disorder and infants are occasionally severely affected, in most people the features are age dependent, with the diagnosis not suspected until adolescence or later. Small AVMs (or telangiectases) close to the surface of the skin and mucous membranes often rupture and bleed after slight trauma. The most common clinical manifestation is spontaneous and recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Approximately 25% of individuals with HHT have GI bleeding, which most commonly begins after age 50 years. Large AVMs often cause symptoms when they occur in the brain, liver, or lungs; complications from bleeding or shunting may be sudden and catastrophic.

HHT is caused by mutations in a number of genes involved in the TGF-β/BMP signaling cascade:

  • ENG, encoding the cell surface co-receptor endoglin
  • ACVRL1 (ALK1), encoding a cell surface receptor
  • SMAD4, encoding an intracellular signaling molecule
  • At least two other genes that have not been identified

Sturge-Weber syndrome (SWS) (OMIM 185300) is characterized by the intracranial vascular anomaly leptomeningeal angiomatosis, which most often involves the occipital and posterior parietal lobes. The most common symptoms and signs are facial cutaneous vascular malformations (port-wine stains), seizures, and glaucoma. No RASA1 mutations were identified in nine persons with SWS who represented simplex cases (i.e., a single occurrence in a family) [Zhou et al 2011]. In another study, no RASA1 mutations were identified in 37 individuals with SWS [Revencu et al 2013a].

Somatic mosaic mutations in GNAQ have been reported in individuals with Sturge-Weber syndrome [Shirley et al 2013].

Klippel-Trenaunay-Weber syndrome (KTS) (OMIM 149000) or Klippel-Trenaunay syndrome is characterized by capillary malformations with slow flow vascular malformations typically in association with hypertrophy of the related bones and soft tissues. Diagnostic criteria for KTS have been proposed [Oduber et al 2008]. No RASA1 mutations to date have been identified in individuals with typical Klippel-Trenaunay syndrome [Revencu et al 2013b]. Since there are no AVF lesions in KTS, clinical prognosis is generally better than in PKWS.

PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and Proteus-like syndrome:

  • CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium. Affected individuals usually have macrocephaly, trichilemmomas, palmoplantar keratoses, and oral papillomatosis and present by the late 20s.
  • BRRS is a congenital disorder characterized by macrocephaly, intestinal hamartomatous polyposis, lipomas, and pigmented macules of the glans penis.
  • PS is a complex, highly variable disorder involving congenital malformations and hamartomatous overgrowth of multiple tissues, as well as connective tissue nevi, epidermal nevi, and hyperostoses [Turner et al 2004].
  • Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS.

The diagnosis of PHTS relies on identification of a PTEN disease-causing mutation.

Vascular anomalies observed in PHTS are usually fast flow, intramuscular, and associated with ectopic fat; and severely disrupt tissue architecture [Caux et al 2007, Tan et al 2007].

Multiple cutaneous and mucosal venous malformations (VMCM) are characterized by the presence of small, multifocal bluish cutaneous and/or mucosal venous malformations. They are usually present at birth. New lesions appear with time. Small lesions are usually asymptomatic; larger lesions can invade subcutaneous muscle and cause pain. Malignant transformation has not been reported. The diagnosis of VMCM is based on clinical evaluation of the cutaneous lesions. Doppler ultrasound examination and MRI can be used to confirm the venous component and extent of lesions. TEK (also known as TIE2) is the only gene in which mutations are known to be associated with VMCM.

Hereditary glomuvenous malformations (OMIM 138000) are characterized by multiple benign cutaneous lesions derived from arteriovenous shunts. Although clinically they look like any venous malformation, they are more painful on palpation, only partially compressible, and usually not found in mucosa. They have a cobblestone appearance with a consistency harder than that of venous malformations. Histologically, glomuvenous malformations are distinguishable by the presence of pathognomonic rounded cells (glomus cells) around the distended vein-like channels [Brouillard et al 2002]. In addition, familial aggregation is more common than in venous malformations generally, and several pedigrees showing autosomal dominant inheritance have been reported [Boon et al 2004]. Disease-causing mutations were identified in GLMN, the gene encoding glomulin, in families with glomuvenous malformations. Most mutations are truncating mutations [O’Hagan et al 2006].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with a RASA1-related disorder, the following evaluations are recommended:

  • Medical history and physical examination with a focus on symptoms and findings secondary to AVMs/AVFs
  • Brain imaging to identify AVMs/AVFs (e.g., vein of Galen aneurysms and other intracranial AVMs) to allow early identification of macrofistulas that can be treated in infancy prior to the development of symptoms [Revencu et al 2008]
  • Consideration of spine imaging to identify and characterize AVMs/AVFs. Currently no consensus protocols for radiographic evaluation of individuals with RASA1-related disorders have been developed; therefore, discussion with a radiologist is recommended in order to develop an appropriate plan for imaging based on the patient's age and the capabilities and experience of the imaging facility.
  • Consideration of further imaging in individuals with evidence of cardiac overload, to look for causative AVMs/AVFs
  • Medical genetics consultation

Treatment of Manifestations

Capillary malformations (CMs). Referral to a dermatologist can be considered for evaluation of CMs that are of cosmetic concern and discussion of the risks and benefits of intervention.

AVMs/AVFs. The risks and benefits of intervention for AVMs and AVFs must be considered. Depending on the location and symptoms of AVMs/AVFs, a multi-disciplinary team including specialists in interventional radiology, neurosurgery, surgery, cardiology, and dermatology will likely be required to determine appropriate approaches (e.g., embolization vs. surgery).

Cardiac overload. Referral to a cardiologist is indicated if cardiac overload is suspected.

Hemihyperplasia and/or leg length discrepancy. Referral to an orthopedist is recommended in individuals with hemihyperplasia and leg length discrepancy. Lymphangiography to evaluate for lymphatic malformations may be considered. Compression stockings for those with evidence of lymphedema may be considered.

Surveillance

Currently data on long-term development of AVMs/AVFs after initial screening are insufficient. It has been hypothesized that AVMs/AVFs may develop over time [Orme et al 2013], but there have not been reports to date of individuals who had normal imaging screens who subsequently developed AVMs/AVFs. The clinician should have a low threshold to repeat imaging studies if clinical signs/symptoms of AVMs/AVFs become evident.

Agents/Circumstances to Avoid

Although no agents/circumstances resulting in complications of RASA1-related disorders have been reported, a theoretic consideration is avoidance of routine use of anticoagulants unless indicated for treatment of a different medical condition.

Evaluation of Relatives at Risk

Molecular genetic testing for at-risk relatives is appropriate in order to allow early diagnosis and treatment of AVMs/AVFs to reduce/avoid secondary adverse outcomes. It should be noted in particular that at-risk infants are candidates for prompt diagnosis given the early presentation of neurologic complications from intracranial AVMs/AVFs [Revencu et al 2008].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

One adult with CM-AVM and a RASA1 mutation has been reported with a worsening of symptoms during pregnancy. She developed pulmonary and peripheral edema with concern for high-output heart failure that resolved after pregnancy [Durrington et al 2013].

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

RASA1-related disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with a RASA1-related disorder have an affected parent.
  • A proband with a RASA1-related disorder may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is approximately 30% [Revencu et al 2008].
  • If the disease-causing mutation found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are a de novo mutation in the proband or germline mosaicism in a parent. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include targeted mutation testing of both parents for the mutation identified in the proband.

Note: Although most individuals diagnosed with a RASA1-related disorder have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for a RASA1-related disorder because of the possibility of reduced penetrance in a parent.
  • If the disease-causing mutation found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism in one of the parents.

Offspring of a proband. Each child of an individual with a RASA1-related disorder has a 50% chance of inheriting the mutation.

Other family members

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in an affected family member, prenatal testing for pregnancies at increased risk is possible either through a clinical laboratory or a laboratory offering custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Foundation for Facial Reconstruction
    317 East 34th Street
    Room 901
    New York NY 10016
    Phone: 212-263-6656
    Fax: 212-263-7534
    Email: info@nffr.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. RASA1-Related Disorders: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for RASA1-Related Disorders (View All in OMIM)

139150RAS p21 PROTEIN ACTIVATOR 1; RASA1
608354CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION; CMAVM
608355PARKES WEBER SYNDROME

Gene structure. RASA1 is 123 kb long and contains 25 coding exons. It produces a 4.3-kb mRNA product. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Germline mutations in RASA1 cause the RASA1-related disorders discussed in this GeneReview. The approximately 50 mutations reported to date are primarily nonsense, frameshift, or splice site mutations [Eerola et al 2003, Hershkovitz et al 2008a, Hershkovitz et al 2008b, Revencu et al 2008]. A few missense mutations have also been identified within families; however, none has been confirmed as pathogenic using functional studies. No common mutations have been identified. Sequence variants interpreted to be of uncertain significance are not common. Based on the currently identified mutations haploinsufficiency is a suggested mechanism for the disease. Second hits have been proposed as a mechanism for development of the vascular lesions given that Revencu et al [2013a] documented in one individual with Parkes-Weber syndrome with a germline RASA1 mutation a loss of the wild-type RASA1 allele in tissue taken from a neurofibroma from the affected limb.

Normal gene product. RASA1 is a 1047-amino acid p120-RasGTPase-activating protein (p120-RasGAP). The N-terminal contains a Src homology region; the C-terminal contains a pleckstrin homology domain, protein kinase conserved region 2, and a RasGTPase-activating domain.

The protein RASA1 switches the active GTP-bound Ras to the inactive GDP-bound form. It is a negative regulator of the Ras/MAPK-signaling pathway which mediates cellular growth, differentiation, and proliferation from various protein kinases on cell surfaces.

Abnormal gene product. Mutations in RASA1 lead to Ras being constitutively active and resistant to GAPs. Increased risk for tumor development is possible, particularly given the role of RASA1 in the Ras signal transduction pathway.

References

Literature Cited

  1. Boon LM, Mulliken JB, Enjolras O, Vikkula M. Glomuvenous malformation (glomangioma) and venous malformation: distinct clinicopathologic and genetic entities. Arch Dermatol. 2004;140:971–6. [PubMed: 15313813]
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Suggested Reading

  1. Brouillard P, Vikkula M. Genetic causes of vascular malformations. Hum Mol Genet. 2007;16:R140–9. [PubMed: 17670762]
  2. Duffy K. Genetics and syndromes associated with vascular malformations. Pediatr Clin North Am. 2010;57:1111–20. [PubMed: 20888461]
  3. Wooderchak-Donahue WL, McDonald J, O'Fallon B, Upton PD, Li W, Roman BL, Young S, Plant P, Fülöp GT, Langa C, Morrell NW, Botella LM, Bernabeu C, Stevenson DA, Runo JR, Bayrak-Toydemir P. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet. 2013;93:530–7. [PMC free article: PMC3769931] [PubMed: 23972370]

Chapter Notes

Acknowledgments

We acknowledge Dr. Johannes Fredrik Grimmer for his insights.

Revision History

  • 19 December 2013 (me) Comprehensive update posted live
  • 22 February 2011 (me) Review posted live
  • 6 December 2010 (pbt) Original submission
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