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 hemihypertrophy 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]. Increased flow can sometimes be detected in the CMs with the use of a hand-held Doppler.
• 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

Sequence analysis, which detects missense, nonsense, and splice site mutations and small insertions and deletions, is the preferred method of identifying RASA1 mutations. The clinical sensitivity of RASA1 sequencing is extrapolated from data obtained from a large study that used denaturing high-performance liquid chromatography (DHPLC) mutation scanning [Revencu et al 2008].

• A RASA1 mutation was identified in 44 (78%) of 56 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 may be different 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. For example, the mutation detection frequency in the authors' clinical molecular genetics laboratory is 50% in persons said to have multiple capillary malformations with or without other vascular malformations [Authors, unpublished data].

Deletion/duplication analysis. No deletions or duplications involving RASA1 as causative of RASA1-related disorders have been reported, thus the frequency of exonic or whole-gene deletions/duplications is not yet known.

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

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
RASA1	Sequence analysis	Sequence variants 2	Unknown	Clinical
	Deletion/duplication analysis 3	Deletion/duplication of one or more exons or the entire gene	Unknown 4

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

4. No deletions or duplications involving RASA1 as causative of RASA1-related disorders have been reported. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

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

• In a person with characteristic multifocal capillary malformations with or without arteriovenous malformations;
• In a person with the clinical diagnosis of Parkes Weber syndrome, particularly when multifocal CMs are present.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Somatic mutations in RASA1 have been reported in basal cell carcinoma [Friedman et al 1993]. Otherwise, no syndromes other than CM-AVM and Parkes Weber syndrome with multifocal CMs have been associated with mutations in RASA1.

Natural History

The natural history of RASA1-related disorders is primarily based on the landmark publications with the largest cohorts [Eerola et al 2003, Revencu et al 2008]. Table 2 lists the known cases published to date. As more individuals are identified, the understanding of the natural history will likely evolve.

Symptoms from intracranial AVMs/AVFs seem to occur early in life [Revencu et al 2008]. 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. Prospective studies to determine if older individuals become symptomatic with 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.

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]. 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 requiring surgical intervention [Thiex et al 2010].

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.

Individuals with a RASA1 mutation may be at increased risk for tumor development. 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). Whether or not the rate of tumors is increased compared to the general population is unknown.

Genotype-Phenotype Correlations

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

Penetrance

Penetrance is 89%-96% based on two studies from same group:

• Eerola et al [2003] found a mutation in four individuals who had no obvious vascular malformation.
• Revencu et al [2008] found 55 out of 57 RASA1 heterozygotes were affected.

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].

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

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.

Hemihypertrophy and/or leg length discrepancy. Referral to an orthopedist is recommended in individuals with hemihypertrophy and leg length discrepancy.

Surveillance

Currently data on long-term development of AVMs/AVFs after initial screening are insufficient. 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 theoretical consideration is avoiding routine use of anticoagulants unless indicated for treatment of a different medical condition.

Testing 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.

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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

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, Testing Relatives at Risk for information on testing 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must have been identified in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as RASA1-related disorders that do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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Suggested Reading

1. Duffy K. Genetics and syndromes associated with vascular malformations. Pediatr Clin North Am. 2010;57:1111–20. [PubMed: 20888461]
2. Brouillard P, Vikkula M. Genetic causes of vascular malformations. Hum Mol Genet. 2007;16:R140–9. [PubMed: 17670762]

Acknowledgments

We acknowledge Dr. Johannes Fredrik Grimmer for his insights.

Revision History

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