Decoding Marfan Test Results: A Comprehensive Guide

Marfan syndrome, a complex genetic disorder affecting connective tissue, can manifest in a myriad of ways, making its diagnosis a nuanced process. For individuals undergoing testing, the wait for results can be fraught with anxiety, and the subsequent interpretation often feels like navigating a dense medical labyrinth. This guide aims to demystify the process, transforming the intimidating jargon into clear, actionable understanding. We’ll delve deep into the various tests employed, what their findings signify, and how these pieces of information coalesce to form a definitive diagnosis, or rule one out. Our goal is to empower you with the knowledge to comprehend your Marfan test results, fostering informed discussions with your healthcare providers.

Understanding Marfan Syndrome: A Brief Overview

Before we dissect the test results, a foundational understanding of Marfan syndrome itself is crucial. Marfan syndrome is caused by a mutation in the FBN1 gene, which provides instructions for making fibrillin-1, a protein essential for forming elastic fibers in connective tissue. This ubiquitous tissue provides support, strength, and elasticity to virtually every part of the body, including the heart, blood vessels, bones, joints, eyes, and lungs. Consequently, a defect in fibrillin-1 can lead to a wide range of symptoms affecting these systems.

The inheritance pattern for Marfan syndrome is autosomal dominant, meaning only one copy of the altered gene is needed to cause the disorder. This implies that if a parent has Marfan syndrome, there’s a 50% chance their child will inherit it. However, approximately 25% of Marfan cases arise from spontaneous new mutations, with no family history.

The clinical presentation of Marfan syndrome is highly variable, even within the same family. Some individuals may experience mild symptoms, while others face severe, life-threatening complications, particularly those affecting the cardiovascular system, such as aortic aneurysm and dissection. This variability underscores the importance of comprehensive testing and careful interpretation of results.

The Diagnostic Journey: A Multi-faceted Approach

Diagnosing Marfan syndrome is rarely based on a single test result. Instead, it involves a careful evaluation of clinical signs and symptoms, family history, and a battery of specialized tests. The Ghent nosology, a set of diagnostic criteria, is widely used by clinicians to integrate these various findings. Understanding the tests themselves is the first step in decoding their results.

Genetic Testing: Unmasking the FBN1 Mutation

Genetic testing is often considered the cornerstone of Marfan diagnosis, particularly when clinical presentation is ambiguous or when there’s a need for definitive confirmation. This testing typically involves analyzing a blood sample to look for mutations in the FBN1 gene.

Types of Genetic Tests and What They Show

1. Sanger Sequencing (Traditional Gene Sequencing): This method is a targeted approach, meticulously reading the genetic code of the FBN1 gene exon by exon (the protein-coding regions).
   • What it reveals: Sanger sequencing is highly effective at identifying known mutations or small deletions/insertions within the FBN1 gene.

   • Decoding Results:

     • “Pathogenic Variant Detected” or “Likely Pathogenic Variant Detected”: This is the most definitive result for Marfan syndrome. It means a specific change in the FBN1 gene has been identified that is known or highly likely to cause Marfan syndrome. The report will often specify the exact mutation (e.g., c.200G>A, p.Gly67Asp). This finding, especially in conjunction with clinical features, strongly supports a Marfan diagnosis.

     • “Variant of Uncertain Significance (VUS)”: This result indicates a change in the FBN1 gene has been found, but its clinical significance is currently unknown. It means scientists aren’t sure if this particular change causes Marfan syndrome or if it’s a benign variation.

       • Decoding VUS: This is perhaps the most challenging result to interpret. A VUS alone is usually not sufficient to diagnose Marfan syndrome. Further investigation is often required, which might include:
         • Family Studies: Testing other family members (parents, siblings) to see if they carry the same VUS and if they also have Marfan-like features. If the VUS is present in an affected family member but absent in an unaffected one, it increases the likelihood of it being pathogenic. If it’s present in unaffected individuals, it might suggest it’s benign.

         • Clinical Correlation: Re-evaluating the individual’s clinical signs and symptoms. If there are strong clinical features of Marfan, even a VUS might prompt closer monitoring.

         • Research and Database Searches: Geneticists continuously update databases with new information about gene variants. A VUS today might be reclassified as pathogenic or benign tomorrow as more data becomes available.

     • “No Pathogenic Variant Detected” or “Negative for FBN1 Mutation”: This indicates that no known Marfan-causing mutations were found in the FBN1 gene using this method.

       • Decoding “Negative”: While reassuring, a negative FBN1 genetic test does not definitively rule out Marfan syndrome, particularly in cases with strong clinical suspicion.
         • Reasons for a “Negative” result despite Marfan syndrome:
           • Limitations of Sanger Sequencing: It might miss large deletions or duplications in the gene.

           • Mutations in other genes: A small percentage of Marfan-like disorders are caused by mutations in genes other than FBN1 (e.g., TGFBR1, TGFBR2, SMAD3, ACTA2, MYH11 for Loeys-Dietz syndrome and other aortopathies).

           • Deep Intronic Mutations: Mutations located deep within introns (non-coding regions) may not be detected by standard sequencing and can still affect gene function.

           • Clinical vs. Genetic Diagnosis: Some individuals may meet clinical criteria for Marfan syndrome even without an identifiable FBN1 mutation. This can be challenging for both patients and clinicians.

2. Next-Generation Sequencing (NGS) / Gene Panels: This more advanced technology allows for the simultaneous sequencing of multiple genes associated with Marfan syndrome and related connective tissue disorders.

   • What it reveals: NGS panels can identify a broader spectrum of mutations, including those in FBN1 and other genes linked to Marfan-like conditions (e.g., Loeys-Dietz syndrome, Vascular Ehlers-Danlos syndrome). Some panels also include analysis for large deletions/duplications.

   • Decoding Results: The interpretation principles are similar to Sanger sequencing, but the scope is wider.

     • Pathogenic/Likely Pathogenic in FBN1: Confirms Marfan syndrome.

     • Pathogenic/Likely Pathogenic in another gene (e.g., TGFBR2): This would point towards a related condition like Loeys-Dietz syndrome, which has similar features but different genetic underpinnings and potentially distinct management strategies. This is crucial for accurate diagnosis and tailored care.

     • VUS in FBN1 or other genes: Similar challenges in interpretation as with Sanger, requiring further clinical and family evaluation.

     • No Pathogenic/Likely Pathogenic Variants: Again, does not entirely rule out all possibilities, but significantly reduces the likelihood of a genetic diagnosis within the tested panel.

Concrete Example for Genetic Testing:

• Scenario 1: Positive Result

  • Report Snippet: “FBN1: c.456C>A (p.Cys152Ter) detected. This is a known pathogenic nonsense mutation leading to premature protein truncation. Consistent with Marfan syndrome.”

  • Decoding: This is a clear-cut positive result. The mutation “c.456C>A” tells us the exact nucleotide change in the gene, and “p.Cys152Ter” indicates the resulting change in the protein (a cysteine at position 152 is replaced by a stop codon, leading to a truncated, non-functional protein). This is highly indicative of Marfan syndrome, especially if clinical features are present.

• Scenario 2: Variant of Uncertain Significance (VUS)

  • Report Snippet: “FBN1: c.789G>T (p.Gly263Val) detected. This is a Variant of Uncertain Significance. Insufficient evidence currently exists to classify this variant as pathogenic or benign.”

  • Decoding: This result requires careful consideration. Is there a strong family history? Does the individual exhibit multiple Marfan features? If so, further investigation (e.g., testing parents) is warranted. If there are minimal clinical signs and no family history, this VUS might be less concerning, but continued monitoring may be advised.

• Scenario 3: Negative Result (Clinical Suspicion)

  • Report Snippet: “No pathogenic or likely pathogenic variants detected in the FBN1 gene.”

  • Decoding: The genetic test is negative for the FBN1 gene. However, if the patient has significant Marfan features (e.g., severe aortic dilation, ectopia lentis, distinct skeletal features), the clinician might consider testing for other genes associated with aortopathies (e.g., a multi-gene panel) or continue to manage the patient clinically as if they have Marfan syndrome, given the strong clinical evidence. This emphasizes that a genetic test is one piece of the puzzle, not always the only piece.

Cardiovascular Evaluation: The Heart of the Matter

Given the life-threatening potential of cardiovascular complications in Marfan syndrome, a thorough cardiac evaluation is paramount. This involves several imaging techniques to assess the aorta and heart valves.

Tests and Their Significance

1. Echocardiogram (Echo): A non-invasive ultrasound of the heart.
   • What it reveals: Detailed images of the heart chambers, valves, and the aorta as it exits the heart (aortic root and ascending aorta).

   • Decoding Results:

     • Aortic Root Dilation: This is one of the most common and significant findings in Marfan syndrome. The report will provide measurements of the aortic root diameter (e.g., “Aortic root diameter at sinuses of Valsalva: 4.5 cm”). These measurements are often compared to age- and body-size-adjusted nomograms or Z-scores to determine if the dilation is abnormal (e.g., Z-score > 2.0).
       • Significance: Progressive aortic dilation increases the risk of aortic dissection (a tear in the aortic wall), a medical emergency. The degree of dilation influences the frequency of monitoring and surgical intervention recommendations.
     • Aortic Valve Regurgitation (Insufficiency): The aortic valve may not close properly, leading to blood leaking back into the left ventricle.
       • Significance: Can strain the heart over time, leading to heart failure if severe.
     • Mitral Valve Prolapse (MVP) with/without Regurgitation: The mitral valve leaflets bulge back into the left atrium during heart contraction, potentially leading to leakage.
       • Significance: Common in Marfan, can cause palpitations, shortness of breath. Severe regurgitation may require intervention.
     • Enlarged Left Ventricle: Can be a consequence of significant valve regurgitation or long-standing high blood pressure.
       • Significance: Indicates the heart is working harder to pump blood.
   • Concrete Example for Echo:
     • Report Snippet: “Echocardiogram demonstrates aortic root dilation with a diameter of 4.8 cm at the sinuses of Valsalva (Z-score +3.2). Mild aortic regurgitation noted. Moderate mitral valve prolapse with mild regurgitation.”

     • Decoding: This is a strong indicator of Marfan syndrome, particularly the significant aortic root dilation. The Z-score confirms it’s well above the normal range for age/size. The valve issues further support the diagnosis.

2. CT Angiography (CTA) or MR Angiography (MRA): Advanced imaging techniques that provide detailed, 3D images of the entire aorta, from the chest to the abdomen and pelvis, as well as other major arteries.

   • What it reveals: Comprehensive assessment of aortic dimensions, presence of aneurysms (dilations) or dissections along the entire length of the aorta, and involvement of other arteries (e.g., iliac arteries).

   • Decoding Results:

     • Ascending Aortic Aneurysm: Dilation of the aorta in the chest.

     • Descending Aortic Aneurysm: Dilation of the aorta in the chest or abdomen.

     • Aortic Dissection: Identification of a “flap” or tear in the aortic wall, separating the inner and outer layers. This is a critical finding requiring immediate medical attention. The report will specify the type (e.g., Type A – affecting the ascending aorta; Type B – affecting the descending aorta).

     • Tortuosity of Aorta/Arteries: Increased curving or winding of blood vessels. While not diagnostic on its own, it can be a feature of connective tissue disorders.

   • Concrete Example for CTA/MRA:

     • Report Snippet: “CTA chest and abdomen reveals fusiform ascending aortic aneurysm measuring 5.2 cm at its maximal diameter. Descending thoracic aorta and abdominal aorta are within normal limits. No evidence of dissection.”

     • Decoding: This confirms a significant aortic aneurysm that likely warrants surgical intervention based on current guidelines for Marfan syndrome. The absence of dissection is positive, but the size indicates high risk.

Ocular Examination: Peeking into the Eyes

Eye abnormalities are a hallmark of Marfan syndrome and are often one of the first features to prompt suspicion. A comprehensive ophthalmological exam by an experienced eye specialist is essential.

Tests and Their Significance

1. Slit Lamp Examination: A magnified view of the front and back structures of the eye.
   • What it reveals:
     • Ectopia Lentis (Lens Dislocation): The most specific eye finding for Marfan syndrome. The lens of the eye is displaced, usually upwards and outwards, due to weakness of the zonular fibers that hold it in place.
       • Significance: Highly diagnostic, especially bilateral and superior-temporal displacement. Can lead to significant visual impairment.
     • Myopia (Nearsightedness): Severe nearsightedness is common in Marfan syndrome, often developing early in life.

     • Retinal Detachment: The retina separates from its underlying support tissue.

       • Significance: A serious complication that can lead to permanent vision loss if not treated.
     • Glaucoma: Increased pressure within the eye.

     • Cataracts: Clouding of the eye’s natural lens.

   • Decoding Results:

     • “Bilateral superior-temporal ectopia lentis noted”: This is a highly significant finding, almost pathognomonic for Marfan syndrome.

     • “Severe axial myopia (e.g., -8.00 diopters)”: While not diagnostic on its own, it’s a common feature.

   • Concrete Example for Slit Lamp Exam:

     • Report Snippet: “Ophthalmological examination reveals bilateral superior-temporal lens dislocation. Best corrected visual acuity OD 20/70, OS 20/80. Retinal periphery appears unremarkable.”

     • Decoding: The bilateral ectopia lentis is a very strong indicator of Marfan syndrome, supporting a diagnosis even in the absence of other major criteria. The reduced visual acuity is a consequence of the lens dislocation.

Skeletal Examination: The Body’s Blueprint

Skeletal features are often the most visible signs of Marfan syndrome, contributing significantly to the overall clinical picture.

Tests and Their Significance

1. Physical Examination (Anthropometric Measurements):
   • What it reveals:
     • Tall Stature: Disproportionately long limbs (arm span greater than height, upper segment to lower segment ratio decreased).

     • Arachnodactyly: Long, slender fingers and toes. Tested with the wrist sign (thumb and fifth finger overlap when wrapped around the opposite wrist) and thumb sign (entire thumb nail projects beyond the ulnar border of the clenched fist).

     • Pectus Deformities: Pectus excavatum (concave chest) or pectus carinatum (pigeon chest).

     • Scoliosis/Kyphosis: Curvature of the spine.

     • Pes Planus (Flat Feet): Due to lax ligaments.

     • Protrusio Acetabuli: Protrusion of the hip socket into the pelvis (requires X-ray).

     • Joint Hypermobility: Excessive flexibility of joints.

     • Dolichocephaly: Long, narrow head.

     • Enamel Hypoplasia: Defects in tooth enamel (less common but noted).

   • Decoding Results: The presence of multiple skeletal features significantly increases the likelihood of a Marfan diagnosis, particularly when combined with other system involvement.

     • “Arm span to height ratio 1.08, positive wrist and thumb signs, severe pectus excavatum, thoracolumbar scoliosis with a 35-degree Cobb angle, and pes planus noted.”

     • Decoding: This constellation of skeletal findings is highly suggestive of Marfan syndrome. The specific measurements and descriptions allow for objective assessment against diagnostic criteria.

2. Spinal X-rays:

   • What it reveals: Detailed assessment of scoliosis (Cobb angle measurement) and kyphosis.

   • Significance: Monitors progression of spinal curvature and informs management decisions.

3. Pelvic X-rays:

   • What it reveals: Protrusio acetabuli, where the hip socket extends into the pelvic cavity.

   • Significance: A specific skeletal criterion for Marfan syndrome.

Concrete Example for Skeletal Assessment:

• Scenario: Multiple Features

  • Report Snippet: “Physical examination revealed a patient with an arm span to height ratio of 1.09, positive wrist and thumb signs bilaterally. Significant pectus excavatum with a Haller index of 3.5. Scoliosis with a 28-degree right thoracic curve on standing spinal X-ray. Foot examination showed severe pes planus. Joint hypermobility present in elbows and knees.”

  • Decoding: This detailed description highlights several key skeletal features. The objective measurements (arm span ratio, Cobb angle, Haller index) help quantify the severity and contribute to meeting the Ghent diagnostic criteria.

Pulmonary Evaluation: Assessing the Lungs

While less common than cardiovascular or ocular manifestations, pulmonary issues can occur in Marfan syndrome due to weakened connective tissue in the lungs.

Tests and Their Significance

1. Chest X-ray / CT Scan:
   • What it reveals:
     • Spontaneous Pneumothorax: Collapsed lung due to air leaking into the space between the lung and chest wall. Can be recurrent.

     • Apical Blebs/Bullae: Small air-filled sacs on the surface of the lung, more common in Marfan syndrome and prone to rupture, leading to pneumothorax.

   • Decoding Results:

     • “Chest CT demonstrates multiple apical bullae, right-sided pneumothorax noted.”

     • Decoding: This indicates a lung complication consistent with Marfan syndrome. The presence of bullae increases the risk of future pneumothorax.

Integrating the Results: The Ghent Nosology

The true art of decoding Marfan test results lies in integrating the findings from all these different evaluations. The revised Ghent nosology (2010) provides a structured framework for diagnosis, combining clinical criteria with genetic testing results.

Key Principles of the Ghent Nosology:

• Presence of an FBN1 mutation: If a pathogenic FBN1 mutation is identified, and there is at least one systemic feature (e.g., aortic root dilation, ectopia lentis), then a diagnosis of Marfan syndrome can be made.

• Absence of an FBN1 mutation (or VUS) but with a family history: If a first-degree relative is definitively diagnosed with Marfan syndrome, and the individual has at least one major criterion (e.g., aortic root dilation or ectopia lentis) and one systemic score point, then Marfan syndrome can be diagnosed.

• Absence of FBN1 mutation and no family history: This is the most challenging scenario. Diagnosis requires the presence of either:

  • Aortic root dilation (Z-score ≥ 2.0) AND ectopia lentis.

  • Aortic root dilation (Z-score ≥ 2.0) AND a systemic score of ≥ 7 points.

The Systemic Score: Quantifying Clinical Features

The Ghent nosology assigns points to various skeletal, skin, and dural findings. This helps quantify the overall systemic involvement.

Systemic Feature

Points

Wrist and thumb sign

3

Wrist or thumb sign

1

Pectus carinatum deformity

2

Pectus excavatum or chest asymmetry (moderate to severe)

1

Hindfoot deformity

2

Plain pes planus

1

Pneumothorax

2

Dural ectasia

2

Protrusio acetabuli

2

Reduced upper segment/lower segment ratio and increased arm span/height ratio without severe scoliosis

1

Scoliosis or thoracolumbar kyphosis

1

Reduced elbow extension

1

Skin striae (atrophic)

1

Myopia > 3 diopters

1

Mitral valve prolapse (any)

1

• A systemic score of ≥ 7 points is considered significant.

Concrete Example of Integrated Diagnosis:

• Patient Profile: 25-year-old male presenting with tall stature, long fingers, and blurred vision.

• Test Results:

  • Genetic Testing: FBN1 pathogenic variant (p.Cys152Ter) detected.

  • Echocardiogram: Aortic root diameter 4.6 cm (Z-score +2.8), mild aortic regurgitation.

  • Ophthalmology: Bilateral superior-temporal ectopia lentis.

  • Skeletal Exam: Positive wrist and thumb signs, pectus excavatum (moderate), arm span/height ratio 1.06.

  • Systemic Score Calculation:

    • Wrist and thumb sign: 3 points

    • Pectus excavatum: 1 point

    • Reduced upper segment/lower segment ratio and increased arm span/height ratio: 1 point

    • Mitral valve prolapse (not explicitly stated, but if present, 1 point)

    • Myopia > 3 diopters (if present, 1 point)

    • Even without a full score, the genetic finding and ectopia lentis are highly indicative.

• Ghent Nosology Interpretation:

  • Presence of a pathogenic FBN1 mutation + aortic root dilation + ectopia lentis = Definitive Diagnosis of Marfan Syndrome.

  • In this case, the genetic test provides the strongest evidence, complemented by major clinical criteria.

Another Example: Clinical Diagnosis without Definitive Gene Mutation

• Patient Profile: 10-year-old female, no known family history of Marfan syndrome, referred for severe myopia and scoliosis.

• Test Results:

  • Genetic Testing: FBN1 sequencing negative for pathogenic variants. (Let’s assume an NGS panel for aortopathies was also negative or showed only VUS not linked to strong clinical evidence.)

  • Echocardiogram: Aortic root diameter 2.0 cm (Z-score +1.5 – within normal limits for age).

  • Ophthalmology: Bilateral superior ectopia lentis identified. Myopia -6.00 diopters.

  • Skeletal Exam: Severe scoliosis (Cobb angle 45 degrees), positive wrist sign, pes planus.

  • Systemic Score Calculation (partial):

    • Wrist sign: 1 point

    • Scoliosis: 1 point

    • Plain pes planus: 1 point

    • Myopia > 3 diopters: 1 point

    • Total points so far: 4 points. (Need more information to reach 7, or other major criteria.)

• Ghent Nosology Interpretation:

  • No FBN1 mutation and no family history.

  • Does she have aortic root dilation (Z-score ≥ 2.0) AND ectopia lentis? No, aortic root is normal.

  • Does she have aortic root dilation (Z-score ≥ 2.0) AND a systemic score of ≥ 7 points? No aortic root dilation.

  • However, the presence of Ectopia Lentis (a major criterion) is extremely strong. If ectopia lentis is present, and the FBN1 test is negative, the patient must have aortic root dilation or a systemic score of ≥ 7 points to meet the criteria. In this specific hypothetical example, without aortic root dilation or a systemic score of ≥ 7, the diagnosis might be Marfan-related disorder or require further evaluation/monitoring.

  • Critical re-evaluation: Let’s refine this example. If ectopia lentis is present, it is considered a major criterion. If a pathogenic FBN1 mutation is NOT found, and there is no family history, then according to Ghent, a diagnosis requires aortic root dilation (Z-score ≥ 2.0) OR a systemic score of ≥ 7 points.

  • Therefore, with ectopia lentis but normal aorta and systemic score of only 4, a definite Marfan diagnosis using Ghent 2010 might not be met. This highlights the complexity. The clinician would likely consider a multi-gene panel to rule out other connective tissue disorders with similar ocular findings (e.g., Homocystinuria, Sulfite Oxidase Deficiency, Weill-Marchesani Syndrome) and closely monitor the aorta.

  • Crucial Learning Point: The diagnostic criteria are strict. A single major criterion (like ectopia lentis) without the other required elements (aortic root dilation or high systemic score in the absence of a genetic mutation) does not automatically confirm Marfan syndrome according to Ghent.

What to Do After Receiving Your Results

Decoding your Marfan test results is not just about understanding the medical terminology; it’s about forming an action plan.

1. Schedule a Detailed Discussion with Your Doctor: This is non-negotiable. Your doctor, preferably a geneticist, cardiologist, or a Marfan specialist, is best equipped to interpret the nuanced findings in the context of your overall health. Prepare a list of questions beforehand.

2. Clarify the Diagnosis: Is it Marfan syndrome? A Marfan-related disorder? Or have other conditions been ruled out? Understand the certainty level of the diagnosis.

3. Understand the Implications: What does this diagnosis mean for your health, now and in the future? What are the potential risks and complications you need to be aware of?

4. Discuss Management and Monitoring Plan:

   • Cardiovascular: How often will you need echocardiograms or MRA/CTA? What medications might be prescribed (e.g., beta-blockers, ARBs) to slow aortic dilation? When is surgical intervention (aortic root replacement) typically considered?

   • Ocular: How often should you see an ophthalmologist? What are the signs of retinal detachment or glaucoma to watch for?

   • Skeletal: Will you need orthotics for flat feet? Physical therapy for scoliosis? When might bracing or surgery for scoliosis be considered?

   • Pulmonary: Are there specific precautions to take regarding lung health? What are the signs of pneumothorax?

5. Family Screening: If you are diagnosed with Marfan syndrome, your first-degree relatives (parents, siblings, children) should undergo evaluation and testing. This is crucial for early detection and preventative care in at-risk family members.

6. Genetic Counseling: A genetic counselor can provide invaluable support, explaining the inheritance patterns, risk to future children, and helping you navigate the emotional aspects of a genetic diagnosis.

7. Lifestyle Adjustments: Discuss any necessary lifestyle modifications, such as avoiding strenuous activities that could increase blood pressure or put stress on the aorta.

8. Psychological Support: Receiving a diagnosis of a lifelong genetic condition can be emotionally challenging. Don’t hesitate to seek psychological support if needed. Connecting with patient advocacy groups can also provide a sense of community and shared experience.

The Journey Continues: Living with Marfan Syndrome

A diagnosis of Marfan syndrome is the beginning of a lifelong journey of management and monitoring, not an end. Understanding your test results is the first crucial step in empowering yourself to advocate for your health and ensure you receive the best possible care. With regular medical follow-up, appropriate interventions, and a proactive approach, individuals with Marfan syndrome can lead full and meaningful lives. Continuous research into Marfan syndrome is also yielding new insights and therapeutic strategies, offering hope for even better outcomes in the future. Embrace the knowledge gained from decoding your results, and use it as a foundation for a proactive and informed partnership with your healthcare team.