What Is Bannayan-Riley-Ruvalcaba Syndrome

Introduction to bannayan-riley-ruvalcaba syndrome (BRRS)

Definition and overview

Bannayan-Riley-Ruvalcaba Syndrome (BRRS) is an autosomal dominant genetic disorder categorized within the hamartomatous polyposis syndrome family, alongside conditions like Peutz-Jeghers Syndrome, juvenile polyposis, and Cowden Disease. Hamartomas, which are non-cancerous growths characterized by disorganized hyperplastic tissue, are a hallmark of these syndromes. Distinctive features commonly observed in individuals with BRRS encompass macrocephaly (enlarged head), lipomas (benign fatty growths), intestinal hamartomatous polyps, vascular anomalies, Hashimoto's thyroiditis (an autoimmune thyroid disorder), and distinctive pigmented spots.¹

Historical background and discovery

In 1980, Ruvalcaba observed two males displaying enlarged heads, intestinal polyps, and distinctive penis pigmentation. Cohen subsequently recognized it as Ruvalcaba-Myhre syndrome. Over time, similar cases emerged, with some termed Ruvalcaba-Myhre-Smith syndrome.

Back in 1971, Bannayan established a connection between enlarged heads and the presence of fatty and hemangioma growths. In 1960, Riley and Smith noted associations of large heads, pseudo-papilledema, and hemangiomas.

Initially perceived as separate inherited conditions, experts by the mid-1980s began to question their potential connection. The notion arose that they might share a common origin.

To amalgamate these conditions, the suggested term is Bannayan-Riley-Ruvalcaba syndrome. This gesture pays homage to the original researchers and promotes understanding of the field's progression. This voyage further enriches our grasp of these syndromes.²

Clinical presentation

Physical characteristics and features

1. Macrocephaly and facial characteristics

Individuals with this condition typically have a head circumference that measures at least 2.5 standard deviations above the mean, indicating significant enlargement. However, their ventricular size, which relates to the fluid-filled spaces in the brain, remains within the normal range. Notably, some patients exhibit a delayed closure of the anterior fontanel, the soft spot on the front of the head.

Characteristic facial features include ocular hypertelorism, where the eyes are spaced farther apart than usual. Around 60% of cases exhibit down-slanting palpebral fissures, which are the angles formed by the upper and lower eyelids. Roughly 15% of affected individuals experience issues such as strabismus, a condition where the eyes do not align properly, or amblyopia, commonly referred to as "lazy eye," where one eye does not develop normal vision.

Upon detailed eye examination using a slit lamp, approximately 35% of patients present with prominent Schwalbe lines, which are specific structures in the eye's angle that drains fluid. Furthermore, visible corneal nerves may also be observed in some cases, indicating certain alterations within the cornea.

It's noteworthy that pseudopapilledema has been noted in a subset of individuals with this condition. This term refers to the appearance of optic nerve head swelling, resembling papilledema, which is true optic nerve swelling, but in this case, it's not due to increased intracranial pressure. Notable references to such findings were made by Riley and Smith in 1960, as well as Dvir et al. in 1988.³

1. Dermatological manifestations

Pigmented macules, which are dark spots, are commonly present on the head and shaft of the penis in most affected males. These marks can be quite subtle and might not be noticed unless specifically looked for.⁴

In a majority of patients, there are growths called cutaneous angiolipomas. These growths can either be contained within a capsule or spread out through the tissue. In some cases, other types of growth, like lymphangiomyomas or angiokeratomas, have been discovered. These growths can vary in terms of how many there are, how big they are, where they're located, and how they appear under a microscope. In a few cases, some patients have a small number of café-au-lait spots, which are light brown skin markings, on their trunk and lower limbs.

There are also a couple of unique cases: One patient showed skin lesions that resembled acanthosis nigricans, a condition characterized by dark, thickened patches of skin. Another individual had extra nipples. These observations were reported by Ruvalcaba and colleagues in 1980.

Internal manifestations

1. Gastrointestinal polyps and hamartomas

Benign growths called hamartomatous polyps, often found in multiple numbers, tend to be concentrated in the far end of the small intestine (distal ileum) and the colon. These growths can sometimes lead to a condition called intussusception, where a portion of the intestine folds into another section or cause bleeding from the rectum. These polyps have been identified in around 45% of patients. It's worth noting that while some of these growths are visible during childhood, others might not become apparent until later in life, even during middle age. These observations were recorded by DiLiberti et al. in 1984, as well as by Foster and Kilkoyne in 1986.⁵

1. Lipomas and vascular anomalies

Typically, hamartomatous masses arising from mesodermal tissue are primarily discrete growths called lipomas, which make up about 75% of cases. Hemangiomas, a different type of growth, are much rarer and have been found in fewer than 10% of cases. In approximately 20% of patients, the growths consist of a mix of these types. While most of these tissue irregularities are located beneath the skin (as mentioned earlier), they can also occur within the skull (about 20% of cases) or in the bone (around 10% of cases).

It's important to note that some of the lipomas can be aggressive, leading to significant complications. This was highlighted by observations made by Miles et al. in 1984.⁶

Within a specific subset of individuals affected by BRRS, there are abnormalities observed in their blood vessels. These abnormalities involve different types, such as arteriovenous shunts, arteriovenous anomalies, and arteriovenous fistulas. These terms essentially describe instances where the connections between arteries and veins aren't quite normal. These irregularities can vary from the excessive growth of smaller blood vessels to the development of larger, balloon-like bulges known as aneurysms.

The exact range and nature of these vascular issues, as well as the reasons they occur, are not fully understood. In other words, we don't yet have a complete grasp of why these blood vessel abnormalities occur and how they manifest in such a diverse manner within this syndrome.⁷

1. Thyroid abnormalities

Thyroid-related pathologies linked to Bannayan-Riley-Ruvalcaba Syndrome (BRRS) encompass a range of complexities. Individuals with BRRS may experience an enlarged thyroid gland (goitre) along with several specific issues within the thyroid. These can include the presence of Multiple Adenomatous Nodules (MAN), a condition involving multiple growths in the thyroid. Additionally, Papillary Thyroid Carcinoma (PTC), a type of thyroid cancer, might occur. Lymphocytic Thyroiditis (LT), where the immune system affects the thyroid, and Chronic Cervical Hyperplasia (CCH), characterized by the increase in certain cells in the thyroid, are also potential findings.⁸

Genetics and molecular basis

Inheritance pattern

Bannayan-Riley-Ruvalcaba Syndrome (BRRS) is generally inherited in an autosomal dominant pattern. This means that if a person has one copy of the altered gene associated with BRRS, they can develop the syndrome, even if their other gene copy is normal. In some cases, BRRS can also occur due to spontaneous genetic mutations without a family history. When an individual with BRRS has children, there's a 50% chance that each child will inherit the altered gene and, therefore, be at risk of developing the syndrome.⁹

PTEN gene mutation

PTEN is like a controller that keeps a specific pathway in our cells from going haywire and causing cancer. In many cancers, this controller doesn't work properly. It can happen in different ways, like losing a part of the control or making it silent. This makes the pathway that can lead to cancer more active. We looked at how this happens in common types of cancer and studied how PTEN is managed. Sometimes, the amount of PTEN protein goes down in cancer cells, which might make the pathway even more problematic.

1. Role of PTEN gene

The PTEN gene acts as a kind of "supervisor" within our cells. It helps control a signalling pathway that's important for cell growth, survival, and division. This pathway is like a set of instructions that tells cells when to grow and multiply and when to stop. The PTEN gene's job is to make sure these instructions are followed correctly. It does this by regulating a molecule called PIP3, which is part of the signalling pathway. When the PTEN gene works properly, it prevents the pathway from becoming too active, which could lead to uncontrolled cell growth and potentially cancer. However, sometimes changes or problems in the PTEN gene can cause the pathway to go awry, contributing to the development of various health issues, including cancer.¹⁰

1. Link to other syndromes (Cowden syndrome)

Bannayan-Riley-Ruvalcaba Syndrome (BRRS) is closely related to other syndromes such as Cowden Syndrome and Proteus Syndrome. These syndromes share some common features and genetic factors. Cowden Syndrome, like BRRS, is caused by mutations in the PTEN gene and is characterized by multiple hamartomas and an increased risk of various cancers. Both syndromes can involve skin, thyroid, and digestive tract issues, as well as an increased risk of developing certain types of tumours.

Proteus Syndrome, on the other hand, is characterized by the overgrowth of tissues and often includes skin abnormalities, vascular malformations, and risk of developing various tumours. While there are similarities between these syndromes, each has its own unique set of features and manifestations.

The overlap and connection between these syndromes highlight the complex nature of genetic disorders and how they can affect different systems in the body. Genetic testing and consultation with medical professionals familiar with these syndromes are essential for accurate diagnosis, management, and appropriate medical care for individuals with these conditions.¹¹

1. A spectrum of mutations and variability

The spectrum of mutations and variability in genetic disorders like Bannayan-Riley-Ruvalcaba Syndrome (BRRS) underscores the complexity of these conditions. Mutations, which are changes in the genetic code, can occur in different parts of the associated genes. In the case of BRRS, mutations in the PTEN gene can lead to a wide range of effects.

The variability in how these mutations impact individuals is remarkable. Even though people with BRRS share the same underlying genetic cause, the specific symptoms and their severity can vary significantly. This variability can manifest as differences in the types of growth that develop, the age at which symptoms appear, and the combination of health issues experienced.

This variability isn't uncommon in genetic disorders. It is influenced by factors like specific mutations, other genetic variations, and interactions with the environment. Some individuals may only exhibit mild symptoms, while others might have more severe manifestations.

Diagnosis

Clinical criteria and evaluation

Bannayan-Riley-Ruvalcaba Syndrome (BRRS) is a congenital disorder characterized by distinct features, including an enlarged head (macrocephaly), the presence of non-cancerous growths in the intestines (hamartomatous polyposis), fatty growths (lipomas), and pigmented spots on the penis.

Macrocephaly refers to having a larger-than-normal head size. Hamartomatous polyposis involves the development of abnormal growths in the intestines, which are non-cancerous but can cause issues. Lipomas are fatty growths under the skin. Pigmented spots on the penis are areas with darker pigmentation.

These various characteristics collectively define BRRS and help doctors identify and diagnose this syndrome.¹²

Genetic testing and molecular diagnosis

The diagnosis of PHTS is confirmed in an individual by detecting a specific genetic change in one copy of the PTEN gene through molecular genetic testing. This change, known as a heterozygous germline PTEN pathogenic variant, helps medical professionals establish the presence of the syndrome.

Differential diagnosis from related syndromes

When trying to identify Bannayan-Riley-Ruvalcaba Syndrome (BRRS), it's important to distinguish it from similar conditions that share some features. One such condition is called AKT1-related Proteus syndrome, which involves excessive growth in certain body parts, but it's different from BRRS in how it affects the body. Another condition, Juvenile Polyposis Syndrome (JPS), causes growths in the digestive system, but the type of growths and when they appear are distinct from those in BRRS. Birt-Hogg-Dubé syndrome causes skin problems that might look similar, but it has its own unique kind of kidney tumours. Neurofibromatosis type 1 (NF1) also has some similar skin signs, but it shows up differently in other ways. Nevoid Basal Cell Carcinoma Syndrome (NBCCS) has its own skin and bone features that set it apart from BRRS. Lastly, Peutz-Jeghers syndrome comes with growths in the digestive system and changes in skin colour, but these growths look and behave differently from those in BRRS. Proper diagnosis is important to make sure people with BRRS get the right care.¹²

Medical management

Surveillance and screening protocols

When dealing with Bannayan-Riley-Ruvalcaba Syndrome (BRRS), it's important to follow specific guidelines for cancer screening and prevention. These guidelines are tailored to each type of cancer and take into account the age at which the condition was diagnosed. For individuals under 18 years old with BRRS, healthcare providers might recommend:

• Starting yearly thyroid ultrasounds at the age of 7 to monitor the thyroid gland.
• Undergoing a yearly skin check along with a physical examination to catch any skin-related issues.
• Undergoing evaluations to monitor brain development and learning progress.
• Annual hemoglobin test, which measures a haemoglobin in the blood, to detect early signs of growth  in the intestines.

By adhering to these specific recommendations, individuals with BRRS can actively engage in preventive measures and ensure that any potential health concerns are identified and addressed at an early stage.

Multidisciplinary approach to care

The management of Bannayan-Riley-Ruvalcaba Syndrome (BRRS) involves a comprehensive and multidisciplinary approach to care. Since there is no specific cure for BRRS, the focus is on addressing the diverse range of symptoms and potential complications that can arise.

A multidisciplinary team of healthcare professionals, including geneticists, oncologists, endocrinologists, dermatologists, and other specialists, collaborate to provide personalized care. This team approach ensures that every aspect of the syndrome is addressed, from routine monitoring to early detection of cancers associated with PTEN gene mutations.

Regular screenings and tests, such as thyroid ultrasounds, skin examinations, and cancer screenings, are essential components of this approach. By closely following recommended guidelines, individuals with BRRS can receive timely interventions and proactive measures that help manage potential health risks.

This holistic approach emphasizes not only the physical well-being but also the emotional and psychological aspects of living with BRRS. By combining the expertise of various medical professionals, the multidisciplinary approach strives to enhance the quality of life and overall health outcomes for individuals affected by BRRS.

Surgical interventions

As BRRS is associated with various growths and tumours, surgical procedures might be considered to remove or manage these growths. For example, surgery might be used to remove lipomas (benign fatty tumours), intestinal polyps, or other abnormal tissue growths. The decision for surgery is made on a case-by-case basis, considering factors such as the size, location, and potential impact of the growth.¹³

Prognosis and complications

Risk of malignancies (breast, thyroid, colorectal)

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is associated with an increased risk of certain types of malignancies, which are cancerous growths. Individuals with BRRS have a higher likelihood of developing cancers compared to the general population. These malignancies can include thyroid cancer, although it's relatively rare, and other types of tumours like breast, kidney, and colorectal cancers. The risk varies among individuals and can be influenced by factors such as genetic mutations and family history. Regular medical check-ups and screenings are crucial for early detection and management of any potential malignancies. Individuals with BRRS need to work closely with their healthcare team to monitor their health and take proactive steps to reduce their cancer risk.

Long-term outcomes and quality of life

The long-term outcomes and quality of life for individuals with Bannayan-Riley-Ruvalcaba syndrome (BRRS) vary based on factors like symptom severity and medical interventions. Regular medical check-ups and screenings are crucial due to the increased risk of health issues, including cancers and developmental delays. Physical symptoms like an enlarged head and fatty tumours can impact self-esteem. Surgical interventions can help. Support groups and counselling offer information and emotional support. A multidisciplinary care approach involving specialists can improve outcomes and provide a fulfilling life while managing BRRS challenges.

Potential impact on psychological well-being

The physical manifestations of BRRS, such as macrocephaly and skin abnormalities, might impact self-esteem and body image, potentially leading to feelings of self-consciousness or social discomfort. The need for medical screenings, interventions, and surgeries can also contribute to emotional stress. Additionally, the uncertainty surrounding the risk of developing certain cancers or other health issues can cause anxiety. Psychological support, including counselling, support groups, and a strong network of family and friends, can play a vital role in helping individuals cope with these challenges and enhance their overall psychological well-being.

Current research and future directions

Advances in understanding the syndrome

The PTEN gene, which plays a crucial role in controlling cell growth, can be altered by genetic mutations. These mutations are responsible for various conditions, including Bannayan-Riley-Ruvalcaba syndrome (BRRS), which is part of the PTEN hamartoma tumour syndrome. Initially, gastrointestinal polyps were seen as harmless in BRRS, but recent studies have shown that they can have mixed types and pose an increased risk of colon cancer. Ongoing research aims to understand the potential for these polyps to become cancerous and to evaluate the effectiveness of screening and surveillance for colon cancer in individuals with BRRS. Recent studies involving colonoscopies on BRRS patients have revealed the presence of colon polyps in all cases, with multiple polyp types in 40% of cases. This suggests that BRRS can be considered a mixed polyposis syndrome. To manage the risk of colon cancer, experts recommend colonoscopies for colorectal cancer surveillance, starting either at age 35 or 10 years earlier than the earliest diagnosis of colorectal cancer in a first-degree relative, whichever comes first. Further research is needed to explore long-term outcomes and clinical approaches for individuals with BRRS.¹³

Exploration of targeted therapies

By understanding the molecular pathways disrupted by PTEN gene mutations, scientists aim to develop drugs that can selectively target and restore normal cellular function. These therapies could potentially slow down or even halt the progression of BRRS symptoms, including the growth of hamartomatous polyps and the increased risk of various cancers. 

Genetic counseling and family planning considerations

Genetic counselling is about giving families information on inherited disorders so they can make informed choices. Bannayan-Riley-Ruvalcaba syndrome (BRRS) is caused by changes in the PTEN gene. These changes can be inherited or happen spontaneously. Parents might carry the changed gene, and testing can confirm this. Siblings' risk depends on their parents' gene status. Predictive testing for at-risk family members needs the specific changed gene. For those planning families, genetic counselling offers insights into family planning options.

Case studies and patient perspectives

Real-life experiences of individuals with BRRS

Let me tell you about a young man's experience with Bannayan-Riley-Ruvalcaba syndrome (BRRS). When he was born, he faced difficulties with his growth and development. As he grew older, he had seizures and faced problems with his blood, like anaemia. He had to undergo surgery to remove a lump from his neck, and he also got some warts on his face. His vision wasn't perfect, and later, he needed surgery for a problem in his belly.

When he reached his twenties, he had a checkup. He was taller and heavier than many people his age, and his head was larger too. His face looked a bit different, and his eyes had a slanted appearance. He had some issues with his teeth and gums, which could be related to a medication he was taking. He had dark spots around his nails and even in a private area. His back had a significant curve, making it difficult for him to stand straight.

Tests showed that his problems were linked to a change in a specific gene called PTEN. This gene is important for our body's growth control. This gene change caused his health challenges, and it's a part of BRRS. Even though we don't know much about his family history, his story helps us understand how this condition can affect someone's life and health. It shows why it's important to recognize and manage conditions like BRRS early on.⁹

Challenges, coping strategies, and support networks

Living with Bannayan-Riley-Ruvalcaba syndrome (BRRS) can bring about various challenges, but there are strategies and support networks that can help individuals navigate these hurdles. BRRS is a genetic condition that can lead to physical and medical difficulties such as growth issues, tumours, and other health concerns. These challenges can impact daily life, self-esteem, and emotional well-being.

Coping strategies

Medical Care: Regular visits to healthcare providers who are knowledgeable about BRRS are essential. They can offer proper monitoring, guidance, and treatments tailored to your needs.

Education: Learning about BRRS and its effects empowers you to take charge of your health, make informed decisions, and advocate for yourself.

Healthy Lifestyle: Adopting a balanced diet, staying active, and following medical recommendations contribute to better overall health and well-being.

Communication: Openly discussing challenges and concerns with healthcare providers, family, and friends helps you feel understood and supported.

Emotional Support: Connecting with others who have BRRS through support groups or online communities provides a sense of belonging and a platform to share experiences.

Mental Health: Seeking professional help for mental health concerns, such as anxiety or depression, equips you with tools to manage emotions effectively.

Self-Care: Practicing relaxation techniques, mindfulness, and engaging in hobbies can help reduce stress and enhance your quality of life.

Family and Friends: Cultivating a strong support network of loved ones who understand the challenges can have a positive impact on your journey.

Advocacy: Learning about your rights and available resources empowers you to advocate for yourself and navigate challenges effectively.

Positive Outlook: Focusing on your strengths and accomplishments rather than limitations boosts self-esteem and motivation.

Remember, each person's experience with BRRS is unique. Discovering what works best for you, seeking professional guidance when needed, and connecting with supportive individuals can make living with BRRS more manageable. Your resilience and determination can make a significant difference in your journey with BRRS.

Conclusion

Recap of key points

• A rare genetic disorder caused by PTEN gene mutations.
• Features include large head size, skin lesions, lipomas, and developmental delays.
• Thyroid and gastrointestinal issues can occur.
• Genetic testing identifies PTEN mutations.
• Family history and clinical evaluation are vital.
• No cure, but symptom management is crucial.
• Regular check-ups, screenings, and counselling are important.
• Coping strategies and support networks help.
• Early intervention and medical care improve outcomes.
• Research and targeted therapies hold promise.
• A multidisciplinary approach empowers individuals.
• Education and support networks are essential.

Importance of early detection and holistic management

Timely Diagnosis: Identifying PTEN mutations early allows prompt medical care and screenings to catch potential issues.

Comprehensive Care: Holistic management considers physical, emotional, and psychological aspects, enhancing quality of life.

Empowerment: Education and support empower individuals to manage their health actively and make informed decisions.

Prevention: Regular screenings prevent complications and enable early intervention if malignancies are detected.

Personalized Approach: Tailored care plans involving medical professionals, therapists, and support networks optimize outcomes.

Advancing Research: Early intervention contributes to research and fosters innovations in BRRS understanding and treatments.