Ruvalcaba Syndrome Research Articles

A systematic review of Bannayan – Riley – Ruvalcaba syndrome

Bannayan–Riley–Ruvalcaba syndrome (BRRS) is a rare overgrowth condition caused by a pathogenic variant in the phosphatase and tensin homolog (PTEN) gene and belongs to a group of disorders called PTEN hamartoma tumor syndrome (PHTS). The diagnosis is often complicated by great phenotypic diversity. Furthermore, to this date treatment options are limited. Here we performed a systematic review using PubMed, Cochrane, and Scopus databases to identify cases of pediatric patients diagnosed with BRRS and summarized information about the clinical presentation, treatment, and long-term patient care. A total of 83 pediatric patients with BRRS were identified. The most common clinical findings were macrocephaly (77%) and developmental disorders (63%). Surgical interventions were the treatment of choice, described in 19 articles. Patient surveillance was proposed in 15 case reports and mostly aimed at periodic cancer screening. Recognition of BRRS clinical symptoms and early referral to a geneticist is important for better disease control and overall prognosis. As targeted treatment is still lacking, symptom relief and long-term surveillance remain the main management strategies.

A Pediatric Case of Bannayan–Riley–Ruvalcaba Syndrome with Recurrent Iron Deficiency Anemia

A Pediatric Case of Bannayan–Riley–Ruvalcaba Syndrome with Recurrent Iron Deficiency Anemia

Novel Mutation C.7348C>T in NF1 Gene Identified by Whole-Exome Sequencing in Patient with Overlapping Clinical Symptoms of Neurofibromatosis Type 1 and Bannayan–Riley–Ruvalcaba Syndrome

Neurofibromatosis type 1 (NF-1) is an autosomal dominant disorder provoking benign cutaneous and nerve sheath tumors. The cutaneous tumors termed as plexiform neurofibromas, which some of them are extremely visible, and can influence the quality of life. They can also develop into invasive forms of carcinomas and infiltrate into multiple tissues, thus endangering the patient’s life. The loss-of-function mutations in NF1 gene are responsible for NF-1 type. Due to the large size of NF1 gene (~350 kb and 60 exons), exist some pseudogenes on another locus, and lack mutation hotspot the molecular characterizing of patients is complex. In this study, we reported a patient showed symptoms of both NF-1 and Bannayan–Riley–Ruvalcaba syndrome (BRRS), then performed a whole-exome sequencing (WES) and a data analysis for molecular characterization. These results showed a single heterozygous nucleotide variant (c.7348C>T) in NF1 gene, which results in a premature stop codon (p.Arg2450Ter) and a truncated protein, causing clinical symptoms of the patient. According to the results, WES is a quick and cost-effective approach for molecular diagnosis of the mixed phenotype of NF-1.

2568 A Unique Case Presentation of Small Bowel Intussusception

INTRODUCTION: Intussusception is a life-threatening condition and can cause ischemia of the small intestine if not intervened promptly. When present in adults, intussusception typically is caused by a neoplasm, adhesions of the small bowel, or resultant of weight loss surgeries. Below we describe a unique intervention provided to a case presentation of intussesception. CASE DESCRIPTION/METHODS: 21 y.o. year old female with a past medical history of chronic abdominal pain, PTSD, suicide attempts, gender dysphoria, gastroesophageal reflux disease, depression, presented to the emergency department with secondary to abnormally low hemoglobin, abdominal pain, nausea and vomiting. She described pain in the epigastric abdominal region. She had no known family history of colon cancer, colonic polyps or other malignancies. She was noted to have a hemoglobin of 4.4 with no overt bleeding. She was tested negative for celiac serologies. She was evaluated with a CT scan of the abdomen and pelvis with IV contrast which showed long segment of proximal jejunal intussusception with associated inflammatory changes. The surgical team approached the gastroenterology team to attempt to reduce the intussusception prior to surgical resection. As a result of which a push enteroscopy was performed where in a normal esophagus, with erythematous mucosa in the gastric fundus and gastric body were seen. The duodenum was normal. An intussusception was encountered after the C-loop of the duodenum, around the proximal jejunum. This was reduced with the scope. A vascular appearing jejunal mass was seen. Biopsy was not attempted given the vascular appearance. A tattoo was applied. The patient subsequently underwent jejunal resection with small bowel anastomosis. The pathology of the mass resulted as benign hamartomatous polyp with surface erosion and no dysplasia. The patient's symptoms and anemia resolved post operatively. In addition she was evaluated with an upper endoscopy and flexible sigmoidoscopy previously which were within normal limits. DISCUSSION: Hamartomatous polyps of the small intestine can be associated with Cowden syndrome, Bannayan-Riley Ruvalcaba syndrome (BRRS), and juvenile polyposis syndrome (JPS). The above mentioned patient is unique as she does not meet criteria for any of these syndromes. In addition the emergent symptom relief was provided by endoscopic reduction of the intussusception providing the surgeons for a planned elective procedure rather than an emergent procedure.

PTEN Hamartoma Tumor Syndrome: A Clinical Overview.

The phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a grouping of related genetic disorders that has been linked to germline mutations in the PTEN gene. These disorders include Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome, adult Lhermitte–Duclos disease, and autism spectrum disorders associated with macrocephaly. The majority of the clinical information available on PHTS, however, is related to individuals diagnosed with CS. There is still much to be learned about this disorder, since diagnostic criteria for CS were only established in 1996, before the identification of the PTEN gene, and were based primarily on features seen in cases reported in the existing literature. More recently, however, data from several large series of patients have shown that a number of the clinical features associated with PTEN mutations are either more or less common than previously reported. In addition, we now know that only about 30–35% of patients meeting clinical diagnostic criteria for Cowden syndrome actually have a detectable PTEN mutation. Thus, our understanding of PTEN-related diseases and their management has evolved significantly over time. The United States National Comprehensive Cancer Network (NCCN) has produced and regularly updates practice guidelines which include clinical diagnostic criteria as well as guidelines for PTEN testing and management of patients with mutations. This review will summarize the overall literature on PHTS as well as recent findings which are broadening our understanding of this set of disorders.

Lichen planus hypertrophicus‐inversus occurring in a patient with Bannayan–Riley–Ruvalcaba syndrome

Lichen planus hypertrophicus‐inversus occurring in a patient with Bannayan–Riley–Ruvalcaba syndrome

Germline TTN variants are enriched in PTEN-wildtype Bannayan\u2013Riley\u2013Ruvalcaba syndrome

Bannayan–Riley–Ruvalcaba syndrome (BRRS) is a rare congenital disorder classically characterized by macrocephaly in combination with intestinal hamartomatous polyposis, vascular malformations, lipomas, and genital lentiginosis. Germline PTEN mutations have been reported in up to 60% of BRRS patients. The remaining cases are of unknown genetic etiology. We exome-sequenced 35 unrelated PTEN-wildtype patients with classic presentation of BRRS and identified TTN germline missense variants in 12/35 (34%) patients. TTN encodes TITIN, a key structural and functional muscle protein. Exome and TTN-targeted sequencing in an additional unrelated series of 231 BRRS-like patients revealed 37 (16%) additional patients with germline TTN variants. All variants were predicted to be deleterious and equally distributed between the A-band and I-band protein domains. Rare TTN variants (MAF ≤ 0.0001) are enriched in classic BRRS patients compared to BRRS-like (OR = 2.7, 95% CI 1.21-5.94, p = 1.6 × 10-2) and multiple population controls (OR = 2.2, 95% CI 1.01-4.20, p = 4.7 × 10-2). Germline TTN mutations of different genotypes, inheritance patterns, and protein domain enrichment have been identified in multiple cardiac and/or skeletal muscular disorders. Functional interrogation of I-band variant p.Cys5096Arg identified in one of our classic BRRS patients, using CRISPR-Cas9 genome-edited cell lines, reveals an increased growth and lack of contact inhibition phenotype associated with increased levels of or phosphorylation of focal adhesion kinase (FAK) in mutant cells. These findings suggest that TITIN could play a role in overgrowth-relevant pathways and phenotypes. In summary, our observations suggest TTN as a candidate predisposing gene in classic PTEN-wildtype BRRS patients, perhaps suggesting this syndrome join the growing list of Titinopathies.

Say What? Bannayan–Riley–Ruvalcaba Syndrome Presenting with Gastrointestinal Bleeding Due to Hamartoma-Induced Intussusception

Say What? Bannayan–Riley–Ruvalcaba Syndrome Presenting with Gastrointestinal Bleeding Due to Hamartoma-Induced Intussusception

Abstract IA02: The discovery of the hereditary colorectal cancer genes: A historical perspective

Abstract IA02: The discovery of the hereditary colorectal cancer genes: A historical perspective

Clinical presentation of PTEN mutations in childhood in the absence of family history of Cowden syndrome

BackgroundPTEN gene (MIM 601628) is a tumor suppressor gene implicated in PTEN hamartoma tumor syndromes (PHTS) including Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, and Proteus-like syndrome. Bannayan–Riley–Ruvalcaba syndrome is considered as the pediatric form of PHTS. More recently, children presenting autism spectrum disorders with macrocephaly (ASD-M) have been reported. MethodsWe report clinical data from seven patients diagnosed in childhood with a PTEN germline mutation, excluding cases of familial Cowden syndrome. ResultsThis study underlines the variability of phenotype associated with PTEN mutations diagnosed at pediatric age. Most of the patients did not fulfill usual criteria of Bannayan–Riley–Ruvalcaba syndrome or ASD-M. ConclusionPTEN testing should be considered in any child presenting with severe macrocephaly (>+4SD) and another feature of PHTS.

Eponyms in the dermatology literature linked to Latin America

Latin America refers to territories in America where the Spanish or Portuguese languages prevail: Mexico, most of Central and South America, and in the Caribbean, Cuba, the Dominican Republic, and Puerto Rico – in summary, Hispanic America and Brazil [1]. By this definition, Latin America is coterminous with Iberoamerica („Iberian America”) [1]. Latin America has an area of approximately 21,069,500 km2, almost 3.9% of the Earth’s surface or 14.1% of its land surface area. As of 2010, its population was estimated at more than 590 million [1]. Many medical conditions derive their names from either Greek or Latin. In this manuscript, we are reviewing, some selected examples of eponyms, in dermatology literature, linked to the Latin America (Tabl. I) [2-14]. We want also to point out that many scientists in other parts of the world and particularly in USA, for whom medical diseases were eponymously named, were originated from latin America. Just an example is, Bannayan–Riley–Ruvalcaba syndrome (BRRS), which is a dominant autosomal disorder characterized by cutaneous lipomas, macrocephaly, intestinal polyps, and developmental delay [15]. It is named after American physicians. One of them, Rogelio H. Ruvalcaba (born in 1934) received his MD degree from the Universidad de Guadalajara, in Mexico and immigrated to USA. Finally, one can find part of the eponym is originated from Latin America for example, idiopathic atrophoderma of Pasini and Pierini (IAPP), is named after an italian dermatologist Agostino Pasini (1875-1944) and dermatologist from Argentina, Luis Enrique Pierini (1899-1987) (Fig. 8). In 1923, Pasini described the condition under the name progressive idiopathic atrophoderma. In 1936, Pierini and Vivoli extensively studied and defined the condition and its possible link to morphea. Canizares et al, in 1958 renamed it as idiopathic atrophoderma of Pasini and Pierini (IAPP) [16]. There are many clinical and histologic similarities between, atrophoderma of Pasini and Pierini and Linear atrophoderma of Moulin (LAM). LAM was first described by Moulin in 1992 as an acquired unilateral hyperpigmented atrophic band along Blaschko’s lines. EPONYMS IN THE DERMATOLOGY LITERATURE LINKED TO LATIN AMERICA

Cognitive characteristics of PTEN hamartoma tumor syndromes

We sought to characterize cognition in individuals with germline PTEN mutations (n = 23) as well as in PTEN mutation-negative individuals with classic Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (n = 2). Twenty-five individuals completed a comprehensive neuropsychological evaluation. One sample t-tests and effect sizes were used to examine differences in participant test scores compared with normal controls. Composite scores were created for each patient within each of the cognitive domains assessed and classified as above average, average, or below average according to normative standards. χ(2) analyses compared these classifications to expected proportions in normal control samples. The mean intelligence quotient was in the average range, and the range of intellectual functioning was very wide (from extremely low to very superior). However, in a large subset of patients, scores were lower than expected on measures of motor functioning, executive functioning, and memory recall, suggesting disruption of frontal circuits in these participants. This is the first study to characterize cognition in individuals with PTEN mutations and associated syndromes using a comprehensive neuropsychological battery. Contrary to previous reports suggesting an association with intellectual disability, the mean intelligence quotient was average, and there was a broad range of intellectual abilities. Specific evidence of disruption of frontal circuits may have implications for treatment compliance and cancer surveillance, and further investigation is warranted.

Novel PTEN germline mutation in a family with mild phenotype: Difficulties in genetic counseling

PTEN gene (phosphatase and tensin homolog deleted on chromosome ten, MIM 601628) is a tumor suppressor gene implicated in PTEN hamartoma tumor syndromes (PHTS) including Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome and Proteus-like syndrome. PTEN mutations have been more recently reported in children with macrocephaly and autism spectrum disorders or mental retardation, without other symptoms of PHTS. Although tumor risk has not been evaluated in these patients and their relatives, the same surveillance as for Cowden syndrome is usually proposed. We report a family including patients carrying a novel PTEN mutation and presenting with a mild phenotype consisting of macrocephaly, hypotonia during the first year of life and mild learning disabilities, without autistic features. None of these patients exhibited PTHS-related symptoms such as tumors, lipomas, vascular malformations or pigmented macules of the glans penis. This report raises the question of extending the indications of PTEN mutation screening to familial macrocephaly with learning disabilities. Detection of a mutation in this family led to difficult questions about surveillance, genetic counseling and familial information since the mother declined tumor screening and disclosure of genetic risk information to at-risk relatives.

Bannayan-Riley-Ruvalcaba Syndrome with Progressive Spinal Epidural Lipomatosis

We present a case study of an 11-year-old boy with Bannayan-Riley-Ruvalcaba syndrome (BRRS) with macrocephaly, lipomatosis, and penile freckles. BRRS was confirmed by a germline mutation in the phosphatase and tensin homolog (PTEN) gene. Repeated spinal imaging demonstrated an extensive progressive spinal epidural lipomatosis, compressing and dislocating the dural sac, so far without neurological deficits. Patients with BRRS are probably a risk for progressive spinal epidural lipomatosis and should be carefully monitored by neurological examinations and eventually neuroimaging follow-up studies.

Muscle Hemangiomatosis Presenting as a Severe Feature in a Patient with the Pten Mutation: Expanding the Phenotype of Vascular Malformations in Bannayan-Riley-ruvalcaba Syndrome

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a rare autosomal, dominantly-inherited, hamartoma syndrome with distinct phenotypic features. Mutations in the PTEN gene have been identified in PTEN hamartoma tumor syndromes. Our aim was to determine the correlation of phenotype-genotype relationships in a BRRS case. We have evaluated a PTEN mutation in a patient with vascular anomalies and the phenotypic findings of BRRS. We described an 8-year-old girl with the clinical features of BRRS, specifically with vascular anomalies. The mutation in the PTEN gene was identified by DNA sequencing. In our patient, we defined a de novo nonsense R335X (c.1003 C>T) mutation in exon 8, which results in a premature termination codon. Due to vascular anomalies and hemangioma, the patient’s left leg was amputated 1 year after the hemangioma diagnosis. Bannayan - Riley - Ruvalcaba syndrome patients with macrocephaly and vascular anomalies should be considered for PTEN mutation analysis and special medical care.

Recurrent and Extensive Vascular Malformations in a Patient With Bannayan–Riley–Ruvalcaba Syndrome

Bannayan--Riley--Ruvalcaba syndrome (BRRS) is a rare, usually autosomal dominant, disease associated with the PTEN hamartoma tumor syndrome, and it is clinically diagnosed in the presence of the triad of macrocephaly, genital lentiginosis, and intestinal polyposis. Vascular malformations, including arteriolovenous shunts, arteriovenous anomalies, and arteriovenous fistulae, can also be seen in a subset of BRRS patients, varying from local overgrowth of small vessels to large aneurysms. The range of these vascular manifestations and the pathophysiology behind them are not completely understood. In this case study, we report on a patient with BRRS and recurrent vascular malformations of the left lower extremity. We also review the current literature, with a specific focus on the breadth of vascular malformations and reported care of these BRRS patients. Based on the recurrent and sometimes extensive nature of the vascular pathology, it is recommended that physicians monitor BRRS patients closely for early detection and treatment.

Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan–Riley–Ruvalcaba syndrome clinical features

BackgroundCowden syndrome (CS) is associated with benign hamartomatous lesions and risks for thyroid, breast and endometrial cancers. Bannayan–Riley–Ruvalcaba syndrome is an allelic disorder characterised by macrocephaly, intestinal polyps, lipomas, and...

Mucinous cystadenoma of ovary in a patient with juvenile polyposis due to 10q23 microdeletion: Expansion of phenotype

Juvenile polyposis syndrome (JPS) is a hereditary condition characterized by development of gastrointestinal polyps, and caused by mutations in SMAD4 or BMPR1A genes. Juvenile polyps can also be found in a related group of syndromes with multisystemic involvement including Cowden disease, Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba syndrome, and Proteus-like syndrome, all grouped as PTEN hamartoma tumor syndromes (PHTS). In all these conditions including JPS, polyps manifest in older childhood or early adulthood. Infantile juvenile polyposis (JPI) is a rare entity, presenting in the first year of life with severe gastrointestinal symptoms. Many of these patients have associated macrocephaly, hypotonia, and congenital anomalies. It was recently recognized that patients with infantile polyposis have a 10q23 microdeletion, involving both BMPR1A and PTEN genes. There is a major risk for gastrointestinal malignancies in these patients, but the risk for development of other tumors is not known. We describe a patient with a history of infantile polyposis, macrocephaly, developmental delay, hypotonia, and a 10q23 microdeletion. At age 14 she presented with bilateral mucinous cystadenoma of the ovary. This type of tumor was not previously reported in association with JPS, 10q23 microdeletion syndrome, or infantile polyposis. We believe that ovarian cystadenomas may be another neoplastic complication of infantile polyposis, and that our report widens the spectrum of the 10q23 microdeletion phenotype.

Ruvalcaba syndrome revisited

Ruvalcaba syndrome revisited

Bannayan–Riley–Ruvalcaba syndrome: a cause of extreme macrocephaly and neurodevelopmental delay

Background:Bannayan–Riley–Ruvalcaba syndrome (BRRS) is an autosomal dominant condition characterised by macrocephaly, developmental delay and subtle cutaneous features. BRRS results from mutations in the PTEN gene. In adults, PTEN mutations cause...