Bannayan-Riley-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

Bannayan Zonana Syndrome: An Unusual Cause of Intussusception and Protein Losing Enteropathy in a Child

Bannayan-Zonana syndrome (BRRS) is a rare genetic disorder characterized by macrocephaly, numerous soft tissue and visceral hamartomas, and lipomas. Because of the risk of fatal bleeding and visceral neoplasia in adulthood, recognizing this disease is critical. We reported a new pediatric case of BRRS in an 18-month-old female infant with lipomas, macrocephaly, and gastrointestinal hamartomatous polyps that prompted ileo-ileal intussusception and protein-losing enteropathy. Patients with BRRS require a comprehensive approach. Our case is unique in its sporadic occurrence and the presence of protein-losing enteropathy as a gastrointestinal polyposis manifestation. Pediatric patients with multiple lipomas, protein-losing enteropathy, and intestinal intussusception should be assessed for BRRS.

Hamartomatous Polyposis Syndromes: Management and Surveillance Strategies

Introduction: Hamartomatous Polyposis Syndromes (HPS) are a rare group of dominant autosomal inheritance, which is characterized by the development of hamartomatous polyps in the gastrointestinal tract. This syndrome included Juvenile Polyposis syndrome (JPS), Peutz-Jeghers syndrome (PJS), and PTEN Hamartoma Tumour Syndrome (PHTS). PTEN Hamartoma Tumour Syndrome (PHTS) itself includes Cowden Syndrome, Bannayan-Riley-Ruvalcaba Syndrome (BRRS), and Proteus Syndrome.Diagnosis of Hamartum polyarthritis syndrome (HPS) is routinely made based on clinical criteria, but sometimes the diagnosis of this syndrome becomes problematic due to the varying severity of clinical symptoms even within a family.Therefore, today, genetic testing of germ-related mutations associated with this disease is used in the diagnosis process. Management strategy of the syndrome is different due to extra-intestinal symptoms and various cancers. Clinical awareness and early diagnosis of HPS is important, so it is recommended to patients and families at risk for genetic counseling and care. Surveillance in children with HPS might prevent intestinal and extra-intestinal disorders, and reduce the risk of intestinal cancer or breast cancer in adults.

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.

Distinct Alterations in Tricarboxylic Acid Cycle Metabolites Associate with Cancer and Autism Phenotypes in Cowden Syndrome and Bannayan-Riley-Ruvalcaba Syndrome

Germline heterozygous PTEN mutations cause subsets of Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS); these subsets are characterized by high risks of breast, thyroid, and other cancers and, in one subset, autism spectrum disorder (ASD). Up to 10% of individuals with PTENMUT CS, CS-like syndrome, or BRRS have germline SDHx (succinate dehydrogenase, mitochondrial complex II) variants, which modify cancer risk. PTEN contributes to metabolic reprogramming; this is a well-established role in a cancer context. Relatedly, SDH sits at the crossroad of the electron transport chain and tricarboxylic acid (TCA) cycle, two central bioenergetic pathways. Intriguingly, PTENMUT and SDHMUT individuals have reduced SDH catalytic activity, resulting in succinate accumulation; this indicates a common genotype-independent biochemical alteration. Here, we conducted a TCA targeted metabolomics study on 511 individuals with CS, CS-like syndrome, or BRRS with various genotypes (PTEN or SDHx, mutant or wild type [WT]) and phenotypes (cancer or ASD) and a series of 187 population controls. We found consistent TCA cycle metabolite alterations in cases with various genotypes and phenotypes compared to controls, and we found unique correlations of individual metabolites with particular genotype-phenotype combinations. Notably, increased isocitrate (p = 1.2 × 10−3), but reduced citrate (p = 5.0 × 10−4), were found to be associated with breast cancer in individuals with PTENMUT/SDHxWT. Conversely, increased lactate was associated with neurodevelopmental disorders regardless of genotype (p = 9.7 × 10−3); this finding was replicated in an independent validation series (n = 171) enriched for idiopathic ASD (PTENWT, p = 5.6 × 10−4). Importantly, we identified fumarate (p = 1.9 × 10−2) as a pertinent metabolite, distinguishing individuals who develop ASD from those who develop cancer. Our observations suggest that TCA cycle metabolite alterations are germane to the pathobiology of PTEN-related CS and BRRS, as well as genotype-independent ASD, with implications for potential biomarker and/or therapeutic value.

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.

Bannayan-Riley-Ruvalcaba Syndrome, Rare Etiology of Intestinal Hamartomatouspolyposis: A case report

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a rare autosomal dominant congenital disorder, characterized bymacrocephaly, lipomas, hamartomas, and pigmented macule in genitalia.Several dozen cases have been reported in the medical literature, but no case has been reported in Bangladesh. We report a case of BRRS in a 11-year-old male child with recurrent per rectal bleeding with hamartomatouscolonic polyposis & multiple subcutaneous lipomas on the anterior abdominal wall.In addition, patient had macrocephaly, intellectual impairment.Bleeding polyps were removed by colonoscopic polypectomy.
 Bangladesh J Child Health 2019; VOL 43 (1) :62-65

Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations.

Patients with heritable cancer syndromes characterized by germline PTEN mutations (termed PTEN hamartoma tumor syndrome, PHTS) benefit from PTEN-enabled cancer risk assessment and clinical management. PTEN-wildtype patients (~50%) remain at increased risk of developing certain cancers. Existence of germline mutations in other known cancer susceptibility genes has not been explored in these patients, with implications for different medical management. We conducted a 4-year multicenter prospective study of incident patients with features of Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations. Exome sequencing and targeted analysis were performed including 59 clinically actionable genes from the American College of Medical Genetics and Genomics (ACMG) and 24 additional genes associated with inherited cancer syndromes. Pathogenic or likely pathogenic cancer susceptibility gene alterations were found in 7 of the 87 (8%) CS/CS-like and BRRS patients and included MUTYH, RET, TSC2, BRCA1, BRCA2, ERCC2 and HRAS. We found classic phenotypes associated with the identified genes in 5 of the 7 (71.4%) patients. Variant positive patients were enriched for the presence of second malignant neoplasms compared to patients without identified variants (OR = 6.101, 95% CI 1.143–35.98, p = 0.035). Germline variant spectrum and frequencies were compared to The Cancer Genome Atlas (TCGA), including 6 apparently sporadic cancers associated with PHTS. With comparable overall prevalence of germline variants, the spectrum of mutated genes was different in our patients compared to TCGA. Intriguingly, we also found notable enrichment of variants of uncertain significance (VUS) in our patients (OR = 2.3, 95% CI 1.5–3.5, p = 0.0002). Our data suggest that only a small subset of PTEN-wildtype CS/CS-like and BRRS patients could be accounted for by germline variants in some of the known cancer-related genes. Thus, the existence of alterations in other and more likely non-classic cancer-associated genes is plausible, reflecting the complexity of these heterogeneous hereditary cancer syndromes.

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

Abstract 5143: Rats heterozygous for Pten develop fibroadenoma and adenocarcinoma arising from the mammary gland

Abstract To further characterize the function of the tumor suppressor Pten in the role of tumorigenesis we have created a colony of Pten mutant Sprague Dawley (SD) rats. Utilizing zinc finger nuclease technology we introduced a 7bp deletion in Exon 7 of the Pten gene, creating a frameshift mutation and an early stop codon. Pten homozygous null animals are not viable so a colony of heterozygous animals is maintained. Spontaneous tumors of the mammary gland arise in these animals and were removed for staining and pathological analysis. We describe briefly the creation of this model and preliminary genotypic and proteomic characterization. Further we describe pathological observations made on tumor tissues removed from aging Pten heterozygous animals. We have confirmed a reduction in Pten expression by Western Blot utilizing a monoclonal antibody targeting a central locus in the protein. Heterozygous Pten animals develop spontaneous tumors of the mammary gland which were removed if animals demonstrated deteriorating health or any condition within our Humane Care and Use guidelines. Thirty six tissues from 16 animals were submitted for histopathological analysis. Eight of the animals were male, 8 of the animals were female and had a mean lifespan of 159 days (165 male, 153 female). Remaining consistent with human breast cancer incidence in women below 30 years of age, the most common lesion observed is a benign fibroadenoma (30/36 samples). The malignant adenocarcinoma was observed in 5/36 samples submitted. Fibroadenoma only lesions were observed in 12 of the 16 rats while both fibroadenoma and adenocarcinoma was observed in 4 of the 16 rats. Taken together we believe that a Pten heterozygous rat provides an additional tool for the elucidation of the role of Pten in human cancers. This model may also be useful in the study of neurological disorders such as Autism, Parkinson's disease, Alzheimer's disease, obesity, cardiovascular disease, and diabetes. Mutations in Pten strongly correlate with several human disorders including Cowden syndrome, Bannayan-Zonana syndrome, and Lhermitte-Duclos disease. These disorders result in a tumor pathologies including an increased risk for breast cancers. Citation Format: Aaron M. McCoy, Bala Manickam, Lara Reid, Edward Weinstein, Xiaoxia Cui. Rats heterozygous for Pten develop fibroadenoma and adenocarcinoma arising from the mammary gland. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5143. doi:10.1158/1538-7445.AM2015-5143

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.

Oral manifestations of phosphatase and tensin homolog hamartoma tumor syndrome: A report of three cases

Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) encompasses several rare disorders linked to mutations of the PTEN gene, including Cowden disease (CD) and Bannayan-Riley-Ruvalcaba syndrome (BRRS). The authors present a case series involving patients with characteristic periodontal features. The authors assessed three patients, two of whom already had been diagnosed with BRRS: a 60-year-old man and his 33-year-old daughter, both of whom had pathognomonic oral and cutaneous manifestations, and a 26-year-old man affected by multiple micropapillomatous and keratotic periodontal lesions, through which the diagnosis of CD was made. All three patients were referred to the oral medicine unit of the authors' institution because of asymptomatic lesions of the oral mucosa, and two of them underwent incisional biopsy. This series of cases emphasizes that oral health care workers always should perform a more careful visual inspection of the oral cavity without neglecting a macroscopic analysis of the gingival pattern. The knowledge of these diseases and their clinical features, associated with a multidisciplinary approach, allows clinicians to achieve remarkable diagnostic success. Gingival manifestations may represent one of the primary clinically detectable manifestations of these rare systemic diseases, in respect of which an early diagnosis could decrease the associated mortality and morbidity.

Cowden Syndrome and the PTEN Hamartoma Tumor Syndrome: How to Define Rare Genetic Syndromes

Cowden syndrome (OMIM No. 158350) and Bannayan-Riley-Ruvalcaba syndrome (BRRS) (OMIM No. 153480) are autosomal dominant conditions described before the genetic testing era. The early reports of Cowden syndrome were by adult physicians and dermatologists who recognized a pattern of benign and malignant tumors affecting the breast and thyroid, accompanied by characteristic acral keratosis and trichilemmomas of the skin (1,2,3). BRRS was described by pediatricians and clinical geneticists, with the principle features being macrocephaly, delayed development, lipomata, hemangiomas, and vascular malformations, along with pigmented macules of the penis (4,5). Both conditions are caused by mutations in the PTEN gene (OMIM+601728) (6,7). There is no definite association between the type or position of mutation within the PTEN gene and the clinical presentation of the patient. Both conditions have been described in different members of the same family with the same mutations, and it is clear that meticulous examination reveals features of childhood-onset BRRS in adults presenting with the features of Cowden syndrome and vice versa. It is therefore generally accepted that they are one condition, with variable expression and age-related penetrance (8,9,10,11). Genetic heterogeneity has been reported with reports of Cowden-like patients(ie, those who do not fulfill criteria for PTEN hamartoma syndrome [PHTS]) with mutations in SDHB, SDHD, AKT, and PIK3CA, as well as hypermethylation of the promoter of the KLLN gene (12,13,14,15).

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

Differential expression of PTEN gene correlates with phenotypic heterogeneity in three cases of patients showing clinical manifestations of PTEN hamartoma tumour syndrome

Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS) and proteus syndrome are disorders known as PTEN hamartoma tumour syndrome (PHTS), that can show remarkable clinical overlap and are all caused by germline PTEN mutations.We here present two families, one affected by CS and the other affected by BRRS, both carriers of specific pathogenetic missense mutation in exon 5 of PTEN gene, within the catalitic domain. Both PHTS families exhibited extremely variable phenotypes, showing inter- and intra- familial variability. One of the two characterised mutations, the c.320A- > T; p.107Asp- > Val, identified in the CS family, was not previously described in the literature. Furthermore, the BRRS family, carrier of the c.406 T- > C; p.136Cys- > Arg mutation, shows a substantial alteration of PTEN protein expression that well correlates with intra-familial phenotypic variability.Finally, we describe an apparently sporadic case of an 80-year-old man, with a very low level of PTEN mRNA and protein expression, both in healthy and tumour colon mucosa, associated with a very atypical phenotype. He developed a metastatic colorectal carcinoma, macrocephaly and pheochromocytoma.According to literature data, our observations confirm that PTEN mutations of catalytic domain can cause different syndromes. We suggest that PTEN expression could represent one of the mechanisms involved in the remarkable heterogeneity of the clinical PHTS manifestations within affected families. Furthermore, constitutive strong decrease of PTEN expression in colon normal mucosa could be associated with late onset of colorectal cancer.