Bannayan-Riley-Ruvalcaba Syndrome Research Articles

Genetics of Carney Complex and Related Familial Lentiginoses, and other Multiple Tumor Syndromes

Carney complex is a multiple endocrine neoplasia (MEN) syndrome that affects the adrenal cortex, the pituitary and thyroid glands, and the. gonads. The complex is also associated with skin and mucosa pigmentation abnormalities and myxoid and other neoplasms of mesenchymal and neural crest origin. Thus, this syndrome also belongs to another group of genetic disorders, the lentiginoses (or lentigenoses), which include the Peutz-Jeghers, LEOPARD, arterial dissections and lentiginosis, and Laugier-Hunziker syndromes, Cowden disease and Ruvalcaba-Myhre-Smith (Bannayan-Zonana) syndrome and the centrofacial, benign patterned and segmental lentiginoses, all of which can be associated with a variety of developmental defects. The inheritance of Carney complex, just like that of the other MENs and the lentiginoses, is autosomal dominant. Genetic loci or genes have been identified for Carney complex, Peutz-Jeghers and Ruvalcaba-Myhre-Smith syndromes, but not for other lentiginoses. Elucidation of the molecular defect...

Alternative splicing of the Drosophila PTEN gene

Mutations in the human PTEN gene have been identified in a number of different tumour types, and in the hamartomatous polyposis syndromes Cowden disease and Bannayan-Zonana syndrome. The PTEN gene encodes a phosphatase that antagonises phosphoinositide 3-kinase (PI3K) signalling by removing the 3′ phosphate from phosphatidylinositol 3,4,5-trisphosphate (PtdIns (3,4,5)P 3). Here we show that the PTEN gene is conserved in the invertebrate Drosophila melanogaster and demonstrate that the gene undergoes alternative splicing.

PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome.

Germline mutations in the tumour suppressor gene PTEN have been implicated in two hamartoma syndromes that exhibit some clinical overlap, Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increased risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documented in BRR. The partial clinical overlap in these two syndromes is exemplified by the hallmark features of BRR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional features observed in BRR, which may also occur in a minority of CS patients, include Hashimoto's thyroiditis, vascular malformations and mental retardation. Pigmented macules of the glans penis, delayed motor development and neonatal or infant onset are noted only in BRR. In this study, constitutive DNA samples from 43 BRR individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both CS and BRR, were screened for PTEN mutations. Mutations were identified in 26 of 43 (60%) BRR cases. Genotype-phenotype analyses within the BRR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, BRR or BRR/CS overlap family ( P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family ( P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRR patients ( P = 0.028). In contrast to a prior report, no significant difference in mutation status was found in familial versus sporadic cases of BRR ( P = 0.113). Comparisons between BRR and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and BRR when compared with BRR alone ( P = 0.002). Among CS, BRR and BRR/CS overlap families that are PTEN mutation positive, the mutation spectra appear similar. Thus, PTEN mutation-positive CS and BRR may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.

Phenotypic findings of Cowden syndrome and Bannayan-Zonana syndrome in a family associated with a single germline mutation in PTEN

Cowden syndrome (CS) and Bannayan-Zonana syndrome (BZS) are two hamartoma syndromes with distinct phenotypic features. Although partial clinical overlap exists between CS and BZS, they are considered to be separate...

Identification of PTEN mutations in five families with Bannayan-Zonana syndrome.

Germline mutations in PTEN, a putative tumor suppressor gene, has been identified in 2 autosomal dominant inherited hamartoma syndromes, Cowden syndrome (CS) and Bannayan-Zonana syndrome (BZS). While both diseases exhibit distinct phenotypic features, there seems to be a partial clinical overlap between the 2 diseases. To date, 9 families with BZS have been screened for PTEN mutations, of which 5 were found to exhibit mutations in this gene. We report 5 novel germline mutations in the PTEN coding sequence from 5 unrelated families with the BZS phenotype. While all the mutations we identified are novel in BZS, 1003C-->T (nonsense mutation) and 209+5G-->A (putative splice site mutation) have been previously reported in unrelated families with CS and Lhermitte Duclos disease. Interestingly, 1 of the families has an individual with BZS and 1 with CS phenotype, associated with a single PTEN mutation, 885insA. These data support the notion that CS and BZS may be within the spectrum of the same primary disorder.

076 Brain hamartoma in an infant with Bannayan-Riley-Ruvalcaba syndrome

076 Brain hamartoma in an infant with Bannayan-Riley-Ruvalcaba syndrome

Carney Complex, Peutz-Jeghers Syndrome, Cowden Disease, and Bannayan-Zonana Syndrome Share Cutaneous and Endocrine Manifestations, But Not Genetic Loci

Carney complex (CC), Peutz-Jeghers syndrome (PJS), Cowden disease (CD), and Bannayan-Zonana syndrome (BZS) share clinical features, such as mucocutaneous lentigines and multiple tumors (thyroid, breast, ovarian, and testicular neoplasms), and autosomal dominant inheritance. A genetic locus has been identified for CC on chromosome 2 (2p16), and the genes for PJS, CD, and BZS were recently identified; genetic heterogeneity appears likely in both CC and PJS. The genes for PJS and CD/BZS, STK11/LKB1 and PTEN, respectively, may act as tumor suppressors, because loss of heterozygosity (LOH) of the PJS and CD/BZS loci has been demonstrated in tumors excised from patients with these disorders. We studied 2 families with CC in whom the disease could not be shown to segregate with polymorphic markers from the 2p16 locus. Their members presented with lesions frequently seen in PJS and the other lentiginosis syndromes. We also tested 16 tumors and cell lines established from patients with CC for LOH involving the PJS and CD/BZS loci. DNA was extracted from peripheral blood, tumor cell lines, and tissues and subjected to PCR amplification with primers from microsatellite sequences flanking the STK11/LKB1 and PTEN genes on 19p13 and 10q23, respectively, and a putative PJS locus on 19q13. All loci were excluded as candidates in both families with LOD scores less than −2 and/or by haplotype analysis. LOH for these loci was not present in any of the tumors that were histologically identical to those seen in PJS. The overall rate of LOH for the PJS and CD/BZS loci in tumors from patients with CC was less than 10%. We conclude that despite substantial clinical overlap among CC, PJS, CD, and BZS, LOH for the STK11 and PTEN loci is an infrequent event in CC-related tumors. Linkage analysis excluded the PJS and CD/BZS loci on chromosomes 19 (19p13 and 19q13) and 10 (10q23) from harboring the gene defect(s) responsible for the phenotype in these 2 families.

Bannayan-zonana syndrome: a rare autosomal dominant syndrome with multiple lipomas and hemangiomas: A case report and review of literature

BACKGROUND Bannayan-Zonana syndrome is a rare hamartomatous disorder, characterized by macrocephaly, multiple lipomas, and hemangiomas. Inheritance is by autosomal dominant transmission with few reported sporadic cases. Male predominance is also reported. METHODS We describe a patient who presented with multiple subcutaneous lipomas, mild macrocephaly, and an extradural spinal hemangioma. Other affected family members and 24 other previously reported cases are discussed. RESULTS Spinal hemangiomas have not been described previously with this syndrome. The patient also had a “malignant bone tumor” removed from his humerus 20 years ago. Two of the patient’s siblings also had lymphoma, which is an unusual accompaniment not reported previously. Only the male members in the family showed multiple subcutaneous lipomas. CONCLUSION Some patients with Bannayan-Zonana syndrome may have hamartomatous lesions producing cord compression or intracerebral hemorrhage, or they may rarely have other malignant tumors; therefore it is important that neurosurgeons are aware of the entity. The early diagnosis of BZS is also important for genetic counseling.

Pten is essential for embryonic development and tumour suppression.

The PTEN gene encodes a dual-specificity phosphatase mutated in a variety of human cancers. PTEN germline mutations are found in three related human autosomal dominant disorders, Cowden disease (CD), Lhermitte-Duclos disease (LDD) and Bannayan-Zonana syndrome (BZS), characterized by tumour susceptibility and developmental defects. To examine the role of PTEN in ontogenesis and tumour suppression, we disrupted mouse Pten by homologous recombination. Pten inactivation resulted in early embryonic lethality. Pten-/- ES cells formed aberrant embryoid bodies and displayed an altered ability to differentiate into endodermal, ectodermal and mesodermal derivatives. Pten+/- mice and chimaeric mice derived from Pten+/- ES cells showed hyperplastic-dysplastic changes in the prostate, skin and colon, which are characteristic of CD, LDD and BZS. They also spontaneously developed germ cell, gonadostromal, thyroid and colon tumours. In addition, Pten inactivation enhanced the ability of ES cells to generate tumours in nude and syngeneic mice, due to increased anchorage-independent growth and aberrant differentiation. These results support the notion that PTEN haploinsufficiency plays a causal role in CD, LDD and BZS pathogenesis, and demonstrate that Pten is a tumour suppressor essential for embryonic development.

PTEN/MMAC1/TEP1 involvement in primary prostate cancers.

The PTEN/MMAC1/TEP1 gene, located at 10q23.3, is a tumor suppressor gene responsible for the familial cancer syndromes Cowden disease and Bannayan-Zonana syndrome, and is commonly somatically mutated in several types of cancers. Mutations of the PTEN gene have been found in prostate cancer cell lines and LOH at 10q22-24 in prostate tumors have also been described with a high frequency. To determine the role of this gene in prostate tumorigenesis, we therefore analysed 22 primary tumors for loss of heterozygosity (LOH) within the 10q22-23 region such that tumors hemizygous at those loci may be examined for somatic PTEN mutations. Losses of heterozygosity of at least one locus was found in 12 (55%) of the 22 tumors DNAs. Among these, six tumors exhibited allele loss in the interval between D10S1765 and D10S541 wherein lies the PTEN gene. We searched the entire coding region of PTEN for somatic mutations in these six tumors. One somatic mutation (17%), a 1 bp deletion, was detected in exon 7 of the gene, in one tumor, indicating that somatic mutations of the PTEN gene may occur in primary prostate tumors.

A highly conserved processed PTEN pseudogene is located on chromosome band 9p21.

PTEN/MMAC1/TEP1, encoding a dual-specificity phosphatase, is a tumor suppressor gene which has recently been cloned and mapped to chromosome 10q23.3. We have shown that germline mutations of PTEN are present in individuals with two hamartoma syndromes: Cowden Syndrome, associated with a predisposition to breast and thyroid cancers, and Bannayan-Zonana syndrome. Somatic mutations of PTEN have been reported in a variety of human cancer cell lines, suggesting a potential role for this gene in the pathogenesis of human malignancies. We report the identification of a highly conserved PTEN processed pseudogene, psiPTEN, which shares over 98% homology with the coding region of functional PTEN, and its localisation to chromosome 9p21. The high sequence homology of psiPTEN with the PTEN transcript may potentially lead to misinterpretation when performing mutation analyses based on cDNA templates. Caution should be exerted when using such screening approaches.

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation.

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.

MACROCEPHALY WITH MULTIPLE SOFT TISSUE AND VISCERAL HAMARTOMAS ("BANNAYAN-ZONANA" SYNDROME): Case report

Since its first description few cases of the rare association of macrocephaly with multiple soft tissue and visceral hamartomas (Bannayan-Zonana syndrome) have been reported. In this paper we report a case of a 7 year old child in whom lipomas of the abdomen and right flank have been treated with liposuction. We could find no previous evidence that this surgical technique has been used in the treatment of this syndrome.

Deletion ofPTEN in a patient with Bannayan-Riley-Ruvalcaba syndrome suggests allelism with Cowden disease

We report on an 18-month-old boy with an interstitial deletion at 10q23.2-q24.1. This region includes the PTEN gene, mutations of which have been reported to cause Cowden disease. Our patient presented with manifestations of Bannayan-Riley-Ruvalcaba (BRR) syndrome. The BRR syndrome is a rare disorder which presents most commonly in childhood. Cowden disease is a disease of adulthood and is inadequately described in children. Because of the considerable phenotypic overlap between the two disorders, and the cytogenetic and molecular findings in our patient, we suggest that BRR syndrome and Cowden disease are allelic.

P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase.

Protein tyrosine phosphatases (PTPs) have long been thought to play a role in tumor suppression due to their ability to antagonize the growth promoting protein tyrosine kinases. Recently, a candidate tumor suppressor from 10q23, termed P-TEN, was isolated, and sequence homology was demonstrated with members of the PTP family, as well as the cytoskeletal protein tensin. Here we show that recombinant P-TEN dephosphorylated protein and peptide substrates phosphorylated on serine, threonine, and tyrosine residues, indicating that P-TEN is a dual-specificity phosphatase. In addition, P-TEN exhibited a high degree of substrate specificity, showing selectivity for extremely acidic substrates in vitro. Furthermore, we demonstrate that mutations in P-TEN, identified from primary tumors, tumor cells lines, and a patient with Bannayan-Zonana syndrome, resulted in the ablation of phosphatase activity, demonstrating that enzymatic activity of P-TEN is necessary for its ability to function as a tumor suppressor.

Germline mutations in PTEN are present in Bannayan-Zonana syndrome

Germline mutations in PTEN are present in Bannayan-Zonana syndrome

Serum serotonin, lactate and pyruvate levels in infantile autistic children

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.

Long‐chain 3‐hydroxyacyl‐Coenzyme A dehydrogenase (L‐CHAD) deficiency in a patient with the Bannayan‐Riley‐Ruvalcaba syndrome

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is an autosomal dominant condition of macrocephaly in combination with lipomas/hemangiomas, hypotonia, developmental delay, and a lipid myopathy. The etiology of the lipid storage myopathy has been unclear. We describe a black boy with findings of BRRS who also has a defect in long-chain fatty acid oxidation expressed in cultured skin fibroblasts as a deficiency of long-chain-L-3-hydroxyacyl-CoA dehydrogenase (L-CHAD). He also has an abnormal brain MRI and increased size of both lower limbs. We present this child because of his unusual combination of findings, and postulate that L-CHAD deficiency may be the cause of the lipid myopathy in BRRS.

Bannayan-Zonana syndrome associated with lipomas, hemangiomas, and lymphangiomas

Bannayan-Zonana syndrome is a rare disorder characterized by macrocephaly and multiple soft tissue and visceral hamartomas. This report presents a sporadic patient with macrocephaly, lipomas, hemangiomas, and lymphangiomas who died of cardiac and respiratory failure due to progressive cervicomediastinal arteriovenous fistulous hemangiomas at the age of 9 years.

Correlation of skeletal muscle biopsy with phenotype in the familial macrocephaly syndromes.

The muscle biopsy results from 14 children with macrocephaly and hypotonia/weakness were correlated with clinical findings compatible with any of the autosomal dominant macrocephaly syndromes. Thirteen of the 14 had evidence of lipid storage myopathy, either generalised or focal. All 13 had examinations consistent with either benign familial macrocephaly, Ruvalcaba-Myhre-Smith syndrome, or Bannayan-Zonana syndrome. These results suggest that all three of these disorders may represent phenotypic variability at a single genetic locus.