Renal transplantation in Birt-Hogg-Dubé syndrome: should we?

BACKGROUND: Birt-Hogg-Dubé (BHD) Syndrome is a rare genodermatosis caused by a mutation on folliculin gene, with a strong link to renal cancer. To date few patients with such condition have reached dialysis stage, as nephron-sparing surgery is usually possible at the time of diagnosis. To our best knowledge no patient with BHD syndrome has been submitted to renal transplantation. CASE PRESENTATION: We report the case of a woman diagnosed with multifocal bilateral renal cell carcinoma that underwent bilateral radical nephrectomy and was started on a regular hemodialysis program at the age of 29. While on hemodialysis program she was diagnosed clinically with BHD syndrome and molecular testing confirmed an heterozygous mutation on FLCN gene. The patient has been kept on surveillance program for 2 years with no clinical complications from the genetic syndrome and in complete remission from renal cancer. Though there has not been any report of a patient with BHD being transplanted, risks and benefits for this patient were weighted. She has been considered apt by the transplant team and is currently waitlisted for cadaveric renal transplantation. DISCUSSION: It is a matter of discussion which should be cancer-free period for anephric patients with an inherited cancer syndrome to be candidates for renal transplant. So far BHD syndrome has not been causally associated with any other neoplastic disorder elsewhere. Accepting cancer biology is very complex and knowledge of the behaviour of this genetic syndrome is limited to a few cases reported worldwide, the authors believe that renal transplantation is the best treatment option for this young patient. The choice of post transplantation immunosuppression is debatable, but considering experience in other inherited cancer syndromes a maintenance scheme with mTOR inhibitor will be favoured.

Identification of novel genetic causes of Rett syndrome-like phenotypes.

BACKGROUND: The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach. METHODS AND RESULTS: We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants. Examination by MRI and muscle biopsies was also performed. Pathogenic genomic imbalances were found in two patients (10.5%): an 18q21.2 deletion encompassing four exons of the TCF4 gene and a mosaic UPD of chromosome 3. Variants in genes previously implicated in neurodevelopmental disorders (NDD) were identified in six patients (32%): de novo variants in EEF1A2, STXBP1 and ZNF238 were found in three patients, maternally inherited X linked variants in SLC35A2, ZFX and SHROOM4 were detected in two male patients and one homozygous variant in EIF2B2 was detected in one patient. Variants were also detected in five novel NDD candidate genes (26%): we identified de novo variants in the RHOBTB2, SMARCA1 and GABBR2 genes; a homozygous variant in EIF4G1; compound heterozygous variant in HTT. CONCLUSIONS: Network analysis reveals that these genes interact by means of protein interactions with each other and with the known RTT genes. These findings expand the phenotypical spectrum of previously known NDD genes to encompass RTT-like clinical presentations and identify new candidate genes for RTT-like phenotypes.

New mutations in the ATM gene and clinical data of 25 AT patients.

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, oculocutaneous telangiectasias, chromosomal instability, radiosensitivity, and cancer predisposition. The gene mutated in the patients, ATM, encodes a member of the phosphatidylinositol 3-kinase family proteins. The ATM protein has a key role in the cellular response to DNA damage. Truncating and splice site mutations in ATM have been found in most patients with the classical AT phenotype. Here we report of our extensive ATM mutation screening on 25 AT patients from 19 families of different ethnic origin. Previously unknown mutations were identified in six patients including a new homozygous missense mutation, c.8110T>C (p.Cys2704Arg), in a severely affected patient. Comprehensive clinical data are presented for all patients described here along with data on ATM function generated by analysis of cell lines established from a subset of the patients.

LEGClust- a clustering algorithm based on layered entropic subgraphs.

Hierarchical clustering is a stepwise clustering method usually based on proximity measures between objects or sets of objects from a given data set. The most common proximity measures are distance measures. The derived proximity matrices can be used to build graphs, which provide the basic structure for some clustering methods. We present here a new proximity matrix based on an entropic measure and also a clustering algorithm (LEGClust) that builds layers of subgraphs based on this matrix, and uses them and a hierarchical agglomerative clustering technique to form the clusters. Our approach capitalizes on both a graph structure and a hierarchical construction. Moreover, by using entropy as a proximity measure we are able, with no assumption about the cluster shapes, to capture the local structure of the data, forcing the clustering method to reflect this structure. We present several experiments on artificial and real data sets that provide evidence on the superior performance of this new algorithm when compared with competing ones.

Month of birth and risk of multiple sclerosis in a Portuguese population.

BACKGROUND: Several studies analyzing the month of birth (MOB) of multiple sclerosis (MS) patients and the risk of the disease have been published; as a whole, MS patients were found to be predominantly born in spring months, leading to the current assumption that MOB is somewhat related to the risk of MS. OBJECTIVE: Estimate the risk of MS by MOB in a Portuguese population. METHODS: MS patients sample was obtained from the database of patients attended at our MS clinic and born in the districts of Porto, Braga and Viana do Castelo. The control sample was composed of the live births records in the same time period and geographical area. We applied the Hewitt test for seasonality. RESULTS: We found 421 patients that satisfied the conditions to enter the study. The rank-sums for successive 6-month segments indicate the July-December period as of higher incidence; however, the corresponding rank-sum (48) was not statistically significant according to the Hewitt test (p>0.05). CONCLUSION: Our data does not support the seasonality hypothesis of MOB as risk factor for MS in Portugal. However we are aware that the analysis of a larger MS sample could shed more light in this issue.