Responses of wild small mammals to arsenic pollution at a partially remediated mining site in Southern France.

Partial remediation actions at a former gold mine in Southern France led to a mosaic of contaminated and rehabilitated zones. In this study, the distribution of arsenic and its potential adverse effects on small mammals were investigated. The effectiveness of remediation for reducing the transfer of this element into wildlife was also discussed. Arsenic levels were measured in the soil and in the stomach contents, livers, kidneys, and lungs of four small mammal species (the wood mouse (Apodemus sylvaticus), the Algerian mouse (Mus spretus), the common vole (Microtus arvalis), and the greater white-toothed shrew (Crocidura russula)). The animals were caught at the former extraction site, in zones with three different levels of remediation treatments, and at a control site. Arsenic concentrations in the soil were highly spatially heterogeneous (ranging from 29 to 18,900 µg g(-1)). Despite the decrease in arsenic concentrations in the remediated soils, both wood mice and Algerian mice experienced higher oral exposure to arsenic in remediated zones than in the control area. The accumulated arsenic in their organs showed higher intra-zonal variability than the arsenic distribution in the soil, suggesting that, in addition to remediation processes, other variables can help explain arsenic transfer to wildlife, such as the habitat and diet preferences of the animals or their mobility. A weak but significant correlation between arsenic concentration and body condition was observed, and weak relationships between the liver/kidney/lung mass and arsenic levels were also detected, suggesting possible histological alterations.

Can Body Condition and Somatic Indices be Used to Evaluate Metal-Induced Stress in Wild Small Mammals?

Wildlife is exposed to natural (e.g., food availability and quality, parasitism) and anthropogenic stressors (e.g., habitat fragmentation, toxicants). Individual variables (e.g., age, gender) affect behaviour and physiology of animals. Together, these parameters can create both great inter-individual variations in health indicators and interpretation difficulties. We investigated the relevance of body condition and somatic indices (liver, kidneys) as indicators of health status in wood mice (Apodemus sylvaticus, n = 560) captured along a metal pollution gradient in four landscape types (30 sampling squares 500-m sided). The indices were calculated using a recently proposed standard major axis regression instead of an ordinary least square regression. After considering age and gender for the body condition index, no landscape type influence was detected in the indices. However, important index variability was observed between sampling squares; this effect was included as a random effect in linear models. After integrating all individual and environmental variables that may affect the indices, cadmium (Cd) concentrations in both the liver and kidneys were negatively related to body condition and liver indices only for individuals from highly contaminated sites. Lead in the liver was negatively related to the liver index, and Cd in kidneys was positively linked to the kidney index, potentially suggesting metal-induced stress. However, interpretation of these indices as a wildlife ecotoxicology tool should be performed with caution due to the sensitivity of potentially confounding variables (e.g., individual factors and environmental parameters).

Delineation of a region responsible for panhypopituitarism in 20p11.2.

We report on the case of a young woman with a de novo 20p11.21p11.23 deletion, discovered by array-CGH. She has behavioral troubles with autistic traits, intellectual disability, panhypopituitarism, severe hypoglycemia, epilepsy, and scoliosis. The majority of the reported 20p deletions are located on the 20p12 region, covering the JAG1 gene responsible for the Alagille syndrome. More proximal deletions are even rarer, with very few cases described in the literature to date. The deletion carried by our patient is, to our knowledge, the smallest described de novo proximal 20p11.2 deletion. It was first discovered by 0.5 Mb BAC array-CGH, further delineated using an oligonucleotide array, and finally confirmed by fluorescence in situ hybridization. The deletion is 4.22 Mb in size, with the exact location on chr20: 19.810.034-24.031.344 (Feb. 2009, GRCh37/hg19). In light of the other reported cases that display genomic and phenotypic overlap with our patient, we discuss the phenotype of our patient, in order to further delineate the 20p proximal deletion phenotype. We propose a minimal critical region responsible for panhypopituitarism with global developmental delay, intellectual disability, scoliosis and facial dysmorphism. Moreover, considering the deleted genes, we highlight the impact of the deletion of this minimal critical region on the Shh signaling pathway.

Renal cell carcinoma and a constitutional t(11;22)(q23;q11.2): case report and review of the potential link between the constitutional t(11;22) and cancer.

We observed a t(11;22)(q23-24;q11.2-12) and monosomy 3 in renal tumor cells from a 72-year-old man. The hypothesis of a primitive peripheral neuroectodermal tumor (PPNET) located in the kidney was promptly excluded: Histologically, the tumor was a clear cell renal cell carcinoma (RCC) and we did not observe an EWSR1 gene rearrangement. The constitutional origin of this alteration was established. We report on the second case of RCC in a patient with a constitutional t(11;22). The t(11;22)(q23;q11.2) is the main recurrent germline translocation in humans. Unbalanced translocation can be transmitted to the progeny and can cause Emanuel syndrome. Our observation alerts cancer cytogeneticists to the fortuitous discovery of the constitutional t(11;22) in tumor cells. This translocation appears grossly similar to the t(11;22)(q24;q12) of PPNET and should be evoked if present in all cells of a tumor other than PPNET. This is important when providing appropriate genetic counseling. Moreover, the potential oncogenic role of the t(11;22) and its predisposing risk of cancer are under debate. The family history of the patient revealed a disabled brother who died at an early age from colon cancer and a sister with breast cancer. This observation reopens the issue of a link between the constitutional t(11;22) and cancer, and the utility of cancer prevention workups for t(11;22) carriers.

Winchester syndrome: the progression of radiological findings over a 23-year period.

Winchester syndrome (WS) is a rare autosomal recessive syndrome resulting in multicentric osteolysis. Only a few cases of WS have been described in the literature worldwide. It has recently been shown to be caused by mutation in the gene encoding matrix metalloproteinase-2 (MMP2). We report a patient affected by WS with a proven mutation of the MMP2 gene and describe the progression of radiological findings over a 23-year period. To our knowledge there is no comparable article concerning the WS in the literature.

Predator dietary response to prey density variation and consequences for cestode transmission.

The functional response of predators to prey density variations has previously been investigated in order to understand predation patterns. However, the consequences of functional response on parasite transmission remain largely unexplored. The rodents Microtus arvalis and Arvicola terrestris are the main prey of the red fox Vulpes vulpes in eastern France. These species are intermediate and definitive hosts of the cestode Echinococcus multilocularis. We explored the dietary and contamination responses of the red fox to variations in prey density. The dietary response differed between the two prey species: no response for M. arvalis and a type III-like (sigmoidal) response for A. terrestris that shows possible interference with M. arvalis. The fox contamination response followed a type II shape (asymptotic) for both species. We conclude that fox predation is species specific and E. multilocularis transmission is likely to be regulated by a complex combination of predation and immunologic factors. These results should provide a better understanding of the biological and ecological mechanisms involved in the transmission dynamics of trophically transmitted parasites when multiple hosts are involved. The relevance of the models of parasite transmission should be enhanced if non-linear patterns are taken into account.

A neonatal polyvisceral failure linked to a de novo homoplasmic mutation in the mitochondrially encoded cytochrome b gene.

Mutations within the mitochondrially encoded cytochrome b (MTCYB) gene are heteroplasmic and lead to severe exercise intolerance. We describe an unusual clinical presentation secondary to a novel homoplasmic mutation within MTCYB. The m.15635T>C transition (S297P) was carried by a newborn who presented with a polyvisceral failure. This mutation was responsible for a complex III deficiency. It was homoplasmic in all tissues tested and was undetectable in patient's mother. Functional analyses, including studies on patient's cybrid cell lines, demonstrate the pathogenicity of this variant. Our data show that mutations within MTCYB can be responsible for severe phenotype at birth.

Evolution of a patient with Bohring-Opitz syndrome.

We detailed the story from birth to the age of 5 years 9 months, of the oldest patient reported with a Bohring-Opitz syndrome with the three main diagnostic criteria: characteristic facial appearance, fixed contractures of the upper limbs and severe feeding difficulties. The facial anomalies described in our patient were microcephaly, bitemporal narrowing, "puffy" cheeks, forehead naevus flammeus, hypoplastic orbital ridges, prominent eyes, broad nasal bridge, high arched palate, buccal-alveola frenula and retrognathism. The magnetic resonance imaging (MRI) of the brain showed a hypoplastic corpus callosum and a narrowed upper cervical canal; and the cervical MRI showed a malformation of the atlas consisting in an agenesis of the anterior arch and an anterior slip of the posterior arch. We focused on her neurological and nutritional evolution. Despite the gastrostomy and a Nissen fundoplication at age 7 months, she still had developmental growth delays overall (<3rd centile). At 3 years 9 months of age, she began to put on weight quickly, which seemed to be atypical. Meanwhile she developed epilepsy, which was controlled with specific drugs. Currently, she is 5 years 9 months old and has significant psychomotor retardation, although this disease is often fatal in early childhood, due to obstructive apnea and unexplained bradycardia.

Partial Xp11.23-p11.4 duplication with random X inactivation: clinical report and molecular cytogenetic characterization.

Partial duplications of the short arm of the X chromosome are relatively rare and have been described in males and females. We describe a 4 10/12-year-old girl presenting with developmental delay, severe language retardation and minor anomalies with slightly elevated head circumference (+1.8 SD), prominent forehead, wide palpebral fissures and anteverted nares. No pigmentary dysplasia of the skin was present. The external genitalia were normal. The karyotype completed by cytogenetic analysis with the Whole Chromosome Painting probe of chromosome X revealed a de novo partial duplication of the short arm of an X chromosome. In order to further characterize the duplicated segment, we used a series of BAC probes extending from band Xp11.22 to Xp22.1. BACs from Xp11.23 to Xp11.4 were duplicated. The karyotype was finally defined as 46,X,dup(X)(p11p11).ish dup(X)(p11.23p11.4)(WCPX+,RP11-416I6++,RP11-386N14++,RP11-466C12++). The X-inactivation status was studied using the human androgen receptor (HUMARA) and the FRAXA locus methylation assay. Unexpectedly, the two X chromosomes were found to be randomly inactivated, in the proband. Indeed, usually, in women with structurally abnormal X chromosome, the abnormal X chromosome is preferentially inactivated and those patients share an apparent normal phenotype. So, we speculate that in the present case, the phenotype of the patient could be explained by a functional disomy of the genes present in the duplicated region. We will discuss the possible implication of these genes on the observed phenotype.

The spectrum of parathyroid gland dysfunction associated with the microdeletion 22q11.

OBJECTIVE: Clinical features associated with microdeletion of chromosome 22q11 (del(22)(q11)) are highly variable. Increased awareness of this condition is needed among specialists such as endocrinologists to reduce diagnostic delay and improve clinical care. The purpose of this study was to describe the phenotype of patients with del(22)(q11), focusing on parathyroid gland dysfunction. DESIGN AND METHODS: Charts of 19 patients, including one kindred of three, known to have del(22)(q11) diagnosed by fluorescence in situ hybridization (FISH) were reviewed from the register of the department of Medical Genetics. Major clinical features including hypoparathyroidism phenotype were collected. RESULTS: Parathyroid dysfunction was present in 8 out of 16 patients (50%). Six patients were diagnosed with overt hypoparathyroidism. Hypocalcemia manifested as laryngeal stridor within the first days of life (n = 3), seizures in infancy (n = 1) and adolescence (n = 2). The connection between hypoparathyroidism and diagnosis of del(22)(q11) was belated at the median age of 18 years. One patient had presented with transient neonatal hypoparathyroidism, and one patient had latent hypoparathyroidism. Within the kindred family, the phenotype variability including that of parathyroid dysfunction was as marked as between unrelated individuals. Standard karyotype failed to detect the deletion in 15 out of 19 cases. CONCLUSIONS: Abnormal parathyroid function in the del(22)(q11) ranges from severe neonatal hypocalcemia to latent hypoparathyroidism. Del(22)(q11) should be considered as a potential cause of hypocalcemia even in young adult. When suspected, the diagnosis requires investigation by FISH. Furthermore, long-term calcemia follow-up is needed in normocalcemic patients with del(22)(q11) because of the possible evolution to hypocalcemic hypoparathyroidism.

Unbalanced inherited complex chromosome rearrangement involving chromosome 8, 10, 11 and 16 in a patient with congenital malformations and delayed development.

Complex chromosome rearrangements (CCR) are rare structural chromosome aberrations that can be found in patients with phenotypic abnormalities or in phenotypically normal patients presenting, however, recurrent miscarriages or infertility. Conventional karyotype generally allows their identification. However, molecular cytogenetic methods can reveal subtle rearrangements. We report, here, the identification of an unbalanced maternally inherited CCR in a boy with multiple congenital malformations and delayed development. High-resolution karyotype completed by molecular cytogenetic prompted us to precise the rearrangements. The healthy mother was found to carry a balanced de novo CCR that implicates four chromosomes (8, 10, 11 and 16), six breakpoints, three translocations and an insertion. The malsegregation of this CCR had led, in her son, to partial 10p12.3 to 10p14 deletion, a chromosomal region associated with the DiGeorge like phenotype.

The role of muscle biopsy in analysis of the dystrophin gene in Duchenne muscular dystrophy: experience of a national referral centre.

Although the majority (65%) of boys with Duchenne muscular dystrophy (DMD) carry a deletion in the dystrophin gene, finding mutations in the remaining families is vital for counselling. We have provided a comprehensive mutation service as a national referral centre for France for over 10 years and we report here our experience. Mutation screening is on mRNA from a muscle biopsy. We have detected 79 mutations in 89 samples referred with a diagnosis of DMD, which is the most comprehensive survey to date of the full range of nondeletion mutations. Although some mutations were nonsense mutations, some frameshift mutations and some splicing mutations, all of them led to the generation of premature stop codons or a shortened product which could be detected using the Protein Truncation Test. We recommend a protocol which is robust and sensitive applied to the entire coding region reverse-transcribed from dystrophin transcripts from muscle biopsy.