Co-occurrence of genomic imbalances on Xp22.1 in the SHOX region and 15q25.2 in a girl with short stature, precocious puberty, urogenital malformations and bone anomalies

BACKGROUND: Mutations of SHOX represent the most frequent monogenic cause of short stature and related syndromes. The genetic alterations include point mutations and deletions/duplications spanning both SHOX and its regulatory regions, although microrearrangements are confined to either the downstream or upstream enhancers in many patients. Mutations in the heterozygous state have been identified in up to 60-80% of Leri-Weill Dyschondrosteosis (LWD; MIM #127300) and approximately 4-5% of Idiopathic Short Stature (ISS; MIM#300582) patients. Homozygous or compound heterozygous mutations as well as biallelic deletions of SHOX and/or the enhancer regions result in a more severe phenotype, which is known as Langer Mesomelic Dysplasia (LMD; MIM #249700). CASE PRESENTATION: A 17 year old girl, presented with severe short stature, growth hormone deficiency (GHD), precocious puberty, dorsal scoliosis, dysmorphisms and urogenital malformations. She was born with agenesis of the right tibia and fibula, as well as with a supernumerary digit on the left foot. Array comparative genomic hybridization (aCGH) analysis detected the presence of two distinct duplications on Xp22.1 flanking the SHOX coding sequence and involving its regulatory regions. An additional duplication of 1.6-2.5 Mb on 15q25.2 that included 13 genes was also identified. The girl was adopted and the parent's DNA was not available to establish the origin of the chromosome imbalances. CONCLUSIONS: The complex phenotype observed in our patient is probably the result of the co-occurrence of rearrangements on chromosomes Xp22.1 and 15q25.2. The duplicated region on 15q25.2 region is likely to contain dosage-sensitive genes responsible for some of the clinical features observed in this patient, whereas the extreme short stature and the skeletal anomalies are likely attributable to the comorbidity of GHD and copy number variants in the SHOX region

Diagnostic and Therapeutic Challenges of Malignant Pleural Mesothelioma

Malignant pleural mesothelioma is a rare cancer characterized by a very poor prognosis. Exposure to asbestos is the leading cause of malignant pleural mesothelioma. The preinvasive lesions, the mesothelial hyperplasia and its possible evolution are the focus of the majority of the studies aiming to identify the treatable phase of the disease. The role of BAP-1 and MTAP in the diagnosis of mesothelioma in situ and in the prognosis of malignant pleural mesothelioma is the main topic of recent studies. The management of preinvasive lesions in mesothelioma is still unclear and many aspects are the subject of debate. The diagnosis, the disease staging and the accurate, comprehensive assessment of patients are three key instants for an appropriate management of patients/the disease

Global Gene Expression Profiling Of Human Pleural Mesotheliomas: Identification of Matrix Metalloproteinase 14 (MMP-14) as Potential Tumour Target

BACKGROUND:The goal of our study was to molecularly dissect mesothelioma tumour pathways by mean of microarray technologies in order to identify new tumour biomarkers that could be used as early diagnostic markers and possibly as specific molecular therapeutic targets. METHODOLOGY:We performed Affymetrix HGU133A plus 2.0 microarray analysis, containing probes for about 39,000 human transcripts, comparing 9 human pleural mesotheliomas with 4 normal pleural specimens. Stringent statistical feature selection detected a set of differentially expressed genes that have been further evaluated to identify potential biomarkers to be used in early diagnostics. Selected genes were confirmed by RT-PCR. As reported by other mesothelioma profiling studies, most of genes are involved in G2/M transition. Our list contains several genes previously described as prognostic classifier. Furthermore, we found novel genes, never associated before to mesotheliom that could be involved in tumour progression. Notable is the identification of MMP-14, a member of matrix metalloproteinase family. In a cohort of 70 mesothelioma patients, we found by a multivariate Cox regression analysis, that the only parameter influencing overall survival was expression of MMP14. The calculated relative risk of death in MM patients with low MMP14 expression was significantly lower than patients with high MMp14 expression (P = 0.002). CONCLUSIONS:Based on the results provided, this molecule could be viewed as a new and effective therapeutic target to test for the cure of mesothelioma

A Long Contiguous Stretch of Homozygosity Disclosed a Novel STAG3 Biallelic Pathogenic Variant Causing Primary Ovarian Insufficiency: A Case Report and Review of the Literature

Primary ovarian insufficiency (POI) refers to an etiologically heterogeneous disorder characterized by hypergonadotropic hypogonadism that represents a major cause of infertility in women under 40 years of age. Most cases are apparently sporadic, but about 10–15% have an affected first-degree relative, indicating a genetic etiology. Pathogenic variations in genes involved in development, meiosis and hormonal signaling have been detected in the hereditary form of the disorder. However, most cases of POI remain unsolved even after exhaustive investigation. A 19-year-old Senegalese female affected by non-syndromic POI presented with primary amenorrhoea and answered well to the hormonal induction of puberty. In order to investigate the presence of a genetic defect, aCGH-SNP analysis was performed. A 13.5 Mb long contiguous stretch of homozygosity (LCSH) was identified on chromosome 7q21.13-q22.1 where the exome sequencing revealed a novel homozygous 4-bp deletion (c.3381_3384delAGAA) in STAG3. Pathogenic variants in this gene, encoding for a meiosis-specific protein, have been previously reported as the cause of POI in only eight families and recently as the cause of infertility in a male. The here-identified mutation leads to the truncation of the last 55 amino acids, confirming the important role in meiosis of the STAG3 C-terminal domain

Spatial segregation of home ranges between neighbouring colonies in a diurnal raptor

Enhancement of information transfer has been proposed as a key driver of the evolution of coloniality. Transfer of information on location of food resources implies that individuals from the same colony share foraging areas and that each colony can be associated to a speciic foraging area. In colonial breeding vertebrates, colony-speciic foraging areas are often spatially segregated, mitigating intercolony intraspeciic competition. By means of simultaneous GPS tracking of lesser kestrels (Falco naumanni) from neighbouring colonies, we showed a clear segregation of space use between individuals from diferent colonies. Foraging birds from diferent neighbouring colonies had home ranges that were signiicantly more segregated in space than expected by chance. This was the case both between large and between small neighbouring colonies. To our knowledge, the lesser kestrel is the only terrestrial species where evidence of spatial segregation of home ranges between conspeciics from neighbouring colonies has been demonstrated. The observed spatial segregation pattern is consistent with the occurrence of public information transfer about foraging areas and with the avoidance of overexploited areas located between neighbouring colonies. Our indings support the idea that spatial segregation of exploited areas may be widespread among colonial avian taxa, irrespective of colony size

Testing for the cytosine insertion in the VNTR of the MUC1 gene in a cohort of Italian patients with autosomal dominant tubulointerstitial kidney disease

INTRODUCTION: Medullary cystic kidney disease type 1 (MCKD1; OMIM #174000) is a familial progressive tubule-interstitial nephropathy belonging to the recently defined group of autosomal dominant tubulointerstitial kidney diseases (ADTKD). CASE REPORT: A specific type of cytosine insertion in the extracellular variable number tandem repeat (VNTR) domain of the MUC1 gene causing the disease was tested in a group of 21 families with ADTKD. We identified this type of MUC1 mutation in two families, whose affected members are described in detail in this case report. Affected (ADTKD-MUC1) members developed end-stage renal disease (ESRD) with a higher incidence (p = 0.033) and at a younger age (p = 0.013) than probands with ADTKD but without this type of mutation. All patients with MUC1-associated kidney disease shared a rather unspecific tubule-interstitial laboratory pattern without medullary cysts, leading to ESRD between the age of 33 and 47 years. We were not able to identify any single common extra-renal feature among affected patients, even if they had various comorbidities, which are described in detail. CONCLUSIONS: We identified this type of MUC1 mutation in 9.5 % of families from an ADTKD Italian cohort; larger studies are needed to better define the criteria for genetic testing for this type of mutation

Novel GLI2 mutations identified in patients with Combined Pituitary Hormone Deficiency (CPHD): Evidence for a pathogenic effect by functional characterization

CONTEXT: The Gli-family of zinc-finger transcription factors regulates the Sonic Hedgehog (Shh) signalling pathway that plays a key role in early pituitary and ventral forebrain development. Heterozygous GLI2 loss of function mutations in humans have been reported in holoprosencephaly (HPE), HPE-like phenotypes associated with pituitary anomalies and combined pituitary hormone deficiency with or without other extra-pituitary findings. OBJECTIVE: The aim of this study was the search for GLI2 mutations in a cohort of Italian CPHD patients and the assessment of a pathogenic role for the identified variants through in vitro studies. PATIENTS: One hundred forty-five unrelated CPHD patients diagnosed with or without extra-pituitary manifestations were recruited from different Italian centres. METHODS: The GLI2 mutation screening was carried out through direct sequencing of all the 13 exons and intron-exon boundaries. Luciferase reporter assays were performed to evaluate the role of the detected missense variants. RESULTS: Five different novel heterozygous non-synonymous GLI2 variants were identified in five patients. The mutations were three missense (p.Pro386Leu, p.Tyr575His, p.Ala593Val), one frameshift (p.Val1111Glyfs*19) and one nonsense (p.Arg1226X). The latter two mutants are likely pathogenic since they lead to a truncated protein. The in vitro functional study of the plasmids bearing two of the three missense variants (namely p.Tyr575His and p.Ala593Val) revealed a significant reduction in transcriptional activity. CONCLUSION: In conclusion, the analysis of GLI2 in individuals with CPHD led to the identification of five variations with a likely negative impact on the GLI2 protein, confirming that GLI2 is an important causative gene in CPHD. The functional in vitro study analysis performed on the missense variations were useful to strengthen the hypothesis of pathogenicity

Case report: Better late than never, but sooner is better: switch from CSII to sulfonylureas in two patients with neonatal diabetes due to KCNJ11 variants

Neonatal diabetes mellitus (NDM) is a rare genetic disease characterized by severe hyperglycemia requiring insulin therapy with onset mostly within the first 6 months and rarely between 6-12 months of age. The disease can be classified into transient (TNDM) or permanent neonatal diabetes mellitus (PNDM), or it can be a component of a syndrome. The most frequent genetic causes are abnormalities of the 6q24 chromosomal region and mutations of the ABCC8 or KCNJ11 genes coding for the pancreatic beta cell’s potassium channel (KATP). After the acute phase, patients with ABCC8 or KCNJ11 mutations treated with insulin therapy can switch to hypoglycemic sulfonylureas (SU). These drugs close the KATP channel binding the SUR1 subunit of the potassium channel and restoring insulin secretion after a meal. The timing of this switch can be different and could affect long-term complications. We describe the different management and clinical outcome over the time of two male patients with NDM due to KCNJ11 pathogenetic variants. In both cases, continuous subcutaneous insulin infusion pumps (CSII) were used to switch therapy from insulin to SU, but at different times after the onset. The two patients kept adequate metabolic control after the introduction of glibenclamide; during the treatment, insulin secretion was evaluated with c-peptide, fructosamine, and glycated hemoglobin (HbA1c), which were within the normal range. In neonates or infants with diabetes mellitus, genetic testing is an indispensable diagnostic tool and KCNJ11 variants should be considered. A trial of oral glibenclamide must be considered, switching from insulin, the first line of NDM treatment. This therapy can improve neurological and neuropsychological outcomes, in particular in the case of earlier treatment initiation. A new modified protocol with glibenclamide administered several times daily according to continuous glucose monitoring profile indications, was used. Patients treated with glibenclamide maintain good metabolic control and prevent hypoglycemia, neurological damage, and apoptosis of beta cells during long‐term administration