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Biomedical subjects

M C Digilio

Publications and source records attributed to M C Digilio.

At least 19 recordsLinked to original sources
PubMed2005

Two high throughput technologies to detect segmental aneuploidies identify new Williams-Beuren syndrome patients with atypical deletions.

OBJECTIVE: To develop and compare two new technologies for diagnosing a contiguous gene syndrome, the Williams-Beuren syndrome (WBS). METHODS: The first proposed method, named paralogous sequence quantification (PSQ), is based on the use of paralogous sequences located on different chromosomes and quantification of specific mismatches present at these loci using pyrosequencing technology. The second exploits quantitative real time polymerase chain reaction (QPCR) to assess the relative quantity of an analysed locus. RESULTS: A correct and unambiguous diagnosis was obtained for 100% of the analysed samples with either technique (n = 165 and n = 155, respectively). These methods allowed the identification of two patients with atypical deletions in a cohort of 182 WBS patients. Both patients presented with mild facial anomalies, mild mental retardation with impaired visuospatial cognition, supravalvar aortic stenosis, and normal growth indices. These observations are consistent with the involvement of GTF2IRD1 or GTF2I in some of the WBS facial features. CONCLUSIONS: Both PSQ and QPCR are robust, easy to interpret, and simple to set up. They represent a competitive alternative for the diagnosis of segmental aneuploidies in clinical laboratories. They have advantages over fluorescence in situ hybridisation or microsatellites/SNP genotyping for detecting short segmental aneuploidies as the former is costly and labour intensive while the latter depends on the informativeness of the polymorphisms.

Aneuploidy↗
PubMed2005

Pure trisomy 19p syndrome in an infant with an extra ring chromosome.

We report a 12-month-old infant evaluated for severe hypotonia, psychomotor retardation, and facial dysmorphisms, including round face, high prominent forehead, downward slanted palpebral fissures, hypertelorism, short nose, chubby cheeks, long philtrum, anteverted lower lip, low-set asymmetric and dysmorphic ears. Karyotype analysis disclosed an extra mosaic ring chromosome, which included the whole 19p arm. Four additional patients with supernumerary ring 19 chromosomes have been reported, but none of them had pure trisomy 19p.

Chromosome Banding↗
PubMed2004

High frequency of subtelomeric rearrangements in a cohort of 92 patients with severe mental retardation and dysmorphism.

About 5-10% of patients with dysmorphisms, severe mental retardation, and normal standard karyotype are affected by subtelomeric chromosome rearrangements. Sequence homology between different chromosomes and variability between homologs make these regions more susceptible to breakage and reunion. We analyzed the telomeric regions of 92 of these patients, selected with strict clinical criteria. Fifteen individuals (16.3%) had subtelomeric rearrangements. Nine had a unique anomaly, which in one case had been inherited from a balanced parent. Six subjects had double segmental imbalances, including three de novo imbalances. This study provides further evidence for the plasticity of subtelomeric regions, which often results in cryptic rearrangements, and recommends stringent criteria for selecting patient candidates to telomere analysis.

Child↗
PubMed2003

Absorption of sugars and amino acids by the epidermis of Aphidius ervi larvae.

Aphidius ervi Haliday (Hymenoptera, Braconidae) is an endophagous parasitoid of several aphid species of economic importance, widely used in biological control. The definition of a suitable artificial diet for in vitro mass production of this parasitoid is still an unresolved issue that, to be properly addressed, requires a deeper understanding both of its nutritional needs and of the functional properties of the larval epithelia involved in nutrient absorption. The experimental evidence presented in this paper unequivocally demonstrates that the uptake of sugars and amino acids takes place through the body surface of the larval stages of A. ervi. These nutrients are efficiently absorbed by the larval epidermis, but the transport rate progressively declines over time. The epidermis exhibits a cross-reactivity to antibodies raised against the mammalian facilitative glucose transporter GLUT2 and the sodium cotransporter SGLT1. The analysis of sugar transport sensitivity to specific inhibitors indicates the involvement of GLUT2-like transporters, while a role for SGLT1-like transporters is not supported. The peculiar pathways of nutrient absorption in A. ervi larvae further corroborate the general idea that the pre-imaginal stages of endophagous koinobiont Hymenoptera, like Metazoan parasites, show a high degree of physiological integration with their hosts.

Absorption↗
PubMed2003

Spectrum of clinical variability in familial deletion 22q11.2: from full manifestation to extremely mild clinical anomalies.

The 22q11.2 deletion (del22q11.2) syndrome is a genetic condition with wide interfamilial and intrafamilial variability in clinical expression. The aim of the present study was to review the prevalence of parental transmission in our series of patients with del22q11.2, and to analyse clinical findings of the affected parents. Parental transmission of del22q11.2 in our series was 17.2% (15/87), with a preferential maternal transmission (10/15). One or more major features of del22q11.2 were found in all deleted parents, but one of the mothers showed extremely mild clinical anomalies. The present data demonstrate that it should be current policy to test both parents of patients with del22q11.2, irrespective of the parental phenotype, in view of the fact that extremely mild clinical features can be detected in parents of deleted patients. This would provide accurate genetic counselling to del22q11.2 families, as relatively asymptomatic parents must be advised of the 50% risk of transmitting the deletion in a subsequent pregnancy. Various genetic and non-genetic factors, including modifier genes at separate loci, mosaicism, unstable mutations, allelic variations at the haploid locus, chance and environmental interaction, can be hypothesized to be involved in variable clinical expression, even in the same family.

Chromosomes, Human, Pair 22↗
PubMed2003

Biased T-cell receptor repertoires in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome).

Chromosome 22q11.2 deletion (del22q11.2) syndrome (DiGeorge syndrome/velocardiofacial syndrome) is a common syndrome typically consisting of congenital heart disease, hypoparathyroidism, developmental delay and immunodeficiency. Although a broad range of immunologic defects have been described in these patients, limited information is currently available on the diversity of the T-cell receptor (TCR) variable beta (BV) chain repertoire. The TCRBV repertoires of nine patients with del22q11.2 syndrome were determined by flow cytometry, fragment size analysis of the third complementarity determining region (CDR3 spectratyping) and sequencing of V(D)J regions. The rate of thymic output and the phenotype and function of peripheral T cells were also studied. Expanded TCRBV families were detected by flow cytometry in both CD4+ and CD8+ T cells. A decreased diversity of TCR repertoires was also demonstrated by CDR3 spectratyping, showing altered CDR3 profiles in the majority of TCRBV families investigated. The oligoclonal nature of abnormal peaks detected by CDR3 spectratyping was confirmed by the sequence analysis of the V(D)J regions. Thymic output, evaluated by measuring TCR rearrangement excision circles (TRECs), was significantly decreased in comparison with age-matched controls. Finally, a significant up-regulation in the percentage, but not in the absolute count, of activated CD4+ T cells (CD95+, CCR5+, HLA-DR+), IFN-gamma - and IL-2-expressing T cells was detected. These findings suggest that the diversity of CD4 and CD8 TCRBV repertoires is decreased in patients with del22q11.2 syndrome, possibly as a result of either impaired thymic function and/or increased T-cell activation.

Adolescent↗
PubMed2002

Identification of a novel NOG gene mutation (P35S) in an Italian family with symphalangism.

Symphalangism (SYM or SYM1) is an autosomal dominant disorder characterized by multiple joint fusions. The disease is caused by mutations of the NOG gene, that maps to chromosome 17q22. So far, only six independent NOG mutations have been identified. We have analysed an Italian family in which father and son had bilateral symphalangism and detected a novel NOG mutation (P35S), originated in the father from a c.914C>T transition. A different mutation in the same codon (P35R) has been previously described. Comparison between different noggin gene hortologs shows that codon 35 is conserved. Therefore, this codon should play an important role in NOG gene function. This is the first mutation described for NOG after the initial report of NOG mutations being causative of SYM.

Amino Acid Sequence↗
PubMed2002

Two novel mutations of the human delta7-sterol reductase (DHCR7) gene in children with Smith-Lemli-Opitz syndrome.

We analyzed seven unrelated children with the Smith-Lemli-Opitz syndrome (SLOS) for mutations in the delta7-sterol reductase gene by using SSCP and direct sequencing. We identified two novel mutations (V330M and R363C) in the DHCR7 gene. Reported mutations found in this study were T93M (3/14 alleles), E448K (2/14), and W151X, G244R, P329L, and R446Q (each found in one allele). The so-called common IVS8-1 G --> C was found in three alleles, confirming its relative rarity among Italian SLOS families. By using a scoring system, clinical severity did not seem to correlate with 7DHC levels and type of mutation. Expanding the spectrum of mutations in SLOS, our study does not support direct genotype-phenotype correlation.

Alleles↗
PubMed2001

Exercise testing and 24-hour ambulatory blood pressure monitoring in children with Williams syndrome.

The aim of the study was to assess workload capacity and blood pressure (BP) response to treadmill exercise and 24-hour BP monitoring in children with Williams syndrome. Seventeen children were examined (8 males and 9 females) whose mean age was 13.8 +/- 3.6 years. Six patients were on antihypertensive therapy. Each patient underwent clinical examination and measurement of BP at rest, during exercise, and during 24-hour monitoring. Two-dimensional echocardiogram and echo-Doppler of renal arteries were performed. The test was stopped for muscular fatigue or reduced cooperation. The patients, when compared to a population of healthy children, had reduced total time of exercise (7.3 +/- 1.9 vs 14.3 +/- 2.6 min, p < 0.001) and, at the same workload, increased heart rate (167 +/- 19 vs 145 +/- 16 beats/min, p < 0.001) and increased maximum systolic BP (146 +/- 27 vs 128 +/- 12 mmHg, p = 0.01). Ambulatory blood pressure measurement values showed higher systolic blood pressure both during daytime and nighttime. Our study confirms that children and adolescents with Williams syndrome are at high risk for hypertension, probably related to the alterations of large arteries. The data relating to the synthesis of elastin may have a direct relationship to the compliance of the arterial system, leading to hypertension.

Adolescent↗
PubMed2001

Complete transposition of the great arteries: patterns of congenital heart disease in familial precurrence.

BACKGROUND: Transposition of the great arteries (TGA) is considered to be associated only rarely with genetic syndromes and to have a low risk of precurrence among relatives of affected patients. Because most family studies have involved a relatively small number of patients and evaluated all types of TGA as a single group, we performed a large, prospective study investigating the precurrence of congenital heart disease in families of children with complete, nonsyndromic TGA. METHODS AND RESULTS: From January 1997 through December 2000, 370 patients with nonsyndromic, complete TGA were consecutively evaluated and enrolled in the study. The occurrence of cardiac and noncardiac anomalies among relatives of the probands was investigated. Relatives with congenital heart disease were found in 37 of 370 families (10%), including 5 of 37 families (13.5%) with more than one affected relative. TGA itself was the most common precurrent malformation: complete TGA occurred in 6 families and congenitally corrected TGA occurred in 5 families. Precurrence risks for congenital heart disease were calculated at 1.8% (8 of 436) for siblings, 0.5% (4 of 740) for parents, 0.5% (16 of 3261) for first cousins, 0.2% (4 of 2101) for uncles/aunts, and 0.06% (1 of 1480) for grandparents. CONCLUSIONS: The present study shows that TGA is not always sporadic in families. Precurrence of concordant cardiac defects within affected family members supports monogenic or oligogenic inheritance of TGA in certain kindreds. Moreover, the occurrence of complete TGA and congenitally corrected TGA among first-degree relatives in several different families strongly suggests an underlying pathogenetic link between these 2 malformations that has been previously unrecognized.

Adolescent↗
PubMed2001

Ext-mutation analysis in Italian sporadic and hereditary osteochondromas.

Osteochondromas represent the largest group of benign tumors of bone. Multiple osteochondromatosis or hereditary multiple exostoses (EXT) is an autosomal dominant inherited disorder characterized by the presence of multiple benign cartilage-capped exostoses. EXT is genetically heterogeneous with at least 3 chromosomal loci: EXT1 (8q24.1), EXT2 (11p11-p13), and EXT3 (19p). In <5% of EXT patients, the inactivation of both copies of EXT alleles (LOH) is associated with malignant transformation. We have analyzed the EXT1 and EXT2 genes in 9 unrelated EXT families and in a patient with a sporadic osteochondroma, all originating from Italy. Four families show an EXT1 mutation, consisting of a small deletion in 3 of them and a small insertion in the 4th. All these mutations lead to premature termination of translation and thus a truncated EXT1 protein. Three families presented EXT2 mutations consisting of nucleotide substitutions leading to alterations of the third intron splice-site, to an amino acid substitution and to a nonsense mutation. All these mutations cosegregate with the disease phenotype. The sporadic osteochondroma patient carried a novel missense mutation in exon 11 of EXT2 gene, leading to an amino acid substitution. Seven of these mutations have never been described before. EXT2 missense mutations were also confirmed by amino acids conservation between human and mouse and by analysis of a healthy control population. In conclusion, our study provide further evidence that loss of function of the EXT1 or EXT2 gene is the main cause of EXT supporting the putative tumor-suppressor function of these genes.

Adolescent↗
PubMed2001

Congenital heart defects in Kabuki syndrome.

Kabuki makeup (Niikawa-Kuroki) syndrome (KS) is characterized by distinct facial anomalies, mental retardation, congenital heart defect (CHD), and skeletal malformations. In the present study we analyze cardiac characteristics and differences in sex prevalence of specific CHDs in our series of patients with KS and review published reports from the literature. Between January 1992 and February 2000, 60 patients (37 males and 23 females) with KS underwent phenotypic and cardiac evaluations at our hospital. CHD was diagnosed in 35 (58%) of our patients. Aortic coarctation (COA) (23%), atrial septal defect (ASD) (20%), and ventricular septal defect (VSD) (17%) were the most frequent CHDs in our series and in previous reports from the literature. Male preponderance was noted in patients with COA. In conclusion, CHD is a cardinal feature of KS. There is an overlap between cardiac malformations of KS and those of Turner syndrome. Male preponderance in patients with KS and COA supports the hypothesis that genes located on the X chromosome may be involved in determining KS in some patients. The high prevalence of CHD prompts accurate re-examination of patients evaluated by pediatric cardiologists in order to identify mild and still unrecognized cases of KS.

Abnormalities, Multiple↗
PubMed2001

Coeliac disease in Williams syndrome.

BACKGROUND: Coeliac disease (CD) has been reported in several patients affected by chromosomal disorders, including Down syndrome (DS) and Turner syndrome (TS). CD has also been found in sporadic Williams syndrome (WS) patients. In this study, CD was evaluated in a consecutive series of patients with WS, in order to estimate if the prevalence of CD in WS patients is higher than in the general population. METHODS AND RESULTS: A consecutive series of 63 Italian patients with WS was studied by analysing the dosage of antigliadin antibodies (AGA) IgA and antiendomisium antibodies (AEA). In patients with positive AGA and AEA, small bowel biopsy was performed. The prevalence of CD in our WS population was compared with that estimated in a published series of 17 201 Italian students. Seven WS patients were found to be positive for AGA IgA and AEA. Six of them underwent small bowel biopsy, which invariably disclosed villous atrophy consistent with CD. The prevalence of CD in the present series of WS patients was 9.5% (6/63), compared to 0.54% (1/184) in the Italian students (p<0.001). CONCLUSION: The present results suggest that the prevalence of CD in WS is higher than in the general population and is comparable to that reported in DS and TS. AGA and AEA screening is recommended in patients with WS.

Adolescent↗
PubMed2001

Pulmonary atresia with ventricular septal defect: prevalence of deletion 22q11 in the different anatomic patterns.

BACKGROUND: Pulmonary atresia with ventricular septal defect (PA-VSD) is one of the most common cardiac defects associated with DiGeorge syndrome. The pattern of the pulmonary circulation determines the complexity of this type of heart disease. The aim of this study was to establish the prevalence of DiGeorge syndrome with deletion 22q11 in patients with simple and complex PA-VSD. METHODS: Since 1993 we have studied 128 consecutive patients affected by PA-VSD. In 90 of our patients the PA-VSD was considered "simple" (group I), because it was not associated with any other cardiac defects. In the other 38 children the PA-VSD was considered "complex" (group II) owing to the presence of heterotaxia, tricuspid atresia, a double-inlet left ventricle, transposition of the great arteries and congenitally corrected transposition of the great arteries. RESULTS: In group I, 38 patients (42%) had genetic syndromes or major extracardiac anomalies; deletion 22q11 was detected in 31% of cases. Major aortopulmonary collateral arteries were present in 50% of group I patients and in 57% of those with deletion 22q11. In group II, 10 patients (26%) had genetic syndromes or major extracardiac anomalies but none had deletion 22q11 (p < 0.005); in no case was the presence of major aortopulmonary collateral arteries observed (p < 0.005). CONCLUSIONS: PA-VSD is an anatomically and morphogenetically heterogeneous disease: in the setting of DiGeorge syndrome or velocardiofacial syndrome, PA-VSD is associated with a peculiar cardiac pattern and is due to deletion 22, whereas in case of nonsyndromic PA-VSD or when this disease is associated with different syndromes or with other types of cardiac defects, it is due to other morphogenetic mechanisms.

Child Welfare↗