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P Grammatico

Publications and source records attributed to P Grammatico.

At least 19 recordsLinked to original sources
PubMed2006

A novel Leu153Ser mutation of the Fanconi anemia FANCD2 gene is associated with severe chemotherapy toxicity in a pediatric T-cell acute lymphoblastic leukemia.

Fanconi anemia (FA) is an autosomal recessive disease characterized by pancitopenia, congenital malformations, predisposition to cancers and chromosomal instability. We report the clinical and molecular features of a patient initially identified as a potential FA case only because of chemotherapy toxicity during the treatment of a T-lineage acute lymphoblastic leukemia (ALL). Cells from this patient showed a moderate chromosomal instability, increasing sensitivity to DNA crosslinking agents but normal response to ionizing radiation. The analysis of FA proteins demonstrated a marked reduction of FANCD2 (>95%), but normal levels of FANCA or FANCG. Interestingly, this defect was associated with a homozygous missense mutation of FANCD2, resulting in a novel amino-acid substitution (Leu153Ser) at residue Leu153, which is highly conserved through evolution. The FANCD2(L153S) protein, whose reduced expression was not due to impaired transcription, was detected also in its monoubiquitinated form in the nucleus, suggesting that the mutation does not affect post-translation modifications or subcellular localization but rather the stability of FANCD2. Therefore, the hypomorphic Leu153Ser mutation represents the first example of a FANCD2 defect that might promote clonal progression of tumors, such as T-ALL, and severe chemotherapy toxicity in patients without any clinical manifestations typical of FA.

Amino Acid Substitution↗
PubMed2006

De novo pure 12q22q24.33 duplication: first report of a case with mental retardation, ADHD, and Dandy-Walker malformation.

We present a patient with a de novo 12q nonmosaic pure duplication characterized by multiple minor anomalies and Dandy-Walker malformation. A neurological and behavioral assessment revealed psychomotor retardation and attention deficit/hyperactivity disorder (ADHD), with neurobehavioral abnormalities (auto- and heteroaggressive behavior). Fluoxetine therapy in this case markedly improved the neurobehavioral profile, with a decreased level of aggression. To define the extension of the duplicated region, we performed FISH analyses by using YAC probes. The analyses revealed a tandem duplication of the 12q22q24.33 region, with the proximal breakpoint located between 96.5 and 97.6 cM and the distal one between 154 and 161 cM. This is the first case of pure de novo duplication involving the 12q22q24.33 region. To better define the clinical phenotype associated with 12q partial duplication, we compared our case with the four patients with similar pure duplications previously described.

Abnormalities, Multiple↗
PubMed2006

Homozygous p.M172K mutation of the TFR2 gene in an Italian family with type 3 hereditary hemochromatosis and early onset iron overload.

The p.M172K TFR2 mutation was identified in two Italian siblings aged 32 and 40 years old with primary iron overload. The two patients showed a severe increase in serum iron indices. From the age of 25, the male sib also revealed abnormal levels of hepatic enzymes, presumably in relation to iron induced liver damage. Clinical findings seem to evidence that type 3 hemochromatosis can be more serious than classic hemochromatosis. This report adds two more type 3 hereditary hemochromatosis cases which suggest that TFR2 mutations could be more frequently involved in non-HFE hemochromatosis than has been actually thought.

Adult↗
PubMed2005

Mutation analysis of the NSD1 gene in a group of 59 patients with congenital overgrowth.

Sotos syndrome is characterized by pre- and post-natal overgrowth, typical craniofacial features, advanced bone age, and developmental delay. Some degree of phenotypic overlap exists with other overgrowth syndromes, in particular with Weaver syndrome. Sotos syndrome is caused by haploinsufficiency of the NSD1 (nuclear receptor SET domain containing gene 1) gene. Microdeletions involving the gene are the major cause of the syndrome in Japanese patients, whereas intragenic mutations are more frequent in non-Japanese patients. NSD1 aberrations have also been described in some patients diagnosed as Weaver syndrome. Some authors have suggested a certain degree of genotype-phenotype correlation, with a milder degree of overgrowth, a more severe mental retardation, and a higher frequency of congenital anomalies in microdeleted patients. Data on larger series are needed to confirm this suggestion. We report here on microdeletion and mutation analysis of NSD1 in 59 patients with congenital overgrowth. Fourteen novel mutations, two previously described and one microdeletion were identified. All patients with a NSD1 mutation had been clinically classified as "classical Sotos," although their phenotype analysis demonstrated that some major criteria, such as overgrowth and macrocephaly, could be absent. All patients with confirmed mutations shared the typical Sotos facial gestalt. A high frequency of congenital heart defects was present in patients with intragenic mutations, supporting the relevance of the NSD1 gene in the pathogenesis of this particular defect.

Adolescent↗
PubMed2004

HAMP gene mutation c.208T>C (p.C70R) identified in an Italian patient with severe hereditary hemochromatosis.

Hepcidin is a recently identified hormone peptide involved in regulation of iron homeostasis. HAMP gene mutations have been described to date in five families with iron overload. We have identified the c.208T>C (p.C70R) mutation in the HAMP gene in a patient affected by a severe form of hereditary hemochromatosis. The variant, occurring in a highly conserved amino acid, disrupts one of the 4 intramolecular disulphide bonds present in hepcidin molecules of all vertebrates, and is presumably able to destabilize the peptide structure. The investigated patient was also found to harbor a heterozygous HFE c.845G>A (p.C282Y) mutation that may have contributed in increasing his iron burden.

Amino Acid Substitution↗
PubMed2004

Fetal cells in maternal blood: a six-fold increase in women who have undergone amniocentesis and carry a fetus with Down syndrome: a multicenter study.

Fetal nucleated red blood cells (FNRBCs) circulate in the maternal blood throughout pregnancy. Even if the frequency of fetal cells in the maternal circulation remains to be ascertained, complications of pregnancy such as fetal cells aneuploidies, preeclampsia, abnormal Doppler of the uterine artery without symptoms of preeclampsia, fetal growth restriction and polyhydramnios are associated with an increased feto-maternal trafficking. Based on these observations, previous studies have suggested that determination of the fetal nucleated red blood cell count (FNRBCC) might be a useful non-invasive screening test, either alone or in combination with existing maternal tests, for the non-invasive assessment of aneuploidies, in particular Down syndrome (DS). In this paper we have evaluated the distribution of FNRBCC in a set of 18 normal pregnancies and 18 pregnancies with a trisomy 21-affected fetus, matching for gestational age, maternal age, and, when possible, fetal gender, in order to quantify the difference in the number of fetal cells between the two populations. Maternal blood was collected from each pregnant woman two to three weeks after amniocentesis after knowing the cytogenetic results. Correlation of FNRBCC with the gestational week and clinical status (affected vs. non affected) by multiple regression analysis provided significant results (p < 0.001). Adjusted values of FNRBCC were 48 +/- 10.2 in controls and 301 +/- 17.01 in DS cases, corresponding to a 6.27 fold increase. These retrospective results prompt a prospective evaluation of the use of FNRBCC for screening purposes.

Adult↗
PubMed2003

Cytogenetic and molecular characterization of a de novo 4q24qter duplication and correlation to the associated phenotype.

We report on a newborn with severe psychomotor retardation, minor anomalies, congenital heart defects, thumb and urogenital abnormalities. Cytogenetic analysis showed a 4q24qter duplication, never described before, as the result of a de novo t(4;14). The extension of the duplicated 4q region was defined by FISH using YAC probes. The breakpoint was localized between 106.3cM (YAC 800f2, D4S1572) and 111 cM (YAC 744e4, D4S1564). Comparing our patient with those previously reported in literature, we observed some features mature frequently reported in these patients: psychomotor retardation, retromicrognathia, low set and/or malformed ears and some more specific traits: congenital cardiac defects, hypoplastic thumb and urogenital abnormalities.

Abnormalities, Multiple↗
PubMed2003

Clinical management and molecular cytogenetic characterization in a 45,X/46,X,idic(Yp) patient with severe hypospadia.

Cryptorchidism and proximal hypospadia in a newborn are highly suspicious for an intersex disorder, and proper investigations should be planned immediately after birth. In some hypospadic patients, the presence of a palpable gonad in the scrotum may induce to assign the male sex, whereas the anatomy of internal and external genitalia could be extremely complex, requiring an accurate evaluation before any definitive attribution of gender. The authors present a case of an infant, referred to the hospital for surgical treatment of a proximal hypospadia, who showed ambiguous external genitalia, absence of the right gonad, a partially dysgenetic left testis, and presence of both müllerian and wolffian structures. Cytogenetic analysis detected a mosaicism with a cell line showing an isodicentric Yp chromosome and a second one, a 45, X chromosomal complement. Because the baby had been assigned previously to male gender, he underwent a staged masculinizing correction of the genital anomalies. The authors discuss the necessity of a careful evaluation of these patients at birth by a multispecialistic team, for appropriate sex assignment and for the assessment of the risk of neoplastic degeneration.

Chromosomes, Human, Y↗
PubMed2002

Two novel mutations and a new STK11/LKB1 gene isoform in Peutz-Jeghers patients.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominantly inherited disorder with variable expression and incomplete penetrance characterized by mucocutaneous pigmentation, predisposition to hamartomatous intestinal polyposis, and various other neoplasms. It occurs in approximately 1 in 8,300 to 29,000 live births. In nearly 50% of patients PJS is caused by germ line mutations in the STK11/LKB1 serine/threonine kinase gene, the only kinase gene currently known to act as a tumor suppressor. We have performed a mutation search in the STK11/LKB1 gene in 8 sporadic cases and 3 PJS families using a combination of different screening techniques. We have identified four mutations, two of which I177N and the IVS2+1A->G, were previously unreported. We have also evaluated the presence of cDNA alterations by means of RT-PCR analysis and direct cDNA sequencing and have found two aberrant transcripts in a single PJS case despite the lack of any apparent genomic alteration. Finally, we report the presence of a novel STK11/LKB1 cDNA isoform observed in all the normal subjects studied as well as in the majority of the PJS patients.

AMP-Activated Protein Kinase Kinases↗
PubMed2001

Defining the breakpoints of proximal chromosome 14q rearrangements in nine patients using flow-sorted chromosomes.

The breakpoints of deletions and translocations in the proximal chromosome 14q region were defined in nine patients, four of whom have not been reported previously. The aberrant chromosomes were isolated by flow cytometry and used to map the chromosome 14 deletion or translocation breakpoints. The parental origins of deletions were ascertained as paternal in five cases and maternal in one. With the draft genomic sequence for human chromosome 14 available, gene searches were performed on selected intervals of the 14q11.2-q21 region to identify candidate genes for the observed phenotype in some of those affected. Gain of function of the gene PAX9 on chromosome 14 is a possible candidate for a t(14;18) patient affected with mesomelic bone dysplasia. Furthermore, a compilation of other human chromosome 14q proximal deletion and translocation cases was obtained from a search on cytogenetic databases. These findings suggest a locus for myelofibrosis at chromosome 14q13. This study contributes to useful information for identifying disease genes in this region.

Child↗
PubMed2001

CDKN2A novel mutation in a patient from a melanoma-prone family.

CDKN2A is thought to be the main candidate gene for melanoma susceptibility. Deletion or mutations in the CDKN2A gene may produce an imbalance between functional p16 and cyclin D, causing abnormal cell growth. We here describe a novel mutation consisting of a 1 bp deletion at nucleotide position 201 (codon 67) (CACGGcGCG) resulting in a truncated protein (stop codon 145). The patient, a female subject from a melanoma-prone family, presented at the age of 47 years with a superficial spreading melanoma of the trunk. Her father had colon cancer at the age of 43 years and melanoma at 63 years, her uncle suffered from gastric cancer, and her grandfather had laryngeal cancer.

Adult↗
PubMed2000

Dot-and-fleck retinopathy in Alport syndrome caused by a novel mutation in the COL4A5 gene.

PURPOSE: To describe an unusual form of dot-and-fleck retinopathy in a slower progressive form of X-linked Alport syndrome, caused by a novel missense mutation in the COL4A5 gene. METHOD: Ophthalmic examination, polymerase chain reaction, and single-strand conformational polymorphism analysis of genomic DNA were performed in the proband. RESULTS: Ophthalmoscopy revealed classic dot-and-fleck retinopathy but located in an unusual site. A novel COL4A5 gene mutation changing glycine to cysteine at 177 was identified. CONCLUSIONS: Although there is no correlation between mutation site and the resulting phenotype in Alport syndrome, our findings suggest that further novel mutations and different ocular manifestations may be associated with Alport syndrome.

Adult↗
PubMed1999

3p13 region: a possible location of a tumor suppressor gene involved in uveal melanoma.

To contribute to a better understanding of the role of chromosomal rearrangements in the tumorigenesis of uveal melanoma, we present a case in which a structural aberration of chromosome 3 could indicate the specific region in which an uveal melanoma tumor suppressor gene could be located. We obtained a primary cell culture, characterized by cytogenetic study, through GTG- and CBG-banding techniques by using a mechanical dissection of a tumor sample obtained from an uveal melanoma. Cytogenetic analysis performed in the primary cell culture highlighted the presence of a structural rearrangement involving chromosomes 3 and 22. A t(3;22)(p13;p11) was observed as the only present clonal aberration. The 3p13 breakpoint involved in the aberration observed in our case could be essential in restricting the candidate region for the locus of an uveal melanoma tumor suppressor gene located on chromosome 3.

Choroid Neoplasms↗
PubMed1999

Antioxidant pattern in uveal melanocytes and melanoma cell cultures.

PURPOSE: To investigate the antioxidant status of cultured uveal melanocytes from patients with uveal melanoma and uveal melanoma cells to characterize some of the biochemical properties of these cells in respect to the normal cutaneous melanocytes. METHODS: The fatty acid pattern of membrane phospholipids, intracellular vitamin E level, and superoxide dismutase (SOD) and catalase activities were studied in uveal melanocytes (n = 10) and uveal melanoma cell (n = 10) cultures, by gas chromatography mass spectrometry or by spectrophotometer. RESULTS: Among the uveal melanocyte cultures, two groups were differentiated, according to catalase activity: group A with catalase values comparable to those of cutaneous ones and higher SOD activity and group B with catalase values 2 SD lower (P<0.001) and lower SOD activity. Vitamin E concentration was not significantly different between melanoma cells and melanocytes, whereas a significantly higher percentage of polyunsaturated fatty acids was found in melanoma cells and the B group of melanocytes (P = 0.022). In uveal melanoma cells SOD activity was significantly lower than that detected in uveal melanocytes (P< 0.005). CONCLUSIONS: These results show a different pattern of antioxidants in uveal melanocytes with respect to cutaneous ones, possibly related to the anatomic distribution. However, as in cutaneous melanocytes, two subgroups were identified on the basis of the antioxidant pattern that could be the expression of a constitutional increased susceptibility to oxidative stress in some subjects. Moreover, an imbalance of the antioxidants was observed in melanoma cells, possibly related to the disease status and progression.

Adult↗
PubMed1999

46,XX,der(2)t(2;10)(2pter-->2q37::10p13-->10pter)[127]/45,X,der(2)t(2;10) (2pter-->2q37::10p13-->10pter)[23]. Karyotype-phenotype correlation and genetic counselling in complex karyotypes.

We describe a female child with complex cytogenetic anomalies consisting in partial trisomy of the short arm of chromosome 10, terminal deletion of the long arm of chromosome 2 and--at the same time--a mosaicism for X monosomy. To our knowledge, this is the first case reported in which 10p trisomy is associated to a 2qter deletion. Due to the scarcity of cases reported with pure trisomy, it has not been possible to define the 10p+ syndrome precisely yet. Comparison of our proband's phenotype to both the 2q37 deletion and 10p trisomy showed more features described in 2q37- subjects than in 10p+ ones. We also discuss the difficulties of genetic counseling in children with complex aberrations.

Abnormalities, Multiple↗
PubMed1998

HLA-DR and -DQ alleles in Italian patients with melanoma.

Controversial data have been reported about HLA alleles and susceptibility to melanoma. Our investigation was undertaken to analyze the relationship between HLA alleles distribution in patients with melanoma and susceptibility to the tumor, in order to study the possible correlation between HLA class II DQA1, DQB1 and DRB1 genes involved in immune recognition, and melanoma, usually considered a highly immunogenic tumor. We therefore typed by means of PCR-SSP (sequence-specific primers) 53 Italian patients and 53 healthy random controls coming from the same geographic area. We observed a decrease of all haplotypes bearing DQB1*0301, DQB1*0302 and DQB1*0303 alleles but not of haplotype DRB1*11;DQA1*0501;DQB1*0301. Our results seem to support the hypothesis of a protective role of some DQ3-bearing haplotypic combinations in melanoma.

Alleles↗