Paolo Simi

Correlation Between Cytogenetic and Histopathological Findings in 65 Human Meningiomas

The correlations between cytogenetic and histopathological findings were analyzed in 65 cases of human meningiomas. Clonal chromosome abnormalities were present in 28 cases (43%). The overall female/male ratio was 1.7, but it was 1.1 in the group of 28 cases with chromosomal abnormalities. Abnormalities of chromosome 22 as sole abnormality predominate in the female patients. The mean age of patients with normal karyotype was significantly lower (50.7 years) than that of patients with chromosome changes (57.3 years). The tumor origin was predominantly at the base in the patients with normal karyotype but different at the convexity, falx cerebri, and spinal cord. The five abnormal cases from the spinal cord all showed involvement of chromosome 22. The proportion of chromosome anomalies was different in the various histological types, and a significant difference was found between the meningotheliomatous (23%) and psammomatous (58%) types. The cytogenetically abnormal cases of the psammomatous type all showed involvement of chromosome 22. In three patients with multiple meningiomas, we found different karyotypes in the different tumors of the same patient, which may indicate a multifocal origin of the tumors.

Volumetric Bone Mineral Density in Young Women with Turner’s Syndrome Treated with Estrogens or Estrogens plus Growth Hormone

To explore the effects of estrogen replacement therapy (ERT) and recombinant growth hormone (GH) treatment on bone mineral density (BMD) in Turner’s syndrome, we assessed volumetric BMD (vBMD), which is less dependent on body and bone sizes, in these patients at final height. The areal BMD (aBMD) was measured in 26 young women with Turner’s syndrome (age range 17.5–25.0 years) by dual-energy X-ray absorptiometry, and vBMD was calculated. Patients were subdivided as group 1 (n = 12; ERT alone) and group 2 (n = 14; GH + ERT). Years of estrogen exposure were not different between the groups (group 1: 6.4 ± 1.5 years; group 2: 5.3 ± 1.7 years); in group 2, GH therapy was 5.3 ± 1.4 years. Final heights were significantly higher in group 2 than in group 1 (148.1 ± 3.0 vs. 142.0 ± 2.8 cm; p < 0.0001) as well as aBMD (1.073 ± 0.118 vs. 0.968 ± 0.122 g/cm2; p < 0.04). vBMD was higher in group 2 but not significantly different from group 1 (0.374 ± 0.030 vs. 0.358 ± 0.027 g/cm3; p = 0.169). aBMD was reduced with respect to the normative values in both groups (group 1: –1.97 ± 1.04 SDS, p < 0.0001 vs. 0; group 2: –0.93 ± 1.01 SDS, p < 0.005 vs. 0), whereas vBMD was not (group 1: –0.07 ± 0.79 SDS; group 2: 0.42 ± 0.82 SDS). Our data suggest that: in Turner’s syndrome GH administration improves final height and aBMD, but it does not significantly increase vBMD; aBMD reduction in Turner’s syndrome is likely due to the impaired growth and reduced bone size; Turner’s patients on ERT from adolescence show vBMD values in the normal range in young adulthood.

Recessive cancer genes in meningiomas? An analysis of 31 cases

Cytogenetic studies on 31 human meningiomas revealed clonal abnormalities in 14 of them. Monosomy 22 was present in three cases as the only abnormality, and in five it was associated with monosomy 18, monosomy 14, loss of X, loss of Y, and trisomy 20, respectively. We found a number of rearrangements involving chromosome #22: an i psu dic(22)(pter----q11::q11----pter) in two cases and a t(18;22)(q12;q11) in another case. Two cases showed a complex translocation involving #7 and #14: t(2;7;14)(q23;q36;q22) and t(1;7;14)(q25;q32;q22), respectively. Other clonal chromosome abnormalities were del(1p) (present in two cases); der(9)t(9;?)(q34;?); der(7)t(7;?)(q31;?); der(22)t(22;?)(q11;?); and a 9p+ chromosome. The relevance for the pathogenesis of human meningiomas of these chromosome anomalies is also discussed with reference to the previous literature. The possible involvement of recessive cancer genes present on the long arm of chromosome #22 is also discussed.

Isolated 6q terminal deletions: an emerging new syndrome.

Deletions of the distal part of the 6q chromosome have not been associated with a clearly distinctive and recognizable phenotype. In order to determine if a “6q terminal deletion syndrome” could be delineated, we compared the phenotype of two new cases with those patients reported in literature presenting with a similar deletion. Cases with more complex karyotypes were excluded. The deletion in our patients was accurately analyzed by loss of heterozygosity (LOH) and fluorescence in situ hybridization (FISH) with a panel of probes located around the putative breakpoint. Interestingly, the breakpoints were located in 6q26 in both our patients, distally to clone RP11‐150P20 and proximally to clone RP11‐152P19, with a deletion size of approximately 8 Mb. The breakpoints fall within the fragile site FRA6E. From a careful evaluation of the selected patients, a common phenotype emerged, including psychomotor retardation, hypotonia, seizures, short neck, and typical facial anomalies, along with nonspecific anomalies. While these features are shared by other chromosome syndromes and are not sufficient on their own for a clinical diagnosis, when considered together, the pattern can allow the identification of the “6q terminal deletion syndrome.” Moreover, the potential role of FRA6E in generating these deletions is suggested.

Syndromic craniosynostosis due to complex chromosome 5 rearrangement and MSX2 gene triplication

Craniosynostosis is a common birth defect (∼1/3,000 births) resulting from chromosome imbalances, gene mutations or unknown causes. We report a 6‐month‐old female with multiple sutural synostosis and prenatal onset growth deficiency, developmental delay, facial dysmorphism, congenital heart defect, and inguinal hernia. An integrated approach of standard cytogenetics, mBAND, locus‐specific FISH, and 75 kb resolution array‐CGH disclosed a complex chromosome 5 rearrangement, resulting in 3 paracentric inversions, 2 between‐arm insertions, and partial duplication of 5q35. An extra copy of the MSX2 gene, which maps within the duplicated segment and is mutated in Boston‐type craniosynostosis, was confirmed by molecular cytogenetic studies. Our study confirms that early fusion of cranial sutures commonly observed in the dup(5q) syndrome is caused by triplication of the MSX2 gene and strongly supports the crucial role of this gene in the development of craniofacial structures.

Homeobox HOXA10 gene analysis in cryptorchidism

BACKGROUND In male mice, targeted disruption of the homeobox gene hoxa10 causes cryptorchidism and infertility. Genetic alterations in exon 1 of HOXA10 have been found in a high number of boys with cryptorchidism. AIM To evaluate whether mutations of HOXA10 can be a common cause of cryptorchidism. PATIENTS AND METHODS Genomic DNA was extracted from 18 patients with cryptorchidism (age 7-44 years; unilateral n = 13; no familial cases) and 28 healthy controls (age 9-39 years). HOXA10 was amplified by PCR and all coding sequences of exon 1 and 2 were sequenced. The PCR products were digested by ScrFI restriction enzyme and the restriction fragments obtained were analyzed on 2% agarose gel. RESULTS One silent polymorphism, G-->A substitution at position 1203, was detected in 2/18 patients (11.1%). The same polymorphism was detected in 3/28 controls (10.7%). CONCLUSIONS These data on HOXA10 analysis indicate that alterations of this gene may be more rare in males with cryptorchidism than previously suggested. This finding agrees with the rare occurrence of INSL3 gene mutations in human cryptorchidism, but needs to be confirmed in a larger series of selected patients.

Can growth hormone treatment in boys without growth hormone deficiency impair testicular function

Four young male subjects (age range, 17 4/12 to 25 5/12 years), previously treated with human growth hormone for non-growth hormone-dependent short stature, showed reduced testicular volume and hypergonadotropic hypogonadism. They also showed impaired spermatogenesis and altered testicular texture as determined by ultrasonography. No clinical or laboratory finding showed disease associated with testicular dysfunction. An unfavorable gonadal outcome could occur in boys without growth hormone deficiency treated with human growth hormone.

Cytogenetic and molecular evaluation of 241 small supernumerary marker chromosomes: cooperative study of 19 Italian laboratories

Purpose: We evaluated the experiences of 19 Italian laboratories concerning 241 small supernumerary marker chromosomes (sSMCs) with the aim of answering questions arising from their origin from any chromosome, their variable size and genetic content, and their impact on the carriers phenotype.Methods: Conventional protocols were used to set up the cultures and chromosome preparations. Both commercial and homemade probes were used for the fluorescent in situ hybridization analyses.Results: A total of 113 of the 241 sSMCs were detected antenatally, and 128 were detected postnatally. There were 52 inherited and 172 de novo cases. Abnormal phenotype was present in 137 cases (57%), 38 of which were antenatally diagnosed. A mosaic condition was observed in 87 cases (36%). In terms of morphology, monocentric and dicentric bisatellited marker chromosomes were the most common, followed by monocentric rings and short-arm isochromosomes. The chromosomes generating the sSMCs were acrocentric in 132 cases (69%) and non-acrocentric chromosomes in 60 cases (31%); a neocentromere was hypothesized in three cases involving chromosomes 6, 8, and 15.Conclusion: The presented and published data still do not allow any definite conclusions to be drawn concerning karyotype–phenotype correlations. Only concerted efforts to characterize molecularly the sSMCs associated or not with a clinical phenotype can yield results suitable for addressing karyotype–phenotype correlations in support of genetic counseling.

Alterations of Fas (APO-1/CD 95) gene and its relationship with p53 in non small cell lung cancer

The Fas (APO-1/CD95) system regulates a number of physiological and pathological processes of cell death. The ligand for Fas induces apoptosis by interacting with a transmembrane cell surface Fas receptor. The key role of the Fas system has been studied mostly in the immune system, but Fas mutations, one of the possible mechanisms for resistance to apoptosis signaling, may be involved in the pathogenesis of non-lymphoid malignancies as well. To better understand the potential involvement of Fas system in non-small cell lung cancer (NSCLC) we evaluated Fas and Fas-ligand mRNA expression by polymerase chain reaction in 102 tumor samples and in 44 normal surrounding tissues. Although over 60% of the human NSCLC analysed expressed both genes, they seem to be unable to induce apoptosis in vivo by autocrine suicide. In this regard, we investigated in 79 cases, the promoter and the entire coding region of the Fas gene by polymerase chain reaction, single strand conformation polymorphism and DNA sequencing for detecting putative alterations. Sixteen tumors (20.25 %) were found to have Fas alterations, in promoter and/or exon region. In all cases samples carried heterozygous alterations and mostly showed simultaneous mutations of p53 gene. Moreover, the quantitative analysis of Fas mRNA expression showed high levels of Fas messenger associated with p53 wild-type status alone. Taken together, these findings point to an involvement of Fas/Fas-ligand system in the development of NSCLC, suggesting that the loss of its apoptotic function might be linked to p53 alterations which contribute to the self-maintenance of cancer cells.

Torque Teno Virus Viremia Load Size in Patients with Selected Congenital Defects of Innate Immunity

ABSTRACT Plasma loads of torque teno virus (TTV) among individuals differ extensively beginning early in life, suggesting a role for innate immunity. Here, congenital mannose-binding lectin deficiencies, but not deficiencies in respiratory ciliary function, correlated with increased TTV loads. Notably, however, the presence of either disorder was associated with particularly high TTV loads.