Pachydermoperiostosis: an update.

Pachydermoperiostosis (PDP) is a rare genodermatosis, characterized by pachydermia, digital clubbing, periostosis and an excess of affected males. Although an autosomal dominant model with incomplete penetrance and variable expression has been proved, both autosomal recessive and X-linked inheritance have been suggested. However, at present, genetic heterogeneity is not fully supported. The aim of this study is to review the clinical and pedigree data of 68 published PDP families, including 204 patients. This analysis has confirmed an autosomal dominant mutation in 37 families and suggested the existence of an autosomal recessive form in the remaining families. The two forms may differ in clinical severity, intrafamilial variability and prevalence of some features. Additionally, the marked skewed sex ratio could not be easily explained by an X-linked mutation, but alternative explanations (i.e. testosterone promoting proliferation) are discussed.

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.

Quantitative ultrasound of the hand phalanges in a cohort of monozygotic twins: influence of genetic and environmental factors.

OBJECTIVE: Our objective was to evaluate the similarities and differences in bone mass and structure between pairs of monozygotic twins as measured by means of the quantitative ultrasound (QUS) technique. DESIGN: A cohort of monozygotic twins was measured by QUS of the hand phalanges using the DBM sonic bone profiler (IGEA, Carpi, Italy). The parameters studied were amplitude-dependent speed of sound (AD-SoS), ultrasound bone profile index (UBPI), signal dynamics (SDy) and bone transmission time (BTT). Linear correlation coefficients, multivariate linear analysis and the ANOVA test were used to assess intrapair associations between variables and to determine which factors influence the intrapair differences in QUS variables. PATIENTS: One hundred and six pairs of monozygotic twins were enrolled in the study, 68 females and 38 males in the age range 5 to 71 years. RESULTS: Significant intrapair correlations were obtained in the whole population and separately for males and females, regarding height ( r =0.98-0.99, p <0.0001), weight ( r =0.95-0.96, p <0.0001), AD-SoS ( r =0.90-0.92, p <0.0001), BTT ( r =0.94-0.95, p <0.0001) and other QUS parameters ( r >0.74, p <0.0001). Multivariate analysis revealed that intrapair differences between AD-SoS, SDy, UBPI and BTT are significantly influenced by age in the whole population and in the female population. Furthermore, the ANOVA test showed, for the female group, a significant increase in the intrapair differences in SDy and UBPI above 40 years. CONCLUSIONS: A relative contribution of genetic factors to skeletal status could be observed by phalangeal QUS measurement in monozygotic twins. A significant increase in the intrapair difference in QUS parameters with increasing age and onset of menopause also suggests the importance of environmental factors in the female twin population.

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.

A gene for familial isolated chronic nail candidiasis maps to chromosome 11p12-q12.1.

Chronic mucocutaneous candidiases (CMC) are a group of rare disorders where an altered immune response against Candida leads to persistent and/or recurrent infections of the skin, nails, and mucous membranes. We analysed a five-generation Italian family with an isolated form of CMC, affecting nails only, in the presence of low serum concentration of intercellular adhesion molecule I (ICAM-1). We excluded linkage to candidate regions on chromosomes 2p (CMC with thyroid disease), 21q22.3 (APECED), and 19q13 (ICAM-1). We then carried out a genome-wide scan and assigned the CMC locus to a 19 cM pericentromeric region on chromosome 11.

Mapping of a new autosomal dominant non-syndromic hearing loss locus (DFNA43) to chromosome 2p12.

Hearing impairment (HI) is the most frequent sensory defect with wide genetic heterogeneity. Approximately 80% of genetic hearing loss is non-syndromic and 15-25% of exhibit autosomal dominant inheritance. We analysed an Italian three generation family in which non-syndromic hearing impairment is transmitted as an autosomal dominant trait. Onset of HI in all affected subjects occurred in the second decade of life, with subsequent gradual progression from moderate to profound loss. HI was bilateral and symmetrical, involving all frequencies. After exclusion of the known DFNA loci with markers from the Hereditary Hearing Loss Homepage (URL: http://dnalab-www.uia.ac.be/dnalab/hhh), a genome wide scan was carried out using 358 highly informative microsatellite markers. Significant linkage (Zmax=4.21, theta=0) was obtained with chromosome 2p12 markers. The results were confirmed by multipoint analysis (Zmax=4.51), using the location score method. Haplotype analysis defined a 9.6 cM disease gene interval on chromosome 2 without overlap with the other identified loci. Fine mapping and identification of candidate genes are in progress.

[Genetic screenings: state of the art and perspectives for public health]. / Gli screening genetici: stato dell'arte e prospettive per la sanità pubblica.

Management of genetic data needs the fulfillment of technical requirements, involving ethics, law, and social issues. Introduction of genetic information in preventive medicine implies complex consequences and specialized expertise. Genetic screenings represent a promising tool, but further advances are needed to provide their effective and appropriate use in the respect of the privacy. Application areas, tests validation procedures and availability of effective laboratory and qualified service networks are considered. The Authors present main laws and bioethics guidelines in the field.

Genomic organization, physical mapping, and involvement in Yq microdeletions of the VCY2 (BPY 2) gene.

VCY2 is a gene positioned within the AZFc locus of the Y chromosome, a region frequently deleted in infertile males. To investigate the involvement of this gene in idiopathic male infertility, we studied its genomic organization and localization. Analysis of the genomic structure demonstrated that the VCY2 gene is composed of 9 exons spanning 21 kb. FISH analysis on interphase nuclei with specific probes for exons 4-6, 7, and 8 demonstrated the presence of a single gene copy, and Fiber-FISH on relaxed chromatin indicated that VCY2 is located within the DAZ gene cluster. PCR, Southern blot, and FISH analysis on infertile patients with Yq microdeletions demonstrated the absence of VCY2 in all cases where deletions involved the DAZ gene, raising the question about the role of the VCY2 gene loss in the phenotype reported for DAZ-deleted patients.

Fine mapping of the PSORS4 psoriasis susceptibility region on chromosome 1q21.

Psoriasis is a chronic skin disorder affecting approximately 2% of the Caucasian population. Family clustering of the disease is well established and nonparametric linkage analyzes have mapped disease susceptibility loci on chromosomes 6p (PSORS1) and 17q (PSORS2). Nonconfirmed evidence for linkage is also available for chromosomes 2q 3q, 4q (PSORS3), 8q, 16q, and 20p. We mapped an additional susceptibility locus on chromosome 1q21 (PSORS4). In this study, we have carried out a linkage disequilibrium analysis, in order to achieve a finer localization. We recruited 79 triads from continental Italy and typed them at five loci spanning the 1.6 Mb region generating the highest multipoint LOD scores in our previous linkage study. We observed significant evidence for association with D1S2346 marker (p = 0.004). Results consistent with this data were obtained by typing an independent sample that included 28 patients and 56 controls, originating from Sardinia. In fact, p values of 0.02 were observed with both D1S2346 and D1S2715 markers. We sought further confirmation of our results by typing both samples with two novel markers (140J1C and 140J1D) flanking D1S2346. Marker 140J1D generated a p value of 0.003 in the continental Italy sample where a D1S2346/140J1D haplotype was found with a higher frequency among patients' chromosomes. Altogether our data indicate that the 1q21 susceptibility gene may be localized in the genomic interval spanned by D1S2346 and 140J1D. This report provides evidence supporting the refinement of a non-HLA psoriasis susceptibility locus.

Distinctive metaphyseal chondrodysplasia simulating cartilage hair hypoplasia.

We report on a 5(1/2) year-old Italian girl with a distinctive form of metaphyseal chondrodysplasia simulating cartilage hair hypoplasia. The pattern of metaphyseal changes and the associated bony abnormalities differentiate this patient from all the recognized forms of metaphyseal chondrodysplasia.

Spectral karyotyping (SKY) refinement of a complex karyotype with t(20;21) in a Ph-positive CML patient submitted to peripheral blood stem cell transplantation.

A patient with a Ph-positive chronic myeloid leukaemia (CML) was submitted to allogeneic peripheral blood stem cell transplantation from an HLA-haploidentical related donor 7 years after the diagnosis. Six months later, he showed a disease relapse while cytogenetic analysis displayed a complex karyotype. To characterise the chromosomal rearrangements spectral karyotype (SKY) analysis was used. This redefined all chromosome rearrangements and revealed a t(20;21)(q11;q22). FISH analysis with a specific probe for the AML1 gene disclosed disruption of this gene which was partially translocated on to the long arm of chromosome 20. It is likely that this rearrangement, unusual for CML, was implicated in the disease evolution towards blastic crisis (BC).

Short arm rearrangements of sex chromosomes with haploinsufficiency of the SHOX gene are associated with Leri-Weill dyschondrosteosis.

Twelve patients with different features of Turner syndrome, and with Xp and Yp rearrangements involving the pseudoautosomal region (PAR1) are described. In all patients, FISH analysis showed loss of one copy of the Short Stature Homeobox (SHOX)-containing gene. Ten patients had short stature and one disproportionate (mesomelic) normal stature, while the last one had normal stature. Skeletal abnormalities, including shortened ulna, were detected in nine subjects, and in six of them Madelung deformity was observed. These clinical data indicated a genotype phenotype correlation between haploinsufficiency of SHOX, and short stature and skeletal abnormalities.

Narrowing the Duane syndrome critical region at chromosome 8q13 down to 40 kb.

Duane syndrome (MIM 126800) is an autosomal dominant disorder characterised by primary strabismus and other ocular anomalies, associated with variable deficiency of binocular sight. We have recently identified a < 3 cM smallest region of deletion overlap (SRO) by comparing interstitial deletions at band 8q13 in two patients (one described by Vincent et al, 1994, and the other by Calabrese et al, 1998). Here we report on another patient with Duane syndrome carrying a reciprocal translation t(6;8)(q26;q13). FISH and PCR analyses using a YAC contig spanning the SRO narrowed the Duane region to a < 1 cM interval between markers SHGC37325 and W14901. In addition, the identification and mapping of two PAC clones flanking the translocation breakpoint, allowed us to further narrow the critical region to about 40 kb. As part of these mapping studies, we have also refined the map position of AMYB, a putative candidate gene, to 8q13, centromeric to Duane locus. AMYB is expressed in brain cortex and genital crests and has been previously mapped to 8q22.

FISH analysis in detecting 9p duplication (p22p24).

Authors report on a case of partial 9p duplication, involving the 9p22-9p24 region. This represents the second case of such duplication in which the breakpoints were precisely defined using fluorescence in situ hybridisation (FISH) with chromosome 9 specific painting and YAC DNA probes, localised onto 9p22-9p24 region. FISH analysis pinpointed chromosome breakpoints in dup(9)(p22p24) and excluded an insertion or a translocation from other chromosomes. The present report supports the segment 9p22-9p24 as the critical region for the observed phenotype of the duplication 9p syndrome.

Loss of the SHOX gene associated with Leri-Weill dyschondrosteosis in a 45,X male.

A male patient is reported with a 45,X karyotype and Leri-Weill dyschondrosteosis (LWD). FISH analysis with SHOX and SRY gene probes was carried out. One copy of both SHOX and SRY was detected in interphase nuclei, clarifying the origin of LWD and the male phenotype. Molecular results suggested that the 45,X karyotype arose through two independent events. The first occurred at paternal meiosis leading to an unequal crossing over between the short arms of the X and Y chromosomes. As a consequence, the SRY gene was translocated onto Xp, thereby explaining the male phenotype of the patient. The second event probably occurred at maternal meiosis or at the early stages of the zygote resulting in the loss of the maternal X chromosome.

X/Y translocation in a family with Leri-Weill dyschondrosteosis.

An X/Y translocation associated with Leri-Weill dyschondrosteosis (LWD) was detected in a boy and in his mother. FISH analysis with specific probes for SHOX and SRY displayed no signal on the der(X), while one signal for SHOX was detected on the normal X chromosome in the mother, and one signal each for SHOX and SRY was detected on the normal Y chromosome in the proband.