Duplication of Yq- and proximal Yp-arms with deletion of almost all PAR1 (including SHOX) in a young man with non-obstructive azoospermia, short stature and skeletal defects.

Duplications of Yq arm (and AZF) seems to be tolerated by fertile males, while mutations, deletions, duplications or haploinsufficiency of SHOX can originate a wide range of phenotypes, including short stature and skeletal abnormalities. We report a case of non-obstructive azoospermia in a young man with short stature, skeletal anomalies, normal intelligence and hormonal parameters. This male showed a very singular Y-chromosome aberration, consisting of a duplication of Yq and proximal regions of Yp, with a deletion of almost all PAR1 in Yptel, including SHOX. CBA- and RBA-banding and FISH-mapping with telomeric, centromeric, AZF and SHOX probes were used. These results were confirmed by array CGH, which revealed the following karyotype constitution: arr [hg19] Xp22.33 or Yp11.32p11.31 (310,932-2,646,815 or 260,932-2,596,815) ×1, Yp11.2q12 (8,641,183-59,335,913) ×2. We conclude that the haploinsufficience of SHOX may be the cause of short stature and skeletal defects in the patient, while the non-obstructive azoospermia could be related to the lack of X-Y pairing during meiosis originated by the anomalous configuration of this chromosome abnormality and large deletion which occurred in Yp-PAR1.

Simvastatin inhibits the expression of stemness­related genes and the metastatic invasion of human cancer cells via destruction of the cytoskeleton.

Statins are a class of drugs that inhibit the rate-limiting steps in the cholesterol biosynthesis pathway. They act by inhibiting 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate. Blocking of mevalonate synthesis leads to inhibition of the farnesylation and geranylgeranylation of several functional proteins, such as RhoA and other small guanosine triphosphate-binding proteins, that are important in maintaining the undifferentiated status of the cells. In the present study, we hypothesized that simvastatin, likely through the inhibition of farnesylation and geranylgeranylation of Rac1, Cd42 and RhoA, induces a destruction/restructuration of the cytoskeleton that decreases mechanical strain transfer to the nuclei, inducing the loss of transmission of regulatory signals from the cytoskeleton to the nucleoskeleton. Although this remains at present a hypothesis and is not easy to define if the de-structuration of the cytoskeleton is a secondary effect of simvastatin treatment or the inhibition of post-translational protein modification have a precise role in the structuration of actin cytoskeleton, we speculate that these signal variations could inhibit the expression of certain stemness genes, which could therefore be considered nucleoskeleton-associated and mechanically regulated genes. On the other hand, the restructuration of the cytoskeleton inhibits the formation of lamellipodia and filopodia, which likely decreases the capability of cancer cells to invade the extracellular matrix, thereby modulating the equilibrium between proliferation, differentiation and metastatic invasion in human cancer cells. On the basis of our results we think that simvastatin, alone or in combination with conventional drugs, may have a possible role in cancer therapy.

A case of polimalformed fetus with a microdeletion of CTNNA3 gene.

We report a case of a male fetus of 20 weeks of gestation with plurimalformed observed by transonic scan and confirmed by MR. The karyotype was 46, XY. Molecular analysis showed a microdeletion of about 100 kb in the CTNNA3 gene.

Congenital megaurethra in a fetus with Meckel syndrome and in a fetus with female pseudoermanphroditism. The first report of these occurrences.

OBJECTIVE: the purpose of this paper is to report the first case of megaurethra in a fetus with Meckel syndrome and in a fetus with femal pseudoermaphroditism. RESULTS: the former case refers to a fetus of 13 weeks gestation with the three following prominent anomalies, observed by transonic scan and confirmed by autopsy: congenital megaurethra, anal atresia, single umbelical artery. The latter case refers to a fetus of 18 weeks gestation. Autopsy confirmed penile malformation and revealed ovaries in the abdomen. The karyotype was 46,XX with normal molecular karytype. The megaurethra was discovered by sonography at 18 weeks gestation. Autopsy confirmed penile malformation and revealed ovaries in the abdomen. The karyotype was 46,XX with normal molecular karyotype (Array-CGH, 1 Mb of resolution). METHODS: transonic scan, autopsy, karyotype, array-CGH. CONCLUSIONS: the first prenatal cases of two genetic syndromes with megaurethra have been reported, concening respectively a fetus with Meckel syndrome and a fetus with femal pseudoermaphroditism. The latter was confirmed by both autopsy and the normal female 46,XX karyotype.