Isoform of fibronectin mediates bone loss in patients with primary biliary cirrhosis by suppressing bone formation.

Osteoporosis is a major cause of morbidity and decreased quality of life in patients with chronic cholestatic liver disease. It is established that this osteoporosis results from decreased bone formation, but the mechanisms for the interaction between liver and bone remain elusive. The aim of this study was to test the hypothesis that an increase in the production of cellular fibronectins during liver disease may result in decreased osteoblast-mediated mineralization and thus explain the decrease in bone formation. We performed a prospective cross-sectional study in patients with primary biliary cirrhosis and matched controls, followed by experiments on human and mouse osteoblasts in culture and injections in mice in vivo. In patients with primary biliary cirrhosis, the oncofetal domain of fibronectin correlated significantly with the decrease in osteocalcin, a marker of bone formation (r = -0.57, p < 0.05). In vitro, amniotic fluid fibronectin (aFN) containing mainly the oncofetal domain and EIIIA domain resulted in decreased osteoblast-mediated mineralization in human osteoblasts (69% decrease at 100 microg/ml; p < 0.01) and mouse osteoblasts (71% decrease; p < 0.05). Removing the EIIIA domain from aFN similarly suppressed mineralization by osteoblasts (78% decrease; p < 0.05). Injection of labeled aFN in mice showed that it infiltrates the bone, and its administration over 10 days resulted in decreased trabecular BMD (17% drop; p < 0.05), mineralizing surface (30% drop; p < 0.005), and number of osteoblasts (45% drop; p < 0.05). Increased production of a fibronectin isoform containing the oncofetal domain and its release in the circulation in patients with primary biliary cirrhosis is at least partially responsible for the decrease in bone formation seen in these patients. This establishes that a molecule that has thus far been viewed as an extracellular matrix protein exerts hormone-like actions.

Trisomy 8q and partial trisomy 22 in a 43-year-old man with moderate intellectual disability, epilepsy and large cell non-Hodgkin lymphoma.

Partial trisomies are chromosome abnormalities resulting in a broad range of malformations depending on the size and location of the chromosomal rearrangement. Whereas diagnosis of these syndromes is usually made in early childhood, few descriptions exist about the clinical picture in adulthood. We report on a patient diagnosed at the age of 43 years with a 47,XY,+der(22)t(8;22)(q24.13;q11.21) karyotype and predominant clinical features of trisomy 8q. To our knowledge, this is the oldest patient described with a partial trisomy 8. The patient presented with moderate intellectual disability, a past history of epilepsy and facial anomalies. In addition, a large cell non-Hodgkin lymphoma was diagnosed in adulthood. Detailed breakpoint mapping by single nucleotide polymorphism (SNP) arrays showed that the derivative chromosome contains a full-length copy of the C-MYC oncogene. Given that trisomy 8q is the most frequent secondary chromosomal abnormality in hematological diseases, the possibility of a genetic predisposition for these disorders in patients with 8q duplication is raised.

High incidence and intraclonal heterogeneity of chromosome 11 aberrations in patients with newly diagnosed multiple myeloma detected by multiprobe interphase FISH.

In multiple myeloma, additional copies of chromosome 11 material, reported to confer an unfavorable prognosis, have been found in 20-45% of patients. To assess the incidence and extent of chromosome 11 aberrations, we performed interphase fluorescence in situ hybridization on CD138+ bone marrow plasma cells of 50 newly diagnosed myeloma patients, using seven locus-specific probes for chromosome 11, one for 13q14.3, and a probe set for translocation t(11;14). In 33 of 50 patients, chromosome 11 aberrations were found. Results indicated a marked intraclonal heterogeneity: in 13 patients, trisomy 11; in 10 patients, subclones with trisomy 11 and partial trisomies 11q coexisted; in 6 patients, only a partial trisomy 11q; and in 6 patients, a tetrasomy or partial tetrasomy 11. The coexistence of subclones with varying extent and copy numbers of chromosome 11 material indicates ongoing structural changes and clonal evolution. Hybridization results delineated 11q23 and 11q25 as the most frequently gained regions, which supports a relevant pathogenetic role of genes on 11q23 and 11q25. To confirm the high incidence of 11q23 gains, a further 50 patients (total n=100) were analyzed for 11q23 and 13q14.3. Myeloma with gains of 11q23 showed a low frequency of deletion 13q14.3 and may prove to be a distinct subgroup of this disease.

Three new 46,XX male patients: a clinical, cytogenetic and molecular analysis.

BACKGROUND: XX males range phenotypically from completely masculinised individuals to true hermaphrodites and include a subset of SRY negative patients. The correlation between genotype (SRY+/-) and phenotype is still unclear. AIM: To report three new patients with this rare condition, one of whom was diagnosed prenatally and another was SRY negative, and to verify in our patients whether the presence of SRY results in a more masculinised phenotype. PATIENTS AND METHODS: We present two phenotypically normal XX male patients (10 and 13.5 years) and one 3.1 years old XX male with ambiguous external male genitalia Prader IV. The patients were diagnosed by clinical, hormonal, sonographic, genetic and histological criteria. RESULTS: Basal hormonal status was normal for phenotype but an excessive response to GnRH testing was noticed in the second patient together with insufficient hCG stimulation in all three patients. Pelvic ultrasound displayed male structures without Müllerian ducts; testicular biopsy, performed only in the intersex patient, showed Sertoli and Leydig cell hypoplasia. Chromosome analysis confirmed 46,XX karyotype. FISH analysis and molecular analysis by PCR were positive for Yp fragments/SRY gene on Xp in two patients and negative in the patient with ambiguous external genitalia. CONCLUSIONS: In our observation Y chromosome-specific material containing the SRY gene translocated to the X chromosome results in a completely masculinised phenotype. In the intersex patient, incomplete masculinisation without SRY suggests a mutation of one or more downstream non-Y testis-determining genes.

Survival up to age 10 years in a patient with partial duplication 6q: case report and review of the literature.

Partial duplication of chromosome 6q has been recognized as a distinct dysmorphic syndrome with severe psychomotor and growth retardation, typical craniofacial features including microcephaly and microstomia, neck webbing, congenital contractures, and variable internal malformations. Most patients have died in the first year of life. We describe the clinical features and disease course in a boy with a duplication of 6q23.3-qter who lived up to the age of 10 years and discuss similarities with other patients.

Multicolor chromosomal bar coding characterizes a de novo interstitial deletion (5)(q33.3q35.2) in a child with multiple congenital malformations.

We describe a boy with multiple congenital anomalies including a complex heart defect, club feet, adducted thumbs, and facial dysmorphic features. He died at the age of 2 months following cardiac surgery. G-banding analysis identified an abnormal chromosome 5q suspected to be an interstitial deletion (5)(q33q35). Breakpoints of the deleted segment were confirmed as del(5)(q33.3q35) by multicolor fluorescence in situ hybridization (FISH) using two sets of combinatorially labeled band specific YAC clones. Findings are discussed in view of previously published cases.

Study of 30 patients with unexplained developmental delay and dysmorphic features or congenital abnormalities using conventional cytogenetics and multiplex FISH telomere (M-TEL) integrity assay.

Cryptic subtelomeric chromosome rearrangements are a major cause of mild to severe mental retardation pointing out the necessity of sensitive screening techniques to detect such aberrations among affected patients. In this prospective study a group of 30 patients with unexplained developmental retardation and dysmorphic features or congenital abnormalities were analysed using the recently published multiplex FISH telomere (M-TEL) integrity assay in combination with conventional G-banding analysis. The patients were selected by one or more of the following criteria defined by de Vries et al.: (a) family history with two or more affected individuals, (b) prenatal onset growth retardation, (c) postnatal growth abnormalities, (d) facial dysmorphic features, (e) non-facial dysmorphism and congenital abnormalities. In addition, we included two patients who met these criteria and revealed questionable chromosome regions requiring further clarification. In four patients (13.3%) cryptic chromosome aberrations were successfully determined by the M-TEL integrity assay and in two patients with abnormal chromosome regions intrachromosomal aberrations were characterized by targetted FISH experiments. Our results accentuate the requirement of strict selection criteria prior to patient testing with the M-TEL integrity assay. Another essential precondition is high-quality banding analysis to identify structural abnormal chromosomes. The detection of familial balanced translocation carriers in 50% of the cases emphasizes the significance of such an integrated approach for genetic counselling and prenatal diagnosis.