Analysis of a familial three way translocation involving chromosomes 3q, 6q, and 15q by high resolution banding and fluorescent in situ hybridisation (FISH) shows two different unbalanced karyotypes in sibs.

We report on a familial three way translocation involving chromosomes 3, 6, and 15 identified by prometaphase banding and fluorescence in situ hybridisation (FISH). Two mentally retarded sibs with different phenotypic abnormalities, their phenotypically normal sister and mother, and two fetuses of the phenotypically normal sister were analysed. The terminal regions of chromosomes 3q, 6q, and 15q were involved in a reciprocal translocation, in addition to a paracentric inversion of the derivative chromosome 15. Conventional cytogenetic studies with high resolution GTG banding did not resolve this rearrangement. FISH using whole chromosome paints (WCPs) identified the chromosomal regions involved, except the aberrant region of 3q, which was undetectable with these probes. Investigation of this region with the subtelomeric FISH probe D3S1445/D3S1446 showed a balanced karyotype, 46,XX,t(3;15;6) (q29;q26.1;q26), inv der(15) (q15.1q26.1) in two adult females and one fetus. It was unbalanced in two sibs, showing two different types of unbalanced translocation resulting in partial trisomy 3q in combination with partial monosomy 6q in one patient and partial trisomy 15q with partial monosomy 6q in the other patient and one fetus. These represent apparently new chromosomal phenotypes.     

Bloom''s Syndrome. VII. Progress report for 1978

The Bloom's Syndrome Registry was published in this journal in 1977. Now, in the first in a series of progress reports, recent accessions to the Registry are recorded, new instances of neoplasia are listed, and recent clinical observations and experimental results of general interest are cited.     

Enzymhistochemie des klassischen und des ultrakurzen Morbus Hirschsprung

Hirschsprung's disease is the most important type of gastrointestinal dysmotility in neonatal pathology. Aberrant craniocaudal migration of neural crest stem cells results in an intestinal aganglionic segment of variable length. In 'classical' Hirschsprung's disease (60-75% of cases), the aganglionic segment spans the rectum and sigma. Ultrashort Hirschsprung's disease (5-10%) is restricted to the most distal 3-4 cm or immediate rectoanal transition only.In the normal enteric nervous system, myenteric ganglia modulate the parasympathetic innervation of the sacral roots S2-S4. The absence of myenteric ganglia in Hirschsprung's disease results in massively increased parasympathetic activity with abundant acetylcholine release and pseudo-obstruction in the aganglionic segment. This can be demonstrated in an enzyme histochemical reaction for acetylcholinesterase on frozen sections, which is sufficient to diagnose the classical disease in rectal mucosal biopsies. In ultrashort Hirschsprung's disease, increased acetylcholinesterase activity is demonstrable only in nerve fibres of the muscularis mucosae and submucosa, but not the lamina propria mucosae. Submucosal and myenteric ganglia are physiologically scarce in the most distal rectum; absence of ganglia in a biopsy of the rectoanal transition must not be (wrongly) interpreted as ultrashort Hirschsprung's disease. Therefore, a diagnosis of ultrashort Hirschsprung's disease can be made exclusively using an enzyme histochemical reaction for acetylcholinesterase.     

Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors.

BACKGROUND: Sorafenib (BAY 43-9006), a novel, oral multi-kinase inhibitor, blocks serine/threonine and receptor tyrosine kinases in the tumor and vasculature. Sorafenib demonstrated single-agent activity in Phase I studies, and was tolerated and inhibited tumor growth in combination with doxorubicin in preclinical studies. This Phase I dose-escalation study determined the safety, pharmacokinetics and efficacy of sorafenib plus doxorubicin. PATIENTS AND METHODS: Thirty-four patients with refractory, solid tumors received doxorubicin 60 mg/m(2) on Day 1 of 3-week cycles, and oral sorafenib from Day 4 of Cycle 1 at 100, 200 or 400 mg bid. RESULTS: Common drug-related adverse events were neutropenia (56%), hand-foot skin reaction (44%), stomatitis (32%), and diarrhea (32%). The maximum tolerated dose was not reached. One patient with pleural mesothelioma achieved a partial response (modified WHO criteria) and remained on therapy for 39.7 weeks. Fifteen patients (48%) achieved stable disease for >/=12 weeks. Doxorubicin exposure increased moderately with sorafenib 400 mg bid. The pharmacokinetics of sorafenib and doxorubicinol were not affected. CONCLUSION: Sorafenib 400 mg bid plus doxorubicin 60 mg/m(2) was well tolerated. The increased doxorubicin exposure with sorafenib 400 mg bid did not result in significantly increased toxicity; low patient numbers make the clinical significance of this unclear. These promising efficacy results justify further clinical investigation.     

Characterization of deletions at the retinoblastoma locus in patients with bilateral retinoblastoma

DNA samples from 92 unrelated patients with bilateral retinoblastoma were analyzed by Southern blot hybridization with cDNA and genomic clones of the retinoblastoma (RB-1) gene. Qualitative and quantitative evaluation of the Southern blot patterns showed a deletion of all or part of the RB-1 gene in 15 patients. Deletion hot spots were not detected. The study shows that 16% of germ cell mutations are detectable by Southern blot hybridization, but that densitometric analysis is required in most cases.     

Molekulare Genetik und Diagnostik des Retinoblastoms Bedeutung für die Ophthalmologische Praxis *

Das Retinoblastom (RB) wird durch den Funktionsverlust beider Kopien des Retinoblastomgens (RB 1) bedingt. Die erbliche Disposition zum RB wird durch Keimbahnmutationen im RB 1-Gen verursacht und autosomal-dominant vererbt. Bei nichterblichem RB sind beide Mutationen somatisch. Die Bestimmung von RB 1-Mutationen in DNA aus Blut erlaubt eine genaue Risikoprognose. Durch die Anwendung mehrerer Analyseverfahren k?nnen die Mutationen bei der Mehrzahl der Patienten mit erblichem RB identifiziert werden. Diese führen meist zu einem vollst?ndigen Funktionsverlust des betroffenen Allels. Patienten mit solchen Keimbahnmutationen entwickeln nahezu immer Tumoren, zumeist in beiden Augen. Bei etwa 5% der Keimbahnmutationen hingegen bleibt die Funktion teilweise erhalten. Diese Patienten sind oft nur einseitig betroffen oder sogar tumorfrei (unvollst?ndige Penetranz). Unvollst?ndige Penetranz wird auch bei Patienten mit Deletionen beobachtet, die neben dem Genort des RB 1 auch noch weitere Gene betreffen. Etwa 20% der Patienten mit einseitig isoliertem RB haben RB 1-Keimbahnmutationen. Da eine Mutationsanalyse im Tumor die Identifikation dieser Patienten erlaubt, sind molekulargenetische Untersuchungen auch hier hilfreich.      

HLA-A,B,C,DR typing and 17-OHP determination for second trimester prenatal diagnosis of 21-hydroxylase deficient CAH

In 18 families at risk for the HLA-linked, 21-hydroxylase deficient form of autosomal recessive congenital adrenal hyperplasia (CAH), prenatal diagnosis (PD) was performed using two methods: (1) HLA-A,B,C typing and in the latter 11 cases also DR typing of cultured amniotic fluid cells (AFC) using the standard microcytotoxicity assay, and (2) measurement of second trimester amniotic fluid 17-hydroxyprogesterone (17-OHP) concentration using gel chromatography and radioimmunoassay. The accuracy of the prenatal predictions was confirmed by postnatal HLA typing of umbilical cord blood lymphocytes and by clinical evaluation. In 16/18 families, both HLA typing of AFC and 17-OHP measurements proved informative for PD. The predictions of both methods were concordant in 14/16 families (88 per cent). In ten of these families, a normal fetus was predicted, and in four, an affected fetus; all pregnancies were carried to term and all predictions were confirmed postnatally. In 2/16 cases (12 per cent), however, the predictions were discordant: the prenatal HLA typing indicated an affected fetus, whereas the 17-OHP values predicted a normal fetus. Both pregnancies were continued and two healthy boys were delivered. The discordance proved to be due to a 'missed' HLA antigen in one case and to serologically cross-reactive HLA antigens in the second. Finally, in 2/18 cases, prenatal assessment of fetal genotype had to rely on HLA typing alone as 17-OHP measurement was not performed in one family and in the second family the 17-OHP values obtained were not informative due to inadvertent continuation of hormone therapy to the date of amniocentesis. In both cases, the HLA typing data accurately predicted a normal fetus. In conclusion, a combination of HLA typing of cultured AFC and 17-OHP measurements of amniotic fluid permits accurate prenatal diagnosis of CAH in most cases (88 per cent). In addition, the supplementary use of HLA-DR typing of AFC as presented here for the first time proved helpful in families with HLA-A,B homozygosity due to parental sharing of antigens and can be informative for identifying HLA-B/21-OH recombinant haplotypes.     

Application of linkage analysis to genetic counselling in families with hereditary retinoblastoma.

Six families with retinoblastoma in more than one member were investigated with DNA markers linked to the retinoblastoma locus because direct analysis had not disclosed the gene defect. In all of the families we could identify the affected chromosome and predict the genetic risk with a high level of confidence (90 to 99%). In one patient the test helped to detect tumour development earlier than usually possible. Several subjects were found not to carry a mutation, thus obviating frequent ophthalmological examinations under anaesthesia as would be necessary otherwise. These results show that linkage analysis can be successfully applied to genetic counselling in families with hereditary retinoblastoma.