Novel RB1 gene constitutional mutations found in Polish patients with familial and/or bilateral retinoblastoma.

Retinoblastoma is the most common intraocular malignancy in children. It is estimated that 60 percent of cases are nonhereditary and unilateral, 15% are hereditary and unilateral, and 25 percent are hereditary and bilateral. Hereditary predisposition for retinoblastoma is caused by germline mutations in the RB1 gene and is transmitted in an autosomal dominant manner. Most of the reported mutations are unique to one family, but there are sites where mutations are recurrent. We have performed RB1 gene mutation analysis in eight patients with familial and/or bilateral retinoblastoma by DNA/RNA sequencing. Constitutional mutations were found in five out of eight patients. Three mutations were novel: g.IVS7+5G>A, g.156709T>A, and g.IVS21+1G>A (p.G203-E240del, p.Y659X, and p.I703-E737del).

Measurement of phenylalanine in blood on filter paper as a method of monitoring PKU treatment.

OBJECTIVES: Phenylketonuria (PKU) is a genetic disease with autosomal recessive inheritance. In Poland the microbiological Guthrie test for this disease was replaced by an enzymatic colorimetric test. The question is whether the colorimetric test might be used in monitoring treatment of PKU. SETTING: In 80 patients with PKU on routine treatment monitoring of serum phenylalanine concentrations (SPh) was compared with phenylalanine concentrations in blood on filter paper (PhBFP). METHODS: Measurements of SPh were by a fluorimetric method (McCaman and Robins), and those of PhBFP were by an enzymatic colorimetric method. RESULTS: The regression analysis of SPh compared with PhBFP gave the equation y=0.9219x+0.2389; for the reversed ratio: it gave y=1.0220x+0.55083. The correlation was 0.97 at p<0.05. DISCUSSION: Concentrations of SPh accepted for children with PKU are not uniform. In the Cracow centre, the range of accepted SPh concentrations are 2-6 mg/dl for children and <12 mg/dl for older patients. The concentrations of PhBFP accepted are somewhat higher than SPh, range from 4 to 10 mg/dl, and are a good indicator of an appropriate diet. CONCLUSIONS: (1) The comparison indicated that colorimetric measurements of PhBFP are effective in monitoring therapeutic PKU management. Tests can be performed more often and are more comfortable both for the patients and their parents. (2) The comparative results indicated a concentration of PhBFP ranging from 4 to 10 mg/dl to be the accepted value for children treated for PKU.

[Molecular studies in a population of children with bronchial asthma. I. Polymorphism in the promotor region of gene CD14]. / Badania molekularne w populacji dzieci chorych na astme oskrzelowa. Cz. I. Polimorfizm regionu promotorowego genu CD14.

UNLABELLED: Allergic asthma is associated with the recruitment of the inflammatory cells into the bronchial mucosa. Surface expression of CD14, a marker of activation and differentiation of macrophages/monocytes, was suggested to protect against Th-2 response. OBJECTIVE: To investigate clinical effects of genetic polymorphism of CD14 promoter in asthmatic children. METHODS: In ISAAC survey, 50 children with asthma were identified (wheezing in the last year, serum IgE level > 150 kIU/l, positive bronchial challenge test with aerolized hypertonic saline) and 73 children without the above signs. Age range of surveyed children was 13-14 years. Genotypic pattern of CD14 promoter -159 C to T transition was assessed by RFLP method. RESULTS: There was no difference in the allelic (0.36 vs. 0.38 for -159T) or genotype frequencies (0.12 vs. 0.15 for -159TT) of CD14 polymorphism between allergic asthmatics and controls. Moreover, there was no relationship between CD14 genotype and serum IgE level or bronchial hyper-responsiveness. CONCLUSION: Our results do not confirm the association of CD14 polymorphism (promoter -159 C to T transition) with asthma in Polish children.

[Chromosome aberrations in patients with papillary thyroid cancer and other neoplasms]. / Aberracje chromosomalne u chorych z rakiem brodawkowatym tarczycy i innymi nowotworami.

Cancer is essentially a genetic disease resulting from congenital or acquired alterations in some cells of the patient. Such changes may occur in particular oncogens and are responsible for the tumour phenotype of the affected population of cells. In contrast, unaltered tumour-suppressor genes are responsible for suppressing the neoplastic phenotype, and their inactivation by deletion or mutation permits cancerous development in the affected cells. The genetic model of carcinogenesis is based on the idea mutations at the DNA level, what creates a functional imbalance between the oncogenes and the tumour-suppressor genes, resulting in uncontrolled clonal proliferation. The ret/PTC oncogene is unique to papillary thyroid cancer. The paper presents a correlation analysis between chromosomal changes in papillary thyroid cancer and abnormalities of chromosomes in patients with breast cancer and chronic lymphocytic leukemia.

[Genetic background of retinoblastoma]. / Genetyczne podloze siatkówczaka plodowego.

Retinoblastoma is a malignant tumour of the eye ball, which develops as a result of the mutation of both alleles of RB-1 gene. Molecular mechanisms and their implications in clinical diagnosis and genetic counselling in retinoblastoma families are discussed.

Molecular analysis of alleles segregation at RFLPs within RB-1 gene in four families with hereditary retinoblastoma.

Four families with suspected hereditary retinoblastoma in proband and one other family member were examined by genetic segregation analysis of the RB-1 gene loci with specific RFLPs of chromosome 13. Two families, TA-6 and partially CK-46, were informative using this method. In TA-6 family healthy sister (TA-6/10) of the proband was shown not to be a carrier of the mutant RB-1 gene. These results show that the segregation analysis of RB-1 gene loci with specific RFLPs, used as the DNA markers, could be helpful in the genetic diagnosis and counselling in families with hereditary retinoblastoma.

Familial four breakpoint complex chromosomal rearrangement as a cause of monosomy 9p22-->pter and trisomy 10p11.2-->pter and 11q21 analysed by dual and triple colour FISH.

A familial four breakpoint complex chromosomal rearrangement involving chromosomes 9, 10, and 11 was ascertained through a child with dysmorphic features, hypertrophic cardiomyopathy, and hypotonia. A cryptic insertion, invisible in G banded chromosomes was identified by fluorescence in situ hybridisation (FISH) using chromosome specific libraries. Possible mechanisms of its formation as well as karyotype-phenotype correlation are discussed.

Genetic counseling in carriers of reciprocal chromosomal translocations involving long arm of chromosome 16.

Families with balanced chromosomal changes ascertained by unbalanced progeny, miscarriages, or by chance are interested in their probability for unbalanced offspring and other unfavorable pregnancy outcomes. This is usually done based on the original data published by Stengel-Rutkowski et al. several decades ago. That data set has never been updated. It is particularly true for the subgroup with low number of observations, to which belong reciprocal chromosomal translocations (RCTs) with breakpoint in an interstitial segment of 16q. The 11 pedigrees from original data together with the new 18 pedigrees of RCT carriers at risk of single-segment imbalance detected among 100 pedigrees of RCT carriers with breakpoint position at 16q were used for re-evaluation of the probability estimation for unbalanced offspring at birth and at second trimester of prenatal diagnosis, published in 1988. The new probability rate for unbalanced offspring after 2 : 2 disjunction and adjacent-1 segregation for the total group of pedigrees was 4 +/- 3.9% (1/25). In addition, the probability estimate for unbalanced fetuses at second trimester of prenatal diagnosis was calculated as 2/11, i.e. 18.2 +/- 11.6%. The probability rates for miscarriages and stillbirths/early deaths were about 16 +/- 7.3% (4/25) and <2% (0/25), respectively. Considering different segment lengths of 16q, higher probability rate (0/8, i.e. <6.1%) for maternal RCT carriers at risk of distal 16q segment imbalance (shorter segment) was obtained in comparison with the rate (0/10, i.e. <4.8%) for RCT at risk of proximal segment imbalance (longer segment). It supports findings obtained from the original data for RCT with other chromosomes, where the probability for unbalanced offspring generally increased with decreasing length of the segments involved in RCT. Our results were applied for five new families with RCT involving 16q, namely three at risk of single-segment imbalance [t(8;16)(q24.3;q22)GTG, ish(wcp8+,wcp16+;wcp8-,wcp16+), t(11;16)(q25;q22)GTG, and t(11;16)(q25;q13)GTG] and two with RCT at risk of double-segment imbalance [t(16;19)(q13;q13.3)GTG, isht(16;19)(q13;q13.3) (D16Z3+,16QTEL013-D19S238E+,TEL19pR-; D16Z3-, D19S238E-,TEL19pR+), and t(16;20)(q11.1;q12)GTG, m ish,t(16;20)(wcp16+,wcp20+;wcp16+,wcp20+)]. They have been presented in details to illustrate how the available empiric data could be used in practice for genetic counseling.