Abnormalities in tooth morphology, structure and dentition in two children with chromosome aberrations. Translocation trisomy 13 and trisomy 21.

PURPOSE: Dental malformations due to chromosomal trisomies are rarely described and need an intensive cooperation between pediatricians, orthodonticians and human geneticists to enable the collection of data and to extend the investigations on specific parameters of the teeth. RESULTS: Here we present tooth studies of two children with trisomies 13 (Pätau-syndrome) and 21 (Down-syndrome): the dentition, the tooth morphology and the structure as well as the composition were investigated over a period of six years. Both male patients showed a delayed and abnormal dentition. Morphologic and structural changes compared to the general population were also detectable; whereas, the composition of the teeth was unchanged in enamel, dentin, and the border between them. CONCLUSIONS: The abnormalities in all parameters investigated were more pronounced in the patient with Pätau-syndrome than in the child with Down-syndrome.

Submicroscopic unbalanced translocation resulting in del10p/dup13q detected by subtelomere FISH.

Chromosomal rearrangements involving the (sub)telomeres are an important cause of human genetic diseases: with the development of advanced molecular cytogenetic methods they have been identified as a major cause of mental retardation and/or congenital malformation syndromes. We identified a cryptic unbalanced de novo translocation 10p/13q by subtelomere FISH in a boy with mental and growth retardation (karyotype: 46,XY,der(10)t(10;13)(p15.1;q34)(D10S2488-,D13S296+)). Craniofacial dysmorphisms included frontal bossing, epicanthal folds, long philtrum, thin upper lip, short nose, mild retrognathy and a flat midface. In addition the patient had ASDII, a pyloric stenosis, bilateral inguinal hernias and cryptorchidism. His psychomotor development was significantly delayed. Microsatellite typing revealed the paternal origin of the two chromosomes involved in the rearrangement. By comparing our case with previously published patients with similar aberrations we conclude that the congenital malformations in our case are associated with the partial 10p deletion. The craniofacial features might be attributed to the 13q duplication. The identification of a 10p/13q translocation in our case highlights the importance of searching for cryptic subtelomeric imbalances in mentally retarded patients and helps to further delineate genotype-phenotype correlations in rare chromosomal disturbances.

Global brain dysmyelination with above-average verbal skills in 18q- syndrome with a 17 Mb terminal deletion.

BACKGROUND: Patients with the karyotypic finding of a terminal deletion in the long arm of chromosome 18 (18q- syndrome) commonly display cerebral dysmyelination and developmental delay. To our knowledge, all reported cases characterized by molecular analysis who had no mental retardation as confirmed by neuropsychological testing had a chromosomal breakpoint within the two most distal bands, 18q22 or 18q23, leading to a deletion of 16 Mb or less. AIMS OF THE STUDY: It was the aim of this study to improve the karyotype-phenotype correlation in 18q- syndrome by thoroughly analyzing the deletion size and the mental and radiologic status in a 23-year-old woman with a terminal 18q deletion. We performed cytogenetic and molecular cytogenetic analysis, brain MRI, and extended neuropsychological testing. RESULTS: Molecular karyotyping revealed a 17 Mb deletion of terminal 18q with a breakpoint in 18q21.33 and no evidence for mosaicism. While brain MRI demonstrated severe global dysmyelination, the patient showed a neuropsychological pattern that allowed for normal psychosocial and job achievement. After delayed development in childhood, the patient caught up during puberty and showed normal verbal intelligence and skills at 23 years. However, visual, visual-spatial, visual-constructional, and executive functions were found to be severely impaired. CONCLUSION: Here, we present a patient with one of the largest terminal 18q deletions reported in an individual without obvious mental retardation. Our analysis extends the phenotypic spectrum for individuals with breakpoints in 18q21.33. In addition, this study highlights the fact that severe global dysmyelination may not be associated with general cognitive deficits.

Chromosomal aberrations in 130 patients with multiple myeloma studied by interphase FISH: diagnostic and prognostic relevance.

The study described the molecular cytogenetic characterization of myeloma cells in 130 patients via interphase fluorescence in situ hybridization. Nine repetitive DNA probes (for chromosomes 3, 7, 9, 11, 15, 17, 18, X, and Y) as well as seven single-copy DNA probes (for chromosomes 13, 17, 21, and two each for chromosomes 5 and 22) were used for the hybridizations. Using this panel of probes, we were able to show aberrations in 86% of patients. Most of them had one to three aberrations. There was a distinct correlation between the number of aberrations per patient and the tumor stage. Thus, the proportion of patients with 8-12 aberrations increased from 16% in stage II to 26% in stage III. There were marked differences among the chromosomes with respect to the prevalence of genomic losses and gains and deletions of gene loci. Chromosomes 3, 5, 7, 9, 11, 15, and 21 showed a preference for genomic gains. Losses were most often found for chromosomes 13 and 17 (locus specific) as well as for the X and Y chromosomes. The frequency of monosomies and trisomies were approximately the same for chromosomes 15 and 18, which indicates a skewed pattern of distribution. We found two specific aberrations that caused distinct changes in the survival rates of the patients: deletion 13q14 (28% of patients) and translocation of the IGH locus 14q32 (79% of 39 patients who were analyzed separately). The results obtained in this study yielded data of extremely relevant prognostic value.

Sperm analyses, genetic counselling and therapy in an infertile carrier of a supernumerary marker chromosome 15.

PURPOSE: A supernumerary marker chromosome (SMC) was analysed after lymphocyte culture of a patient with oligoasthenoteratozoospermia (OAT) before ICSI treatment. MATERIAL AND METHODS: By additional molecular cytogenetic investigations the marker could be identified as a heterochromatic derivate of chromosome 15 [karyotype: 47,XY,+der(15)]. RESULTS: Sperm analyses by interphase FISH showed a normal monosomy 15 in 82% and an additional marker in 17% of the cells. In spite of these findings a pregnancy could not be induced. The brother of the patient showed the same chromosome abnormality and an OAT-syndrome as well. CONCLUSIONS: ICSI-treatment lead to a normal pregnancy and to the birth of a healthy boy. The genetic risk factors of both marker carriers are analysed in detail.

Application of specific cytologic, cytogenetic and molecular-cytogenetic techniques for the characterization of solid tumors.

Investigations of solid tumors have shown that a very specific characterization of aberrant tissues can best be performed using a combination of cytologic, cytogenetic and molecular-cytogenetic methods. Thus, cytological analyses may serve to examine various features of tumors cultivated in vitro, e.g. growth peculiarities, cell morphology, specific details of cell division and mitotic rates, and anomalies of the spindle apparatus. Besides, chromosomal diagnostics characterizing non-specific aberrations focuses on the pathological karyotype and its evolution and heterogeneity, as well as on the development of secondary chromosomal aberrations. In the field of molecular-cytogenetic diagnostics we emphasize particularly the combination of metaphase and interphase analyses and the investigation of specific structural aberrations by fluorescence in situ hybridization (FISH). In contrast to the method of comparative genomic hybridization (CGH), the spectrum of applications for both methods is discussed. The findings described in this paper were obtained primarily from the analysis of 68 tumors of the urogenital tract (20 kidney tumors, 33 bladder tumors, 15 testis tumors).

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.

Unbalanced translocation 8;Y (45,X,dic(Y;8)(q11.23;p23.1)): case report and review of terminal 8p deletions.

A boy with a rare unbalanced de novo Y/autosome translocation is presented. Main clinical features in the boy comprised a psychomotor delay, talipes planus, a dolichocephalus, low set and retroverted ears, supraorbital fullness of subcutaneous tissue and a bulbous nasal tip. Chromosomal analysis on amniocytes showed a single X chromosome and a derivative 8p (Karyotype: 45,X,der(8)GTG). The following DAPI staining revealed the inactivated centromere of the chromosome Y located on 8p and the absence of heterochromatic material Yq. Microsatellite analysis on fetal blood DNA using markers between SRY on Yp and DYS 240 on Yq proved presence of the spermatogenetic relevant factors. A terminal deletion of 8p was confirmed by FISH postnatally. Molecular genetic reassessment revealed the monosomy 8p to be of maternal origin; the translocation can thus be proven to have occurred in the zygote. The breakpoint in 8p was localised distal to GATA4, a gene which is involved in heart development; the finding that our patient did not suffer from cardiac problems agrees with the disomic presence of GATA4. Only the application of FISH combined with microsatellite analysis allowed a precise correlation between clinical phenotype and a subtle deletion of terminal 8p; furthermore, a recurrence risk for the parents could be excluded.

Supernumerary marker chromosomes derived from chromosome 15: analysis of 32 new cases.

Small supernumerary marker chromosomes (SMC) are a heterogeneous group of chromosomes with an estimated frequency of approximately 0.14-0.72 per 1000 newborns and higher frequencies in particular populations such as the mentally retarded or infertile males. With a frequency of about 50%, derivatives of chromosome 15 represent the most common SMC. Here we present the results of a detailed analysis of 32 SMC(15) carriers who were ascertained in pre- or post-natal routine cytogenetic diagnostics. SMC(15) with euchromatic content led to mental and psychomotor retardation. In contrast, SMC(15) without euchromatin were found to have no influence on the carrier's phenotype but were detected with a high incidence among infertile males. The majority of SMC(15) are pseudodicentric homologous rearrangements. Based on our investigations a further characterization of der(15) was possible.

Familial ovarian dysgerminomas (Swyer syndrome) in females associated with 46 XY-karyotype.

An asymptomatic woman (age 38 years) with a family history of ovarian malignancies was referred for presymptomatic genetic testing of mutations in the BRCA genes. A familial Swyer syndrome with the occurrence of dysgerminomas is the most likely diagnosis. However, in our case, all known causes of this heterogeneous disorder have been excluded pointing to the existence of another yet unknown genetic locus. The family history revealed three affected paternal aunts. Two of them developed ovarian malignancies at 13 and 15 years of age, and died at ages 19 and 20. The third aunt, 82 years old, was affected by this disease at the age of 35. She underwent hormonal treatment for 3 years starting at the age of 15 because of primary amenorrhea. Under this treatment she developed nearly complete secondary sexual characteristics. Karyotype analysis revealed a normal male karyotype (46 XY, QFQ). Pelvic ultrasound showed an uterus of normal size, incompatible with an androgen resistance syndrome or a defect in testosterone biosynthesis. We excluded a mutation in the sex-determining region on chromosome Y (SRY) by direct sequencing of the SRY gene. An involvement of the subtelomeric region of chromosome 9p (9p 24.3) recently reported to be involved in XY-sex reversal phenotypes was excluded by molecular testing for loss of heterozygosity as well as fluorescence in situ hybridization studies. Analyses of the DAX1 gene in the dosage sensitive sex reversal locus on chromosome Xp21 by Southern blot analysis showed no duplications.

[Uniparental disomy 7 in the pathogenesis of Silver-Russell syndrome]. / A 7-es kromoszóma uniparentalis disomiája a Silver-Russel-syndroma kóreredetében.

The authors report the frequency and the clinical signs of uniparental disomy of chromosome 7 in Silver-Russell syndrome patients. A cohort of 73 families were typed with Short Tandem Repeat markers from chromosomes 7. In 6 patients maternal uniparental disomy 7 (UPD7) was detected. Summarising their data and those from the literature, an overall frequency of maternal uniparental disomy 7 of approximately 10% can be estimated. Allelic distribution in two of their maternal uniparental disomy 7 families indicates complete isodisomy whereas allelic patterns in the other four families are consistent with partial and complete heterodisomy, respectively. The clinical features of maternal uniparental disomy 7 patients do not show any deviation from the non-uniparental disomy 7 patients. Additionally, there was not hint for possible influences of iso- or heterodisomy, possibly associated with different stages of mosaicism. Their results demonstrate the necessity to screen SRS patients for UPD7 although the effect of UPD7 cannot be correlated to the SRS phenotype yet. Furthermore, an association between UPD for chromosomes other than 7 and SRS seems to be negligible. Vice versa, maternal UPD7 is not detectable in non-SRS patients. Therefore, testing for maternal UPD7 can be restricted to SRS families, searching for other UPDs in this population does not seem to be reasonable. Additionally, cytogenetic analysis should also be performed in SRS patients: identification of commonly involved chromosomal regions should allow narrowing down a SRS-relevant region.

[Bardet-Biedl syndrome: aspects of nephro-urology and human genetics]. / Bardet-Biedl-Syndrom: nephrourologische und humangenetische Aspekte.

Bardet-Biedl syndrome is a genetically heterogeneous autosomal recessive complex of features in which five gene loci have been described up to now. The diagnosis of this rare syndrome is based on the main manifestations hypogonadism, age-dependent increasing obesity and reduction of renal function, age-dependent progressive retinal degeneration with blindness as well as postaxial polydactyly and mental retardation. The life expectancy is short. Problems of early diagnostics, secondary hyperparathyroidism as well as surgical reconstruction of the genitals and kidney replacement therapy are discussed.

Combination of hypospadias and maldescended testis as cardinal symptoms in gonosomal chromosome aberrations.

Intersexual genitals or distinct hypospadias in combination with maldescended testis can be caused by endocrinological as well as chromosomal abnormalities. Even in early childhood such clinical findings require specific diagnostic procedures and subsequent treatment which is often invasive but has special importance as regards the early diagnosis of gonadal tumors. We present a child with cryptorchidism on the right, inguinal testis on the left and penoscrotal hypospadias. Cytogenetic analyses revealed a mosaic karyotype 45, X/46, X, idic (Yp) with unequal distribution of the mosaic in different tissues. In consequence of this chromosomal aberration the patient had mixed gonadal dysgenesis which is associated with an increased risk of tumor development in the aberrant gonads. The principles of pediatric, urological, cytogenetic and endocrinological diagnostics and the mode of data collection in the presented case are described and discussed. Furthermore, a protocol for preventive screening is presented, which combines urological and endocrinological investigations in males with malformations of the genito-urinary tract to minimize the risk of tumor development in the aberrant gonads.

[Aberrations of chromosome 18 and their significance in genetic counseling]. / A 18-as kromoszóma rendellenességeinek eredete és jelentósége a genetikai tanácsadásban.

In order to get information on the origin of chromosome 18 aberrations trisomy 18 cases were analysed as well as different chromosome 18 rearrangements. In total, their study population consisted of 100 trisomy 18 patients and their parents, 67 out of which have already been published. Additionally, seven families were analysed with structural aberrations of chromosome 18 including four patients with tetrasomy 18p. Determination of parent and cell stage of origin was performed by short tandem repeat typing (STR, microsatellites). These investigations revealed that the additional chromosomal material in the majority of the chromosomal 18 aberrations was maternal in origin (97/107). In most of the cases the nondisjunction occurred during maternal meiosis II. This was in agreement with findings of other groups. Thus, independently from the type of aberration, there was a predisposition of chromosome 18 for nondisjunction in maternal meiosis II. In this respect, chromosome 18 seemed to be unique among human autosomes. Furthermore, these results showed that molecular genetic analyses of chromosomal aberrations and their formation mechanisms were meaningful tools in genetic counselling situations: in 5 cases where cytogenetic investigations could not performed, the clinical diagnosis of Edwards syndrome could be confirmed by molecular findings. Thus, in these cases other genetic diseases with differing types of inheritance could be excluded from being the cause of the observed malformations. In a further structural rearrangement of chromosome 18, the origin could be determined as being mitotic, therefore a recurrence risk could be excluded for this couple.

Formation of uniparental disomy 7 delineated from new cases and a UPD7 case after trisomy 7 rescue. Presentation of own results and review of the literature.

Maternal uniparental disomy for the entire chromosome 7 (matUPD7) has been reported several times in Silver-Russell syndrome (SRS) and growth-restricted patients. Here we present our results from the analysis of an abortion with confined placental mosaicism (CPM) for trisomy 7 which showed a maternal meiotic origin of the trisomy in the placenta and rescue to maternal UPD7 in foetal membrane. Furthermore, two newly detected SRS cases with maternal UPD7 revealed isodisomy and partial heterodisomy, respectively. Summarising these results with those published previously on the origin of UPD7, similar numbers of isodisomy (n=11) and cases with complete or partial heterodisomy (n=12) have been reported. In respect to the different formation mechanisms of UPD, complete isodisomy should be the result of a post-zygotic mitotic segregation error, whereas heterodisomic UPDs should be caused by trisomic rescue after meiotic non-disjunction events. In maternal UPD7, 50% of cases seem to be caused by post-zygotic mitotic segregation errors, which is similar to the situation in trisomy 7. This result corresponds to the situation in trisomy 8 but is in contrast to observations in the frequent aneuploidies. Thus, the different findings in these aberrations reflect the presence of multiple factors that act to ensure normal segregation, varying in importance for each chromosome.

Cytogenetic and andrological status and ICSI-results in couples with severe male factor infertility.

AIM: To pursue whether cytogenetic aberrations correlate with specific spermatological or hormonal abnormalities. METHODS: 305 infertile couples were investigated. All male partners were referred to a complete andrological work-up with physical examination, determination of hormones, HIV testing and semen analysis. Cytogenetic analysis was carried out in both partners by means of standard techniques using cultured lymphocytes from peripheral blood. RESULTS: Among the 305 couples, 10 men (3.2%) and 10 women (3.2%) showed constitutional chromosomal aberrations, including reciprocal translocations (n = 7), Robertsonian translocations (n = 3), inversions (n = 3), other structural aberrations (n = 4) and sex chromosome aberration (n = 3). In addition to the impaired sperm count in most of the patients, a tendency to an increased proportion of spermatozoa with acrosome defect was observed. CONCLUSION: Chromosomal aberrations may contribute to the low fertilization and pregnancy rates in the infertile couples.

Analysis of a de novo complex chromosome rearrangement involving chromosomes 4, 11, 12 and 13 and eight breakpoints by conventional cytogenetic, fluorescence in situ hybridization and spectral karyotyping.

A complex chromosome rearrangement (CCR) with eight breakpoints resulting in four derivative chromosomes (4, 11, 12 and 13) was detected prenatally in a male fetus of a twin pregnancy. The karyotype of the female second fetus was normal. The apparently balanced de novo CCR was identified by classical cytogenetic methods and fluorescence in situ hybridization (FISH). We compared these findings with results from spectral karyotyping (SKY).

Type and frequency of chromosome aberrations in 781 couples undergoing intracytoplasmic sperm injection.

Cytogenetic investigations were performed in 781 couples prior to intracytoplasmic sperm injection (ICSI) because of severe male infertility or fertilization failures in previous in-vitro fertilization attempts. Out of these 1562 patients, 1012 had a normal karyotype without any aberrations (64.8%), 204 patients had an abnormal karyotypes (13.1%). These chromosome aberrations included constitutional aberrations (4.4%), fragile sites of autosomes (3.0%), low level mosaicism of sex chromosomes (4.0%) and secondary structural chromosome aberrations (4.2%). Combinations of different types of abnormalities were stated. Another 346 patients (22.1%) showed single cell aberrations; the significance of these is unclear at the moment. Constitutional chromosome aberrations were detected in 69 patients. The following chromosome aberrations were observed: 35 sex chromosomal aberrations (comprising hyperploidies of X or Y chromosomes, mosaicisms and derivative X and Y chromosomes), 34 autosomal aberrations including 14 reciprocal translocations, five Robertsonian translocations, six inversions, one marker chromosome, one trisomy 18 mosaicism and seven other structural aberrations. Three autosomal regions showed fragile sites: 6q13 in 2.9% of the patients, 17p12 and 10q24 in 0.05% each. In conclusion, our data show that a high number of infertile couples in an ICSI programme are affected by chromosome aberrations which occur in both sexes. It is suggested that a chromosomal analysis should be performed on both partners before ICSI treatment is initiated.