Wolf-Hirschhorn syndrome due to a 3:1 segregation of a maternal balanced t(4;15)(p16.3;q11) translocation.

The Wolf-Hirschhorn syndrome (WHS) is characterized by severe pre- and postnatal growth retardation, specific pattern of dysmorphisms, and severe developmental delay. These clinical findings are the result of a deletion within the short arm of chromosome 4. Most cases occur de novo and are of paternal origin. Cases due to a balanced translocation are mostly of maternal origin and the deletion of distal 4p, including the WHS critical region, is often combined with a duplication of the other chromosomal segment involved in the rearrangement. Here, we report on a newborn female infant with WHS and pure tertiary monosomy due to a 3:1 segregation of a balanced maternal 4;15 translocation. In this context, importance of fluorescence in situ hybridization (FISH) with specific probes to determine the exact breakpoints in unbalanced chromosomal rearrangements with breakpoints localized around known microdeletion syndromes is emphasized.

Parental origin and mechanisms of formation of cytogenetically recognisable de novo direct and inverted duplications.

Cytogenetic, FISH, and molecular results of 20 cases with de novo tandem duplications of 18 different autosomal chromosome segments are reported. There were 12 cases with direct duplications, three cases with inverted duplications, and five in whom determination of direction was not possible. In seven cases a rearrangement between non-sister chromatids (N-SCR) was found, whereas in the remaining 13 cases sister chromatids (SCR) were involved. Paternal and maternal origin (7:7) was found almost equally in cases with SCR (3:4) and N-SCR (4:3). In the cases with proven inversion, there was maternal and paternal origin in one case each. Twenty three out of 43 cytogenetically determined breakpoints correlated with common or rare fragile sites. In five cases, including all those with proven inverse orientation, all breakpoints corresponded to common or rare fragile sites. In at least two cases, one with an interstitial duplication (dup(19)(q11q13)) and one with a terminal duplication (dup(8) (p10p23)), concomitant deletions (del(8) (p23p23.3) and del(19)(q13q13)) were found.

Penoscrotal hypospadias and coarctation of the aorta with mixed gonadal dysgenesis.

A 45,X/46,Xidic(Y)(q11.2) mosaicism was found in a 4-year-old boy. The clinical appearance was characterized by bilateral cryptorchidism, penoscrotal hypospadias, short penis, and coarctation of the aorta. The latter is the only abnormality also seen in Turner syndrome. A biopsy of the gonads revealed normal prepubertal testicular tissue. A chromosome analysis in all boys with penoscrotal, scrotal, or perineal hypospadias and a thorough examination of the heart in children with 45,X/46,XY mosaicism are recommended.

Parental origin and mechanisms of formation of triploidy: a study of 25 cases.

Triploidy is one of the most frequently observed chromosome abnormalities in spontaneous abortions in humans. The parental origin of the additional chromosome set is known to have a major impact on the phenotype of the foetuses and to result in differences in size and structure of the placenta. Early studies based on cytogenetic polymorphisms indicated a preponderant diandric origin of the triploidies; such detection method, however, is known to be prone to error. Other studies revealed a predominant digynic origin in cases with longer intrauterine survival. It is now thought that, to some extent, a detection bias in favour of cases with associated partial hydatidiform moles may account for the high incidences of diandric cases reported in some studies. Furthermore, depending on the gestational age of the cases analysed there may indeed be differences in the proportion of diandric and digynic triploidies. We investigated the parental origin and mechanisms of formation of triploidy in a group of 25 probands with gestational ages ranging from 8 to 37 weeks. DNA samples were extracted from foetal material and from blood samples of the parents, and were analysed using microsatellite markers. The parental origin of the triploidies was found to be maternal in 20 cases and paternal in 5. Regarding the digynic cases, an error at meiosis I was inferred in 10 cases, whereas in the other half an error occurred at meiosis II. All five diandric cases included in this study were found to be due to dispermy. No significant differences in the average maternal ages were found amongst the different subgroups of patients.

Recombinant balanced and unbalanced translocations as a consequence of a balanced complex chromosomal rearrangement involving eight breakpoints in four chromosomes.

We report on a family with a balanced complex chromosomal rearrangement (CCR) involving eight breakpoints between chromosomes 6, 7, 18, and 21 in the father. All three sons inherited one derivative chromosome from the father and in addition each inherited a different recombinant chromosome resulting in a partial trisomy 6q in the first, an apparently balanced karyotype in the second, and a partial trisomy 7q in the third son. Fluorescence in situ hybridisation (FISH) and microsatellite analysis were essential for the identification of the breakpoints. In addition, the results were confirmed by a 24-colour FISH experiment using the spectral karyotyping (SKYtrade mark) system. Paternal origin of the de novo CCR in the father was demonstrated for the first time by haplotype analysis. This is the second report of a CCR leading to simpler but unbalanced translocations in offspring as a consequence of recombination during gametogenesis, and the first report of a family case of CCR exhibiting as many as eight breakpoints in the transmitting carrier. The initial prediction that viable offspring would be quite unlikely had to be revised after the birth of three children. Genetic counselling of carriers of balanced complex rearrangements has to consider a higher probability for unbalanced recombinations than has been so far commonly assumed.

Isochromosomes 12p and 9p: parental origin and possible mechanisms of formation.

In a recent study Bugge et al and Kotzot et al reported that isochromosomes 18p originate mainly from maternal meiosis II nondisjunction, followed by misdivision. In order to determine if there is a common mechanism for isochromosome formation, three cases with mosaicism for an additional isochromosome 12p and three cases with tetrasomy 9p were studied. Two probands with isochromosomes 12p and the three cases with isochromosome 9p showed 3 alleles (two different maternal alleles and one paternal allele) at several loci mapping to distal 12p and 9p, respectively. Maternal heterozygosity for distal markers was reduced to homozygosity for markers closer to the centromere in both i(12p) cases and in one i(9p) case. For one patient with isochromosome 12p, the maternal band was clearly stronger than the paternal one at some loci, but two distinct maternal alleles were never seen. For one foetus and the patient with tetrasomy 9p, distal markers showed maternal heterozygosity. All proximal markers were not informative in these two i(9p) cases. Our findings indicate common features in different autosomal isochromosomes: the origin of the isochromosomes analysed in predominantly maternal; and a common mechanism appears to underlie their formation, namely due to meiosis II nondisjunction followed by a rearrangements leading to duplication of the short and loss of the long arm.

A 5-year-old girl with interstitial deletion of 3p14: clinical, psychologic, cytogenetic, and molecular studies.

An interstitial deletion of segment 3p14 (breakpoints 3p21.1 and 3p13) was found in a 5-year-old short, microcephalic, and mentally retarded girl with a pattern of anomalies comprising a wide forehead, short up-slanting palpebral fissures, small nose and ears, hypoplasia of larynx, trachea, and bronchi, clino- and camptodactyly of little fingers, and sacral vertebral fusion. Determination of microsatellites mapping to the deleted segment demonstrated that the deletion had occurred in the paternal germ line. This is the seventh patient with a deletion of 3p14, and comparison with the six previously reported cases does not yet allow definition of a specific pattern of minor and major anomalies.

Trisomy first, translocation second, uniparental disomy and partial trisomy third: a new mechanism for complex chromosomal aneuploidy.

A 2-year-old, short, microcephalic and developmentally retarded boy revealed a pattern of multiple minor anomalies, hypospadias and a dysplastic right kidney. Maternal age at delivery was 41 years. His karyotype showed two cell lines, one apparently normal, the other with a 1p+ chromosome. FISH examinations showed that the segment attached to 1p was from chromosome 16, and molecular investigations disclosed maternal heterodisomy 16, except for the segment (16)(pter-->p13.1) for which there was mosaicism between trisomy and uniparental disomy (UPD). Most likely, the zygote was trisomic for chromosome 16 due to a maternal meiosis I nondisjunction; a somatic rearrangement would have then occurred at an early postzygotic stage whereby a segment of the paternal chromosome 16 was translocated onto 1p. Subsequently, the paternal chromosomes 16 and 16p- had been lost in the normal and the translocation cell line, respectively. The chromosome aberration was detected secondary to the disclosure of maternal UPD 16 because of the demonstration of a paternal band at several loci on distal 16p. This case shows that chromosome aberrations may be formed in a more complicated manner than primarily assumed. Hence, the phenotype might also be due to underlying factors such as UPD or undetected mosaicism in addition to the more obvious implications of the chromosome rearrangement itself (e.g. partial trisomy).

Interstitial deletion, del(4)(q12q21.1), owing to de novo unbalanced translocation in a 2 year old girl: further evidence that the piebald trait maps to proximal 4q12.

A very short, microcephalic, and mentally retarded 2 year old girl showed minor anomalies including prominent occiput, delayed closure of the anterior fontanelle, high frontal hairline, prominent ears, upward slanting palpebral fissures, a small nose with bulbous tip, delayed tooth eruption and bone maturation, and short and tapering fingers and toes. She did not have a white forelock. Cytogenetic investigation disclosed a de novo unbalanced translocation between chromosomes 4 and 18 with deletion of 4q12-->q21.1. Molecular investigation showed lack of a paternal allele for the microsatellite markers D4S392 and D4S398. This case shows indirect evidence that the piebald gene maps to proximal 4q12.

Multiple congenital anomalies including the Rieger eye malformation in a boy with interstitial deletion of (4) (q25-->q27) secondary to a balanced insertion in his normal father: evidence for haplotype insufficiency causing the Rieger malformation.

A 7 year old boy with minor facial anomalies, the Rieger eye malformation, reduced vision, genital anomalies, and severe mental retardation had deletion of the segment 4q24-->q26. His phenotypically normal father had a balanced insertion of that segment into the distal long arm of chromosome 6: 46,XY,ins(6;4)(q26;q24q26). Microsatellite loci flanking the RIEG gene on 4q25 were deleted giving indirect evidence of deletion of this locus. This finding and the normal ocular findings in the insertion carrier father show that haplotype insufficiency can cause the Rieger eye malformation.

Serum parameters and nuchal translucency in first trimester screening for fetal chromosomal abnormalities.

OBJECTIVE: To assess the relation between serum parameters and nuchal translucency in pregnancies affected by fetal aneuploidy in the first trimester. DESIGN: Retrospective study of different serum parameters collected prior to chorionic villus sampling and measurement of nuchal translucency in relation to fetal aneuploidy. SETTING: Switzerland (German and Italian sector) and Bregenz, Austria. POPULATION: One thousand one hundred and fifty-one women aged 25 to 44 years at 10 to 13 weeks of gestation undergoing chorionic villus sampling, mostly for advanced maternal age. Fetal aneuploidy was found in 23 pregnancies including four cases of trisomy 21, five of trisomy 18 and one case of trisomy 13. MAIN OUTCOME MEASURE: Fetal karyotype, serum levels of free beta-hCG, pregnancy-associated plasma protein A (PAPP-A) and alpha-fetoprotein and the measurement of nuchal translucency. RESULTS: Serum PAPP-A was decreased in all common chromosomal abnormalities. Free beta-hCG levels were increased in trisomy 21 but decreased in trisomy 18, whereas alpha-fetoprotein was low in trisomy 21, 18 and other chromosomal abnormalities. Nine of twenty-three abnormal embryos had evidence of an increased nuchal translucency. Nuchal translucency, however, did not seem to be associated with any alteration in the levels of the biochemical parameters in either chromosomally normal or abnormal embryos. A low serum PAPP-A or an increased nuchal translucency was seen in two-thirds of all pregnancies with chromosomal abnormalities. CONCLUSION: A nuchal translucency > or = 3 mm and depressed serum PAPP-A levels have a good predictive value in the detection of fetal aneuploidy at 10 to 13 weeks of pregnancy. Serum free beta-hCG and alpha-fetoprotein levels may give additional information. An increased nuchal translucency was not associated with altered serum parameters. This would allow these different markers to be used in combination.

Molecular studies of translocations and trisomy involving chromosome 13.

Twenty-four cases of trisomy 13 and one case with disomy 13, but a de novo dic(13,13) (p12p12) chromosome, were examined with molecular markers to determine the origin of the extra (or rearranged) chromosome. Twenty-one of 23 informative patients were consistent with a maternal origin of the extra chromosome. Lack of a third allele at any locus in both paternal origin cases indicate a somatic duplication of the paternal chromosome occurred. Five cases had translocation trisomy: one de novo rob(13q14q), one paternally derived rob(13q14q), two de novo t(13q13q), and one mosaic de novo t(13q13q)/r(13). The patient with a paternal rob(13q14q) had a maternal meiotic origin of the trisomy; thus, the paternal inheritance of the translocation chromosome was purely coincidental. Since there is not a significantly increased risk for unbalanced offspring of a t(13q14q) carrier and most trisomies are maternal in origin, this result should not be surprising; however, it illustrates that one cannot infer the origin of translocation trisomy based on parental origin of the translocation. Lack of a third allele at any locus in one of the three t(13q13q) cases indicates that it was most likely an isochromosome of postmeiotic origin, whereas the other two cases showed evidence of recombination. One balanced (nontrisomic) case with a nonmosaic 45, -13, -13, +t(13;13) karyotype was also investigated and was determined to be a somatic Robertsonian translocation between the maternal and paternal homologues, as has been found for all balanced homologous Robertsonian translocations so far investigated. Thus, it is also incorrect to assume in de novo translocation cases that the two involved chromosomes are even from the same parent. Despite a maternal origin of the trisomy, we cannot therefore infer anything about the parental origin of the chromosomes 13 and 14 involved in the translocation in the de novo t(13q14q) case nor for the two t(13;13) chromosomes showing a meiotic origin of the trisomy.

Kallmann syndrome in a boy with a t(1;10) translocation detected by reverse chromosome painting.

Prometaphase chromosomes from a 16 year old boy with hypogonadotrophic hypogonadism and anosmia (Kallmann syndrome) showed a tiny chromosome fragment attached to the long arm of one chromosome 1 without a visible reciprocal translocation chromosome. Chromosome painting with libraries from chromosomes 1 and X excluded a t(X;1) translocation, but failed to detect a second translocation chromosome. Through reverse chromosome painting, an unbalanced der(1), t(1;10) (q44;q26) translocation could be detected. This is the third case of Kallmann syndrome with a de novo rearrangement between two autosomes. The distal long arm of chromosome 1 may contain a candidate locus for a gene, mutations of which may cause the Kallmann phenotype; a 10q location seems less likely.

[Trisomy-21 screening using AFPplus in the eastern part of Switzerland]. / Trisomie-21-Screening mit AFPplus in der östlichen Landeshälfte der Schweiz.

Two years after introduction of maternal serum screening for Down's syndrome in German-speaking Switzerland, based on measurements of alpha-fetoprotein, unconjugated estriol and total beta-HCG, results were analyzed of the two cytogenetic laboratories in Zurich and of a separate collective of the Department of Obstetrics at the University of Zurich. In a total of 489 cases with increased risk for Down's syndrome (> or = 1:380 at term) 19 (1:26; approximately 4%) had an abnormal fetal karyotype from which 16 had a trisomy 21. 13 out of these 16 mothers were aged below 35 years. Thus, after ultrasound, maternal serum screening detects the highest percentage of fetuses with chromosomal abnormalities. At the Department of Obstetrics 2962 serum screening tests were performed during a period of 2 1/2 years. 14.6% of the women were > or = 35 years old, 7.6% showed increased risk and 14 fetuses had an abnormal karyotype including 10 with Down's syndrome. 7 of these 10 were detected by the serum test. Nevertheless, the limited sensitivity of serum screening, its limitation predominantly to detection of fetuses with Down's syndrome and the rather late stage of screening, make effective first trimester screening mandatory.

Molecular studies of chromosomal mosaicism: relative frequency of chromosome gain or loss and possible role of cell selection.

Studies of uniparental disomy and origin of nonmosaic trisomies indicate that both gain and loss of a chromosome can occur after fertilization. It is therefore of interest to determine both the relative frequency with which gain or loss can contribute to chromosomal mosaicism and whether these frequencies are influenced by selective factors. Thirty-two mosaic cases were examined with molecular markers, to try to determine which was the primary and which was the secondary cell line: 16 cases of disomy/trisomy mosaicism (5 trisomy 8, 2 trisomy 13, 1 trisomy 18, 4 trisomy 21, and 4 involving the X chromosome), 14 cases of 45,X/46,XX, and 2 cases of 45,X/47,XXX. Of the 14 cases of mosaic 45,X/46,XX, chromosome loss from a normal disomic fertilization predominated, supporting the hypothesis that 45,X might be compatible with survival only when the 45,X cell line arises relatively late in development. Most cases of disomy/trisomy mosaicism involving chromosomes 13, 18, 21, and X were also frequently associated with somatic loss of one (or more) chromosome, in these cases from a trisomic fertilization. By contrast, four of the five trisomy 8 cases were consistent with a somatic gain of a chromosome 8 during development from a normal zygote. It is possible that survival of trisomy 8 is also much more likely when the aneuploid cell line arises relatively late in development.

Trisomy 17p11-pter: unbalanced pericentric inversion, inv(17)(p11q25) in two patients, unbalanced translocations t(4;17)(q27;p11) in a newborn and t(4;17) (p16;p11.2) in a fetus.

Three patients and one fetus with almost complete trisomy 17p due to familial rearrangements are described. Two patients followed unbalanced transmission of a familial pericentric inversion, and one patient and one fetus were due to unbalanced segregation of familial translocations. In the inversion family, another two patients with multiple malformations had died before chromosome examination could be performed. The pattern of congenital anomalies as revealed from eleven cases of trisomy 17p11-pter include as the most prominent features: prenatal growth retardation, microcephaly, downslanting palpebral fissures, small mouth, small mandible, poorly shaped ears, short and webbed neck, genital hypoplasia, clinodactyly of fingers, crowding of toes, a high incidence of congenital heart defects and hernias. Postnatal survival is short mainly in patients with congenital heart defects. From the age of about 6 years onward, clinical findings become more distinct, with some signs of Charcot-Marie-Tooth neuropathy (pes cavus, adducted thumbs, dorsiflexed hallux, camptodactyly and limitation of movements in different joints), and the nose gets narrow and sharp, with hypoplastic alae.

Intrachromosomal triplication of 15q11-q13.

A 7 year old girl with intrachromosomal triplication 46,XX,-15,+der(15)(pter-->q13::q13-->q11::q11-->qter) resulting in tetrasomy of 15q11-q13 is reported. Fluorescence in situ hybridisation confirmed that the tetrasomic region included the entire segment normally deleted in Prader-Willi and Angelman syndrome patients, and breakpoints were similar to those reported in two tandem duplications of 15q11-q13. The middle repeat was inverted, suggesting a possible origin through an inverted duplication intermediate. Microsatellite analysis showed that the rearrangement was of maternal origin and involved both maternal homologues. Clinical findings included multiple minor anomalies (a fistula over the glabella, epicanthic folds, downward slanting palpebral fissures, ptosis of the upper lids, strabismus, a broad and bulbous tip of the nose, and small hands and feet), motor and mental retardation, a seizure disorder, and limited verbal abilities. In addition, immunological examination disclosed a selective immunodeficiency. The overall phenotype did not clearly resemble that of cases with tetrasomy 15pter-q13 associated with an extra inv dup(15)(pter-->q13:q13-->pter) chromosome. The latter aberration causes more severe mental deficit and intractable seizures, but less marked phenotypic alterations, although some overlap in mild facial dysmorphic features is present. A number of features common to Angelman syndrome were also observed in the patient.

Biparental inheritance of chromosome 21 polymorphic markers indicates that some Robertsonian translocations t(21;21) occur postzygotically.

Robertsonian translocations between acrocentric chromosomes are the most common structural chromosomal rearrangements in humans and many other organisms, and several mechanisms for their formation have been proposed. We have analyzed highly informative DNA polymorphisms in a family with a non-mosaic de novo Robertsonian translocation 21q;21q, to determine the parental origin of the two 21q arms of the rearranged chromosome. The genotypes indicated a biparental origin, i.e. one 21q was paternal and the other maternal. These results imply that in some cases the formation of the rob(21q;21q) occurs in the zygote or in the first few postzygotic mitotic divisions.