Trisomy 7 mosaicism prenatally misdiagnosed and maternal uniparental disomy in a child with pigmentary mosaicism and Russell- Silver syndrome

Prenatal diagnosis of true mosaic trisomy 7 is rare in amniotic fluid and can be misinterpreted as pseudomosaic. The phenotype is highly variable and may be modified by a maternal uniparental disomy of chromosome 7 leading to mild Russell-Silver syndrome (RSS). We report here the third postnatal case of mosaic trisomy 7 with maternal uniparental disomy of chromosome 7 in a boy presenting a mild RSS. Fetal karyotype performed in amniocentesis for intrauterine growth retardation was considered normal. Mosaic trisomy 7 was diagnosed after birth, on fibroblasts karyotype performed for blaschkolinear pigmentary skin anomalies and failure to thrive. Maternal uniparental disomy of chromosome 7 was observed in blood sample. Retrospectively, trisomic 7 cells were identified in one prenatal long-term flask culture revealing a prenatal diagnosis failure. This report emphasizes the difficulty of assessing fetal mosaicism and distinguishing it from pseudomosaicism in cultured amniocytes. It is important to search for uniparental disomy as an indirect clue of trisomy 7 mosaicism and a major prognosis element. Although there are only few prenatal informative cases, detection of trisomy 7 in amniocentesis appears to be associated with a relatively good outcome when maternal uniparental disomy has been ruled out.     

Segmental maternal heterodisomy of the proximal part of chromosome 15 in an infant with Prader-Willi syndrome

Uniparental disomy (UPD) 15, detected in patients with Prader-Willi (PWS) and Angelman syndromes, has to date always involved the entire chromosome 15. We report the first case of segmental maternal uniparental heterodisomy confined to a proximal part of chromosome 15 in a child with clinical features of PWS. This unusual finding can be explained by the rare combination of three consecutive events: a trisomy 15 zygote caused by a maternal meiosis I error, early postzygotic mitotic recombination between maternal and paternal chromatids, and, finally, trisomy rescue by the loss of the rearranged chromosome 15 containing the paternal 15q11-q13 segment.     

Advanced parental age in maternal uniparental disomy (UPD): implications for the mechanism of formation

Uniparental disomy (UPD) describes the inheritance of a pair of chromosomes from only one parent. Meiotic nondisjunction followed by trisomy rescue is considered to be the major mechanism of formation. A literature search for cases with whole chromosome UPD other than UPD 15 was performed. Information on parental age was available in 111 cases with maternal UPD and in 34 cases with paternal UPD. In 52 out of 74 cases with maternal heterodisomy, information on the time of nondisjunction was also available. Around two-thirds of these cases were due to a maternal meiosis I error. Compared with the mean maternal age of 30.0 years in Bavarian mothers, in the year 2000 an advanced mean maternal age of 34.8 years was found in cases with maternal heterodisomy (n=74; P<0.0001). Almost no difference in the mean maternal age was observed between meiosis I errors (35.56 years; n=30) and meiosis II errors (35.78 years; n=14). The mean maternal age was 31.46 years in cases with maternal isodisomy and a normal karyotype (n=24), and the mean paternal age was 31.48 years in cases with paternal isodisomy (n=28). The various mean parental ages in heterodisomic and isodisomic cases are considered to reflect strongly the different mechanisms of formation: trisomy rescue or gamete complementation, which implies a meiotic nondisjunction in maternal heterodisomic UPD, and postzygotic somatic reduplication in cases with paternal and maternal isodisomic UPD.     

The contribution of uniparental disomy to congenital development defects in children born to mothers at advanced childbearing age

Most instances of maternal uniparental disomy (UPD) start as trisomies and, similar to the latter, show a significant increase of mean maternal age at delivery. To investigate the incidence of UPD in offspring of older mothers, we investigated two groups of patients: 1) 50 patients with unclassified developmental defects born to mothers 35 years or older at delivery were tested for UPD for all autosomes by means of microsatellite marker analysis; 2) The incidence of UPD versus other etiologies in correlation, with maternal age below versus 35 years and above at delivery was studied in patients investigated in our laboratory for maternal UPD 15 (Prader-Willi syndrome, PWS), paternal UPD 15 (Angelman syndrome, AS), and maternal UPD 7 (Silver-Russell syndrome, SRS). In group 1, four patients of 50 showed UPD for an autosome that clarified the etiology of their developmental problems: a 27-year-old woman with growth retardation and early puberty disclosed maternal heterodisomy 14; a 15-year-old girl revealed paternal isodisomy 15; a 6-year-old boy with suspected Smith-Lemli-Opitz syndrome was shown to have maternal heterodisomy 16 with additional mosaic partial trisomy 16(pter-p13); a 16-month-old girl with intrauterine growth retardation and a dysmorphic pattern revealed maternal heterodisomy 7. In group 2 the offspring of older mothers showed a clear increase of UPD compared with the mothers below 35 years at delivery. The binomial distribution gave P-values of 1.9 x 10(-10), 2.6 x 10(-4), and 0.01 for PWS, AS, and SRS, respectively. The correlation between increase of paternal UPD 15 with advanced maternal age might be explained by maternal non-disjunction leading to hypohaploid gamete (nullisomy) for chromosome 15 with subsequent or concomitant duplication of the paternal homologue (paternal isodisomy). The three UPD 15 AS cases with mothers older than 35 years at delivery revealed isodisomy, whereas the three cases from younger mothers showed heterodisomy. This study confirms the hypothesis that uniparental disomy is a not negligible cause of congenital developmental anomalies in children of older mothers.     

Comprehensive 4-year follow-up on a case of maternal heterodisomy for chromosome 16

Uniparental disomy for chromosome 16 has been previously identified in fetal deaths and newborn infants with limited follow-up. Thus there is a lack of information about the long-term effects of maternal uniparental disomy 16 on growth and development. We present a case of maternal heterodisomy for chromosome 16 and a comprehensive 4-year physical and cognitive evaluation. Cytogenetic analysis of chorionic villus obtained at 10 weeks gestation for advanced maternal age showed trisomy 16. At 15 weeks, amniocentesis demonstrated low level mosaicism 47,XY,+16[1]/46,XY[25]. Decreased fetal growth was noted in the last 2 months of pregnancy and the infant was small for gestational age at birth. Molecular studies revealed only maternal alleles for chromosome 16 in a peripheral blood sample from the child, consistent with maternal uniparental heterodisomy 16. Although short stature remains a concern, there appears to be no major cognitive effects of maternal disomy 16. Clinical evaluation and follow-up on additional cases should further clarify the role of placental mosaicism and maternal disomy 16 in intrauterine growth retardation and its effects on long-term growth in childhood. © 1996 Wiley-Liss, Inc.     

Pre- and postnatal findings in trisomy 17 mosaicism

Trisomy 17 mosaicism is one of the rarest autosomal trisomies in humans. Thus far, only 23 cases have been described, most of them detected prenatally. In only five instances has mosaicism been demonstrated in lymphocytes and/or fibroblasts postnatally, and only in these have multiple congenital anomalies (MCA), facial dysmorphisms, and mental retardation been reported. Patients with trisomy 17 mosaicism at amniocentesis and a normal karyotype in blood and fibroblasts (n = 17) were always healthy. Here, we report on pre- and postnatal clinical, cytogenetic, molecular-cytogenetic, and molecular findings in four patients with trisomy 17 mosaicism. The first case was detected in cultured but not in short-term chorionic villi and amniocytes. Due to MCA on prenatal ultrasound examination the pregnancy was terminated. The second patient is a 13-month-old healthy boy, in whom low level trisomy 17 mosaicism was detected in cultured chorionic villi only. The third patient is a 2-year-old girl with growth retardation, developmental delay, MCA, and trisomy 17 mosaicism in amniocytes, fibroblasts, and placenta, but not in blood and buccal smear. The fourth patient is a 9-year-old boy with growth and mental retardation, sensoneurinal hearing loss, and MCA. Cytogenetic analyses showed trisomy 17 mosaicism in amniocytes, skin fibroblasts, and urinary sediment cells, whereas in blood and buccal smear a 46,XY karyotype was found. Molecular investigations in all four cases indicated biparental inheritance of chromosome 17. Formation of trisomy was most likely due to a maternal meiosis I error in Patient 1 and a postzygotic non-disjunction of the paternal chromosome 17 in Patient 4. Cerebellar malformations, reported in two cases from the literature and in two reported here may be a specific feature of trisomy 17 mosaicism. Since the aberration has rarely been reported in lymphocytes, chordocentesis is not indicated in prenatal diagnosis. Prenatal genetic counseling for trisomy 17 mosaicism in chorionic villi or amniocytes should consider that the clinical significance remains uncertain.     

Prader-Willi syndrome in a child with mosaic trisomy 15 and mosaic triplo-X: a molecular analysis.

A 3.3 year old girl with Prader-Willi syndrome (PWS) and mosaicism for two aneuploidies, 47,XXX and 47,XX,+15, is presented. The triplo-X cell line was found in white blood cells and fibroblasts, the trisomy 15 cell line in 50% of the fibroblasts. Using methylation studies of the PWS critical region and by polymorphic microsatellite analysis, the existence of uniparental maternal heterodisomy for chromosome 15 was shown in white blood cells. This provided a molecular explanation for the PWS in this child. In fibrolasts, an additional paternal allele was detected for markers on chromosome 15, which is in agreement with the presence of mosaicism for trisomy 15 in these cells. This example provides direct evidence for trisomic rescue by reduction to disomy as a possible basis for PWS. Whereas the trisomy 15 was caused by a maternal meiosis I error, the triplo-X resulted from a postzygotic gain of a maternal X chromosome, as shown by the finding of two identical maternal X chromosomes in the 47,XXX cell line. Because the triplo-X and the trisomy 15 were present in different cell lines, gain of an X chromosome occurred either in the same cell division as the trisomy 15 rescue or shortly before or after.     

Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. Down Syndrome Collaborative Group.

BACKGROUND. Over the past 20 years, the parental origin of the extra chromosome in children with trisomy 21 has been investigated with cytogenetic methods of identifying morphologic variations in chromosome 21. These studies have concluded that the origin of the extra chromosome 21 was maternal in approximately 80 percent of cases and paternal in about 20 percent. METHODS. We studied 200 families, each with a single child with trisomy 21, using DNA polymorphisms as markers to determine the parental origin of the nondisjunction causing the extra chromosome 21. These polymorphisms spanned a region of about 120 centimorgans on the long arm of chromosome 21, from the D21S13 locus (the most centromeric) to the COL6A1 gene (the most telomeric). RESULTS. The parental origin of nondisjunction could be determined for all but 7 of the 200 children. It was maternal in 184 children (proportion [+/- SE], 95.3 +/- 1.5 percent) and paternal in 9 (4.7 +/- 1.5 percent). In a subgroup of 31 families, we compared the results of DNA analysis with those of traditional cytogenetic analysis. According to the cytogenetic analyses, nondisjunction originated in the mother in 26 cases (84 percent) and in the father in 5 (16 percent). DNA analysis demonstrated the origin as maternal in 29 (94 percent) and paternal in 2 (6 percent). With the cytogenetic analyses, there were three false determinations of paternal origin. CONCLUSIONS. In trisomy 21 the extra chromosome 21 is maternal in origin in about 95 percent of the cases, and paternal in only about 5 percent--considerably less than has been reported with cytogenetic methods. DNA polymorphic analysis is now the method of choice for establishing the parental origin of nondisjunction.     

Third case of paternal isodisomy for chromosome 7 with cystic fibrosis: a new patient presenting with normal growth

Many patients with maternal uniparental disomy of chromosome 7 (UPD7) have been described, mainly with intrauterine and postnatal growth retardation or with Silver-Russell syndrome. In contrast, only three cases of paternal UPD7 have been reported, all associated with recessive disorders. Here, we report on the clinical and molecular data of the third patient with paternal UPD7 and cystic fibrosis. Pre- and postnatal growth were normal. These findings support the hypothesis that paternal isodisomy for human chromosome 7 may have no phenotypic effect on growth.     

Third Prader-Willi syndrome phenotype due to maternal uniparental disomy 15 with mosaic trisomy 15

We report on a boy with mosaicism for trisomy 15 and Prader-Willi syndrome (PWS) due to maternal isodisomy for chromosome 15. His phenotype is consistent with PWS and trisomy 15 mosaicism. Although our patient is unusual in having maternal isodisomy rather than the more common maternal heterodisomy, we think that his more severe PWS phenotype is due to his trisomy 15 mosaicism rather than to homozygosity for deleterious chromosome 15 genes. We propose that individuals with PWS have one of three similar but distinctive phenotypes depending on the cause of their condition. Patients with paternal deletions have the typical PWS phenotype, patients with maternal UPD have a slightly milder phenotype with better cognitive function, and those with maternal UPD and mosaic trisomy 15 have the most severe phenotype with a high incidence of congenital heart disease. These phenotype-genotype differences are useful to guide the work-up of patients with suspected PWS and to provide prognostic counseling for families.     

Familial reciprocal translocation t(7;16) associated with maternal uniparental disomy 7 in a Silver‐Russell patient

We present the case of a maternal heterodisomy for chromosome 7 in the daughter of a t(7;16)(q21;q24) reciprocal translocation carrier. The proband was referred to the hospital for growth retardation and minor facial dysmorphism without mental retardation. A diagnosis of Silver‐Russell syndrome was suspected. Chromosomal analysis documented a 46,XX,t(7;16)(q21;q24)mat chromosome pattern. Microsatellite analysis showed a normal biparental inheritance of chromosome 16 but a maternal heterodisomy of chromosome 7. Occurrence of uniparental disomy (UPD) is a well‐recognized consequence of chromosomal abnormalities that increase the rate of meiotic nondisjunction, mainly Robertsonian translocations and supernumerary chromosomes. Although reciprocal translocations should, theoretically, be also at increased risk of UPD, only three cases have been reported so far. However, because the association between uniparental disomy and reciprocal translocation may exist with an underestimated frequency, prenatal diagnosis is recommended when clinically relevant chromosomes for UPD are involved. © 2002 Wiley‐Liss, Inc.     

Familial reciprocal translocation t(7;16) associated with maternal uniparental disomy 7 in a Silver-Russell patient

We present the case of a maternal heterodisomy for chromosome 7 in the daughter of a t(7;16)(q21;q24) reciprocal translocation carrier. The proband was referred to the hospital for growth retardation and minor facial dysmorphism without mental retardation. A diagnosis of Silver-Russell syndrome was suspected. Chromosomal analysis documented a 46,XX,t(7;16)(q21;q24)mat chromosome pattern. Microsatellite analysis showed a normal biparental inheritance of chromosome 16 but a maternal heterodisomy of chromosome 7. Occurrence of uniparental disomy (UPD) is a well-recognized consequence of chromosomal abnormalities that increase the rate of meiotic nondisjunction, mainly Robertsonian translocations and supernumerary chromosomes. Although reciprocal translocations should, theoretically, be also at increased risk of UPD, only three cases have been reported so far. However, because the association between uniparental disomy and reciprocal translocation may exist with an underestimated frequency, prenatal diagnosis is recommended when clinically relevant chromosomes for UPD are involved.     

Mosaic trisomy 17 in amniocytes: phenotypic outcome, tissue distribution, and uniparental disomy studies.

Mosaicism for trisomy 17 in amniocyte cultures is a rare finding, whilst postnatal cases are exceptional. In order to gain insight into the possible effects of the distribution of the trisomic line and of uniparental disomy (UPD) on embryofoetal development, we have performed follow-up clinical, cytogenetic and molecular investigations into three newly detected prenatal cases of trisomy 17 mosaicism identified in cultured amniotic fluid. In the first case, the pregnancy ended normally with the birth of a healthy girl, and analysis of newborn lymphocytes and of multiple extra-embryonic tissues was indicative of confined placental mosaicism. The second case was also associated with a normal pregnancy outcome and postnatal development, and only euploid cells were found in peripheral blood after birth. However, maternal isodisomy 17 consequent to a meiosis II error and loss of a chromosome 17 homologue was detected in peripheral lymphocytes postnatally. In the third case, pathological examination after termination of pregnancy showed growth retardation and minor dysmorphisms, and the trisomic line was detected in foetal skin fibroblasts. In addition, biparental derivation of chromosome 17 was demonstrated in the euploid lineage. These results, together with previously reported data, indicate that true amniotic trisomy 17 mosaicism is more commonly of extra-embryonic origin and associated with normal foetal development. Phenotypic consequences may arise when the trisomic line is present in foetal tissues. Case 2 also represents the first observation of maternal UPD involving chromosome 17; the absence of phenotypic anomalies in the child suggests that chromosome 17 is not likely to be subject to imprinting in maternal gametes.     

Pigmentary mosaicism following the lines of Blaschko in a girl with a double aneuploidy mosaicism: (47,XX,+7/45,X)

We report on a 6-year-old girl with linear streaks of apparent hypopigmentation and hyperpigmentation following the Blaschko lines, growth retardation, bupthalmos of the left eye, and mild mental retardation. She had a 45,X karyotype in lymphocytes. In cultured fibroblasts a double aneuploidy mosaicism was detected, consisting of a cell line with trisomy for chromosome 7 and a cell line with monosomy for the X-chromosome and no cell line with a normal karyotype. Cutis tricolor or three levels of pigmentation in different skin areas suggested presence of a third, probably normal cell line. Double aneuploidy mosaicism of a cell line with monosomy X and a cell line with trisomy of an autosome is a rare finding. The combination of monosomy X with trisomy of chromosomes 8, 10, 13, 18, and 21 has been reported, but not the combination with trisomy 7. In the 45,X cell line, microsatellite analysis showed loss of the maternal X-chromosome, and presence of a maternal and paternal chromosome 7. The 47,XX,+7 cell line showed a paternal and a maternal X-chromosome, and a paternal and two identical maternal chromosomes 7. Mechanisms that might explain this double aneuploidy mosaicism are discussed.     

Third Prader‐Willi syndrome phenotype due to maternal uniparental disomy 15 with mosaic trisomy 15

We report on a boy with mosaicism for trisomy 15 and Prader‐Willi syndrome (PWS) due to maternal isodisomy for chromosome 15. His phenotype is consistent with PWS and trisomy 15 mosaicism. Although our patient is unusual in having maternal isodisomy rather than the more common maternal heterodisomy, we think that his more severe PWS phenotype is due to his trisomy 15 mosaicism rather than to homozygosity for deleterious chromosome 15 genes. We propose that individuals with PWS have one of three similar but distinctive phenotypes depending on the cause of their condition. Patients with paternal deletions have the typical PWS phenotype, patients with maternal UPD have a slightly milder phenotype with better cognitive function, and those with maternal UPD and mosaic trisomy 15 have the most severe phenotype with a high incidence of congenital heart disease. These phenotype–genotype differences are useful to guide the work‐up of patients with suspected PWS and to provide prognostic counseling for families. Am. J. Med. Genet. 93:215–218, 2000. © 2000 Wiley‐Liss, Inc.     

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. © 1996 Wiley-Liss, Inc.     

Der(22)t(11;22) resulting from a paternal de novo translocation, adjacent 1 segregation, and maternal heterodisomy of chromosome 22.

The t(11;22) (q23;q11) translocation is the most frequently identified familial reciprocal translocation in humans. In translocation carriers, 3:1 meiotic segregation with tertiary trisomy can occur resulting in abnormal progeny with the der(22) as the supernumary chromosome. Affected children have a distinct phenotype with multiple anomalies and severe mental retardation. We have identified a child with developmental delay and multiple anomalies consistent with the der(22) phenotype. Cytogenetic analysis showed an abnormal chromosome complement of 47,XX,+der(22)t(11;22)(q23; q11) in all 50 cells analysed. FISH analysis using chromosome 11 and 22 painting probes showed a pattern consistent with a reciprocal translocation of the distal bands 11q23 and 22q11 respectively. Parental karyotypes were normal. RFLP analysis of locus D22S43, which maps above the t(11;22) breakpoint, showed that the der(22) was paternal in origin and indicated that the normal chromosomes 22 were the probable result of maternal heterodisomy. RFLP analysis of locus D22S94, which maps below the t(11;22) breakpoint, also suggested that both normal chromosomes 22 of the child represented the two maternal homologues. Non-paternity was excluded through the analysis of 10 microsatellite markers distributed on 10 different chromosomes and three VNTRs on three different chromosomes. To the best of our knowledge, this is the first reported case of a patient with an abnormal karyotype resulting from a de novo translocation in the paternal germline with probable unbalanced adjacent 1 segregation and maternal non-disjunction of chromosome 22 in meiosis I.     

Paternal nondisjunction in trisomy 21: excess of male patients

Paternal nondisjunction accounts for approximately 5% of casesof trisomy 21. We have studied 36 cases of free trisomy 21,in which the supernumerary chromosome was of paternal origin,with DNA markers in the pericentromeric region and along thelong arm of chromosome 21. Fifteen of the paternal cases wereconsistent with melosis II errors, 8 with mitotic errors andonly 7 with melosis I nondisjunction. This contrasts markedlywith maternally derived trisomy 21, in which meiosis I errorspredominate. An excess of males was observed in the meloticcases (21 maies:6 females), highly significantly different froma 1.06 ratio. A significant difference in mean maternal agewas found between cases of paternal origin (28.1 years) andthose of maternal origin (31.8 years, n=429). This indicatesthat the maternal age effect is confined to maternal nondisjunction.     

Trisomy 7 mosaicism, maternal uniparental heterodisomy 7 and Hirschsprung's disease in a child with Silver-Russell syndrome

Prenatal trisomy 7 is usually a cell culture artifact in amniocytes with normal diploid karyotype at birth and normal fetal outcome. In the same way, true prenatal trisomy 7 mosaicism usually results in a normal child except when trisomic cells persist after birth or when trisomy rescue leads to maternal uniparental disomy, which is responsible for 5.5-7% of patients with Silver-Russell syndrome (SRS). We report here on the unusual association of SRS and Hirschsprung's disease (HSCR) in a patient with maternal uniparental heterodisomy 7 and trisomy 7 mosaicism in intestine and skin fibroblasts. HSCR may be fortuitous given its frequency, multifactorial inheritance and genetic heterogeneity. However, the presence of the trisomy 7 mosaicism in intestine as well as in skin fibroblasts suggests that SRS and HSCR might possibly be related. Such an association might result from either an increased dosage of a nonimprinted gene due to trisomy 7 mosaicism in skin fibroblasts (leading to SRS) and in intestine (leading to HSCR), or from an overexpression, through genomic imprinting, of maternally expressed imprinted allele(s) in skin fibroblasts and intestine or from a combination of trisomy 7 mosaicism and genomic imprinting. This report suggests that the SRS phenotype observed in maternal uniparental disomy 7 (mUPD(7)) patients might also result from an undetected low level of trisomy 7 mosaicism. In order to validate this hypothesis, we propose to perform a conventional and molecular cytogenetic analysis in different tissues every time mUPD7 is displayed.