Duplication of chromosome region 4q28.3-qter in monozygotic twins with discordant phenotypes

We describe monozygotic twins with partially discordant phenotypes who were found to have a duplication of chromosome region 4q28.3-qter. The duplicated region of chromosome 4 resulted from an unbalanced segregation of a balanced maternal (4;22)(q28.3;p13) translocation. Duplication of the long arm of chromosome 4 has been described in >60 patients; however, it usually results from the unbalanced segregation of a parental balanced translocation and has an associated monosomy. Twenty cases of dup 4q without an associated monosomy have been reported, and this is the only case of dup 4q28. 3-qter. All cases of dup 4q are reviewed, and phenotypic aspects are analyzed. Issues of monozygotic twinning and other birth defects also are addressed.     

Two pairs of male monozygotic twins discordant for Wiedemann-Beckwith syndrome

Wiedemann-Beckwith syndrome (WBS) is a congenital anomaly syndrome which classically consists of exomphalos, macroglossia, and gigantism. The syndrome is also associated with a variety of minor anomalies and affected individuals have an increased risk of developing rare embryonal cell tumors. To date, 15 monozygotic (MZ) twin pairs have been reported of which 13 are discordant for WBS. All except one pair of the discordant WBS twin pairs have been female. We report two pairs of male MZ twins, each discordant for WBS. © 1996 Wiley-Liss, Inc.     

Monozygotic twins discordant for 18q21.2qter deletion detected by array CGH in amniotic fluid

Discordant chromosomal anomalies in monozygotic twins may be caused by various timing issues of erroneous mitosis and twinning events. Here, we report a prenatal diagnosis of heterokaryotypic monozygotic twins discordant for phenotype. In a 28-year-old woman, ultrasound examination performed at 26 weeks of gestation, detected intrauterine growth restriction and unilateral cleft lip and palate in twin B, whereas twin A had normal fluid, growth and anatomy. Molecular karyotyping in twin B identified a 18q21.2qter deletion, further confirmed by FISH analysis on amniocytes. Interestingly, in twin A, cytogenetic studies (FISH analysis and karyotype) on amniocytes were normal. Genotyping with microsatellite markers confirmed the monozygosity of the twins. At 32 weeks of gestation, selective termination of twin B was performed by umbilical cord coagulation and fetal blood samples were taken from the umbilical cord in both twins. FISH analyses detected mosaicism in both twins with 75% of cells being normal and 25% harboring the 18qter deletion. After genetic counseling, the parents elected to terminate the second twin at 36 weeks of gestation. In postmortem studies, FISH analyses revealed mosaicism on several tissues in both twins. Taking into account this observation, we discuss the difficulties of genetic counseling and management concerning heterokaryotypic monozygotic twins.     

Phenotypic discordance in monozygotic twins with 22q11.2 deletion

We report on male monozygotic twins with 22q11.2 deletion and discordant phenotypes. The twins had twin-to-twin transfusion syndrome. Twin 1, the smaller of the pair, had Tetralogy of Fallot, a characteristic facial appearance, swallowing dysfunction, anal atresia, short stature, and mental retardation, whereas twin 2 had a characteristic facial appearance but no other signs of the 22q11 deletion syndrome. Fluorescence in situ hybridization analysis showed a microdeletion on chromosome 22q11.2 in both twins. Zygosity analysis gave a probability of monozygosity greater than 99.999%. These observations indicate that environmental factors or postzygotic events play a role in the phenotypic variability in the twins. Am. J. Med. Genet. 78:319–321, 1998. © 1998 Wiley-Liss, Inc.     

Non-random X chromosome inactivation in an affected twin in a monozygotic twin pair discordant for Wiedemann-Beckwith syndrome

Wiedemann-Beckwith syndrome (WBS) is a syndrome including exomphalos, macroglossia, and generalized overgrowth. The locus has been assigned to 11p15.5, and genomic imprinting may play a part in the expression of one or more genes involved. Most cases are sporadic. An excess of female monozygotic twins discordant for WBS have been reported, and it has been proposed that this excess could be related to the process of X chromosome inactivation. We have therefore studied X chromosome inactivation in 13-year-old monozygotic twin girls who were discordant for WBS. In addition, both twins had Tourette syndrome. The twins were monochorionic and therefore the result of a late twinning process. This has also been the case in previously re-ported discordant twin pairs with infor-mation on placentation. X chromosome inactivation was determined in DNA from peripheral blood cells by PCR analysis at the androgen receptor locus. The affected twin had a completely skewed X inactiva-tion, where the paternal allele was on the active X chromosome in all cells. The unaf-fected twin had a moderately skewed X in-activation in the same direction, whereas the mother had a random pattern. Further studies are necessary to establish a possible association between the expression of WBS and X chromosome inactivation. © 1995 Wiley-Liss, Inc.     

Duplication 9q34→qter identified by chromosome painting

We have studied an infant with multiple anomalies and a 46,XY,12p+ karyotype. Parental chromosomes were normal, and it was not possible to determine the identity of the extra material on chromosome 12 cytogenetically. Chromosome painting with probes from a chromosome 9 library identified this material as coming from chromosome 9, and cytogenetics established the duplication as 9q34→qter. Comparison of this patient with others reported with partial dup(9q) documented excellent concordance of minor anomalies, most notably dolichocephaly, “;deep-set”; eyes, short horizontal palpebral fissures, beaked nose, micrognathia, arachnodactyly, and developmental delay. Identification of cytogenetically indeterminate abnormalities by molecular cytogenetics is very important, as it permits prognosis to be offered for families of newborn infants with unbalanced karyo-types. © 1993 Wiley-Liss, Inc.     

Duplication 6q24 → 6qter in an infant from a balanced paternal translocation

Duplication of 6q24 → 6qter was identified by GTG banding in an infant girl whose father was a balanced translocation carrier 46,XY,t(3;6)(p26 → q2402). At birth and at 4 mo she had proportionate short stature, microcephaly, asymmetric micrognathia, bow-shaped upper vermilion, long upper lip, submucous cleft palate, antimongoloid slant of palpebral fissures, telecanthus, prominant eyes, short neck with anterior and lateral webbing, short sternum, overlapping toes, wrist contractures, and hypertonicity. Later she was noted to have psychomotor retardation. Eleven previously published cases and our patient suggest that duplication of 6q (involving at least 6q25 → 6qter) produces a highly characteristic syndrome.     

Duplication 6q22→qter: Definition of the phenotype

We report on a girl with duplication of 6q22.32 → qter and microcephaly, frontal bossing, facial anomalies, and webbed neck. She has congenital heart disease, renal hypoplasia, and hearing loss along with severe developmental delay. Published reports of seven other patients are reviewed and compared. The most frequent anomalies include microcephaly, abnormal face, webbed neck, congenital heart disease, limb contractures, and developmental delay. Am. J. Med. Genet. 78:123–126, 1998. © 1998 Wiley-Liss, Inc.     

Familial tandem duplication of bands q31.1 to q32.3 on chromosome 4 with mild phenotypic effect

We describe a family carrying a direct duplication of an interstitial segment of the distal long arm of chromosome 4(q31.1q32.3) with a mild clinical phenotype. Affected family members include a 27-year-old woman and 2 of her 4 children, 1 of whom also has Klinefelter syndrome. Although 8 cases of simple duplications or insertions of 4q material have been described, only 3 include bands q31–q32, and these involve additional adjacent material. Affected members of the pedigree reported here have some of the manifestations of previously described cases of duplication 4q, but are less severely affected, suggesting that the genetic material in this region is well tolerated as a partial trisomy. Am. J. Med. Genet. 73:119–124, 1997. © 1997 Wiley-Liss, Inc.     

Duchenne muscular dystrophy in monozygotic twins: Deletion of 5′ fragments of the gene

A recombinant DNA study for deletion evaluation was performed in a 4 generation family with Duchenne muscular dystrophy (DMD) in twins. The patients were 6 years old, had a history of progressive difficulty in walking since age 4, and showed weak gluteals, iliopsoas, latissimus dorsi, rhomboids, lower trapezius, sternocleidomastoids, pseudohypertrophic calves, and tight heelcords. Both patients had high serum creatine kinase of 19,000 and 11,000 IU, respectively, and the muscle biopsy of the left vastus lateralis showed dystrophic alterations. Both twins had the same red cell types for ABO, Rh, CDE, MNSs, Kelly, Lewis, Duffy, and Kidd. HLA typing also detected the same antigens in both twins: A2, B44, DR4, and DR5. Cytogenetic studies were consistent with 46, XY male individuals with normal banding pattern. By cDNA probes the entire DMD gene was surveyed for missing or abnormal-sized restriction fragments. Both twin boys showed absence of 8.5, 8.0, 4.6, 4.2, and 3.1 kb fragments on Hind III blots and absence of 13.5, 3.7, 2.9, and 1.4 kb fragments on Bgl II blots both hybridized with cDNA l-2a corresponding to most 5′ region of the DMD gene. The mother and other relatives of the patient did not show deletion. These findings strongly suggest that the deletion in the DMD monozygotic twins represents a new mutation.     

Holoprosencephaly in monozygotic twins – clinical and computer tomographic findings

Of monozygotic male twins with holoprosencephaly, one showed by computer tomographic (CAT) scan a mild type with orbital hypotelorism, flat nose, bilateral cleft lip, and cleft palate associated with an intermaxillary rubital hypotelorism, flat nose, absent nasal bridge, and median cleft lip. Lymphocyte chromosomes were apparently normal. A review of the literature shows a heterogenous patient material in that most pertinent cases involved dizygotic twins, and some of these presumably had chromosome abnormalties.     

DNA methylation studies on imprinted loci in a male monozygotic twin pair discordant for Beckwith–Wiedemann syndrome

Tierling S, Souren NY, Reither S, Zang KD, Meng‐Hentschel J, Leitner D, Oehl‐Jaschkowitz B, Walter J. DNA methylation studies on imprinted loci in a male monozygotic twin pair discordant for Beckwith–Wiedemann syndrome. Beckwith–Wiedemann syndrome (BWS) is one of the most prevalent congenital disorders predominantly caused by epigenetic alterations. Here we present an extensive case study of a monozygotic monochorionic male twin pair discordant for BWS. Our analysis allows to correlate BWS symptoms, like a protruding tongue, indented ears and transient neonatal hypoglycaemia, to an abnormal methylation at the KvDMR1. DNAs extracted from peripheral blood, skin fibroblasts, saliva and buccal swab of both twins, their sister and parents were analysed at 11 differentially methylated regions (DMRs) including all four relevant DMRs of the BWS region. The KvDMR1 was exclusively found to be hypomethylated in all cell types of the affected BWS twin, while the unaffected twin and the relatives showed normal methylation in fibroblasts, buccal swab and saliva DNA. Interestingly, the twins share a common blood‐specific hypomethylation phenotype most probably caused by a feto‐fetal transfusion between both twins. Because microsatellite analysis furthermore revealed a normal biparental karyotype for chromosome 11, our results point to an exclusive correlation of the observed BWS symptoms to locally restricted epimutations at the KvDMR1 of the maternal chromosome.     

Partial duplication 4q and deletion 1p36 in monozygotic twins with discordant phenotypes

We report on monozygotic (MZ) twins with a de novo chromosome abnormality consisting of a partial duplication of chromosome 4 (q25-qter) and deletion of chromosome 1p36. These infants had dysmorphic facial features and other clinical manifestations similar to those described with the previously delineated duplication 4q and deletion 1p36 phenotypes and two other reported cases of combined partial duplication 4q and deletion 1p36. However, the twins were discordant for a number of congenital anomalies. The discordant phenotypes described in these genetically identical infants demonstrate that nongenetic factors may play a significant role in the phenotypic differences in patients with recognized chromosome duplication and deletion syndromes, which are usually attributed to the individual genotypic differences in the duplicated and/or deleted chromosome segments.     

Trisomy 1q42→qter in a sister and brother: Further delineation of the “trisomy 1q42→qter Syndrome”

We report on a 22-year-old woman and her 21-year-old brother with mild mental retardation, long face, prominent forehead, retrognathia, and (relative) macrocephaly. At birth they were small for date, their length is now below the 10th centile. Chromosome analysis demonstrated a nearly pure trisomy 1q42→qter in both patients due to unbalanced segregation of a paternal reciprocal balanced translocation 46,XY,t(1;15) (q42;p11). This is the second report of a nearly pure trisomy 1q42→qter. When comparing the manifestations of our patients with those of other reported cases we conclude that the most characteristic clinical manifestations of this syndrome are macrocephaly, prominent forehead, micro/retrognathia, large fontanelle, intrauterine growth retardation, postnatal growth retardation, and mental retardation. © 1995 Wiley-Liss, Inc.     

Duplication in chromosome 15q in a boy with the Prader-Willi syndrome; further cytogenetic confusion

We describe a six-year-old boy with the typical features of Prader-Willi syndrome. Cytogenetic investigation revealed a chromosome aberration that has not been described yet, i.e. a duplication in the proximal half of 15q. Based upon banding-pattern the exact nature of the duplicated part could not be delineated. Both parents had a normal karyotype. Various hypotheses concerning the relationship between Prader-Willi syndrome and various chromosome 15 abnormalities are discussed.     

Malformation syndrome of duplication 12q24.1→qter

While duplication and deletion of the short arm of chromosome 12 cause well-recognized syndromes, duplication of the long arm of chromosome 12 is rarely observed. We are reporting a duplication of chromosome 12 distal to band q24.1 in a five-month-old child. His chromosome constitution is 46,XY,-4, + der(4),t(4:12)(p16;q24.1)mat. The balanced translocation is also carried by his maternal grandmother and two of the mother's brothers. The malformation syndrome consisted of unusual facial appearance and anomalies of the musculoskeletal, cardiovascular, genitourinary, and central nervous systems. Four previously reported patients had similar break points on chromosome 12 with similar malformations; therefore, phenotype-karyotype correlation suggests a definitive malformation syndrome associated with duplication of chromosome region 12q24.1→qter.