Cerebellar hypoplasia, zonular cataract, and peripheral neuropathy in trisomy 17 mosaicism

Trisomy 17 mosaicism in liveborns is an extremely rare chromosomal abnormality, with only three cases reported in the literature. Here we describe a 7-year-old boy with trisomy 17 mosaicism. The chromosome abnormality was detected by amniocentesis and was confirmed postnatally in cultured skin fibroblasts. The main clinical features were mental retardation and growth reduction, peripheral motor and sensory neuropathy, hypoplastic cerebellar vermis, zonular cataract, and body asymmetry. In our patient, and in the three earlier described cases, the additional chromosome 17 was detected in skin fibroblasts, not in peripheral lymphocytes. Molecular investigations excluded uniparental disomy of chromosome 17 in our patient. The extra chromosome 17 probably originated from a postzygotic mitotic nondisjunction of the maternal chromosome 17. In most cases of trisomy 17 mosaicism detected in amniocytes the chromosome abnormality seems to be confined to extra-embryonic tissues and clinically normal children are born. If, however, there are also ultrasound abnormalities, the possibility of fetal trisomy 17 mosaicism should certainly be considered. If postnatal karyotyping is limited to blood the diagnosis of trisomy 17 mosaicism could easily be missed. Therefore, we recommend chromosome analysis to be based on cultured skin fibroblasts in all cases where mental retardation is accompanied by postnatal growth retardation, body asymmetry, peripheral neuropathy, and cerebellar hypoplasia or zonular cataract.     

Prenatal diagnosis of 45,X/46,XY mosaicism with postnatal confirmation in a phenotypically normal male infant

Prenatal detection of chromosome mosaicism has always been a diagnostic dilemma. In 21 reported cases of chromosomal mosaicism in cultured amniotic fluid cells, only two cases had cytogenetic confirmation of the mosaicism. All 21 pregnancies resulted in either phenotypically normal liveborns or grossly normal abortuses. We report a case of XO/XY mosaicism detected prenatally and confirmed postnatally in a grossly normal male infant. The indication for prenatal cytogenetic diagnosis was advanced maternal age (38 years). A diagnosis of XO/XY mosaicism was made from two separate culture flasks of amniotic fluid cells, with 45,X cells predominating (86.4 % ). The Y chromosome was of normal size but carried no fluorescent band. The parents were counseled and were advised that the phenotype of XO/XY mosaicism can range from relative normality to sexual maldevelopment. They decided to continue this pregnancy. The infant was born at term and was a grossly normal male with normal penis and descended, normal-sized testes. Leukocyte culture from the cord blood and a skin fibroblast culture confirmed the mosaicism of XO/XY. The father's Y chromosome was of identical size and carried a small fluorescent band. It appears that an altered Y chromosome may be predisposed to anaphase lag leading to mosaicism.     

Mosaic trisomy 22: A case presentation and literature review of trisomy 22 phenotypes

In a case of mosaic trisomy 22 the trisomic cells were detected primarily in fibroblasts. Results of initial lymphocyte chromosome analysis were normal. However, mosaicism was suspected because the patient had hypomelanosis of Ito, hemiatrophy, failure to thrive, and mental retardation. Mosaicism was confirmed in cultured fibroblasts. Repeat cytogenetic analysis of peripheral blood demonstrated a low level of trisomic metaphase cells, which was confirmed by interphase fluorescent in situ hybridization (FISH) analysis. Molecular studies supported maternal disomy in the child's disomic cells. The phenotype of this condition overlaps that of non-mosaic trisomy 22 chromosome mosaicism in general and to some extent the Ullrich-Turner syndrome phenotype. Improved cytogenetic and molecular techniques now allow better delineation of aneuploidy syndromes. Molecular and FISH studies added information about this case (mosaicism and uniparental disomy) not appreciated by routine cytogenetic analysis of lymphocytes. The detection of low-level mosaicism and/or uniparental disomy in such cases may change the clinical classification and our understanding of pathogenesis and recurrence risk of these disorders. Am. J. Med. Genet. 71:406–413, 1997. © 1997 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.     

Trisomy/tetrasomy 21 mosaicism in CVS: interpretation of cytogenetic discrepancies between placental and fetal chromosome complements

Trisomy/tetrasomy 21 mosaicism was found in chorionic villi (semidirect preparation) obtained from a 40 year old pregnant woman. Since both cell lines were abnormal, the couple elected for pregnancy termination. Placenta and fetal tissue samples were obtained for cytogenetic study. Long term cultured villi showed a non-mosaic trisomy 21 karyotype, while other tissues showed either a normal karyotype or normal/trisomy21 mosaicism. These discrepancies could be explained by a modified "bottle neck" embryogenic model with a trisomic zygote and a non-disjunction event taking place in one of the first divisions. Our case emphasises the need for confirmatory studies in other tissues when mosaicism is encountered in chorionic villi, even if all cell lines are abnormal.     

Prenatal diagnosis of trisomy 4 mosaicism

Trisomy 4 mosaicism is rare. To our knowledge only two cases of prenatally diagnosed trisomy 4 mosaicism have been reported. One case resulted in a normal liveborn male, the other resulted in an abnormal liveborn female. The karyotype of our case at the time of amniocentesis was 47,XY,+4[3]/ 46,XY[33] and resulted in a normal liveborn male. FISH analysis using an alpha satellite chromosome 4 probe was performed to confirm the cytogenetic findings. Follow-up chromosome analysis of cord blood, peripheral blood, foreskin, and umbilical cord fibroblasts showed a normal 46,XY male karyotype in all cells. FISH analysis of cord blood, umbilical cord fibroblasts, and amniotic fluid cells demonstrated two signals in 246 nuclei (i.e., 46,XY) and three signals in six nuclei (i.e., 47,XY,+4). Here we describe the present case of trisomy 4 mosaicism, the literature is reviewed, and the significance of this finding is discussed.     

Use of Y chromosome specific probes to detect low level sex chromosome mosaicism

An individual found to be a true hermaphrodite at laparotomy, is presented. Cytogenetic studies which initially disclosed a 46,XX karyotype, conflicted with the anatomic presence of a testis. More extensive analysis of peripheral lymphocytes and skin fibroblasts revealed low level 46,XX/69,XXY mosaicism. DNA hybridization studies, using highly repeated Y chromosome specific probes, confirmed the rare presence of Y chromosome bearing cells. Such combined clinical and molecular studies can have an important impact on diagnosis and management of cases in which sex chromosome mosaicism is suspected.     

Patient with trisomy 6 mosaicism

Trisomy 6 and trisomy 6 mosaicism were found in chorionic villi cell culture and short term incubation in a prenatal diagnosis at 12 weeks of gestation in a pregnancy with a growth retarded fetus showing nuchal translucency. The child was born in the 25th gestational week with a number of malformations including heart defects, deep-set ears, cleft right hand, cutaneous syndactylies, and overlapping toes of irregular shape and length. Trisomy 6 was not found in peripheral blood lymphocytes but was confirmed in umbilical cord fibroblasts. Currently, at the age of 2-3/4 years, the development of the child is relatively normal despite considerable growth delay. At the age of two years, she developed a papular erythema clinically suggestive of epidermal nevi. Cytogenetic analysis of fibroblast cultures derived from skin from a right hand finger and the inguinal area confirmed the presence of a trisomy 6 mosaicism. This is the first observation of a liveborn with trisomy 6 mosaicism.     

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.     

Trisomy 18 mosaicism in an adult with normal intelligence

A healthy 30-year-old woman was discovered unexpectedly to have trisomy 18/normal chromosome mosaicism. She was ascertained because of a history of three spontaneous abortions following the birth of a healthy son. Trisomy 18 was present in 18% of her lymphocytes and 2% of her cultured skin fibroblasts. She had several minor malformations associated with trisomy 18 syndrome. She is, to our knowledge, the first person who has clinical stigmata of trisomy 18 but has normal intelligence and leads a normal family life.     

Prenatal diagnosis of trisomy 20 mosaicism indicating esophageal and rectal origin

Trisomy 20 mosaicism in cultured amniotic fluid cells has in only a few cases been confirmed in fetal tissue. This may lead to the assumption that the trisomic cells are of extra-fetal origin and interruption of the pregnancy is not advisable. Chromosome analysis of numerous fetal tissues indicated in two cases the presence of one or more trisomy 20 cell clones in rectum and esophagus, respectively. The clinical significance of trisomy 20 mosaicism in single organs remains to be elucidated. Besides the karyotype, genetic counselling should take into account all accessible information of the pregnancy, e.g. ultra-sound, serum alpha-fetoprotein values and obstetrical history.     

Low-level mosaicism of trisomy 14: phenotypic and molecular characterization

Trisomy 14 mosaicism is a rare cytogenetic abnormality with a defined and recognizable clinical phenotype. We present a detailed clinical history and physical findings of five patients with low-level mosaicism of trisomy 14 detected by array-based comparative genomic hybridization (array-CGH) analysis or by routine chromosome analysis. These patients exhibited growth and developmental delays with variable severity, congenital anomalies, pigmentary skin lesions, and dysmorphic features. The phenotype of our patients was compared with previously described cases. This report suggests that trisomy 14 mosaicism may be more common than has been previously appreciated and also illustrates the important application of array-CGH to detect low-level mosaic chromosome abnormalities. We predict that a wider application of the array-CGH technology will significantly increase the detection rate of low-level mosaicism and will subsequently improve our ability to provide a diagnosis for patients with dysmorphic features, congenital anomalies, and developmental delay.     

Discordant phenotype in monozygotic twins with mosaic trisomy 12p in lymphocytes

We report on monochorionic diamniotic male twins discordant for the trisomy 12p syndrome. Trisomy 12p mosaicism with a supernumerary der(12)(pter > q12) was detected in approximately 50% of lymphocytes in both children. Fluorescence in situ hybridisation (FISH) revealed a high grade mosaicism of approximately 77% trisomy 12p cells in buccal smear and 85% in hair follicles in the affected twin, while in the normal developing brother an additional 12p chromosome fragment could not be detected in those tissues. Instead, in 3% of buccal smear and hair follicle cells a minute supernumerary marker chromosome comprising central portions of chromosome 12 was observed. Trisomy 12p mosaicism, confined to the lymphocytes of the unaffected twin, may be due to prenatal twin-to-twin transfusion, explaining the conspicuously discordant clinical phenotype. We discuss the possible sequence of events leading to the cytogenetic findings and compare the clinical phenotype presented in the affected twin with other cases of trisomy 12p and tetrasomy 12p (Pallister-Killian syndrome).     

Asymmetry and skin pigmentary anomalies in chromosome mosaicism.

We report six persons mosaic for a chromosome anomaly. All were mentally retarded and dysmorphic. Unilateral or asymmetrical features were found in all cases, in one an unusual transverse terminal limb anomaly, and in the others various degrees of hemiatrophy of the left side of the body. Five of the subjects had skin pigmentary anomalies which were distributed in the lines of Blaschko. The abnormal cell lines found were ring chromosome 22, trisomy 22, a large acrocentric marker, a deletion of 18q, a deletion of 8q, and triploidy. In four cases the clinical diagnosis was only confirmed by skin biopsy. In one case low level mosaicism in blood was fortuitously detected because of cytogenetic fragile X screening and confirmed in a skin biopsy. The sixth case was of dynamic mosaicism of a non-mosaic deletion 18q with a chromosome 18 derived marker present in a proportion of cells. Chromosome mosaicisn may cause subtle and asymmetrical clinical features and can require repeated cytogenetic investigations. The diagnosis should be actively sought as it enables accurate genetic counselling to be given.     

Trisomy 20 mosaicism in two unrelated girls with skin hypopigmentation and normal intellectual development

The prenatal diagnosis of trisomy 20 mosaicism presents a challenge for practitioners and parents. The diagnosis implies an uncertain risk for an inconsistent set of physical and developmental findings, as well as a substantial chance for a child that is normal physically and developmentally. We report two girls (ages nine years one month and eight years one month) with normal intelligence and hypopigmented skin areas. Both girls were born after a prenatal diagnosis of trisomy 20 mosaicism in amniocytes. Case 1 had 83% and 57% trisomy 20 cells from two separate amniocenteses and Case 2 had 90% trisomy 20 cells from an amniocentesis. Trisomy 20 was confirmed after birth in urinary sediment (25%) and chorionic villus cells (15%) in Case 1, while cord blood lymphocytes (30 cells) and skin fibroblasts (50 cells) had only 46,XX cells. Trisomy 20 was confirmed after birth in urinary sediment (100%), placenta (100%), cord (10%), amniotic membrane (50%), and skin fibroblasts (30%) in Case 2, while cord blood lymphocytes (100 cells) had only 46,XX cells. This is the first report of a hypopigmented pigmentary dysplasia associated with isolated trisomy 20 mosaicism. Our patients are the oldest reported children with trisomy 20 mosaicism confirmed after birth.     

Cytogenetic and molecular investigations of Y chromosome sequences and their role in Turner syndrome

It has been proposed that all live born females with Turner syndrome carry a cell line containing two sex chromosomes, which may be present at a low level of mosaicism (Hook & Warburton, 1983; Hassold et al . 1985; 1988; Connor & Loughlin, 1989). If the second sex chromosome is a Y, these patients are at risk of developing gonadoblastoma. In this study, 50 patients found to have a 45,X karyotype by conventional cytogenetic analysis, were screened by the polymerase chain reaction (PCR), for the presence of Y chromosome sequences. Two patients were positive for six of the eight Y chromosome loci tested and additional cytogenetic analysis confirmed the presence of a marker chromosome, in 8% and 3% of cells respectively. Fluorescence in situ hybridization (FISH) was used to confirm that the markers were of Y chromosome origin and helped to elucidate their structure. In addition, four other patients were found to have a Y chromosome by initial routine cytogenetic analysis. FISH, in conjunction with PCR, elucidated the structure of the Y chromosomes. This study illustrates the value of using a combination of cytogenetic and molecular techniques, to identify Y chromosome sequences in Turner syndrome.     

Chromosomal mosaicism in amniotic fluid cell cultures

Six cases of chromosomal mosaicism detected in amniotic fluid cultures are described. In five of these there was no evidence of fetal mosaicism. In one case fetal mosaicism was demonstrated but only by the study of fibroblasts since blood cultures showed only normal cells. The implications of amniotic fluid mosaicism are discussed and it is concluded that this usually does not indicate fetal mosaicism. The value of repeated amniocentesis in the diagnosis of fetal mosaicism was demonstrated by findings in three of the cases. It is recommended that amniotic fluid cultures be harvested in situ for chromosome studies and that cytogenetic results be expressed as number of colonies karyotyped rather than as number of cells analyzed.     

Pallister-Killian syndrome: normal karyotype in prenatal chorionic villi, in postnatal lymphocytes, and in slowly growing epidermal cells, but mosaic tetrasomy 12p in skin fibroblasts.

We report on two patients with Pallister-Killian syndrome: an 18 month old male infant followed since the neonatal period and a 4 year old boy. Prenatal diagnosis by chorionic villi sampling (CVS) in the first case showed a normal karyotype without mosaicism. Chromosome analysis on peripheral lymphocytes of the newborn also showed a normal karyotype. The clinical diagnosis of Pallister-Killian syndrome was made after the first year of life because of the typical facial dysmorphism and other characteristic clinical features, such as frontotemporal alopecia, depigmented area of the skin, sensorineural hearing loss, and severe psychomotor retardation. Chromosome analysis from skin fibroblasts now showed an isochromosome 12p mosaicism. The origin of the extra chromosome was confirmed by in situ hybridisation using a chromosome 12 specific library. In the second case chromosomal analysis from peripheral lymphocytes at the age of 19 months showed a normal karyotype 46,XY. Following the clinical diagnosis of Pallister-Killian syndrome a superficial skin biopsy was performed which showed very poor and slow growth of cells and a normal karyotype. Because of the typical symptoms a larger and deeper skin biopsy was performed from which there was rapid growth of fibroblasts. Now the diagnosis was established on the basis of the presence of an i(12p) extra chromosome in 69% of the metaphases.     

Dilemma of trisomy 20 mosaicism detected prenatally: Is it an innocent finding?

The clinical significance of mosaicism trisomy 20 detected prenatally following amniocentesis remains uncertain, due to the rarity of liveborn cases with inconsistent clinical findings, the short postnatal follow-up, and failure in evaluating other fetal tissues for the presence of the trisomy. We report on a 15 month-old 46,XX chromosome constitution in white blood cells, while skin fibroblasts demonstrated trisomy 20 mosaicism (54%) by fluorescence in situ hybridization (FISH) analysis. Clinical examination of the baby showed only minor phenotypic signs (bilateral epicanthal folds, delayed closure of fontanel with no other gross anomalies), but demonstrated a considerable developmental delay in gross and fine motor skills along with hypotonicity. This is the second oldest described liveborn with trisomy 20 mosaicism confirmed in skin fibroblasts. This cytogenetic aberration along with her developmental delay suggests that the two findings are related and that aberration affects various fetal tissues and is not confined to extra-embryonic tissue as suggested previously. Yet, an undiagnosed condition may be the cause of the child's developmental delay. Based on this case and following a review of the literature we suggest that when mosaic trisomy 20 is identified in amniocytes, further evaluation is required. Cord blood should be analyzed preferably by FISH. During counseling the parents should be advised of an additional risk, such as developmental delay, even when fetal cord karyotype and detailed ultrasonic scan are normal. Am. J. Med. Genet. 77:72–75, 1998. © 1998 Wiley-Liss, Inc.     

Pre- and postnatal diagnosis of trisomy 4 mosaicism

A liveborn girl with 46,XX/47,XX+4 mosaicism is reported for the first time. The diagnosis of true mosaicism was established initially in the assay of cultured amniotic fluid cells, although fetal blood obtained by percutaneous umbilical blood sampling showed a 46,XX chromosome constitution. The liveborn infant had manifestations previously reported in dup(4p) and dup(4q) syndromes. Cells in cord and arterial blood samples also were 46,XX, but cultures of placenta and bilateral forearm skin biopsies showed 46,XX/47,XX,+4 mosaicism. This case illustrates the disadvantage of chromosome analysis from blood alone when tissue-specific mosaicism is present.