Trisomy 22 mosaicism syndrome and Ullrich-Turner stigmata

Mosaic trisomy 22, ascertained in three unrelated patients, was found to be associated with body asymmetry and signs of the Ullrich-Turner syndrome including short stature, ptosis, webbed neck, nevi, cubitus valgus, dysplastic nails, malformed great vessels, and abnormal ovaries. These anomalies in trisomy 22 mosaicism have not been emphasized heretofore. In each of our patients, trisomy 22 mosaicism was found only in fibroblasts. In one patient, the trisomy resulted from a paternal first meiotic nondisjunction, and in the 46,XX cells, both chromosomes 22 were of paternal origin.     

Detection of low level sex chromosome mosaicism in Ullrich-Turner syndrome patients

Ullrich-Turner syndrome (UTS) is most commonly due to a 45,X chromosome defect, but is also seen in patients with a variety of X-chromosome abnormalities or 45,X/46,XY mosaicism. The phenotype of UTS patients is highly variable, and depends largely on the karyotype. Patients are at an increased risk of gonadoblastoma when a Y-derived chromosome or chromosome fragment is present. Since constitutional mosaicism is present in approximately 50% of UTS patients, the identification of minor cell populations is clinically important and a challenge to laboratories. We identified 50 females with a 45,X karyotype as the sole abnormality or as part of a more complex karyotype. Twenty two (44%) had a 45,X karyotype; mosaicism for a second normal or structurally abnormal X was observed in 24 (48%) samples, and mosaicism for Y chromosomal material in 4 (8%) cases. To further investigate the possibility of mosaicism in the 22 patients with an apparently non-mosaic 45,X karyotype, we performed FISH using centromere probes for the X and Y chromosomes. A minor XX cell line was identified in 3 patients, and the 45,X result was confirmed in 19 samples. No samples with XY mosaicism were identified. We describe our validation process for a FISH assay to be used in clinical practice to identify XX or XY mosaicism. FISH as an adjunct to karyotype analysis provides a sensitive and cost-effective technique to identify sex chromosome mosaicism in UTS patients.     

Fat distribution in overweight patients with Ullrich-Turner syndrome.

Overweight patients with Ullrich-Turner syndrome (UTS) and control children with similar weight/height and indices of overweight were studied to clarify the unique fat distribution in the syndrome. Triceps and ulnar skin-fold thickness (SFT) in UTS patients was significantly less than that of obese children without the syndrome. The means of SFT at the subscapular and paraumbilical regions were also less in the patients than control girls, though significance was not documented. Thus, increased body weight in UTS children seems mainly to be due to excess of adipose tissue, not in the limbs but on the trunk, and/or due to the increment of lean body mass.     

Increased low-level chromosome 21 mosaicism in older individuals with Down syndrome

During a study of the familial aggregation of Down syndrome (DS) and Alzheimer disease (AD), we observed an increase in mosaicism for disomy 21 in older individuals with DS. In a total of 213 DS subjects who were studied cytogenetically, only 1 of 121 (0.8%) under age 45 exhibited mosaicism, while 14 of 92 (15.2%) who were age 45 or older had mosaicism. Mosaicism in this report connotes “low-level” mosaicism, where all 15 individuals exhibited a modal chromosome number of 47 (i.e., trisomy 21), and at least two cells lacked one of the three chromosomes 21. The occurrence of aneuploidy for chromosomes 15, 17, and X increased with age, and an inverse correlation between chromosome loss and size was also observed. Because older individuals had not been karyotyped at birth, it was not possible to determine whether our observations were due to either increased survival of mosaic individuals or accumulation of disomy 21 cells via increased chromosome loss with aging of the trisomy 21 individual. Using a modeling approach involving life table methods, we obtained results that suggested acquired mosaicism as the predominant mechanism to explain our findings. These results support the hypothesis that as individuals with DS age, there is an increased loss of chromosome 21. Am. J. Med. Genet. 68:147–151, 1997 © 1997 Wiley-Liss, Inc.     

FISH analysis in Prader-Willi and Angelman syndrome patients

We report on a combined high resolution cytogenetic and fluorescent in situ hybridization study (FISH) on 15 Prader-Willi syndrome (PWS) and 14 Angelman syndrome (AS) patients. High resolution banding showed a microdeletion in the 15q11-q13 region in 7 out of 15 PWS patients, and FISH analysis of the D15S11 and SNRPN cosmids demonstrated absence of the critical region in three additional cases. Likewise 8 out of 14 AS patients were found to be deleted with FISH, using the GABRB3 specific cosmid, whereas only 4 of them had a cytogenetically detectable deletion. © 1995 Wiley-Liss, Inc.     

Fat distribution in overweight patients with Ullrich-Turner syndrome

Overweight patients with Ullrich-Turner syndrome (UTS) and control children with similar weight/height and indices of overweight were studied to clarify the unique fat distribution in the syndrome. Triceps and ulnar skinfold thickness (SFT) in UTS patients was significantly less than that of obese children without the syndrome. The means of SFT at the subscapular and paraumbilical regions were also less in the patients than control girls, though significance was not documented. Thus, increased body weight in UTS children seems mainly to be due to excess of adipose tissue, not in the limbs but on the trunk, and/or due to the increment of lean body mass.     

Relatively longer hand in patients with Ullrich-Turner syndrome

We analyzed the total hand length (HL) and length of noncarpal bones (NCL) in 50 Japanese patients with Ullrich-Turner syndrome (UTS) and in 443 other patients with short stature used as controls. In each patient group we calculated relative HL (RHL= HL/height) and relative NCL (RNCL= NCL/height). UTS patients had significantly greater RHL than controls. The greater RHL in UTS patients is mainly due to their longer, short tubular bones. The RHL is not affected by ages and karyotypes of UTS patients or growth hormone treatments given to them. We conclude that relatively longer hands are a common manifestation of UTS and that this parameter is useful for the diagnosis of the syndrome among short females, who usually need chromosome analysis.     

Psychosocial aspects of patients with the Ullrich-Turner syndrome

Family and social background and psychosexual and psychomotor development were studied on 24 patients with the Ullrich-Turner syndrome ranging in age from 9 months to 18 years. Infancy is often characterized by mild feeding problems and sleeping difficulty. Early motor development is normal or mildly delayed but acquisition of speech and toilet training appear to be appropriate for age. Social skills are excellent. Psychopathology is not a significant aspect of the Ullrich-Turner syndrome. Psychological tests support the findings of verbal IQ exceeding performance IQ, space-form perceptual deficits, and visual motor deficit. No difference of intelligence was found between apparently nonmosaic and mosaic types of Ullrich-Turner syndrome. The degree of parental understanding and appropriate attitudes toward the patient and the syndrome largely depend on good family relationships, the socieconomic level of the family, parents' personalities and their ability to cope with the implications of the syndrome, and appropriate physician's counseling.     

Mosaic Down syndrome in a patient with low-level mosaicism detected by microarray

Down syndrome (DS) is the most common aneuploidy in liveborns with an estimated frequency of 1 in 650-1,000 births. Approximately 1-2% of all live-born DS individuals have mosaicism. The correlation between the percentage of mosaicism and the severity of the phenotype in mosaic trisomy 21 has been determined in previous studies. Patients with low percent of trisomy 21 have less phenotypic manifestations, higher IQs, and better overall survival. We report on a 1-day-old baby girl with subtle features of DS and low-level trisomy 21 mosaicism (8-13% in lymphocytes, 31% in buccal cells) with normal high resolution chromosome analysis. The aneuploidy was detected by 6.0 SNP microarray and confirmed by fluorescent in situ hybridization (FISH). Further studies to detect mosaicism are recommended from blood (using interphase FISH) or other tissues in the evaluation of a child with features of DS and a normal blood metaphase karyotype. SNP microarray technology appears to be a useful adjunct, being able to detect low-level mosaicism in these cases.     

Ullrich-Turner syndrome in monozygotic twins

We report on the Ullrich-Turner syndrome in monozygotic twin sisters. The first twin had the syndrome with a 45,X chromosome constitution. The second twin had only minor manifestations of the syndrome with 46,XX/45,X mosaicism. The literature on the Ullrich-Turner syndrome in twins is reviewed.     

Recognizing Ullrich-Turner syndrome by discriminant analysis of craniofacial structure

In the present paper, we propose an efficient strategy for identification of craniofacial anomalies in the Ullrich-Turner syndrome (UTS). Standardized portrait- and profile-photographs were taken of 21 UTS patients with X-monosomy and 21 normal females. Twenty-seven craniofacial parameters were read from the photographs. The data were analyzed by discriminant analysis, a multivariate statistical method. The result was a function represented by a linear combination of all those craniofacial parameters which best separate the two groups. The discriminant function was applied to 15 additional patients with UTS of various cytogenetic types. All 15 patients were classified correctly. The technique facilitates syndrome-recognition and is a contribution toward the study of karyotype-phenotype relations. © 1996 Wiley-Liss, Inc.     

Evidence of a normal mean telomere fragment length in patients with Ullrich-Turner syndrome.

Clinical and epidemiological studies suggest that premature ageing and increased morbidity and mortality is present in Ullrich-Turner syndrome. We studied telomere restriction fragment length (TRFL) in 30 women with Ullrich-Turner syndrome and 30 age-matched control women. All Turner women had the 45,X karyotype verified by karyotyping. We found no difference in the mean TRFL in the young age group (TS: 7011+/-521 vs C: 7285+/-917 bp, P = 0.3), or in the older age group (TS: 7357+/-573 vs C: 7221+/-621 bp, P = 0.6). In conclusion, our data suggest that Ullrich-Turner syndrome is not associated with excessive telomere loss, at least when studied in peripheral blood leucocytes, and thus quite different from other premature ageing syndromes.     

FISH analysis of terminal deletions in patients diagnosed with cri-du-chat syndrome

Most patients with cri-du-chat syndrome have a de novo deletion of the short arm of chromosome 5 (5p). In order to perform extensive phenotype-genotype correlation studies, a relatively easy method for the precise determination of the extent of a patient's deletion is essential. Towards this purpose, a set of minimally overlapping YAC clones that span 5p was identified. A BAC that maps at or near the 5p telomere was also used. A total of 110 patients with previously determined de novo terminal deletions by standard cytogenetic approaches were reanalyzed using the YAC clones and fluorescent in situ hybridization (FISH). Of the 110 samples, 4 patients were determined to have interstitial deletions, 1 patient had an unbalanced translocation, and no deletion could be detected in 2 patients. The FISH results in the 7 patients affect the clinical prognosis for some of these patients. These results demonstrate the need for supplementing standard cytogenetics with FISH analysis when an abnormal karyotype is detected.     

Frequency of Y chromosomal material in Mexican patients with Ullrich-Turner syndrome

Cytogenetic studies have shown that 40–60% of patients with Ullrich-Turner syndrome (UTS) are 45,X, whereas the rest have structural aberrations of the X chromosome or mosaicism with a second cell line containing a structurally normal or abnormal X or Y chromosome. However, molecular analysis has demonstrated a higher proportion of mosaicism, and studies in different populations have shown an extremely variable frequency of Y mosaicism of 0–61%. We used Southern blot analysis and polymerase chain reaction (PCR) to detect the presence of Ycen, ZFY, SRY, and Yqh in 50 Mexican patients with UTS and different karyotypes to determine the origin of marker chromosomes and the presence of Y sequences. Our results indicated the origin of the marker chromosome in 1 patient and detected the presence of Y sequences in 4 45,X patients. Taken together, we found a 12% incidence of Y sequences in individuals with UTS. The amount of Y-derived material was variable, making the correlation between phenotype and molecular data difficult. Only 1 patient had a gonadoblastoma. We discuss the presence of Y chromosomes or Y sequences in patients with UTS and compare our frequency with that previously reported. Am. J. Med. Genet. 76:120–124, 1998. © 1998 Wiley-Liss, Inc.     

Long-term follow-up in females with Ullrich-Turner syndrome

The infrequent band of 3.2-kb of the apolipoprotein A-I/C-III polymorphic region has previously been found to be associated with coronary artery disease and with hypertriglyceridaemia in Caucasians. We studied the apolipoprotein A-I/C-III gene cluster polymorphism in 97 Saudi Arabians in relation to coronary artery disease. Patients were categorized as being with or without coronary artery disease on the basis of coronary angiography. Genomic blotting of Sac I-digested chromosomal DNA with the use of an apolipoprotein A-I gene probe revealed 4.2-kb and 3.2-kb hybridization bands. The genotype frequency of patients with and without coronary artery disease was not different. The frequency of the 3.2-kb allele occurred in 16% of patients with coronary artery disease and in 21% of patients with normal coronary arteries (non-significant). In conclusion, we have not been able to confirm in Saudi Arabians associations previously reported in Caucasians of the 3.2-kb band and coronary artery disease.     

Short bi-iliac distance in prenatal Ullrich-Turner syndrome

The purpose of the present study is to evaluate the bi-iliac distance and the caudo-cranial position of the iliac bones in Ullrich-Turner syndrome (UTS) fetuses compared to recently published standards for normal fetuses. Whole-body radiographs in antero-posterior projections of 24 UTS fetuses (crown-rump lengths, 106-220 mm) were included in the study. From each radiograph, two horizontal (outer and inner bi-iliac distances) and two vertical (caudo-cranial) positions compared to the vertebral column were measured to estimate the position of the iliac bones. The present investigation revealed that both the outer and inner bi-iliac distances were significantly shorter in UTS fetuses than in normal fetuses. We also found that for the inner bi-iliac distance, the growth rate in UTS fetuses was significantly lower than in normal fetuses. This finding suggests not only a lesser growth but also a different growth pattern compared to normal fetuses. Regarding the caudo-cranial position of the iliac bones compared to the lower vertebral column, there was no significant difference for the lower caudo-cranial position, but the upper caudo-cranial position was significantly lower in UTS fetuses than in normal fetuses. The bi-iliac distance and the iliac bone position have not previously been described in Ullrich-Turner syndrome fetuses.