An active ring X and haploinsufficiency of SHOX contribute to short stature,congenital anomalies,and developmental delay in a female

We report on a female infant with short stature and mesomelic limb shortening, multiple congenital abnormalities, developmental delay, and Rieger anomaly. Cytogenetic analysis revealed a complex rearrangement of the sex chromosomes in this patient. In addition to a normal X chromosome, a derivative Y [der(Y)] chromosome composed of X and Y material and a ring X [r(X)] were present. Consistent with the fact that this infant had normal female genitalia, the SRY gene was not detected in the Y chromosome portion of the der(Y). By fluorescence in situ hybridization (FISH), XIST was present on the normal X and the r(X), but not on the der(Y). The normal X was late replicating (inactive) and the r(X) early replicating (active) in all lymphocyte metaphases examined. As the X chromosome material on the der(Y) cannot be inactivated, the unusual skew of activation toward the r(X) presumably resulted in the least amount of functional disomy of X‐linked genes in the cells of this patient. Deletion of one copy of the SHOX gene was detected in this patient. Haploinsufficiency of this gene is known to be correlated with short stature and mesomelic limb shortening. © 2002 Wiley‐Liss, Inc.     

X‐chromosome duplications in males with mental retardation: pathogenic or benign variants?

Gijsbers ACJ, den Hollander NS, Helderman‐van de Enden ATJM, Schuurs‐Hoeijmakers JHM, Vijfhuizen L, Bijlsma EK, van Haeringen A, Hansson KBM, Bakker E, Breuning MH, Ruivenkamp CAL. X‐chromosome duplications in males with mental retardation: pathogenic or benign variants? Studies to identify copy number variants (CNVs) on the X‐chromosome have revealed novel genes important in the causation of X‐linked mental retardation (XLMR). Still, for many CNVs it is unclear whether they are associated with disease or are benign variants. We describe six different CNVs on the X‐chromosome in five male patients with mental retardation that were identified by conventional karyotyping and single nucleotide polymorphism array analysis. One deletion and five duplications ranging in size from 325 kb to 12.5 Mb were observed. Five CNVs were maternally inherited and one occurred de novo. We discuss the involvement of potential candidate genes and focus on the complexity of X‐chromosomal duplications in males inherited from healthy mothers with different X‐inactivation patterns. Based on size and/or the presence of XLMR genes we were able to classify CNVs as pathogenic in two patients. However, it remains difficult to decide if the CNVs in the other three patients are pathogenic or benign.     

Noninactivation of a portion of Xq28 in a balanced X-autosome translocation

We present a balanced translocation (X;9) (q28;q21) in which the normal X chromosome is preferentially active. The derivative X chromosome is inactive in 93% of fibroblasts, but the X portion translocated onto chromosome 9 is not inactivated, as apparent from DNA methylation and chromosome replication patterns. Consequently, the patient is functionally disomic for the part of Xq28 distal to the locus LICAM.     

Reduced fertility in women with X chromosome abnormality

One patient with the karyotype 46, X, del(X)(p 11.23) and three patients with 45, X/46, XX mosaicism were fertile or showed normal ovarian function. The patient with the Xp deletion has two daughters with the same chromosomal abnormality. A study of these patients and of others reported in the literature indicated that fertility of patients with X chromosomal abnormality has a markedly shorter duration than fertility of the normal female. Menopause commonly occurred during the second and third decade of age. We suggest that such fertility is related to the rate of germ cell attrition and hypothesize that germ cell attrition in the human female is influenced by genes of multiple effect which are carried on the X chromosome. The more of these genes which are present the slower the rate of germ cell attrition.     

45X/46X,r(X) with syndactyly and severe mental retardation

Two white females, age 2 1/2 and 33 years, respectively, were investigated because of severe mental retardation associated with neurologic abnormalities, coarse face, and soft tissue syndactyly involving upper and lower limbs. Each had cytogenetic findings of a mosaic variant of Ullrich-Turner syndrome with X ring chromosome in peripheral lymphocyte and skin fibroblasts. Early X replication occurred in one-third of the X ring chromosomes; there was no evidence for X-autosome translocation involving either X and an autosomal duplication; results of studies for fragility of the X chromosomes were unremarkable. In situ hybridization with an X centromere probe was positive for the ring. To our knowledge, the unusual constellation of cytogenetic, physical, and mental findings seen in these 2 individuals has not been reported previously.     

Generalized histiocytosis X in the elderly: a light and electron microscope and monoclonal antibody study

Two elderly female patients are described with generalized histiocytosis X (Letterer-Siwe disease). In each case, a definitive diagnosis was not established until ultrastructural and immunoperoxidase investigations had been performed. The histopathological findings in skin biopsies from each patient were similar. Light microscopy demonstrated a bandlike epidermotrophic cellular infiltrate which included large atypical cells (histiocytosis X cells). Electron microscopy showed that these cells contained Birbeck granules. Monoclonal antibody studies demonstrated the presence of T6, T4 and HLA-DR surface antigens. Lysozyme and alpha-I-antitrypsin were absent from the cells. The associated cellular infiltrate included T4 and T8 positive lymphocytes. It is possible that more cases of generalized histiocytosis X in adults will be identified with the increasing use of specialized histopathological techniques and that the disease is more common than currently believed.     

Preaxial acrofacial dysostosis (Nager syndrome) associated with an inherited and apparently balanced X;9 translocation: Prenatal and postnatal late replication studies

We report on an infant with preaxial acrofacial dysostosis (Nager syndrome) who was diagnosed prenatally as having an apparently balanced X/autosome translocation [46,X,t(X;9)(p22.1;q32)mat] inherited from a previously diagnosed mosaic translocation carrier mother [46,XX/46,X,t(X;9)(p22.1;q32)]. Replication studies on amniocytes showed the normal X chromosome to be late replicating while the same studies repeated on the infant's lymphocytes showed the translocated X chromosome to be late replicating in most cells. Late replication studies of the mother's lymphocytes demonstrated that the normal X chromosome was late replicating in most cells. The presence of Nager syndrome in this infant may be the result of critical break-points and/or position effects on chromosome 9, inducing expression of a gene responsible for the syndrome. © 1993 Wiley-Liss, Inc.     

Familial occurrence of isodicentric X chromosomes with different breakpoints

We report two cases of an idic (X) chromosome found in relatives with Turner's syndrome. A 21-year-old female revealed a non-mosaic form of X isochromosome of the long arms with two C-band regions, i.e. dic(X)(qter----cen----p11::p11----cen----qter). Her 46-year-old aunt with Turner's syndrome had an X chromosome with long arm breakpoints at site q21 and chromosomal mosaicism, i.e. 45,X/46,X, dic(X)(pter----q21::q21----pter)(78/22). The relative rarity of reports about familial Turner's syndrome with structural abnormality may suggest a coincidence. However, it is difficult to exclude familial predisposition to X isochromosome formation in this family.     

Germline mosaicism at the fragile X locus

We have identified a fragile X syndrome pedigree where the disorder is associated with a molecular deletion. The deletion was present in the DNA of 2 sons but was absent in the mother's somatic cell (lymphocyte) DNA. The results are consistent with the deletion arising as a postzygotic event in the mother, who therefore is germinally mosaic. This finding has important implications for counseling fragile X families with deletion mutations. © 1995 Wiley-Liss, Inc.     

Functional disomies of the X chromosome influence the cell selection and hence the X inactivation pattern in females with balanced X-autosome translocations: A review of 122 cases

We reviewed 122 cases of balanced X-autosome translocations in females, with respect to the X inactivation pattern, the position of the X break point and the resulting phenotype. In 77% of the patients the translocated X chromosome was early replicating in all cells analysed. The break points in these cases were distributed all along the X chromosome. Most of these patients were either phenotypically normal or had gonadal dysgenesis, some had single gene disorders, and less than 9% had multiple congenital anomalies and/or mental retardation. In the remaining 23% of the cases the translocated X chromosome was late replicating in a proportion of cells. In these cells only one of the translocation products was reported to replicate late, while the remaining portion of the X chromosome showed the same replication pattern as the homologous part of the active, structurally normal X chromosome. The analysis of DNA methylation in one of these cases confirmed noninactivation of the translocated segment. Consequently, these cells were functionally disomic for a part of the X chromosome. The presence of disomic cells was highly prevalent in translocations with break points at Xp22 and Xq28, even though spreading of X inactivation onto the adjacent autosomal segment was noted in most of these cases. This suggests that selection against cells with a late replicating translocated X is driven predominantly by a functional disomy X, and that the efficiency of this process depends primarily on the position of the X break point, and hence the size of the noninactivated region. Since the persistence of cells with a late replicating translocated X was usually associated with mental retardation and other abnormalities, it is concluded that the outcome of the selection process against the functional disomy X is the major determinant of the clinical status in most patients with balanced X-autosome translocations.     

X linked mental retardation: a clinical guide

Mental retardation is more common in males than females in the population, assumed to be due to mutations on the X chromosome. The prevalence of the 24 genes identified to date is low and less common than expansions in FMR1, which cause Fragile X syndrome. Systematic screening of all other X linked genes in X linked families with mental retardation is currently not feasible in a clinical setting. The phenotypes of genes causing syndromic and non‐syndromic mental retardation (NLGN3, NLGN4, RPS6KA3(RSK2), OPHN1, ATRX, SLC6A8, ARX, SYN1, AGTR2, MECP2, PQBP1, SMCX, and SLC16A2) are first discussed, as these may be the focus of more targeted mutation analysis. Secondly, the relative prevalence of genes causing only non‐syndromic mental retardation (IL1RAPL1, TM4SF2, ZNF41, FTSJ1, DLG3, FACL4, PAK3, ARHGEF6, FMR2, and GDI) is summarised. Thirdly, the problem of recurrence risk where a molecular genetics diagnosis has not been made and what proportion of the male excess of mental retardation is due to monogenic disorders of the X chromosome are discussed.     

Phenotypic variation in Melnick‐Needles syndrome is not reflected in X inactivation patterns from blood or buccal smear

Melnick‐Needles syndrome is a rare putative X‐linked dominant bone dysplasia. The patients have short stature, characteristic facial features, and a normal intelligence. The skeletal dysplasia includes S‐shaped curvature of tubular bones and sclerosis of the base of the skull. The phenotype of affected individuals varies, even within families. This could be related to X chromosome inactivation. We report here on a very mildly affected mother and her two severely affected daughters with characteristic features of Melnick‐Needles syndrome. In addition, the two daughters had very similar pigmented nevi on their back. X chromosome inactivation analysis of blood DNA revealed a skewed X inactivation pattern in all three affected females, with the normal X chromosome as the predominating active X chromosome. The X inactivation pattern was similar in buccal smear and blood DNA in the mother and one of the daughters, whereas the other daughter had a skewed pattern in blood only. X chromosome inactivation in blood and buccal smear DNA therefore does not explain the phenotypic variation in this family. The skewed X chromosome inactivation is in agreement with X‐linked inheritance of Melnick‐Needles syndrome and suggests a critical role of the Melnick‐Needles gene in hematopoietic cell proliferation. Clinical evidence indicates that Melnick‐Needles syndrome is allelic to the otopalatodigital syndromes, which have been assigned to Xq26‐28. Haplotype analysis of the X chromosomes in this family was in agreement with the localization of the gene for Melnick‐Needles syndrome to Xq25‐qtel. © 2002 Wiley‐Liss, Inc.     

Molecular and cytogenate analysis of an X/autosomal translocation: 45, X, dic(X;17)(p22.2;p13)

We present an unusual case of monosomy 17p13-pter and monosomy Xp22.2-pter due to a dicentric translocation chromosome X/17 in a female newborn with severe anomalies. The karyotype was identified as 45, X, dic(X;17)(p22.2;p13) by high resolution GTG banding in lymphocytes. R banding showed the translocational X-chromosome to be late replicating, and there was no spreading of X-inactivation onto the autosomal segment. Furthermore, it could be demonstrated by C banding that the X-centromere in the translocation chromosome was inactive.
The results of short tandem repeat (STR) typing confirmed the partial monosomy X and 17 as well as the paternal origin of the two chromosomes X and 17 which were involved in the translocation chromosome formation. The cell stage of the structural rearrangement was consistent with paternal meiosis as well as with postzygotic mitosis. The monosomy was confirmed in lymphocytes and fibroblasts, and mosaicism was not detected.     

The design of X ray equipment for use in operating rooms

X rays have been employed frequently during orthopaedic surgery. Recent developments in epuipment designed for use in the operating room have increased demand for X ray apparatus as a valuable aid for other kinds of surgery. Alongside the growing demand for both preoperative fluoroscopic examinations and the production of radiographs while the patient is in the operating room, there is an increase in demand for more advanced X ray facilities. Higher X-ray power, larger field size of the image intensifier and better sterility are the main facilities asked for by the surgeon. The advantages and disadvantages of permanently installed X ray units are discussed; the advantages and disadvantages of higher electrical power and the application of large-screen image intensifiers are also examined. Some hints are given on planning X ray equipment for the operating room and on how to solve the problems associated with the processing and reading of films.     

Cytogenetic guidelines for fragile X studies tested in routine practice

Several organizations have proposed guidelines for fra(X) studies on peripheral blood lymphocytes. To evaluate these guidelines, we reviewed 1,033 consecutive specimens referred for fra(X) analysis. Each specimen was cultured with medium 199 and RPMI 1640 with 5-fluorodeoxyuridine or excess thymidine. The karyotype and expression of fra(X) were established from 20 GTL- or QFQ-banded cells and by screening of up to 130 more banded cells. We found anomalies other than fra(X) in 37 (3.6%) of the patients. We found 4% or more fra(X) cells in 38 (3.7%) cases from 36 unrelated families, including 33 (3.9%) of 850 males and 5 (2.7%) of 183 females. Another 4 females had 1 to 3% fra(X) cells. Six specimens were fra(X)-positive in only one stress system, and 32 were positive in 2 systems. To find the first 2 fra(X) cells in males, we needed to study up to 36 cells in 31 cases, 50 in one case, and 57 in another. To find the first 2 fra(X) cells in females, we needed to study up to 17 cells in 4 cases and 57 in another. A strong family history of fra(X) occurred in 5 patients, and each one was fra(X)-positive. Some manifestations of the fragile X syndrome occurred in 507 cases, 17 (3%) of which were fra(X)-positive. Abnormalities considered unlikely to be the fragile X syndrome occurred in 103 cases, 3 (3%) of which were fra(X)-positive. Use of chromosome breakage and fra(3)(p14) as quality control indicators of the fra(X) stress systems was found to be unreliable. Our findings support most of the proposed guidelines for fra(X) studies but indicate a need for modifications of others. © 1992 Wiley-Liss, Inc.     

基于CDMA 1X的远程心电监护系统的研制

近年来,远程心电监护技术不断发展,但国内现有的远程心电监护系统仍存在诸如实时性差、患者的活动范围受限、诊断的准确性和科学性差等问题.基于CDMA 1X(code division multiple access,CDMA)的远程心电监护系统充分利用CDMA 1X网络的技术和资源优势,采用便携式心电监护终端,可以随时随地监护,提高了监护的实时性、准确性和科学性.本文介绍了系统的基本框架、软硬件的设计与实现,分析论述了系统的技术特点,并对系统的应用前景作了预测.