A clinical, cytogenetic, and molecular study of 40 adults with the Prader-Willi syndrome.

A clinical, cytogenetic, and molecular study has been carried out on 40 adults with a firm diagnosis of Prader-Willi syndrome. A cytogenetically detectable deletion was observed in 58% while further subjects had a deletion which was detectable by molecular methods only, giving a total of 76%. Four cases of maternal uniparental disomy (UPD) were all female. Three of them were heterodisomic while the fourth was isodisomic. Two male probands were heterozygous at all loci tested yet did not have UPD. Although methylation studies showed that one of them had a single band using probe PW71, the other one had two bands. Psychiatric studies suggest that females with maternal UPD are indistinguishable psychologically from those with a paternal deletion in 15q11q13.     

Roberts syndrome: clinical and cytogenetic aspects

Roberts syndrome is reported in two sibs of consanguineous parents. Both infants had severe tetraphocomelia, facial clefting, and other serious malformations. In addition they were found to have an unusual cytogenetic abnormality with distortion of the normal sister chromatid relationship in many chromosomes.     

High-resolution cytogenetic studies in patients with Prader-Willi syndrome

We investigated 24 patients with Prader-Willi syndrome by the high-resolution banding technique. Their history and clinical findings were also examined in some detail. Twelve had interstitial deletion of 15q; del(15) (q11.2q13) in 11 cases and del(15) (q11.2q12) in one case. Six revealed normal karyotypes at about 500-850 bands per haploid-set level. In an additional six cases, no deletion was detected. However, we took the results as tentative, as the observed karyotypes were at the 400-bands level. During the course of this study, it was realized that a small deletion in the proximal 15q could be easily overlooked when a mitotic spread around 400-bands or less per haploid-set level was used. There was no distinct difference in the clinical features of patients with interstitial deletion and those with a normal karyotype. Two cases in the latter group lacked some of the typical features of the former group, e.g. poor fetal vigor, neonatal feeding difficulty, hypotonia, and delayed motor development.     

Turner syndrome: a cytogenetic and molecular study

Two hundred and eleven patients with a clinical diagnosis of Turner syndrome were studied. We report (i) the cytogenetic results, (ii) the frequency of cryptic mosaicism and (iii) the parental age and the parental origin of the abnormality. We scored 100 cells from blood cultures and found 97 patients to have a 45,X constitution, 15 to be 45,X/46,XX or 45,X/47,XXX mosaics, 86 to have a structurally abnormal X and 13 to have a structurally abnormal Y chromosome. Molecular methods were used to look for cryptic X and Y chromosome mosaicism in patients with a 45,X constitution. Two cryptic X but no cryptic Y mosaics were detected. In 74% of the 45,X patients the X was maternal in origin. The i(Xq)s were approximately equally likely to involve the paternal or maternal chromosome, while the majority of deletions and rings and virtually all the abnormal Y chromosomes were paternal in origin. We suggest that the preponderance of paternal errors in Turner syndrome may result from the absence of pairing along the greater part of the XY bivalent during paternal mei I, which may make the sex chromosomes particularly susceptible to both structural and non-disjunctional errors during male gametogenesis.     

Molecular and cytogenetic studies of the Prader-Willi syndrome.

Twenty-seven subjects with the Prader-Willi syndrome (PWS) were studied. Sixteen (59%) had a cytogenetic deletion involving chromosome 15q11-13. Nine were non-deletional and two patients had structural rearrangements of chromosome 15: 47,XY, + del(15)(pter----q12), var(15)(p11) and 45,XX,t(14q15q). At the DNA level, a greater proportion of patients (74%) showed loss of one chromosome 15q11-13 allele using a combination of densitometry and RFLP analysis. Deletion sizes were variable with 13 of 20 detectable both cytogenetically and with probe pML34 (D15S9). The remaining seven had microdeletions at the pML34 locus. Heterogeneity was further seen in three subjects who had cytogenetic deletions but normal DNA studies. In one patient there was evidence of a duplication at the pML34 locus. A new molecular rearrangement was identified with probe p3.21 (D15S10) in two patients and their mothers. Fifteen family studies were performed. In all 10 families where there was a molecular deletion, this was shown to have arisen de novo. DNA mapping confirmed that the paternal 15q allele was lost in three patients with PWS.     

Renal cancer: cytogenetic and molecular genetic aspects

To date, much progress has been made in the fields of cytogenetics and molecular genetics of renal tumors. The previous and recent findings have delineated the characteristics of the various tumors, particularly the cytogenetic and molecular differences that exist between papillary and nonpapillary clear cell renal cell carcinomas (RCCs). At the same time, new cytogenetic subtypes have emerged [e.g., t(X;1)] in subtypes of RCC, while in others (e.g., Wilms tumors) several new cytogenetic abnormalities and consequent molecular involvement have been found. In addition to Wilms tumor, papillary RCC, and clear-cell RCC, cytogenetic and fluorescence in situ hybridization analyses have been performed on several other tumors of the kidney, including chromophobic carcinoma, metanephric adenoma, collecting duct carcinoma, transitional cell carcinoma, congenital mesoblastic nephroma, and malignant rhabdoid tumors of the kidney. This review is therefore intended to present a concise update on the cytogenetic and molecular data on renal tumors, focusing mainly on the clinical usefulness of the findings reported in the literature.     

Prader-Willi syndrome in a brother and sister without cytogenetic or detectable molecular genetic abnormality at chromosome 15q11q13

We report on a 12-year-old boy and his 7-year-old sister with the Prader-Willi syndrome. They both had severe initial hypotonia with feeding problems and later developed an increasing appetite. Both sibs have almond-shaped eyes, triangular mouth, hypogonadism, retarded growth, and mental retardation. An older brother suffered from severe hypotonia and died at 7 days of age. The children have normal chromosomes by high-resolution technique and have inherited the same chromosomes 15 short arm polymorphisms from their parents. The family was informative for one of four DNA markers specific for the 15q11q13 region. No deletion was found using this marker. The parents were healthy and unrelated. Autosomal recessive inheritance or a paternally inherited submicroscopic deletion are possible explanations for the sib occurrence in this family. © Wiley-Liss, Inc.     

MLL amplification in myeloid malignancies: clinical,molecular, and cytogenetic findings

Structural rearrangements involving the MLL gene at 11q23 are common recurring abnormalities in de novo and therapy-related hematologic disorders. MLL rearrangement most often results from translocation or partial tandem duplication, although recent published reports suggest a different mechanism by which MLL might participate in leukemogenesis: MLL amplification. We report two patients with myeloid disorders who showed amplification of MLL at diagnosis and who, like the majority of reported cases, had an older age at onset and on aggressive clinical course. Additionally, we summarize the salient clinical, cytogenetic and molecular findings of the 29 other cases of MLL amplification that have thus far been reported.     

Intrachromosomal triplications: molecular cytogenetic and clinical studies

A newborn boy had meconium aspiration syndrome, hypospadias, a supernumerary digit on the left hand, hyperbilirubinemia, a fractured right clavicle, osteopenia, liver calcification, and mild pulmonary hyperplasia. Cytogenetic studies showed a chromosome 13 with additional material in 33% of the metaphases. The add(13) was considered to be a probable duplication of 13q12q22. The 13 paint probe hybridized to the add(13) from end to end. Fluorescence in situ hybridization (FISH) studies using retinoblastoma probe (RB)-1 that maps to 13q14 and D13S585 that maps to 13q32-q33 gave one signal for RB and three signals for D13S585. The pattern of the three signals from the 13q32q33 region and the G-banding pattern was best explained as a triplication of 13q22q33, with an inverted middle repeat resulting in tetrasomy for this segment. Mosaicism was confirmed by FISH using a D13S585 probe on a buccal smear. Three triplications detected in our laboratory were compared 13q22q33, 15q11q13, and 2q11.2q21. FISH was critical in identifying triplications 13q22q33 and 15q11q13. The hybridization pattern also indicated an inverted middle repeat. We conclude that intrachromosomal triplications may be more prevalent than previously assumed and they probably share a common mechanism in their formation. When the G-bands do not correspond exactly to a duplication or to a tandem triplication, an important consideration is that the majority of triplications have an inverted middle repeat. Triplications can be mistaken for duplications. Therefore, in assessing duplications, FISH confirmation is recommended.     

Toxocariasis: clinical aspects,epidemiology, medical ecology,and molecular aspects

Toxocariasis is caused by a series of related nematode species (ascarids) that routinely infect dogs and cats throughout the world. The eggs from these ascarids are common environmental contaminants of human habitation, due largely to the fact that many kinds of dogs and cats serve as pets, while countless others run wild throughout the streets of most urban centers. The eggs, present in dog and cat feces, become infectious within weeks after they are deposited in the local environment (e.g., sandboxes, city parks, and public beaches, etc.). Humans, particularly children, frequently ingest these eggs by accident and become infected. Infection in humans, in contrast to their definitive hosts, remains occult, often resulting in disease caused by the migrating larval stages. Visceral larva migrans (VLM) and ocular larva migrans (OLM) are two clinical manifestations that result in definable syndromes and present as serious health problems wherever they occur. Diagnosis and treatment of VLM and OLM are difficult. These issues are summarized in this review, with emphasis on the ecology of transmission and control of spread to both humans and animals through public health initiatives employing treatment of pets and environmental intervention strategies that limit the areas that dogs and cats are allowed within the confines of urban centers.     

Molecular cytogenetic aspects of hematological malignancies: clinical implications

The field of molecular cytogenetics has had a great impact on many aspects of medical and basic sciences. During the past 30 years, the application of molecular cytogenetic methodologies has resulted in remarkable advances in the field of cancer genetics and cytogenetics. These advances have led to the establishment of chromosome patterns as diagnostic and prognostic indexes in an array of acute and chronic leukemias and lymphomas, as key information in BMT, and as guides for the localization of oncogenes and tumor suppressor genes that are apparently responsible for the development of neoplastic states. With such information, the physician is in a more favorable position to devise therapy, appraise diagnosis, and plan follow-up.     

Dicentric Y chromosomes. First part: cytogenetic and molecular aspects

Dicentric Y chromosomes have been reviewed twice in 1994 by Hsu et al. and in 1995 by Tuck-Muller et al. who showed that dic(Y) are the most common Y structural abnormalities and that their influence on gonadal and somatic development is extremely variable. The prediction of their phenotypic consequences is often difficult because of the variety of genomic sequences concerned by duplications and deletions, because of the variable degrees of mosaicism (cell line 45,X in particular) and at the end, because of identification and analysis technical difficulties of the structure of the rearranged Y chromosome. The clinical specter of this cytogenetic abnormality is rather wide going from almost-normal or infertile males, to females with or without stigmas of Turner syndrome. Middle phenotypes consist of various degrees of genital ambiguities. However, clinical expression seems to be related to the genomic capital of the Y chromosome, mainly the Y genes involved in the control of the process of the determination of gonads (Yp) and spermatogenesis (Yq) as well as control of the growth and the skeletal development (Yp). Here, we report a third comprehensive review of the literature concerning dicentric Y chromosomes reported since 1994. In the light of previous reviews as well as the recent data of the genetic cartography of the Y chromosome, we try, in this first part, to determine characteristics of reported dicentric Y chromosomes as well as their chromosomal mechanics, their mitotic stability and finally their cytogenetic and molecular investigations.     

Fragile X syndrome: clinical,cytogenetic and molecular screening among autism spectrum disorder children in Indonesia

Fragile X testing is a priority in the evaluation of autism spectrum disorders (ASD) cases because identification of the FMR1 mutation leads to new treatment options. This study is focused on determining the prevalence of the FMR1 gene mutation among ASD cases in Indonesia. DSM‐IV‐TR criteria were administered to diagnose ASD; symptom severity was classified using the Childhood Autism Rating Scale. Cytogenetic analysis, polymerase chain reaction, and Southern blot for FMR1 gene analysis were carried out to confirm the diagnosis of fragile X syndrome. The fragile X site and FMR1 full mutation allele were identified in 3 out of 65 (4.6%) and 4 out of 65 (6.15%) children aged 3–17 years (57 boys and 8 girls), respectively. The Fragile X laboratory workup is essential in the evaluation of patients with ASD. Molecular analysis is most accurate, while cytogenetic documentation of the fragile X site can also be useful if molecular testing is not available.     

Neonatal diagnosis of Prader-Willi syndrome and its implications

Although Prader-Willi syndrome (PWS) patients usually first present with neonatal hypotonia and feeding difficulty, they later show hyperphagia, obesity and mental retardation. Since deletions of chromosomes 15q11-q13 are noted in most PWS patients cytogenetic analysis allows one to diagnose infants suspected of PWS with a greater certainty. We report on 5 hypotonic infants clinically suspected of PWS in the first 3 months of life, whose diagnosis was confirmed by cytogenetic studies showing monosomy of 15q11-q13. Early diagnosis of PWS can lead to prevention of obesity, but counseling of parents has been difficult. Although there are significant benefits to the early diagnosis of PWS, the cost-effectiveness and practicality of screening all hypotonic infants using high resolution cytogenetic analysis has been addressed systematically.     

Ring 22 duplication/deletion mosaicism: clinical, cytogenetic, and molecular characterisation

A patient with several features consistent with duplication of 22q11.2 (cat eye syndrome or CES) was found to be mosaic for a dicentric double ring chromosome 22 on postnatal karyotyping of peripheral blood. The initial karyotype was 46,XX,r(22)(p12q13) [46]/46,XX,dic r(22)(p12q13; p12q13)[4]. The amount of material duplicated in the dic r(22) was determined to include and extend beyond the CES critical region into 22q13.3. However, karyotyping of lymphocytes and fibroblasts, at 27 and 13 months of age respectively, showed no dic r(22) present in any of the cells examined. We suggest that the CES features in this patient, and potentially in other ring cases with CES phenotypic features, might result from a high level of mosaicism for a dic r(22) during early fetal development. Usually this unstable dic r(22) is subsequently lost from most cells.