A familial "balanced" 3;9 translocation with cryptic 8q insertion leading to deletion and duplication of 9p23 loci in siblings.

A child with phenotypic features of the 9p- syndrome, including metopic craniosynostosis, small ears, abdominal wall defect, and mental retardation, as well as hypopigmentation, was found to have a cytogenetically balanced 3;9 translocation, with breakpoints at 3p11 and 9p23, inherited from his phenotypically normal father. Molecular analysis showed heterozygous deletion of the TYRP (tyrosinase-related protein) locus, as well as loci D9S157, D9S274, D9S268, and D9S267, in the child but in neither parent. FISH analysis of the proband''s father indicated that loci deleted in his son, including TYRP, were present on neither the der(3) nor the der(9) translocation products but had been inserted into the long arm of chromosome 8. Therefore, the apparent deletion of these loci in the proband was the result of meiotic segregation of the father''s 3;9 translocation chromosomes together with his normal chromosome 8 (not bearing the insertion from 9p23). Neither the deletion of these 9p23 loci from the translocation chromosomes nor their insertion into 8q was detectable by standard chromosome banding techniques. The proband''s sister exhibited speech delay, mild facial dysmorphism, and renal malformation, and her karyotype was 46,XX. Molecular analysis showed that she had inherited normal chromosomes 3 and 9, as well as the chromosome 8 with the insertion of 9p23 material, from her father.(ABSTRACT TRUNCATED AT 250 WORDS)     

The XXXXY Chromosome Anomaly: Report of Three New Cases and Review of 30 Cases from the Literature

The majority of abnormal sex chromosome complexes in the male have been considered to be variants of Klinefelter''s syndrome but an exception should probably be made in the case of the XXXXY individual who has distinctive phenotypic features. Clinical, radiological and cytological data on three new cases of XXXXY syndrome are presented and 30 cases from the literature are reviewed. In many cases the published clinical and radiological data were supplemented and re-evaluated. Mental retardation, usually severe, was present in all cases. Typical facies was observed in many; clinodactyly of the fifth finger was seen in nearly all.Radiological examination revealed abnormalities in the elbows and wrists in all the 19 personally evaluated cases, and other skeletal anomalies were very frequent. Cryptorchism is very common and absence of Leydig''s cells may differentiate the XXXXY chromosome anomaly from polysomic variants of Klinefelter''s syndrome. The relationship of this syndrome to Klinefelter''s syndrome and to Down''s syndrome is discussed.     

Human Chromosomes: II. Preparation,Analysis and Diagnostic Implications of Abnormalities

This presentation is designed to show the diagnostic implications of chromosomal abnormalities, and how in some cases chromosome analysis may be helpful in prognosis and counselling. Most males with Klinefelter''s syndrome have chromatinpositive nuclei and an abnormal sex chromosome complex (usually XXY). In Turner''s syndrome many such females have chromatin-negative nuclei and a deficient sex chromosome complex (usually XO). Multiple-X females have unusual chromatin patterns (two or three masses of sex chromatin) and abnormal sex chromosome complexes (XXX, XXXX, XO/XXX, etc.). One of the parents of a translocation mongol may carry a translocation chromosome and pass it to future children. Cytogenetic data are therefore essential for genetic counselling. Mosaic and deletion mongols may show incomplete manifestations of mongolism, which make diagnosis difficult; chromosome analysis is helpful in diagnosis, and in prognosis concerning mental development. Abnormal chromosome numbers result from non-disjunction, usually during gametogenesis. The error may occur, however, during cleavage, producing cells with different chromosome complements (mosaicism). Visible structural abnormalities of chromosomes result from deletions or translocations of chromosome fragments.     

Familial cancer on a Scottish island.

When the causes of death were determined in 18 relations of a child with Fanconi''s anaemia 10 deaths were found to be due to carcinoma of various organs. Cases of osteogenic sarcoma, leukaemia, and Marfan''s syndrome were also discovered among relatives. The family was from a remote community in the hebrides and there was considerable intermarriage. Suggestive evidence of heterozygosity was found by chromosome analysis.     

A Service for Human Chromosome Studies in Saskatchewan

A service has been developed in Saskatchewan to make available the results of studies of human chromosomes, the material being forwarded to the laboratory by local transport facilities. During the first year of this project chromosome studies were requested for five doubtful cases of trisomy-21 (two were found to be normal) and for 20 definite cases of trisomy-21 in young patients (two had translocations but the parents of both these children had normal karyotypes). Eleven confirmed cases of Turner''s syndrome, two of Klinefelter''s syndrome, and one each of the D and E syndromes were also studied. The largest group for which studies were requested comprised 36 patients with mental retardation; only two abnormal karyotypes were encountered in this group.     

Waardenburg's Syndrome and Heterochromia Iridum in a Deaf School Population

Waardenburg''s syndrome consists of lateral displacement of the inner canthi of the eyes (dystopia canthorum), a broad nasal root and confluent eyebrows, heterochromia iridum, a white forelock and congenital deafness. The syndrome is inherited as a dominant, but affected individuals do not necessarily have all of the characteristics cited.Five hundred and fourteen pupils at a school for the deaf were screened for features of this syndrome. Three cases were discovered. Eleven other deaf children were found to have heterochromia iridum and two more had white forelocks. The interocular dimensions of the remaining children were recorded as standards by which to judge the presence of dystopia canthorum. The results of chromosomal analysis in two cases with Waardenburg''s syndrome were normal.The findings provide further evidence that Waardenburg''s syndrome is a distinct entity and call in question Mackenzie''s concept of a comprehensive “first arch syndrome”.     

Chromosome studies in a neonatal population

The results of chromosome studies on 6809 consecutive newborn infants are presented. One hundred and one (1.48%) were heterozygous for a marker chromosome, the significance of which is not at present clear. Twenty-two infants (0.32%) had a major chromosome abnormality. Only six of these infants (0.09%) had a clinically recognizable abnormal phenotype (Down''s syndrome). The occult chromosome abnormalities included five sex chromosome abnormalities (one 47,XYY; two 47,XXY; two 47,XXX) and 11 balanced translocations. Seven of these were t(DqDq) and four were reciprocal translocations. The results of the present survey are combined with four other similar neonatal surveys in which a total of 23,328 newborns have been screened. Of these, 117 (0.5%; range 0.65-0.32%) had major chromosome abnormalities. The majority of these (72.7%) would not have been detected at birth without chromosome studies, an important fact in the context of prenatal diagnosis of chromosome disease and the early ascertainment of high-risk families.     

Effect of an oral serotonin antagonist,ketanserin, on plasma ACTH concentrations in Nelson's syndrome.

A study was performed to see whether ketanserin, a serotonin antagonist, would reduce the raised concentrations of adrenocorticotrophic hormone (ACTH) in patients with Nelson''s syndrome. Six patients who had undergone bilateral adrenalectomy for Cushing''s disease and who had Nelson''s syndrome were given ketanserin 40 mg twice daily and placebo, for at least two months each, in a double blind crossover study. Ketanserin had no effect on ACTH concentrations. In healthy people serotonin seems to have a stimulatory role in the regulation of ACTH secretion, and the effect of ketanserin in reducing the ACTH response to hypoglycaemia suggested that it might prove useful in Nelson''s syndrome. These results show that it is not indicated in these patients.     

Bone Marrow-Derived Stem Cell (BMDSC) Transplantation Improves Fertility in a Murine Model of Asherman's Syndrome

Asherman''s Syndrome is characterized by intrauterine adhesions or fibrosis resulting as a consequence of damage to the basal layer of endometrium and is associated with infertility due to loss of normal endometrium. We have previously shown that bone marrow derived stem cells (BMDSCs) engraft the endometrium in mice and humans and Ischemia/reperfusion injury of uterus promoted BMDSCs migration to the endometrium; however, the role of BMDSCs in Asherman''s syndrome has not been characterized. Here a murine model of Asherman''s syndrome was created by traumatizing the uterus. We evaluate stem cell recruitment and pregnancy after BMDSCs transplantation in a model of Asherman''s syndrome. In the Asheman''s syndrome model, after BMDSC transplant, the Y chromosome bearing CD45-cells represented less than 0.1% of total endometrial cells. Twice the number of Y+CD45- cells was identified in the damaged uterus compared to the uninjured controls. There was no significant difference between the damaged and undamaged uterine horns in mice that received injury to a single horn. In the BMDSC transplant group, 9 of the 10 mice conceived, while only 3 of 10 in the non-transplanted group conceived (Chi-Square p = 0.0225); all mice in an uninjured control group conceived. The time to conception and mean litter size were not different between groups. Taken together, BMDSCs are recruited to endometrium in response to injury. Fertility improves after BMDSC transplant in Asherman''s Syndrome mice, demonstrating a functional role for these cells in uterine repair. BMDSC transplantation is a potential novel treatment for Asherman''s Syndrome and may also be useful to prevent Asherman''s syndrome after uterine injury.     

The Sex Chromosomes in Evolution and in Medicine

The recent emergence of human cytogenetics has a firm foundation in studies on other forms of life. Historical highlights are Mendel''s studies on the garden pea (published in 1865 but lost in an obscure journal until 1900); formulation of cytogenic postulates by Sutton and Boveri (1902-1903); Bridges'' discovery of chromosome abnormalities in Drosophila (1916), followed by numerous similar studies in plants; and demonstration of the chromosomal basis of the syndromes of Down, Klinefelter and Turner in man (1959).The sex chromosomes (XX and XY) evolved from a pair of undifferentiated autosomes of a premammalian ancestor, the X chromosome changing less than the Y as they evolved. Eleven numerical abnormalities of the sex chromosomes are known in man, and knowledge of their effects on development is accumulating. The abnormal complexes range in size from the XO error of Turner''s syndrome to the XXXXY error of a variant of Klinefelter''s syndrome.     

Five cases of cyclical Cushing's syndrome.

Reported cases of cyclical Cushing''s syndrome are rare. Of 14 successive patients with Cushing''s syndrome nine collected sequential urine samples for the estimation of cortisol:creatinine ratio. Five had cyclical Cushing''s syndrome while two had considerable variation in urinary cortisol excretion without a cyclical pattern being established. Two of the five patients with a cyclical syndrome had paradoxical responses to dexamethasone. In only one patient with a cyclical pattern did the cortisol:creatinine ratio fall after treatment with bromocriptine or cyproheptadine, or both. The high incidence of the cyclical form of Cushing''s syndrome has important clinical implications. A high index of suspicion of the syndrome is required in patients with symptoms or signs of Cushing''s syndrome but with normal cortisol values, in patients with fluctuating cortisol values, and in patients with anomalous responses to dexamethasone. Because of possible variations in steroidogenesis the results of drug studies in Cushing''s syndrome must be interpreted cautiously.     

De Lange Syndrome: Report of 20 Cases

Typus Degenerativus Amstelodamensis or Amsterdam dwarfism, a syndrome of unknown etiology characterized by mental retardation, a distinctive face, characteristic hands and feet, defective growth and other minor malformations, was first described by Cornelia de Lange in 1933. Approximately 69 cases, including nine autopsies, have been reported in the literature. In this paper we present a further 20, with illustrations of the syndrome from infancy to puberty (including de Lange''s original three cases). The historical, physical, laboratory and radiographic findings of de Lange''s three patients and our 20 are tabulated. Autopsy findings in one of our patients are reported and the literature is briefly reviewed.Although some observers have recently reported chromosome abnormalities in de Lange''s syndrome, we feel that the diagnosis is made from the history and physical examination and that there are no definitive laboratory aids which can confirm the diagnosis. Chromosome studies in all 20 of our patients were normal and the genetic implications are discussed.     

Predictive value of SS-B precipitating antibodies in Sjo?gren's syndrome.

As part of a screening programme several patients were identified with antibodies to the nuclear antigen SS-B. Fifteen were examined and 11 found to have Sjögren''s syndrome, though this had not been suspected by most of the referring physicians. In contrast, among a group of 17 patients with overt Sjögren''s syndrome, most of whom also had rheumatoid arthritis, only one had antibodies to SS-B. Patients presenting with polyarthralgia found to be SS-B positive may be likely to develop Sjögren''s syndrome but unlikely to develop rheumatoid arthritis. The detection of SS-B antibodies may antedate clinical evidence of Sjögren''s syndrome by months or even years. These results emphasise the clinical heterogeneity of Sjögren''s syndrome.     

Was Young's syndrome caused by exposure to mercury in childhood?

OBJECTIVE--To determine whether the incidence of chronic sinusitis, bronchitis, or bronchiectasis in men with obstructive azoospermia (Young''s syndrome) has fallen in men born after 1955 when calomel (mercurous chloride) was removed from teething powders and worm medication in the United Kingdom. DESIGN--A prospective study of aetiological factors in subfertile men with epididymal obstruction operated on between 1975 and 1993. SETTING--Central London. SUBJECTS--274 men with obstructive azoospermia undergoing epididymovasostomy; date of birth was recorded and illness in childhood, persistent nasal or respiratory symptoms, and previous urinary or genital infection were asked about. MAIN OUTCOME MEASURE--Site of epididymal block and association with possible aetiological factors, related to date of birth. RESULTS--146 men had hold up in the head of the epididymis (capital blocks): 119 (82%) had Young''s syndrome, and 11 gave a definite history of pink disease (mercury intoxication) in childhood. 128 had obstruction lower down towards the tail of the epididymis (caudal blocks): 64 (50%) had a history of genital or urinary infection, and only three had Young''s syndrome; none had had pink disease. The incidence of Young''s syndrome fell significantly from 114 (50%) of 227 men born up to 1955 to eight (17%) of 47 men born since then. CONCLUSIONS--The decline in incidence of Young''s syndrome in those born after 1955 is similar to that observed with pink disease, suggesting that both conditions may have had a similar aetiology--mercury intoxication.     

Prenatal and postnatal prevalence of Turner's syndrome: a registry study.

OBJECTIVE--To study prevalence of Turner''s syndrome in Denmark and to assess validity of prenatal diagnosis. DESIGN--Study of data on prenatal and postnatal Turner''s syndrome in Danish Cytogenetic Central Register. SUBJECTS--All registered Turner''s syndrome karyotypes (100 prenatal cases and 215 postnatal cases) during 1970-93. MAIN OUTCOME MEASURES--Prevalence of Turner''s syndrome karyotypes among prenatally tested fetuses and Turner''s syndrome among liveborn infants. RESULTS--Among infant girls, prevalence of Turner''s syndrome was 32/100,000. Among female fetuses tested by amniocentesis, prevalence of Turner''s syndrome karyotypes was 176/100,000 (relative risk of syndrome, 6.74 compared with prevalence among untested pregnancies). Among female fetuses tested by chorion villus sampling, prevalence of syndrome karyotypes was 392/100,000 (relative risk, 16.8). We excluded prenatal tests referred because of results of ultrasound scanning: among fetuses tested by amniocentesis revised relative risk was 5.68, while revised relative risk among fetuses tested by chorion villus sampling was 13.3. For 29 fetuses with prenatal diagnosis of possible Turner''s syndrome, pregnancy was allowed to continue and 24 children were live born. Thirteen of these children were karyotyped postnatally, and diagnosis of Turner''s syndrome had to be revised for eight, seven being normal girls and one boy. This gives tentative predictive value of amniocentesis in diagnosing Turner''s syndrome of between 21% and 67%. There was no significant relation between mother''s age and risk of Turner''s syndrome. CONCLUSIONS--Discrepancy between prenatal and postnatal prevalence of Turner''s syndrome challenges specificity of prenatal examination in diagnosing Turner''s syndrome.     

Chromosome Analysis before Birth and its Value in Genetic Counselling

Chromosome analysis of amniotic cell cultures was achieved in 29 out of 30 consecutive patients who were referred for genetic counselling during pregnancy. Amniocentesis was performed without any apparent untoward maternal or fetal complication. The only pregnancy terminated was that of a carrier of X-linked granulomatous disease, in whom the amniotic cells showed that the fetus was male and also had Down''s syndrome (trisomy G). Chromosome analysis in the remaining 28 patients showed normal karyotypes. The interval between amniocentesis and a definitive karyotype varied from 7 to 31 (average 18·4) days.The reliability of chromosome analysis from amniotic cell culture and of fetal sex determination by means of the sex chromatin and Y-fluorescence techniques was studied further in amniotic fluid from cases of therapeutic abortion and of rhesus incompatibility. The fetal sex was correctly determined in all cases. It is concluded that antenatal diagnosis of genetic disease by amniocentesis now permits a more practical approach to genetic counselling.     

Sj?rgren's syndrome treated with bromhexine: a randomised clinical study.

Existing treatment for Sjögren''s syndrome is unsatisfactory, and uncontrolled observations have suggested that bromhexine may be effective. Twenty-nine patients with Sjögren''s syndrome were therefore assigned to two randomised double-blind crossover trials with bromhexine and placebo, each comprising two two-week periods. In the first trial bromhexine 24 mg/day was given by mouth; in the second the dose was increased to 48 mg/day. After each treatment period the Schirmer test response, break-up time, Bijsterveld score, and the time taken for the patient to eat a dry biscuit were recorded, as well as the patient''s estimate of moistness in the eyes and mouth. In the second (higher-dose) trial values on the Schirmer test were significantly higher after bromhexine than after placebo and the break-up time was also increased after bromhexine, which suggested that the drug has a dose-dependent effect on lacrimal gland secretion in Sjögren''s syndrome. It had no effect on salivary gland function. Bromhexine is therefore valuable in the treatment of Sjögren''s syndrome.     

Rapid detection of Down's syndrome using quantitative real-time PCR (qPCR) targeting segmental duplications on chromosomes 21 and 11

Objective

Development of a qPCR test for the detection of trisomy 21 using segmental duplications.

Methods

Segmental duplications in the TTC3 gene on chromosome 21 and the KDM2A gene on chromosome 11 were selected as molecular markers for the diagnostic qPCR assay. A set of consensus primers selected from the conserved regions of these segmental duplications were used to amplify internal diverse sequences that were detected and quantified with different probes labeled with distinct fluorescence. The copy numbers of these two fragments were determined based on the ΔCq values of qPCR. The results of qPCR for prenatal and neonatal screening of Down's syndrome were compared with the conventional karyotype analysis by testing 82 normal individuals and 50 subjects with Down's syndrome.

Results

The ΔCq values of segmental duplications on chr21 and 11 ranged between 0.33 and 0.75 in normal individuals, and between 0.91 and 1.18 in subjects with Down's syndrome. The ΔCq values of these two segmental duplications clearly discriminated Down's syndrome from normal individuals (P < 0.001). Furthermore, the qPCR results were consistent with karyotype analysis.

Conclusion

Our qPCR can be used for rapid prenatal and neonatal screening of Down's syndrome.