Showing papers in "Journal of Medical Genetics in 1993"

Complications of the naevoid basal cell carcinoma syndrome: results of a population based study.

Abstract: There are many potential complications which have been reported in association with the naevoid basal cell carcinoma syndrome. We have been able to show the relative frequencies of these problems in a population based study of 84 cases in the north west of England. The major complications of basal cell carcinomas and jaw cysts occur in over 90% of patients by 40 years of age, but may both occur before 10 years of age. Less well described complications are ovarian calcification or fibroma (24%), medulloblastoma (5%), cardiac fibroma (3%), cleft palate (5%), and ophthalmic abnormalities such as squint or cataract (26%). This study more clearly defines the possible complications of the syndrome and gives clearer guidelines for counselling and screening affected and at risk persons.

DiGeorge syndrome: part of CATCH 22.

Abstract: DiGeorge syndrome (DGS) comprises thymic hypoplasia, hypocalcaemia, outflow tract defects of the heart, and dysmorphic facies. It results in almost all cases from a deletion within chromosome 22q11. We report the clinical findings in 44 cases. We propose that DiGeorge syndrome should be seen as the severe end of the clinical spectrum embraced by the acronym CATCH 22 syndrome; Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, and Hypocalcaemia resulting from 22q11 deletions.

Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: implications for genetic counselling and prenatal diagnosis.

Abstract: Deletions of chromosome 22q11 have been seen in association with DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). In the present study, we analysed samples from 76 patients referred with a diagnosis of either DGS or VCFS to determine the prevalence of 22q11 deletions in these disorders. Using probes and cosmids from the DiGeorge critical region (DGCR), deletions of 22q11 were detected in 83% of DGS and 68% of VCFS patients by DNA dosage analysis, fluorescence in situ hybridisation, or by both methods. Combined with our previously reported patients, deletions have been detected in 88% of DGS and 76% of VCFS patients. The results of prenatal testing for 22q11 deletions by FISH in two pregnancies are presented. We conclude that FISH is an efficient and direct method for the detection of 22q11 deletions in subjects with features of DGS and VCFS as well as in pregnancies at high risk for a deletion.

Incontinentia pigmenti (Bloch-Sulzberger syndrome).

Abstract: Incontinentia pigmenti (IP) is a rare genodermatosis and was probably first described as early as 1906 by Garrod,' but the credit is given to Bardach,2 Bloch,3 Siemens,4 and Sulzberger5 for defining the condition during the 1920s, although only the names of Bloch and Sulzberger feature in the eponym. It is a multisystem, ectodermal disorder accompanied by dermatological, dental, and ocular features and in a minority of cases may be associated with neurological deficit. The typical phenotype is a result of functional mosaicism, a phenomenon which occurs in X linked dominant disorders because of lyonisation. The name incontinentia pigmenti describes the characteristic, albeit non-specific, histological feature where there is incontinence of melanin from the melanocytes in the basal layer of the epidermis into the superficial dermis.

Imprinting in Albright's hereditary osteodystrophy.

Abstract: Review of published reports of Albright's hereditary osteodystrophy (AHO) involving two or more generations shows a marked excess of maternal transmission Full expression of the gene (AHO + hormone resistance, pseudohypoparathyroidism) occurs in maternally transmitted cases and partial expression (AHO alone) when the gene is inherited from the father, suggesting the involvement of genomic imprinting in the expression of this disorder

Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22q11.

Abstract: The conotruncal anomaly face syndrome was described in a Japanese publication in 1976 and comprises dysmorphic facial appearance and outflow tract defects of the heart. The authors subsequently noted similarities to Shprintzen syndrome and DiGeorge syndrome. Chromosome analysis in five cases did not show a deletion at high resolution, but fluorescent in situ hybridisation using probe DO832 showed a deletion within chromosome 22q11 in all cases.

Microdeletions of chromosomal region 22q11 in patients with congenital conotruncal cardiac defects.

Abstract: Congenital conotruncal cardiac defects occur with increased frequency in patients with DiGeorge syndrome (DGS). Previous studies have shown that the majority of patients with DGS or velocardiofacial syndrome (VCFS) have a microdeletion within chromosomal region 22q11. We hypothesised that patients with conotruncal defects who were not diagnosed with DGS or VCFS would also have 22q11 deletions. Seventeen non-syndromic patients with one of three types of conotruncal defects most commonly seen in DGS or VCFS were evaluated for a 22q11 deletion. DNA probes from within the DiGeorge critical region were used. Heterozygosity at a locus was assessed using restriction fragment length polymorphisms. Copy number was determined by dosage analysis using Southern blot analysis of fluorescence in situ hybridisation of metaphase spreads. Five of 17 patients were shown to have a 22q11 deletion when evaluated by dosage analysis. This study shows a genetic contribution to the development of some conotruncal cardiac malformations and alters knowledge regarding the risk of heritability of these defects in certain cases.

Methodology for Genetic Studies of Twins and Families

Abstract: for each condition v; orientate the reader and give th personal flavour. There are inconsistencies in logy, for example, Down synd under D, other trisomies under syndrome is under K, triple X mosome XXX syndrome', XX under X, Turner syndrome u 45,X/48,XXYY mosaicism und minor criticism, but it adds to produced by the book's inflex and its air of encyclopaedic aut] Although it may be useful a prenatal diagnosis publication' this is not an ideal source o: when advising families about a is doubtful whether the format for a practical reference boc rapidly moving field. Methodology for Genetic Twins and Families. Mich Lon R Cardon. (Pp496; £99. Kluwer Academic Publishers. This book deals with the analys family data by model fitting, the computer package LISRE widely used package for struct modelling which has recently t particularly by quantitative ger The first few chapters focus etics and statistics before movin nations of model fitting. T chapters are fairly clear a chapters 6 and 7 are difficult fo maticians, the authors do say Lo be the most tents of these two chapters can be skipped. yout results in However, for those unfamiliar with LISnd findings of REL, the assimilation of chapter 8 is crucial an inordinate in order to understand the successive ive and critical chapters and to comprehend the LISREL vould help to scripts. The remaining chapters deal with the e book a more application of LISREL to univariate and multivariate genetic analyses and become the terminoprogressively more difficult, so that the last [rome is listed few chapters are hard to follow for those T, Klinefelter unfamiliar with LISREL. under 'ChroThe positive aspects of this book are that YY syndrome the beginning chapters start from scratch and under T, and allow for the reader having little previous ler 4. This is a experience in this field. The chapter on ithe irritation matrix algebra is particularly clear. Although ;ible approach on first glance this book looks very mathemahority. tical, if followed carefully and in order, the as a survey of authors take the reader logically through s up to 1991, each step. Thus with perseverance, most f information explanations can be followed by those with pregnancy. It little mathematical expertise. In addition, the is appropriate inclusion of real twin data to illustrate the )k in such a different types of model is very helpful. The main criticism of the book is that the title suggests more than the book actually N R DENNIS gives. The book is primarily focused on the LISREL program and its applications. LISREL scripts are incorporated into each Studies of chapter. Thus it consists of a specific introLael C Neale, duction to the uses and methods of LISREL .00.) London: in analysing data, rather than a general text 1992. on the analysis of twin data. In conclusion this book is not suitable as sis of twin and general reading for those who want an intromainly using duction to analysing twin data. It is too _L. This is a specific, requires too much perseverance and tural equation motivation to work through, and may be been taken up offputting to a novice. However, it is likely to neticists. be useful and of great interest to those who on basic genare specifically planning to learn how to use ig on to explaLISREL. More experienced quantitative he first five geneticists, who are non-LISREL users, will nd although also find it useful as an overview. ir non-mathethat the conANITA THAPAR

Gametic but not somatic instability of CAG repeat length in Huntington's disease.

Abstract: Instability of a CAG repeat in 4p16.3 has been found in Huntington's disease (HD) chromosomes. Unlike a similar repeat in the fragile X syndrome, the expanded HD repeat showed no evidence of somatic instability in a comparison of blood, lymphoblast, and brain DNA from the same persons. Four pairs of monozygotic HD twins displayed identical CAG repeat lengths suggesting that repeat size is determined in gametogenesis. In contrast with the fragile X syndrome and with HD somatic tissue, mosaicism was readily detected as a diffuse spread of repeat lengths in DNA from HD sperm samples. Typically, the modal repeat size was larger in the sperm DNA than in corresponding lymphoblast DNA, with the greatest degree of gametic mosaicism coinciding with the longest somatic CAG repeats. These data indicate that the developmental timing of repeat instability appears to differ between HD and fragile X syndrome, and that the fundamental mechanisms leading to repeat expansion may therefore be distinct.

Deletion 9p and sex reversal.

Abstract: We report a case of a female infant with a de novo deletion of the short arm of chromosome 9, sex reversal, and an apparently intact SRY gene. Sex reversal has been reported in a number of subjects with a normal Y chromosome and a deletion of the terminal segment of the short arm of chromosome 9. The factors controlling early development of the male testes are unknown. There are likely to be many genes involved and we present additional evidence that one of these is situated on the end of the short arm of chromosome 9.

Classification of microphthalmos and coloboma.

Abstract: A new classification of microphthalmos and coloboma is proposed to bring order to the complexity of clinical and aetiological heterogeneity of these conditions. A phenotypic classification is presented which may help the clinician to give a systematic description of the anomalies. The phenotype does not predict the aetiology but a systematic description of ocular and systemic anomalies improves syndrome identification. There are two major classes, total and partial microphthalmos, and a subclassification which follows the embryology of the anomalies. The aetiological classification consists of three classes: (1) genetic (monogenic and chromosomal), (2) prenatally acquired (teratological agents and intrauterine deformations), and (3) associations. Genetic disorders give rise to malformations; prenatally acquired anomalies are disruptions or deformations. The aetiological classification can be applied to other congenital birth defects and improves counselling of families. Recurrence risks vary considerably between the classes.

Prenatal diagnosis from maternal blood: simultaneous immunophenotyping and FISH of fetal nucleated erythrocytes isolated by negative magnetic cell sorting.

Abstract: Fetal nucleated cells in the maternal circulation constitute a potential source of cells for the non-invasive prenatal diagnosis of fetal genetic abnormalities. We have investigated the use of the Magnetic Activated Cell Sorter (MACS) for enriching fetal nucleated erythrocytes. Mouse monoclonal antibodies specific for CD45 and CD32 were used to deplete leucocytes from maternal blood using MACS sorting, thus enriching for fetal nucleated erythrocytes which do not express either of these antigens. However, significant maternal contamination was present even after MACS enrichment preventing the accurate analysis of fetal cells by interphase fluorescence in situ hybridisation (FISH). To overcome this problem, we used simultaneous immunophenotyping of cells with the mouse antifetal haemoglobin antibody, UCH gamma, combined with FISH analysis using chromosome X and Y specific DNA probes. This approach enables selective FISH analysis of fetal cells within an excess of maternal cells. Furthermore, we have confirmed the potential of the method for clinical practice by a pilot prospective study of fetal sex in women referred for amniocentesis between 13 and 17 weeks of gestation.

Suicide risk in Huntington's disease.

Abstract: In order to evaluate the relevance of suicide risk in families affected by Huntington's disease (HD), 2793 subjects registered with the National Huntington's Disease Research Roster were studied. Suicide was the reported cause of death in 205 subjects (7.3%). This group included affected and possibly affected subjects, subjects at 50% and 25% risk, possibly at risk subjects, and normal relatives. In all categories suicide was more frequent than in the general US population. The data suggest that suicide is quite frequent in some families with HD. This increased suicide risk must be carefully considered in planning genetic counselling for predictive testing in HD.

Uniparental disomy explains the occurrence of the Angelman or Prader-Willi syndrome in patients with an additional small inv dup(15) chromosome.

Abstract: A patient with Angelman syndrome and a 46,XY/47,XY,+inv dup(15)(pter-->q11: q11-->pter) karyotype and a patient with Prader-Willi syndrome and a 46,XY/47,XY,+inv dup(15)(pter-->q12: q12-->pter) karyotype were investigated with molecular markers along chromosome 15. Paternal uniparental isodisomy was found for all informative markers in the first case which indicates that this, rather than the presence of the extra chromosome, is the cause of the Angelman syndrome phenotype. Similarly, the PWS patient showed maternal uniparental distomy with absence of PWS region material on the inv dup(15) chromosome. If (1) marker chromosomes are an occasional by product of 'rescuing' a trisomic fertilisation, or (2) if duplication of the normal homologue in a zygote which has inherited a marker in place of the normal corresponding chromosome 'rescues' an aneuploid fertilisation, or (3) if the presence or formation of a marker chromosome increases the probability of non-disjunction, then uniparental disomy might be found occasionally in other subjects with de novo marker chromosomes.

Childhood onset autosomal dominant polycystic kidney disease in sibs: clinical picture and recurrence risk. German Working Group on Paediatric Nephrology (Arbeitsgemeinschaft für Pädiatrische Nephrologie.

Abstract: In a systematic study on the clinical picture and genetics of cystic kidneys in children, in association with the German working group on paediatric nephrology (Arbeitsgemeinschaft fur Padiatrische Nephrologie), we have investigated 79 children with early manifestation of autosomal dominant polycystic kidney disease (ADPKD). They belonged to 64 families (64 index patients and 15 affected sibs). Early manifestation was defined in this study as clinical symptoms (hypertension, proteinuria, impaired renal function, palpably enlarged kidneys) occurring before the age of 15 years. In order to estimate the recurrence risk to sibs of a previously diagnosed patient with early manifesting ADPKD, we found that 15 out of a total of 65 sibs of the 64 index patients (45% of the theoretically expected 32.5 gene carriers) showed comparable early manifestation. Another 10 symptom free children were diagnosed sonographically as having ADPKD before the age of 18 years, so that the total number of affected sibs was 25/65 in the study group, representing 76% of the gene carriers. Although the gene in childhood manifesting ADPKD can be transmitted through both sexes, a statistically significant (p < 0.05) maternal predominance was observed (M:F = 23:41). In affected sibs ages of onset, initial presentation, and the development of complications appeared to be similar in the majority of families. Our data indicate a high recurrence risk to sibs for early manifestation of ADPKD which has important implications for genetic counselling and clinical care of affected families and gives clues to the underlying genetic mechanism of childhood onset ADPKD.

Mendelian cytogenetics. Chromosome rearrangements associated with mendelian disorders.

Abstract: The first successful mapping of a mendelian disorder by chromosome rearrangements was that of the Duchenne muscular dystrophy locus to Xp21.1-5 Since then, chromosome aberrations which delete, truncate, or otherwise rearrange and mutate specific genes have not only helped in the mapping of other disease loci,6 but have turned out to be key elements for the rapid isolation of disease genes by positional cloning strategies.7 Accordingly, a listing of the clinical disorders in which associated chromosome rearrangements have been described forms a part of the Human Gene Mapping Workshops.6 Although the early success led to a proposal for systematic cytogenetic analysis of subjects with mendelian disorders,8 this has rarely been done. A common feeling is that, as mutations, these rearrangements are rare exceptions. The aim of the present review is to document that they may be rare, but are not exceptions, and to focus on factors which may influence their occurrence and facilitate their detection.

DiGeorge syndrome: an historical review of clinical and cytogenetic features.

Abstract: It is now over 28 years since Dr Angelo DiGeorge' commented on a paper by Dr Max Cooper and colleagues2 regarding the congenital absence of the thymus. At the 1965 Society for Pediatric Research (SPR) meeting, Dr Cooper gave a paper showing that the lymphoid system of the chicken consisted of two different components, the bursal system and the thymic system. Ablation of the bursal system caused agammaglobulinaemia but did not affect cellular immunity. However, thymectomy impaired cellular immunity. In his comment, Dr DiGeorge noted that there was a group of infants with congenital absence of the thymus who might represent a human homologue of the thymectomised chicks. DiGeorge and his co-worker, Dr James Arey, had noted three infants with congenital absence of the parathyroids who also had no evidence of thymic tissue. As DiGeorge stated, \"the concurrent absence of both structures is not surprising if one recognizes that both are derived from common primordia. Furthermore, this association has been previously recorded although its physiologic significance has not been recognized.\"' Just before the 1965 SPR meeting, DiGeorge and colleagues (Drs Harold Lischner, Catherine Dacou-Voutetakis, and Hope Punnett) were in the process of studying a fourth infant with congenital hypoparathyroidism who was predicted to have absence of the thymus. In addition to the absence of the thymic shadow on chest radiograph, the infant had abnormal cellular immunity with persistent candidiasis, negative monilial skin test, and failure to reject a homologous skin graft, although the lymphocyte count, plasma cell numbers in lymph nodes, and serum immunoglobulins were normal. The infant was also noted to be 'runted' in spite of adequate control of serum calcium levels. DiGeorge suggested that all infants with congenital hypoparathyroidism should be studied for defects in cellular immunity. This was contrary to the prevailing notion that patients with absent thymus would have normal immunoglobulins and normal total peripheral blood lymphocyte counts. As DiGeorge had mentioned, thymic aplasia was first noted by Harrington3 in 1829 and later in association with congenital hypoparathyroidism by Lobdell4 in 1959. In spite of those earlier papers and the lack of a published paper by DiGeorge, Dr Robert A Good dubbed this association 'DiGeorge syndrome'.5 DiGeorge's first published paper on the subject actually did not appear until 1968 in the British Defects: Original Article Series with the proceedings of a Sanibel Island meeting on the development of the immune system.6 For additional information about the early history of DGS, I refer you to DiGeorge's paper.6 After several additional case reports ofDGS and evaluation of 18 additional cases, Dr Harold Lischner outlined the first categorisation of third and fourth branchial pouch defects in an editorial comment.7 Lischner suggested three categories. The first is the III-IV pharyngeal pouch syndrome which he defined as \"congenital malformation, hypoplasia (with normal histology), or absence of the thymus and/or parathyroid glands, including significant maldescent of those organs so that they are located in the neck or other abnormal sites.\" Additional anomalies were noted, especially of the great vessels, micrognathia, ear defects, oesophageal atresia, blunted nose, thyroid anomalies, and endocardial cushion. DiGeorge syndrome was defined as those cases of the IIIIV pharyngeal pouch syndrome in which no thymic tissue was noted on careful postmortem examination, even in an ectopic position. The third category was partial DiGeorge syndrome in which the cases of III-IV pharyngeal pouch syndrome had defective cell mediated immunity or thymic hypoplasia by reduced thymic weight (<2 g). In addition, Lischner noted seven generalisations about partial DGS which still hold true.7 (1) Cell mediated immunity is grossly depressed. (2) Most lymphocytes in the peripheral blood and lymph nodes will be B cells. (3) The absolute lymphocyte count will usually be slightly or moderately depressed but may be normal. (4) Responsiveness of peripheral blood lymphocytes to phytohaemagglutinin in vitro may be depressed but not consistently. (5) Lymph nodes will be grossly depleted on lymphocytes in the deep cortical areas. (6) There may be some depression of antibody responses to specific immunisation, thought to be the result of the required interaction of T lymphocytes with B lymphocytes. (7) Serum immunoglobulins will be within or near the normal range. Although by 1979, DiGeorge had evaluated Institute for Molecular Genetics and Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Texas 77030, USA. F Greenberg

Integrated study of 100 patients with Xp21 linked muscular dystrophy using clinical, genetic, immunochemical, and histopathological data. Part 1. Trends across the clinical groups.

Abstract: This multidisciplinary study was undertaken to record the variation in gene and protein expression in a large cohort of patients with well defined clinical phenotypes. The patients, whose ages ranged from 4 years to 66 years, spanned a wide range of disease severity. They represented the first 100 patients who had been examined in Newcastle, had undergone a muscle biopsy, and provided a blood sample for DNA analysis. The study had three aims: to observe any trends in the analyses across the clinical groups, to correlate gene and protein expression in individual patients, and to use the data collected to assess the relative usefulness of different techniques in the diagnosis and prognosis of patients with Duchenne and Becker dystrophy (DMD/BMD). In part 1, we describe the clinical assessment of the patients and the trends that were observed across the cohort. The patients were divided into seven groups. Group 1 had severe DMD (n = 21), group 2 had milder DMD (n = 20), group 3 were intermediate D/BMD patients (n = 9), group 4 had severe BMD (n = 5), and group 5 were more typical BMD patients (n = 31). Some patients were too young to be classified (n = 7) and a group of all the female patients were also classified separately (n = 7). The number of DMD and BMD patients was about equal, in accord with disease prevalence in the north of England, but an unusually high proportion were sporadic cases. Dystrophin labelling (performed with up to three antibodies) on both blots and sections increased gradually across the clinical groups. All histopathological indices, except the proportion of fat in biopsy sections, showed clear trends across the groups.

Population studies of the fragile X: a molecular approach.

Abstract: The fragile X mutation can now be recognised by a variety of molecular techniques. We report a pilot screening survey of a population of children with mental impairment in which we used Southern blotting methods to detect the fragile X mutation, augmented by cytogenetic studies on children whose phenotype suggested a possible chromosome abnormality. There were 873 children with special educational needs in our survey and 310 fulfilled our criteria for testing. A sample was obtained from 254, of whom four were found to have a full fra(X) mutation (delta L) and none to have a premutation. The number of CGG repeats in our population of X chromosomes was measured by PCR analysis and the genotype at the closely linked polymorphic locus FRAXAC1 established. The distribution of CGG repeat numbers was very similar to that of the control population reported by Fu et al and the distribution of FRAXAC1 alleles almost identical to that of the control population reported by Richards et al. Among the non-fragile X chromosomes, we found a very significant correlation between the size of the CGG repeat and the FRAXAC1 genotype. There was a dearth of A and D genotypes in subjects with a small number of CGG repeats and an excess of the A genotype in those with a large number of CGG repeats. These observations are considered in the light of the reported disequilibrium between the A (and possibly also the D) genotype and the fra(X) mutation.

Guidelines for the diagnosis of fragile X syndrome. National Fragile X Foundation.

Abstract: Direct DNA analysis of the fragile X mutation has become available with the isolation of DNA probes that detect the unstable DNA sequence containing the CGG repeat. We present the various alternatives of combinations of probes and enzymes that can be used for the diagnosis of fragile X syndrome. An overview is given of all the different available probes. A different protocol is presented for postnatal and prenatal diagnosis of fragile X syndrome. This includes Southern blot analysis as well as direct analysis of the CGG repeat by PCR amplification. We discuss the role of constitutional cytogenetic analysis in the diagnosis of mentally retarded subjects and cytogenetic analysis for the diagnosis of fragile X syndrome.

Five year study of prenatal testing for Huntington's disease: demand, attitudes, and psychological assessment.

Abstract: Adult predictive and prenatal testing programmes for Huntington's disease (HD) in Canada have been available since 1986. However, the demand for prenatal testing and the reasons why some people choose not to have the prenatal test for this late onset disorder have not been well documented. In addition, the knowledge and attitudes of adult predictive testing candidates and their partners about prenatal testing are not well known nor are the psychological effects of prenatal testing well understood. As of September 1991, 425 subjects had entered the Canadian Collaborative Study of Predictive Testing and, of these, 47 subjects or their partners had become pregnant. Of this group, 14 (30%) couples requested prenatal testing, 24 (51%) couples did not want prenatal testing, and nine (19%) at risk subjects had already received a decreased risk through adult predictive testing and, therefore, were not eligible for the prenatal test. Of the 14 couples who initially requested prenatal testing, seven withdrew. Thus, demand for the prenatal test by eligible candidates was 7/38 or 18%, which is much lower than the 32 to 65% expected based on early survey data. The most frequently cited reason for declining prenatal testing was the hope that a cure would be found in time for their children. While the majority of adult predictive testing candidates (71%) in our study had accurate information about definitive prenatal testing, many (63%) did not have a correct understanding of exclusion prenatal testing. Although no serious adverse events such as suicide planning or admission to psychiatric hospital have occurred, a particular need for careful counselling was identified for those at risk candidates and their partners who have one prenatal test and feel compelled to use the test again in future pregnancies. Even though prenatal testing for HD is not requested as often originally expected, it still remains a desired option for some at risk persons and their partners.

Neurofibromatosis type 1 (NF1): knowledge, experience, and reproductive decisions of affected patients and families.

Abstract: Eighty-one subjects (56 affected patients and 25 parents of isolated affected cases) from 63 families with neurofibromatosis type 1 (NF1) on the North Western Regional Genetic Family Register (NWRGFR) were interviewed. Patients were interviewed either before (n = 26) or after (n = 55) genetic counselling. In the group as a whole, knowledge of the clinical features and the genetic aspects of the condition was poor (mean score 7 within the range of 0 to 18). The following factors were significantly associated with higher knowledge: (1) genetic counselling, (2) higher social class, (3) child with NF1, (4) when NF1 had influenced reproductive decisions, (5) young age at diagnosis, and (6) member of a patient support group. The majority of the affected subjects perceived themselves to be more severely affected than by medical classification, with persons who had been diagnosed later in life, had a child with NF1, or who were concerned about the cosmetic aspects of the disease perceiving themselves to be more severely affected. Assessment of the psychosocial effects of NF1 at different stages of life showed that 63% of affected subjects experienced difficulties at school and 48% said that the condition, particularly cosmetic aspects, caused anxiety during adolescence (n = 54). These difficulties may have contributed to later problems with career attainment and confidence in relationships. Seventy-seven percent of parents stated that their child was experiencing difficulties at school relating to NF1 (n = 51). Of the subjects at risk of having a child with NF1 and who knew about NF1 before having their family (n = 32), 45% said that it had influenced their reproductive decisions. Of 29 subjects who were still considering children, 41% wished to have prenatal diagnosis in a future pregnancy, but only three subjects stated that they would terminate an affected pregnancy.

The genetics of malignant hyperthermia.

Abstract: Malignant hyperthermia susceptibility remains the commonest cause of death owing to general anaesthesia. This is despite the availability of presymptomatic testing, admittedly by a highly invasive method, and a recognised treatment for implementation immediately a patient shows signs of developing a crisis. Recently the finding of linkage to markers from chromosome 19q13.1-13.2 and the identification of mutations in a candidate gene held out hope of genetic diagnosis being available. However, it is likely that only about 50% of families have a mutation of the skeletal muscle calcium release channel gene. With this degree of genetic heterogeneity, presymptomatic testing based on DNA markers can only be offered at present to a limited number of families where linkage to markers from 19q13.1-13.2 has been clearly shown.

Clinical and molecular studies in fragile X patients with a Prader-Willi-like phenotype.

Abstract: A special subphenotype of the fragile X syndrome is reported which is characterised by extreme obesity with a full, round face, small, broad hands/feet, and regional skin hyperpigmentation. It resembles the Prader-Willi syndrome (PWS) and might therefore be named 'Prader-Willi-like'. Unlike the PWS, these PW-like fragile X patients lack the neonatal hypotonia with feeding problems during infancy followed by hyperphagia from toddlerhood. We describe five new fragile X patients and present a clinical update of three previously described patients with the PW-like phenotype. In one family, segregation of either the classical Martin-Bell or the PW-like phenotype was observed and in another family there was repeated transmission of the PW-like phenotype. Previously, one of the patients had been misdiagnosed as having classical PWS, based on clinical findings. Molecular studies of the FMR-1 gene showed the typical full mutations as seen in fragile X syndrome males. Molecular analysis of the 15q11-13 region, which is deleted in the majority of classical PWS patients, did not show any detectable abnormalities. In a group of 26 patients with suspected Prader-Willi syndrome but without detectable molecular abnormalities of chromosome 15, one fragile X patient was found. These clinical and molecular findings illustrate the necessity to perform DNA analysis of the FMR-1 gene in mentally retarded patients presenting with a PW phenotype but without the PWS specific cytogenetic/molecular abnormalities of chromosome 15.

Epidermal mosaicism and Blaschko's lines.

Abstract: To test the hypothesis that epidermal rather than dermal mosaicism determines Blaschko's lines in hypomelanosis of Ito (HI), we studied the distribution of chromosomal mosaicism in four patients. In two, mosaicism had not been detected in lymphocytes or dermal fibroblasts, but was clearly shown in epidermal keratinocytes; furthermore, the abnormal cell line was confirmed to the hypopigmented epidermis and the normal epidermis contained only normal cells. Negative findings in the other two patients might be because of mosaicism which was undetected either because it was submicroscopic or because it was present in melanocytes, which have not yet been studied. These preliminary results support the ideas that (1) Blaschko's lines represent single clones of epidermal cells; (2) in patients with HI and severe neurological involvement mosaicism, if detectable, is best shown in keratinocytes; and (3) the cytogenetic defect in epidermal cells may be directly responsible for the failure of pigmentation in HI.

Three patients with ring (X) chromosomes and a severe phenotype.

Abstract: Three patients with mosaicism and a cell line containing a small ring (X) chromosome are described. Their phenotype is similar to several previously reported patients with a 45,X/46,X,r(X) karyotype and a phenotype far more severely affected than expected in Turner's syndrome. The clinical picture includes mental retardation, a facial appearance reminiscent of the Kabuki make up syndrome, and limb anomalies. Some of the patients also had streaky hyperpigmentation of the skin in a pattern suggesting dermal mosaicism. It has been hypothesised that the severe phenotype might be the result of the small r(X) chromosome remaining active. However, there is little critical evidence to support this suggestion, while there is considerable evidence against it, including (1) a similar phenotype in 45,X/46,X,r(Y) patients, (2) the late replication of some of the small r(X) chromosomes associated with this phenotype, and (3) the expression of XIST in some of the affected patients.

Familial amyloidotic polyneuropathy in Sweden: a pedigree analysis.

Abstract: Extended genealogical studies were performed on the heredity patterns in Swedish patients with familial amyloidotic polyneuropathy (FAP) using Swedish historical archives. The population studied included 239 patients: 109 patients were linked to five large pedigrees and 80 patients belonged to 30 smaller pedigrees or nuclear families. In the remaining 50 cases, no genealogical links were found. Differences in mean ages of onset between the different pedigrees were found, although a considerable variation within the pedigrees was also present. There was a tendency for later ages of onset among older generations than younger ones: descendants of affected mothers seem to be more prone to anticipation in age of onset than descendants of affected fathers. Furthermore, there seems to be a tendency for earlier ages of onset among patients with a carrier mother than a carrier father. Some extended pedigrees, from the Skelleftea and Pitea areas, are presented in detail. The former go back into the middle of the 17th century. One important conclusion is that the mutational event may have occurred in late mediaeval times.

The morbid anatomy of the human genome : chromosomal location of mutations causing disease

Abstract: Information is given in tabular form derived from a synopsis of the human gene map which has been updated continuously since 1973 as part of Mendelian Inheritance in Man (Johns Hopkins University Press, 10th ed, 1992) and of OMIM (Online Mendelian Inheritance in Man, available generally since 1987). The part of the synopsis reproduced here consists of chromosome by chromosome gene lists of loci for which there are associated disorders (table 1), a pictorial representation of this information (fig 1a-d), and an index of disorders for which the causative mutations have been mapped (table 2). In table 1, information on genes that have been located to specific chromosomal positions and are also the site of disease producing mutations is arranged by chromosome, starting with chromosome 1 and with the end of the short arm of the chromosome in each case. In table 2 an alphabetized list of these disorders and the chromosomal location of the mutation in each case are provided. Both in the 'Disorder' field of table 1 and in table 2, the numbers 1, 2, or 3 in parentheses after the name of the disorder indicate that its chromosomal location was determined by mapping of the wildtype gene (1), by mapping of the clinical phenotype (2), or by both strategies (3).

Cockayne's syndrome: correlation of clinical features with cellular sensitivity of RNA synthesis to UV irradiation.

Abstract: Cockayne's syndrome (CS) is a rare autosomal recessive disorder with dwarfism, mental retardation, and otherwise clinically heterogeneous features. In cultured CS fibroblasts, the failure of RNA synthesis to recover to normal rates after UV-C irradiation provides a useful and relatively simple diagnostic test. We have measured post-UV-C RNA synthesis in 52 patients for whom a clinical diagnosis of CS was considered a possibility. Twenty-nine patients showed the defect characteristic of CS cells, and 23 had a normal response. We have attempted to correlate the cellular diagnosis with the different clinical features of the disorder. Clinical details of the patients were obtained from referring clinicians in the form of a questionnaire. Our results show that, apart from the cardinal features of dwarfism and mental retardation, sun sensitivity correlated best with a positive cellular diagnosis. Pigmentary retinopathy, gait defects, and dental caries were also good positive indicators, although several patients with a positive cellular diagnosis did not have these features.