NSD1 mutations generate a genome-wide DNA methylation signature.

Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1(+/-)-specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1(+/-) signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing.

Factors affecting the appreciation generated through applying human factors/ergonomics (HFE) principles to systems of work.

This retrospective study examined the levels of appreciation (applause) given by clients to Human Factors/Ergonomic (HFE) specialists after they have modified the systems of work. Thirteen non-academic projects were chosen because the HFE interventions involved changed the way workers work at their workplaces. Companies involved range from multi-national corporations and military organizations with thousands of employees to small trading companies with less than 10 employees. In 5 cases the HFE recommendations were fully adopted and well appreciated. In 4 they were largely ignored and not appreciated, with partial adoption and some appreciation in the other 4 cases. Three factors that predict appreciation were identified: (i) alignment between the benefits HFE can provide and the project's key performance indices; (ii) awareness of HFE among the client's senior management; and (iii) a team organization appropriate for applying HFE recommendations. Having an HFE specialist on the client's side can greatly increase levels of appreciation, but lack of such a specialist will not affect levels of appreciation. A clear contractual requirement for HFE intervention does not promote appreciation significantly, but its absence can greatly reduce levels of appreciation. These relationships are discussed using the Kano's model of quality. Means to generate greater appreciation of the benefits of HFE are discussed.

Ambiguous genitalia, impaired steroidogenesis, and Antley-Bixler syndrome in a patient with P450 oxidoreductase deficiency.

Cytochrome P450 oxidoreductase deficiency is a recently established autosomal recessive disease characterised by ambiguous genitalia, impaired steroidogenesis, and skeletal malformations, referred to as Antley-Bixler syndrome. Clinical manifestations in affected patients are highly variable. We report on a girl with P450 oxidoreductase deficiency who presented with virilisation at birth. There was transient maternal virilisation during pregnancy as well. She was initially diagnosed with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency and/or aromatase deficiency. At 1 year of age, skeletal abnormalities suggestive of Antley-Bixler syndrome were detected. Molecular analysis of the fibroblast growth factor receptor 2 (FGFR2) gene was normal but POR gene analysis showed that she was homozygous for an R457H missense mutation. The diagnosis, P450 oxidoreductase deficiency, was confirmed. Results of her endocrine studies and urinary steroid profiling are also presented.

Severe neonatal manifestations of Costello syndrome.

BACKGROUND: Costello syndrome (CS) is due to mutations in HRAS, with the most common mutation being c.34G>A (p.G12S), found in most patients in all the published series. A small number of less common mutations have been reported. POPULATION STUDIED: HRAS mutation analysis has been undertaken in 74 predominantly British patients with a possible diagnosis of CS. A HRAS mutation was found in 27 patients, 15 of whom have been previously reported. PHENOTYPE ANALYSIS: Four cases had an unusually severe phenotype, associated in three cases with two unusual mutations, c.35G>A, p.G12D in two cases and c.34G>T, p.G12C in the other. Hypoglycaemia, renal abnormalities, severe early cardiomyopathy, congenital lung and airway abnormalities, pleural and pericardial effusion, chylous ascites and pulmonary lymphangectasia are confirmed as part of the clinical spectrum seen in CS. A lung pathology resembling alveolar capillary dysplasia is reported in one case. CONCLUSION: These cases illustrate that the diagnosis of CS may be difficult in the newborn period, and should be considered in the differential diagnosis of the sick newborn infant with multisystem disease. Study of more cases will be required to establish if there is a definite association between severe disease and less common mutations.

A study on body weight perception and weight control behaviours among adolescents in Hong Kong.

OBJECTIVE: To examine the relationships between body weight perceptions, estimated body mass index, gender, and weight control behaviours. DESIGN: Cross-sectional survey. SETTING: Three secondary schools in Hong Kong. PARTICIPANTS: A total of 1132 secondary school forms 1 and 3 students. MAIN OUTCOME MEASURES: The strength of agreement between perceived weight and estimated body mass index, and the association between perceived weight, estimated body mass index, and weight control behaviours. RESULTS: A total of 14% of students were estimated to be overweight or obese. The agreement between actual (estimated) body mass index and perceived weight was poor in females and fair in males (Kappa 0.137 and 0.225, respectively). In females, there was no evidence of a relationship between body mass index and weight control behaviours. However, there was a relationship between perceived weight and weight control behaviours such that females who perceived themselves as overweight were more likely to exercise, restrict caloric intake, self medicate with diet pills, purge, or use laxatives. In males, there was evidence of a relationship between perceived weight, body mass index, and weight control behaviours. Males who perceived themselves as overweight or were overweight, were more likely to exercise or restrict caloric intake. CONCLUSIONS: Body weight perceptions are not in agreement with actual weight in adolescents. This discrepancy is more marked in females who use a variety of weight control behaviours. These behaviours are motivated by perceived weight rather than actual (estimated) body mass index. Overweight adolescents should be encouraged to adopt appropriate weight control behaviours for their health needs.

Chromosomal abnormalities and FMR1 gene premutation in Chinese women with premature menopause.

OBJECTIVE: To study the prevalence of chromosomal abnormalities and FMR1 gene premutation in Chinese women with premature menopause in Hong Kong. DESIGN: Retrospective study. SETTING: Clinical Genetic Service, Hong Kong. PARTICIPANTS: Chinese women with premature menopause referred for cytogenetic study from January 1983 to November 2003. MAIN OUTCOME MEASURES: Chromosomal abnormalities, FMR1 gene premutation. RESULTS: Chromosomal abnormalities were present in 15.6% of Chinese women who suffered premature menopause. X-chromosome abnormality was involved in over 80% of cases. FMR1 gene premutation was present in 0.86% of 116 cases screened for this abnormality. The predominance of X-chromosome abnormality accounted for the shorter stature, younger menopausal age, and higher prevalence of dysmorphic features among the cytogenetically abnormal patients. However, on logistic regression, no clinical feature was significantly correlated with cytogenetic abnormality. CONCLUSIONS: The prevalence of chromosomal abnormalities among Hong Kong Chinese women who suffer premature menopause was comparable with that of Caucasian and Chinese populations elsewhere. Because clinical features are poor predictors of cytogenetic abnormality, a pragmatic approach to screening is advocated. The carrier rate of fragile X premutation in these women appeared lower than that of Caucasians. Nevertheless, a search for FMR1 gene premutation, in addition to conventional chromosomal study, has important implication for prenatal diagnosis and fertility management for the extended family.

Cytogenetic analysis of patients with primary and secondary amenorrhoea in Hong Kong: retrospective study.

OBJECTIVE: To estimate the incidence and type of chromosomal abnormalities in patients with primary and secondary amenorrhoea in Hong Kong. DESIGN: Cytogenetic analysis and retrospective review. SETTING: Clinical Genetic Service, Department of Health, Hong Kong. PATIENTS: Case records of 549 patients with either primary (n=237) or secondary (n=312) amenorrhoea referred to the Clinical Genetic Service from 1 January 1991 to 30 April 2002 were reviewed. All these patients with amenorrhoea would have karyotyping (G banding) performed. MAIN OUTCOME MEASURES: Clinical characteristics of patients, and incidence and type of chromosomal abnormalities in the local population. RESULTS: Sex chromosome anomaly was found in 24.5% and 9.9%, respectively, of women with primary and secondary amenorrhoea. In those with primary amenorrhoea, male karyotype was identified in 8.4% and X-chromosome abnormalities in 16.0%. CONCLUSION: The incidence of chromosomal abnormalities in women with amenorrhoea is similar to that reported in the literature. Chromosomal abnormalities are identified often enough to warrant karyotyping of all women with amenorrhoea.

Williams-Beuren syndrome in the Hong Kong Chinese population: retrospective study.

OBJECTIVE: To estimate the incidence and document the clinical characteristics of Williams-Beuren syndrome in the Hong Kong Chinese population. DESIGN: Cytogenetic analysis and retrospective study. SETTING: Clinical Genetic Service, Department of Health, Hong Kong. PATIENTS: Forty-one Chinese patients with Williams-Beuren syndrome. MAIN OUTCOME MEASURES: From 1 January 1995 to 30 June 2002, fluorescence in situ hybridisation was used to confirm diagnoses in 41 cases of Williams-Beuren syndrome by detecting chromosome 7q microdeletion. Case records were reviewed, the incidence of the condition in the local population was estimated, and the main clinical characteristics were determined. RESULTS: The minimal incidence of Williams-Beuren syndrome in this locality was estimated to be approximately 1 per 23500 live births. Common dysmorphic facial features included periorbital fullness (83%), full lips (80%), a long philtrum (51%), a flat nasal bridge (41%), and abnormal teeth (37%). No patients had a stellate iris. The majority (82%) had at least one documented cardiac anomaly; among these patients, peripheral pulmonary stenosis was diagnosed in 61% and supravalvular aortic stenosis in 45%. Nearly all (93%) of the study group exhibited developmental delay. CONCLUSION: As in the West, patients with Williams-Beuren syndrome in the Hong Kong Chinese population display craniofacial dysmorphism, cardiovascular anomalies, and mental deficiency. Supravalvular aortic stenosis-the cardiac defect most commonly associated with Williams-Beuren syndrome in western countries-is less common than peripheral pulmonary stenosis in this region. Studies involving periodic cardiovascular evaluation are needed to confirm if this difference is significant.

Dentatorubral-pallidoluysian atrophy in two Chinese families in Hong Kong.

We report on two Hong Kong Chinese families with dentatorubral-pallidoluysian atrophy. Two children in one family presented with progressive myoclonic epilepsy syndrome, and two children in the other family presented with ataxochoreo-athetoid symptoms. Early-onset childhood dentatorubral-pallidoluysian atrophy involved mental retardation, whereas myoclonic epilepsy was the predominant complaint in later-onset childhood version of the disease. Aspiration pneumonia was common in the late stage of disease. Dentatorubral-pallidoluysian atrophy is an autosomal dominant condition attributed to CAG trinucleotide repeats in the dentatorubral-pallidoluysian atrophy gene. The four children in this series had 63 to 79 CAG repeats. The expanded allele was inherited from the father in both families. One father had 54 CAG repeats and was asymptomatic; the other had 66 repeats and had an unsteady gait. Because the radiological, electroencephalographic, and electrophysiological findings were non-specific, we suggest that DRPLA gene testing should be performed in any child presenting with a variable combination of myoclonic epilepsy, mental retardation or developmental regression, and ataxochoreo-athetosis.

Neonatal screening in Hong Kong and Macau.

For the implementation of the neonatal screening program, the following factors have to be considered for the selection of conditions to be screened and evaluation of outcome. These include the factors pertaining to public health impact, availability and acceptability of the screening system, and other social issues involved in the implementation. In the context of Hong Kong, Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency and Congenital Hypothyroidism (CHT) have been highlighted in the early 1980s for consideration. A territory wide program for screening these conditions was started in 1984. Since then, over 99% of all newborns in Hong Kong was screened. Of these, around 70% were delivered in public hospitals, and the remaining were from private hospitals. Pre-screening education was emphasized, and 95% of pregnant ladies received information about this screening program from the Maternity and Child Health Centers run by the Department of Health, Hong Kong. For those who were born in public hospitals, the incidence of CHT was 1 in 2404 (269/646,580), while that of G6PD deficiency was 4.5% in male newborns and 0.3% in female newborns. This paper highlights details of the screening program, including its outcome evaluation. In Macau, CHT screening has not been started. Instead, G6PD deficiency screening commenced in 1977 in one of the two major hospitals where most newborns are delivered. Methodology and results of this program are presented.

Gaucher disease with pulmonary involvement in a 6-year-old girl: report of resolution of radiographic abnormalities on increasing dose of imiglucerase.

We report resolution of ground-glass appearance in high-resolution computed tomography of chest in a 6-year-old girl who had Gaucher disease with pulmonary involvement. This radiographic abnormality, which developed during the course of enzyme replacement therapy at doses between 20 to 60 U/kg/2 weeks, resolved when the dose was increased to 100 U/kg/2 weeks. This case illustrates the importance of trial of escalating dosage in the face of failure of response at lower doses.

Missense mutations of the fibrillin-1 gene in two Chinese patients with severe Marfan syndrome.

OBJECTIVE: To describe two Chinese patients with severe forms of Marfan syndrome and to report findings of mutational analysis of the fibrillin-1 (FBN1) gene. METHODS: Two Chinese patients were studied, one suffering from Marfan syndrome of infantile onset and the other of neonatal onset. Their clinical features were described. Mutational analysis of the FBN1 gene was performed using polymerase chain reaction (PCR) technique and direct sequencing of exons 23-32, where the mutational hotspots for severe forms of Marfan syndrome are located. RESULTS: Two missense mutations were successfully identified, a G3037A transition and an A3083T transversion, the latter being an unreported mutation. CONCLUSION: Taking advantage of the clustering phenomenon of mutations in severe forms of marfan syndrome, one can identify FBN1 mutations in these patients by first screening the mutational hotspots, thus reducing the effort that would otherwise be much greater because of the size of the gene.

Trinucleotide CGG repeat in the FMR1 gene in Chinese mentally retarded patients.

The fragile X syndrome of mental retardation is related to the number of trinucleotide CGG repeats at the 5'-untranslated region of the FMR1 gene located on the X-chromosome. We have studied X-chromosomes from 649 unaffected Chinese subjects and 324 patients with mild mental retardation. All study subjects were unrelated. The CGG repeat number was analysed by electrophoresis of a polymerase chain reaction followed by gel transfer and hybridisation with a 32P-labeled (CCG)5 probe. The DNA samples having detectable CGG expansion were further analysed by Southern blot analysis with probe StB12.3 after restriction digestion by EcoR I and Eag I. For the unaffected Chinese subjects, a different distribution pattern of CGG allele size from Caucasians was observed. It was a bimodal pattern and the CGG repeat number ranged from 19 to 54. The most common CGG repeat allele was 29 compared with 30 in Caucasians. The second mode appeared at 36 repeats. There was mild statistical difference in the repeat patterns between the mentally retarded patients and unaffected subjects, although the essential features were similar. Among the mentally retarded patients, one male had an unmethylated full mutation and one female had a full mutation. The fragile X prevalence was 0.6%, which is lower than two previous studies in Chinese mentally retarded patients utilising cytogenetic analysis. Our results indicate that a large-scale screening program would be worthwhile to determine the prevalence of the fragile X syndrome in the Chinese population.

Adequacy and pitfalls of G6PD deficiency counseling in Hong Kong.

Glucose-6-Phosphate-Dehydrogenase (G6PD) deficiency is common in Hong Kong with an incidence of 4.5% in male and 0.36% in female (Lo et al. 1996).The Neonatal Screening Unit of Clinical Genetic Service started its territory-wide neonatal screening program for G6PD deficiency and congenital hypothyroidism in 1984 (Lam et al, 1986). Because of insufficient manpower and resource, we have been giving health counseling on the phone to parents of G6PD deficient babies and then refer them to nearby maternal and child health centres for monitoring of jaundice. The disease, mode of inheritance, recurrence risk and the precaution against certain medicines (Chan 1996) and chemicals are explained. The purpose (Lam, 1994) is to reassure the parents that their G6PD deficient babies can be as normal as everyone and that they can have normal life. Nevertheless, it has not been established whether telephone counseling has any effect on the affected family in the form of psychological trauma (Marteau, 1989; Fyro, 1987; Li et al, 1996) or significant influence on the decision on future reproduction. This study tried to evaluate the service from the parents' point of view by 1) gathering information on parents' awareness and perception of G6PD deficiency, 2) determination of parents' attitude towards the telephone counseling, and 3) finding out the effect of G6PD deficiency on parents' decision on future reproduction. Over 300 parents were contacted by telephone, and were asked to respond to questions on a questionnaire . The telephone interview focused on parents' understanding of G6PD deficiency, their attitude towards this disease and the possible effect on future reproduction decision. Results showed that over 90% of cases that we had counseled attended the maternal and child health centres. Most of them accepted the presence of G6PD deficiency in their family which did not affect their decision on future pregnancy. Telephone counseling failed to establish a helping relationship with the parent as face to face counseling was more personal. The findings revealed that though telephone counseling had its shortcoming it served the target group effectively. Telephone counseling is still the method of choice for the G6PD deficiency counseling in this locality.

Pallister-Killian syndrome: the first reported case in Hong Kong.

Pallister-Killian syndrome was first described in 1977 by Pallister, et al. It is a multiple congenital anomalies/mental retardation syndrome caused by mosaic tetrasomy of chromosome 12p. The chromosomal abnormality is often missed if only peripheral lymphocytes are examined, and bone marrow or cultured skin fibroblasts may be required for confirmation. Here we report the first case in Hong Kong.

Burton skeletal dysplasia: the second case report.

We describe a 2-year-old girl with clinical and radiological findings of Burton skeletal dysplasia. This rare disorder shows some similarities to Kniest dysplasia. Short stature, joint stiffness, microstomia, and pursed lips are characteristic clinical findings. Platyspondyly with cervical kyphosis, but no coronal clefts, and bowing of the long bones are distinctive radiographic findings.