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.

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.

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.

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.

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.

Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots.

Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills after a period of normal development in infant girls. The responsible gene, encoding methyl-CpG binding protein 2 (MeCP2), was recently discovered. Here we explore the spectrum of phenotypes resulting from MECP2 mutations. Both nonsense (R168X and R255X) and missense (R106W and R306C) mutations have been found, with multiple recurrences. R168X mutations were identified in six unrelated sporadic cases, as well as in two affected sisters and their normal mother. The missense mutations were de novo and affect conserved domains of MeCP2. All of the nucleotide substitutions involve C-->T transitions at CpG hotspots. A single nucleotide deletion, at codon 137, that creates a L138X stop codon within the methyl-binding domain was found in an individual with features of RTT and incontinentia pigmenti. An 806delG deletion causing a V288X stop in the transcription-repression domain was identified in a woman with motor-coordination problems, mild learning disability, and skewed X inactivation; in her sister and daughter, who were affected with classic RTT; and in her hemizygous son, who died from congenital encephalopathy. Thus, some males with RTT-causing MECP2 mutations may survive to birth, and female heterozygotes with favorably skewed X-inactivation patterns may have little or no involvement. Therefore, MECP2 mutations are not limited to RTT and may be implicated in a much broader phenotypic spectrum.

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.

Interstitial Dup(1p) with findings of Kabuki make-up syndrome.

We describe a male patient with interstitial duplication of the short arm of chromosome 1 with breakpoints involving 1p13.1 and 1p22.1. The patient presented with some clinical findings of Kabuki make-up syndrome (KMS), including mental retardation, small head, eversion of the lateral part of lower eyelids, epicanthic folds, lateral flare of the eyebrows, short columella, and persistent fetal finger pads. This cytogenetic finding may provide clues for gene mapping of the syndrome.