De novo WNT5A-associated autosomal dominant Robinow syndrome suggests specificity of genotype and phenotype.

Robinow Syndrome (RS), a rare skeletal dysplasia syndrome, is characterized by dysmorphic features resembling a fetal face, mesomelic limb shortening, hypoplastic external genitalia in males, and renal and vertebral anomalies. Both autosomal dominant and autosomal recessive patterns of inheritance have been reported. Since the description of autosomal dominant Robinow Syndrome (ADRS; OMIM 180700) in 1969 by Meinhard Robinow and colleagues, the molecular etiology remained elusive until only recently. WNT5A was proposed to be the candidate gene for ADRS, as mutations were found in two affected families, one of those being the originally described index family. We report three families with RS caused by novel heterozygous WNT5A mutations, which were confirmed in the first family by whole exome sequencing, and in all by Sanger sequencing. To our knowledge, this is the largest number of published families with ADRS in whom a WNT5A mutation was identified. Families 1 and 2 are the first cases showing de novo inheritance in the affected family members and thus strengthen the evidence for WNT5A as the causative gene in ADRS. Finally, we propose WNT5A mutation specificity in ADRS, which may affect interactions with other proteins in the Wnt pathway.

X-linked congenital ptosis and associated intellectual disability, short stature, microcephaly, cleft palate, digital and genital abnormalities define novel Xq25q26 duplication syndrome.

Submicroscopic duplications along the long arm of the X-chromosome with known phenotypic consequences are relatively rare events. The clinical features resulting from such duplications are various, though they often include intellectual disability, microcephaly, short stature, hypotonia, hypogonadism and feeding difficulties. Female carriers are often phenotypically normal or show a similar but milder phenotype, as in most cases the X-chromosome harbouring the duplication is subject to inactivation. Xq28, which includes MECP2 is the major locus for submicroscopic X-chromosome duplications, whereas duplications in Xq25 and Xq26 have been reported in only a few cases. Using genome-wide array platforms we identified overlapping interstitial Xq25q26 duplications ranging from 0.2 to 4.76 Mb in eight unrelated families with in total five affected males and seven affected females. All affected males shared a common phenotype with intrauterine- and postnatal growth retardation and feeding difficulties in childhood. Three had microcephaly and two out of five suffered from epilepsy. In addition, three males had a distinct facial appearance with congenital bilateral ptosis and large protruding ears and two of them showed a cleft palate. The affected females had various clinical symptoms similar to that of the males with congenital bilateral ptosis in three families as most remarkable feature. Comparison of the gene content of the individual duplications with the respective phenotypes suggested three critical regions with candidate genes (AIFM1, RAB33A, GPC3 and IGSF1) for the common phenotypes, including candidate loci for congenital bilateral ptosis, small head circumference, short stature, genital and digital defects.

Anorectal malformations and pregnancy-related disorders: a registry-based case-control study in 17 European regions.

OBJECTIVE: To identify pregnancy-related risk factors for different manifestations of congenital anorectal malformations (ARMs). DESIGN: A population-based case-control study. SETTING: Seventeen EUROCAT (European Surveillance of Congenital Anomalies) registries, 1980-2008. POPULATION: The study population consisted of 1417 cases with ARM, including 648 cases of isolated ARM, 601 cases of ARM with additional congenital anomalies, and 168 cases of ARM-VACTERL (vertebral, anal, cardiac, tracheo-esophageal, renal, and limb defects), along with 13 371 controls with recognised syndromes or chromosomal abnormalities. METHODS: Multiple logistic regression analyses were used to calculate adjusted odds ratios (ORs) for potential risk factors for ARM, such as fertility treatment, multiple pregnancy, primiparity, maternal illnesses during pregnancy, and pregnancy-related complications. MAIN OUTCOME MEASURES: Adjusted ORs for pregnancy-related risk factors for ARM. RESULTS: The ARM cases were more likely to be firstborn than the controls (OR 1.6, 95% CI 1.4-1.8). Fertility treatment and being one of twins or triplets seemed to increase the risk of ARM in cases with additional congenital anomalies or VACTERL (ORs ranging from 1.6 to 2.5). Maternal fever during pregnancy and pre-eclampsia were only associated with ARM when additional congenital anomalies were present (OR 3.9, 95% CI 1.3-11.6; OR 3.4, 95% CI 1.6-7.1, respectively), whereas maternal epilepsy during pregnancy resulted in a five-fold elevated risk of all manifestations of ARM (OR 5.1, 95% CI 1.7-15.6). CONCLUSIONS: This large European study identified maternal epilepsy, fertility treatment, multiple pregnancy, primiparity, pre-eclampsia, and maternal fever during pregnancy as potential risk factors primarily for complex manifestations of ARM with additional congenital anomalies and VACTERL.

Cytoplasmic localization of PML particles in laminopathies.

There is growing evidence that laminopathies, diseases associated with mutations in the LMNA gene, are caused by a combination of mechanical and gene regulatory distortions. Strikingly, there is a large variability in disease symptoms between individual patients carrying an identical LMNA mutation. This is why classical genetic screens for mutations appear to have limited predictive value for disease development. Recently, the widespread occurrence of repetitive nuclear ruptures has been described in fibroblast cultures from various laminopathy patients. Since this phenomenon was strongly correlated with disease severity, the identification of biomarkers that report on these rupture events could have diagnostic relevance. One such candidate marker is the PML nuclear body, a structure that is normally confined to the nuclear interior, but leaks out of the nucleus upon nuclear rupture. Here, we show that a variety of laminopathies shows the presence of these cytoplasmic PML particles (PML CPs), and that the amount of these protein aggregates increases with severity of the disease. In addition, between clinically healthy individuals, carrying LMNA mutations, significant differences can be found. Therefore, we postulate that detection of PML CPs in patient fibroblasts could become a valuable marker for diagnosis of disease development.

Sanfilippo B in an elderly female psychiatric patient: a rare but relevant diagnosis in presenile dementia.

OBJECTIVE: Sanfilippo B is a rare autosomal recessive mucopolysaccharidosis (MPS IIIB) caused by a deficiency of N-acetyl-alpha-D-glucosaminidase (NAGLU). METHOD: A mild mentally retarded elderly female patient is described with a slowly progressive dementia who had given birth to a daughter who developed normally. RESULTS: Metabolic screening revealed an enhanced concentration of heparan sulfate in urine. Enzymatic assay demonstrated deficiency of N-acetyl-alpha-D-glucosaminidase. Mutations in the NAGLU gene were found. One mentally retarded and hospitalized elder brother was also found to have MPS IIIB, whereas a second brother, who had died earlier, is suspected to have had the same metabolic disorder. Prior to the development of dementia, both the patient and her brother showed autistic like features, signs of ideomotor apraxia and weakness in verbal comprehension. CONCLUSION: Screening for metabolic disorders, in particular MPSes, should always be considered in patients with a history of mental deficit and dementia or progressive functional decline.

A Feingold syndrome case with previously undescribed features and a new mutation.

Feingold syndrome (FS) is a dominantly inherited combination of microcephaly with or without learning disabilities, hand and foot abnormalities, short palpebral fissures and esophageal/duodenal atresia. The syndrome has autosomal dominant inheritance with full penetrance, and variable expressivity. Digital anomalies are almost always present. The gene for FS is localized to a 2.2 cM region in 2p23-p24. We report on the first Turkish family with Feingold syndrome. The propositus is a male infant with microcephaly, frontal balding, brachymesophalangy of the second and fifth fingers, bilateral syndactyly of toes 2-3, facial anomalies, choanal atresia and focal epilepsy. His father has microcephaly, and more severe hands and feet abnormalities. One of his brothers died because of eosofageal atresia. Clinical presentation of the family was suggestive of Feingold syndrome, and genetic testing of the MYCN gene confirmed the diagnosis. The missense mutation we report here has not been described previously. FS is an autosomal dominant condition, and therefore, the diagnosis has important implications for genetic counseling.

An 8.35 Mb overlapping interstitial deletion of 8q24 in two patients with coloboma, congenital heart defect, limb abnormalities, psychomotor retardation and convulsions.

Chromosome analysis in two young patients with multiple congenital anomalies revealed a de novo interstitial deletion of 8q that has not been reported before. The deletions were overlapping by 8.35 Mb (8q24.21q24.23). The clinical features shared by our patients were coloboma, VSD, digital abnormalities, congenital dislocation of a hip, feeding problems, psychomotor delay and convulsions. The deletion included the region for Langer-Giedion syndrome (TRPS1 and EXT1) in the girl only. However, she is too young to present features of this syndrome, apart from dysmorphic features like a bulbous nose and notched alae nasi. Several genes are present in the commonly deleted region, including genes with unknown function, and genes for which haploinsufficiency is known to have no phenotypic effect in mice (Wnt1). A gene that might play a role in the convulsions of our patients is KCNQ3.

[Congenital long QT-syndrome: the cause of recurrent syncope and sudden death at a young age]. / Congenitaal lange-QT-tijdsyndroom: oorzaak van recidiverende wegrakingen en plotse dood op jonge leeftijd.

Congenital long QT-syndrome (LQTS) was diagnosed in three patients. The first patient, a 10-year-old girl, presented with recurrent episodes of syncope during swimming and was diagnosed with type 1 LQTS. The second patient, a 36-year-old asymptomatic man, was accidentally diagnosed with type 2 LQTS. His family history revealed syncope and sudden death at a young age after auditory stimuli. Type 3 LQTS was diagnosed post-mortem in a 16-year-old boy who died during his sleep. All clinical diagnoses were confirmed by genetic testing. Congenital LQTS is one of the leading causes of sudden cardiac death at a young age. Mutations in genes encoding for myocardial ion channel proteins lead to a prolonged QT-interval and abnormal ST-T segments in the 12-lead ECG. Patients may present with syncope or sudden cardiac death caused by ventricular tachyarrhythmias. Genotype-specific differences in ECG-abnormalities and triggers for cardiac events may help to distinguish the type of LQTS and make possible the initiation of genotype-specific treatment before the results of genetic testing are known. Identification of the genetic substrate by genetic testing, genotype-specific treatment, and the possibility of treatment with an implantable cardioverter-defibrillator have all led to dramatic improvement in the prognosis of patients with LQTS. Therefore, young patients with unexplained recurrent syncope after specific stimuli and those with atypical forms of epilepsy should be referred for cardiologic evaluation in a specialised centre.

Complex chromosome 17p rearrangements associated with low-copy repeats in two patients with congenital anomalies.

Recent molecular cytogenetic data have shown that the constitution of complex chromosome rearrangements (CCRs) may be more complicated than previously thought. The complicated nature of these rearrangements challenges the accurate delineation of the chromosomal breakpoints and mechanisms involved. Here, we report a molecular cytogenetic analysis of two patients with congenital anomalies and unbalanced de novo CCRs involving chromosome 17p using high-resolution array-based comparative genomic hybridization (array CGH) and fluorescent in situ hybridization (FISH). In the first patient, a 4-month-old boy with developmental delay, hypotonia, growth retardation, coronal synostosis, mild hypertelorism, and bilateral club feet, we found a duplication of the Charcot-Marie-Tooth disease type 1A and Smith-Magenis syndrome (SMS) chromosome regions, inverted insertion of the Miller-Dieker lissencephaly syndrome region into the SMS region, and two microdeletions including a terminal deletion of 17p. The latter, together with a duplication of 21q22.3-qter detected by array CGH, are likely the unbalanced product of a translocation t(17;21)(p13.3;q22.3). In the second patient, an 8-year-old girl with mental retardation, short stature, microcephaly and mild dysmorphic features, we identified four submicroscopic interspersed 17p duplications. All 17 breakpoints were examined in detail by FISH analysis. We found that four of the breakpoints mapped within known low-copy repeats (LCRs), including LCR17pA, middle SMS-REP/LCR17pB block, and LCR17pC. Our findings suggest that the LCR burden in proximal 17p may have stimulated the formation of these CCRs and, thus, that genome architectural features such as LCRs may have been instrumental in the generation of these CCRs.

Anaerobic desulphurisation of thiophenes by mixed microbial communities from oilfields.

Anaerobic enrichment cultures obtained from oil fields degraded various thiophenic compounds i.e. thiophene, benzothiophene and dibenzothiophene, with the concomitant formation of sulphide using hydrogen, lactate and ethanol as possible electron donors. It was demonstrated that dibenzothiophene was converted to biphenyl. However, hydrocarbon products from benzothiophene and thiophene desulphurisation could not be detected. After further enrichment on thiophenic compounds as the sole electron acceptor, the conversion activity disappeared while homo-acetogenic bacteria became abundantly present. In order to gain stable conversions of thiophenic compounds, attempts were made to isolate the sulphide-producing bacteria. Two highly enriched cultures were obtained, which degraded thiophenic compounds, but the activity remained low and homo-acetogenesis remained dominant.