Autistic Disorder in Patients with Williams-Beuren Syndrome: A Reconsideration of the Williams-Beuren Syndrome Phenotype

Abstract Background: Williams-Beuren syndrome (WBS), a rare developmental disorder caused by deletion of contiguous genes at 7q11.23, has been characterized by strengths in socialization (overfriendliness) and communication (excessive talkativeness). WBS has been often considered as the polar opposite behavioral phenotype to autism. Our objective was to better understand the range of phenotypic expression in WBS and the relationship between WBS and autistic disorder

Finger creases lend a hand in Kabuki syndrome.

International audienceKabuki syndrome (KS) is a rare syndrome associating malformations with intellectual deficiency and numerous visceral, orthopedic, endocrinological, immune and autoimmune complications. The early establishment of a diagnostic of KS leads to better care of the patients and therefore prevents complications such as perception deafness, severe complications of auto-immune diseases or obesity. However, the diagnosis of KS remains difficult because based on the appreciation of facial features combined with other highly variable features. We describe a novel sign, namely the attenuation and/or congenital absence of the IPD crease of the third and fourth fingers associated with limitation of flexion of the corresponding joints, which seems to be specific of KS and could help the clinician to diagnose KS

Stratospheric aerosol - Observations, processes, and impact on climate

Interest in stratospheric aerosol and its role in climate have increased over the last decade due to the observed increase in stratospheric aerosol since 2000 and the potential for changes in the sulfur cycle induced by climate change. This review provides an overview about the advances in stratospheric aerosol research since the last comprehensive assessment of stratospheric aerosol was published in 2006. A crucial development since 2006 is the substantial improvement in the agreement between in situ and space-based inferences of stratospheric aerosol properties during volcanically quiescent periods. Furthermore, new measurement systems and techniques, both in situ and space based, have been developed for measuring physical aerosol properties with greater accuracy and for characterizing aerosol composition. However, these changes induce challenges to constructing a long-term stratospheric aerosol climatology. Currently, changes in stratospheric aerosol levels less than 20% cannot be confidently quantified. The volcanic signals tend to mask any nonvolcanically driven change, making them difficult to understand. While the role of carbonyl sulfide as a substantial and relatively constant source of stratospheric sulfur has been confirmed by new observations and model simulations, large uncertainties remain with respect to the contribution from anthropogenic sulfur dioxide emissions. New evidence has been provided that stratospheric aerosol can also contain small amounts of nonsulfate matter such as black carbon and organics. Chemistry-climate models have substantially increased in quantity and sophistication. In many models the implementation of stratospheric aerosol processes is coupled to radiation and/or stratospheric chemistry modules to account for relevant feedback processes

Fifteen years of research on oral–facial–digital syndromes: from 1 to 16 causal genes

Oral–facial–digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753 and IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231 and WDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype

Autistic Disorder in Patients with Williams-Beuren Syndrome: A Reconsideration of the Williams-Beuren Syndrome Phenotype

International audienceBackground: Williams-Beuren syndrome (WBS), a rare developmental disorder caused by deletion of contiguous genes at 7q11.23, has been characterized by strengths in socialization (overfriendliness) and communication (excessive talkativeness). WBS has been often considered as the polar opposite behavioral phenotype to autism. Our objective was to better understand the range of phenotypic expression in WBS and the relationship between WBS and autistic disorder. Methodology: The study was conducted on 9 French individuals aged from 4 to 37 years old with autistic disorder associated with WBS. Behavioral assessments were performed using Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) scales. Molecular characterization of the WBS critical region was performed by FISH. Findings: FISH analysis indicated that all 9 patients displayed the common WBS deletion. All 9 patients met ADI-R and ADOS diagnostic criteria for autism, displaying stereotypies and severe impairments in social interaction and communication (including the absence of expressive language). Additionally, patients showed improvement in social communication over time. Conclusions: The results indicate that comorbid autism and WBS is more frequent than expected and suggest that the common WBS deletion can result in a continuum of social communication impairment, ranging from excessive talkativeness and overfriendliness to absence of verbal language and poor social relationships. Appreciation of the possible co-occurrence of WBS and autism challenges the common view that WBS represents the opposite behavioral phenotype of autism, and might lead to improved recognition of WBS in individuals diagnosed with autism

Duane anomaly, congenital myopathy and severe scoliosis in sibs: new AR syndrome?

We report on two sisters who show a similar pattern of anomalies consisting of bilateral Stilling-Turk-Duane retraction syndrome (type 3), non-progressive hypotonia with delayed motor milestones but normal intelligence, severe, early onset scoliosis, and short stature. Muscular biopsy revealed numerous regenerating fibers, but no specific abnormalities among the non-regenerating fibers. This combination of anomalies has not been previously reported, and could represent a new autosomal recessive syndrome. The only differential diagnosis is Crisfield-Dretakis-Sharpe syndrome, a combination of lateral gaze palsy, ptosis, and scoliosis without hypotonia, recessively inherited

Additional clinical and molecular analyses of TFAP2A in patients with the branchio-oculo-facial syndrome: Previously reported patient

SCOPUS: le.jinfo:eu-repo/semantics/publishe

Additional clinical and molecular analyses of TFAP2A in patients with the branchio-oculo-facial syndrome

The branchio-oculo-facial syndrome (BOFS) is a rare disorder with approximately 50 sporadic and familial cases in the literature. We report on the clinical and molecular analyses of five additional patients with BOFS (two familial and three sporadic). DNA analysis of the TFAP2A gene associated with BOFS using DNA sequencing detected a mutation [c.763A>G (p.Arg255Gly)] in two unrelated patients. This mutation had been reported in another patient and indicates a probable mutational hotspot in the TFAP2A gene. We also detected three new mutations which are restricted to exons 4-6. These gene regions are almost free of any single nucleotide polymorphisms. An evolutionary sequence comparison showed a high degree of sequence conservation from humans to the honey bee (Apis mellifera) in exon 6 showing that this part of the protein is probably essential. Our study represents the second group of BOFS patients with molecular confirmation, expanding the phenotype and spectrum of mutations and limiting it to a restricted part of the gene. © 2010 Wiley-Liss, Inc.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

The spectrum of cardiac anomalies in Noonan syndrome as a result of mutations in the PTPN11 gene

OBJECTIVE. Noonan syndrome is a clinically homogeneous but genetically heterogeneous condition. Type 1 Noonan syndrome is defined by the presence of a mutation in the PTPN11 gene, which is found in ∼40% of the cases. Phenotype descriptions and cardiac defects from cohorts with Noonan syndrome were delineated in the "pregenomic era." We report the heart defects and links to gene dysfunction in cardiac development in a large cohort of patients with type 1 Noonan syndrome. METHODS. This was a retrospective, multicenter study based on clinical history, pictures, and medical and cardiologic workup over time. Data were collected by referral geneticists. Mutation screening was performed by direct sequencing of exons 2, 3, 4, 7, 8, 12, and 13 and their intron-exon boundaries, which harbor 98% of identified mutations the PTPN11 gene. RESULTS. A PTPN11 gene mutation was identified in 104 (38.25%) of 274 patients with Noonan syndrome. Heart defect was present in 85%. The most prevalent congenital heart defects were pulmonary valve stenosis (60%), atrial septal defect, ostium secundum type (25%), and stenosis of the peripheral pulmonary arteries (in at least 15%). Pulmonary valve stenosis and atrial septal defect, ostium secundum type, were significantly associated with the identification of a mutation in the PTPN11 gene. Ventricular septal defect and most left-sided heart defects showed a trend toward overrepresentation in the group without a mutation. CONCLUSION. We compared our data with previous series and integrated the comprehension of molecular PTPN11 gene dysfunction in heart development. Copyright © 2007 by the American Academy of Pediatrics.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

A locus for sacral/anorectal malformations maps to 6q25.3 in a 0.3 Mb interval region

International audiencePartial absence of the sacrum is a rare congenital defect that also occurs as an autosomal-dominant trait, whereas imperforate/ectopic anus is a relatively common malformation, usually observed in multiple congenital anomalies syndromes. We report on a girl born to healthy consanguineous parents (first cousins once removed) with anal imperforation and associated rectovaginal fistula and partial sacral agenesis. Facial dysmorphism included a high forehead, epicanthic folds, downslanting palpebral fissures, hypertelorism and a depressed nasal root. Brain MRI showed a bilateral opercular dysplasia with a unilateral (right) pachygyria; MRI and X-ray imaging of the spine disclosed a tethered cord associated with partial sacral agenesis. She showed a moderate developmental delay. Ophthalmologic examination evidenced bilateral microphthalmos and relative microcornea. Cytogenetic studies in our patient disclosed a pure de novo 6q25.3 --> qter deletion. By genotype analysis, we detected in our patient a maternal allele loss encompassing D6S363 and D6S446. Pure distal 6q deletion is a rare anomaly, reported in association with sacral/anorectal malformations (sacral agenesis, anal imperforation/ectopia) and never with cortical dysplasia. Pooling deletion mapping information in patients with pure terminal and interstitial 6q deletion allowed us to define a critical region spanning 0.3 Mb between the markers D6S959 and D6S437 for sacral/anal malformations. We hypothesize that haploinsufficiency for a gene within the deleted region may impair normal development of caudal structures, possibly acting on the notochordal development. European Journal of Human Genetics (2006) 14, 971-974. doi:10.1038/sj.ejhg.5201635; published online 17 May 2006