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Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1BCSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive webbased survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1BID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features., We are grateful for the assistance of Pepijn Cox in setting up the website www.arid1bgene.com. This study has made use of data generated by the Human Disease Genes website series, www.humandiseasegenes.com. This work was financially supported by grants from the Netherlands Organisation for Health Research and Development (917-86-319 to B.B.A.d.V., 912-12-109 to B.B.A.d.V.)

HERC1 is a member of HERC protein family of ubiquitin ligases and is a negative regulator of the mTOR pathway. It is also a guanine nucleotide exchange factor for ARF and Rab family GTPases. Biallelic mutations in HERC1 were recently shown to cause a human phenotype with overgrowth and intellectual disability as main features. Herein we describe clinical features in another patient with homozygous novel mutation in HERC1. Moderate to severe intellectual disability, hypotonia, macrocephaly, tall stature, and facial features appear as main clinical features of the condition. Kyphoscoliosis and seizures frequently accompany and autistic features might be another feature as recent studies also implicate. HERC1 mutations should be considered in differential diagnosis of severe intellectual disability and behavioural problems, particularly in patients testing negative for fragile X and KANSL1 mutations.

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.

WOS: 000327800400004, PubMed ID: 23906836, Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. Denovodominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation ( NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies., German Federal Ministry of Education and Research (BMBF)Federal Ministry of Education & Research (BMBF) [01GM1211A, 01GM1211B]; TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [112S398]; ERARE-ANR CraniRareFrench National Research Agency (ANR); German Federal Ministry of Education and ResearchFederal Ministry of Education & Research (BMBF) [01GS08167]; DFGGerman Research Foundation (DFG) [BO 1955/2-3, WU 314/6-2]; Volkswagen FoundationVolkswagen [86042]; Telethon ItalyFondazione Telethon [GTB12001], This work was part of the CRANIRARE-2 Network funded by the German Federal Ministry of Education and Research (BMBF) (01GM1211A to B. W., 01GM1211B to D. W.), the TUBITAK (112S398 to H. K.) and ERARE-ANR CraniRare to S. L. This work was also funded by a grant (MRNET) from the German Federal Ministry of Education and Research (01GS08167 to D. W.), by DFG grants (BO 1955/2-3 and WU 314/6-2 to S. B. and D. W.) and by the Volkswagen Foundation (ref 86042 to A. W.). The biobank "Cell lines and DNA bank of Rett syndrome, X linked Mental Retardation and other genetic diseases", member of the Telethon Network of Genetic Biobanks (project no. GTB12001), funded by Telethon Italy, provided us with specimens.

GRID2 is a member of the ionotropic glutamate receptor family of excitatory neurotransmitter receptors. GRID2 encodes the glutamate receptor subunit delta-2, selectively expressed in cerebellar Purkinje cells. The phenotype associated with loss of GRID2 function was described only in mice until now, characterized by different degrees of cerebellar ataxia and usually relatively mild abnormalities of the cerebellum. This work describes for the first time the human phenotype associated with homozygous partial deletion of GRID2 in 3 children in one large consanguineous Turkish family. Homozygous deletion of exons 3 and 4 of GRID2 (94 153 589-94 298 037 bp) in the proband and similarly affected cousins, and heterozygous deletions in parental DNA were shown using Affymetrix® 6.0 single-nucleotide polymorphism array, confirmed by real-time polymerase chain reaction. The phenotype includes nystagmus, hypotonia with marked developmental delay in gross motor skills in early infancy followed by a static encephalopathy course with development of cerebellar ataxia, oculomotor apraxia, and pyramidal tract involvement.

Progressive pseudorheumatoid dysplasia (PPRD) is a genetic, non-inflammatory arthropathy caused by recessive loss of function mutations in WISP3 (Wnt1-inducible signaling pathway protein 3; MIM 603400), encoding for a signaling protein. The disease is clinically silent at birth and in infancy. It manifests between the age of 3 and 6 years with joint pain and progressive joint stiffness. Affected children are referred to pediatric rheumatologists and orthopedic surgeons; however, signs of inflammation are absent and anti-inflammatory treatment is of little help. Bony enlargement at the interphalangeal joints progresses leading to camptodactyly. Spine involvement develops in late childhood and adolescence leading to short trunk with thoracolumbar kyphosis. Adult height is usually below the 3rd percentile. Radiographic signs are relatively mild. Platyspondyly develops in late childhood and can be the first clue to the diagnosis. Enlargement of the phalangeal metaphyses develops subtly and is usually recognizable by 10 years. The femoral heads are large and the acetabulum forms a distinct lip overriding the femoral head. There is a progressive narrowing of all articular spaces as articular cartilage is lost. Medical management of PPRD remains symptomatic and relies on pain medication. Hip joint replacement surgery in early adulthood is effective in reducing pain and maintaining mobility and can be recommended. Subsequent knee joint replacement is a further option. Mutation analysis of WISP3 allowed the confirmation of the diagnosis in 63 out of 64 typical cases in our series. Intronic mutations in WISP3 leading to splicing aberrations can be detected only in cDNA from fibroblasts and therefore a skin biopsy is indicated when genomic analysis fails to reveal mutations in individuals with otherwise typical signs and symptoms. In spite of the first symptoms appearing in early childhood, the diagnosis of PPRD is most often made only in the second decade and affected children often receive unnecessary anti-inflammatory and immunosuppressive treatments. Increasing awareness of PPRD appears to be essential to allow for a timely diagnosis. (C) 2012 Wiley Periodicals, Inc.

ABS TRACT Noonan syndrome (NS), is an autosomal dominant disorder commonly seen in child hood and is characterized by short stature, congenital heart defects and facial abnormalities (espe cially in adults) along with thoracic deformity. Lymphatic dysplasia can be seen with this syndrome causing chylothorax by development of fistulas between thoracic duct and pleural space or it can directly occur by malformation of thoracic lymphatic vessels. Hence, chylothorax can also be seen. Herein, we present a case with this syndrome and chylothorax secondary to possible lymphatic dysplasia. We achieved a great success with ocreotide and medium chain trigliserides in the man agement of chylothorax and hence suggest this therapy to other clinicians.

The X-linked dominant trait focal dermal hypoplasia (FDH, Goltz syndrome) is a developmental defect with focal distribution of affected tissues due to a block of Wnt signal transmission from cells carrying a detrimental PORCN mutation on an active X-chromosome. Molecular characterization of 24 unrelated patients from different ethnic backgrounds revealed 23 different mutations of the PORCN gene in Xp11.23. Three were microdeletions eliminating PORCN and encompassing neighboring genes such as EBP, the gene associated with Conradi-Hunermann-Happle syndrome (CDPX2). 12/24 patients carried nonsense mutations resulting in loss of function. In one case a canonical splice acceptor site was mutated, and 8 missense mutations exchanged highly conserved amino acids. FDH patients overcome the consequences of potentially lethal X-chromosomal mutations by extreme skewing of X-chromosome inactivation in females, enabling transmission of the trait in families, or by postzygotic mosaicism both in male and female individuals. Molecular characterization of the PORCN mutations in cases diagnosed as Goltz syndrome is particularly relevant for genetic counseling of patients and their families since no functional diagnostic test is available and carriers of the mutation might otherwise be overlooked due to considerable phenotypic variability associated with the mosaic status.

Background: Parapneumonic effusions cause significant morbidity and mortality despite current developments in diagnostic and therapeutic approaches. Causative microorganisms may remain unidentified in a significant number of patients by cultures and Gram smears. Polymerase chain reaction (PCR) is a molecular technique for the detection of causative bacteria; however, its efficiency in pleural fluids is less known. Objectives: The present study was performed to compare the efficiency of PCR in the detection of the three most common organisms (Staphylococcus aureus, Streptococcus pneumoniae and Haemophylus influenzae) with conventional methods. Methods: Twenty-eight consecutive patients with parapneumonic pleural effusions were studied. On admission, pleural fluid samples were obtained for Gram staining, routine culture and PCR analysis for S. aureus, S. pneumoniae and H. influenzae. Results: PCR analysis allowed detection of 11 microorganisms in 10 patients (35.7%), whereas pleural fluid cultures detected the etiological agent in only 2 (7.1%). S. pneumoniae was the most frequent agent. Conclusions: Pleural fluid cultures may have low diagnostic yields, partly due to prior antibiotic use. Pleural fluid PCR analysis may improve the etiologic diagnosis in parapneumonic pleural effusions, with technical advances leading to higher yields than obtained in this study.

Study objectives Biochemical and inflammatory markers in pleural inflammation were evaluated in pediatric cases of parapneumonic effusions, and interleukin (IL)-8 and tumor necrosis factor (TNF)-α concentrations were tested for possible differentiation of the complicated nature of effusions. Patients Twenty-eight patients (12 female) who were admitted to Hacettepe University Childrens’ Hospital over a 2-year period were included in the study. Measurements Patients were grouped according to the stage of effusion. Pleural fluid leukocyte count, neutrophil ratio, pH, protein, glucose levels, lactate dehydrogenase (LDH) levels, TNF-α levels, IL-8 levels, and nitrite levels were obtained. Results Of these patients, 13 had empyema, 10 had complicated parapneumonic effusions (CPEs), and 5 had uncomplicated parapneumonic effusions (UPEs). Protein and glucose levels decreased, leukocyte count, neutrophil ratio, TNF-α levels, nitrite levels, and IL-8 levels increased progressively as the stage of the disease progressed. IL-8 levels, but not TNF-α and nitrite levels, were statistically different among the groups. IL-8, TNF-α, and nitrite levels all correlated positively with each other (all p ≤ 0.001), and pH correlated negatively with these markers (all p ≤ 0.001). At a cutoff value of 76.6 pg/mL, TNF-α discriminated between CPEs and UPEs with a sensitivity of 50%, a specificity of 100%, and an accuracy of 78%. At a cutoff value of 701.6 pg/mL, IL-8 differentiated CPE and UPE with a sensitivity of 80%, a specificity of 80%, and an accuracy of 86%. Conclusions Progressive changes in common biochemical markers ( ie , pH, and protein, glucose, and LDH levels) are interrelated during stages of pleural inflammation. IL-8 may be used as an alternative marker for discriminating between CPEs and UPEs in pediatric parapneumonic effusions.

Intellectual disability (ID) has a prevalence of 3% and is classified according to its severity. An underlying etiology cannot be determined in 75–80% in mild ID, and in 20–50% of severe ID. After it has been shown that copy number variations involving short DNA segments may cause ID, genome-wide SNP microarrays are being used as a tool for detecting submicroscopic copy number changes and uniparental disomy. This study was performed to investigate the presence of copy number changes in patients with ID of unidentified etiology. Affymetrix ® 6.0 SNP microarray platform was used for analysis of 100 patients and their healthy parents, and data were evaluated using various databases and literature. Etiological diagnoses were made in 12 patients (12%). Homozygous deletion in NRXN1 gene and duplication in IL1RAPL1 gene were detected for the first time. Two separate patients had deletions in FOXP2 and UBE2A genes, respectively, for which only few patients have recently been reported. Interstitial and subtelomeric copy number changes were described in 6 patients, in whom routine cytogenetic tools revealed normal results. In one patient uniparental disomy type of Angelman syndrome was diagnosed. SNP microarrays constitute a screening test able to detect very small genomic changes, with a high etiological yield even in patients already evaluated using traditional cytogenetic tools, offer analysis for uniparental disomy and homozygosity, and thereby are helpful in finding novel disease-causing genes: for these reasons they should be considered as a first-tier genetic screening test in the evaluation of patients with ID and autism.

Osteogenesis imperfecta is a clinically and genetically heterogeneous brittle bone disorder that results from defects in the synthesis, structure, or posttranslational modification of type I procollagen. Dominant forms of OI result from mutations in COL1A1 or COL1A2, which encode the chains of the type I procollagen heterotrimer. The mildest form of OI typically results from diminished synthesis of structurally normal type 1 procollagen, whereas moderately severe to lethal forms of OI usually result from structural defects in one of the type 1 procollagen chains. Recessively inherited OI, usually phenotypically severe, has recently been shown to result from defects in the prolyl-3-hydroxylase complex that lead to the absence of a single 3-hydroxyproline at residue 986 of the alpha 1 (I) triple helical domain. We studied a cohort of five consanguineous Turkish families, originating from the Black Sea region of Turkey, with moderately severe recessively inherited OI and identified a novel locus for OI on chromosome 17. In these families, and in a Mexican-American family, homozygosity for mutations in FKBP10, which encodes FKBP65, a chaperone that participates in type 1 procollagen folding, was identified. Further, we determined that FKBP10 mutations affect type I procollagen secretion. These findings identify a previously unrecognized mechanism in the pathogenesis of OI.

Pediatric pleural effusions present a changing profile over time, both in terms of etiological subgroups and causative microorganisms in parapneumonic effusions. This retrospective study aimed to review pediatric pleural effusions in a large cohort over a 29-year period, with special emphasis on the etiological subgroups and microbiological causes of parapneumonic effusions. The medical records of 492 pediatric patients were reviewed for a comparison of subgroups of pleural effusions and microbiological causes of parapneumonic effusions between three decades. Parapneumonic effusions (381 patients) made up 77.4% of the group. Tuberculous pleurisy decreased, but malignant effusions doubled in number over time. A causative microorganism was identified in 34.6% overall, with Staphylococcus aureus and Streptococcus pneumoniae being the two most common. Relative frequency of S. aureus decreased, whereas pneumococci and Haemophilus influenzae were more frequent in recent years.

Pseudo-trisomy 13 is defined in chromosomally normal patients with holoprosencephaly and associating features suggestive of trisomy 13. An autosomal recessive pattern of inheritance for this situation is most likely, but a gene for this condition has not yet been mapped. A fetus is presented with phenotypic features reminiscent of trisomy 13 but a normal karyotype, 46, XY. The pregnancy was terminated due to severe fetal malformations. In autopsy, the fetus had semilobar holoprosencephaly, hydrocephaly and dysmorphic features such as hypotelorism, cleft lip, a flat nose with a single nostril, low-set ears, postaxial polydactyly in all extremities, left unilateral pes equinovarus and pulmonary segmentation defect on the right. The parents were 2nd cousins once removed. Holoprosencephaly and polydactyly with or without other findings in chromosomally normal patients should raise the suspicion of pseudo-trisomy 13 syndrome, particularly when parental consanguinity is present.

Parapneumonic effusions cause significant morbidity and mortality despite current developments in diagnostic and therapeutic approaches. Causative microorganisms may remain unidentified in a significant number of patients by cultures and Gram smears. Polymerase chain reaction (PCR) is a molecular technique for the detection of causative bacteria; however, its efficiency in pleural fluids is less known.The present study was performed to compare the efficiency of PCR in the detection of the three most common organisms (Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae) with conventional methods.Twenty-eight consecutive patients with parapneumonic pleural effusions were studied. On admission, pleural fluid samples were obtained for Gram staining, routine culture and PCR analysis for S. aureus, S. pneumoniae and H. influenzae.PCR analysis allowed detection of 11 microorganisms in 10 patients (35.7%), whereas pleural fluid cultures detected the etiological agent in only 2 (7.1%). S. pneumoniae was the most frequent agent.Pleural fluid cultures may have low diagnostic yields, partly due to prior antibiotic use. Pleural fluid PCR analysis may improve the etiologic diagnosis in parapneumonic pleural effusions, with technical advances leading to higher yields than obtained in this study.

Biochemical and inflammatory markers in pleural inflammation were evaluated in pediatric cases of parapneumonic effusions, and interleukin (IL)-8 and tumor necrosis factor (TNF)-alpha concentrations were tested for possible differentiation of the complicated nature of effusions.Twenty-eight patients (12 female) who were admitted to Hacettepe University Childrens' Hospital over a 2-year period were included in the study.Patients were grouped according to the stage of effusion. Pleural fluid leukocyte count, neutrophil ratio, pH, protein, glucose levels, lactate dehydrogenase (LDH) levels, TNF-alpha levels, IL-8 levels, and nitrite levels were obtained.Of these patients, 13 had empyema, 10 had complicated parapneumonic effusions (CPEs), and 5 had uncomplicated parapneumonic effusions (UPEs). Protein and glucose levels decreased, leukocyte count, neutrophil ratio, TNF-alpha levels, nitrite levels, and IL-8 levels increased progressively as the stage of the disease progressed. IL-8 levels, but not TNF-alpha and nitrite levels, were statistically different among the groups. IL-8, TNF-alpha, and nitrite levels all correlated positively with each other (all por = 0.001), and pH correlated negatively with these markers (all por = 0.001). At a cutoff value of 76.6 pg/mL, TNF-alpha discriminated between CPEs and UPEs with a sensitivity of 50%, a specificity of 100%, and an accuracy of 78%. At a cutoff value of 701.6 pg/mL, IL-8 differentiated CPE and UPE with a sensitivity of 80%, a specificity of 80%, and an accuracy of 86%.Progressive changes in common biochemical markers (ie, pH, and protein, glucose, and LDH levels) are interrelated during stages of pleural inflammation. IL-8 may be used as an alternative marker for discriminating between CPEs and UPEs in pediatric parapneumonic effusions.

Williams syndrome (WS) is a well-known microdeletion syndrome characterized by specific facial features, retardation in growth and development, typical personality and cardiac defects. Poor growth potential is further affected by central precocious puberty (CPP) which is frequent in these patients. A WS patient with CPP is presented, whose pubertal development and bone age progression were arrested by administration of GnRH analogues. The case is reported to discuss the role of GnRH analogues for management of CPP in patients with WS.