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A cohort of five consanguineous Turkish families, originating from the Black Sea region of Turkey, with moderately severe recessively inherited osteogenesis imperfecta (OI) were studied to identify a novel locus for OI on chromosome 17. The identified mutations in FKBP10 which encodes FKBP65, a chaperone that participates in type 1 procollagen folding were found to affect type 1 procollagen secretion.

Abstract: 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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM PUBLISHER]

Pseudo-trisomy 13 is defined in chromosomally normal patients withholoprosencephaly 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. [ABSTRACT FROM AUTHOR]

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., (Copyright © 2012 Wiley Periodicals, Inc.)

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-Hünermann-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., (Copyright 2009 Wiley-Liss, Inc.)

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.