Ischiospinal dysostosis (ISD) is a polytopic dysostosis characterized by ischial hypoplasia, multiple segmental anomalies of the cervicothoracic spine, hypoplasia of the lumbrosacral spine and occasionally associated with nephroblastomatosis. ISD is similar to, but milder than the lethal/semilethal condition termed diaphanospondylodysostosis (DSD), which is associated with homozygous or compound heterozygous mutations of bone morphogenetic protein-binding endothelial regulator protein (BMPER) gene. Here we report for the first time biallelic BMPER mutations in two patients with ISD, neither of whom had renal abnormalities. Our data supports and further extends the phenotypic variability of BMPER-related skeletal disorders.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0380-0) contains supplementary material, which is available to authorized users.

We and others have reported mutations in LONP1, a gene coding for a mitochondrial chaperone and protease, as the cause of the human CODAS (cerebral, ocular, dental, auricular and skeletal) syndrome (MIM 600373). Here, we delineate a similar but distinct condition that shares the epiphyseal, vertebral and ocular changes of CODAS but also included severe microtia, nasal hypoplasia, and other malformations, and for which we propose the name of EVEN-PLUS syndrome for epiphyseal, vertebral, ear, nose, plus associated findings. In three individuals from two families, no mutation in LONP1 was found; instead, we found biallelic mutations in HSPA9, the gene that codes for mHSP70/mortalin, another highly conserved mitochondrial chaperone protein essential in mitochondrial protein import, folding, and degradation. The functional relationship between LONP1 and HSPA9 in mitochondrial protein chaperoning and the overlapping phenotypes of CODAS and EVEN-PLUS delineate a family of “mitochondrial chaperonopathies” and point to an unexplored role of mitochondrial chaperones in human embryonic morphogenesis.

Recent discoveries have established the existence of a family of skeletal dysplasias caused by dominant mutations in TRPV4. This family comprises, in order of increasing severity, dominant brachyolmia, spondylo-metaphyseal dysplasia Kozlowski type, and metatropic dysplasia. We tested the hypothesis that a further condition, Spondylo-epiphyseal dysplasia (SED), Maroteaux type (MIM 184095; also known as pseudo-Morquio syndrome type 2), could be caused by TRPV4 mutations. We analyzed six individuals with Maroteaux type SED, including three who had previously been reported. All six patients were found to have heterozygous TRPV4 mutations; three patients had unreported mutations, while three patients had mutations previously described in association with metatropic dysplasia. In addition, we tested one individual with a distinct rare disorder, parastrem- 1443 matic dysplasia (MIM 168400). This patient had a common, recurrent mutation seen in several patients with Kozlowski type spondylo-metaphyseal dysplasia. We conclude that SED Maroteaux type and parastremmatic dysplasia are part of the TRPV4 dysplasia family and that TRPV4 mutations show considerable variability in phenotypic expression resulting in distinct clinicalradiographic phenotypes. Ó

Cerebral, ocular, dental, auricular, skeletal anomalies (CODAS) syndrome (MIM 600373) was first described and named by Shehib et al, in 1991 in a single patient. The anomalies referred to in the acronym are as follows: cerebral-developmental delay, ocular-cataracts, dental-aberrant cusp morphology and delayed eruption, auricular-malformations of the external ear, and skeletal-spondyloepiphyseal dysplasia. This distinctive constellation of anatomical findings should allow easy recognition but despite this only four apparently sporadic patients have been reported in the last 20 years indicating that the full phenotype is indeed very rare with perhaps milder or a typical presentations that are allelic but without sufficient phenotypic resemblance to permit clinical diagnosis. We performed exome sequencing in three patients (an isolated case and a brother and sister sib pair) with classical features of CODAS. Sanger sequencing was used to confirm results as well as for mutation discovery in a further four unrelated patients ascertained via their skeletal features. Compound heterozygous or homozygous mutations in LONP1 were found in all (8 separate mutations; 6 missense, 1 nonsense, 1 small in-frame deletion) thus establishing the genetic basis of CODAS and the pattern of inheritance (autosomal recessive). LONP1 encodes an enzyme of bacterial ancestry that participates in protein turnover within the mitochondrial matrix. The mutations cluster at the ATP-binding and proteolytic domains of the enzyme. Biallelic inheritance and clustering of mutations confirm dysfunction of LONP1 activity as the molecular basis of CODAS but the pathogenesis remains to be explored.

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OBJECTIVE. The purpose of this study was to evaluate the prevalence, radiologic characteristics, and accuracy of diagnosing delaminated tears at the supraspinatus tendon-infraspinatus tendon (SST-IST) on indirect MR arthrography. MATERIALS AND METHODS. Of 531 consecutive shoulders that underwent indirect MR arthrography, 231 shoulders with tears at the SST-IST were included. On the MR images, delaminated tears at the SST-IST, defined as intratendinous horizontal splitting between the articular and bursal layers of the SST-IST with or without different degrees of retraction between the two layers, were identified and classified into six types. Other radiologic findings of the SST-IST, such as the presence of intramuscular cysts, were evaluated. We used video records of 127 arthroscopic surgeries to determine the diagnostic accuracy of indirect MRI for the detection of the delaminated tears at the SST-IST. RESULTS. On MRI, 56% (129/231) of shoulders with SST-IST tears had delaminated tears. Articular-delaminated full-thickness tears (n = 58) and articular-delaminated partial-thickness tears (n = 64) were the most common types. Approximately 82% (36/44) of articular-delaminated full-thickness tears occurring at the SST were combined with articular-delaminated partial-thickness tears at the IST. SST-IST footprint tears and intramuscular cysts were significantly more common in the shoulders with delaminated tears. The sensitivity and specificity of indirect MR arthrography for detection of delaminated tears were 92% and 94%, respectively. CONCLUSION. On indirect MR arthrography, approximately half of the shoulders with SST-IST tears had delaminated tears. The diagnostic accuracy of indirect MR arthrography for detection of delaminated tears was high.

Most pediatric chest diseases are adequately evaluated with chest radiography. However, when chest radiography does not allow identification of the location and nature of an area of increased opacity, ultrasonography (US) can help establish the diagnosis. US may be helpful in evaluation of persistent or unusual areas of increased opacity in the peripheral lung, pleural abnormalities, and mediastinal widening; US is particularly useful in patients with complete opacification of a hemithorax at radiography. In cases of pulmonary parenchymal lesions, identification of air or fluid bronchograms at US and of pulmonary vessels at color flow imaging is useful for differentiating pulmonary consolidation or atelectasis from lung masses and pleural lesions. US allows characterization of pleural fluid collections as simple, complicated, or fibroadhesive, which is important information for planning thoracentesis or thoracotomy. Computed tomography and magnetic resonance imaging are superior to US in evaluation of the mediastinum, but US is a reasonable alternative in certain situations (eg, to avoid unnecessary investigation of a normal thymus simulating a mediastinal mass). In cases of chest wall lesions, US may enable localization of the site of origin to soft tissues or an extrapleural intrathoracic location. Osseous involvement, particularly rib involvement, is easily evaluated with US.

Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL), leptodactylic (lepto-SEMDJL) or Hall type, is an autosomal-dominant skeletal dysplasia manifesting with short stature, joint laxity with dislocation(s), limb malalignment, and spinal deformity. Its causative gene mutation has not yet been discovered. We captured and sequenced the exomes of eight affected individuals in six unrelated kindreds (three individuals in a family and five simplex individuals). Five novel sequence variants in KIF22, which encodes a member of the kinesin-like protein family, were identified in seven individuals. Sanger sequencing of KIF22 confirmed that c.443C>T (p.Pro148Ser) cosegregated with the phenotype in the affected individuals in the family; c.442C>T (p.Pro148Leu) or c.446G>A (p.Arg149Gln) was present in four of five simplex individuals, but was absent in unaffected individuals in their family and 505 normal cohorts. KIF22 mRNA was detected in human bone, cartilage, joint capsule, ligament, skin, and primary cultured chondrocytes. In silico analysis of KIF22 protein structure indicates that Pro148 and Arg149 are important in maintaining hydrogen bonds in the ATP binding and motor domains of KIF22. We conclude that these mutations in KIF22 cause lepto-SEMDJL.