Chondrodysplasia

BACKGROUND: Rare bone diseases account for 5% of all birth defects yet very few have personalised treatments. Developments in genetic diagnosis, molecular techniques and treatment technologies however, are leading to unparalleled therapeutic advance. This review explores the evolving therapeutic landscape of genetic skeletal disorders (GSDs); the key conditions and there key differentials. METHODS: A retrospective literature based review was conducted in December 2018 using a systematic search strategy for relevant articles and trials in Pubmed and clinicaltrials...

Rhizomelic chondrodysplasia punctata (RCDP) is a rare genetic disorder caused by mutations in peroxisomal genes essential for plasmalogen biosynthesis. Plasmalogens are a class of membrane glycerophospholipids containing a vinyl-ether linked fatty alcohol at the sn-1 position that affect functions including vesicular transport, membrane protein function and free radical scavenging. A logical rationale for the treatment of RCDP is therefore the therapeutic augmentation of plasmalogens. The objective of this work was to provide a preliminary characterization of a novel vinyl-ether synthetic plasmalogen, PPI-1040, in support of its potential utility as an oral therapeutic option for RCDP...

BACKGROUND: Schmid-type metaphyseal chondrodysplasia (MCDS) is an autosomal dominant disorder caused by COL10A1 mutations, which is characterized by short stature, waddling gait, coxa vara and bowing of the long bones. However, descriptions of the expressivity of MCDS are rare. METHODS: Two probands and available family members affected with MCDS were subjected to clinical and radiological examination. Genomic DNA of all affected individuals was subjected to whole-exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and in 250 healthy donors...

Progressive deterioration of neuroimaging and electroencephalography (EEG) had been described in rhizomelic chondrodysplasia punctata (RCDP); however, serial EEG data showing sequential EEG changes(before and after seizure onset) is lacking. We report a child with a diagnosis of type 1 RCDP, who had a progressive decline in EEG and radiologic findings over a 5 year period. Her first EEG was normal at the age of 8 months. Follow-up EEG at the age of 2 years showed a mild background slowing as well as frequent 1-2 Hz central-parietal spike wave with midline involvement...

Objective: The integrity of cartilage depends on the correct synthesis of extracellular matrix (ECM) components. In case of insufficient folding of proteins in the endoplasmic reticulum (ER) of chondrocytes, ECM proteins aggregate, ER stress evolves, and the unfolded protein response (UPR) is initiated. By this mechanism, chondrocytes relieve the stress condition or initiate cell death by apoptosis. Especially persistent ER stress has emerged as a pathogenic mechanism in cartilage diseases, such as chondrodysplasias and osteoarthritis...

Non-motile ciliopathies (disorders of the primary cilia) include autosomal dominant and recessive polycystic kidney diseases, nephronophthisis, as well as multisystem disorders Joubert, Bardet-Biedl, Alström, Meckel-Gruber, oral-facial-digital syndromes, and Jeune chondrodysplasia and other skeletal ciliopathies. Chronic progressive disease of the kidneys, liver, and retina are common features in non-motile ciliopathies. Some ciliopathies also manifest neurological, skeletal, olfactory and auditory defects...

The phenotypic spectrum of Type 2 collagenopathies ranges from lethal achondrogenesis Type 2 to milder osteoarthritis with mild chondrodysplasia. All of them are monoallelic except for the two recent reports showing that biallelic variants in COL2A1 can cause spondyloepiphyseal dysplasia congenita in two children. Here we report two additional families with homozygous variants, c.4135C>T (p.Arg1379Cys) and c.3190C>T (p.Arg1133Cys) in COL2A1 resulting in two distinct skeletal dysplasia phenotypes of intermediate severity...

The type-2 peroxisomal targeting signal (PTS2) is one of two peptide motifs destining soluble proteins for peroxisomes. This signal acts as amphiphilic α-helix exposing the side chains of all conserved residues to the same side. PTS2 motifs are recognized by a bipartite complex consisting of the receptor PEX7 and a co-receptor. Cargo-loaded receptor complexes are translocated across the peroxisomal membrane by a transient pore and inside peroxisomes, cargo proteins are released and processed in many, but not all species...

BACKGROUND: 3C/Ritscher-Schinzel syndrome is characterised by congenital cranio-cerebello-cardiac dysplasia, where CCDC22 and WASHC5 are accepted as the causative genes. In combination with the retromer or retriever complex, these genes play a role in endosomal membrane protein recycling. We aimed to identify the gene abnormality responsible for the pathogenicity in siblings with a 3C/Ritscher-Schinzel-like syndrome, displaying cranio-cerebello-cardiac dysplasia, coloboma, microphthalmia, chondrodysplasia punctata and complicated skeletal malformation...

Jansen's metaphyseal chondrodysplasia (JMC) is a rare disease of bone and mineral ion physiology that is caused by activating mutations in the PTHR1. Ligand-independent signaling by the mutant receptors in cells of bone and kidney results in abnormal skeletal growth, excessive bone turn-over, and chronic hypercalcemia and hyperphosphaturia. Clinical features further include short-stature, limb deformities, nephrocalcinosis and progressive losses in kidney function. There is no effective treatment option available for JMC...

BACKGROUND: Axial and extra-axial deceleration in function and progressive joint pain with subsequent development of antalgic gait associated with swellings, and stiffness of the joints with loss of the physiological spine biomechanics were the natural history in this group of patients. Clinical and radiological phenotypes have been analysed carefully to further understand the aetiology behind. METHODS: Seven patients (three children around the age of 9-11 and one child of 17 years old)...

BACKGROUND: Cartilage-hair hypoplasia is a rare autosomal recessive disease, which is characterized by metaphyseal chondrodysplasia and thin hair. It can be accompanied by immunological disorders in varying degrees. CLINICAL CASE: The case of a 35-month-old girl is described. Since her birth, with growth restriction, she has developed pneumonia eleven times, malabsorption syndrome and aganglionic megacolon, which is why she was diagnosed with cartilage-hair hypoplasia, with expression of non-severe combined immunodeficiency...

Genome-wide association studies (GWAS) have commonly been used to identify candidate genes that control economically important traits in livestock. Our objective was to detect potential candidate genes associated mainly with muscle development traits related to dimension of hindquarter in cattle. A next generation sequencing (NGS) dataset to imputed to 12 million single nucleotide polymorphisms (SNPs) (from 1252 Simmental beef cattle) were used to search for genes affecting hindquarter traits using a linear, mixed model approach...

Desbuquois dysplasia (DBQD1 [MIM 251450]) is an autosomal recessive chondrodysplasia with micromelia, severe joint laxity and dislocations, and a characteristic radiographic "monkey wrench" appearance at the proximal femur. Type 1 Desbuquois dysplasia is caused by mutations in CANT1 and is distinct from Type 2, caused by mutations in XYLT1, in that the former has unique hand anomalies including accessory phalangeal ossification centers, advanced carpal bone maturation, and/or axial phalangeal deviation...

Opsismodysplasia (OPS) is a rare but severe autosomal recessive skeletal chondrodysplasia caused by inactivating mutations in the Inppl1/Ship2 gene. The molecular mechanism leading from Ship2 gene inactivation to OPS is currently unknown. Here, we used our Ship2Δ/Δ mouse expressing reduced amount of a catalytically-inactive SHIP2 protein and a previously reported SHIP2 inhibitor to investigate growth plate development and mineralization in vivo, ex vivo and in vitro. First, as observed in OPS patients, catalytic inactivation of SHIP2 in mouse leads to reduced body length, shortening of long bones, craniofacial dysmorphism, reduced height of the hyperthrophic chondrocyte zone and to defects in growth plate mineralization...

BACKGROUND: Cervical spine deformity in rhizomelic chondrodysplasia punctata (RCDP) has been described with different findings reported in the literature. However, available literature provides limited data from a few cases with magnetic resonance imaging (MRI) of the cervical spine. Our report describes the MRI findings in a group of children with RCDP, aiming to reach a better understanding of this pathology. METHODS: An Institutional Review Board-approved RCDP Registry was created at our institution with the goal of identifying pertinent medical issues over the lifespan of individuals with RCDP...

BACKGROUND: Metaphyseal dysplasia without hypotrichosis (MDWH) is a rare form of chondrodysplasia with no extraskeletal manifestations. MDWH is caused by RMRP mutations, but it is differentiated from the allelic condition cartilage-hair hypoplasia (CHH), which in addition to chondrodysplasia is characterised by thin hair, immunodeficiency and increased risk of malignancy. The long-term outcome of MDWH remains unknown. OBJECTIVE: We diagnosed severe agranulocytosis in a subject with RMRP mutations and normal hair...

Regulated growth plate activity is essential for postnatal bone development and body stature, yet the systems regulating epiphyseal fusion are poorly understood. Here, we show that the tissue inhibitors of metalloprotease (TIMP) gene family is essential for normal bone growth after birth. Whole-body quadruple-knockout mice lacking all four TIMPs have growth plate closure in long bones, precipitating limb shortening, epiphyseal distortion, and widespread chondrodysplasia. We identify TIMP/FGF-2/IHH as a novel nexus underlying bone lengthening where TIMPs negatively regulate the release of FGF-2 from chondrocytes to allow IHH expression...

We present a case of cystolitholapaxy using the LithoClast Trilogy lithotripter device per urethra via a rigid 26F nephroscope in a 36-year-old female with chondrodysplasia, paraplegia, contractures, and history of bladder augment managed with clean intermittent catheterization. The stone was 4cm in diameter with an average of 1300 Hounsfield Units, and composed of 45% calcium phosphate, 40% struvite, and 15% ammonium urate. Advantages include faster fragmentation time versus holmium laser, improved safety with suction extraction and improved vision, ability to treat larger stones endoscopically, and control of all variables by one surgeon with only a single foot pedal...

BACKGROUND: X-linked recessive chondrodysplasia punctate (CDPX1) is a rare congenital disorder of bone and cartilage development, caused by a mutation in the arylsulfatase E (ARSE) gene located on chromosome Xp22.3. Although most of the affected men had mild symptoms, some had more severe symptoms, and had a poor prognosis. CASE PRESENTATION: We present the case of a male fetus diagnosed with CDPX1. Ultrasound clearly showed that hypoplasia of the midface, flatness of face, low flatness of the nose, collapse of the tip of the nose, accompanied by severe spinal stenosis and secondary ossification center of the femoral metaphysis appeared in advance...