Congenital Skeletal Dysplasia Research Articles

Cytological findings of rhizomelic chondrodysplasia punctata: A rare skeletal dysplasia

Chondrodysplasia punctata (CDP) is a rare, skeletal dysplasia characterized by stippled, punctuate calcifications around joints and within cartilages. A 4 months old female infant presented to us for aspiration cytology with clinical suspicion of sarcoma due to complaint of ankle swelling and failure to thrive. Fine needle aspiration (FNA) smears were acellular with only calcific deposits. On clinical co-relation depressed nose and frontal bossing were noted. We suspected it to be a case of congenital skeletal dysplasia. Plain X-ray of the lesion was ordered and it revealed stippled calcification in place of ankle bones consistent with chondrodysplasia punctata. The present case is an index case describing the cytology of chondrodysplasia punctata. CDP is mainly a radiologically diagnosed lesion, however the knowledge of its cytological picture through this case will make pathologists alike aware if they encounter such case. The management is basically supportive and rehabilitative.

Surgical Management of Craniomaxillofacial Features in the Otopalatodigital Spectrum Disorders

Otopalatodigital syndrome spectrum disorders are caused by Filamin A (FLNA) gene mutations. Otopalatodigital syndrome spectrum disorders are a group of rare congenital skeletal dysplasia, with specific craniomaxillofacial features including otopalatodigital syndrome type 1 and type 2, Melnick-Needles syndrome, frontometaphyseal dysplasia, terminal osseous dysplasia with pigmentary defects. The authors describe cases of a young girl with Melnick-Needles syndrome and a young boy with frontometaphyseal dysplasia treated in the Oral and Maxillofacial Surgery Department. Both patients had FLNA gene mutation confirmed with molecular genetic analysis. The authors proposed a 4 step treatment of the malformations with good outcomes both aesthetically and functionally, without complication.

Rare Association of Fetal Chondrodysplasia Punctata in Maternal SLE: A Case Report

AbstractChondrodysplasia punctata (CDP) is a rare congenital skeletal dysplasia characterised by punctate bony calcification associated with a diverse spectrum of etiologies, genetic syndromes and prenatal exposures resulting in varied outcomes. The association with maternal autoimmune disease are less reported in prenatal literature. We present a case of fetal CDP detected on prenatal ultrasound in a mother with maternal systemic lupus erythematosus (SLE). Karyotype, postnatal X-ray and genetic mutation analysis were done to confirm the etiology. The purpose of this study was to increase the clinician’s awareness of the association of CDP with maternal SLE in cases with negative reports for genetic mutation analysis, chromosomal abnormality and in the absence of any history of teratogenic drug intake or maternal infection.

Impaired neurite development and mitochondrial dysfunction associated with calcium accumulation in dopaminergic neurons differentiated from the dental pulp stem cells of a patient with metatropic dysplasia

Transient receptor potential vanilloid member 4 (TRPV4) is a Ca2+ permeable nonselective cation channel, and mutations in the TRPV4 gene cause congenital skeletal dysplasias and peripheral neuropathies. Although TRPV4 is widely expressed in the brain, few studies have assessed the pathogenesis of TRPV4 mutations in the brain. We aimed to elucidate the pathological associations between a specific TRPV4 mutation and neurodevelopmental defects using dopaminergic neurons (DNs) differentiated from dental pulp stem cells (DPSCs). DPSCs were isolated from a patient with metatropic dysplasia and multiple neuropsychiatric symptoms caused by a gain-of-function TRPV4 mutation, c.1855C>T (p.L619F). The mutation was corrected by CRISPR/Cas9 to obtain isogenic control DPSCs. Mutant DPSCs differentiated into DNs without undergoing apoptosis; however, neurite development was significantly impaired in mutant vs. control DNs. Mutant DNs also showed accumulation of mitochondrial Ca2+ and reactive oxygen species, low adenosine triphosphate levels despite a high mitochondrial membrane potential, and lower peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression and mitochondrial content. These results suggested that the persistent Ca2+ entry through the constitutively activated TRPV4 might perturb the adaptive coordination of multiple mitochondrial functions, including oxidative phosphorylation, redox control, and biogenesis, required for dopaminergic circuit development in the brain. Thus, certain mutations in TRPV4 that are associated with skeletal dysplasia might have pathogenic effects on brain development, and mitochondria might be a potential therapeutic target to alleviate the neuropsychiatric symptoms of TRPV4-related diseases.

Reference range of fetal thorax using two-dimensional and three-dimensional ultrasound VOCAL technique and application in fetal thoracic malformations

BackgroundTo establish the normal reference range of fetal thorax by two-dimensional (2D) and three-dimensional (3D) ultrasound VOCAL technique and evaluate the application in diagnosing fetal thoracic malformations.MethodsA prospective cross-sectional study was undertaken involving 1077 women who have a normal singleton pregnancy at 13–40 weeks gestational age (GA). 2D ultrasound and 3D ultrasound VOCAL technique were utilized to assess fetal thoracic transverse diameter, thoracic anteroposterior diameter, thoracic circumference, thoracic area, lung volume, thoracic volume and lung-to-thoracic volume ratio. The nomograms of 2D and 3D fetal thoracic measurements were created to GA. 50 cases were randomly selected to calculate intra- and inter-observer reliability and agreement. In addition, the case groups including congenital skeletal dysplasia (SD) (15), congenital diaphragmatic hernia (CDH) (30), pulmonary sequestration (PS) (25) and congenital cystic adenomatoid malformation (CCAM) (36) were assessed by the nomograms and followed up subsequently.ResultsBoth 2D and 3D fetal thoracic parameters increased with GA using a quadratic regression equation. The intra- and inter-observer reliability and agreement of each thoracic parameter were excellent. 2D fetal thoracic parameters could initially evaluate the fetal thoracic development and diagnose the skeletal thoracic deformity, and lung volume, thoracic volume and lung-to-thorax volume ratio were practical to diagnose and differentiate CDH, PS and CCAM.ConclusionWe have established the normal fetal thoracic reference range at 13–40 weeks, which has a high value in diagnosing congenital thoracic malformations.

Accelerated osteoblastic differentiation in patient-derived dental pulp stem cells carrying a gain-of-function mutation of TRPV4 associated with metatropic dysplasia

Metatropic dysplasia (MD) is a congenital skeletal dysplasia characterized by severe platyspondyly and dumbbell-like long-bone deformities. These skeletal phenotypes are predominantly caused by autosomal dominant gain-of-function (GOF) mutations in transient receptor potential vanilloid 4 (TRPV4), which encodes a nonselective Ca2+-permeable cation channel. Previous studies have shown that constitutive TRPV4 channel activation leads to irregular chondrogenic proliferation and differentiation, and thus to the disorganized endochondral ossification seen in MD. Therefore, the present study investigated the role of TRPV4 in osteoblast differentiation and MD pathogenesis. Specifically, the behavior of osteoblasts differentiated from patient-derived dental pulp stem cells carrying a heterozygous single base TRPV4 mutation, c.1855C > T (p.L619F) was compared to that of osteoblasts differentiated from isogenic control cells (in which the mutation was corrected using the CRISPR/Cas9 system). The mutant osteoblasts exhibited enhanced calcification (indicated by intense Alizarin Red S staining), increased intracellular Ca2+ levels, strongly upregulated runt-related transcription factor 2 and osteocalcin expression, and increased expression and nuclear translocation of nuclear factor-activated T cell c1 (NFATc1) compared to control cells. These results suggest that the analyzed TRPV4 GOF mutation disrupts osteoblastic differentiation and induces MD-associated disorganized endochondral ossification by increasing Ca2+/NFATc1 pathway activity. Thus, inhibiting the NFATc1 pathway may be a promising potential therapeutic strategy to attenuate skeletal deformities in MD.

Novel gain-of-function mutation of TRPV4 associated with accelerated chondrogenic differentiation of dental pulp stem cells derived from a patient with metatropic dysplasia

Metatropic dysplasia is a congenital skeletal dysplasia characterized by severe platyspondyly, dumbbell-like deformity of long tubular bones, and progressive kyphoscoliosis with growth. It is caused by mutations in the gene TRPV4, encoding the transient receptor potential vanilloid 4, which acts as a calcium channel. Many heterozygous single base mutations of this gene have been associated with the disorder, showing autosomal dominant inheritance. Although abnormal endochondral ossification has been observed by histological examination of bone in a patient with lethal metatropic dysplasia, the etiology of the disorder remains largely unresolved. As dental pulp stem cells (DPSCs) are mesenchymal stem cells that differentiate into bone lineage cells, DPSCs derived from patients with congenital skeletal dysplasia might be useful as a disease-specific cellular model for etiological investigation. The purpose of this study was to clarify the pathological association between TRPV4 mutation and chondrocyte differentiation by analyzing DPSCs from a patient with non-lethal metatropic dysplasia. We identified a novel heterozygous single base mutation, c.1855C>T in TRPV4. This was predicted to be a missense mutation, p.L619F, in putative transmembrane segment 5. The mutation was repaired by CRISPR/Cas9 system to obtain isogenic control DPSCs for further analysis. The expression of stem cell markers and fibroblast-like morphology were comparable between patient-derived mutant and control DPSCs, although expression of TRPV4 was lower in mutant DPSCs than control DPSCs. Despite the lower TRPV4 expression in mutant DPSCs, the intracellular Ca2+ level was comparable at the basal level between mutant and control DPSCs, while its level was markedly higher following stimulation with 4α-phorbol 12,13-didecanoate (4αPDD), a specific agonist for TRPV4, in mutant DPSCs than in control DPSCs. In the presence of 4αPDD, we observed accelerated early chondrocyte differentiation and upregulated mRNA expression of SRY-box 9 (SOX9) in mutant DPSCs. Our findings suggested that the novel missense mutation c.1855C>T of TRPV4 was a gain-of-function mutation leading to enhanced intracellular Ca2+ level, which was associated with accelerated chondrocyte differentiation and SOX9 upregulation. Our results also suggest that patient-derived DPSCs can be a useful disease-specific cellular model for elucidating the pathological mechanism of metatropic dysplasia.

Mechanistic insights into skeletal development gained from genetic disorders.

A complex cascade of highly regulated processes of cell fate determination, differentiation, proliferation and transdifferentiation dictate the patterning, morphogenesis and growth of the vertebrate skeleton, perturbation of which results in malformation. In humans over 450 different dysplasias involving the skeletal system constitute a significant fraction of documented Mendelian disorders. The combination of clinical, phenotypic characterization of rare human skeletal dysmorphologies, the discovery of causative mutations and functional validation in animal models has contributed enormously to the understanding of molecular control of skeletal development. These studies revealed a myriad of genes and pathways, such as WNT, Hedgehog (HH), planar cell polarity and primary cilia, as key regulators for skeletal patterning, growth and homeostasis. The generation of mouse models recapitulating human congenital skeletal dysplasia has provided mechanistic insights into the diverse pathologies caused by single gene mutations, integrated action of developmental pathways such as WNT and HH and the role of stress responses. Technological developments in whole genome and exome sequencing have accelerated the discovery of disease-causing mutations and are changing approaches for diagnosis. The discovery that non-coding variants and disorganization of the 3D genome are associated with limb patterning disorders has revealed an additional level of complexity in the regulatory framework of skeletal development and disease mechanisms. This chapter focuses on a selection of human skeletal pathologies which illustrate how new findings about the coding and noncoding genome, combined with functional modeling, are contributing to deeper understanding of skeletal development, mechanisms of disease, with therapeutic potential for chondrodysplasias.

Normal development of sacrococcygeal centrum ossification centers in the fetal spine: a postmortem magnetic resonance imaging study

To describe the temporal pattern of the appearance of the S1-Co1 centrum ossification centers (COCs) and provide reference data for the S1-S5 COCs and sacral length at various gestational ages (GAs). Postmortem magnetic resonance imaging (MRI) was performed on 71 fetuses (GA, 17-42weeks) using the 3D dual-echo steady-state with water excitation T2 sequence in the sagittal plane. To confirm the reliability of this sequence, the MRI data were compared with the CT and histologic data obtained from two fetuses (GAs, 21 and 30weeks). The presence or absence of each sacrococcygeal COC was recorded. Sacral length and S1-S5 COC height, sagittal diameter, transverse diameter, cross-sectional area, and volume were measured. All fetuses showed S1-S3 COCs by 17weeks, S4 COCs by 19weeks, and S5 COCs by 28weeks. The S4, S5, and Co-1 COCs were visualized in 70 (98.59%), 51 (71.83%), and 21 (29.58%) fetuses, respectively. Sacral length, height, sagittal, and transverse diameters increased linearly, while cross-sectional area and volume increased exponentially with advancing GA. Mean growth rates of the sagittal and transverse diameters, cross-sectional area, and volume, but not of height, significantly differed among the S1-S5 vertebrae. We have presented the timing of appearance of individual sacrococcygeal COCs and the age-specific, normative MRI reference values for sacral length and the morphometric parameters of the sacral COCs, which are of clinical importance in the diagnosis of congenital sacral abnormalities and skeletal dysplasia.

Homeostasis and Disorder of Musculoskeletal System.Diagnosis and Treatment of Congenital Musculoskeletal Diseases.

Congenital skeletal dysplasias have been considered to be fundamentally untreatable diseases. However, molecular diagnosis by genetic testing has become more prevalent, and efforts are being made to develop novel therapies based on the pathogenesis. As treatments for osteogenesis imperfecta, in addition to anti-resorptive agents, neutralizing antibodies against sclerostin and transforming growth factor(TGF)-β and chemical chaperones can be beneficial. Enzyme replacement therapy using bone-targeting recombinant alkaline phosphatase has been recently developed to treat hypophosphatasia and has much improved the prognosis of the patients affected with severe forms of the disease. To treat the severe short stature in achondroplasia, drugs targeting the fibroblast growth factor receptor 3(FGFR3)-mediated signal are in development for clinical use.

Revisiting scoliosis in the KNM-WT 15000 Homo erectus skeleton

Owing to its completeness, the 1.5 million year old Nariokotome boy skeleton KNM-WT 15000 is central for understanding the skeletal biology of Homo erectus. Nevertheless, since the reported asymmetries and distortions of Nariokotome boy's axial skeleton suggest adolescent idiopathic scoliosis, possibly associated with congenital skeletal dysplasia, it is questionable whether it still can be used as a reference for H. erectus. Recently, however, the presence of skeletal dysplasia has been refuted. Here, we present a morphological and morphometric reanalysis of the assertion of idiopathic scoliosis. We demonstrate that unarticulated vertebral columns of non-scoliotic and scoliotic individuals can be distinguished based on the lateral deviation of the spinous process, lateral and sagittal wedging, vertebral body torsion, pedicle thickness asymmetry, and asymmetry of superior and inferior articular facet areas. A principal component analysis of the overall asymmetry of all seven vertebral shape variables groups KNM-WT 15000 within non-scoliotic modern humans. There is, however, an anomaly of vertebrae T1–T2 that is compatible with a short left convex curve at the uppermost thoracic region, possibly due to injury or local growth dysbalance. Asymmetries of the facet joints L3–L5 suggest a local right convex curve in the lower lumbar region that probably resulted from juvenile traumatic disc herniation. This pattern is incompatible with adolescent idiopathic scoliosis or other types of scoliosis, including congenital, neuromuscular or syndromic scoliosis. It is, however, consistent with a recent reanalysis of the rib cage that did not reveal any asymmetry. Except for these possibly trauma-related anomalies, the Nariokotome boy fossil therefore seems to belong to a normal H. erectus youth without evidence for adolescent idiopathic scoliosis or other severe pathologies of the axial skeleton.

A Novel GUSB Mutation in Brazilian Terriers with Severe Skeletal Abnormalities Defines the Disease as Mucopolysaccharidosis VII

Hundreds of different human skeletal disorders have been characterized at molecular level and a growing number of resembling dysplasias with orthologous genetic defects are being reported in dogs. This study describes a novel genetic defect in the Brazilian Terrier breed causing a congenital skeletal dysplasia. Affected puppies presented severe skeletal deformities observable within the first month of life. Clinical characterization using radiographic and histological methods identified delayed ossification and spondyloepiphyseal dysplasia. Pedigree analysis suggested an autosomal recessive disorder, and we performed a genome-wide association study to map the disease locus using Illumina’s 22K SNP chip arrays in seven cases and eleven controls. A single association was observed near the centromeric end of chromosome 6 with a genome-wide significance after permutation (pgenome = 0.033). The affected dogs shared a 13-Mb homozygous region including over 200 genes. A targeted next-generation sequencing of the entire locus revealed a fully segregating missense mutation (c.866C>T) causing a pathogenic p.P289L change in a conserved functional domain of β-glucuronidase (GUSB). The mutation was confirmed in a population of 202 Brazilian terriers (p = 7,71×10−29). GUSB defects cause mucopolysaccharidosis VII (MPS VII) in several species and define the skeletal syndrome in Brazilian Terriers. Our results provide new information about the correlation of the GUSB genotype to phenotype and establish a novel canine model for MPS VII. Currently, MPS VII lacks an efficient treatment and this model could be utilized for the development and validation of therapeutic methods for better treatment of MPS VII patients. Finally, since almost one third of the Brazilian terrier population carries the mutation, breeders will benefit from a genetic test to eradicate the detrimental disease from the breed.

Stüve–Wiedemann syndrome and related bent bone dysplasias

Stüve-Wiedemann syndrome (SWS) is a severe congenital skeletal dysplasia associated with life threatening dysautonomic manifestations. Newborns affected with this condition exhibit distinctive shortening and bowing of the long bones with reduced bone volume. The majority of affected newborns die early due to neuromuscular complications namely hyperthermia, apnea, and swallowing difficulties. In this review, we provide an overall picture on the clinical, including long-term management, molecular and cellular aspects of SWS and discuss briefly other related bent bone dysplasias.

P08.01: The role of color Doppler in the diagnosis of fetal malformations

Ultrasound measurement of nuchal translucency thickness is nowadays a widely used tools to evaluate the risk of fetal chromosomal abnormality in a combined screening with maternal biochemistry evaluation. Up to 75% of aneuploid fetuses have increased NT, but increased NT is also found in about 5% of normal karyotyping fetuses. In normal karyotypes, high NT thickness can be associated with different abnormalities such as congenital heart disease, skeletal dysplasias, metabolic and neuromuscular disorders or simply to a physiological fetal development. We present a case of increased nuchal translucency with normal karyotyping fetus and developmental disorder. A 28-year-old gravida 1 para 0 woman presented at 10 weeks 4 days (crown–rump length = 40.4 mm) for a first-trimester ultrasound evaluation. An increased NT measurement of 4.0 mm was noted (>99th centile) and 1 weeks later, still remained. Result of the amniocentesis was that of a normal 46, XO. A fetal echocardiogram performed at 20 weeks was within normal limits. The remainder of the pregnancy was uneventful and the patient delivered a full-term female infant weighing 3.52 kilogram, Apgar score was (9/10). At 40 days of age, the child visited hospital for asymmetric cervical positioning. Cervical spine x-ray and neck sonogram was normal. 4 month later, developmental delay was noted and the child started rehabilitation training for torticolis. Increased NT in first trimester with normal karyotype fetus, motor development delayed with the unrecognizable syndrome should be considered.

Prenatal diagnosis of congenital skeletal dysplasias by fetal helical computed tomography and genetic testing

Prenatal diagnosis of congenital skeletal dysplasias by fetal helical computed tomography and genetic testing

Prenatal diagnosis of brachytelephalangic chondrodysplasia punctata: case report

Brachytelephalangic chondrodysplasia punctata is a rare congenital skeletal dysplasia. Within the heterogeneous group of chondrodysplasia punctata, the brachytelephalangic type is noteworthy because it has a better prognosis than do the other types. We report a case of brachytelephalangic chondrodysplasia punctata diagnosed by ultrasound imaging at 30 weeks' gestation; it was associated with polyhydramnios and a normal cervical spinal canal. Imaging features are described and differential diagnosis with other forms of chondrodysplasia punctata is discussed.

Congenital skeletal dysplasia with pathological fracture at multiple sites: report of three cases

Congenital skeletal dysplasia with pathological fracture at multiple sites: report of three cases

Brachytelephalangic chondrodysplasia punctata with severe spinal cord compression: report of four new cases

Brachytelephalangic chondrodysplasia punctata (CDPX1, OMIM: #302950) is a rare congenital skeletal dysplasia caused by arylsulfatase E deficiency (OMIM: #300180). Although the symptoms are usually mild, severe spinal cord compression by dysplastic vertebras may develop. We report four new cases with severe cervical spinal canal narrowing documented by radiography, magnetic resonance imaging (MRI), and autopsy. In all, nine cases of CDPX1 with severe cervical spinal cord compression have now been described. Because these cases account for a large proportion of all reported CDPX1 cases, we believe that an antenatal suspicion of CDPX1 should lead to genetic counseling and to investigations for spinal cord compression. After birth, this complication must be routinely anticipated, and we suggest spinal MRI in all CDPX1 infants. Unless spinal cord compression is confidently ruled out, we recommend that these newborns receive the same care as trauma patients suspected of craniocervical junction disruption.

Autosomal recessive omodysplasia: Early prenatal diagnosis and a possible clue to the gene location

Autosomal recessive omodysplasia (ARO), a rare congenital skeletal dysplasia, is characterized by micromelia and craniofacial anomalies. Upper and lower limbs are affected in contrast to the dominant form in which the lower limbs are normal. Radiographic features include shortening and distal tapering of the humerus and femur, proximal radioulnar diastasis, and anterolateral radial head dislocation. We present a recurrence of ARO in a family, detected on prenatal ultrasound at 13 weeks of gestation. Chromosome analysis of the products of conception and the affected sibling showed a paternally-inherited paracentric inversion of 15q13 to q21.3. Due to similarities in the clinical phenotype between diastrophic dysplasia and this condition, testing for DTDST mutation was performed with no mutation detected.

小児の外傷性股関節脱臼の１症例

We report a case of traumatic dislocation of the hip in a child.A three-year-old boy fell down, and his right knee was hit on the ground. Just after the accident, he could not move his right leg because of severe pain in his right hip. When he came to our hospital, he kept his right hip in a flexion, internal rotation and adduction position. A hard mass was palpable in the right gluteal region. The X-ray findings showed right hip posterior dislocation without fracture and no congenital skeletal dysplasia of the hip was seen. Four hours after his injury, he received closed reduction under general anesthesia, followed by skin traction in the abduction position of his right hip.Ten days after reduction, MRI and CT showed that there was no fracture and cartilage damage. He felt no hip pain and started to walk on full weight bearing.Nine months after the incident, MRI showed no significant abnormal findings such as bone necrosis and dysplasia of the hip, and the patient had no complaints of problems in daily life.