Compressive Myelopathy Secondary to TRPV4 Skeletal Dysplasia: Spondylometaphyseal Dysplasia, Kozlowski Type.

Transient receptor potential vanilloid 4 channel ( TRPV4 ) gene mutations have been described in skeletal system and peripheral nervous system pathology. The case described here is a 9-year-old male child patient, born to a nonconsanguineous marriage with normal birth history who had difficulty in walking and stiffness of joints for the last 7 years, and progressive weakness of all four limbs and urine incontinence for 1 year following falls. Physical examination showed below-average weight and height and short trunk. Musculoskeletal examination revealed bony prominence bilaterally in the knee joints and contractures in knee and elbow joints with brachydactyly; muscle tone was increased, with brisk deep tendon reflexes. Skeletal survey showed platyspondyly with anterior beaking with metaphyseal dysplasia. Magnetic resonance imaging of the spine revealed atlantoaxial instability with hyperintense signal changes at a cervicomedullary junction and upper cervical cord with thinning and spinal canal stenosis suggestive of compressive myelopathy with platyspondyly and anterior beaking of the spine at cervical, thoracic and lumbar vertebrae. Exome sequencing revealed a heterozygous de novo variant c.2389G > A in exon 15 of TRPV4 , which results in the amino acid substitution p.Glu797Lys in the encoded protein. The characteristics observed indicated spondylometaphyseal dysplasia, Kozlowski type (SMD-K). The child underwent surgical intervention for compressive myelopathy by reduction of atlantoaxial dislocation with C1 lateral mass and C2 pars fusion using rib graft and fixation using screws and rods. To conclude, for any child presenting with progressive kyphoscoliosis, short stature, platyspondyly, and metaphyseal changes, a diagnosis of SMD-K should be considered and the patient and family should be advised to avoid spinal injuries.

Thermal Nonlinear Klein-Gordon Equation for Nano-/Micro-Sized Metallic Particle-Attosecond Laser Pulse Interaction.

In this study, a rigorous analytical solution to the thermal nonlinear Klein-Gordon equation in the Kozlowski version is provided. The Klein-Gordon heat equation is solved via the Zhukovsky "state-of-the-art" mathematical techniques. Our study can be regarded as an initial approximation of attosecond laser-particle interaction when the prevalent phenomenon is photon-electron interaction. The electrons interact with the laser beam, which means that the nucleus does not play a significant role in temperature distribution. The particle is supposed to be homogenous with respect to thermophysical properties. This theoretical approach could prove useful for the study of metallic nano-/micro-particles interacting with attosecond laser pulses. Specific applications for Au "nano" particles with a 50 nm radius and "micro" particles with 110, 130, 150, and 1000 nm radii under 100 attosecond laser pulse irradiation are considered. First, the cross-section is supposed to be proportional to the area of the particle, which is assumed to be a perfect sphere of radius R or a rotation ellipsoid. Second, the absorption coefficient is calculated using a semiclassical approach, taking into account the number of atoms per unit volume, the classical electron radius, the laser wavelength, and the atomic scattering factor (10 in case of Au), which cover all the basic aspects for the interaction between the attosecond laser and a nanoparticle. The model is applicable within the 100-2000 nm range. The main conclusion of the model is that for a range inferior to 1000 nm, a competition between ballistic and thermal phenomena occurs. For values in excess of 1000 nm, our study suggests that the thermal phenomena are dominant. Contrastingly, during the irradiation with fs pulses, this value is of the order of 100 nm. This theoretical model's predictions could be soon confirmed with the new EU-ELI facilities in progress, which will generate pulses of 100 as at a 30 nm wavelength.

Metatropic Dysplasia of Nonlethal Variant in a Chinese Child - A Case Report.

Metatropic dysplasia (MD), is a rare skeletal dysplasia occurring predominantly in infants characterized by a distinctive long torso and short limbs; it is as a result of mutations in the TRPV4 gene. However, a clear distinction between various forms of skeletal dysplasias caused by the transient receptor potential vanilloid 4 (TRPV4) gene is difficult but could be achieved by a combination of gene sequencing, medical and radiological criteria. We hereby report a case of a 14-month old girl who presented with an abnormal stature. The diagnosis of nonlethal MD was confirmed by X-ray with dumbbell-shaped long bones, platyspondyly, and delayed carpal ossification, as well as broadened pelvis with marginally widened ilia, epiphyseal plates, and slightly flattened acetabula. Furthermore, gene sequencing confirmed gene mutation on exon 15 of the TRPV4 gene with a heterozygous missense mutation (c.2396C > T), but no mutation was present in her parents. Our findings recorded metatropic dysplasia with the c.2396C > T mutation in the TRPV4 gene in China. This mutation caused changes in amino acid of TRPV4, which can induce growth retardation in children.

Combined Phenotypes of Spondylometaphyseal Dysplasia-Kozlowski Type and Charcot-Marie-Tooth Disease Type 2C Secondary to a TRPV4 Pathogenic Variant.

TRPV4, a nonselective calcium permeable ion channel, is expressed broadly in many organs including bone and neurons. Pathogenic variants in TRPV4 are known to cause both a spectrum of skeletal dysplasias and neuropathies. Recent publications have documented a few patients who have a combined phenotype of skeletal dysplasia and neuropathy secondary to TRPV4 pathogenic variants. We present an additional patient who has an overlapping neuromuscular and skeletal phenotype secondary to a TRPV4 pathogenic variant. The patient has spondylometaphyseal dysplasia-Kozlowski type and Charcot-Marie-Tooth disease type 2C. This and prior reports illustrate that TRPV4-related skeletal dysplasias and TRPV4-related neuropathies are not fully distinct disorders secondary to unique sets of pathogenic variants as originally postulated, but rather are 2 phenotypes on the same spectrum that may or may not overlap. We suggest that evaluation for patients presenting with any TRPV4-related disorder include assessment for both skeletal and neurological findings.

Protein informatics combined with multiple data sources enriches the clinical characterization of novel TRPV4 variant causing an intermediate skeletal dysplasia.

BACKGROUND: Transient receptor potential cation channel subfamily V member 4 (TRPV4) is an ion channel permeable to Ca2+ that is sensitive to physical, hormonal, and chemical stimuli. This protein is expressed in many cell types, including osteoclasts, chondrocytes, and sensory neurons. As such, pathogenic variants of this gene are associated with skeletal dysplasias and neuromuscular disorders. Pathogenesis of these phenotypes is not yet completely understood, but it is known that genotype-phenotype correlations for TRPV4 pathogenic variants often are not present. METHODS: Newly characterized, suspected pathogenic variant in TRPV4 was analyzed using protein informatics and personalized protein-level molecular studies, genomic exome analysis, and clinical study. RESULTS: This statement is demonstrated in the family of our proband, a 47-year-old female having the novel c.2401A>G (p.K801E) variant of TRPV4. We discuss the common symptoms between the proband, her father, and her daughter, and compare her phenotype to known TRPV4-associated skeletal dysplasias. CONCLUSIONS: Protein informatics and molecular modeling are used to confirm the pathogenicity of the unique TRPV4 variant found in this family. Multiple data were combined in a comprehensive manner to give complete overall perspective on the patient disease and prognosis.

Expanding the Clinical Spectrum of Phenotypes Caused by Pathogenic Variants in PLOD2.

Osteogenesis imperfecta (OI) is a strikingly heterogeneous group of disorders with a broad range of phenotypic variations. It is also one of the differential diagnoses in bent bone dysplasias along with campomelic dysplasia and thanatophoric dysplasia and can usually be distinguished by decreased bone mineralization and bone fractures. Bent bone dysplasias also include syndromes such as kyphomelic dysplasia (MIM:211350) and mesomelic dysplasia Kozlowski-Reardon (MIM249710), both of which have been under debate regarding whether or not they are a real entity or simply a phenotypic manifestation of another dysplasia including OI. Bruck syndrome type 2 (BRKS2; MIM:609220) is a rare form of autosomal recessive OI caused by biallelic PLOD2 variants and is associated with congenital joint contractures with pterygia. In this report, we present six patients from four families with novel PLOD2 variants. All cases had multiple fractures. Other features ranged from prenatal lethal severe angulation of the long bones as in kyphomelic dysplasia and mesomelic dysplasia Kozlowski-Reardon through classical Bruck syndrome to moderate OI with normal joints. Two siblings with a kyphomelic dysplasia-like phenotype who were stillborn had compound heterozygous variants in PLOD2 (p.Asp585Val and p.Ser166*). One infant who succumbed at age 4 months had a bent bone phenotype phenotypically like skeletal dysplasia Kozlowski-Reardon (with mesomelic shortening, camptodactyly, retrognathia, cleft palate, skin dimples, but also with fractures). He was homozygous for the nonsense variant (p.Trp561*). Two siblings had various degrees of Bruck syndrome caused by the homozygous missense variant, p.His687Arg. Furthermore a boy with a clinical presentation of moderate OI had a possibly pathogenic homozygous variant p.Trp588Cys. Our experience of six patients with biallelic pathogenic variants in PLOD2 expands the phenotypic spectrum in the PLOD2-related phenotypes. © 2017 American Society for Bone and Mineral Research.

Displasia espondilometafisaria tipo Kozlowski / Spondylometaepiphyseal dysplasia of Kozlowski type

La displasia espondilometafisaria kozlowski es un tipo de displasia ósea, que está comprendida dentro de un grupo de desórdenes que afecta fundamentalmente la metáfisis de huesos tubulares, con preferencia por la columna vertebral. Está caracterizada por alteraciones de diversa gravedad a nivel de las vértebras, con un patrón de herencia autosómico dominante. Se presenta un caso valorado en consulta de genética clínica por baja talla, con deformidad en tórax y alteraciones radiológicas en columna vertebral, con metáfisis irregulares. Se realizó revisión de la literatura y se estudiaron las radiografías, efectuándose el diagnóstico clínico de esta afección. Se ofreció asesoramiento genético a la familia (AU)

Kozlowski spondylometaepiphyseal dysplasia (smed) is a type of bone dysplasia, which is included in a group of disorders that primarily affects the metaphysis of tubular bones, mostly the vertebral column. It is characterized by alterations of diverse severity at the level of the vertebrae, with an autosomal dominant pattern of heredity. This study presents a case assessed in the office of clinical genetics with short height, thoracic deformity and radiographic abnormalities in the vertebral column with irregular metaphysis. A bibliographic review was carried out and radiographs were studied, what determined the clinical diagnosis of this condition. Appropriate genetic counseling to the family was given (AU)

Kozlowski type spondylometaphyseal dysplasia:one case report / 临床儿科杂志

Objective To investigate the clinical characteristics and diagnostics of Kozlowski type spondylometaphyseal dysplasia (SMDK). Methods The clinical features, laboratory tests and genetic testing of one SMDK case were analyzed. Re-sults A eight-year-old male patient had more than 6 years course of disease. The clinical manifestations were stubby limbs, ifn-gers and toes, varus deformity, knee valgus deformity, scoliosis and lordosis and severe metaphyseal changes. The heterozygous mutations were detected in TRPV4 and NXX3-2 genes. Conclusions Typical clinical features combined with genetic diagnosis facilitate early detection and accurate diagnosis of SMDK.

A Case of Spondylometaphyseal Dysplasia ( Kozlowski type ) / 대한정형외과학회잡지

Spondylometaphyseal dysplasia (SMD) is an extremely rare, which affects the spine and metaphy-ses of the tubular bones on terms of enchondrogenesis. Children who had Kozlowski dwarfism, type of SMD are not recognized until they reach school age since they have normal clinical feature, weight and size in early childhood. Authors experienced a typical case of Kozlowski type of SMD in a 10 years old male who had i) generalized platyspondyly with anterior tapering of vertebrae ii) generalized metaphyseal dysplasia iii) minimal changes in the carpal and tarsal bones. This case is to be reported with review of references.