Metatropic Dysplasia Research Articles

Trends in Serum Cytokine Expression in Pediatric Skeletal Dysplasia.

The skeletal dysplasias are a heterogeneous group of genetic conditions caused by abnormalities of growth, development, and maintenance of bone and cartilage. Little is known about the roles that cytokines play in the inflammatory and non-inflammatory pathophysiology of skeletal dysplasia. We sought to test our hypothesis that cytokines would be differentially expressed in children with skeletal dysplasia as compared to typically growing controls. Cytokine levels were analyzed using the Cytokine Human Magnetic 25-Plex Panel (Invitrogen, Waltham, MA, USA); 136 growing individuals with skeletal dysplasia and compared to a cohort of 275 healthy pediatric control subjects. We focused on the expression of 12 cytokines across nine dysplasia cohorts. The most common skeletal dysplasia diagnoses were: achondroplasia (58), osteogenesis imperfecta (19), type II collagenopathies (11), multiple epiphyseal dysplasia (MED: 9), diastrophic dysplasia (8), metatropic dysplasia (8), and microcephalic osteodysplastic primordial dwarfism type II (MOPDII: 8). Of the 108 specific observations made, 45 (41.7%) demonstrated statistically significant differences of expression between controls and individuals with skeletal dysplasia. Four of the 12 analyzed cytokines demonstrated elevated expression above control levels in all of the dysplasia cohorts (interleukin 12 [IL-12], IL-13, interferon γ-induced protein 10 kDa [IP-10], regulated on activation, normal T cell expressed and secreted [RANTES]) and two demonstrated expression below control levels across all dysplasia cohorts (monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein-1β [MIP-1β]). The highest levels of overexpression were seen in MOPDII, with expression levels of IP-10 being increased 3.8-fold (p < 0.0001). The lowest statistically significant levels of expressions were in type II collagenopathies, with expression levels of MCP-1 being expressed 0.43-fold lower (p < 0.005). With this data, we hope to lay the groundwork for future directions in dysplasia research that will enhance our understanding of these complex signaling pathways. Looking forward, validating these early trends in cytokine expression, and associating the observed variations with trends in the progression of dysplasia may offer new candidates for clinical biomarkers or even new therapeutics. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

TRPV4-mediated Ca2+ deregulation causes mitochondrial dysfunction via the AKT/α-synuclein pathway in dopaminergic neurons.

Mutations in the gene encoding the transient receptor potential vanilloid member 4 (TRPV4), a Ca2+ permeable nonselective cation channel, cause TRPV4-related disorders. TRPV4 is widely expressed in the brain; however, the pathogenesis underlying TRPV4-mediated Ca2+ deregulation in neurodevelopment remains unresolved and an effective therapeutic strategy remains to be established. These issues were addressed by isolating mutant dental pulp stem cells from a tooth donated by a child diagnosed with metatropic dysplasia with neurodevelopmental comorbidities caused by a gain-of-function TRPV4 mutation, c.1855C > T (p.L619F). The mutation was repaired using CRISPR/Cas9 to generate corrected isogenic stem cells. These stem cells were differentiated into dopaminergic neurons and the pharmacological effects of folic acid were examined. In mutant neurons, constitutively elevated cytosolic Ca2+ augmented AKT-mediated α-synuclein (α-syn) induction, resulting in mitochondrial Ca2+ accumulation and dysfunction. The TRPV4 antagonist, AKT inhibitor, or α-syn knockdown, normalizes the mitochondrial Ca2+ levels in mutant neurons, suggesting the importance of mutant TRPV4/Ca2+/AKT-induced α-syn in mitochondrial Ca2+ accumulation. Folic acid was effective in normalizing mitochondrial Ca2+ levels via the transcriptional repression of α-syn and improving mitochondrial reactive oxygen species levels, adenosine triphosphate synthesis, and neurite outgrowth of mutant neurons. This study provides new insights into the neuropathological mechanisms underlying TRPV4-related disorders and related therapeutic strategies.

A neonate with metatropic dysplasia: A case report

Metatropic dysplasia is a rare form of skeletal dysplasia in which characteristic clinical and imaging features are found at birth. The short limbs with relatively long trunk seen in the neonatal period change to short trunk in childhood due to progressive kyphoscoliosis. This rare condition should be diagnosed in the neonatal period to avoid diagnostic dilemma in later life. A 2-day-old baby girl was referred for a skeletal survey study to diagnose the underlying skeletal dysplasia. The metatropic dysplasia was diagnosed based on plain radiographic findings. This case report highlights the characteristic radiographic findings of this rare disease entity.

Novel denovo TRPV4 mutation identified in a Chinese family with metatropic dysplasia inhibits chondrogenic differentiation

Novel denovo TRPV4 mutation identified in a Chinese family with metatropic dysplasia inhibits chondrogenic differentiation

Sleep‐disordered breathing and its management in children with rare skeletal dysplasias

Sleep-disordered breathing (SDB) is common in patients with skeletal dysplasias. The aim of our study was to analyze SDB and respiratory management in children with rare skeletal dysplasias. We performed a retrospective analysis of patients with spondyloepiphyseal dysplasia congenita (SEDC), metatropic dysplasia (MD), spondyloepimetaphyseal dysplasia (SEMD), acrodysostosis (ADO), geleophysic dysplasia (GD), acromicric dysplasia (AD), and spondylocostal dysplasia (SCD) between April 2014 and October 2020. Polygraphic data, clinical management, and patients' outcome were analyzed. Thirty-one patients were included (8 SEDC, 3 MD, 4 SEMD, 1 ADO, 4 GD, 3 AD, and 8 SCD). Sixteen patients had obstructive sleep apnea (OSA): 11 patients (2 with SEDC, 1 with SEMD, 1 with ADO, 1 with GD, 2 with AD, and 4 with SCD) had mild OSA, 2 (1 SEMD and 1 GD) had moderate OSA, and 3 (1 SEDC, 1 MD, 1 SEMD) had severe OSA. Adenotonsillectomy was performed in one patient with SCD and mild OSA, and at a later age in two other patients with ADO and AD. The two patients with moderate OSA were treated with noninvasive ventilation (NIV) because of nocturnal hypoxemia. The three patients with severe OSA were treated with adenotonsillectomy (1 SEDC), adeno-turbinectomy and continuous positive airway pressure (CPAP; 1 MD), and with NIV (1 SEMD) because of nocturnal hypoventilation. OSA and/or alveolar hypoventilation is common in patients with skeletal dysplasias, underlining the importance of systematic screening for SDB. CPAP and NIV are effective treatments for OSA and nocturnal hypoventilation/hypoxemia.

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.

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.

Metatropic Dysplasia - Description of a Newborn with Suspected Epiphyseal Dysplasia

Metatropic Dysplasia - Description of a Newborn with Suspected Epiphyseal Dysplasia

Metatropic Dysplasia: A Description of a Newborn With Suspected Epiphyseal Dysplasia

The paper presents a female neonate with a suspected skeletal defect that was eventually diagnosed as metatropic dysplasia. This is the first case of this disease in our clinic. Clinical course of the disease was discussed as well as findings of additional examinations and the differentiation from other diseases with a similar clinical picture. Newborns have a narrow and elongated chest with extremely short limbs, with bones resembling dumbbells. Other problems associated with dysplasia involve the spine (the vertebrae are excessively flattened), and any excessive movement of the cervical spine may lead to spinal cord damage. The chest may be sunken or excessively bowed which may lead to disable full lung expansion that constrains breathing; also joint deformities occur such as contractures limiting movements in the largest joints. In the collected genetic material no TRPV4 mutation was discovered. There are slightly more than 80 cases of this disease described worldwide. J Endocrinol Metab. 2019;9(5):165-170 doi: https://doi.org/10.14740/jem598

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.

The Management of Kyphosis in Metatropic Dysplasia

DesignRetrospective review. ObjectiveTo describe the presentation and progression, and compare treatments of severe thoracic kyphosis in a cohort of patients with metatropic dysplasia. Summary of Background DataMetatropic dysplasia is a rare skeletal dysplasia characterized by several abnormalities, including severe platyspondyly and vertebral wedging. These lead to marked kyphoscoliosis that begins in the first year of life and progresses to a stiff, short thorax and restrictive lung disease. There is no study that specifically addresses treatment of kyphosis in this cohort. MethodsA 12-year retrospective chart review at a single institution was performed to identify metatropic dysplasia patients. Comparison between four main treatment groups—observation, bracing, anterior release and growing construct, and anterior release and final fusion—were made radiographically with regard to thoracolumbar, T2–T12, and major Cobb kyphosis; sagittal vertical alignment; and C7–kyphosis apex distance, taken at presentation, pre- and posttreatment, and final follow-up. ResultsTwenty patients with metatropic dysplasia presented at an average age of 3.1 years with a kyphosis of 75°, and were followed an average of 8.5 years. Those treated surgically presented with an average of 86.7° kyphosis, 88 mm C7–kyphosis apex distance, and 50 mm positive sagittal vertical alignment (SVA). Postsurgical reduction of kyphosis averaged 43° with less than 4° loss of correction in all groups except the constructs involving rib fixation. Recent use of staged thoracoscopic anterior soft tissue release, halo traction, and growing rod construct has produced the most dramatic results with average kyphosis correction of 71° and evidence of anterior bony remodeling. In those treated with observation, kyphosis progressed less than a quarter degree per year. ConclusionsThoracic kyphosis in metatropic dysplasia does not uniformly progress in all patients and therefore can be initially observed. In those who progress, several surgical options exist including growth-friendly constructs that have demonstrated success without a higher rate of complications. Level of EvidenceLevel IV.

Metatropic Dysplasia: A Description of a Newborn With Suspected Epiphyseal Dysplasia

The paper presents a female neonate with a suspected skeletal defect that was eventually diagnosed as metatropic dysplasia. This is the first case of this disease in our clinic. Clinical course of the disease was discussed as well as findings of additional examinations and the differentiation from other diseases with a similar clinical picture. Newborns have a narrow and elongated chest with extremely short limbs, with bones resembling dumbbells. Other problems associated with dysplasia involve the spine (the vertebrae are excessively flattened), and any excessive movement of the cervical spine may lead to spinal cord damage. The chest may be sunken or excessively bowed which may lead to disable full lung expansion that constrains breathing; also joint deformities occur such as contractures limiting movements in the largest joints. In the collected genetic material no TRPV4 mutation was discovered. There are slightly more than 80 cases of this disease described worldwide. J Endocrinol Metab. 2019;9(5):165-170 doi: https://doi.org/10.14740/jem598

Characteristic Diagnostic Clues of Metatropic Dysplasia: The Lumbothoracic Humpback with Dumbbell Appearance of the Long Bones.

Metatropic dysplasia (MD) is a rare skeletal dysplasia associated with heterozygous mutations in the TRPV4 gene. We describe a 28-month-old boy with knock-knees referred for metabolic investigation suspected of carrying vitamin D-resistant rickets. He has received regular vitamin D prophylaxis at the usual dose. Laboratory investigations revealed normal values for calcium, phosphorus and alkaline phosphatase. He was short (-3.5 SDS), his mental development was normal, and he started to walk at the age of 22 months. The diagnostic clue for the diagnosis of metatropic dysplasia was the presence of the hump back in the upper lumbar and lower thoracic vertebrae, in addition to a long and narrow chest. An X-ray survey of the skeleton revealed platyspondyly, dysplastic metaphyses with dumbbell appearance of the long bones, kyphoscoliosis, and narrow and elongated thorax with short ribs. This is the first patient with MD in the Republic of Macedonia. Knock-knees were the cause of his referral, as a peculiarity of his phenotype. The very presence of the hump back, and the dumbbell appearance of the long bones distinguished the MD from other bone dysplasias with similar characteristics. We believe that the presence of those two features can shorten the path to accurate diagnosis in the crowded field of overlapping skeletal dysplasias. The diagnosis of MD in this patient was further confirmed by the discovery of the mutation c.2396C>T; p.Pro799Leu (P799L) of the TRPV4 gene.

Metatropic dysplasia in third trimester of pregnancy and a novel causative variant in the TRPV4 gene

Prenatal diagnosis of skeletal dysplasias is particularly difficult for many reasons and differentiating these disorders in the prenatal period can be challenging because they are rare and many of the ultrasound findings are not necessarily pathognomonic for a specific disorder. The diagnosis is often made just after birth or exitus. The prenatal diagnosis of osteochondrodysplasias is based predominantly upon fetal ultrasound findings and it focuses substantially on the possible lethality of the disorder, without always being able to find a specific name for the disorder.Metatropic dysplasia is a rare osteochondrodysplasia due to mutations in the TRPV4 gene: TRPV4 is a cation channel, non-selectively permeable to calcium, encoded by a gene on chromosome 12q24.11; it is widely expressed and involved in many different physiological processes through responses to several different stimuli (physical, chemical, and hormonal) in ciliated epithelial cells. The exact incidence of this disorder is not known, however less than a hundred cases have been reported at present, with only two prenatal reports but without any reference to the molecular test.We describe the first report of molecular diagnosis of metatropic dysplasia carried out in prenatal diagnosis: the molecular testing of the TRPV4 (transient receptor potential cation channel, subfamily V, member 4, MIM *605427) gene in our case, in fact, detected a causative variant, confirming the diagnostic suspicion, which was made possible thanks also to the utilization of MRI and CT scan. In our case different imaging methods together with the close cooperation of a multidisciplinary team and test availability, allowed an accurate diagnosis.

Metatropic dysplasia-a skeletal dysplasia with challenging airway and other anesthetic concerns.

Metatropic dysplasia is a rare form of skeletal dysplasia requiring multiple anesthetics for surgical and imaging procedures, most of which are orthopedic procedures. We provide centralized care to patients with skeletal dysplasia at our tertiary care pediatric hospital, and we were able to collect the largest number of metatropic dysplasia patients reported to date. The aim of this retrospective study was to describe and characterize the anesthetic difficulties in this high-risk population. Medical charts of all patients with metatropic dysplasia were reviewed to collect data, including anesthetics performed, difficulties, and complications related to the anesthetic care, co-morbid conditions, and related events. Twenty-three patients with metatropic dysplasia underwent 188 anesthetics with 61% of the anesthetics having been administered for orthopedic procedures. Fourteen of 23 (60.8%) progressively became difficult to intubate over the course of their care, with 12 out of 14 having undergone cervical spine fusion. These 14 patients had a total of 133 procedures. Sixty procedures (45.1%) had an airway described as difficult. Glidescope was the difficult airway tool most commonly used (68%) with flexible fiberoptic scope used 12% and Miller or Macintosh blade used 18% of the time. In addition to the airway difficulties, spinal canal narrowing or stenosis was widely prevalent, and no neuraxial anesthetic was performed in any of our patients. Difficult airway is the most common co-morbid condition present in patients with metatropic dysplasia, especially if their cervical spine has been fused. Familiarity with the difficulties involving the airway and its management is critical in safe and successful management of anesthesia in this high-risk population.

Clinical and genetic study on a family with metatropic dysplasia due to transient receptor potential vanilloid 4 gene mutation

Objective To summarize the clinical, radiographic and genetic features of a family with metatropic dysplasia, in order to improve the level of understanding and diagnosis of this disease. Methods The proband, a one-year old boy, was diagnosed as metatropic dysplasia.His mother was 26 years old with mildly phenotype.Their clinical features and bone X-ray findings were analyzed.The DNA samples of the proband and his parents were collected.The coding exons and flanking introns regions of transient receptor potential vanilloid 4 (TRPV4) gene were amplified by polymerase chain reaction(PCR) and analyzed by DNA automatic detector.The pathology, diagnosis, treatment and prognosis were expounded. Results The symptoms of the boy were characterized by short extremities, a short trunk with progressive kyphoscoliosis, and craniofacial abnormalities that include a prominent forehead, midface hypoplasia, and a squared-off jaw.His motor development was slightly delayed.Mental development was normal.Bone X ray of the boy showed platyspondyly and severe metaphyseal enlargement with shortening of long bones and irregularities and delayed ossification of epiphysis.The patient and his mother were heterozygous for the nucleotide substitutions c. 2396>T (p.P799L) in TRPV4 gene. Conclusions The patient and his mother with metatropic dysplasia were diagnosed with TRPV4 gene analysis.The patient showed typical clinical features.His mother was mild.Metatropic dysplasia had signi-ficantly clinical heterogeneity.Gene analysis is helpful for the diagnosis. Key words: Spondyloepiphyseal dysplasia; Metatropic dysplasia; Transient receptor potential vanilloid 4 channel protein; Transient receptor potential vanilloid 4 gene mutation

Metatropic dysplasia is associated with increased fracture risk

Metatropic dysplasia is associated with increased fracture risk

Метатропная дисплазия: клиническая и молекулярная диагностика, медико-генетическое консультирование

Metatropic dysplasia (MTD; OMIM #156530) is a rare spondyloepimetaphyseal dysplasia with autosomal dominant inheritance. Here we present the results of the clinical, radiological and molecular genetic diagnosis of MTD in a circassian girl with novel de novo p.Pro82Leu (NG_017090.1:g.23856C>T, c.245C>T) mutation in exon 1 of the TRPV4 gene. Considering gonadal mosaicism prenatal diagnosis in MTD families for the next pregnancies is recommended.

William Menzies Clow

<h3>Background</h3> Mutations in <i>TRPV4</i>, a gene that encodes a Ca²⁺ permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski...

Metatropic dysplasia is associated with increased fracture risk and increased markers of bone turnover

Metatropic dysplasia is associated with increased fracture risk and increased markers of bone turnover