Raras
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Displasia epifisária múltipla
ORPHA:251CID-11 · LD24.61DOENÇA RARA

As displasias epifisárias múltiplas (DEMs) são caracterizadas por alterações nas cartilagens de crescimento dos ossos, causando dor nas articulações ainda na infância ou adolescência, inflamações frequentes nos ossos e cartilagens (osteocondrite) e artrose que surge cedo. As DEMs formam um grupo de doenças diversas, com sintomas que variam bastante entre os pacientes, e são classificadas de DEM 1 a DEM 6.

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Introdução

O que você precisa saber de cara

📋

As displasias epifisárias múltiplas (DEMs) são caracterizadas por alterações nas cartilagens de crescimento dos ossos, causando dor nas articulações ainda na infância ou adolescência, inflamações frequentes nos ossos e cartilagens (osteocondrite) e artrose que surge cedo. As DEMs formam um grupo de doenças diversas, com sintomas que variam bastante entre os pacientes, e são classificadas de DEM 1 a DEM 6.

Publicações científicas
458 artigos
Último publicado: 2026

Escala de raridade

CLASSIFICAÇÃO ORPHANET · BRASIL 2024
1-9 / 100 000
Ultra-rara
<1/50k
Muito rara
1/20k
Rara
1/10k
Pouco freq.
1/5k
Incomum
1/2k
Prevalência
5.0
Europe
Início
Infancy
+ neonatal
🏥
SUS: Sem cobertura SUSScore: 0%
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Sinais e sintomas

O que aparece no corpo e com que frequência cada sintoma acontece

Partes do corpo afetadas

🦴
Ossos e articulações
88 sintomas
😀
Face
15 sintomas
💪
Músculos
7 sintomas
🧠
Neurológico
5 sintomas
👂
Ouvidos
4 sintomas
👁️
Olhos
3 sintomas

+ 62 sintomas em outras categorias

Características mais comuns

Atrofia cerebral
Dedo em forma de fuso
Micrognatia
Concentração elevada de creatina quinase circulante
Cifose cervical
Contratura em flexão
190sintomas
Sem dados (190)

Os sintomas variam de pessoa para pessoa. Abaixo estão as 190 características clínicas mais associadas, ordenadas por frequência.

Atrofia cerebralCerebral atrophy
Dedo em forma de fusoSpindle-shaped finger
MicrognatiaMicrognathia
Concentração elevada de creatina quinase circulanteElevated circulating creatine kinase concentration
Cifose cervicalCervical kyphosis

Linha do tempo da pesquisa

Publicações por ano — veja quando o interesse científico cresceu
Anos de pesquisa1desde 2026
Total histórico458PubMed
Últimos 10 anos116publicações
Pico202516 papers
Linha do tempo
2026Hoje · 2026🧪 2012Primeiro ensaio clínico📈 2025Ano de pico
Publicações por ano (últimos 10 anos)

Encontrou um erro ou informação desatualizada? Sugira uma correção →

Genética e causas

O que está alterado no DNA e como passa nas famílias

Genes associados

9 genes identificados com associação a esta condição. Padrão de herança: Autosomal dominant, Autosomal recessive.

COL9A2Collagen alpha-2(IX) chainDisease-causing germline mutation(s) inTolerante
FUNÇÃO

Structural component of hyaline cartilage and vitreous of the eye

LOCALIZAÇÃO

Secreted, extracellular space, extracellular matrix

VIAS BIOLÓGICAS (2)
Collagen biosynthesis and modifying enzymesCollagen chain trimerization
MECANISMO DE DOENÇA

Multiple epiphyseal dysplasia 2

A generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. Radiological examination of the skeleton shows delayed, irregular mineralization of the epiphyseal ossification centers and of the centers of the carpal and tarsal bones. Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank and the milder Ribbing types. The Fairbank type is characterized by shortness of stature, short and stubby fingers, small epiphyses in several joints, including the knee, ankle, hand, and hip. The Ribbing type is confined predominantly to the hip joints and is characterized by hands that are normal and stature that is normal or near-normal.

OUTRAS DOENÇAS (4)
epiphyseal dysplasia, multiple, 2Stickler syndrome, type 5multiple epiphyseal dysplasia due to collagen 9 anomalyobsolete autosomal recessive Stickler syndrome
HGNC:2218UniProt:Q14055
COL9A1Collagen alpha-1(IX) chainDisease-causing germline mutation(s) inTolerante
FUNÇÃO

Structural component of hyaline cartilage and vitreous of the eye

LOCALIZAÇÃO

Secreted, extracellular space, extracellular matrix

VIAS BIOLÓGICAS (2)
Collagen biosynthesis and modifying enzymesCollagen chain trimerization
MECANISMO DE DOENÇA

Multiple epiphyseal dysplasia 6

A generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. Radiological examination of the skeleton shows delayed, irregular mineralization of the epiphyseal ossification centers and of the centers of the carpal and tarsal bones. Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank and the milder Ribbing types. The Fairbank type is characterized by shortness of stature, short and stubby fingers, small epiphyses in several joints, including the knee, ankle, hand, and hip. The Ribbing type is confined predominantly to the hip joints and is characterized by hands that are normal and stature that is normal or near-normal.

OUTRAS DOENÇAS (4)
epiphyseal dysplasia, multiple, 6Stickler syndrome, type 4multiple epiphyseal dysplasia due to collagen 9 anomalyobsolete autosomal recessive Stickler syndrome
HGNC:2217UniProt:P20849
KIF7Kinesin-like protein KIF7Disease-causing germline mutation(s) inTolerante
FUNÇÃO

Essential for hedgehog signaling regulation: acts both as a negative and positive regulator of sonic hedgehog (Shh) and Indian hedgehog (Ihh) pathways, acting downstream of SMO, through both SUFU-dependent and -independent mechanisms (PubMed:21633164). Involved in the regulation of microtubular dynamics. Required for proper organization of the ciliary tip and control of ciliary localization of SUFU-GLI2 complexes (By similarity). Required for localization of GLI3 to cilia in response to Shh. Neg

LOCALIZAÇÃO

Cell projection, ciliumCytoplasm, cytoskeleton, cilium basal body

VIAS BIOLÓGICAS (2)
Hedgehog 'on' stateHedgehog 'off' state
EXPRESSÃO TECIDUAL(Ubíquo)
Cervix Ectocervix
23.0 TPM
Aorta
21.6 TPM
Ovário
20.7 TPM
Cervix Endocervix
20.1 TPM
Útero
19.2 TPM
OUTRAS DOENÇAS (5)
multiple epiphyseal dysplasia, Al-Gazali typehydrolethalus syndrome 2acrocallosal syndromehydrolethalus syndrome
HGNC:30497UniProt:Q2M1P5
COL2A1Collagen alpha-1(II) chainDisease-causing germline mutation(s) inAltamente restrito
FUNÇÃO

Type II collagen is specific for cartilaginous tissues. It is essential for the normal embryonic development of the skeleton, for linear growth and for the ability of cartilage to resist compressive forces

LOCALIZAÇÃO

Secreted, extracellular space, extracellular matrix

VIAS BIOLÓGICAS (10)
Integrin cell surface interactionsMET activates PTK2 signalingDevelopmental Lineage of Pancreatic Ductal CellsAssembly of collagen fibrils and other multimeric structuresSignaling by PDGF
MECANISMO DE DOENÇA

Spondyloepiphyseal dysplasia congenital type

Disorder characterized by disproportionate short stature and pleiotropic involvement of the skeletal and ocular systems.

OUTRAS DOENÇAS (22)
Legg-Calve-Perthes diseasespondylometaphyseal dysplasia, Schmidt typeplatyspondylic dysplasia, Torrance typeKniest dysplasia
HGNC:2200UniProt:P02458
MATN3Matrilin-3Disease-causing germline mutation(s) inTolerante
FUNÇÃO

Major component of the extracellular matrix of cartilage and may play a role in the formation of extracellular filamentous networks

LOCALIZAÇÃO

Secreted

VIAS BIOLÓGICAS (2)
Post-translational protein phosphorylationRegulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
MECANISMO DE DOENÇA

Multiple epiphyseal dysplasia 5

A generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. Radiological examination of the skeleton shows delayed, irregular mineralization of the epiphyseal ossification centers and of the centers of the carpal and tarsal bones. Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank and the milder Ribbing types. The Fairbank type is characterized by shortness of stature, short and stubby fingers, small epiphyses in several joints, including the knee, ankle, hand, and hip. The Ribbing type is confined predominantly to the hip joints and is characterized by hands that are normal and stature that is normal or near-normal. Multiple epiphyseal dysplasia type 5 is relatively mild and clinically variable. It is primarily characterized by delayed and irregular ossification of the epiphyses and early-onset osteoarthritis.

EXPRESSÃO TECIDUAL(Ubíquo)
Nervo tibial
19.7 TPM
Pulmão
12.4 TPM
Brain Spinal cord cervical c-1
6.4 TPM
Substância negra
5.6 TPM
Fibroblastos
5.2 TPM
OUTRAS DOENÇAS (3)
multiple epiphyseal dysplasia type 5spondyloepimetaphyseal dysplasia, matrilin-3 typeosteoarthritis susceptibility 2
HGNC:6909UniProt:O15232
SLC26A2Sulfate transporterDisease-causing germline mutation(s) inTolerante
FUNÇÃO

Sulfate transporter which mediates sulfate uptake into chondrocytes in order to maintain adequate sulfation of proteoglycans which is needed for cartilage development (PubMed:11448940, PubMed:15294877, PubMed:20219950, PubMed:7923357). Mediates electroneutral anion exchange of sulfate ions for oxalate ions and of sulfate and oxalate ions for chloride ions (PubMed:20219950). Mediates exchange of sulfate and oxalate ions for hydroxyl ions and of chloride ions for bromide, iodide and nitrate ions (

LOCALIZAÇÃO

Cell membraneApical cell membrane

VIAS BIOLÓGICAS (2)
Transport and metabolism of PAPSInorganic anion exchange by SLC26 transporters
MECANISMO DE DOENÇA

Diastrophic dysplasia

An autosomal recessive disease characterized by osteochondrodysplasia with clinical features including dwarfism, spinal deformation, and specific joint abnormalities.

EXPRESSÃO TECIDUAL(Ubíquo)
Cólon transverso
64.2 TPM
Glândula salivar
48.3 TPM
Glândula adrenal
27.9 TPM
Esôfago - Mucosa
14.7 TPM
Pulmão
14.3 TPM
OUTRAS DOENÇAS (4)
multiple epiphyseal dysplasia type 4diastrophic dysplasiaatelosteogenesis type IIachondrogenesis type IB
HGNC:10994UniProt:P50443
COMPCartilage oligomeric matrix proteinDisease-causing germline mutation(s) inTolerante
FUNÇÃO

Plays a role in the structural integrity of cartilage via its interaction with other extracellular matrix proteins such as the collagens and fibronectin. Can mediate the interaction of chondrocytes with the cartilage extracellular matrix through interaction with cell surface integrin receptors (PubMed:16051604, PubMed:16542502). Could play a role in the pathogenesis of osteoarthritis (PubMed:16542502). Potent suppressor of apoptosis in both primary chondrocytes and transformed cells. Suppresses

LOCALIZAÇÃO

Secreted, extracellular space, extracellular matrix

VIAS BIOLÓGICAS (2)
Integrin cell surface interactionsECM proteoglycans
MECANISMO DE DOENÇA

Multiple epiphyseal dysplasia 1

A generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. Radiological examination of the skeleton shows delayed, irregular mineralization of the epiphyseal ossification centers and of the centers of the carpal and tarsal bones. Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank and the milder Ribbing types. The Fairbank type is characterized by shortness of stature, short and stubby fingers, small epiphyses in several joints, including the knee, ankle, hand, and hip. The Ribbing type is confined predominantly to the hip joints and is characterized by hands that are normal and stature that is normal or near-normal.

OUTRAS DOENÇAS (3)
carpal tunnel syndrome 2multiple epiphyseal dysplasia type 1pseudoachondroplasia
HGNC:2227UniProt:P49747
CANT1Soluble calcium-activated nucleotidase 1Disease-causing germline mutation(s) inTolerante
FUNÇÃO

Calcium-dependent nucleotidase with a preference for UDP. The order of activity with different substrates is UDP > GDP > UTP > GTP. Has very low activity towards ADP and even lower activity towards ATP. Does not hydrolyze AMP and GMP (PubMed:12234496, PubMed:15006348, PubMed:15248776, PubMed:16835225). Involved in proteoglycan synthesis (PubMed:22539336)

LOCALIZAÇÃO

Endoplasmic reticulum membraneGolgi apparatus, Golgi stack membraneCell membrane

VIAS BIOLÓGICAS (1)
Neutrophil degranulation
MECANISMO DE DOENÇA

Desbuquois dysplasia 1

A chondrodysplasia characterized by severe prenatal and postnatal growth retardation (less than -5 SD), joint laxity, short extremities, progressive scoliosis, round face, midface hypoplasia, prominent bulging eyes. The main radiologic features are short long bones with metaphyseal splay, a 'Swedish key' appearance of the proximal femur (exaggerated trochanter), and advance carpal and tarsal bone age. Two forms of Desbuquois dysplasia are distinguished on the basis of the presence or absence of characteristic hand anomalies: an extra ossification center distal to the second metacarpal, delta phalanx, bifid distal thumb phalanx, and phalangeal dislocations.

VIAS REACTOME (1)
OUTRAS DOENÇAS (3)
Desbuquois dysplasia 1epiphyseal dysplasia, multiple, 7Desbuquois dysplasia
HGNC:19721UniProt:Q8WVQ1
COL9A3Collagen alpha-3(IX) chainDisease-causing germline mutation(s) inTolerante
FUNÇÃO

Structural component of hyaline cartilage and vitreous of the eye

LOCALIZAÇÃO

Secreted, extracellular space, extracellular matrix

VIAS BIOLÓGICAS (2)
Collagen biosynthesis and modifying enzymesCollagen chain trimerization
MECANISMO DE DOENÇA

Multiple epiphyseal dysplasia 3

A generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. Radiological examination of the skeleton shows delayed, irregular mineralization of the epiphyseal ossification centers and of the centers of the carpal and tarsal bones. Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank and the milder Ribbing types. The Fairbank type is characterized by shortness of stature, short and stubby fingers, small epiphyses in several joints, including the knee, ankle, hand, and hip. The Ribbing type is confined predominantly to the hip joints and is characterized by hands that are normal and stature that is normal or near-normal.

OUTRAS DOENÇAS (5)
Stickler syndrome, type 6epiphyseal dysplasia, multiple, 3multiple epiphyseal dysplasia due to collagen 9 anomalyobsolete autosomal recessive Stickler syndrome
HGNC:2219UniProt:Q14050

Variantes genéticas (ClinVar)

704 variantes patogênicas registradas no ClinVar.

🧬 COL9A2: NM_001852.4(COL9A2):c.186+5G>T ()
🧬 COL9A2: NM_001852.4(COL9A2):c.708_727dup (p.Lys243fs) ()
🧬 COL9A2: NM_001852.4(COL9A2):c.1345del (p.Leu449fs) ()
🧬 COL9A2: NM_001852.4(COL9A2):c.1285A>T (p.Lys429Ter) ()
🧬 COL9A2: NM_001852.4(COL9A2):c.619C>T (p.Gln207Ter) ()
Ver todas no ClinVar

Classificação de variantes (ClinVar)

Distribuição de 1,355 variantes classificadas pelo ClinVar.

339
339
677
Patogênica (25.0%)
VUS (25.0%)
Benigna (50.0%)
VARIANTES MAIS SIGNIFICATIVAS
COL2A1: NM_001844.5(COL2A1):c.2957C>T (p.Pro986Leu) [Likely pathogenic]
COL2A1: NM_001844.5(COL2A1):c.2464-2A>T [Likely pathogenic]
SLC26A2: NM_000112.4(SLC26A2):c.1651_1652dup (p.Ser551fs) [Pathogenic]
SLC26A2: NM_000112.4(SLC26A2):c.1946_1947del (p.Ile649fs) [Pathogenic]
SLC26A2: NM_000112.4(SLC26A2):c.-26+1G>T [Likely pathogenic]

Diagnóstico

Os sinais que médicos procuram e os exames que confirmam

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Tratamento e manejo

Remédios, cuidados de apoio e o que precisa acompanhar

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Onde tratar no SUS

Hospitais de referência no Brasil e o protocolo oficial do SUS (PCDT)

🇧🇷 Atendimento SUS — Displasia epifisária múltipla

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Publicações mais relevantes

🥈Melhor nível de evidência: Observacional
Timeline de publicações
118 papers (10 anos)
#1

Genotype-phenotype correlations in PSACH/EDM1 patients with COMP gene variants: a comprehensive review of 830 cases.

Frontiers in endocrinology2026

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia-1 (EDM1) are two rare skeletal diseases that represent distinct endpoints of a continuous phenotypic spectrum with substantial clinical overlap, caused by variants in the gene coding cartilage oligomeric matrix protein (COMP). To summarize the clinical characteristics of PSACH/EDM1 and variants of COMP gene, as well as to explore the correlations between them. PubMed, China National Knowledge Infrastructure, and Wanfang were searched for case reports and case series of patients with genetic diagnosis of PSACH/EDM1 from the inception to 24 March 2025. The clinical characteristics and gene variants of enrolled patients were analyzed and compared to explore genotype-phenotype correlation. A total of 830 PSACH/EDM1 patients (471probands) harboring 224 different variants of COMP gene were enrolled from 106 articles, with missense variants accounting for the majority (80.8%). Exon 13 (183 probands, 38.9%) and type III (T3) repeat domain (413 probands, 87.7%) were the most commonly affected regions, with c.1417_1419del (p.Asp473del) being the most common hotspot variant. Compared with EDM1, PSACH manifested earlier age of onset (p < 0.001), shorter stature (p < 0.001), higher rates of lower limb deformity (p < 0.001), joint laxity (p = 0.041), anterior beaking of the vertebra and irregular/flared metaphysis (p < 0.001), while lower rate of joint pain/osteoarthritis (p < 0.001) and abnormal femoral head (p = 0.008). Missense variants in T3-4 and T3-5 were more likely to cause EDM1 (all p < 0.001), while those in T3-1 and T3-6 to T3-8 were associated with a greater frequency of PSACH (p = 0.002 to 0.023). Majority of in-frame variants were found in PSACH, as c.1417_1419del (p.Asp473del) being PSACH specific. PSACH exhibits more severe phenotypes than EDM1, even with phenotypic overlap. In-frame variants are more strongly associated with PSACH, as the hotspot variant p.Asp473del exclusively identified in PSACH. In contrast, missense variants in T3-4 and T3-5 show a stronger association with EDM1.

#2

Human pluripotent stem cell model of multiple epiphyseal dysplasia with MATN3 mutation identifies altered matrix organisation and upregulation of the cholesterol biosynthesis pathway.

Osteoarthritis and cartilage2026 Feb 04

Multiple epiphyseal dysplasia (MED), caused by mutations in MATN3, is a chondrodysplasia affecting the cartilage growth plate and is characterised by delayed epiphyseal ossification, short stature, and early onset osteoarthritis. Here we generated an in vitro human pluripotent stem cell (hPSC) model of cartilage growth-plate development to identify pathogenic mechanisms underlying MED. hPSCs were differentiated to chondrocytes via a mesenchymal intermediate, followed by TGFβ3+BMP2 induced chondrogenic pellet culture. MATN3-mutant hPSCs were generated by reprogramming MED patient PBMCs or by CRISPR-Cas9 gene editing to introduce a MATN3 mutation in a hESC line. RNAseq was used to assess chondrogenesis and identify MED pathogenic mechanisms. Transmission electron microscopy (TEM) was used to assess extracellular matrix assembly. The resultant hPSC-derived cartilage pellets displayed a typical cartilage morphology and strongly expressed cartilage matrix markers, e.g., collagen II and matrilin-3. Matrilin-3 protein was detected within both the matrix and cells of heterozygous mutant hPSC-cartilage pellets. RNAseq of mutant hPSC-cartilage pellets revealed significant enrichment for 'ECM organisation' and 'cholesterol biosynthesis' pathway genes as well as sightly increased expression of some unfolded protein response (UPR) marker genes. MATN3 mutant hPSC-derived cartilage pellets displayed abnormal matrix assembly, distended ER, accumulation of lipid droplets, and increased cholesterol content. Our model revealed mutant matrilin-3 induces cholesterol biosynthesis pathway upregulation and abnormal matrix assembly during MED pathogenesis. This study provides new insights into the molecular mechanisms underlying MED and highlights potential therapeutic targets.

#3

Total knee arthroplasty with simultaneous triplanar osteotomy of the distal femur using patient-specific instrumentation : A case report.

Orthopadie (Heidelberg, Germany)2026 Jan

Performing a one-stage periarticular osteotomy in conjunction with total knee arthroplasty (TKA) constitutes a technically complex procedure. In such demanding cases, a personalized approach utilizing patient-specific instrumentation (PSI) may serve as an advantageous option to achieve optimal precision in bone cuts, thereby enhancing both clinical and radiological postoperative outcomes. We present a case report of a 22-year-old man with multiple epiphyseal dysplasia (MED) resulting in knee osteoarthritis with complex femoral deformity and restricted (passive at 30-120° and active at 80-120°) range of movement (ROM). Simultaneous TKA and triplanar osteotomy with the use of PSI stabilized with the prosthesis stem was performed. The treatment resulted in correct limb and implant positioning. The functional improvement and bone union were confirmed 1 year after TKA. The patient did not report any pain in the operated joints and achieved passive 0-120° and active 10-120° ROM of the operated right knee. Although the latest reports do not demonstrate improved clinical outcomes for PSI in periarticular osteotomies and TKAs separately, we highlight the benefits of PSI in complex deformities, particularly in patients requiring a combination of these two methods. ZWECK: Die Durchführung einer einzeitigen periartikulären Osteotomie in Verbindung mit einer Knietotalendoprothese (TEP) ist ein technisch komplexes Verfahren. In solch anspruchsvollen Fällen kann ein personalisierter Ansatz mit patientenspezifischem Instrumentarium (PSI) eine vorteilhafte Option sein, um eine optimale Präzision der Knochenschnitte zu erreichen und dadurch sowohl die klinischen als auch die radiologischen postoperativen Ergebnisse zu verbessern. Wir berichten über den Fall eines 22-jährigen Mannes mit multipler epiphysärer Dysplasie (MED), die zu einer Kniearthrose mit komplexer Femurdeformität und eingeschränktem Bewegungsumfang (ROM; passiv bei 30-120° und aktiv bei 80-120°) führte. Es wurde eine gleichzeitige TEP und triplanare Osteotomie unter Verwendung eines mit dem Prothesenschaft stabilisierten PSI durchgeführt. Die Behandlung führte zu einer korrekten Positionierung der Extremität und des Implantats. Die funktionelle Verbesserung und die Knochenvereinigung wurden ein Jahr nach der TEP bestätigt. Der Patient berichtete über keinerlei Schmerzen in den operierten Gelenken und erreichte einen passiven ROM von 0‑120° und einen aktiven ROM von 10-120° für das operierte rechte Knie. Obwohl die neuesten Berichte keine verbesserten klinischen Ergebnisse für PSI bei periartikulären Osteotomien und TEP separat belegen, heben wir die Vorteile der PSI bei komplexen Deformitäten hervor, insbesondere bei Patienten, die eine Kombination dieser beiden Methoden benötigen.

#4

Elevated MMP9 Expression-A Potential In Vitro Biomarker for COMPopathies.

International journal of molecular sciences2025 Dec 15

The intracellular retention of misfolded extracellular matrix proteins is a common disease mechanism in various rare skeletal diseases. This discovery has driven the study of ER stress and the unfolded protein response (UPR) as a promising therapeutic target in several skeletal dysplasias. In the case of COL10A1 mutations, targeting the UPR resulted in a clinical trial of the repurposed drug carbamazepine; however, for other closely related skeletal disorders, treatment with carbamazepine was ineffective, indicating the need for suitable markers for in vitro screenings of potential drug treatments. Mutations in cartilage oligomeric matrix protein (COMP), a cartilage structural protein, cause both multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH); together referred to as the COMPopathies, which result from the intracellular retention of mutant COMP to varying degrees. In contrast to other closely related skeletal disorders, caused by mutations in cartilage structural proteins, the involvement of the UPR is less clear, and so far, no common COMPopathy marker has been identified. Here, using cell models of COMPopathies, we identified MMP9 upregulation as a common feature of six pathogenic COMP variants that do not induce a prominent UPR. We further show that the archetypal p.V194D matrilin-3 MED variant (which causes MED) does not induce MMP9 expression, suggesting that MMP9 upregulation could serve as a specific marker of COMPopathies in vitro.

#5

From Protein Misfolding to Extracellular Matrix Disorganisation: Understanding Disease Pathology in Rare Skeletal Dysplasias.

International journal of molecular sciences2025 Oct 15

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are rare, autosomal dominant skeletal dysplasias characterised by disproportionate short stature, joint deformities, and early-onset osteoarthritis. These conditions result from mutations in key cartilage extracellular matrix (ECM) components, including cartilage oligomeric matrix protein (COMP), matrilin-3, and type IX collagen. Although genetically and clinically heterogeneous, PSACH and MED share convergent pathogenic mechanisms. Misfolded mutant ECM proteins are retained within the endoplasmic reticulum (ER) of growth plate chondrocytes, triggering chronic ER stress and impairing chondrocyte proliferation, differentiation, and survival. Moreover, some of the mutant protein is secreted and incorporated into the matrix, leading to altered collagen fibrillogenesis, disrupted proteoglycan distribution, and compromised biomechanical integrity. These alterations extend beyond cartilage, impacting tendons, ligaments, and muscle-tendon junctions, contributing to joint laxity, impaired force transmission, and mild myopathy. This review discusses the structural and functional consequences of ECM disorganisation in PSACH and MED, highlighting its central role in disease progression and emphasising the importance of considering ECM abnormalities when developing therapeutic strategies for rare short stature-associated skeletal disorders.

Publicações recentes

Ver todas no PubMed

📚 EuropePMC250 artigos no totalmostrando 115

2026

Genotype-phenotype correlations in PSACH/EDM1 patients with COMP gene variants: a comprehensive review of 830 cases.

Frontiers in endocrinology
2026

Human pluripotent stem cell model of multiple epiphyseal dysplasia with MATN3 mutation identifies altered matrix organisation and upregulation of the cholesterol biosynthesis pathway.

Osteoarthritis and cartilage
2025

Elevated MMP9 Expression-A Potential In Vitro Biomarker for COMPopathies.

International journal of molecular sciences
2025

Exome Sequencing Identifies a Novel Splicing Variant in COL9A3 Resulting in Multiple Epiphyseal Dysplasia: A Case Report.

Molecular genetics &amp; genomic medicine
2025

From Protein Misfolding to Extracellular Matrix Disorganisation: Understanding Disease Pathology in Rare Skeletal Dysplasias.

International journal of molecular sciences
2025

Genetic Analysis of Familial Developmental Dysplasia of the Hip Associated With a Heterozygous Variant in the COMP Gene: A Case Report.

Molecular genetics &amp; genomic medicine
2026

Total knee arthroplasty with simultaneous triplanar osteotomy of the distal femur using patient-specific instrumentation : A case report.

Orthopadie (Heidelberg, Germany)
2025

Clinical outcomes of total hip arthroplasty in patients with multiple epiphyseal dysplasia: a single centre study of eighty eight hips at a mean of sixteen year follow-up.

International orthopaedics
2025

Concurrent mutations in RNU4ATAC, PLEC, and CD96 in a child with severe short stature and skeletal dysplasia: a case report.

Italian journal of pediatrics
2025

[Skeletal dysplasias-Multidisciplinary orthopedics].

Orthopadie (Heidelberg, Germany)
2025

C-type natriuretic peptide and collagen X marker are aberrant in skeletal dysplasias.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
2025

Wolcott-Rallison syndrome: late-onset diabetes, multiple epiphyseal dysplasia, and acute liver failure - a case report.

Journal of pediatric endocrinology &amp; metabolism : JPEM
2025

[Clinical analysis in 15 pediatric patients with osteochondrodysplasias related to COMP gene variants].

Zhonghua er ke za zhi = Chinese journal of pediatrics
2025

Recognizing multiple epiphyseal dysplasia in children presenting with joint pain: a commonly overlooked skeletal dysplasia.

European journal of pediatrics
2025

Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene.

Clinical genetics
2025

Mental health conditions, physical functioning, and health-related quality of life in adults with a skeletal dysplasia: a cross-sectional multinational study.

Orphanet journal of rare diseases
2025

An Interesting Case of Multiple Epiphyseal Dysplasia Masquerading as Myopathy in a Southeast Asian Girl.

Cureus
2024

Staged Bilateral Total Hip Arthroplasty in an Adolescent Patient With Multiple Epiphyseal Dysplasia and Bilateral Avascular Necrosis.

Arthroplasty today
2024

Component Mix-Match for Anatomic Total Shoulder Arthroplasty Revision: A Case Report.

Cureus
2025

COL9A1-related disorder with pectus carinatum, without epiphyseal dysplasia: case report and review of literature.

Skeletal radiology
2025

From Desbuquois Dysplasia to Multiple Epiphyseal Dysplasia: The Clinical Impact of a CANT1 Variant Across Five Unrelated Families.

American journal of medical genetics. Part A
2024

Multiple Osteochondritis Dissecans as Main Manifestation of Multiple Epiphyseal Dysplasia Caused by a Novel Cartilage Oligomeric Matrix Protein Pathogenic Variant: A Clinical Report.

Genes
2024

Two families with spondylo-epi-metaphyseal dysplasia due to compound heterozygocity in the vWFA domain of MATN3.

European journal of medical genetics
2024

A Modified 4-in-1 Stanisavljevic Procedure for Treating Obligatory or Congenital Patellar Dislocations in Children: A Surgical Technique.

HSS journal : the musculoskeletal journal of Hospital for Special Surgery
2024

Biallelic variants in SLC26A2 cause multiple epiphyseal dysplasia-4 by disturbing chondrocyte homeostasis.

Orphanet journal of rare diseases
2024

[Analysis of genetic variants and molecular pathogenesis in a Chinese pedigree affected with Multiple epiphyseal dysplasia].

Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics
2024

Multiple Epiphyseal Dysplasia With Knee Joint Locking Symptoms Caused by Intra-articular Loose Bodies.

Cureus
2024

Total Knee Arthroplasty in Patients Who Have Skeletal Dysplasia: A Center's Experience With a Mean 9-Year Follow-Up.

The Journal of arthroplasty
2024

Further characterization of ARSK-related mucopolysaccharidosis type 10.

American journal of medical genetics. Part A
2023

Joint Space Widening in Multiple Epiphyseal Dysplasia.

Deutsches Arzteblatt international
2024

Stemless total shoulder arthroplasty for multiple epiphyseal dysplasia in a 52-year-old patient: a case report.

JSES international
2023

Trends in Serum Cytokine Expression in Pediatric Skeletal Dysplasia.

JBMR plus
2023

The molecular mechanisms of glycosaminoglycan biosynthesis regulating chondrogenesis and endochondral ossification.

Life sciences
2023

The favorable outcome of Bernese periacetabular osteotomy for the hip osteoarthritis in multiple epiphyseal dysplasia.

Orphanet journal of rare diseases
2023

Recurrent Mutation (p.Arg718Pro) in the COMP Gene with Clinical Heterogeneity of Pseudoachondroplasia.

Molecular syndromology
2023

Onychodystrophy with Multiple Epiphyseal Dysplasia: Literature Review.

Skin appendage disorders
2024

Clinical Experience from a Single Tertiary Care Center: Neonatal Diabetes Mellitus with Multiple Epiphyseal Dysplasia-Wolcott-Rallison's Syndrome.

Journal of pediatric genetics
2023

Multiple epiphyseal dysplasia tip 5: Case report a rare skeletal dysplasıa presenting with repetitive joint pain in children.

International journal of surgery case reports
2023

[Clinical and genetic characteristics of 9 rare cases with coexistence of dual genetic diagnoses].

Zhonghua er ke za zhi = Chinese journal of pediatrics
2023

Curcumin Reduces Pathological Endoplasmic Reticulum Stress through Increasing Proteolysis of Mutant Matrilin-3.

International journal of molecular sciences
2023

SLC26A2/DTDST Spectrum: A Cohort of 12 Patients Associated with a Comprehensive Review of the Genotype-Phenotype Correlation.

Molecular syndromology
2023

A case of congenital multiple epiphyseal dysplasia from the Late Migration Period graveyard in Drnholec (Czech Republic).

International journal of paleopathology
2023

Does Flexion Varus Osteotomy Improve Radiographic Findings Compared With Patients Treated in a Brace for Late-onset Legg-Calvé-Perthes Disease?

Clinical orthopaedics and related research
2022

Clinical and Genetic Characteristics of Multiple Epiphyseal Dysplasia Type 4.

Genes
2022

Wolcott-Rallison syndrome: a case series of three patients.

Pediatric endocrinology, diabetes, and metabolism
2022

Exome sequencing revealed USP9X and COL2A1 mutations in a large family with multiple epiphyseal dysplasia.

Bone
2022

Double-layered patella management in total knee arthroplasty for secondary osteoarthritis: A case report.

Journal of ISAKOS : joint disorders &amp; orthopaedic sports medicine
2022

Identification of recurrent pathogenic alleles using exome sequencing data: Proof-of-concept study of Russian subjects.

European journal of medical genetics
2021

Health-related Quality of Life in Adult Patients with Multiple Epiphyseal Dysplasia and Spondyloepiphyseal Dysplasia.

Progress in rehabilitation medicine
2021

Massager-Induced Anterior Subcapsular Cataracts and Keratoconus in a Patient With Multiple Epiphyseal Dysplasia.

Cureus
2022

Clinical, Biochemical, Radiological, Genetic and Therapeutic Analysis of Patients with COMP Gene Variants.

Calcified tissue international
2021

Description of Joint Alterations Observed in a Family Carrying p.Asn453Ser COMP Variant: Clinical Phenotypes, In Silico Prediction of Functional Impact on COMP Protein and Stability, and Review of the Literature.

Biomolecules
2021

A unique case of skeletal dysplasia in an adult male in Late Iron Age Switzerland.

International journal of paleopathology
2021

SLC26A2-Associated Diastrophic Dysplasia and rMED-Clinical Features in Affected Finnish Children and Review of the Literature.

Genes
2021

An iPS cell line SDUBMSi0011-A from a multiple epiphyseal dysplasia patient carrying c. 1076T > G mutation in the SMOC2 gene.

Stem cell research
2021

Outcomes of complex primary total knee arthroplasties performed with custom cutting guides.

The Knee
2021

Recessive multiple epiphyseal dysplasia and Stargardt disease in two sisters.

Molecular genetics &amp; genomic medicine
2021

Heterozygous COL9A3 variants cause severe peripheral vitreoretinal degeneration and retinal detachment.

European journal of human genetics : EJHG
2021

Expanding the phenotypic spectrum of RPL13-related skeletal dysplasia.

American journal of medical genetics. Part A
2021

Can Chiari Osteotomy Favorably Influence Long-term Hip Degradation in Multiple Epiphyseal Dysplasia and Pseudoachondroplasia?

Journal of pediatric orthopedics
2020

Age Dependent Progression of Multiple Epiphyseal Dysplasia and Pseudoachondroplasia Due to Heterozygous Mutations in COMP Gene.

Prague medical report
2021

Bilateral double-layered patella in a patient with advanced knee osteoarthritis.

Folia morphologica
2020

Mutations in COMP cause familial carpal tunnel syndrome.

Nature communications
2021

Multiple epiphyseal dysplasia and related disorders: Molecular genetics, disease mechanisms, and therapeutic avenues.

Developmental dynamics : an official publication of the American Association of Anatomists
2020

A novel COMP mutation in a Chinese family with multiple epiphyseal dysplasia.

BMC medical genetics
2020

Multiple occurrence of premature polyarticular osteoarthritis in an early medieval Bohemian cemetery (Prague, Czech Republic).

International journal of paleopathology
2020

Joint Replacements in Individuals With Skeletal Dysplasias: One Institution's Experience and Response to Operative Complications.

The Journal of arthroplasty
2020

A novel p.A191D matrilin-3 variant in a Vietnamese family with multiple epiphyseal dysplasia: a case report.

BMC musculoskeletal disorders
2020

Spondylo-epi-metaphyseal dysplasia due to a homozygous missense mutation in the gene encoding Matrilin-3 (T120M).

Bone reports
2020

A de novo frameshift FGFR1 mutation extending the protein in an individual with multiple epiphyseal dysplasia and hypogonadotropic hypogonadism without anosmia.

European journal of medical genetics
2019

Patients with musculoskeletal dysplasia undergoing total joint arthroplasty are at increased risk of surgical site Infection.

Orthopaedics &amp; traumatology, surgery &amp; research : OTSR
2019

Exome-wide copy number variation analysis identifies a COL9A1 in frame deletion that is associated with hearing loss.

European journal of medical genetics
2019

XBP1 signalling is essential for alleviating mutant protein aggregation in ER-stress related skeletal disease.

PLoS genetics
2019

[Research status of correlation between type IX collagen gene and musculoskeletal diseases].

Zhongguo gu shang = China journal of orthopaedics and traumatology
2019

Exome sequencing reveals a novel COL2A1 mutation implicated in multiple epiphyseal dysplasia.

American journal of medical genetics. Part A
2019

Mesencephalic astrocyte-derived neurotropic factor is an important factor in chondrocyte ER homeostasis.

Cell stress &amp; chaperones
2018

Pathogenic gene screening in 91 Chinese patients with short stature of unknown etiology with a targeted next-generation sequencing panel.

BMC medical genetics
2018

An Infant With Neonatal Diabetes and Double Outlet Right Ventricle - Wolcott- Rallison syndrome.

Medical archives (Sarajevo, Bosnia and Herzegovina)
2019

Recessive multiple epiphyseal dysplasia - Clinical characteristics caused by rare compound heterozygous SLC26A2 genotypes.

European journal of medical genetics
2018

Lowry-Wood syndrome: further evidence of association with RNU4ATAC, and correlation between genotype and phenotype.

Human genetics
2019

Periacetabular Osteotomy Improves Pain and Function in Patients With Lateral Center-edge Angle Between 18° and 25°, but Are These Hips Really Borderline Dysplastic?

Clinical orthopaedics and related research
2018

Alu-Alu mediated intragenic duplications in IFT81 and MATN3 are associated with skeletal dysplasias.

Human mutation
2018

Articulated Hip Distraction for Impingement of the Deformed Femoral Head in a Patient with Multiple Epiphyseal Dysplasia: A Case Report.

JBJS case connector
2018

Two novel mutations of COMP in Japanese boys with pseudoachondroplasia.

Human genome variation
2018

Dual novel mutations in SLC26A2 in two siblings with multiple epiphyseal dysplasia 4 from a Chinese family: a case report.

BMC medical genetics
2018

Deformity correction with total knee arthroplasty for severe knee osteoarthritis accompanying extra-articular femoral deformity: the results are promising.

Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA
2018

Cartilage oligomeric matrix protein: COMPopathies and beyond.

Matrix biology : journal of the International Society for Matrix Biology
2018

Hybrid total hip arthroplasty for multiple epiphyseal dysplasia.

Orthopaedics &amp; traumatology, surgery &amp; research : OTSR
2018

The expanding phenotype of RNU4ATAC pathogenic variants to Lowry Wood syndrome.

American journal of medical genetics. Part A
2018

Novel mutations in the cartilage oligomeric matrix protein gene identified in two Taiwanese patients with pseudoachondroplasia and multiple epiphyseal dysplasia.

Pediatrics and neonatology
2017

Traumatic separation of osseous segments in a double-layered patella.

International journal of surgery case reports
2018

Multiple SLC26A2 mutations occurring in a three-generational family.

European journal of medical genetics
2017

Modyfied wedge osteotomy for osteoarthritis of elbow secondary to osteochondritis dissecans in adolecent with multiple epiphyseal dysplasia. A case report.

Journal of orthopaedics
2017

Early Osteoarthritis and Double-Layered Patella in a Patient With Multiple Epiphyseal Dysplasia.

Archives of rheumatology
2017

MED resulting from recessively inherited mutations in the gene encoding calcium-activated nucleotidase CANT1.

American journal of medical genetics. Part A
2018

Homozygosity for a missense variant in COMP gene associated with severe pseudoachondroplasia.

Clinical genetics
2017

Double-Layered Patella (DLP) in Multiple Epiphyseal Dysplasia (MED).

Journal of the Belgian Society of Radiology
2017

Diagnosis with Multiple Epiphyseal Dysplasia Using Whole-exome Sequencing in a Chinese Family.

Chinese medical journal
2017

The fate of hips that are conservatively treated in multiple epiphyseal dysplasia.

Journal of pediatric orthopedics. Part B
2016

Partial double-layered patella in a nondysplasic adolescent.

Journal of pediatric orthopedics. Part B
2016

Extensive Arthroscopic Chondroplasty for Cartilage Hyperplasia of the Femoral Condyle Causing Recurrent Knee Locking in a Patient With Multiple Epiphyseal Dysplasia.

Arthroscopy techniques
2016

Beaulieu-Boycott-Innes syndrome: an intellectual disability syndrome with characteristic facies.

Clinical dysmorphology
2017

Multiple epiphyseal dysplasia mimicking osteoarthritis due to acetabular dysplasia: A report of a familial case with a COMP mutation.

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association
2016

Tissue-engineered cartilage implantation for the chondral lesion in a patient with multiple epiphyseal dysplasia.

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association
2016

THE 3rd W522X MUTATION IN EIF2AK3 GENE FROM TURKEY: A NEW PATIENT WITH WOLCOTT-RALLISON SYNDROME.

Genetic counseling (Geneva, Switzerland)
2015

Bilateral Second Carpal Row Duplication Associated with Multiple Epiphyseal Dysplasia.

Journal of wrist surgery
2015

New therapeutic targets in rare genetic skeletal diseases.

Expert opinion on orphan drugs
2015

Multiple functions of the first EGF domain in matrilin-3: Secretion and endoplasmic reticulum stress.

International journal of molecular medicine
2015

Paleopathological Study of Dwarfism-Related Skeletal Dysplasia in a Late Joseon Dynasty (South Korean) Population.

PloS one
2015

Forearm lengthening by distraction osteogenesis: A report on 5 limbs in 3 cases.

The journal of medical investigation : JMI
2015

Single-Stage Corrective Osteotomies for Multiple Angular Deformities Around the Knee Joint with Patellar Instability in a Patient with Multiple Epiphyseal Dysplasia: A Case Report.

JBJS case connector
2015

The utility of mouse models to provide information regarding the pathomolecular mechanisms in human genetic skeletal diseases: The emerging role of endoplasmic reticulum stress (Review).

International journal of molecular medicine
2015

Increased classical endoplasmic reticulum stress is sufficient to reduce chondrocyte proliferation rate in the growth plate and decrease bone growth.

PloS one
2015

Multiple epiphyseal dysplasia.

The Journal of the American Academy of Orthopaedic Surgeons
2015

A study of the clinical and radiological features in a cohort of 93 patients with a COL2A1 mutation causing spondyloepiphyseal dysplasia congenita or a related phenotype.

American journal of medical genetics. Part A
Ver todos os 250 no EuropePMC

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Doenças relacionadas

Doenças com sintomas parecidos — ajudam quem ainda está buscando diagnóstico

Ordenadas pelo número de sintomas em comum.

Referências e fontes

Bases de dados externas citadas neste artigo

Publicações científicas

Artigos indexados no PubMed ligados a esta doença no grafo RarasNet — título, periódico e PMID direto da fonte, sem intermediação de IA.

  1. Genotype-phenotype correlations in PSACH/EDM1 patients with COMP gene variants: a comprehensive review of 830 cases.
    Frontiers in endocrinology· 2026· PMID 41798190mais citado
  2. Human pluripotent stem cell model of multiple epiphyseal dysplasia with MATN3 mutation identifies altered matrix organisation and upregulation of the cholesterol biosynthesis pathway.
    Osteoarthritis and cartilage· 2026· PMID 41651153mais citado
  3. Total knee arthroplasty with simultaneous triplanar osteotomy of the distal femur using patient-specific instrumentation : A&#xa0;case report.
    Orthopadie (Heidelberg, Germany)· 2026· PMID 40911070mais citado
  4. Elevated MMP9 Expression-A Potential In Vitro Biomarker for COMPopathies.
    International journal of molecular sciences· 2025· PMID 41465495mais citado
  5. From Protein Misfolding to Extracellular Matrix Disorganisation: Understanding Disease Pathology in Rare Skeletal Dysplasias.
    International journal of molecular sciences· 2025· PMID 41155349mais citado
  6. Exome Sequencing Identifies a Novel Splicing Variant in COL9A3 Resulting in Multiple Epiphyseal Dysplasia: A Case Report.
    Mol Genet Genomic Med· 2025· PMID 41194747recente

Bases de dados e fontes oficiais

Identificadores e referências canônicas usadas para montar este verbete.

  1. ORPHA:251(Orphanet)
  2. MONDO:0016648(MONDO)
  3. GARD:10756(GARD (NIH))
  4. Variantes catalogadas(ClinVar)
  5. Busca completa no PubMed(PubMed)
  6. Q1452604(Wikidata)

Dados compilados pelo RarasNet a partir de fontes abertas (Orphanet, OMIM, MONDO, PubMed/EuropePMC, ClinicalTrials.gov, DATASUS, PCDT/MS). Este conteúdo é informativo e não substitui avaliação médica.

Conteúdo mantido por Agente Raras · Médicos e pesquisadores podem colaborar

Displasia epifisária múltipla
Compêndio · Raras BR

Displasia epifisária múltipla

ORPHA:251 · MONDO:0016648
Prevalência
1-9 / 100 000
Herança
Autosomal dominant, Autosomal recessive
CID-11
Início
Infancy, Neonatal
Prevalência
5.0 (Europe)
MedGen
UMLS
C0026760
EuropePMC
Wikidata
Papers 10a
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