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The hips of patients with DDH, AVN, MPS and ML. A) X ray of the pelvis of a patient with DDH of the left hip (9 months), compared to the right normal hip. It shows a shallow, lateralized and anteverted acetabulum, with a smaller epiphysis of the left femoral head with luxation, B) MPS I patient (11 months), C) ML II patient (13 months), both x-rays show hypoplasia of the basis of the os ilium (shaped like an ear of Mickey mouse), steep and narrow, dysplastic acetabulum and a normal femoral epiphysis. B) shows also subluxation of the right femoral head with formation of a neo-acetabulum typically seen in MPS I patients. D, E, F, G; X-rays of hemi-pelvises of D) an aged matched control (6 years), E) patient with AVN (5 years), F) patient with rapidly progressive MPS VI (5 years), G) patient with ML III (5 years). In D and E the os ileum and acetabulum are normal, F and G show the typical abnormal shape of the os ileum (hypoplastic basis of the os ileum, with a dysplastic acetabulum (neo-acetabulum)). The femoral head is normal in D, and in E deformation of the epiphysis (lateral and central part of the femoral head) (star), F and G abnormal ossification of the epiphysis (central and medial site of the femoral heads) (arrow head).
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The hips are frequently involved in inheritable diseases which affect the bones. The clinical and radiological presentation of these diseases may be very similar to common hip disorders as developmental dysplasia of the hip, osteoarthritis and avascular necrosis, so the diagnosis may be easily overlooked and treatment may be suboptimal.
Mucopolysac...
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Context 1
... coverage of the femoral head at the anterior, lateral and superior site. The femoral head is small compared to the acetabulum, there is excessive femoral neck anteversion and the femur neck is short with an increased neck shaft angle [48]. In contrast, the femoral head in the MPS and ML patients is large compared to the dysplastic acetabulum (Fig. 8). Hip ultrasound is recommended in infants younger than 4 months for screening for DDH [76]. With this method diseases like MPS and ML can be easily missed for example by difficulties in anatomical interpretation [36] and it would be preferable to use other imaging modalities like hip x-ray and or ...
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... avascular necrosis, not related to MPS and ML, the necrosis is often present at the lateral site of the femoral heads (Fig. 8). In MPS abnormal ossification of the epiphysis is characteristically observed at the central and medial part of the femoral head [33]. Bilateral ossification abnormalities in the proximal epiphysis, which may mimic avascular necrosis, are typically found in MPS IVA, VI, VII and in ML III and should trigger suspicion of the diagnosis ...
Citations
... There are multiple musculoskeletal manifestations seen in MPS including craniocervical stenosis, C1-C2 instability, kyphoscoliosis, abnormal epiphyseal formation, genu valgum, short stature, and hypermobility [4,5]. Early-onset debilitating joint pain is common in MPS, with the hip being one of the most commonly affected joints to develop end-stage arthritis [6]. ...
Mucopolysaccharidosis encompasses multiple lysosomal storage disorders that are relevant to the orthopedic surgeon as they lead to disruption in bone and cartilage development. These patients may present with early-onset joint pain, including end-stage hip arthritis warranting total hip replacement. The altered hip anatomy in this disorder is of specific importance to the arthroplasty surgeon as it presents challenges when reconstructing the proximal femur and acetabulum and informs implant choice. We present a 17-year-old patient with end-stage bilateral hip arthritis who underwent staged bilateral total hip arthroplasty. We discuss technical considerations in surgical technique and the consequences of acetabular and femoral deformity on implant selection.
... Rights reserved. mucopolysaccharidosis of type 1 (Cobos et al. 2015), an autosomal recessive disorder that commonly involves the hips, with similar clinical and radiological presentation as DDH (Oussoren et al. 2021). ...
Developmental dysplasia of the hip (DDH) is a common condition involving instability of the hip with multifactorial etiology. Early diagnosis and treatment are critical as undetected DDH is an important cause of long-term hip complications. Better diagnostics may be achieved through genetic methods, especially for patients with positive family history. Several candidate genes have been reported but the exact molecular etiology of the disease is yet unknown. In the present study, we performed whole exome sequencing of DDH patients from 28 families with at least two affected first-degree relatives. Four genes previously not associated with DDH ( METTL21B , DIS3L2 , PPP6R2 , and TM4SF19 ) were identified with the same variants shared among affected family members, in more than two families. Among known association genes, we found damaging variants in DACH1 , MYH10 , NOTCH2, TBX4, EVC2 , OTOG , and SHC3 . Mutational burden analysis across the families identified 322 candidate genes, and enriched pathways include the extracellular matrix, cytoskeleton, ion-binding, and detection of mechanical stimulus. Taken altogether, our data suggest a polygenic mode of inheritance for DDH, and we propose that an impaired transduction of the mechanical stimulus is involved in the etiopathological mechanism. Our findings refine our current understanding of candidate causal genes in DDH, and provide a foundation for downstream functional studies.
... In newborn mice abnormal anlagen of tracheal and articular cartilage was reported, indicating that cartilage pathology can already start during development (Evers et al., 1996). Studies from human cartilage biopsies of MPS I, II and III patients showed severe cartilage damage and abnormal chondrocytes (Oussoren et al., 2011;Oussoren et al., 2021), but limited information is available on the development of cartilage pathology in human patients with MPS VI. ...
Mucopolysaccharidosis type VI (MPS VI) is a metabolic disorder caused by disease-associated variants in the Arylsulfatase B (ARSB) gene, resulting in ARSB enzyme deficiency, lysosomal glycosaminoglycan accumulation, and cartilage and bone pathology. The molecular response to MPS VI that results in cartilage pathology in human patients is largely unknown. Here, we generated a disease model to study the early stages of cartilage pathology in MPS VI. We generated iPSCs from four patients and isogenic controls by inserting the ARSB cDNA in the AAVS1 safe harbor locus using CRISPR/Cas9. Using an optimized chondrogenic differentiation protocol, we found Periodic acid–Schiff positive inclusions in hiPSC-derived chondrogenic cells with MPS VI. Genome-wide mRNA expression analysis showed that hiPSC-derived chondrogenic cells with MPS VI downregulated expression of genes involved in TGF-β/BMP signalling, and upregulated expression of inhibitors of the Wnt/β-catenin signalling pathway. Expression of genes involved in apoptosis and growth was upregulated, while expression of genes involved in glycosaminoglycan metabolism was dysregulated in hiPSC-derived chondrogenic cells with MPS VI. These results suggest that human ARSB deficiency in MPS VI causes changes in the transcriptional program underlying the early stages of chondrogenic differentiation and metabolism.
... As tooth development shares similarities with bone development, alterations would be expected in teeth as well. 3,[12][13][14][15] Available literature on orofacial abnormalities in MPS, ML II, and III consists of case reports, case series, and cohort studies, with limited patient numbers included. It is unclear if and to what extent orofacial abnormalities occur in all subtypes of MPS, ML II, and III and if the type of abnormalities differ between different subtypes, and what percentage of patients is affected. ...
Mucopolysaccharidoses (MPSs) and mucolipidosis II and III (ML II and III) often manifest with orofacial (progressive) abnormalities, which may have a major impact on quality of life. However, because these patients have multiple somatic health issues, orofacial problems are easily overlooked in clinical practice and available literature on this topic solely consists of case reports, small case series, and small cohort studies. The aim of this systematic review was to gain more insight in the nature and extent of orofacial abnormalities in MPS, ML II, and III. A systematic review of all previously published articles addressing orofacial abnormalities in MPS, ML II, and III was performed. Both clinical studies and case reports were included. Outcome was the described orofacial abnormalities, subdivided into abnormalities of the face, maxilla, mandible, soft tissues, teeth, and occlusion. The search resulted in 57 articles, describing orofacial features in 340 patients. Orofacial abnormalities were present in all subtypes of MPS, ML II, and III, and consisted of thickened lips, a hypoplastic midface, a high‐arched palate, hypoplastic condyles, coronoid hyperplasia, macroglossia, gingival hyperplasia, thick dental follicles, dentigerous cysts, misshapen teeth, enamel defects, and open bite. Orofacial abnormalities are present in all subtypes of MPS, ML II, and III. As orofacial abnormalities may cause complaints, evaluation of orofacial health should be part of routine clinical care.
Deficiency of iduronate 2-sulfatase (IDS) causes Mucopolysaccharidosis type II (MPS II), a lysosomal storage disorder characterized by systemic accumulation of glycosaminoglycans (GAGs), leading to a devastating cognitive decline and life-threatening respiratory and cardiac complications. We previously found that hematopoietic stem and progenitor cell-mediated lentiviral gene therapy (HSPC-LVGT) employing tagged IDS with insulin-like growth factor 2 (IGF2) or ApoE2, but not receptor-associated protein minimal peptide (RAP12x2), efficiently prevented brain pathology in a murine model of MPS II. In this study, we report on the effects of HSPC-LVGT on peripheral pathology and we analyzed IDS biodistribution. We found that HSPC-LVGT with all vectors completely corrected GAG accumulation and lysosomal pathology in liver, spleen, kidney, tracheal mucosa, and heart valves. Full correction of tunica media of the great heart vessels was achieved only with IDS.IGF2co gene therapy, while the other vectors provided near complete (IDS.ApoE2co) or no (IDSco and IDS.RAP12x2co) correction. In contrast, tracheal, epiphyseal, and articular cartilage remained largely uncorrected by all vectors tested. These efficacies were closely matched by IDS protein levels following HSPC-LVGT. Our results demonstrate the capability of HSPC-LVGT to correct pathology in tissues of high clinical relevance, including those of the heart and respiratory system, while challenges remain for the correction of cartilage pathology.
Lysosomal Storage Disorders (LSDs) are a diverse group of inherited, monogenic diseases caused by functional defects in specific lysosomal proteins. The lysosome is a cellular organelle that plays a critical role in catabolism of waste products and recycling of macromolecules in the body. Disruption to the normal function of the lysosome can result in the toxic accumulation of storage products, often leading to irreparable cellular damage and organ dysfunction followed by premature death. The majority of LSDs have no curative treatment, with many clinical subtypes presenting in early infancy and childhood. Over two thirds of LSDs present with progressive neurodegeneration, often in combination with other debilitating peripheral symptoms. Consequently, there is a pressing unmet clinical need to develop new therapeutic interventions to treat these conditions. The blood-brain barrier is a crucial hurdle that needs to be overcome in order to effectively treat the CNS, adding considerable complexity to therapeutic design and delivery. Enzyme replacement therapy (ERT) treatments aimed at either direct injection into the brain, or using blood-brain barrier constructs are discussed, alongside more conventional substrate reduction and other drug related therapies. Other promising strategies developed in recent years, include gene therapy technologies specifically tailored for more effectively targeting treatment to the CNS. Here we discuss the most recent advances in CNS targeted treatments for neurological LSDs with a particular emphasis on gene therapy-based modalities, such as AAV and HSCGT approaches that encouragingly, at the time of writing are being evaluated in LSD clinical trials in increasing numbers. If safety, efficacy and improved quality of life can be demonstrated, these therapies have the potential to be the new standard of care treatments for LSD patients. This article is protected by copyright. All rights reserved.
Purpose: Hepatomegaly, splenomegaly and hepatosplenomegaly in children can be due to infections, genetic liver diseases, hematological diseases or malignancies, autoimmune disorders, and also inborn errors of metabolism (IEM). Some IEM’s have specific treatments which should be started before irreversible complications occur. The aim of this study is to evaluate the etiological causes of visceromegaly in pediatric patients and assess the clinical findings of patients having an IEM. Materials and Methods: In this study, medical records of 93 patients who were referred to Pediatric Metabolism Unit in a tertiary care hospital with the suspicion of IEM-related hepatomegaly, splenomegaly or hepatosplenomegaly were reviewed retrospectively. Results: 45 patients had hepatomegaly, 18 had splenomegaly and 30 had hepatosplenomegaly. A total of 52 patients were diagnosed as having an IEM. 32 patients were lost to follow-up. The eventual diagnoses of 9 patients were not IEM. Conclusion: IEMs present from prenatal period to adulthood. Awareness of clinicians and diagnostic algorithms can prevent delayed diagnosis and enable early treatment for treatable IEMs or provide genetic counseling for the patient’s family.
Glycosaminoglycans, (GAGs, mucopolysaccharides) are essential constituents of connective tissue, including cartilage and vessel walls. They are composed of long sugar chains, containing highly sulfated, alternating uronic acid and hexosamine residues, assembled into repeating units. The polysaccharide chains are bound to specific core proteins within complex macromolecules called proteoglycans (PG). GAGs are grouped in two families: sulfated GAGs, mainly represented by chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS), heparan sulfate (HS) and heparin (◘ Fig. 41.1) and nonsulfated GAGs including mainly hyaluronan (HA). PG biosynthesis involves several enzymes and transporters in four main steps: core protein synthesis, GAG synthesis (including the linker tetrasaccharide and subsequent chain elongation), GAG sulfation and PG secretion. Core protein synthesis occurs in the rough endoplasmic reticulum where some early modifications, such as N-glycosylation, take place. The core protein then moves to the Golgi apparatus for GAG biosynthesis (see also ► Chaps. 43 and 44). Degradation of GAGs takes place inside the lysosomes and requires several acid hydrolases. Deficiencies of specific degradative enzymes are the cause of a variety of eponymous disorders, collectively termed mucopolysaccharidoses (MPSs).
Background
Developmental dysplasia of the hip (DDH) is a common condition involving instability of the hip with multifactorial etiology. Early diagnosis and treatment are critical as undetected DDH is an important cause of long-term hip complications. Better diagnostics may be achieved through genetic methods, especially for patients with positive family history. Several candidate genes have been reported but the exact molecular etiology of the disease is yet unknown.
Results
In the present study, we performed whole exome sequencing of DDH patients from 29 families with at least two affected first-degree relatives. We identified PPP6R2 as a novel DDH gene as two rare missense mutations were identified in three families co-segregating with disease. Mutational burden analysis across the families identified 455 candidate genes, with many genes involved in mechanotransduction, in particular the cilia, the cytoskeleton, the extracellular matrix, and the Notch pathway.
Conclusions
Here we report for the first time a previously uncorrelated gene with DDH, PPP6R2. Taken altogether, the data suggest a polygenic mode of inheritance for DDH, and we propose that impaired mechanotransduction is involved in the etiopathological mechanism.
