Multiple Epiphyseal Dysplasia Research Articles

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

BackgroundTotal knee arthroplasty (TKA) in patients who have skeletal dysplasia is a technically challenging surgery due to deformity, joint contracture, and associated co-morbidities. Patients presenting with this condition have traditionally been treated with conservative measures, leading to poor outcomes. The aim of this study was to follow up on patients who had skeletal dysplasia following total knee arthroplasty, specifically with regards to clinical outcomes. MethodsA total of 31 knees (22 patients) with skeletal dysplasia that had undergone total knee arthroplasty in our institution were included in our study. The mean follow-up from index surgery was 110.3 months (range; 20 to 291). The type of dysplasia, implant used, and clinical outcomes with patient-reported outcome measures (PROMs) are presented. ResultsThere were eight patients (36.3%) who had a diagnosis of achondroplasia, followed by multiple epiphyseal dysplasia (31.8%) and spondyloepiphyseal dysplasia (22.7%). There were fourteen men and eight women who had a mean age of 51 years (range, 28 to 73). Custom implants were required in twelve cases (38.7%), custom jigs were used in six cases (19.4%), and robotic assisted surgery was used in two (6.5%) total knee arthroplasties. Hinged prostheses were used in seventeen cases (54.8%), posterior stabilized in nine (29.0%), and cruciate retaining implants in five (16.1%). There was one patient who sustained an intra-operative medial tibial plateau fracture treated with concomitant open reduction and internal fixation. There was one revision that occurred during the follow-up period with a patella resurfacing for continued anterior knee pain. Post-operatively, Oxford knee scores improved on average by 12.2 points. The 10- and 20-year all-cause revision-free survival was 96.8 respectively. ConclusionDespite the technical challenges and complexity associated with this unique patient cohort, we demonstrated excellent implant survivorship and clinical outcomes post-total knee arthroplasty with mid- to long-term follow up of over 20 years. We recommend pre-operative cross-sectional imaging for precise planning and implant templating with multidisciplinary team decision-making. Despite our results, functional outcomes remain inferior to primary arthroplasty within the general population, though we still recommend this treatment modality to appropriately counseled patients.

Further characterization of ARSK-related mucopolysaccharidosis type 10.

Mucopolysaccharidosis type 10 is caused by biallelic variants in ARSK, which encodes for a lysosomal sulfatase. To date, seven patients with a mild phenotype resembling spondyloepiphyseal dysplasia or multiple epiphyseal dysplasia have been described. In this report, we present two novel ARSK variants and report clinical and radiological findings of three patients. The patients' initial complaints were hip or knee pain and a waddling gait. All patients showed normal intelligence, normal hearing and eye examinations, and none had organomegaly. While typical dysostosis multiplex findings were not observed, mild platyspondyly with anterior beaking of some vertebral bodies, irregular vertebral endplates, wide ribs, inferior tapering of the ilea with a poorly developed acetabulum, irregularity of the central part of the femoral head, delayed ossification of the carpals were noted. Remarkably, all patients showed metaphyseal striation of the long bones, a crucial diagnostic clue to identify ARSK-related MPS type 10. Interestingly, vertebral involvement regressed during follow-up. On the other hand, hip dysplasia progressed in all patients. In conclusion, this study provides valuable long-term results on a recently discovered form of MPS.

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.

Differential diagnosis of juvenile idiopathic arthritis and multiple epiphyseal dysplasia: Experience of multidisciplinary interaction

Introduction. Juvenile idiopathic arthritis (JIA) is a common multifactorial disease characterized by the presence of chronic inflammation in the joints, entheses and other structures of the musculoskeletal system in combination with a certain range of extraskeletal disorders. Vast variety of JIA clinical variants and the variability of the disease course make primary and differential diagnosis difficult, which often leads to a delayed start of treatment and an inadequate choice of medical therapy or, conversely, an excess of medication. In the range of differential diagnostic conditions that have similar symptoms and are manifested by severe arthralgia, gait disturbance, joint stiffness, as well as the presence of effusion and gradual progression of bone destruction mainly in the epiphyseal plate, one should remember about hereditary skeletal dysplasias, primarily from a genetically heterogeneous group of multiple epiphyseal dysplasias (MED). The aim of the study – description of the clinical and genetic characteristics of three patients with various genetic variants of MED and defining approaches for their differential diagnosis with JIA. Materials and methods. There were three patients from three unrelated families aged from 7 to 13 years old under our supervision. To clarify the diagnosis, a genealogical analysis, a clinical examination of patients and first-degree relatives, as well as an assessment of X-ray images of long tubular bones were carried out. Molecular genetic confirmation of the MED diagnosis types 1 and 2 was based on the results of custom panel sequencing consisting of 166 genes responsible for the development of hereditary skeletal pathology. To clarify the molecular genetic diagnosis of MED type 4, an analysis of the SLC26A2 gene was performed using automated Sanger sequencing. Results. Anamnestic, clinical, radiological, and molecular genetic characteristics of three unrelated patients with different genetic types of MED caused by variants in the COMP, SLC26A2, and COL9A2 genes were analyzed. The first symptoms of the disease in observed patients with three different genetic variants of MED occurred at the age of 2–3 years old and were characterized by gait disturbance and climbing stairs difficulties. Gradually, these symptoms were accompanied by pain in large joints. According to the ultrasound examination of the joints, signs of synovitis were noted, as a result they were diagnosed with JIA (polyarticular variant, seronegative for rheumatoid and antinuclear factor) and immunosuppressive therapy were prescribed without significant effect. The atypical course of the JIA was the reason for additional examination of patients by an orthopedist and geneticist. Careful analysis of the large joints radiographs made it possible to suspect one of the variants of MED in our patients based on the detection of distinctive signs, which were characterized by abnormal ossification (diminished size and flattening) of the epiphyses and abnormal shape and structure of the femoral head epiphysis. Molecular genetic analysis was performed to confirm the diagnosis. As a result, a pathogenic variant of the nucleotide sequence in the COMP gene was detected in one of the patients, two pathogenic variants in the SLC26A2 gene in another patient, and one pathogenic variant in the COL9A2 gene in the third patient, which made it possible to confirm the final diagnosis of MED type 1 with an autosomal dominant type of inheritance, MED type 4 with an autosomal recessive type of inheritance and MED type 2 with an autosomal dominant type of inheritance, respectively. Based on the results of our own research and analysis of the literature data, key directions for the differential diagnosis of MED and JIA were formulated. It is shown that the analysis of the X-ray images of patients is essential in differential diagnosis. Conclusion. Despite the significant overlap of the clinical symptoms between JIA and MED, the key to the early diagnosis of MED is a comprehensive examination, which included genealogical analysis, features of clinical manifestations and disease course in combination with distinctive radiological signs including delayed ossification of the epiphyses of tubular bones typical for MED. However, the question remains about the probability of a combined nature of osteoarticular disorders, i. e., the possible development of JIA in patients with hereditary skeletal dysplasias which requires in-depth study in the future.

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

BackgroundMultiple epiphyseal dysplasia (MED) is a rare congenital bone dysplasia. Patients with MED develop secondary hip osteoarthritis as early as the third to the fourth decade. Currently, there is no consensus on the prevention of the progressive hip osteoarthritis secondary to MED. The Bernese periacetabular osteotomy (PAO) is a joint-preserving surgery to reshape acetabulum and extend femoral head coverage. However, there is no documentary evidence for the effect of the procedure on MED hips.Patients and methodsWe analyzed the preliminary outcomes following the Bernese PAO in 6 MED hips. The average age at the time of surgery was 14.3 years (range from 11.4 to 17.2 years). For our study interest of time efficiency, radiographic parameters were analyzed preoperatively and 1 year postoperatively. The hip function was evaluated by the Harris Hip Score (HHS) before and after surgery.ResultsThe mean follow-up time was 1.7 years. The mean lateral center–edge angle increased from 3.8° to 47.1° (p = 0.02), anterior center–edge angle increased from 7.3° to 35.1° (p = 0.02), and acetabulum index decreased from 27.8° to 14.6° (p = 0.04). The femoral head coverage ratio increased from 66.8% to 100% (p = 0.02). The post-operative anteroposterior pelvic radiograph demonstrated all preoperative broken Shenton lines were reversed. The mean HHS improved from 67.3 to 86.7 (p = 0.05).ConclusionBernese PAO is a feasible treatment for hip disorders in MED patients. It reshapes acetabular and femoral morphology efficiently. In our study, the preliminary results showed the procedure not only improved radiographic outcomes but also hip function.

HIP SURGERY IN GENETIC SKELETAL DISORDERS: RISKY BUSINESS?

Genetic skeletal disorders constitute a rare and heterogeneous bone diseases often leading to poor quality of life. Several surgical options are available. The surgeon must deal with specific features (bone deformity, previous procedures, abnormal bone quality, stiffness or instability, muscle weakness). The questions concern the feasibility of the procedures and the surgical strategy.55 patients (26 W, 29 M) were reviewed between 2016 and 2022. The mean age of the patients was 35 years (17–71). The diagnosis included 9 hereditary multiple exostoses, 8 osteogenesis imperfecta, 6 multiple epiphyseal dysplasia congenita, 6 achondroplasia, 4 osteopetrosis, 3 pycnodysostosis, 3 hypophosphatemic rickets, 3 fibrous dysplasia, 2 mucopolysaccharidosis, and 10 miscellaneous. 25 patients were referred for hip problems (40 hips). 4 patients (7 hips) requiring a THA have not been operated (4 planned). 4 patients (6 hips) had a proximal femoral fixation (2 osteotomies, 4 fracture fixations). 17 patients (27 hips) sustained a THA (25 primary, 2 revisions). All of them were operated by one operator, using a posterolateral approach and standard implants (including 7 dysplastic and 2 short stems). No customized implant has been used.As regard the 27 THAs, the mean follow up was 4.2 years (1–12). The early complications included 2 femoral cracks and 1 femur fracture. There were 2 revisions (1 cup loosening at 2 years, 1 stem loosening at 4 years). No infection nor dislocation occurred. All the patients were satisfied with their treatment and regain some autonomy. 3 THA were considered as unfeasible.Constitutional bone diseases need a multidisciplinary program of care. The indication for surgery is based on a mutual trust patient/surgeon, a careful evaluation of benefits/risks, and an accurate imaging to anticipate the difficulties. The expected results are a better function and quality of life, and a stability over time.

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

Objective: To analyze the clinical and genetic characteristics of pediatric patients with dual genetic diagnoses (DGD). Methods: Clinical and genetic data of pediatric patients with DGD from January 2021 to February 2022 in Peking University First Hospital were collected and analyzed retrospectively. Results: Among the 9 children, 6 were boys and 3 were girls. The age of last visit or follow-up was 5.0 (2.7,6.8) years. The main clinical manifestations included motor retardation, mental retardation, multiple malformations, and skeletal deformity. Cases 1-4 were all all boys, showed myopathic gait, poor running and jumping, and significantly increased level of serum creatine kinase. Disease-causing variations in Duchenne muscular dystrophy (DMD) gene were confirmed by genetic testing. The 4 children were diagnosed with DMD or Becker muscular dystrophy combined with a second genetic disease, including hypertrophic osteoarthropathy, spinal muscular atrophy, fragile X syndrome, and cerebral cavernous malformations type 3, respectively. Cases 5-9 were clinically and genetically diagnosed as COL9A1 gene-related multiple epiphyseal dysplasia type 6 combined with NF1 gene-related neurofibromatosis type 1, COL6A3 gene-related Bethlem myopathy with WNT1 gene-related osteogenesis imperfecta type XV, Turner syndrome (45, X0/46, XX chimera) with TH gene-related Segawa syndrome, Chromosome 22q11.2 microduplication syndrome with DYNC1H1 gene-related autosomal dominant lower extremity-predominant spinal muscular atrophy-1, and ANKRD11 gene-related KBG syndrome combined with IRF2BPL gene-related neurodevelopmental disorder with regression, abnormal movement, language loss and epilepsy. DMD was the most common, and there were 6 autosomal dominant diseases caused by de novo heterozygous pathogenic variations. Conclusions: Pediatric patients with coexistence of double genetic diagnoses show complex phenotypes. When the clinical manifestations and progression are not fully consistent with the diagnosed rare genetic disease, a second rare genetic disease should be considered, and autosomal dominant diseases caused by de novo heterozygous pathogenic variation should be paid attention to. Trio-based whole-exome sequencing combining a variety of molecular genetic tests would be helpful for precise diagnosis.

Distinctive Cranial Abnormalities in Children with Early Infancy Insulin Dependent Diabetes in Connection with Wolcott-Rallison Syndrome

Background: Abnormal craniofacial contour and deformities of the appendicular skeleton of the lower limbs can occur in connection with a long list of skeletal dysplasia. The natural history of chronic/unusual disorders can be a precise key factor towards a successful diagnostic process. Material and Methods: Three unrelated children aged 18-months, 2 and 7 year (two boys and one girl) presented with generalised skeletal mal-development compatible with multiple epiphyseal dysplasia. However, in the early months of life these children have been diagnosed with early infancy insulin dependent diabetes. Strikingly, all manifested Wormian bones over the lambdoid sutures. In addition to Progressive malalignment of the lower limbs and thoracic kyphosis associated with significant growth deficiency were the major skeletal abnormalities. Endochondral ossification was diffusely affected associated with multiple epiphyseal dysplasia and appearance of irregular and fragmented epiphyses. Results: Based on early permanent neonatal or early-infancy insulin-dependent diabetes, associated with the clinical and radiological phenotypic characterizations of multiple epiphyseal dysplasia and growth retardation as the major abnormalities in these children. Wolcott-Rallison syndrome was the highly likely diagnosis. The most interesting findings in this study; The Wormian bones, not only involved the lambdoid sutures, but also extended to involve the occipitomastoid suture. We confirmed our diagnosis via sequence analysis which revealed a homozygous nonsense gene mutation (EIF2AK3) resulting in a premature stop codon (c.2707 C&gt;T, p.R903X). Parents in two families were identified as heterozygous carriers of this mutation. Conclusion: The significance of this study is to point out the importance of analysing the skull bones in children with skeletal dysplasia. Interestingly, for the first time we detected the downward bulging of the occiput because of the abundancy of the Wormian bones (sites of maximal skull bone fragility) along the lambdoid and the occipito-mastoid sutures is by itself a highly alarming sign of progressive weakness of the weight-bearing zone (which is represented by the lambdoid and the occipitomastoid sutures). The exerting load of the cerebrum on these vulnerable and soft sutures can lead to brain swelling (a serious condition). Despite that lower limb defects in children are the most frequent deformities encountered in the departments of paediatric orthopaedics, because of the real or apparent detrimental effect that they have on gait and upright activity, and it draw immediate and alarming attention to parents. But, nevertheless, it is the responsibility of physicians to pay prompt attention for the necessity to scrutinize the skulls and the craniocervical junction in patients with long term bone disorders.

A CASE REPORT ON WOLCOTT RALLISON SYNDROME

A Case Report of Wolcott–Rallison syndrome, it is a rare, autosomal recessive disorder with infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, osteopenia, mental retardation or developmental delay, and hepatic and renal dysfunction as main clinical findings. Patients have most common history of consanguineous marriage. Patients with WRS have mutations in the EIF2AK3 gene, which encodes the eukaryotic translation initiation factor 2-alpha kinase 3. Most common cause of death is fulminant hepatitis in early childhood.The EIKF2AK3 gene codes for PERK (pancreatic endoplasmic reticulum kinase),an explanation for the spectrum of symptoms.PERK is associated with the activity of beta cells in the pancreas.A broad range of bodily systems is affected, including pancreas, kidney, liver,bone, and nervous system, because of deficient stress response to improperly folded proteins inside the endoplasmic reticulum. A two months old male child born out of non-consanguineous marriage, Hindu by religion, presented with complain of fever since 4 days, respiratory distress since 12 hours. Patient was admitted and on regular blood sugar screening on arrival was high. Repeat random blood sugar was also elevated.Arterial blood gas was done which was suggested metabolic acidosis.Due to persistent high blood sugar,insulin drip was started and HbA1c was done which was 11 gm% and other investigations done. Diagnosis of neonatal diabetes mellitus was kept and managed accordingly. Studies for other endocrinopathies and autoimmune disease done which was negative. Child was having normal growth and development according to age. Genetic studies for neonatal diabetes was planned and EIKF2AK3 gene mutation was found homozygous. Both the parents were heterozygous for the mutation. So diagnosis was kept and regular follow up was advised.Key-words:Infant,Neonatal Diabetes,Endocrinopathy

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

The intracellular retention of mutant cartilage matrix proteins and pathological endoplasmic reticulum (ER) stress disrupts ossification and has been identified as a shared disease mechanism in a range of skeletal dysplasias including short limbed-dwarfism, multiple epiphyseal dysplasia type 5 (EDM5). Although targeting ER stress is an attractive avenue for treatment and has proven successful in the treatment of a related skeletal dysplasia, to date no drugs have proven successful in reducing ER stress in EDM5 caused by the retention of mutant matrilin-3. Our exciting findings show that by using our established luciferase ER stress screening assay, we can identify a "natural" chemical, curcumin, which is able to reduce pathological ER stress in a cell model of EDM5 by promoting the proteasomal degradation mutant matrilin-3. Therefore, this is an important in vitro study in which we describe, for the first time, the success of a naturally occurring chemical as a potential treatment for this currently incurable rare skeletal disease. As studies show that curcumin can be used as a potential treatment for range of diseases in vitro, current research is focused on developing novel delivery strategies to enhance its bioavailability. This is an important and exciting area of research that will have significant clinical impact on a range of human diseases including the rare skeletal disease, EDM5.

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

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

Long Term Outcomes and Survivorship of Bilateral Lower Limb Arthroplasties in Patients with Multiple Epiphyseal Dysplasia

Background: Multiple epiphyseal dysplasia (MED) a rare form of skeletal dysplasia with early-onset osteoarthritis affecting the hip and knee joints. There is paucity of evidence regarding the long term outcomes of arthroplasty in this patient cohort. This is the first study to describe the outcomes of bilateral arthroplasty of the hip and knee in patients with MED. Methods: A prospective study of patients with MED who underwent bilateral staged total hip arthroplasty (THA) and bilateral simultaneous total knee arthroplasty (TKA) between July 2013 to April 2014. Preoperative and postoperative clinical and radiographic assessment including functional outcomes namely Merle d’aubigne score, Harris hip score (HHS), Knee society score (KSS) and numeric rating scale (NRS) for pain were recorded in prospective database and evaluated. Results: 3 patients (female - 1 / male - 2) with MED who underwent bilateral lower limb arthroplasty of the hip and knee were reviewed periodically with an average followup of 7.31 years. Mean preoperative Merle d'Aubigné score (6.33 ± 0.58), HHS (31.83 ± 5.31) and KSS (28.67 ± 7.97) increased following bilateral lower limb arthroplasty with mean postoperative Merle d'Aubigné score (16.33 ± 0.58), HHS (84.33 ± 5.99) and KSS (86.33 ± 7.09) (P&lt;0.001). Mean NRS decreased from 7.33 ± 0.58 in the preoperative period to 0.67 ± 0.58 at the most recent followup (P&lt;0.001). One patient had heterotrophic ossification following THA. There were no revisions. Conclusions: Bilateral lower limb arthroplasty of the hip and knee is a good treatment option to restore function and mobility in MED patients with advanced degenerative arthritis. Careful preoperative planning, meticulous surgical techniques, patient focussed postoperative rehabilitation with multidisciplinary team approach are vital to ensure good functional outcomes and implant survivorship.

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

Diagnosis of rare skeletal diseases is based primarily on clinical phenotype and radiographic analysis. Genetic etiology of these heterogeneous diseases remains largely unknown. Here, we report the identification of two genomic mutations using exome sequencing from patients with multiple epiphyseal dysplasia (MED) of an unusual family in autosomal dominant and X-linked inheritance. A dominant mutation (c.2224G>A; p.Gly687Ser) in the known causal COL2A1 gene was identified in three patients with MED, deformed femoral heads and vertebral dysplasia. Furthermore, a hemizygous mutation (c.2830G>A; p.Ala944Thr) in the USP9X gene was identified in the fourth patient with short stature, MED, deformed femoral head, thoracic and lumbar platyspondyly, right ankle condyle dysplasia, and subchondral sclerosis. This is the first identification of an X-linked candidate causative gene in a patient with MED, suggesting a new clinical entity. Our findings shed a new light on the role of USP9X in MED-associated disorders.

Clinical and Genetic Characteristics of Multiple Epiphyseal Dysplasia Type 4.

Multiple epiphyseal dysplasias (MED) are a clinically and genetically heterogeneous group of skeletal dysplasias with a predominant lesion in the epiphyses of tubular bones. Variants in the SLC26A2 gene cause their autosomal recessive form (rMED or MED type 4). The accumulation of data regarding the genotype–phenotype correlation can help in the diagnosis and proper management of these patients. The aim of this study was to survey the clinical and genetic characteristics of 55 patients with MED type 4 caused by variants in the SLC26A2 gene. Diagnosis confirmation was carried out by radiography and custom panel sequencing consisting of 166 genes responsible for the development of hereditary skeletal pathology. This was followed by the validation of the identified variants using automated Sanger sequencing (for six patients) and the direct automatic Sanger sequencing of the coding sequence and the adjacent intron regions of the SLC26A2 gene for 49 patients. Based on the clinical and genetic analysis of our sample of patients, two main MED type 4 phenotypes with early and late clinical manifestations were identified. An early and more severe form of the disease was observed in patients with the c.835C > T variant (p.Arg279Trp), and the late and milder form of the disease was observed in patients with the c.1957T > A variant (p.Cys653Ser) in the homozygous or compound heterozygous state with c.26 + 2T > C. It was also shown that only three pathogenic variants were found in 95.3% of the alleles of Russian patients with MED type 4: c.1957T > A (p.Cys653Ser), c.835C > T (p.Arg279Trp), and c.26 + 2T > C; thus, it can be assumed that the primary analysis of these variants will contribute to the optimal molecular genetic diagnostics of MED type 4.

A Novel Homozygous Variant in the COMP Gene Causing a Multiple Epiphyseal Dysplasia 1 with Autosomal Recessive Inheritance

Multiple epiphyseal dysplasia type 1 is one of the most common autosomal dominant types of the genetically heterogeneous group of skeletal dysplasias characterized by impaired ossification of the epiphyses of long bones. To date, it is known that the disease is caused by heterozygous variants in the COMP gene and is characterized by a significant variability in the clinical manifestations. We report the first case of a patient with MED 1 caused by novel homozygous single nucleotide variant c.2170dupG (p.Val724Glyfs*20) in the COMP gene identified by whole-exome sequencing. The following segregation analysis in the family found a detected variant in heterozygous state in healthy consanguineous parents of the proband. Clinical and radiological examination revealed the atypical signs of epiphyseal dysplasia including limited range of extension and supination of both forearms, severe bilateral ulnar clubhand, plano-valgus deformity of the feet and generalized muscle weakness with gait disturbances. Among the clinical features, myopathic signs were the most prominent. The radiological and neurophysiological data can be helpful in the differential diagnostics with the congenital myopathies. The novel homozygous variant in the COMP gene that caused multiple epiphyseal dysplasia 1 with autosomal recessive inheritance can contribute to the more detailed description of genotype–phenotype correlations, which will allow research to understand better the role of the C-terminal domain of COMP.

Treatment outcomes of hips in patients with epiphyseal dysplasia.

Hip containment surgeries in multiple epiphyseal and spondyloepiphyseal dysplasia (MED/SED) patients aim to improve the mechanical environment of the hip joint. The purpose of this study was to determine if surgical intervention to improve femoral head coverage improved radiographic and clinical outcomes. A retrospective study identified patients with MED/SED seen in clinic between May 2000 and September 2017, with a minimum of 2-year follow-up. Patient charts/radiographs were reviewed for radiographic hip measurements, pain, and gait. Sixty-nine hips in 35 patients were identified. Forty-four hips were treated nonoperatively and 25 were treated surgically. The mean age at diagnosis was 6.2 years. The mean follow-up was 7.7 years for the surgical group and 7.1 years for the nonsurgical group. The mean postoperative follow-up was 5.4 years. Acetabular index decreased from initial to final visit by 9.0° in the surgical group and 1.6° in the nonsurgical group. Tonnis angle decreased by 13.5° in the surgical group and 1.5° in the nonsurgical group. Center edge angle increased by 19.0° in the surgical group and 7.1° in the nonsurgical group. Hips in the surgical group were 6.1 times more likely to experience an improvement in pain compared with hips in the nonsurgical group. Gait at the final follow-up was similar among the two groups. In this study cohort, containment surgery provided increased femoral head coverage; however, there was equal femoral head deformation despite intervention. Hips treated surgically were more likely to experience an improvement in pain; however, gait alterations did not improve.

Posterior Interosseous Nerve Palsy Associated with Multiple Epiphyseal Dysplasia

AbstractMultiple epiphyseal dysplasia is a condition that courses with a retarded epiphyseal development and may cause joint dysmorphia. We report a case of posterior interosseous nerve palsy in a child with dysplasia. After a physical examination and complementary diagnostic tests that revealed posterior interosseous nerve compression neuropathy, surgical neurolysis og the posterior interosseous nerve was performed at level of the the arcade of Frohse. The satisfactory evolution of the patient confirmed our diagnosis. Attention must be paid to the onset of signs or symptoms of nerve compression in these patients.

EP467: Prenatal genetic testing can lead to (almost) self-fulfilling prophecy: Diastrophic dysplasia as an example

From a diagnostic perspective, variants in SLC26A2 gene cause the spectrum of skeletal dysplasias including in-utero lethal achondrogenesis type 1B (OMIM: 600972), atelosteogenesis type 2 (OMIM: 256050), diastrophic dysplasia (OMIM: 222600) and multiple epiphyseal dysplasia (OMIM: 226900). Historically, individuals diagnosed with atelosteogenesis type 2 have had poor health outcomes and die in the perinatal period, whereas those with diastrophic dysplasia have had longer, potentially even typical lifespans. However, objective criteria to distinguish these two conditions prenatally does not exist. As is the case with many skeletal dysplasias, and recessive conditions in general, genetic testing alone cannot predict where along the spectrum of conditions an infant will present. With advancements in medical technology, we begin to question the potential of infants diagnosed with “lethal” skeletal dysplasias based on findings of a genetic test report. We present two children from two different families who endured unnecessary trauma in their quest to seek care for their child. In both cases, a prenatal ultrasound in the second trimester noted concerns for skeletal dysplasia, prompting an amniocentesis. Testing identified compound heterozygous variants in the SLC26A2 gene. Based on the interpretation of the genetic testing report and ultrasound findings, both families, in different institutions, were provided a diagnosis of atelosteogenesis type 2. This was counseled as a lethal skeletal dysplasia, and options presented were termination or comfort care if the choice was made to continue to term. Both families opted to continue the pregnancy and following delivery were discharged on hospice to homes that were not equipped for a new infant. Both infants had cleft palates, and neither family was trained on how to properly feed their baby. In both cases, once the infant outlived expectations and the family chose to pursue life-sustaining therapies, they faced significant challenges obtaining the necessary medical care for their child. At a few months of age, both infants, who had survived to this point despite any medical interventions, were admitted to the hospital due to malnutrition and weight loss upon their first visit with a specialist. Parents are faced with life-altering decisions when the diagnosis of a “lethal” skeletal dysplasia is given in a prenatal setting. When families decide to continue a pregnancy with a suspected poor prognosis, it is imperative that counseling include recognition of the nuance of a spectrum of disorders and the possibility for survival with life-sustaining interventions. If comfort care is agreed upon, a plan should be made on how a family could seek medical care if the child outlives expectations and/or the family wants to reassess their child’s care plan after delivery.

EP267: De novo COL11A1 and COL9A2 variants corresponding to Stickler syndrome phenotype

Stickler Syndrome is a rare clinically and genetically heterozygous connective tissue disorder with variable clinical presentation including serious vision (eg, myopia, cataract, and retinal detachment), hearing loss (eg, sensorineural, mixed and/or conductive), craniofacial abnormalities (midface underdevelopment and cleft palate) and joint problems (eg, precocious arthritis, spondyloepiphyseal dysplasia). Stickler syndrome is associated with pathogenic variants in the COL2A1, COL11A1, COL11A2, COL9A1, COL9A2 and COL9A3 genes are present. This syndrome is mainly inherited as an autosomal dominant pathology. We are presenting the case of a 15-year-old female who was referred to genetics by cardiology due to hypoglycemia, tachycardia and to rule out Marfan syndrome due to Marfanoid habitus. Upon physical examination there was evidence of joint hyperlaxity and decreased muscle tone. She also presented mild thoracolumbar dextroscoliosis of 25 degrees in curvature documented by spine X-rays. A connective tissue disorder gene panel was requested. The results indicate that the patient is heterozygous for variants in three genes: COL11A1, COL9A2 and NEPRO. The COL11A1 gene is responsible for providing the blueprint to synthesize a component of type XI collagen, which is commonly located in cartilage. Type XI collagen can also be found in the inner ear, the vitreous and in the nucleus pulposus. A sequence variant c.4718C>T in the COL11A1 gene was identified in this patient. This change is expected to cause an amino acid substitution p.Ser1573Leu, which has not been reported in the literature. Pathogenic variants in COL11A1 have been associated with autosomal dominant Stickler syndrome type II, autosomal dominant Marshall syndrome, autosomal dominant deafness 37 as well as autosomal recessive fibrochondrogenesis 1. COL9A2 gene provides the blueprint for synthesizing a part of a large molecule called type IX collagen, which is more flexible than other types of collagen. A sequence variant designated as c.1553G>T was documented in this gene and is expected to result in an amino acid substitution designated as p.Arg518Leu. Pathogenic variants in COL9A2 have been linked with autosomal recessive Stickler syndrome type V and autosomal multiple epiphyseal dysplasia 2. This variant has not been reported in the literature. The NERPRO (Nucleolus and neural progenitor protein) gene could be involved in cortex development as part of the Notch signaling pathway and it may also be involved in preimplantation embryo development. A NEPRO gene sequence variant designated as c.871G>A was documented as well. This sequence variant is expected to result in an amino acid substitution p.Val291Met. This variant has not been reported in the literature. Fifteen years old female with genetic variants on COL11A1, COL9A2 and NEPRO genes. The patient presents scoliosis, myopia, and amblyopia, micrognathia, hyperlaxed joints and hypotonia. The COL11A1 and the COL9A2 genes has been associated with autosomal dominant and autosomal recessive Stickler syndrome phenotypes respectively. Stickler syndrome is a connective tissue disorder that can include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate (either alone or as part of the Robin sequence). The COL11A1 variant has not been reported in the medical literature associate to the disease however predictive algorithms suggest the possibility of a deleterious effect on the protein. The patient also has a genetic variant on the COL9A2 gene that has not been associate to the disease but haploinsufficiency mechanisms may also be playing a role in this patient phenotype.

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

Whole exome sequencing (WES) is a powerful tool for the cataloguing of population-specific genetic diseases. Within this proof-of-concept study we evaluated whether analysis of a small number of individual exomes is capable of identifying recurrent pathogenic alleles. We considered 106 exomes of subjects of Russian origin and revealed 13 genetic variants, which occurred more than twice and fulfilled the criteria for pathogenicity. All these alleles turned out to be indeed recurrent, as revealed by the analysis of 1045 healthy Russian donors. Eight of these variants (NAGA c.973G>A, ACADM c.985A>C, MPO c.2031-2A>C, SLC3A1 c.1400T>C, LRP2 c.6160G>A, BCHE c.293A>G, MPO c.752T>C, FCN3 c.349delC) are non-Russian-specific, as their high prevalence was previously demonstrated in other European populations. The remaining five disease-associated alleles appear to be characteristic for subjects of Russian origin and include CLCN1 c.2680C>T (myotonia congenita), DHCR7 c.453G>A (Smith-Lemli-Opitz syndrome), NUP93 c.1162C>T (steroid-resistant nephrotic syndrome, type 12), SLC26A2 c.1957T>A (multiple epiphyseal dysplasia) and EIF3F c.694T>G (mental retardation). These recessive disease conditions may be of particular relevance for the Russian Federation and other countries with a significant Slavic population.