Early insights into the role of Exoc6B associated with spondyloepimetaphyseal dysplasia with joint laxity type 3 in primary ciliogenesis and chondrogenic differentiation in vitro.

BACKGROUND: Spondyloepimetaphyseal dysplasia with joint laxity type 3 (SEMDJL3) is a rare skeletal dysplasia associated with EXOC6B, a component of the exocyst complex, involved in vesicle tethering and exocytosis at the plasma membrane. So far, EXOC6B and the pathomechanisms underlying SEMDJL3 remain obscure. METHODS AND RESULTS: Exoc6b was detected largely at the perinuclear regions and the primary cilia base in ATDC5 prechondrocytes. Its shRNA lentiviral knockdown impeded primary ciliogenesis. In Exoc6b silenced prechondrocytes, Hedgehog signaling was attenuated, including when stimulated with Smoothened agonist. Exoc6b knockdown deregulated the mRNA and protein levels of Col2a1, a marker of chondrocyte proliferation at 7- and 14-days following differentiation. It led to the upregulation of Ihh another marker of proliferative chondrocytes. The levels of Col10a1, a marker of chondrocyte hypertrophy was enhanced at 14 days of differentiation. Congruently, Axin2, a canonical Wnt pathway modulator that inhibits chondrocyte hypertrophy was repressed. The expression of Mmp13 and Adamts4 that are terminal chondrocyte hypertrophy markers involved in extracellular matrix (ECM) remodelling were downregulated at 7 and 14 days of chondrogenesis. Bglap that encodes for the most abundant non-collagenous bone matrix constituent and promotes ECM calcification was suppressed at 14 days of chondrocyte differentiation. ECM mineralization was assessed by Alizarin Red staining. Gene expression and ciliogenesis were investigated by reverse transcription quantitative real-time PCR, immunoblotting, and immunocytochemistry. CONCLUSIONS: These findings provide initial insights into the potential role of Exoc6b in primary ciliogenesis and chondrogenic differentiation, contributing towards a preliminary understanding of the molecular pathomechanisms underlying SEMDJL3.

Spondyloepimetaphyseal dysplasia with joint laxity type 2: Aggregating the literature and reporting on the life of a 66-year-old man.

Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type (SEMDJL2), is a rare bone dysplasia that results from hotspot (amino acids148/149) mutations in KIF22. Clinically, affected individuals present with generalized joint laxity, limb malalignment, midface hypoplasia, gracile digits, postnatal short stature, and occasionally, tracheolaryngomalacia; additionally, radiological features include severe epi-metaphyseal abnormalities and slender metacarpals. This report evaluates the progression of SEMDJL2 throughout the life of the oldest individual reported in the literature-a 66-year-old man with a pathogenic KIF22 variant (c.443C > T, p.Pro148Leu). The proband developed many of the clinical and radiological alterations consistent with the presentation of other individuals in the literature. Interestingly, throughout his life, joint limitation progressed, beginning with knee and elbow stricture (year 20), and later, limitation of the shoulders, hips, ankles, and wrists (year 40). This differs from previous case reports, where joint limitation is identified in 1-to-2 joints. Cumulatively, the progressive body-wide joint limitation resulted in early retirement (year 45) and difficulty completing daily tasks and managing personal hygiene culminating in the need for assisted living (year 65). In conclusion, we report on the clinical and radiological developments of a 66-year-old man with SEMDJL2, that developed significant joint limitation in adulthood.

Risk factors for hamstring strain injury in male college American football players -a preliminary prospective cohort study.

BACKGROUND: Given the frequency of hamstring strain injuries (HSI) among male college American football players, several studies have attempted to determine whether certain risk factors can predict their occurrence. However, no consensus on modifiable risk factors for HSIs in male college American football players has yet been reached to prevent these injuries. This study aimed to clarify risk factors for HSI prospectively in college male American football players. METHODS: A total of 78 male college American football players, whose positions were limited to skill positions, were medically assessed for potential risk factors of HSI. The preseason medical assessment included anthropometric measurements, joint laxity and flexibility, muscle flexibility, muscle strength, and balance ability. RESULTS: HSI occurred in a total of 25 thighs from 25 players (32.1%). Injured players had significantly lower hamstring flexibility (p = 0.02) and hamstring to quadriceps strength ratio (H/Q) (p = 0.047) compared to uninjured players. Additionally, injured players had significantly lower general joint laxity scores, especially for the total (p = 0.04), hip (p = 0.007), and elbow (p = 0.04) scores, compared to uninjured players. CONCLUSIONS: Lower hamstring flexibility, lower hamstring to quadriceps strength ratio, and lower general joint laxity score were identified as risk factors for HSI in male college American football players placed in skill positions. The muscle flexibility and H/Q ratio could be useful in preventing HSI in such players.

Arthroscopic modified Broström procedure achieved similar favorable short term outcomes to open procedure for chronic lateral ankle instability cases with generalized joint laxity.

PURPOSE: To compare the short-term clinical outcomes of the open versus arthroscopic modified Broström procedure in generalized joint laxity (GJL) patients. METHODS: From January 2018 to January 2020, 64 consecutive patients with chronic lateral ankle instability (CLAI) and GJL (Beighton score ≥ 4) were prospectively enrolled into two groups: those who underwent the open modified Broström procedure (open group, n = 32) and those who underwent the arthroscopic modified Broström procedure (arthroscopic group, n = 32). Patients underwent an open or arthroscopic modified Broström procedure based on the time when they attended the clinic for consultation. All patients were followed-up at 3, 6, 12, and 24 months postoperatively. The clinical outcomes were evaluated using the visual analogue scale (VAS), American Orthopaedic Foot and Ankle Society (AOFAS) score, and Karlsson score, and the radiographic outcomes were assessed using stress radiography at 24 months postoperatively. The time to return to work and the failure rate were also evaluated and compared. RESULTS: Follow-up was completed for 31 patients in the open group and 30 patients in the arthroscopic group. No significant differences were found between the two groups in terms of demographic characteristics, Beighton score (6.2 ± 1.9 vs. 5.5 ± 1.4, n.s.), or duration of symptoms. There were no significant differences in the functional scores before surgery and at 6, 12 and 24 months postoperatively or in the mean anterior translation of the talus and talar tilt angle on stress radiography at 24 months postoperatively between the open and arthroscopic groups. Compared to the open group, the arthroscopic group showed a significantly earlier return to work (6.8 ± 2.1 vs. 8.1 ± 2.4 weeks, p = 0.006). There was no significant difference in terms of the failure rate between the open and arthroscopic groups (16.1% vs. 23.3%, n.s.). CONCLUSION: Arthroscopic modified Broström procedure achieved similar short-term outcomes to the open procedure for GJL patients. Arthroscopic modified Broström procedure showed an earlier return to work than the open modified Broström procedure and was an alternative to open surgery for CLAI patients with GJL. LEVEL OF EVIDENCE: III. CLINICAL TRIAL REGISTRATION: This study is a prospective study NCT05284188.

The anterior talofibular ligament ratio was greater in young men with generalized joint laxity than in those without generalized joint laxity.

PURPOSE: This study aimed to evaluate the relationship between generalized joint laxity (GJL) and stress ultrasonographic (US) findings of the anterior talofibular ligament (ATFL) of healthy young men. METHODS: The ATFL lengths of healthy young men were consecutively measured in the stress and nonstress positions. The ATFL ratio was calculated as an indicator of lateral ankle laxity. GJL was evaluated using the Beighton score (BS), and a BS of ≥ 5 was considered GJL. The manual anterior drawer test (ADT) was also performed. The results of stress US and ADT were compared between subjects with and without GJL, and the correlation between GJL and US findings was examined. RESULTS: A total of 13 subjects with GJL and 95 without GJL were included in the study. The mean BSs in the GJL and no-GJL groups were 5.9 ± 0.9 and 1.1 ± 1.3, respectively (p < 0.0001). The GJL group showed a higher grade of ADT than the no-GJL group (p < 0.0001). Significant differences were found in the stress ATFL length (23.6 ± 1.8 mm vs. 21.7 ± 1.8 mm, p = 0.002) and ATFL ratio (1.15 ± 0.06 vs. 1.07 ± 0.03, p < 0.0001) between the GJL and no-GJL groups. Spearman's correlation coefficients showed a moderate correlation between the BS and ATFL ratio (r = 0.45, p < 0.0001). CONCLUSION: The present study showed significant differences in the ATFL ratio and stress ATFL length between young men with and without GJL. The BS was moderately correlated with the lateral ankle laxity in this population. LEVEL OF EVIDENCE: Level IV.

Does Generalized Joint Laxity Affect Postoperative Alignment and Clinical Outcomes Following Medial Opening-Wedge High Tibial Osteotomy?

BACKGROUND: The purpose of this study was to investigate whether generalized joint laxity affects the postoperative alignment and clinical outcomes of medial opening-wedge high tibial osteotomy (MOWHTO). METHODS: A total of 198 patients who underwent MOWHTO was divided into two groups according to absence or presence of generalized joint laxity. Generalized joint laxity was measured using the Beighton and Horan criteria, and a score of 4 or more out of 9 was defined as generalized joint laxity. A weight bearing line (WBL) ratio of 55% to 70% was considered an acceptable postoperative lower limb alignment range; WBL over 70% was defined as overcorrection and less than 55% as undercorrection. The WBL ratio was investigated before and 2 years after surgery, and the Western Ontario McMaster University Osteoarthritis Index scale score (WOMAC) was evaluated for patient-reported outcomes (PRO) of MOWHTO. There were 147 (73.7%) patients in the nongeneralized joint laxity group and 51 (26.3%) in the generalized joint laxity group. Preoperatively, there was no difference between the two groups in hip-knee-ankle (HKA) angle or WBL ratio (all P > .05). RESULTS: At 2 years postoperatively, the generalized joint laxity group showed significantly higher HKA angle and WBL ratio than the nongeneralized joint laxity group (all P < .05). There was a significant difference in the distribution ratio of undercorrection, normocorrection, and overcorrection patients between the two groups (P < .05). There were no differences between the two groups in preoperative and postoperative WOMAC scores (all, P > .05). CONCLUSION: The generalized joint laxity significantly affected postoperative over correction of alignment following MOWHTO. However, there was no significant difference in PRO between the patients who did and did not have generalized joint laxity after MOWHTO until 2 years.

What is the utility of hip arthroscopy in patients with joint laxity? A contemporary systematic review of patient-reported and surgical outcomes.

INTRODUCTION: The purpose of this study was to systematically review the literature to understand the contemporary outcomes for patients with joint laxity managed with hip arthroscopy. MATERIALS AND METHODS: A search was performed utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statement guidelines. All literature related to joint laxity in hip arthroscopy patients was identified. Inclusion criteria consisted of patient-reported outcomes and Beighton and Horan Joint Mobility Index scoring. Study quality was assessed using the Methodological Index of Non-Randomized Studies criteria. RESULTS: Seven articles were identified, including 412 patients (416 hips). Patients were predominantly female (range 83-100%). Mean patient age ranged from 13-69 years. Five studies consisting of 370 hips reported a range of 75 to 100% undergoing labral repair, 0 to 13% labral debridement, 0 to 7% labral reconstruction, 43 to 100% capsular closure, 94 to 99% femoroplasty, 3 to 80% rim resection, and 9 to 50% subspine decompression for surgical management. Post-operative follow-up range was 6-99 months. The mean range of improvement in Hip Outcomes Score Activities of Daily Living, Hip Outcomes Score-Sports Subscale, modified Harris Hip Score, Visual Analog Scale, and 12 item Short Form Health Survey were 17.6-31.3, 31.3-35.1, 22.5-53.8, - 2.79-8, and 12.4-16.9 respectively. CONCLUSION: Generalized ligamentous laxity patients managed with hip arthroscopy were predominantly young women. At short-term follow-up, mean patient-reported outcomes were positive, with improvement postoperatively in activities of daily living, sports, and quality of life.

Evaluation of the short-term outcomes of anatomic ACL reconstruction with hamstring autograft in patients with generalized joint laxity: A retrospective case-control study.

PURPOSE: The outcomes of anterior cruciate ligament reconstruction (ACLR) in patients with generalized joint laxity (GJL) are not clearly understood. In this study, we compared the outcomes of ACLR with quadruple hamstring autograft between GJL and non-GJL patients. METHODS: In a retrospective case-control study, 36 patients with GJL, according to the Beighton and Horan Joint Mobility Index, who underwent ACLR surgery, were included. Forty-four group-matched non-GJL patients were included in the control group. The mean follow-up of the patients was 20.65 ± 6.93 months. The outcomes of ACLR were evaluated by the Lachman test, pivot shift test, anterior tibial translation and KT-1000 side-to-side difference, and International Knee Documentation Committee (IKDC) scale. RESULTS: The results of the Lachman and pivot shift test were not significantly different between the GJL and non-GJL patients (P = 0.67 and P = 0.27, respectively). The mean anterior tibial translation was 7.06 ± 1.41 mm in the GJL group and 6.11 ± 1.53 mm in the non-GJL group (P = 0.006). The mean KT-1000 side-to-side difference was 2.25 ± 1.31 mm in the case and 2.5 ± 1.44 mm in the control group (P = 0.42). The mean IKDC score of the patients was not significantly different between the GJL and non-GJL groups (66.1 ± 20.6 vs. 69.9 ± 16.1, P = 0.35). ACLR failure occurred in 2 (5.5%) patients of the GJL group and no patients of the control group (P = 0.21). CONCLUSION: The present findings suggest ACLR with quadruple hamstring autograft as an adequate treatment for GJL patients, at least in short-term follow-up.

Biallelic loss-of-function variants in EXOC6B are associated with impaired primary ciliogenesis and cause spondylo-epi-metaphyseal dysplasia with joint laxity type 3.

Spondylo-epi-metaphyseal dysplasias with joint laxity, type 3 (SEMDJL3) is a genetic skeletal disorder characterized by multiple joint dislocations, caused by biallelic pathogenic variants in the EXOC6B gene. Only four individuals from two families have been reported to have this condition to date. The molecular pathogenesis related to primary ciliogenesis has not been enumerated in subjects with SEMDJL3. In this study, we report two additional affected individuals from unrelated families with biallelic pathogenic variants, c.2122+15447_2197-59588del and c.401T>G in EXOC6B identified by exome sequencing. One of the affected individuals had an intellectual disability and central nervous system anomalies, including hydrocephalus, hypoplastic mesencephalon, and thin corpus callosum. Using the fibroblast cell lines, we demonstrate the primary evidence for the abrogation of exocytosis in an individual with SEMDLJ3 leading to impaired primary ciliogenesis. Osteogenesis differentiation and pathways related to the extracellular matrix were also found to be reduced. Additionally, we provide a review of the clinical and molecular profile of all the mutation-proven patients reported hitherto, thereby further characterizing SEMDJL3. SEMDJL3 with biallelic pathogenic variants in EXOC6B might represent yet another ciliopathy with central nervous system involvement and joint dislocations.

Improvement in pain and patient-related outcome measures following hip arthroscopy in patients with femoroacetabular impingement syndrome and concomitant generalized ligamentous laxity: a systematic review.

PURPOSE: Within orthopaedic sports medicine, concomitant ligamentous laxity is often found to be a negative prognostic factor for post-operative outcomes following various procedures. The effect of ligamentous laxity on outcomes following hip arthroscopy remains infrequently reported. Therefore, the purpose of this study is to report on the outcomes of hip arthroscopy for the treatment of femoroacetabular impingement syndrome (FAIS) with concomitant generalized ligamentous laxity (GLL). METHODS: A systematic search was performed in Medline, EMBASE, CENTRAL, and SPORTDiscus (from inception to April 2021) for studies reporting outcomes following hip arthroscopy for symptomatic FAIS in patients with concomitant GLL. RESULTS: Six studies representing 213 patients and 231 hips were included. Outcomes of pain and functional scores as measured by VAS, Harris Hip Score, and Hip Disability and Osteoarthritis Outcomes Score were tabulated. A mean improvement of 4.8 on VAS was observed. Improvements of 30.0 on HHS, 33.1 for ssHOS, and 23.9 for ADL-HOS were observed. CONCLUSION: Hip arthroscopy is an effective method of alleviating pain and improving function with statistically significant improvements in all PROM in patients with concomitant FAIS with GLL. LEVEL OF EVIDENCE: IV. PROSPERO REGISTRATION: CRD42021248864.

Generalized joint hypermobility does not influence 1-year patient satisfaction or functional outcome after ACL reconstruction.

PURPOSE: The purpose of this study was to evaluate whether generalized joint hypermobility (GJH) influences postoperative results, including return to sport, patientreported outcomes, functional performance (hop tests), muscular strength, and the occurrence of ACL re-injury, in patients 1 year after anterior cruciate ligament (ACL) reconstruction. METHODS: Data was extracted from a regional rehabilitation-specific registry containing information on patients with ACL injury. Patients between the ages of 16-50 years previously undergoing ACL reconstruction with available 1 year follow-up data were eligible for inclusion. Generalized joint hypermobility was assessed using the Beighton score (BS). Patients were examined one year postoperatively in terms of return to sport, patient-reported outcome, hop tests, muscular strength and the occurrence of reinjury. For purpose of analysis, patients were allocated into two groups, depending on the existence of GJH. The KOOS subscale of sports and recreation was considered the primary outcome. Analyses were performed both dichotomously and by using adjusted logistic regression, to consider potential confounders. RESULTS: A total of 356 patients (41% males) were included, of which 76 (24% male) were categorized as having GJH. Patients with GJH had an inferior limb symmetry index preoperatively in terms of knee extension (mean 81.6 [SD 16.4] vs. 91.4 [SD 15.9], p = 0.02) and flexion strength (mean 91.9 vs. 99.1, p = 0.047) compared to patients without GJH. There was no difference between the groups in terms of the primary outcome, nor in any of the other postoperative outcomes. Nine patients (11.8%) in the group with GJH suffered ACL re-injury, compared with 13 patients (4.6%) in the control group (n.s.). CONCLUSION: One year after ACL reconstruction the existence of GJH did not affect postoperative patient satisfaction, strength or functional outcome. No conclusive statements can be made regarding the influence of GJH on the risk of ACL re-injury in this particular study. LEVEL OF EVIDENCE: Level II.

Broadening the phenotypic spectrum of Beta3GalT6-associated phenotypes.

Biallelic mutations in B3GALT6, coding for a galactosyltransferase involved in the synthesis of glycosaminoglycans (GAGs), have been associated with various clinical conditions, causing spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1 or SEMDJL Beighton type), Al-Gazali syndrome (ALGAZ), and a severe progeroid form of Ehlers-Danlos syndrome (EDSSPD2). In the 2017 Ehlers-Danlos syndrome (EDS) classification, Beta3GalT6-related disorders were grouped in the spondylodysplastic EDSs together with spondylodysplastic EDSs due to B4GALT7 and SLC39A13 mutations. Herein, we describe a patient with a previously unreported homozygous pathogenic B3GALT6 variant resulting in a complex phenotype more severe than spondyloepimetaphyseal dysplasia with joint laxity type 1, and having dural ectasia and aortic dilation as additionally associated features, further broadening the phenotypic spectrum of the Beta3GalT6-related syndromes. We also document the utility of repeating sequencing in patients with uninformative exomes, particularly when performed by using "first generations" enrichment capture methods.

Effect of Ligament Properties on Nonlinear Dynamics and Wear Prediction of Knee Prostheses.

Although wear is known as the primary cause of long-time failure of total knee arthroplasty (TKA), it can be vital in short- and midterm TKA failure due to laxity. One of the reasons leading to joint laxity and instability is ligamentous insufficiency. This study, therefore, aims to investigate the effects of insufficient ligaments-related knee laxity on both nonlinear dynamics and wear of TKA. The study hypothesizes (a) ligamentous insufficiency can increase TKA damage; (b) stiffness reduction of each of the posterior cruciate ligament (PCL) and medial-lateral collateral ligaments (MCL-LCL) can differently contribute to TKA damage. A forward dynamics methodology is developed and the ligament behavior is simulated employing an asymmetric nonlinear elastic model. External loads and moment, due to the presence of all soft tissues, e.g., muscles and hip joint reaction forces, applied to the femoral bone are determined using a musculoskeletal approach linked to the developed model. A mesh density analysis is performed and comparing outcomes with that available in the literature allows for the assessment of our approach. From the results acquired, reduced PCL stiffness leads to an increase in linear wear rates and results in the maximum damage in TKAs. However, the maximum linear wear rates on both condyles occur once the stiffness of all ligaments is reduced. Moreover, the worn area of the tibia surface increases with the reduction in MCL-LCL stiffness on the medial condyle. The joint with insufficient PCL also shows a considerable increase in ligament forces right after toe-off.

Loeys-Dietz Syndrome.

Loeys-Dietz syndrome is an autosomal dominant aortic aneurysm syndrome characterized by multisystemic involvement. The most typical clinical triad includes hypertelorism, bifid uvula or cleft palate and aortic aneurysm with tortuosity. Natural history is significant for aortic dissection at smaller aortic diameter and arterial aneurysms throughout the arterial tree. The genetic cause is heterogeneous and includes mutations in genes encoding for components of the transforming growth factor beta (TGFß) signalling pathway: TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3. Despite the loss of function nature of these mutations, the patient-derived aortic tissues show evidence of increased (rather than decreased) TGFß signalling. These insights offer new options for therapeutic interventions.

Prolonged standing behaviour in people with joint hypermobility syndrome.

BACKGROUND: Joint Hypermobility Syndrome (JHS) is a rare Heritable Disorder of Connective tissue characterised by generalised joint laxity and chronic widespread pain. Joint Hypermobility Syndrome has a large impact on patients' day to day activities, and many complain of symptoms when standing for prolonged periods. This study investigates whether people with JHS exhibit the same behaviours to deal with the effects of prolonged standing as people with equal hypermobility and no pain, and people with normal flexibility and no pain. METHODS: Twenty three people with JHS, 22 people with Generalised Joint Hypermobility (GJH), and 22 people with normal flexibility (NF) were asked to stand for a maximum of 15 min across two force-plates. Fidgets were counted and quantified using a cumulative sum algorithm and sway parameters of the quiet standing periods between fidgets were calculated. RESULTS: Average standing time for participants with JHS was 7.35 min and none stood for the full 15 min. All participants with GJH and NF completed 15 min of standing. There were no differences in fidgeting behaviour between any groups. There was a difference in anteroposterior sway (p = .029) during the quiet standing periods. CONCLUSION: There is no evidence to suggest people with JHS exhibit different fidgeting behaviour. Increased anteroposterior-sway may suggest a muscle weakness and strengthening muscles around the ankle may reduce postural sway and potentially improve the ability to stand for prolonged periods.

Shoulder and elbow pathology in the female athlete: sex-specific considerations.

Unique biologic and biomechanical aspects of the female body make women more prone to certain orthopedic injuries. Sex differences are well understood with regard to certain orthopedic pathologies such as anterior cruciate ligament injury, hallux valgus, carpal tunnel, and carpometacarpal joint arthritis; however, sex differences are less commonly discussed with regard to shoulder and elbow pathology. The purpose of this review is to elucidate sex differences specific to sports-related shoulder and elbow injuries in the female athlete population.

Location of Talar Osteochondral Defects in Chronic Lateral Ankle Instability in an Asian Population.

Osteochondral defect of the talus is traditionally described to involve the anterolateral and posteromedial portion of the talar dome in patients with chronic lateral ankle instability. Recent studies challenged this notion with advances in preoperative imaging and arthroscopy. Since Asian patients are more prone to ligamentous laxity, we postulate that the morphology and severity of osteochondral defects may be different in this population. Intraoperative records of 272 patients undergoing modified Broström-Gould procedure were reviewed for arthroscopic evidence of osteochondral defects. We characterized the morphology according to an anatomical 9-grid classification. Talar osteochondral defects were seen in 52 (19.1%) patients with a double lesion present in 1 patient. Medial-sided lesions account for nearly 3-quarters (n = 38, 73.1%) of all lesions and tend to be larger (79.4 ± 55.7 mm2 vs 51.0 ± 28.6 mm2, p =.08). There was no osteochondral defect seen in the central zones. There was no significant gender or age differences between patients with medial and lateral lesions. The most commonly performed procedure was microfracture. Osteochondral defects are commonly encountered in our Asian patients undergoing surgery for chronic lateral ankle instability. Contrary to published data, medial lesions are prevalent with no central lesions seen.

CSGALNACT1-congenital disorder of glycosylation: A mild skeletal dysplasia with advanced bone age.

Congenital disorders of glycosylation (CDGs) comprise a large number of inherited metabolic defects that affect the biosynthesis and attachment of glycans. CDGs manifest as a broad spectrum of disease, most often including neurodevelopmental and skeletal abnormalities and skin laxity. Two patients with biallelic CSGALNACT1 variants and a mild skeletal dysplasia have been described previously. We investigated two unrelated patients presenting with short stature with advanced bone age, facial dysmorphism, and mild language delay, in whom trio-exome sequencing identified novel biallelic CSGALNACT1 variants: compound heterozygosity for c.1294G>T (p.Asp432Tyr) and the deletion of exon 4 that includes the start codon in one patient, and homozygosity for c.791A>G (p.Asn264Ser) in the other patient. CSGALNACT1 encodes CSGalNAcT-1, a key enzyme in the biosynthesis of sulfated glycosaminoglycans chondroitin and dermatan sulfate. Biochemical studies demonstrated significantly reduced CSGalNAcT-1 activity of the novel missense variants, as reported previously for the p.Pro384Arg variant. Altered levels of chondroitin, dermatan, and heparan sulfate moieties were observed in patients' fibroblasts compared to controls. Our data indicate that biallelic loss-of-function mutations in CSGALNACT1 disturb glycosaminoglycan synthesis and cause a mild skeletal dysplasia with advanced bone age, CSGALNACT1-CDG.

Rare Cases of PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome in a Korean Family Identified by Next Generation Sequencing.

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive connective tissue disorder characterized by muscular hypotonia, hyperextensible skin, skin fragility, joint hypermobility, and progressive kyphoscoliosis. The disorder results from a deficiency of the enzyme collagen lysyl hydroxylase 1 due to mutations in the gene PLOD1. We describe the rare cases of kEDS in Korean siblings with two novel compound heterozygous variants, c.926_934del (p.Leu309_Leu311del) and c.2170_2172del (p.Phe724del) in the PLOD1 gene. They had congenital hypotonia, joint laxity, skin hyperextensibility, Marfanoid habitus, high myopia and atrophic scarring. The younger sibling had an early-onset progressive kyphoscoliosis, while the older sibling showed mild scoliosis during childhood. Intrafamilial variability of the clinical severity and age of kyphoscoliosis onset observed in our cases.

Greater knee joint laxity remains in teenagers after anatomical double-bundle anterior cruciate ligament reconstruction compared to young adults.

PURPOSE: There is paucity in studies regarding double-bundle anterior cruciate ligament reconstruction (DB-ACLR) in teenagers. The purpose of this study is to investigate clinical outcome after DB-ACLR and analyze whether any differences exist between teenagers and young adults. METHODS: A retrospective study was performed between 2009 and 2017. Teenagers were defined as patients between 15 and 19 years and young adults between 20 and 25 years old. Isolated anterior cruciate ligament (ACL) injuries with DB-ACLR with minimum two-year follow up were included. Pre and post-operative Lysholm score, Tegner activity scale, KT-2000 arthrometer, manual pivot-shift grade, were assessed with post-operative one-leg hop test, isokinetic knee extensor strength test at 60°/sec, International Knee Documentation Committee Score (IKDC score), and re-injury rate. RESULTS: One-hundred and thirty-one patients, 75 patients in the teenage group (Group A) and 56 patients in the young adult group (Group B), were enrolled. Lysholm score was significantly lower in Group A (89.6 ± 21.1) compared to Group B (95.9 ± 4.6) (p = 0.04). Side to side difference in KT-2000 arthrometer (2.3 ± 2.2 mm vs 1.0 ± 2.3 mm, Group A vs Group B, respectively, p < 0.01) and ratio of post-operative positive pivot shift was significantly greater in Group A (30.7%) compared to Group B (7.1%) (p < 0.01). No significant difference was seen in re-injury rate (n.s.). CONCLUSION: Teenage patients have a greater tendency for residual knee joint laxity after DB-ACLR. Although teenagers and patients in the early twenties are close in age, characteristic in knee joint laxity may be different and, therefore, may require attention upon surgery and post-operative follow-up. LEVEL OF EVIDENCE: III.