Abstract Background Serine residues in the protein backbone of heavily glycosylated proteoglycans are bound to glycosaminoglycans through a tetrasaccharide linker. UXS1 encodes UDP‐glucuronate decarboxylase 1, which catalyzes synthesis of UDP‐xylose, the donor of the first building block in the linker. Defects in other enzymes involved in formation of the tetrasaccharide linker cause so‐called linkeropathies, characterized by short stature, radio‐ulnar synostosis, decreased bone density, congenital contractures, dislocations, and more. Methods Whole exome sequencing was performed in a father and son who presented with a mild skeletal dysplasia, as well as the father's unaffected parents. Wild‐type and mutant UXS1 were recombinantly expressed in Escherichia coli and purified. Enzyme activity was evaluated by LC–MS/MS. In vivo effects were studied using HeparinRed assay and metabolomics. Results The son had short long bones, normal epiphysis, and subtle metaphyseal changes especially in his legs. The likely pathogenic heterozygous variant NM_001253875.1(UXS1):c.557T>A p.(Ile186Asn) detected in the son was de novo in the father. Purified Ile186Asn‐UXS1, in contrast to the wild‐type, was not able to convert UDP‐glucuronic acid to UDP‐xylose. Plasma glycosaminoglycan levels were decreased in both son and father. Conclusion This is the first report linking UXS1 to short‐limbed short stature in humans.

Spondyloepimetaphyseal dysplasia with severe short stature, RPL13 -related (SEMD-RPL13), MIM#618728), is a rare autosomal dominant disorder characterized by short stature and skeletal changes such as mild spondylar and epimetaphyseal dysplasia affecting primarily the lower limbs. The genetic cause was first reported in 2019 by Le Caignec et al., and six disease-causing variants in the gene coding for a ribosomal protein, RPL13 (NM_000977.3) have been identified to date. This study presents clinical and radiographic data from 12 affected individuals aged 2–64 years from seven unrelated families, showing highly variable manifestations. The affected individuals showed a range from mild to severe short stature, retaining the same radiographic pattern of spondylar- and epi-metaphyseal dysplasia, but with varying severity of the hip and knee deformities. Two new missense variants, c.548 G>A, p.(Arg183His) and c.569 G>T, p.(Arg190Leu), and a previously known splice variant c.477+1G>A were identified, confirming mutational clustering in a highly specific RNA binding motif. Structural analysis and interpretation of the variants’ impact on the protein suggests that disruption of extra-ribosomal functions of the protein through binding of mRNA may play a role in the skeletal phenotype of SEMD-RPL13. In addition, we present gonadal and somatic mosaicism for the condition.

Background and purpose — Skeletal maturity is a crucial parameter when calculating remaining growth in children. We compared 3 different methods, 2 manual and 1 automated, in the radiological assessment of bone age with respect to precision and systematic difference. Material and methods — 66 simultaneous examinations of the left hand and left elbow from children treated for leg-length discrepancies were randomly selected for skeletal age assessment. The radiographs were anonymized and assessed twice with at least 3 weeks’ interval according to the Greulich and Pyle (GP) and Sauvegrain (SG) methods by 5 radiologists with different levels of experience. The hand radiographs were also assessed for GP bone age by use of the automated BoneXpert (BX) method for comparison. Results — The inter-observer intraclass correlation coefficient (ICC) was 0.96 for the GP and 0.98 for the SG method. The inter- and intra-observer standard error of the measurement (SEm) was 0.41 and 0.32 years for the GP method and 0.27 and 0.21 years for the SG method with a significant difference (p < 0.001) between the methods and between the experienced and the less experienced radiologists for both methods (p = 0.003 and p < 0.001). In 25% of the assessments the discrepancy between the GP and the SG methodwas > 1 year. There was no systematic difference comparing either manual method with the automatic BX method. Interpretation — With respect to the precision of skeletal age determination, we recommend using the SG method or preferably the automated BX method based on GP assessments in the calculation of remaining growth.

BACKGROUND:Arthrogryposis multiplex congenita (AMC) is a descriptive term that encompasses a group of congenital, aetiologically heterogeneous conditions characterised by multiple joint contractions.CASE PRESENTATION:As a teenager, the index patient was told she had AMC, as did one of her parents. Subsequently, she wondered how her condition might evolve over time, since her affected parent had become wheelchair- dependent. Her history and clinical findings led to genetic testing which identified a causative variant in the COL6A2 gene, revealing an underlying diagnosis of Bethlem myopathy.INTERPRETATION:Adults who have rare monogenic disorders may lack an aetiological diagnosis because of limited access to genetic laboratory testing in the past. Advances in genetic laboratory diagnostics during the last 10−15 years have made testing more widely available. As exemplified by this case, molecular genetic diagnosis may provide benefits such as information concerning prognosis and treatment options.

Mucopolysaccharidosis (MPS) are monogenic, multisystem disorders resulting from enzymatic defects in the degradation of glycosaminoglycans (GAGs). Although each of the 11 MPS subtypes is linked to a specific enzyme deficiency, phenotypic overlap is considerable. Recently, a 12th disorder, MPS type X, due to biallelic variants in the arylsulfatase K gene (ARSK) was reported (Verheyen et al., 2021). We describe herein two additional affected sibs and expand the phenotype. The younger individual (Individual 1) was noted to have a waddling gate as a toddler. At presentation at age 7 years, he complained of stiffness and pain in his legs, and was diagnosed with Legg-Calvé-Perthes disease (LCPD). He experienced increasing pain in his hips, thighs, knees, legs, hands, and back. Radiographic changes in his hips were visible by age 7 years. Additional diagnostic suggestions at that time were multiple epiphyseal dysplasia or Meyers dysplasia. Assessment by a multispecialist skeletal dysplasia clinic at age 8 years 5 months concluded that he might have a MPS given his increasing symptoms as well as his similarly affected sibling. Radiological changes were not present in the hand of Individual 1 at age 2 years, but at age 8 years 5 months several carpal bones were either not ossified or small for his age. Lack of ossification of some carpal bones and osteonecrosis of the femoral heads were suggestive of a mild MPS (Figure 1). The 2 years older sibling (Individual 2) complained of pain in her knees, thighs and hips from age 9 years. By age 10 years, she had developed pain in her legs, ankles, and back. Initial imaging showed slight anterior wedging of her vertebrae and lack of ossification of carpal bones, in keeping with a tentative diagnosis of MPS. Both individuals used paracetamol for pain. On repeated analyzes, urinary GAG quantitation by dimethyl methylene blue (DMB) test was slightly increased in both children. Thin layer chromatography showed a normal glycosaminoglycan profile. Morquio disease, MPS type IVA, was suspected, but both children had normal serum levels of galactose-6-sulfatase and beta-galactosidase. Whole exome sequencing for the sibs and their parents was initially performed assuming that the father was affected due to longstanding complaints of stiffness in his joints. When no molecular cause was detected, the variant data were re-interpreted with both parents considered unaffected. Both children were homozygous, and both parents heterozygous, for a predicted stop variant in ARSK, NM_198150.3:c.1251C > G p.(Tyr417*). The variant is located in the penultimate exon and is predicted to target ARSK-mRNA to nonsense-mediated decay. Urinary GAG excretion in both sibs assessed by HPLC-MS/MS (liquid chromatography–tandem mass spectrometry) analysis detected a threefold increase of dermatan sulfate (DS) while heparan sulfate (HS) was slightly above the upper reference range in Individual 2. The increased DS level is similar to that described in two of four individuals in the original report of MPS type X (Verheyen et al. 2021). Clinical findings in the two children we describe and in the original report are summarized in Table 1. In contrast to the two individuals described by Verheyen et al. for whom data are available, the sibs we report were normocephalic at birth, and did not have recurrent ear infections or sleep apnea as young children. Furthermore, at age 9 years 5 months and at 11 years, respectively, they did not have coarse facial features or short stature, and were not disproportionate. The individuals we report are younger than those reported previously (ages 14–18), which might explain the absence of short stature, a disproportionally short trunk, and coarse facies. Both children have slightly hypomineralized enamel on their permanent teeth. The older sibling had several teeth extracted due to enamel defects and has hypoplasia of a permanent incisor (an enamel pit). Defective enamel might be a feature of MPS type X, analogous to what is seen in MPS type IV (Barker & Welbury, 2000; Ribeiro et al., 2015). Both children had hypermobile interphalangeal finger joints, which is also a feature of MPS type IV (Raff & Byers, 1996). Both individuals have vertical striae in the metaphyses similar to those described by Verheyen et al., but noted at an earlier age (Figure 1). Osteochondral lesions were present in the dorsal aspect of the patellae in Individual 1 and in some metacarpal heads. Similar lesions were seen in the metatarsals of Individual 2 (not shown), this may be a distinguishing feature of MPS type X. In conclusion, the two individuals described herein illustrate that short stature, a short trunk and coarse facies are not necessarily present in young children with MPS type X. A waddling gait and joint pain, accompanied by skeletal radiological changes resembling mild MPS warrants examination for ARSK-related MPS. Normal urinary GAG quantitation does not rule out the diagnosis (Verheyen et al., 2021). As in the four previously published individuals, MPS was suspected, though one of the children we report was originally thought to have LCPD. Bilateral LCPD should result in considering the possibility of MPS type X as well as other MPS subtypes (Mendelsohn et al., 2013). The diagnosis of MPS type X allows for tailored cardiac, ophthalmologic and audiological surveillance, and can inform genetic counseling. Conception and design: Cecilie F. Rustad, Trine E. Prescott, Else Merckoll, Erle Kristensen, Cathrin L. Salvador, Hilde Nordgarden, and Kristian Tveten. Data collection: Cecilie F. Rustad, Trine E. Prescott, Else Merckoll, Erle Kristensen, Cathrin L. Salvador, Hilde Nordgarden, and Kristian Tveten. Data analysis and interpretation: Cecilie F. Rustad, Trine E. Prescott, Else Merckoll, Erle Kristensen, Cathrin L. Salvador, Hilde Nordgarden, and Kristian Tveten. Drafting the article: Cecilie F. Rustad, Trine E. Prescott, Else Merckoll, Erle Kristensen, Cathrin L. Salvador, Hilde Nordgarden, and Kristian Tveten. Critical revision of the article: Cecilie F. Rustad, Trine E. Prescott, Else Merckoll, Erle Kristensen, Cathrin L. Salvador, Hilde Nordgarden, and Kristian Tveten. Final approval: Cecilie F. Rustad, Trine E. Prescott, Else Merckoll, Erle Kristensen, Cathrin L. Salvador, Hilde Nordgarden, and Kristian Tveten. The authors are grateful to the family for their generous contribution to this work. The authors declare no conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.

BACKGROUND Arthrogryposis multiplex congenita (AMC) is a descriptive term that encompasses a group of congenital, aetiologically heterogeneous conditions characterised by multiple joint contractions. CASE PRESENTATION As a teenager, the index patient was told she had AMC, as did one of her parents. Subsequently, she wondered how her condition might evolve over time, since her affected parent had become wheelchair- dependent. Her history and clinical findings led to genetic testing which identified a causative variant in the COL6A2 gene, revealing an underlying diagnosis of Bethlem myopathy. INTERPRETATION Adults who have rare monogenic disorders may lack an aetiological diagnosis because of limited access to genetic laboratory testing in the past. Advances in genetic laboratory diagnostics during the last 10−15 years have made testing more widely available. As exemplified by this case, molecular genetic diagnosis may provide benefits such as information concerning prognosis and treatment options.

The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.

ObjectiveTo compare muscle strength and endurance of the knee extensors between patients with long‐term juvenile dermatomyositis (DM) and controls and between patients with active disease and those with inactive disease, and to explore associations between strength/endurance and 1) clinical parameters, 2) physical activity, and 3) humoral/structural adaptation in the skeletal muscle of patients.MethodsIn a cross‐sectional study (44 patients and 44 age‐ and sex‐matched controls), we tested isometric muscle strength (peak torque, in Nm) and dynamic muscle endurance (total work, in Joules) of the knee extensors, physical activity (measured by accelerometer), and serum myokine levels (by enzyme‐linked immunosorbent assay). Patients were examined with validated tools (clinical muscle tests and measures of disease activity/damage and inactive disease) and using magnetic resonance imaging of the thigh muscles, which included evaluation of the quadriceps cross‐sectional area (CSA). Needle biopsy samples of the vastus lateralis muscle (obtained from 12 patients ages ≥18 years) were assessed by histochemistry.ResultsAfter a mean ± SD disease duration of 21.8 ± 11.8 years, peak torque was lower in patients with juvenile DM compared to controls (mean difference 29 Nm, 95% confidence interval 13–46; P = 0.001). Similarly, total work of the knee extensors was lower in patients compared to controls (median 738J [interquartile range 565–1,155] versus 1,249J [interquartile range 815–1,665]; P < 0.001). Both peak torque and total work were lower in patients with active juvenile DM compared to those with inactive disease (both P < 0.019); in analyses controlled for quadriceps CSA, only total work remained lower in patients with active disease. Moreover, peak torque and total work correlated with findings from clinical muscle tests in patients with active disease (r = 0.57–0.84). Muscle biopsy results indicated that the fiber type composition was different, but capillary density was similar, between patients with active disease and those with inactive disease.ConclusionIn patients with long‐term juvenile DM, both muscle strength and endurance of the knee extensors were lower when compared to matched controls, and also lower in patients with active disease compared to those with inactive disease. Our results indicate a need for more sensitive muscle tests in this clinical setting. We hypothesize that impaired muscle endurance in patients with active juvenile DM may be influenced by structural/functional adaptations of muscle tissue independent of muscle size.

Calcium signaling plays a central role in bone development and homeostasis. Store operated calcium entry (SOCE) is an important calcium influx pathway mediated by calcium release activated calcium (CRAC) channels in the plasma membrane. Stromal interaction molecule 1 (STIM1) is an endoplasmic reticulum calcium sensing protein important for SOCE. We generated a mouse model expressing the STIM1 R304W mutation, causing Stormorken syndrome in humans. Stim1R304W/R304W mice showed perinatal lethality, and the only three animals that survived into adulthood presented with reduced growth, low body weight, and thoracic kyphosis. Radiographs revealed a reduced number of ribs in the Stim1R304W/R304W mice. Microcomputed tomography data revealed decreased cortical bone thickness and increased trabecular bone volume fraction in Stim1R304W/R304W mice, which had thinner and more compact bone compared to wild type mice. The Stim1R304W/+ mice showed an intermediate phenotype. Histological analyses showed that the Stim1R304W/R304W mice had abnormal bone architecture, with markedly increased number of trabeculae and reduced bone marrow cavity. Homozygous mice showed STIM1 positive osteocytes and osteoblasts. These findings highlight the critical role of the gain-of-function (GoF) STIM1 R304W protein in skeletal development and homeostasis in mice. Furthermore, the novel feature of bilateral subgingival hair growth on the lower incisors in the Stim1R304W/R304W mice and 25 % of the heterozygous mice indicate that the GoF STIM1 R304W protein also induces an abnormal epithelial cell fate.

Primary chronic osteomyelitis (PCO) is a rare condition that usually affects the mandible. Although most often occurring isolated, it can be part of various systemic and cutaneous syndromes. Takayasu arteritis (TAK) is an autoimmune disease that can co-exist with osteomyelitis, but has only been reported once in conjunction with PCO of the mandible. We present a case of a 27-year old female with PCO of the mandible which was found to have co-existing TAK. Doctors treating patients with PCO should be aware of the associated diseases and actively seek out their signs and symptoms.

Brachyolmia is a skeletal dysplasia characterized by short spine-short stature, platyspondyly, and minor long bone abnormalities. We describe 18 patients, from different ethnic backgrounds and ages ranging from infancy to 19 years, with the autosomal recessive form, associated with PAPSS2. The main clinical features include disproportionate short stature with short spine associated with variable symptoms of pain, stiffness, and spinal deformity. Eight patients presented prenatally with short femora, whereas later in childhood their short-spine phenotype emerged. We observed the same pattern of changing skeletal proportion in other patients. The radiological findings included platyspondyly, irregular end plates of the elongated vertebral bodies, narrow disc spaces and short over-faced pedicles. In the limbs, there was mild shortening of femoral necks and tibiae in some patients, whereas others had minor epiphyseal or metaphyseal changes. In all patients, exome and Sanger sequencing identified homozygous or compound heterozygous PAPSS2 variants, including c.809G>A, common to white European patients. Bi-parental inheritance was established where possible. Low serum DHEAS, but not overt androgen excess was identified. Our study indicates that autosomal recessive brachyolmia occurs across continents and may be under-recognized in infancy. This condition should be considered in the differential diagnosis of short femora presenting in the second trimester.

The ALF transcription factor paralogs, AFF1, AFF2, AFF3 and AFF4 , are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe a new autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its degradation. Consistent with a causative role of AFF3 variants, the mutated AFF3 proteins show reduced clearance. Ten affected individuals were identified, and present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe KIdney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for Seizures, H for Hypertrichosis, I for Intellectual disability and P for Pulmonary involvement), partially overlapping the AFF4 associated CHOPS syndrome. An eleventh individual with a microdeletion encompassing only the transactivation domain and degron motif of AFF3 exhibited overlapping clinical features. A zebrafish overexpression model that shows body axis anomalies provides further support for the pathological effect of increased amount of AFF3 protein.Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformation and neurological anomalies, knock-in animals modeling the microdeletion and the missense variants identified in affected individuals presented with lower mesomelic limb deformities and early lethality, respectively.Transcriptome analyses as well as the partial phenotypic overlap of syndromes associated with AFF3 and AFF4 variants suggest that ALF transcription factors are not redundant in contrast to what was previously suggested

Intranasal bevacizumab injections have been used in treating hereditary hemorrhagic telangiectasia (HHT)‐related epistaxis since 2009. It is believed to be a safe and effective treatment for a selected group of HHT patients in reducing frequency and intensity of epistaxis, with few or none adverse effects. In this case report, however, we will describe a patient who developed bilateral osteonecrosis in the knees while undergoing regular intranasal submucosal bevacizumab injections. Although osteonecrosis previously has been documented in patients receiving bevacizumab intravenously in oncologic doses, thus far it has not been reported in patients treated with intranasal submucosal injections. Laryngoscope , 128:593–596, 2018

In the present study, we evaluate the intra- and interrater agreement of radiological glenohumeral OA using three different classification systems and estimate the prevalence of radiological and clinical glenohumeral OA in patients with type 1 diabetes mellitus (DM1), for over 45 years and controls (The Dialong study).

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Background: Magnetic resonance imaging (MRI) of thigh muscles is increasingly used to assess disease activity and damage extent in chronic myositis, but the validity of the findings is not clear. Here, the primary aim was to compare thigh MRI findings in patients having chronic myositis associated with anti-synthetase syndrome (ASS) and in matched healthy controls.Methods: Cross-sectional analyses of thigh muscle MRI, muscular function and creatinine kinase (CK) were performed in 68 ASS patients (median disease duration 71 months) and 67 controls matched for age and gender. MRI changes associated with disease activity (edema in muscles and fascia) and damage (fatty replacement and muscle volume reduction) were assessed semiquantitatively, giving a total MRI score of 0-78 (total edema 0-42 and total damage 0-36).Results: ASS patients had higher total MRI score than the matched controls (14.1 versus 3.0; p < 0.001) and less muscle strength (p < 0.001). Muscle edema was more frequent in ASS patients than controls (38% versus 12%), as was fatty replacement (42% versus 4%). In ASS patients, we found that the total edema score correlated with CK, but 23% of the patients with normal CK had score > 18. Muscle compartment analyses in ASS patients showed that muscle edema was most pronounced anteriorly, while fatty replacement dominated posteriorly.Conclusions: This study showed, for the first time, the magnitude of difference in muscle MRI findings between chronic myositis cases and matched controls. In ASS patients, muscle MRI appeared to provide useful complementary information to muscle strength and CK levels in the assessment of myositis.

Background and purpose - Different radiographic classifications have been proposed for prediction of outcome in Perthes disease. We assessed whether the modified lateral pillar classification would provide more reliable interobserver agreement and prognostic value compared with the original lateral pillar classification and the Catterall classification.Patients and methods - 42 patients (38 boys) with Perthes disease were included in the interobserver study. Their mean age at diagnosis was 6.5 (3-11) years. 5 observers classified the radiographs in 2 separate sessions according to the Catterall classification, the original and the modified lateral pillar classifications. Interobserver agreement was analysed using weighted kappa statistics. We assessed the associations between the classifications and femoral head sphericity at 5-year follow-up in 37 non-operatively treated patients in a crosstable analysis (Gamma statistics for ordinal variables, gamma).Results - The original lateral pillar and Catterall classifications showed moderate interobserver agreement (kappa 0.49 and 0.43, respectively) while the modified lateral pillar classification had fair agreement (kappa 0.40). The original lateral pillar classification was strongly associated with the 5-year radiographic outcome, with a mean correlation coefficient of 0.75 (95% CI: 0.61-0.95) among the 5 observers. The modified lateral pillar and Catterall classifications showed moderate associations (mean correlation coefficient 0.55 [95% CI: 0.38-0.66] and 0.64 [95% CI: 0.57-0.72], respectively).Interpretation - The Catterall classification and the original lateral pillar classification had sufficient interobserver agreement and association to late radiographic outcome to be suitable for clinical use. Adding the borderline B/C group did not increase the interobserver agreement or prognostic value of the original lateral pillar classification.

Background and purpose — Different radiographic classifications have been proposed for prediction of outcome in Perthes disease. We assessed whether the modified lateral pillar classification would provide more reliable interobserver agreement and prognostic value compared with the original lateral pillar classification and the Catterall classification. Patients and methods — 42 patients (38 boys) with Perthes disease were included in the interobserver study. Their mean age at diagnosis was 6.5 (3–11) years. 5 observers classified the radiographs in 2 separate sessions according to the Catterall classification, the original and the modified lateral pillar classifications. Interobserver agreement was analysed using weighted kappa statistics. We assessed the associations between the classifications and femoral head sphericity at 5-year follow-up in 37 non-operatively treated patients in a crosstable analysis (Gamma statistics for ordinal variables, γ). Results — The original lateral pillar and Catterall classifications showed moderate interobserver agreement (kappa 0.49 and 0.43, respectively) while the modified lateral pillar classification had fair agreement (kappa 0.40). The original lateral pillar classification was strongly associated with the 5-year radiographic outcome, with a mean γ correlation coefficient of 0.75 (95% CI: 0.61–0.95) among the 5 observers. The modified lateral pillar and Catterall classifications showed moderate associations (mean γ correlation coefficient 0.55 [95% CI: 0.38–0.66] and 0.64 [95% CI: 0.57–0.72], respectively). Interpretation — The Catterall classification and the original lateral pillar classification had sufficient interobserver agreement and association to late radiographic outcome to be suitable for clinical use. Adding the borderline B/C group did not increase the interobserver agreement or prognostic value of the original lateral pillar classification.