Arthrogryposis Research Articles

Bmpr1aa modulates the severity of the skeletal phenotype in an fkbp10-deficient Bruck syndrome zebrafish model.

Rare monogenic disorders often exhibit significant phenotypic variability among individuals sharing identical genetic mutations. Bruck syndrome (BS), a prime example, is characterized by bone fragility and congenital contractures, although with a pronounced variability among family members. BS arises from recessive biallelic mutations in FKBP10 or PLOD2. FKBP65, the protein encoded by FKBP10, collaborates with the LH2 enzyme (PLOD2) in type I collagen telopeptide lysine hydroxylation, crucial for collagen cross-linking. To identify potential modifier genes and to investigate the mechanistic role of FKBP10 in BS pathogenesis, we established an fkbp10a knockout zebrafish model. Mass-spectrometry analysis in fkbp10a-/- mutants revealed a generally decreased type I collagen lysyl hydroxylation, paralleled by a wide skeletal variability similar to human patients. Ultrastructural examination of the skeleton in severely affected mutants showed enlarged type I collagen fibrils and disturbed elastin layers. Whole-exome sequencing of 7 mildly and 7 severely affected mutant zebrafish siblings, followed by SNP-based linkage analysis, indicated a linked region on chromosome 13, which segregates with phenotypic severity. Transcriptome analysis identified six differentially expressed genes (DEGs) between mildly and severely affected mutants. The convergence of genes within the linked region and DEGs highlighted bmpr1aa as a potential modifier gene, as its reduced expression correlates with increased skeletal severity. In summary, our study provides deeper insights into the role of FKBP10 in BS pathogenesis. Additionally, we identified a pivotal gene that influences phenotypic severity in a zebrafish model of BS. These findings hold promise for novel treatments in the field of bone diseases.

Long-term Clinical and Radiographic Results of Posteromedial Lateral Release for Neuromuscular Clubfoot Deformity.

Clubfoot occurs in up to 50% of patients with spina bifida (SB) and 90% with arthrogryposis (AR). Many of these patients with neuromuscular clubfoot deformity fail conservative casting and require surgery with posteromedial lateral release (PMLR). Limited data exist for the outcomes of PMLR in patients with SB and AR. Retrospective chart review was performed on PMLR in patients with SB and AR from January 2007 to June 2022, excluding those with follow-up <3 years or incomplete charts. Radiographic measurements were obtained pre-PMLR and post-PMLR when available. In total, 51 patients with 79 cases of clubfeet treated with PMLR at a tertiary children's hospital were identified. Of those, 35 patients with 54 cases of clubfeet treated with PMLR were analyzed, including 22 patients (29 feet) with SB and 13 patients (25 feet) with AR. In the SB cohort, 41% of feet required reoperation at an average of 4.6 years, and 76% of AR feet required reoperation at an average of 4.7 years post-PMLR. In addition, 21% of SB feet and 8% of AR feet required 2 or more reoperations. Talectomy was required post-PMLR in 24% of SB feet and 40% of AR feet at an average of 4.9 and 5.9 years, respectively. Younger age at time of PMLR was associated with significantly increased reoperation rates in AR (P=0.01). Greater change in calcaneus-fifth metatarsal angle after PMLR was associated with a future need for reoperation (P=0.047). Greater talo-first metatarsal angle after PMLR was associated with a future need for reoperations of any kind (P=0.040) in SB. Although PMLR remains a safe and successful treatment in the short term, many neuromuscular clubfeet will require additional procedures. Younger age and greater preoperative versus postoperative changes in calcaneus-fifth metatarsal and postoperative talo-first metatarsal angles were associated with increased reoperation rate. These results help orthopaedic surgeons counsel families about the long-term prognosis of clubfoot treatment in SB and AR. Level IV.

Arthrogryposis Multiplex Congenita in pediatric age: Correlation between Muscle MRI and functional assessment

Arthrogryposis multiplex congenita (AMC) is a group of diseases with joint limitations at two or more distinct joint levels at birth. Joint limitations are not progressive, but the functional consequences have a lifelong impact on patients. In this article we will present the results of our study aimed at evaluating the correlation between muscle fat infiltration on MRI and activity deficiencies and limitations in children with AMC. Our study is one of the first in a pediatric population to establish the link between muscle imaging and functional aspects of AMC.

Letter to the editor of Heliyon re: A novel compound heterozygous variation in the FKBP10 gene causes Bruck syndrome without congenital contractures: A case report. Heliyon. 2024; 10(7): e28680

Letter to the editor of Heliyon re: A novel compound heterozygous variation in the FKBP10 gene causes Bruck syndrome without congenital contractures: A case report. Heliyon. 2024; 10(7): e28680

Do Not Forget the Spine MRI in Children With Arthrogryposis Multiplex Congenita: High Prevalence of Tethered Spinal Cord and Preliminary Clinical Findings Following Detethering.

Arthrogryposis multiplex congenita (AMC) encompasses congenital conditions with joint contractures in 2 or more joints. Patients with AMC may have scoliosis and neural axis malformations. The study aimed to determine the prevalence of tethered spinal cord (TSC), characterized by a low-lying conus medullaris, and secondarily, present preliminary findings following surgical untethering in children with AMC. Patients 18 years of age and younger with a diagnosis of AMC and a spine MRI were identified. The presence of a TSC was defined as a low-lying conus with termination at or below the lower third of the L2 vertebral body. A pediatric neurosurgeon and a pediatric orthopaedic surgeon independently reviewed MRIs. The medical records of patients with AMC who underwent untethering were examined to evaluate preoperative and postoperative clinical findings. The prevalence of TSC in our AMC patients was compared with published normative data using χ2 analysis. Forty-two of 105 AMC patients (40%) had TSCs. There was a greater percentage of patients with AMC and a TSC compared with the unaffected population (P<0.0001). Sixteen patients underwent detethering through filum terminale sectioning. Nine patients had preoperative neurological deficits in addition to their AMC. There were no postoperative complications. All patients had improvement in their bowel and bladder symptoms within 3 months after their detethering procedure. TSC is more prevalent in the pediatric population with AMC compared with those without AMC. MRI is recommended for all patients with AMC due to its high prevalence. Although not a benign procedure, surgical detethering may have potential benefits for children with AMC. Level IV-therapeutic study.

489P PIEZO2-associated distal arthrogryposis: phenotypic spectrum and genotype-phenotype correlations in a multicenter case series

489P PIEZO2-associated distal arthrogryposis: phenotypic spectrum and genotype-phenotype correlations in a multicenter case series

Midterm clinical and radiological outcomes of arthrogryposis-associated clubfoot treated with the Ponseti method: a retrospective observational study and comprehensive literature review

BackgroundThe treatment results of the Ponseti method for arthrogrypotic clubfoot have been described in only a few case series. Further evaluations are necessary.MethodsChildren from two German paediatric orthopaedic hospitals with arthrogryposis-associated clubfoot treated with the Ponseti method between 2004 and 2011 and who were at least five years of age at their last follow-up were retrospectively evaluated. The endpoints were the clinical foot position, necessary surgeries during the follow-up period and radiological constellations. A comprehensive literature review was conducted after a systematic literature search.ResultsSeventeen patients (47% with amyoplasia [AP] and 53% with distal arthrogryposis [DA]) met the inclusion criteria. Thirty-one feet were evaluated. The period between the treatment start and the last follow-up examination covered 8.9 ± 2.5 years. After the last cast removal within the initial Ponseti cast series, 74% of the clinical results were good to excellent. However, the clinical outcomes in the patients with AP were significantly worse. Overall, in 23 feet (74%), at least one major surgery at the age of 2.9 ± 2.2 years was necessary during the clinical course. Major surgeries were much more frequent on the feet of the patients with AP than with DA. Lateral X-rays showed normal age-appropriate radiological angles in 4% of the feet, hindfoot equinus in 19%, under-corrected hindfoot in 44%, under-corrected clubfoot in 26% and rocker bottom deformity in 7%. The radiological residual deformities in AP were much more severe than in DA (p = 0.042). Most of the studies reviewed (11 case series, 144 patients) reported high initial clinical correction rates, followed by high recurrence rates and the need for further surgeries.ConclusionAbout a quarter of the arthrogrypotic patients benefited from the Ponseti therapy without further major surgery. However, the clinically observed high initial correction rate after Ponseti therapy of arthrogrypotic clubfoot was not accompanied by a correction of the bony foot position in the X-rays. The feet of the patients with DA had better outcomes than those of the patients with AP. Therefore, in outcome studies, a clear distinction between patients with AP and those with DA is necessary.

Heterozygous loss-of-function variants in SPTAN1 cause a novel early childhood onset distal myopathy with chronic neurogenic features.

Neurogenetic disorders caused by pathogenic variants in four genes encoding non-erythrocytic spectrins ( SPTAN1, SPTBN1, SPTBN2, SPTBN4) range from peripheral and central nervous system involvement to complex syndromic presentations. Heterozygous pathogenic variants in SPTAN1 are exemplary for this diversity with phenotypes spanning almost the entire spectrum. Through international collaboration we identified 14 families with genetically unsolved distal weakness and unreported heterozygous SPTAN1 loss-of-function variants including frameshift, nonsense and splice-acceptor variants. Clinical data, electrophysiology, muscle CT or MRI and muscle biopsy findings were collected and standardized. SPTAN1 protein, mRNA expression analysis and cDNA sequencing was performed on muscle tissue from two patients. All 20 patients presented with early childhood onset distal weakness. The severity varied both within families and between different families. Foot abnormalities ranged from hammer toes and pes cavus to distal arthrogryposis. Electrophysiology showed mixed myogenic and neurogenic features. Muscle MRI or CT in 10 patients showed fatty infiltration of the distal lower limb anterior compartment and/or selective involvement of the extensor hallucis longus muscle. Muscle biopsy revealed myopathic changes with mild dystrophic and chronic neurogenic changes in 7 patients. Finally, we provide proof for nonsense mediated decay in tissues derived from two patients. We provide evidence for the association of SPTAN1 loss-of-function variants with childhood onset distal myopathy in 14 families. This finding extends the phenotypic spectrum of SPTAN1 loss-of-function variants ranging from intellectual disability to distal weakness with a predominant myogenic cause. SPTAN1 loss-of-function variants, including frameshift, nonsense and splice site variants cause a novel childhood onset distal weakness syndrome with primarily skeletal muscle involvement. Hereditary motor neuropathies and distal myopathic disorders present a well-known diagnostic challenge as they demonstrate substantial clinical and genetic overlap. The emergence of SPTAN1 loss-of-function variants serves as a noteworthy example, highlighting a growing convergence in the spectrum of genotypes linked to both hereditary motor neuropathies and distal myopathies.

Fast-twitch myofibrils grow in proportion to Mylpf dosage in the zebrafish embryo.

Muscle cells become stronger by expanding myofibrils, the chains of sarcomeres that produce contraction. Here we investigate how Mylpf (Myosin Light Chain Phosphorylatable Fast) abundance impacts myofibril assembly in fast-twitch muscle. The two zebrafish Mylpf genes (mylpfa and mylpfb) are exclusively expressed in fast-twitch muscle. We show that these cells initially produce six times more mylpfa mRNA and protein than mylpfb. The combined Mylpf protein dosage is necessary for and proportionate to fast-twitch myofibril growth in the embryo. Fast-twitch myofibrils are severely reduced in the mylpfa -/- mutant, leading to loss of high-speed movement; however, by persistent slow movement this mutant swims as far through time as its wild-type sibling. Although the mylpfb -/- mutant has normal myofibrils, myofibril formation fails entirely in the mylpfa -/- ;mylpfb -/- double mutant, indicating that the two genes are collectively essential to myofibril formation. Fast-twitch myofibril width is restored in the mylpfa -/- mutant by transgenic expression of mylpfa-GFP, mylpfb-GFP, and by human MYLPF-GFP to a degree corresponding linearly with GFP brightness. This correlate is inverted by expression of MYLPF alleles that cause Distal Arthrogryposis, which reduce myofibril size in proportion to protein abundance. These effects indicate that Mylpf dosage controls myofibril growth, impacting embryonic development and lifelong health.

Loss of ZC4H2, an Arthrogryposis Multiplex Congenita Associated Gene, Promotes Osteoclastogenesis in Mice.

ZC4H2 encodes a C4H2-type zinc finger protein, mutations of which lead to a spectrum of diseases known as ZC4H2 associated rare disorders (ZARD). In addition to neurological phenotypes, the most typical symptoms of ZARD are multiple joint contractures of varying degrees, accompanied by abnormal development of muscles and bones, and osteoporosis in some cases. The pathogenic mechanisms of such bone related phenotypes, however, remain unclear. Here, we showed that ZC4H2 is expressed in the developing bones in mice. ZC4H2 knockout mice were neonatal-lethal and smaller in size, with reduced calcification of long bones. Upon induced loss of ZC4H2 postnatally, the femoral bones developed an osteoporosis-like phenotype, with reduced bone mineral density, bone-volume fraction, and trabecular bone number. Knockdown of ZC4H2 showed no clear effect on the expression of osteogenic differentiation genes in in vitro models using mesenchymal stem cells. Interestingly, ZC4H2 knockdown significantly enhanced osteoclast differentiation and bone resorption in induced bone marrow-derived macrophages. We further confirmed that the number of osteoclasts in the long bone of ZC4H2 knockout mice was increased, as well as the expression of the serum bone resorption/osteoporosis marker CTX-1. Our study unveils a new role of ZC4H2 in osteoclast differentiation and bone development, providing new clues on the pathology of ZARD.

Heterogenic Genetic Background of Distal Arthrogryposis-Review of the Literature and Case Report.

Distal arthrogryposis (DA) is a skeletal muscle disorder that is characterized by the presence of joint contractures in various parts of the body, particularly in the distal extremities. In this study, after a systematic review of the literature, we present a case report of a non-consanguineous family. In our case, the first-trimester ultrasound was negative, and the presence of the affected mother was not enough for the parents to consent to us performing invasive amniotic fluid sampling. The second-trimester ultrasound showed clear abnormalities suggestive of arthrogryposis. Whole-exome sequencing was performed and an autosomal dominantly inherited disease-associated gene was identified. In our case, a pathogenic variant in the TNNT3 gene c.188G>A, p.Arg63His variant was identified. The mother, who had bilateral clubfoot and hand involvement in childhood, carried the same variant. The TNNT3 gene is associated with distal arthrogryposis type 2B2, which is characterized by congenital contractures of the distal limb joints and facial dysmorphism. In the ultrasound, prominent clubfoot was identified, and the mother, who also carried the same mutation, had undergone surgeries to correct the clubfoot, but facial dysmorphism was not detected. Our study highlights the importance of proper genetic counseling, especially in an affected parent(s), and close follow-up during pregnancy.

Identification of four TTN variants in three families with fetal akinesia deformation sequence

BackgroundTTN is a complex gene with large genomic size and highly repetitive structure. Pathogenic variants in TTN have been reported to cause a range of skeletal muscle and cardiac disorders. Homozygous or compound heterozygous mutations tend to cause a wide spectrum of phenotypes with congenital or childhood onset. The onset and severity of the features were considered to be correlated with the types and location of the TTN variants.MethodsWhole-exome sequencing was performed on three unrelated families presenting with fetal akinesia deformation sequence (FADS), mainly characterized by reduced fetal movements and limb contractures. Sanger sequencing was performed to confirm the variants. RT-PCR analysis was performed.ResultsTTN c.38,876–2 A > C, a meta transcript-only variant, with a second pathogenic or likely pathogenic variant in trans, was observed in five affected fetuses from the three families. Sanger sequencing showed that all the fetal variants were inherited from the parents. RT-PCR analysis showed two kinds of abnormal splicing, including intron 199 extension and skipping of 8 bases.ConclusionsHere we report on three unrelated families presenting with FADS caused by four TTN variants. In addition, our study demonstrates that pathogenic meta transcript-only TTN variant can lead to defects which is recognizable prenatally in a recessive manner.

Genotype-Phenotype Correlations and Sex Differences in ZC4H2-Associated Rare Disorder

BackgroundZC4H2-associated rare disorder (ZARD) is caused by pathogenic variations in the ZC4H2 gene on the X chromosome. This gene codes for a zinc finger protein involved in neural development. ZARD is characterized by highly variable symptoms, potentially influenced by the sex of the individual. MethodsThe ZC4H2-Associated Rare Disorder Natural History Study is a prospective natural history study conducted among individuals with ZARD that consists of standardized interviews, developmental assessments, and neurological examinations conducted every six months for two years. In this article, we present data from baseline visits with 40 participants, the largest ZARD cohort studied thus far, focusing on genotype-phenotype correlations and sex differences. Fisher exact, maximum likelihood χ2, and Mann-Whitney tests were utilized. ResultsMales tended to have maternally inherited ZC4H2 pathogenic variations, whereas females tended to have de novo variations (P < 0.001). Female participants were more likely to have contractures at birth (P < 0.01), arthrogryposis multiplex congenita (P < 0.001), spasticity on examination (P < 0.1), and lower limb muscle atrophy (P < 0.05). Male participants were more likely to have seizures (P < 0.1), intermittent pain (P < 0.01), severe vision impairment (P < 0.05), dysphagia for solids (P < 0.01), and generalized muscle atrophy (P < 0.05). ConclusionsOur study suggests there is significant overlap in severity and range of symptoms between males and females, although several symptoms are more common in one sex than the other. Further analysis is needed to better understand how pathogenic variation type affects phenotype.

Ophthalmoplegia in a patient with arthrogryposis multiplex congenita 3: A case report and review of literature

Ophthalmoplegia in a patient with arthrogryposis multiplex congenita 3: A case report and review of literature

The experience of caregiving for children with rare musculoskeletal conditions: a qualitative study in arthrogryposis multiplex congenita

BackgroundArthrogryposis multiplex congenita (AMC) is a group of rare musculoskeletal conditions that is associated with complex healthcare needs and long-term follow up. The literature reports significant direct, indirect, and psychosocial costs for caregivers of children with neuromuscular conditions. Due to mobility limitations and frequent hospital visits, caring for a child with AMC is complex. Other challenges experienced by caregivers include financial strain, job changes, changes in interpersonal relationships and abandonment. This study was aimed at exploring the lived experience of caregivers of children with AMC.MethodsThe present study is part of a larger global mixed methods study. In the initial quantitative aspect of the study, caregivers (n = 158) of children and youths with AMC (aged 0–21 years) responded to a cost of care survey on an electronic platform. Of the 158 participants, 13 caregivers then further consented to participate in the qualitative aspect of the study in which a 60-min semi-structured, individual interview was conducted remotely. Open-ended questions were developed to gain a deeper understanding of the direct and indirect costs of care, their impact on the caregivers' lives and the quality of the care-giving experience. Interviews were transcribed, and a coding scheme was developed drawing from both the existing literature and the content of the interviews. A deductive and inductive thematic analysis was used to analyze the qualitative data using the NVivo® qualitative data analysis software.Results and conclusionFive themes describing the experiences of caregivers of children with AMC emerged from the analysis of the qualitative data: 1. Impact of the caregiving experience; 2. Cost of childcare; 3. Support system for care; 4. Managing and navigating care; 5. Supporting the child’s growth and development. In addition to the results of the thematic analysis, specific recommendations shared by the caregivers included the need for support groups and provision of support to youths to prepare them for adolescence. These findings will inform resource allocation, policymaking, and support services for children with rare conditions, their caregivers and families.

Bi-allelic variants in MYH3 cause recessively-inherited arthrogryposis.

Arthrogryposis is a clinical feature defined by congenital joint contractures in two or more different body areas which occurs in between 1/3000 and 1/5000 live births. Variants in multiple genes have been associated with distal arthrogryposis syndromes. Heterozygous variants in MYH3 have been identified to cause the dominantly-inherited distal arthrogryposis conditions, Freeman-Sheldon syndrome, Sheldon-Hall syndrome, and multiple pterygium syndrome. In contrast, MYH3 variants underlie both dominantly and recessively inherited Contractures, Pterygia, and Spondylocarpotarsal Fusion syndromes (CPSFS) which are characterized by extensive bony abnormalities in addition to congenital contractures. Here we report two affected sibs with distal arthrogryposis born to unaffected, distantly related parents. Sequencing revealed that both sibs were homozygous for two ultra-rare MYH3 variants, c.3445G>A (p.Glu1149Lys) and c.4760T>C (p.Leu1587Pro). Sequencing and deletion/duplication analysis of 169 other arthrogryposis genes yielded no other compelling candidate variants. This is the first report of biallelic variants in MYH3 being implicated in a distal arthrogryposis phenotype without the additional features of CPSFS. Thus, akin to CPSFS, both dominant and recessively inherited distal arthrogryposis can be caused by variants in MYH3.

Minimally Invasive Method for Treatment of Syndromic Congenital Vertical Talus Deformity in Children.

Congenital Vertical Talus (CVT) is a rare form of rigid flatfoot commonly seen in patients with underlying neurologic syndromes. This study aims to evaluate the long-term effectiveness of the minimally invasive method for correcting CVT deformity in a large cohort of syndromic patients. A single author recorded preoperative, 2-week postoperative, 1-year postoperative, and most recent radiographic measurements and complications for 25 patients treated with the minimally invasive method from 2006 to 2021. Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires were administered for 12 patients after January 1, 2015, when the institution began collecting PROMIS in all orthopaedic patients. Average follow-up was 55 months (13-111); 18 patients had minimum 24-month follow-up. Forty feet in 25 patients were analyzed. The average preoperative lateral talar axis-first metatarsal base angle (TAMBA) was 68.7 ± 21.3 vs 12.1 ± 8.9 after initial surgical intervention (P < .0001). There was a statistically significant increase in the lateral TAMBA between the initial postoperative and final follow-up visits (13.0 vs 21.6, P = .02). Radiographic recurrence of talonavicular deformity was noted in 12 feet (30.9%); 7 (15.55%) required corrective surgery. Larger preoperative lateral TAMBA was predictive of recurrence. Notably, patients with arthrogryposis experienced higher radiographic recurrence than other syndromic patients (45.0% vs 14.3%, P = .0384). PROMIS scores were within population norms. The study suggests that less than one-third of syndromic CVT patients experienced a radiographic recurrence of talonavicular deformity, with 15% requiring further surgical intervention at an average of 55 months following the initial procedure. A higher incidence of radiographic recurrence occurred in patients with distal arthrogryposis. These findings, along with the satisfactory patient-reported outcomes, suggest that the minimally invasive technique is an effective treatment method for syndromic CVT, underscoring the necessity for clinicians to provide detailed prognoses and consider more intensive follow-up for those at higher risk.

STAC3 disorder: a common cause of congenital hypotonia in Southern African patients.

STAC3 disorder, or Native American myopathy, is characterised by congenital myopathy, hypotonia, musculoskeletal and palatal anomalies, and susceptibility to malignant hyperthermia. A STAC3 c.851 G > C (p.Trp284Ser) pathogenic variant, common in the Lumbee Native American tribe, has been identified in other populations worldwide, including patients of African ancestry. We report on the frequency of STAC3 c.851 G > C in a cohort of 127 patients presenting with congenital hypotonia that tested negative for spinal muscular atrophy and/or Prader-Willi syndrome. We present a clinical retrospective, descriptive review on 31 Southern African patients homozygous for STAC3 c.851 G > C. The frequencies of various phenotypic characteristics were calculated. In total, 25/127 (20%) laboratory-based samples were homozygous for STAC3 c.851 G > C. A carrier rate of 1/56 and a predicted birth rate of 1/12 500 was estimated from a healthy cohort. A common haplotype spanning STAC3 was identified in four patients. Of the clinical group, 93% had a palatal abnormality, 52% a spinal anomaly, 59% had talipes equinovarus deformity/deformities, 38% had arthrogryposis multiplex congenita, and 22% had a history suggestive of malignant hyperthermia. The novel finding that STAC3 disorder is a common African myopathy has important clinical implications for the diagnosis, treatment and genetic counselling of individuals, with neonatal and/or childhood hypotonia with or without arthrogryposis multiplex congenita, and their families. The spread of this variant worldwide and the allele frequency higher in the African/African-American ancestry than the Admixed Americans, strongly indicates that the STAC3 c.851 G > C variant has an African origin which may be due to anancient mutation with migration and population bottlenecks.

A monoallelic UXS1 variant associated with short-limbed short stature.

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. 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. Invivo effects were studied using HeparinRed assay and metabolomics. 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. This is the first report linking UXS1 to short-limbed short stature in humans.

Expanding the spectrum of clinical and genetic characteristics of distal arthrogryposis type 5 caused by heterozygous variants in the PIEZO2 gene

Pathogenic heterozygous variants in the PIEZO2 gene cause distal arthrogryposis type 5 – a rare autosomal dominant disease, which is characterized by the development of congenital contractures, ophthalmoparesis, ptosis and restrictive respiratory disorders. We have presented clinical and genetic characteristics of seven Russian patients with distal arthrogryposis type 5 caused by previously described and newly identified nucleotide variants in the PIEZO2 gene. It was shown that the most severe clinical manifestations were found in patients with newly identified nucleotide variants c.8238G&gt;A (p.Trp274Ter) and c.7095G&gt;T (p.Trp2365Cys), while in patients with other previously described variants c.8181_8183delAGA (p.Glu2727del) and c.2134A&gt;G (p.Met712Val) the clinical phenotype is more moderately expressed. The dynamics of phenotype formation were also noted. It has been shown that the disease progression may occur as the child grows and requires monitoring of this group of patients.