Congenital Contractures and Fractures: A Variant of Bruck Syndrome Type 2.

Bruck syndrome, an exceptionally rare autosomal recessive disorder, manifests as bone fragility and congenital joint contractures. This syndrome is recognized as a fusion of arthrogryposis multiplex congenita and osteogenesis imperfecta and is categorized into Types 1 and 2. Bruck syndrome Type 2 stems from a homozygous mutation in the PLOD2 gene and exhibits characteristics such as osteopenia, congenital contractures with pterygia, femoral bowing, club feet, postnatal shorty stature, severe limb deformity, and progressive scoliosis. In this report, we describe the case of an infant presenting with multiple joint contractures of the distal extremities, bilateral talipes equinovarus deformity, and a history of a right femur fracture at birth, managed through closed reduction and plaster of Paris. The current treatment regimen includes physiotherapy, wrist splinting for wrist extension and thumb abduction, and serial casting of both lower limbs.

Early Diagnosis and Management of Arthrogryposis Multiplex Congenita in a Neonate: A Case Study.

Arthrogryposis multiplex congenita (AMC) is a rare condition characterized by multiple joint contractures at birth, affecting two or more body areas. The clinical examination revealed physical abnormalities indicative of AMC, including joint contractures, clubfeet, and scoliosis. The diagnostic evaluation confirmed the clinical suspicion, and prompt management was initiated to address respiratory distress and potential sepsis. Early diagnosis and multidisciplinary care are essential for optimizing outcomes in neonates with AMC. We present the case of a one-day-old neonate who exhibited immediate respiratory distress upon birth and was born via a lower segment cesarean section (LSCS) to a 31-year-old mother. This case underscores the importance of recognizing prenatal ultrasound findings suggestive of AMC and implementing appropriate postnatal care strategies for affected neonates. Early diagnosis and multidisciplinary care are essential for optimizing outcomes in neonates with AMC.

Infantile Systemic Hyalinosis: A Case Report and Literature Review.

Infantile systemic hyalinosis (ISH) is a very rare disorder belonging to the heterozygous group of genetic fibromatosis. There is a diffuse deposition of hyaline material in the skin, gastrointestinal tract, muscle, lymph node, spleen, thyroid, and adrenal gland due to which it presents clinically with multiple subcutaneous skin nodules, gingival hypertrophy, osteopenia, joint contractures, failure to thrive, and diarrhea with protein-losing enteropathy, and is associated with recurrent infections. The disease is caused by mutations in ANTXR2 also known as the CMG2 gene, which encodes the transmembrane-extracellular matrix assembly. In this report, we describe a nine-month-old male diagnosed with ISH based on the clinical presentation of severe skin lesions, painful joint contractures, diarrhea, and failure to thrive. His diagnosis was confirmed by molecular DNA sequencing of the ANTXR2 gene. Consanguinity and molecular diagnosis will be helpful for early diagnosis and accurate management.

Multisystemic Manifestations of Hyaline Fibromatosis Syndrome: Implications for Diagnosis and Management.

Hyaline fibromatosis syndrome (HFS) is a rare autosomal recessive disorder characterized by the deposition of hyaline material in the skin, soft tissues, and bones. In this report, we discuss a case of a six-month-old male with HFS who presented with faltering growth, chronic diarrhea, multiple joint contractures, joint stiffness, hyperpigmented skin over bony prominences, gingival hypertrophy, patent foramen ovale, and symmetric periventricular hyperintensities on brain MRI. The diagnosis of HFS was confirmed by skin biopsy and genetic testing, which identified a homozygous mutation in the anthrax toxin receptor 2 (ANTXR2) gene. The patient was managed symptomatically with nutritional support, physiotherapy, analgesics, and regular dental care. He also received intralesional corticosteroid therapy, which significantly decreased the size of the skin nodules. His hyperpigmented skin and gingival hypertrophy remained stable, and the patent foramen ovale was managed conservatively. This case report highlights the importance of early diagnosis and management of HFS and the benefits of involving a multidisciplinary team to improve the quality of life of affected individuals.

Infantile Systemic Hyalinosis Presenting as Pseudo-Paralysis in Infancy: Study of Six Cases.

Infantile systemic hyalinosis is a very rare fatal autosomal recessive genetic disorder with a mutation in capillary morphogenesis gene-2- CMG2 /Human anthrax toxin-2 ANTXR2 resulting in spindle cell proliferation, altered collagen metabolism along with extensive deposition of hyaline material in the skin and several tissues. To date only a few cases have been reported in the literature, hence we reported this series. This study is a retrospective chart review of infants diagnosed with infantile systemic hyalinosis from January 2015 through December 2020 at a tertiary care children's hospital in South India. The mean age of presentation was 9.4 months, with a male to female ratio of 1:5. All children were born of consanguineous marriage except one child. All children had symptoms at birth, painful limb movements, multiple joint stiffness, gingival thickening, skin lesions around perianal, perioral areas, and frog-like position. Three (50%) children had stiff skin. Routine tests including complete blood count, liver function test, renal function test, creatine phosphokinase, nerve conduction studies, and metabolic tests were normal in all children. Skin biopsy showed hyalinized collagenous tissue in the dermis. Genetic study results of two cases revealed pathogenic variants in ANTXR2 gene. Infantile systemic hyalinosis should be considered in infants presenting with painful limb movements. The diagnosis helped in avoiding unnecessary investigations and prognostications. The genetic information from proband mutation helped in prenatal diagnosis in two families.

Associations among quality of life, activities, and participation in elderly residents with joint contractures in long-term care facilities: a cross-sectional study.

BACKGROUND: Joint contractures and degenerative osteoarthritis are the most common joint diseases in the elderly population, can lead to limited mobility in elderly individuals, can exacerbate symptoms such as pain, stiffness, and disability, and can interfere with social participation and quality of life, thus affecting mental health. However, relevant studies on this topic are very limited. This study describes the associations of joint contracture categories and sites in elderly residents in long-term care facilities with their quality of life, activities, and participation. METHODS: Elderly individuals with joint contractures who were residents in long-term care facilities were recruited. The World Health Organization (WHO) Quality of Life and the WHO Disability Assessment Schedule 2.0 were used to survey the participants. Correlations, multiple linear regressions, and multiple analyses of variance, with joint contractures as the response variable, were used in the statistical analysis. RESULTS: The final statistical analysis included 232 participants. The explanatory power of contracture sites on activities and participation had a moderate strength of association (η2 = .113). Compared with elderly residents with joint contractures and osteoarthritis isolated to the upper limbs, those with joint contractures and osteoarthritis in both the upper and lower limbs had significantly worse activity and participation limitations. No significant differences in activity and participation were found between elderly residents with joint contractures affecting only the upper limbs and those with joint contractures affecting only the lower limbs (F1,226 = 2.604 and F1,226 = 0.674, nonsignificant). Osteoarthritis had the greatest impact on activity limitations and participation restrictions among elderly residents with joint contractures affecting both the upper and lower limbs (F1,226 = 6.251, p = .014). CONCLUSIONS: Elderly residents in long-term care facilities belonging to minority groups, with a history of stroke, and with osteoarthritis are at a high risk of developing activity limitations and participation restrictions. Moreover, compared with other contraction sites, regardless of osteoarthritis, joint contractures affecting both the upper and lower limbs were associated with the greatest activity limitations and participation restrictions. TRIAL REGISTRATION: This study has been registered in the Chinese Clinical Trial Registry, registration number and date: ChiCTR2000039889 (13/11/2020).

Proposal of an Algorithm to Early Detect Attenuated Type I Mucopolysaccharidosis (MPS Ia) among Children with Growth Abnormalities.

Background and Objectives: Diagnostic delay is common in attenuated Mucopolysaccharidosis Type I (MPS Ia) due to the rarity of the disease and the variability of clinical presentation. Short stature and impaired growth velocity are frequent findings in MPS Ia, but they rarely raise suspicion as paediatric endocrinologists are generally poorly trained to detect earlier and milder clinical signs of this condition. Materials and Methods: Following a consensus-based methodology, a multidisciplinary panel including paediatric endocrinologists, paediatricians with expertise in metabolic disorders, radiologists, and rheumatologists shared their experience on a possible clinical approach to the diagnosis of MPS Ia in children with short stature or stunted growth. Results: The result was the formation of an algorithm that illustrates how to raise the suspicion of MPS Ia in a patient older than 5 years with short stature and suggestive clinical signs. Conclusion: The proposed algorithm may represent a useful tool to improve the awareness of paediatric endocrinologists and reduce the diagnostic delay for patients with MPS Ia.

Factors Associated with Development of New Joint Contractures in Long-Term Care Residents.

OBJECTIVE: Limb contractures are associated with poor outcomes and quality of life in long-term care (LTC) residents. This study examined the rate of developing new joint contracture in the LTC residents and associated risk factors to formulate effective interventions in this critical but understudied area. DESIGN: This is an observational study with data obtained from the Hong Kong Longitudinal Study on LTC Residents between 2005 and 2016. SETTING AND PARTICIPANTS: Trained assessors (nurses, social workers, and therapists) used the Minimum Data Set Resident Assessment Instrument (MDS-RAI 2.0) to collect the data of the residents from 9 residential LTC facilities. MEASURES: Limb contractures were defined as a functional limitation in the range of motion involving the upper or lower limbs. Primary outcomes included annual prevalence of joint contractures and factors that were associated with the development of new joint contractures. RESULTS: We analyzed the data for 1914 older residents (674 males, mean age 83.4 years). During the first 5 years since admission, the annual prevalence of upper limb contractures increased from 29.8% to 36.5%, and lower limb contractures increased from 41.5% to 57.4%. Overall, the increment of the prevalence rate of joint contractures per year ranged from 0.7% to 3.2% for the upper limbs and 0.3% to 6.0% per year for the lower limbs. Impaired mobility, presence of neurologic diseases, and older age were the leading independent risk factors for the development of new joint contractures. CONCLUSIONS AND IMPLICATIONS: Joint contractures are highly prevalent among residents admitted to the LTC facilities, and many residents develop new contractures during the first 5 years of their admission. Immobility appears to be the main modifiable risk factor. Further studies are needed to identify potential strategies to prevent new contractures in this vulnerable group.

Clinical Radiological and Molecular Profile of a Patient Affected With Multicentric Osteolysis Nodulosis and Arthropathy.

Multicentric Osteolysis Nodulosis and Arthropathy (MONA) is an ultra-rare multisystem autosomal recessive disorder characterized by progressive osteolysis, subcutaneous nodules and developing arthropathy. The characteristic radiological signs combined with symptoms resembling juvenile idiopathic arthritis (JIA) set the diagnosis, which is established either by measuring matrix metalloproteinase-2 (MMP-2) enzyme activity through electrophoresis (zymography) or genomic testing. We report the clinical and radiographic findings of a 14-year-old girl with molecularly proven MONA, who presented with painless osteolytic changes of the feet and upper extremities and developed hip arthritis. To this day, no specific therapy has been identified with proven long term relief and control of the disease progression.

A Severe Case of Infantile Systemic Hyalinosis in an Asian Child: A Product of Consanguinity.

Infantile systemic hyalinosis (ISH) is a rare, autosomal recessive disorder characterized by widespread abnormal growth of hyalinized fibrous tissue in skin and mucosae. The typical clinical picture consists of the development of joint contractures, skin lesions, and severe, chronic pain. We report the case of a 2-year-old Pakistani girl, who presented to our clinic with papulonodular lesions, gingival hyperplasia, hypotonia, and joint contractures. Skin biopsy revealed hyaline deposits, and genetic testing revealed a mutation in the protein Anthrax toxin receptor 2 (ANTXR2).

Psychometric validation of the Chinese version of the PaArticular Scales among elderly residents in long-term care facilities with joint contractures.

BACKGROUND: Joint contractures, which affect activity, participation, and quality of life, are common complications of neurological conditions among elderly residents in long-term care facilities. This study examined the reliability and validity of the Chinese version of the PaArticular Scales in a population with joint contractures. METHODS: A cross-sectional study design was used. The sample included elderly residents older than 64 years with joint contractures in an important joint who had lived at one of 12 long-term care facilities in Taiwan for more than 6 months (N = 243). The Chinese version of the PaArticular Scales for joint contractures was generated from the English version through five stages: translation, review, back-translation, review by a panel of specialists, and a pretest. Test-retest reliability, internal consistency reliability, construct validity, and criterion validity were evaluated, and the results were compared with those for the World Health Organization Quality of Life scale and the World Health Organization Disability Assessment Schedule. RESULTS: The Chinese version of the PaArticular Scales had excellent reliability, with a Cronbach α coefficient of 0.975 (mean score, 28.98; standard deviation, 17.34). An exploratory factor analysis showed three factors and one factor with an eigenvalue > 1 that explained 75.176 and 62.83 % of the total variance in the Activity subscale and Participation subscale, respectively. The subscale-to-total scale correlation analysis showed Pearson correlation coefficients of 0.881 for the Activity subscale and 0.843 for the Participation subscale. Pearson's product-moment correlation revealed that the correlation coefficient (r) between the Chinese version of the PaArticular Scales and the World Health Organization Disability Assessment Schedule was 0.770, whereas that for the World Health Organization Quality of Life scale was - 0.553; these values were interpreted as large coefficients. CONCLUSIONS: The underlying theoretical model of the Chinese version of the PaArticular Scales functions well in Taiwan and has acceptable levels of reliability and validity. However, the Chinese version must be further tested for applicability and generalizability in future studies, preferably with a larger sample and in different clinical domains.

Hyaline fibromatosis syndrome: A rare case of multifocal intra-articular involvement.

Hyaline fibromatosis syndrome (HFS) is a rare, progressive, autosomal recessive disorder that presents with connective tissue deposition of amorphous hyaline material within the musculocutaneous tissue and/or visceral organs. HFS presents clinically in infancy or early childhood and can result in severe disability and life threatening complications. Given the rarity of the disorder, the imaging characteristics of HFS are seldom described in the literature. We describe a case of a 25-year-old patient presenting with bilateral knee pain, limited range of motion in her extremities, and lower extremity weakness with detailed MR imaging demonstrating the first case of multifocal intra-articular deposition of hyaline material within several joints.

Implementation of a complex intervention to improve participation in older people with joint contractures living in nursing homes: a process evaluation of a cluster-randomised pilot trial.

BACKGROUND: Joint contractures in frail older people are associated with serious restrictions in participation. We developed the Participation Enabling CAre in Nursing (PECAN) intervention, a complex intervention to enable nurses to promote participation in nursing home residents with joint contractures. The aim of this study was to examine the feasibility of the implementation strategy and to identify enablers and barriers for a successful implementation. METHODS: The implementation of PECAN was investigated in a 6-month pilot cluster-randomised controlled trial (c-RCT). As a key component of the implementation strategy, nominated nurses were trained as facilitators in a one-day workshop and supported by peer-mentoring (visit, telephone counselling). A mixed-methods approach was conducted in conjunction with the pilot trial and guided by a framework for process evaluations of c-RCTs. Data were collected using standardised questionnaires (nursing staff), documentation forms, problem-centred qualitative interviews (facilitators, therapists, social workers, relatives, peer-mentors), and a group discussion (facilitators). A set of predefined criteria on the nursing home level was examined. Quantitative data were analysed using descriptive statistics. Qualitative data were analysed using directed content analysis. RESULTS: Seven nursing homes (n = 4 intervention groups, n = 3 control groups) in two regions of Germany took part in the study. Facilitators responded well to the qualification measures (workshop participation: 14/14; workshop rating: "good"; peer-mentor visit participation: 10/14). The usage of peer-mentoring via telephone varied (one to seven contacts per nursing home). Our implementation strategy was not successful in connection with supplying the intervention to all the nurses. The clear commitment of the entire nursing home and the respect for the expertise of different healthcare professionals were emphasised as enablers, whereas a lack of impact on organisational conditions and routines and a lack of time and staff competence were mentioned as barriers. CONCLUSION: The PECAN intervention was delivered as planned to the facilitators but was unable to produce comprehensive changes in the nursing homes and subsequently for the residents. Strategies to systematically include the management and the nursing team from the beginning are needed to support the facilitators during implementation in the main trial. TRIAL REGISTRATION: German clinical trials register, DRKS00010037 . Registered 12 February 2016.

Compound heterozygous mutation of MUSK causing fetal akinesia deformation sequence syndrome: A case report.

BACKGROUND: Fetal akinesia deformation sequence (FADS) is a broad spectrum disorder with absent fetal movements as the unifying feature. The etiology of FADS is heterogeneous and mostly still unknown. A prenatal diagnosis of FADS relies on clinical features obtained by ultrasound and fetal muscle pathology. However, the recent advances of next-generation sequencing (NGS) can effectively provide a definitive molecular diagnosis. CASE SUMMARY: A fetus presented after 24 wk and 6 d of gestation with absent fetal movements and multiple abnormal ultrasonographic signs. The mother had had a previous abortion due to a similarly affected fetus a year before. A clinical diagnosis of FADS was made. The parents refused cord blood examination and chose abortion. A molecular diagnosis of fetal muscle using NGS of genes found a compound heterozygous mutation in the MUSK gene: c.220C > T (chr9: 113449410 p.R74W) and c.421delC (chr9: 113457745 p.P141fs). CONCLUSION: To our knowledge, this is the first report in China showing that a mutation in MUSK is associated with FADS. This supports previous finding that a lethal mutation of MUSK will cause FADS. A precise molecular diagnosis for genetic counseling and options for a prenatal diagnosis of FADS are very important, especially for recurrent FADS; this may also provide evidence for both prenatal and preimplantation genetic diagnoses.

Facio-scapulo-humeral muscular dystrophy with early joint contractures and rigid spine.

Early joint contractures in childhood or adolescence irrespective of muscle weakness are usually found in Emery-Dreifuss muscular dystrophy and collagen-VI related diseases and only rarely in the early stages of other progressive muscular dystrophies. We report a patient presenting severe elbow contractures and a rigid-spine since his early childhood without any evident muscle weakness, who was diagnosed with facioscapulohumeral muscular dystrophy later in life. This case is interesting since there has been no report, to date, of patients with a phenotype resembling facioscapulohumeral muscular dystrophy also in association with early and prominent elbow contractures and spinal rigidity, since childhood, resembling Emery-Dreifuss muscular dystrophy. Our case further confirmed the phenotypic variability often observed in carriers of D4Z4 reduce allele, and highlights the complexity of a definitive diagnosis in these cases.

A novel mutation in the matrix metallopeptidase 2 coding gene associated with intrafamilial variability of multicentric osteolysis, nodulosis, and arthropathy.

BACKGROUND: MONA, which stands for a spectrum of Multicentric Osteolysis, subcutaneous Nodulosis, and Athropathia, is an ultra rare autosomal recessive disorder caused by mutations in the matrix metallopeptidase 2 (MMP2) gene. To date only 44 individuals, carrying 22 different mutations have been reported. Here we report on two brothers with identical homozygous MMP2 gene mutations, but with clearly different phenotypes. METHODS: Genomic DNA was isolated from the affected brothers and the parents. An iliac crest bone biopsy was taken from the younger patient (index case). The level of matrix metallopeptidase 2 enzyme (MMP2) in serum and synovial fluid of the younger patient was analyzed using gelatin zymography. RESULTS: The DNA analysis revealed a homozygous c.1188C>A transversion on exon 8 of the gene. The affected brothers had the same homozygous variant and the parents were heterozygous to this variant. This variant has been reported as a compound heterozygous mutation on one individual resulting in scleroderma like skin thickening. Bone histomorphometry indicated increased trabecular bone remodeling and turnover. The zymography revealed that the level of MMP2 was completely nonmeasurable in the serum and only a minor gelatinolytic protein band of about similar molecular weight as MMP2 was found in the synovial fluid. CONCLUSIONS: Both the age at the onset and the phenotypic severity of the syndrome in these two brothers were different despite identical genotypes. The younger patients had corneal opacities leading to deteriorating visual acuity. For the first time in this disease, opacities were successfully treated with corneal transplantations.

Improved participation of older people with joint contractures living in nursing homes: feasibility of study procedures in a cluster-randomised pilot trial.

BACKGROUND: Acquired joint contractures have a significant impact on functioning and quality of life in nursing home residents. There is very limited evidence on measures for prevention and treatment of disability due to joint contractures. We have developed the PECAN intervention (Participation Enabling CAre in Nursing) to improve social participation in nursing home residents. A cluster-randomised pilot trial was conducted to assess the feasibility of study procedures in preparation for a main trial according to the UK Medical Research Council (MRC) framework. METHODS: Nursing homes in two regions of Germany were randomly allocated either to the intervention or optimised standard care (control group). All residents with joint contractures aged > 65 years were eligible for the study. The residents' data were collected through structured face-to-face interviews by blinded assessors at baseline, after 3 and 6 months. The primary outcome was social participation, measured by a subscale of the PaArticular Scales. Secondary outcomes included activities and instrumental activities of daily living, health-related quality of life, falls and fall-related consequences. Data on the trial feasibility were collected via documentation forms. RESULTS: Seven out of 12 nursing homes agreed to participate and remained in the trial. Of 265 residents who fulfilled the inclusion criteria, 129 were randomised either to the intervention (n = 64) or control group (n = 65) and analysed. A total of 109 (85%) completed the trial after 6 months. The mean age was 85.7 years (SD 7.0), 80% were women. The severity of the residents' disability differed across the clusters. The completion rate was high (> 95%), apart from the Instrumental Activities of Daily Living Scale. Some items of the PaArticular Scales were not easily understood by residents. The frequency of falls did not differ between study groups. CONCLUSION: Our data confirmed the feasibility of the overall study design. We also revealed the need to improve the procedures for the recruitment of residents and for data collection before implementation into a main trial. The next step will be an adequately powered main trial to assess the effectiveness and cost-effectiveness of the intervention. TRIAL REGISTRATION: German clinical trials register, ID: DRKS00010037 . Registered on 12 February 2016.

Effectiveness of a complex intervention to improve participation and activities in nursing home residents with joint contractures (JointConEval): study protocol of a multicentre cluster-randomised controlled trial [DRKS-ID:DRKS00015185].

BACKGROUND: Nursing home residents are frequently affected by joint contractures, which impacts their participation and daily activities. A complex intervention, the Participation Enabling Care in Nursing (PECAN), was previously developed and pilot tested to address their needs. Its effectiveness and safety will be evaluated in the present study. METHODS/DESIGN: This multicentre cluster-randomised controlled trial will be conducted in 32 nursing homes spread over two regions of Germany. A total of 578 residents over 65 years old with joint contractures will be included. To compare the effect of the PECAN intervention with optimised standard care (usual care and an information session), randomisation will take place at a cluster level. The individually tailored intervention was designed using the biopsychosocial model in the International Classification of Functioning, Disability and Health (ICF) to reduce activity limitations and participation restrictions resulting from existing joint contractures by addressing barriers and by strengthening supportive factors on an individual level and an organisational level. The implementation strategy comprises a facilitators' workshop, a peer mentoring approach including a peer mentor visit and telephone peer counselling, an in-house information event, an information session for the nursing team and a training session on collegial consultation for the facilitators. The in-house information event will also take place in the nursing homes of the control group. The primary outcome is the residents' participation and activities after 12 months of follow-up as assessed using the PaArticular Scales. The secondary outcome is the residents' quality of life. A cost-effectiveness analysis (costs per additional resident who experienced a decrease of ten points in the participation or activities subscale of the PaArticular Scales) and a cost-utility analysis (costs per additional quality adjusted life year) will be conducted. We will investigate barriers and facilitators in a comprehensive process evaluation. DISCUSSION: We expect a clinically relevant improvement of participation and activities in residents with joint contractures. Our findings will provide important insights regarding participation in the situation of the affected individuals. TRIAL REGISTRATION: DRKS, DRKS00015185 . Registered on 1 August 2018. Universal Trial Number U1111-1218-1555. Registered on 26 July 2018.

Bethlem myopathy: a series of 16 patients and description of seven new associated mutations.

BACKGROUND: Bethlem myopathy represents the milder phenotype of collagen type VI-related myopathies. However, clinical manifestations are highly variable among patients and no phenotype-genotype correlation has been described. We aim to analyse the clinical, pathological and genetic features of a series of patients with Bethlem myopathy, and we describe seven new mutations. METHODS: A series of 16 patients with the diagnosis of Bethlem myopathy were analyzed retrospectively from their medical records for clinical, creatine kinase (CK), muscle biopsy, and muscle magnetic resonance (MRI) data. Genetic testing was performed through next-generation sequencing of custom amplicon-based targeted genes panel of myopathies. Mutations were confirmed by Sanger sequencing. RESULTS: The most frequent phenotype consisted of proximal limb weakness associated with interphalangeal and wrists contractures. However, cases with isolated contractures or isolated myopathy were found. CK levels did not correlate with severity of the disease. The most frequent mutation was the COL6A3 variant c.7447A>G, p.Lys2486Glu, with either an homozygous or compound heterozygous presentation. Five new mutations were found in COL6A1 gene and other two in COL6A3 gene, all of them with a dominant heritability pattern. From these, a new COL6A1 mutation (c.1657G>A, p.Glu553Arg) was related to an oligosymptomatic phenotype with predominating contractures in the absence of weakness and a normal muscle MRI. Finally, the most common COL6A1 mutation reported to date that leads to an Ullrich phenotype (c. 868G>A, p.Gly290Arg), has been found here as Bethlem presentation. CONCLUSIONS: Manifestations of Bethlem myopathy are quite variable, so either contractures or weakness may be lacking, and no phenotype-genotype associations can be brought.

Growth impairment and limited range of joint motion in children should raise suspicion of an attenuated form of mucopolysaccharidosis: expert opinion.

Growth impairment together with bone and joint involvement is common to most patients with mucopolysaccharidosis (MPS) disorders. The genetic basis for these metabolic disorders involves various enzyme deficiencies responsible for the catabolism of glycosaminoglycans (GAGs). The incomplete degradation and subsequent accumulation of GAGs result in progressive tissue damage throughout the body. Bone ossification is particularly affected, with the consequent onset of dysostosis multiplex which is the underlying cause of short stature. Joint manifestations, whether joint contractures (MPS I, II, VI, VII) or hyperlaxity (MPS IV), affect fine motor skills and quality of life. Subtle decreases in growth velocity can begin as early as 2-4 years of age. Pediatricians are in the front line to recognize or suspect MPS. However, given the rarity of the disorders and variable ages of symptom onset depending on disease severity, recognition and diagnostic delays remain a challenge, especially for the attenuated forms. Prompt diagnosis and treatment can prevent irreversible disease outcomes.Conclusion: We present a diagnostic algorithm based on growth velocity decline and bone and joint involvement designed to help pediatricians recognize early manifestations of attenuated forms of MPS. We illustrate the paper with examples of abnormal growth curves and subtle radiographic nuances. What is Known: • As mucopolysaccharidoses (MPSs) are rare genetic disorders infrequently seen in clinical practice, there can be a lag between symptom onset and diagnosis, especially of attenuated forms of the disease. • This highlights the need for increased disease awareness to recognize early clinical signs and subsequently initiate early treatment to improve outcomes (normal height potential) and possibly prevent or delay the development of irreversible disease manifestations. What is New: • Growth impairment co-presenting with limited range of joint motion and radiographic anomalies in children should raise suspicions of possible attenuated MPS (AMPS). • Experts present a diagnostic algorithm with detailed focus on the decline in growth velocity, delayed puberty and limitation in joint mobility seen in children with AMPS, to shorten time-to-diagnosis and treatment and potentially improve patient outcome.