Distal Arthrogryposis with Impaired Proprioception and Touch: A Novel Variant in PIEZO2 Gene in Omani Patients and a Genotype-Phenotype Review from a Single-Center Experience.

Distal arthrogryposis with impaired proprioception and touch (DAIPT) is an autosomal recessive neurogenetic disorder caused by homozygous pathogenic variants in the PIEZO2 gene. Here we present four Omani families with multiple affected members with DAIPT. The genetic diagnosis was established by whole exome sequencing and we identified a previously unreported homozygous missense variant PIEZO2 : c.1591T > C, P.(Trp531Arg) in one family with two affected members. All patients showed clinical manifestation shortly after birth including transient respiratory insufficiency, significant hypotonia, and gross motor developmental delay with preserved cognitive function. The skeletal manifestation including arthrogryposis is more pronounced with age as we saw in our older patient. This case report will be of importance for physicians and genetic counsellors for faster diagnosis and for offering carrier testing for at-risk family members as part of the premarital testing program, which could help in reducing the burden of this disorder.

Open reduction for hip dislocation in children with arthrogryposis multiplex congenital: Outcomes of a systematic review.

Introduction: The incidence of hip dislocation (HD) in arthrogryposis multiplex congenital ranges from 15 to 30 %. Besides a stable hip, the ambulation potential of an AMC child is also dependent on severity of associated knee and foot deformations. The primary objective of this review is to determine the proportion of ambulators in AMC children treated by open reduction for HD. Methods: We searched major electronic bibliographic databases for reports on the treatment of HD among AMC children. Based on the surgical approach for open reduction of HD in AMC children, we divided the included studies into groups 1 (Anterior approach open reduction) and 2 (Medial approach open reduction). Results: We pooled 59 children/94 hips in this review from 7 studies. We identified 45 children/71 hips and 14 children/23 hips with a mean age of 20 (4-64) and 4.5 (0.5-11) months in groups 1 and 2, respectively. There were 97 % (44) and 92 %(Obeidat et al., 2011) 13 ambulators in groups 1 and 2, respectively. 47 % and 36 % of hips in groups 1 and 2 required additional procedures besides open reduction for redislocation and maintenance of hip reduction. 31 %22 and 13 %(Fisher et al., 1970 Feb) 3 of the hips sustained avascular necrosis in group 1 and 2. Conclusion: Children with AMC associated HD can be expected to ambulate with and without assistance in 90 % of the cases however, the foot and knee problems also need concomitant management. In children less than 6 months of age the medial approach based open reduction may be more efficacious and less complicating than anterior approach based open reduction however, at a later age anterior approach based open reduction is more effective due to need for pelvic and femur sided additional procedures.

Expansion of the phenotypic spectrum of KARS1-related disorders to include arthrogryposis multiplex congenita and summary of experiences with lysine supplementation.

There are currently multiple disorders of aminoacyl-tRNA synthetases described, including KARS1-related disorder resulting from dysfunctional lysyl-tRNA synthetases. In this report, we describe four novel KARS1 variants in three affected individuals, two of whom displayed arthrogryposis-like phenotypes, suggestive of phenotypic expansion. We also highlight subjective clinical improvement in one subject following lysine supplementation in conjunction with a protein-fortified diet, suggesting its potential as a novel treatment modality for KARS1-related disorders. This report offers additional insight into the etiology and management of KARS1-related disorders and expands our ability to provide guidance to affected individuals and their families.

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

BACKGROUND: ZC4H2-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. METHODS: The 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. RESULTS: Males 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). CONCLUSIONS: Our 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.

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.

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.

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.

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

BACKGROUND: Arthrogryposis 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. METHODS: The 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 CONCLUSION: Five 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.

EVALUATION OF ARTHROGRYPOTIC FOOT TREATMENT: MINIMUM 10 YEARS FOLLOW-UP.

Objective: To evaluate patients with arthrogryposis submitted to extensive surgical treatment with a minimum of 10 years of follow-up regarding the clinical and radiological aspects and the quality of life, using the 36-Item Short Form (SF-36) and the Disease-Specific Instrument (DSI). Methods: A retrospective study selected 33 patients, totaling 64 operated feet. Results: The mean age of the patients was 17.9 years (12-39 years), and the mean follow-up time was 14.8 years (11-17). Amyoplasia represented 78.7% of syndromic diagnoses. Isolated posteromedial lateral release (PMLR) was performed in 21.8% of the feet, 27.2% of which required additional bone surgery, and about 50 feet (78.1%) were submitted to PMLR, lateral column shortening, and/or talectomy. In total, 46 talectomies were performed (71.8% of the feet), out of which 44 were the first procedure of choice. SF-36 questionnaire was evaluated and showed that 93.9% of the patients did not have restrictive and disabling pain, and the same percentage considered themselves as healthy and had good expectations for the future. Conclusion: Arthrogrypotic feet are difficult to treat, require many recurrent surgical procedures, and relapses are the rule. Stiffness is a common feature of these feet, and residual deformities were frequent. Level of Evidence IV; Case Series, Therapeutic Studies.

Objetivo: Avaliar pacientes com artrogripose submetidos a tratamento cirúrgico convencional com um mínimo de 10 anos de seguimento quanto aos aspectos clínicos, radiológicos e qualidade de vida, utilizando o questionário de 36 itens Short Form 36 (SF-36) e o Instrumento específico de Doenças (IED). Método: No estudo retrospectivo foram avaliados 33 pacientes, totalizando 64 pés operados. Resultados: A média de idade foi de 17,9 anos (12-39 anos), e o tempo médio do seguimento foi de 14,8 anos (11-17). A amioplasia representou 78,7% dos diagnósticos sindrômicos. A liberação posteromedial lateral isolada (LP MI) foi realizada em 21,8% dos pés, 27,2%, com cirurgia óssea adicional, e cerca de 50 pés (78,1%) foram submetidos a LPM (liberação póstero medial), encurtamento da coluna lateral e/ou talectomia. Foram realizadas 46 talectomias (71,8% dos pés), sendo em 44 o procedimento de primeira escolha. O questionário SF-36 evidneciou que 93,9% dos pacientes estavam sem dor restritiva e incapacitante, consideravam-se saudáveis, com boas expectativas para o futuro. Conclusão: Os pés artrogripóticos são de difícil tratamento, requerendo muitos procedimentos cirúrgicos recorrentes. A rigidez é uma característica comum desses pés e as deformidades residuais foram frequentes. Estudos futuros poderão mostrar se haverá diferença no resultado do tratamento desses pés aplicando a abordagem inicial atual, mais conservadora. Nível de Evidência: IV; Estudos Terapêuticos; Série de Casos.

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.

Presentation of Rare Phenotypes Associated with the FKBP10 Gene.

Pathogenic variants in the FKBP10 gene lead to a spectrum of rare autosomal recessive phenotypes, including osteogenesis imperfecta (OI) Type XI, Bruck syndrome Type I (BS I), and the congenital arthrogryposis-like phenotype (AG), each with variable clinical manifestations that are crucial for diagnosis. This study analyzed the clinical-genetic characteristics of patients with these conditions, focusing on both known and newly identified FKBP10 variants. We examined data from 15 patients, presenting symptoms of OI and joint contractures. Diagnostic methods included genealogical analysis, clinical assessments, radiography, whole exome sequencing, and direct automated Sanger sequencing. We diagnosed 15 patients with phenotypes due to biallelic FKBP10 variants-4 with OI Type XI, 10 with BS I, and 1 with the AG-like phenotype-demonstrating polymorphism in disease severity. Ten pathogenic FKBP10 variants were identified, including three novel ones, c.1373C>T (p.Pro458Leu), c.21del (p.Pro7fs), and c.831_832insCG (p.Gly278Argfs), and a recurrent variant, c.831dup (p.Gly278Argfs). Variant c.1490G>A (p.Trp497Ter) was found in two unrelated patients, causing OI XI in one and BS I in the other. Additionally, two unrelated patients with BS I and epidermolysis bullosa shared identical homozygous FKBP10 and KRT14 variants. This observation illustrates the diversity of FKBP10-related pathology and the importance of considering the full spectrum of phenotypes in clinical diagnostics.

An Unusual Presentation of Membranous Nephropathy in an Adult With Arthrogryposis: A Case Report.

Membranous nephropathy (MN) is an autoimmune condition that is a common cause of nephrotic syndrome in nondiabetic adults. In this study, we highlight a case of a 22-year-old male with a past medical history of arthrogryposis multiplex congenita (AMC) who initially presented with right flank pain and hematuria. Subsequent workup revealed significant proteinuria with biopsy-proven primary MN. Early detection of the disease is critical to establish treatment promptly and prevent complications such as those resulting from a hypercoagulable state.

A retrospective study on the correction of distal arthrogryposis with a progressive extension brace.

Purpose: Camptodactyly, clasped thumbs, and windblown hands are distinctive features of distal arthrogryposis (DA). Current therapeutic interventions often yield suboptimal effects, predisposing patients to relapses and complications. This study explicates a corrective approach involving a progressive extension brace for the management of DA and evaluates its clinical outcomes. Methods: Between 2015 and 2023, progressive extension braces were used in 32 DA patients, with an average follow-up of 4.8 years. Patients were stratified by age into four groups: 0-1, 1-3, 3-7, and above 7 years. The correction of camptodactyly was assessed based on the total active movement (TAM) of metacarpophalangeal joints (MPJ) and proximal interphalangeal joints (PIPJ), as well as the extensor lag of PIPJ. Clasped thumb correction was evaluated by measuring the thumb-to-index finger metacarpal angle (M1M2 angle) and the degree of deviation at the first MPJ (M1P1 angle). The quality of life for the children was measured using PedsQL 4.0, while parental satisfaction was gauged using the FACE questionnaire. Results: Earlier intervention with a progressive extension brace yielded superior corrective results. Infants aged 0-1 year and toddlers aged 1-3 years achieved average TAM scores of 152° and 126° after correction; however, patients older than 3 years experienced a significant decrease in TAM with the same treatment. Infants and toddlers with DA showed improvement in the average extensor lag from 46° to 6°. The M1M2 angle increased from an average of 38° to 65°, with the M1P1 angle decreasing from an average of 43° to 5°. After the treatment, average PedsQL scores of 94.7 (parent-reported) and 89.3 (child-reported) were achieved. Among the 32 parents, 24 expressed high satisfaction, 5 expressed moderate satisfaction, and 3 expressed fair satisfaction. Conclusion: The early, progressive, and consistent use of an extension brace significantly improved joint mobility and corrected camptodactyly and clasped thumbs. It can be an effective approach to addressing hand deformities in patients with DA.

Arthrogryposis, renal dysfunction, cholestasis syndrome with a novel mutation in two siblings.

This current case series adds to the spectrum of Arthrogryposis renal dysfunction cholestasis (ARC)-associated variants. Increased awareness and early genetic testing for ARC are suggested in cases with failure to thrive, renal tubular dysfunction, and rickets, even when the degree of cholestasis is mild. Prompt identification and intervention may improve the quality of life.

Bilateral Sprengel Deformities, Mirror Movements Synkinesis, and Arthrogryposis Multiplex Congenita: A Novel Combination.

Introduction: Bilateral Sprengel deformities, mirror movements synkinesis, and arthrogryposis are described in different combinations in various syndromes but never together. Case Report: We present a 12-year-old girl who presented with bilateral shoulder deformities and difficulty in coordination while writing. On examination, she was noted to have bilateral Sprengel deformities with flexion contractures of upper-limb joints and mirror movements of both upper and lower-limb joints. Conclusion: In the light of relevant literature, we may speculate that these three have a causal relation and even a genetic basis but further studies are needed to prove the same.

ECEL1 related distal arthrogryposis 5D in an Indian cohort-Report of recognizable musculoskeletal phenotype and a possible founder variant.

Distal arthrogryposis type 5D (DA5D) is clinically characterized by knee extension contractures, distal joint contractures, clubfoot, micrognathia, ptosis, and scoliosis. We report nine affected individuals from eight unrelated Indian families with DA5D. Although the overall musculoskeletal phenotype is not very distinct from other distal arthrogryposis, the presence of fixed knee extension contractures with or without scoliosis could be an important early pointer to DA5D. We also report a possible founder variant in ECEL1 along with four novel variants and further expand the genotypic spectrum of DA5D.

Arthrogryposis multiplex congenita causing hypercapnic respiratory failure and airway obstruction in an adult patient.

This case highlights arthrogryposis multiplex congenita (AMC) as a rare cause of hypercapnoeic respiratory failure and airway obstruction in adults and emphasizes the usage of leak-port in tracheostomy-NIV (non-invasive-ventilation) specially in resource poor setting when the tracheostomy-NIV mask is unavailable.

Bone mineral density in adults with arthrogryposis multiplex congenita: a retrospective cohort analysis.

The primary objective of this study was to evaluate the prevalence of low femoral and lumbar spine bone mineral density (BMD) in adults with arthrogryposis multiplex congenita (AMC). We performed a retrospective cohort analysis of adults with AMC who were enrolled in the French Reference Center for AMC and in the Pediatric and Adult Registry for Arthrogryposis (PARART, NCT05673265). Patients who had undergone dual-energy X-ray absorptiometry (DXA) and/or vitamin D testing were included in the analysis. Fifty-one patients (mean age, 32.9 ± 12.6 years) were included; 46 had undergone DXA. Thirty-two (32/51, 62.7%) patients had Amyoplasia, and 19 (19/51, 37.3%) had other types of AMC (18 distal arthrogryposis, 1 Larsen). Six patients (6/42, 14.3%) had a lumbar BMD Z score less than - 2. The mean lumbar spine Z score (- 0.03 ± 1.6) was not significantly lower than the expected BMD Z score in the general population. Nine (9/40, 22.5%) and 10 (10/40, 25.0%) patients had femoral neck and total hip BMD Z scores less than - 2, respectively. The mean femoral neck (- 1.1 ± 1.1) and total hip (- 1.2 ± 1.2) BMD Z scores in patients with AMC were significantly lower than expected in the general population (p < 0.001). Femoral neck BMD correlated with height (rs = 0.39, p = 0.01), age (rs = - 0.315, p = 0.48); total hip BMD correlated with height (rs = 0.331, p = 0.04) and calcium levels (rs = 0.41, p = 0.04). Twenty-five patients (25/51, 49.0%) reported 39 fractures. Thirty-one (31/36, 86.1%) patients had 25-hydroxyvitamin D levels less than 75 nmol/l, and 6 (6/36, 16.7%) had 25-hydroxyvitamin D levels less than 75 nmol/l. Adults with AMC had lower hip BMD than expected for their age, and they more frequently showed vitamin D insufficiency. Screening for low BMD by DXA and adding vitamin D supplementation when vitamin D status is insufficient should be considered in adults with AMC, especially if there is a history of falls or fractures.

A Case Report: Can Prioritizing Sensory Integration Therapy Help Improve Gross Motor Function in a Rare Case of Neurogenic Arthrogryposis Multiplex Congenita?

Arthrogryposis multiplex congenital (AMC) is a congenital disorder diagnosed with extremity contractures, restricted joint range of motion, foot abnormalities, and hip dislocation. The current literature emphasizes medical and surgical management, but very few studies provide insight into physiotherapy management for AMC. We reported the case of a 16-month-old male diagnosed with AMC, operated on both hips for teratologic dislocation. Physiotherapy examination was conducted, and treatment was planned based on the principles of Sensory Integration Therapy (SIT) and neurodevelopmental technique (NDT) with orthosis to assist in functional recovery. He achieved motor milestones within one year of regular physiotherapy treatment. As per our literature search, this is the first study where an attempt has been made to utilize sensory integration along with NDT for the treatment of AMC, although the clinical presentation of the patient shows more musculoskeletal abnormalities.

Pregnancy in myasthenia gravis: a retrospective analysis of maternal and neonatal outcome from a large tertiary care centre in Germany.

PURPOSE: Myasthenia gravis (MG) is a rare, potentially life-threatening autoimmune disease with fluctuating muscle weakness frequently affecting women of childbearing age. MG can affect maternal as well as neonatal outcome with risk of worsening of myasthenic symptoms in the mothers and risk of transient neonatal myasthenia gravis (TNMG) and arthrogryposis multiplex congenita (AMC) or foetal acetylcholine receptor antibody-associated disorders (FARAD) in the neonates. METHODS: Retrospective analysis of maternal and neonatal outcome in a cohort of pregnant MG patients treated at a tertiary care centre in Germany. RESULTS: Overall, 66 pregnancies were analysed. During 40 (63%) pregnancies, women experienced a worsening of myasthenic symptoms, of whom 10 patients (15.7%) needed acute therapy with IVIg or plasma exchange. There was no case of myasthenic crisis. Rate of caesarean section was comparable to the overall C-section rate at our centre (38% vs. 40%). However, there was a slightly higher rate for operative vaginal delivery (15% vs. 10%) as potential indicator for fatiguing striated musculature in MG patients during the expulsion stage. Rate of TNMG as well as AMC was 3% (two cases each). CONCLUSIONS: Maternal and neonatal outcome in our cohort was favourable with a low rate of myasthenic exacerbations requiring acute therapies and a low rate of TNMG and AMC/FARAD. Our data might help neurologists and obstetricians to advice MG patients with desire to have children.