Arthrogryposis Research Articles

A novel heterozygous TPM2 gene mutation (c.456G>C; p.Lys152Asn) in an Iranian family affected by distal arthrogryposis type 1: a case report

BackgroundDistal arthrogryposis (DA) is a group of clinically and genetically heterogeneous disorders characterized by congenital contractures of the distal limb joints without a neuromuscular disease. This case study seeks to report an affected son from an Iranian family with a diagnosis of DA1 with a rare causative genetic defect.Case presentationHerein, we aimed to figure out the underlying genetic of the subject from an Iranian family with DA1. Whole-exome sequencing (WES) of all known DA1 genes was carried out in the proband of the family. WES identified a novel missense mutation, c.456G>C; p.Lys152Asn, within the TPM2 gene, causing a change in one amino acid (Lysine converted to Asparagine). Moreover, this detected variant was confirmed by Sanger sequencing.ConclusionOur data expand the mutational spectra of TPM2 gene associated DA1 which is vital for screening and genetic diagnosis of the disease. Also, this detected mutation has not yet been described in patients with the DA1 phenotype.

EP448: Multiple pregnancies with fetal akinesia deformation sequence caused by variants in MUSK

Fetal akinesia deformation sequence (FADS), also known as Pena-Shokier Syndrome, is a clinical manifestation of arthrogryposis, abnormal facial features, and pulmonary hypoplasia, and demonstrates a high degree of genetic heterogeneity. Variants within the genes that are involved in the neuromuscular system are most frequently involved. One gene in particular, MUSK, is involved in the formation and maintenance of the neuromuscular junction. Biallelic loss of function variants in this gene have been documented by 5 affected fetuses in a Swedish family and an affected fetus in a Dutch family.

EP454: Fetal exome sequencing for recurrent arthrogryposis identifies a potentially causative variant in the TOR1A gene: A case report

Arthrogryposis multiplex congenita (AMC) describes the development of nonprogressive congenital contractures affecting two or more areas of the body. AMC affects 1 in 3,000 live births. Its onset varies and ranges from 12 to 30 weeks gestation. AMC has high variable expressivity; signs and symptoms can vary greatly in range and severity, even within a family. In most cases, affected infants have contractures of various joints with those of the legs and arms being the most affected. The joints of the shoulders, elbows, knees, wrists, ankles, fingers, toes, and/or hips are also commonly affected.

Abstract 73: A case report of mitochondrial diabetes. arthrogryposis multiplex congenita, diabetes and deafness

Background: Mitochondrial diseases are caused by genetic defects that occur in either the mitochondrial DNA or the nuclear DNA. The heterogeneity, variable expressivity, age independence, and multiorgan system involvement all often lead to delayed diagnoses. Multiple endocrine complications can arise with mitochondrial disease. Foremost is diabetes, which has a prevalence of 11% to 15% in mitochondrial disorders. Age of diagnosis on average is 32 to 38 years but is variable. Arthrogryposis multiplex congenita refers to a group of conditions including multiple congenital contractures in varied areas of the body. We report a case of 16 years female with Arthrogryposis multiplex congenita who presented with diabetes.Case Report: A 16 years female presented with weight loss, polyuria and random blood sugar of 253 mg/dl. Born to non-consanguineous parents. Antenatal history of mother was uneventful. History of bony contractures was present since birth. There was delay of gross motor development. Intelligence is normal. Height is 132 cm (<3rd centile). Attained menarche at 13 years. Cycles are regular. History of bilateral hearing loss was present since childhood. She was started on basal bolus insulin therapy. The clinical features are pointing towards a form of mitochondrial diabetes with GFM2 mutation, Leigh syndrome.

EP092: Germline mosaicism in severe BICD2-associated lower extremity-predominant spinal muscular atrophy type 2 with arthrogryposis multiplex congenita

Lower extremity-predominant spinal muscular atrophy type 2 (SMALED2) is a progressive muscular atrophy disease caused by heterozygous pathogenic variants in the BICD2 gene. The phenotype of SMALED2 is a spectrum of disease currently subdivided into two subgroups--lower extremity-predominant spinal muscular atrophy type 2A (SMALED2A- MIM# 615290) and 2B (SMALED2B- MIM# 618291). Type 2A is well described with early childhood-onset weakness and atrophy predominantly seen in the lower extremities. Type 2B is more severe, with onset in utero with decreased fetal movement.

EP455: Fetal ultrasound presentation and neonatal diagnosis of Freeman-Sheldon syndrome in son of previously undiagnosed adult male

eP455: Fetal ultrasound presentation and neonatal diagnosis of Freeman-Sheldon syndrome in son of previously undiagnosed adult male

Mild Phenotype of Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome 1 Caused by a Novel VPS33B Variant.

The arthrogryposis, renal dysfunction, and cholestasis syndrome (ARCS) is an autosomal recessive multisystem disease caused by variants in VPS33B or VIPAS39. The classical presentation includes congenital joint contractures, renal tubular dysfunction, cholestasis, and early death. Additional features include ichthyosis, central nervous system malformations, platelet dysfunction, and severe failure to thrive. We studied three patients with cholestasis, increased aminotransferases, normal gamma-glutamyl transferase, and developmental and language delay. Whole exome sequencing analysis identified VPS33B variants in all patients: patients 1 and 2 presented a novel homozygous variant at position c.1148T>A. p.(Ile383Asn), and patient 3 was compound heterozygous for the same c.1148T>A. variant, in addition to the c.940-2A>G. variant. ARCS is compatible with the symptomatology presented by the studied patients. However, most patients that have been described in the literature with ARCS had severe failure to thrive and died in the first 6 months of life. The three patients studied here have a mild ARCS phenotype with prolonged survival. Consequently, we believe that the molecular analysis of the VPS33B and VIPAS39 should be considered in patients with normal gamma-glutamyl transferase cholestasis.

RADIOGRAPH BASED DIAGNOSIS OF ARTHROGRYPOSIS MULTIPLEX CONGENITA

Arthrogryposis multiplex congenita (AMC) is a rare disorder, presenting with multiple contractures and limb deformities. Various theories have been proposed for the development of this congenital anomaly. The final diagnosis is made based upon the clinical signs and imaging findings. This case report aims to outline the imaging features that can help radiologists to make the diagnosis of AMC through radiographs and skeletal survey. Since, very few cases have been reported in literature, no specific treatment protocols have been outlined. Therefore, antenatal diagnosis based on characteristic imaging findings is crucial for early termination and parental counselling.

Expanding the mutation and phenotype spectrum of MYH3-associated skeletal disorders

Pathogenic variants in MYH3 cause distal arthrogryposis type 2A and type 2B3 as well as contractures, pterygia and spondylocarpotarsal fusion syndromes types 1A and 1B. These disorders are ultra-rare and their natural course and phenotypic variability are not well described. In this study, we summarize the clinical features and genetic findings of 17 patients from 10 unrelated families with vertebral malformations caused by dominant or recessive pathogenic variants in MYH3. Twelve novel pathogenic variants in MYH3 (NM_002470.4) were identified: three of them were de novo or inherited in autosomal dominant way and nine were inherited in autosomal recessive way. The patients had vertebral segmentation anomalies accompanied with variable joint contractures, short stature and dysmorphic facial features. There was a significant phenotypic overlap between dominant and recessive MYH3-associated conditions regarding the degree of short stature as well as the number of vertebral fusions. All monoallelic variants caused significantly decreased SMAD3 phosphorylation, which is consistent with the previously proposed pathogenic mechanism of impaired canonical TGF-β signaling. Most of the biallelic variants were predicted to be protein-truncating, while one missense variant c.4244T>G,p.(Leu1415Arg), which was inherited in an autosomal recessive way, was found to alter the phosphorylation level of p38, suggesting an inhibition of the non-canonical pathway of TGF-β signaling. In conclusion, the identification of 12 novel pathogenic variants and overlapping phenotypes in 17 affected individuals from 10 unrelated families expands the mutation and phenotype spectrum of MYH3-associated skeletal disorders. We show that disturbances of canonical or non-canonical TGF-β signaling pathways are involved in pathogenesis of MYH3-associated skeletal fusion (MASF) syndrome.

Analysis of CNTNAP1 gene variants in a Chinese pedigree affected with lethal congenital contracture syndrome type 7

To explore the genetic basis for a couple who had developed polyhydramnios during three pregnancies and given birth to two liveborns featuring limb contracture, dyspnea and neonatal death. Whole-exome sequencing (WES) was carried out on fetal tissue and peripheral blood samples from the couple. Suspected variants were verified by Sanger sequencing. The fetus was found to harbor homozygous nonsense c.3718C>T (p.Arg1240Ter) variants of the CNTNAP1 gene, which were respectively inherited from its mother and father. The variant was unreported previously. According to the guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be pathogenic (PVS1+PM2+PP4). The novel homozygous nonsense variants of the CNTNAP1 gene probably underlay the lethal congenital contracture syndrome type 7 (LCCS7) in this pedigree. Above finding has enabled genetic counseling and prenatal diagnosis for the family.

Prenatal imaging features related to RAC3 pathogenic variant and differential diagnoses.

This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. What's already known about this topic? Six individuals between 5- and 19-year-old were reported with pathogenic variants in RAC3 responsible for brain malformations involving midline What does this study add? RAC3-fetopathy is associated with fetal akinesia deformation sequence, and complex brain malformations including corpus callosum agenesis, diencephalosynapsis, kinked brainstem, and vermian hypoplasia The differential diagnoses with prenatal kinked brainstem include fetopathies related to KIAA1109, L1CAM, Walker-Warburg syndrome and tubulinopathies. The present report adds the RAC3 related condition to this list.

Test\u2013retest reliability for performance-based outcome measures among individuals with arthrogryposis multiplex congenita

BackgroundMost individuals with arthrogryposis multiplex congenita, a rare condition characterized by joint contractures in ≥ 2 body regions, have foot and ankle involvement leading to compromised gait and balance. The purpose of this study was to establish between-days, test–retest reliability for performance-based outcome measures evaluating gait and balance, i.e., the 10-m Walk Test, Figure-of-8 Walk Test, 360-degree Turn Test, and modified Four Square Step Test, among adolescents and adults with arthrogryposis multiplex congenita.MethodsThis reliability study included ambulatory participants, aged 10 to 50 years, with a medical diagnosis of arthrogryposis multiplex congenita. Participants completed performance-based measures, in a randomized order, on two separate occasions. Intraclass correlation coefficients with 95% confidence intervals and minimal detectable changes at the 90% and 95% confidence level were calculated.ResultsParticipants included 38 community-ambulators with a median of 13 out of 14 upper and lower joint regions affected. Intraclass correlation coefficient point estimates and 95% confidence intervals ranged from .85-.97 and .70-.98, respectively. Minimal detectable changes were 10 to 39% of sample means and were largest for the modified Four Square Step Test.ConclusionsAmong individuals with arthrogryposis, gait speed per the 10-m Walk Test, as well as non-linear walking and dynamic balance assessment per the Figure-of-8 Walk and 360 Degree Turn Tests, have adequate test–retest reliability enabling evaluation of individual patient changes. Changes in groups of ambulatory individuals with arthrogryposis multiplex congenita may be reliably evaluated with all of the studied outcome measures.

Art and Paediatric Orthopaedics: A Sixteenth Century Lie-down Comedian.

This outstanding painting, by an unknown artist, of a man with multiple deformities compatible with a diagnosis of arthrogryposis multiplex congenita induces the viewer to think deeply about the artist's portrayal of the subject.

Recessive variants in COL25A1 gene as novel cause of arthrogryposis multiplex congenita with ocular congenital cranial dysinnervation disorder.

A proper interaction between muscle-derived collagen XXV and its motor neuron-derived receptors protein tyrosine phosphatases σ and δ (PTP σ/δ) is indispensable for intramuscular motor innervation. Despite this, thus far, pathogenic recessive variants in the COL25A1 gene had only been detected in a few patients with isolated ocular congenital cranial dysinnervation disorders. Here we describe five patients from three unrelated families with recessive missense and splice site COL25A1 variants presenting with a recognizable phenotype characterized by arthrogryposis multiplex congenita with or without an ocular congenital cranial dysinnervation disorder phenotype. The clinical features of the older patients remained stable over time, without central nervous system involvement. This study extends the phenotypic and genotypic spectrum of COL25A1 related conditions, and further adds to our knowledge of the complex process of intramuscular motor innervation. Our observations indicate a role for collagen XXV in regulating the appropriate innervation not only of extraocular muscles, but also of bulbar, axial, and limb muscles in the human.

Embryonic myosin mutations T187I and R672C result in mechanical and structural dysfunction in hiPSC derived skeletal myotubes

Distal arthrogryposis (DA) is a skeletal muscle disorder characterized by joint contractures at various parts of the body, predominantly in the distal extremities. DA is associated with syndromes like Freeman-Sheldon (FSS), caused by mutations in the sarcomeric protein-encoding gene MYH3 responsible for generating embryonic skeletal muscle myosin during development. We previously reported (Racca et al., 2015) that demembranated myofibrils from affected individuals expressing the R672C mutation in MYH3 exhibited lower specific force and prolonged relaxation.

Functional loss of ubiquitin-specific protease 14 may lead to a novel distal arthrogryposis phenotype.

Multiple congenital contractures (MCC) comprise a number of rare, non-progressive conditions displaying marked phenotypic and etiologic heterogeneity. A genetic cause can be established in approximately half of the affected individuals, attributed to genetic defects in the formation and functioning of the central and peripheral nervous system, neuromuscular junctions, skeletal muscles, and connective tissue. Ubiquitin-specific protease 14 (USP14) encodes a major proteasome-associated deubiquitinating enzyme with an established dual role as an inhibitor and an activator of proteolysis, maintaining protein homeostasis. Usp14-deficient mice show a phenotype similar to lethal human MCC phenotypes, with callosal anomalies, muscle wasting, and early lethality, attributed to neuromuscular junction defects due to decreased monomeric ubiquitin pool. We describe a new, autosomal recessive MCC phenotype in three fetuses from two different branches of a consanguineous family, presenting with distal arthrogryposis, underdevelopment of the corpus callosum, and dysmorphic facial features. Exome sequencing identified a biallelic 4-bp deletion (c.233_236delTTCC; p.Leu78Glnfs*11, SCV002028347) in USP14, and sequencing of family members showed segregation with the phenotype. RT-qPCR experiment in an unaffected heterozygote revealed that mutant USP14 was expressed, indicating that abnormal transcript escapes nonsense-mediated mRNA decay. We propose that herein described fetuses represent the first human phenotype of USP14 loss, with callosal anomalies and/or cortical malformations, multiple contractures, and recognizable dysmorphic facial features.

Intrafamilial Variability of the R694C Variant in BICD2 Presenting with Lethal Severe Arthrogryposis

Arthrogryposis multiplex congenita (AMC) is a heterogeneous condition comprising congenital multiple joint contractures, and it is secondary to decreased fetal mobility following environmental/genetic abnormalities. BICD2 pathogenic variants have been associated with autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED2). We report the case of a newborn with decreased fetal movements and ventriculomegaly diagnosed in utero, born with severe AMC, multiple bone fractures, congenital hip dislocation, and respiratory insufficiency that led to neonatal death. His mother had AMC diagnosis without established etiology. Her phenotype characterization was key to guide the genetic investigation. A BICD 2 heterozygous variant (NM_001003800.1; c.2080C &gt; T; p. [Arg694Cys]) was detected both in the mother and the newborn. This variant had previously been reported in 3 cases, all having de novo severe SMALED-type 2B (MIM#618291) phenotype. This is the first report of this variant (p. [Arg694Cys]) presenting with an inherited, severe, and lethal phenotype associated to intrafamilial variability, suggesting a more complex phenotype-genotype correlation than previously stated.

Rare health conditions 54: arthrogryposis multiplex congenita, Edwards syndrome, and offering spiritual support

The purpose of this series is to highlight a range of rare health conditions. Rare health conditions are those that affect no more and usually fewer than 1 person in every 2000 and many HCAs and nurses will encounter some of these conditions, given the high number of them. This 54th article will examine two of these conditions, arthrogryposis multiplex congenita and Edwards syndrome, along with an exploration of the idea of support staff offering spiritual support to those with rare health conditions and their families.

Physical Rehabilitation Based on International Classification of Functioning, Disability and Health (ICF) Model of a Child with Arthrogryposis Multiplex Congenita

Background: Arthrogryposis Multiplex Congenita (AMC) is a condition used to portray inborn contractures with at least two different body limbs behind a general predominance of 1 out of 3000 at live births. The aim of the study was to provide information about appropriate physical rehabilitation protocol using ICF model for the child with AMC.

En kvinne i 50-årene med langvarig muskelsvakhet

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