Contracture Syndrome Research Articles

The pronator contracture syndrome: A new entity in supination restriction.

Forearm rotation is essential for daily activities and functional dexterity, involving both pronation and supination. Forearm rotation limitations can result from various pathologies, often linked to trauma, structural changes in radio-ulnar joints, and interosseous membrane alterations. Soft tissue contracture, such as post-burn scarring or specific neurological conditions, can also restrict forearm rotation. We present two cases of painless restricted passive and active supination, devoid of bony, neurovascular, soft tissue, or congenital abnormalities. We describe a surgical technique to improve forearm rotation in these patients.

Novel PIP5K1C variant identified in a Chinese pedigree with lethal congenital contractural syndrome 3

BackgroundBiallelic pathogenic variants in PIP5K1C (MIM #606,102) lead to lethal congenital contractural syndrome 3 (LCCS3, MIM #611,369), a rare autosomal recessive genetic disorder characterized by small gestational age, severe multiple joint contractures and muscle atrophy, early death due to respiratory failure. Currently, 5 individuals with LCCS3 were reported and 5 pathogenic variants in PIP5K1C were identified. Here, we reported the two fetuses in a Chinese pedigree who displayed multiple joint contractures and other congenital anomalies.MethodsTrio-based whole-exome sequencing (WES) was performed for the parents and the recent fetus to detect the genetic cause for fetus phenotype.ResultsA novel variant, NM_012398.3: c.949_952dup, p.S318Ifs*28 and a previously reported variant, c.688_689del, p.G230Qfs*114 (ClinVar database) in PIP5K1C, were detected in the individuals, and these variants were inherited from the mother and father, respectively. We described the features of multiple joint contractures in our fetuses, including bilateral talipes equinovarus, stiffness in the limbs, extended knees, persistently closed hands and overlapping fingers, which have not been delineated detailedly in previously reported LCCS3 individuals. Furthermore, novel phenotype, bilateral dilated lateral ventricles, was revealed in one fetus.ConclusionsThese findings expanded the genetic variant spectrum of PIP5K1C and enriched the clinical features of LCCS3, which will help with the prenatal diagnosis and genetic counseling for this family.

Prenatal diagnosis of fetal neurogenic megacystis associated with lethal congenital contractural syndrome 2

Abstract Objectives To describe the prenatal diagnosis, unique clinical features, clinical and genetic evaluation, and the pregnancy and neonatal course of two siblings affected by Lethal Congenital Contractural Syndrome 2 (LCCS2). Case presentation We present two cases of LCCS2, a rare autosomal recessive disorder in the arthrogryposis multiplex spectrum of syndromes whose sine qua non feature is the presence of nonobstructive, neurogenic megacystis. The prenatal diagnosis of this syndrome has not been previously reported. This syndrome has been previously studied in detail in an Israeli-Bedouin kindred but it has not been reported in the Americas. Conclusions These two cases illustrate the diagnostic and therapeutic dilemmas associated with this rare genetic abnormality. LCCS2 can be seen in other patient populations besides Israeli-Bedouin. They also suggest the presence of phenotypic variability in the clinical outcomes. Finally, they underscore the need for specialized diagnostic capabilities, the involvement of multidisciplinary teams to support challenging family situations, and the need for shared decision-making.

Minimal Brain Dysfunction, Syndrome of Contractures and Deformities, SoCalled Idiopathic Scoliosis, Problem of Hips and Knees-in 12 Points and 12 Figures

In the article we describe causes and symptoms of 1/ Minimal Brain Dysfunction, the symptoms of 2/ the Syndrome of Contractures and Deformities, 3/ the etiology of the So-Called Idiopathic Scoliosis and present some problems of 4/ hips, knees and ankle joint. The article presents also the rules of prophylaxis and therapy for hips in children and in adults as well proper therapy of the So-Called Idiopathic Scoliosis.

Musculoskeletal defects associated with myosin heavy chain‐embryonic loss of function are mediated by the YAP signaling pathway

Mutations in MYH3, the gene encoding the developmental myosin heavy chain‐embryonic (MyHC‐embryonic) skeletal muscle‐specific contractile protein, cause several congenital contracture syndromes. Among these, recessive loss‐of‐function MYH3 mutations lead to spondylocarpotarsal synostosis (SCTS), characterized by vertebral fusions and scoliosis. We find that Myh3 germline knockout adult mice display SCTS phenotypes such as scoliosis and vertebral fusion, in addition to reduced body weight, muscle weight, myofiber size, and grip strength. Myh3 knockout mice also exhibit changes in muscle fiber type, altered satellite cell numbers and increased muscle fibrosis. A mass spectrometric analysis of embryonic skeletal muscle from Myh3 knockouts identified integrin signaling and cytoskeletal regulation as the most affected pathways. These pathways are closely connected to the mechanosensing Yes‐associated protein (YAP) transcriptional regulator, which we found to be significantly activated in the skeletal muscle of Myh3 knockout mice. To test whether increased YAP signaling might underlie the musculoskeletal defects in Myh3 knockout mice, we treated these mice with CA3, a small molecule inhibitor of YAP signaling. This led to increased muscle fiber size, rescue of most muscle fiber type alterations, normalization of the satellite cell marker Pax7 levels, increased grip strength, reduced fibrosis, and decline in scoliosis in Myh3 knockout mice. Thus, increased YAP activation underlies the musculoskeletal defects seen in Myh3 knockout mice, indicating its significance as a key pathway to target in SCTS and other MYH3‐related congenital syndromes.

Minimal Brain Dysfunctions (MBD): Causes, Clinical Symptoms - Deformity of The Feet, Knees, Hips, Pelvis and Spine Physiotherapy

In the pathology of children, from the orthopedic point of view, there commonly occur problems connected with the Syndrome of Contractures and Deformities described by Professor Hans May from Germany. His observations have been made between 1960 and 1980, additionally, in this subject, there are observations from Lublin (Tomasz Karski and Jacek Karski) from 1995-2023. The second group of causes of pathologies in children which if not properly treated, can also occur in adults leading to problems of locomotor system disorders connected with abnormalities of the Central Nervous System – Minimal Brain Dysfunction (MBD). This article is devoted to the MBD problems.

“Confounding Contractures” A Non-Lethal Presentation of a Lethal Disorder (P11-9.010)

<h3>Objective:</h3> N/A <h3>Background:</h3> The arthrogryposes are a group of non-progressive conditions characterised by multiple joint contractures at birth. They are a heterogenous group of disorders with multiple neurogenic, myopathic and connective tissue aetiologies. The Lethal Congenital Contracture Syndromes (LCCS) are a rare cause of arthrogryposis and are associated with significant perinatal pulmonary abnormalities such as pulmonary hypolasia and high mortality in the neonatal period. <h3>Design/Methods:</h3> We report the case of a 25 year old female who presented at birth with multiple lower limb contractures, bilateral talipes and hip fractures/dislocations. There was no evidence of any cardiorespiratory compromise in the neonatal period. The patient’s early life was dominated by extensive orthopaedic interventions for lower limb contractures and scoliosis, but she had an otherwise unremarkable development with no evidence of cardiac or pulmonary complications and no evidence of intellectual disability. There was a history of an early neonatal death in a brother with a similar phenotype, however no underlying cause was established. Examination demonstrated areflexia but no discernible weakness. <h3>Results:</h3> A muscle biopsy at 3 months showed non-specific myopathic features, but was normal on repeat biopsy aged 21. EMG showed subtle chronic myopathic features. Targeted genetic analysis with congenital myopathy and arthrogryposis panel was unrevealing. Proceeding to whole exome sequencing revealed a homozygous pathogenic variant in the GLDN gene, confirming the diagnosis of Lethal Congenital Contracture Syndrome type 11. <h3>Conclusions:</h3> Despite the diagnosis, which is commonly fatal in the neonatal period, the patient has survived well into adulthood and functioning at a high level independently with no evidence of any pulmonary complications. This highlights a previously unreported case of an adult patient with LCCS 11 without evidence of respiratory compromise, while also highlighting the value of broad genetic testing in this cohort. <b>Disclosure:</b> Dr. Mullane has nothing to disclose. Dr. Donlon has nothing to disclose. Dr. Smyth has nothing to disclose.

Diagnostic work-up and phenotypic characteristics of a family with variable severity of distal arthrogryposis type 2B (Sheldon-Hall syndrome) and TNNT3 pathogenic variant.

Background: Sheldon-Hall syndrome (SHS) or distal arthrogryposis 2B (DA2B) is a rare clinically and genetically heterogeneous multiple congenital contracture syndrome characterized by contractures of the distal joints of the limbs and mild facial involvement, due to pathogenic variants in genes encoding the fast-twitch skeletal muscle contractile myofiber complex (TNNT3, TNNI2, TMP2, and MYH3 genes). Patients and methods: A 16-year-old boy with a history of congenital distal arthrogryposis developed severe kyphoscoliosis and respiratory insufficiency. His mother and younger sister had phenotypes compatible with SHS but to a much lesser extent. Diagnostic work-up included physical examination and whole-body muscular MRI (WBMRI) in all three patients and electroneuromyography (ENMG) and paravertebral muscle biopsy in the proband. DNA sequencing was used to confirm the diagnosis. Results: Physical examination suggested the diagnosis of SHS. No muscle signal abnormalities were found in WBMRI. Large motor unit potentials and reduced recruitment suggestive of neurogenic changes were observed on needle EMG in distal and paravertebral muscles in the proband. DNA sequencing revealed a pathogenic variant in TNNT3 (c.187C>T), which segregated as a dominant trait with the phenotype. Discussion: This is the first report on neurogenic features in a patient with DA2B and a pathogenic variant in TNNT3 encoding the fast-twitch skeletal muscle contractile myofiber complex. A superimposed length-dependent motor nerve involvement was unexpected. Whether developmental disarrangements in number, distribution, or innervation of the motor unit in fetal life might lead to pseudo-neurogenic EMG features warrants further studies, as well as the role of genetic modifiers in SHS variability.

Syndrome of Contractures and Deformities (SofCD): Dysplasia of Hips, Varus Deformity of Shanks, Wry Neck, So-Called Idiopathic Scoliosis Causes Clinic Prophylaxis Therapy

In the article we present one of two main etiopathological groups of pathology of locomotor system. The health of the adults very often depends on the effectiveness of prophylaxis and proper treatment of disorders in the childhood. The treatment of children often can be easy and give good results, what is important for all years of life of everybody. In our experience, the abnormalities described in article are very frequent, due to various reasons. In the article we present one of the causes of pathology.

Novel variants of NEK9 associated with neonatal arthrogryposis: Two case reports and a literature review.

Objective: Pathogenic variants in NEK9 (MIM: 609798) have been identified in patients with lethal congenital contracture syndrome 10 (OMIM: 617022) and arthrogryposis, Perthes disease, and upward gaze palsy (APUG and OMIM: 614262). The shared core phenotype is multiple joint contractures or arthrogryposis. In the present study, three novel variants of NEK9 associated with neonatal arthrogryposis were reported. Methods: The clinical data of two premature infants and their parents were collected. The genomic DNA was extracted from their peripheral blood samples and subjected to trio-whole-exome sequencing (trio-WES) and copy number variation analysis. Results: Using trio-WES, a total of three novel pathogenic variants of NEK9 were detected in the two families. Patient 1 carried compound heterozygous variations of c.717C > A (p. C239*741) and c.2824delA (p.M942Cfs*21), which were inherited from his father and mother, respectively. Patient 2 also carried compound heterozygous variations of c.61G > T (p. E21*959) and c. 2824delA (p. M942Cfs*21), which were inherited from his father and mother, respectively. These variants have not been previously reported in the ClinVar, HGMD, or gnomAD databases. Conclusion: This is the first report about NEK9-related arthrogryposis in neonatal patients. The findings from this study suggest that different types of mutations in NEK9 lead to different phenotypes. Our study expanded the clinical phenotype spectrum and gene spectrum of NEK9-associated arthrogryposis.

Fat grafting in autologous breast reconstruction: applications, outcomes, safety, and complications

Autologous fat grafting is an important surgical technique in aesthetic and reconstructive procedures. Fat grafting for breast reconstruction is now an established procedure for adding volume and improving cutaneous pliability; it can be used independently to replace more invasive flap procedures or implants, or as an adjunct for smaller volume supplementation. The breadth of applications in the breast necessitates diversity in technique and approach, and while there is no universally agreed-upon protocol, basic principles have guided the evolution of some commonly adopted tenets. Broadly, fat grafting outcomes are highly favorable but dependent on patient and procedure factors, requiring learned patient selection and expertise in recipient site assessment. Common complications from fat grafting, such as fat necrosis and the development of nodules, are particularly troublesome for post-oncologic patients, requiring considerable pre-surgical consultation for patient education and managing expectations. In addition to volume and contour augmentation, fat grafting has additional beneficial effects that have recently drawn increased attention including pain reduction from implant capsular contracture or post-mastectomy pain syndrome, improved skin quality and reduced fibrosis following radiation, and possible anti-tumorigenic effects. New developments in clinical fat grafting research that are promising include the use of adipose progenitor cells admixed with lipoaspirate for improved volume retention or alternative biologics such as platelet-rich plasma. Preclinically, research towards safe and effective regenerative medicine approaches is actively underway, with the ultimate goal of achieving predictable and increased graft retention, reducing the number of required surgical procedures and enabling on-table results to reflect procedure outcomes.

Manipulation under Anesthesia versus Non-Surgical Treatment for Patients with Frozen Shoulder Contracture Syndrome: A Systematic Review.

Purpose: To investigate the efficacy of manipulation under anesthesia (MUA) compared to other non-surgical therapeutic strategies for patients with frozen shoulder contracture syndrome (FSCS). Methods: A systematic review of literature was conducted. A literature search was performed in MEDLINE, EMBASE, PEDro, Cochrane Central Library and Scopus. Only randomized controlled trials were included and assessed for critical appraisal through the Cochrane Collaborations tools. Results: Five randomized controlled trials were included. The overall risk of bias (RoB) was high in 4 out of 5 of the included studies. MUA was found to be not superior in terms of reduction of pain and improvement of function when compared to cortisone injections with hydrodilatation (mean regression coefficient MUA −2.77 vs. injection −2.75; 95% CI (−1.11 to 1.15)) and home exercise (mean difference 95% CI: 0.2 (−0.64 to 1.02)) in the short term (3 months), and cortisone injections with hydrodilatation (mean regression coefficient MUA 3.13 vs. injection 3.23; 95% CI (−0.90 to 1.11)) in the long term (>6 months). Moreover, if compared to structured physiotherapy, MUA highlighted a higher Oxford Shoulder Score at final 1-year follow up (mean difference 95% CI: 1.05 (−1.28 to 3.39); p = 0.38). Similar results were obtained for disability, with statistically no significant long-term (>12 months) differences between MUA and home exercise (mean difference 95% CI: 0 (−3.2 to 3.2)) or structured physiotherapy (mean difference 95% CI: −0.50 (−5.70 to 4.70); p = 0.85)). Only two trials reported adverse events. Conclusions: This review suggested that limited and inconsistent evidence currently exists on the efficacy of MUA compared to other non-surgical strategies in the management of patients with FSCS. Future research should focus on clinical trials with higher methodological quality.

Carrying both COL1A2 and FBN2 gene heterozygous mutations results in a severe skeletal clinical phenotype: an affected family

BackgroundOsteogenesis imperfecta (OI) is the most common monogenic disease of the skeletal system and is usually caused by mutations in the COL1A1 or COL1A2 genes. Congenital contractural arachnodactyly syndrome (CCA) is an autosomal dominant hereditary disease of connective tissue. To date, the FBN2 gene is the only gene reported to cause CCA. Researchers found that COL1A2 and FBN2 are both involved in the extracellular matrix organization pathway. These findings suggest that these two genes play an important role in a similar mechanism and may trigger a synergistic effect.MethodsTrio-whole-exome sequencing (Trio-WES) was performed to analyse the underlying genetic cause of a proband with OI in a Chinese family. Sanger sequencing was used to validate the mutations in 3 members of the family with OI with varying degrees of severity of skeletal abnormalities and the members with no clinical signs.ResultA c.3304G > C mutation in the COL1A2 gene (p.Gly1102Arg) and a novel c.4108G > T mutation in the FBN2 gene (p.Glu1370*) were detected in the proband, an affected member of the family. The affected individuals with both mutations present a more severe phenotype, while affected individuals present a milder phenotype if only the mutation in COL1A2 is detected (c.3304G > C). The unaffected individual in this family did not have any mutations in the COL1A2 gene or FBN2 gene.ConclusionOur study is the first clinical report to indicate that patients carrying concomitant mutations in both the COL1A2 and FBN2 genes may present with more severe skeletal abnormalities. Furthermore, our study suggests the possibility of synergistic effects between the COL1A2 and FBN2 genes.

Diabetes mellitus tendino-myopathy: epidemiology, clinical features, diagnosis and management of an overlooked diabetic complication.

Tendino-myopathy, an unexplored niche, is a non-vascular unstated T2DM complication, which is largely disregarded in clinical practice, thus, we aim to explore it in this review. Literature search using published data from different online resources. Epidemiologically, reported prevalence varies around 10-90%, which is marked variable and unreliable. Clinically, diabetic tendino-myopathy is typified by restriction of movement, pain/tenderness, cramps and decreased functions. Moreover, myopathy is characterized by muscle atrophy, weakness and ischemia, and tendinopathy by deformities and reduced functions/precision. In tendonapthy, the three most affected regions are: the hand (cheiroarthropathy, Dupuytren's contracture, flexor tenosynovitis and carpel tunnel syndrome), shoulder (adhesive capsulitis, rotator cuff tendinopathy and tenosynovitis) and foot (Achilles tendinopathy with the risk of tear/rupture), in addition to diffuse idiopathic skeletal hyperostosis. Pathologically, it is characterized by decreased muscle fiber mass and increased fibrosis, with marked extracellular matrix remodeling and deposition of collagens. The tendon changes include decreased collagen fibril diameter, changed morphology, increased packing and disorganization, with overall thickening, and calcification. Diagnosis is basically clinical and radiological, while diagnostic biomarkers are awaited. Management is done by diabetes control, special nutrition and physiotherapy, while analgesics, steroids and surgery are used in tendinopathy. Several antisarcopenic drugs are in the pipeline. This review aims to bridge clinical practice with research and update routine diabetic checkup by inclusion of tendino-myopathies in the list with an emphasis on management.

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.

EP.TH.177Safety profile of SurgiMend Acellular Dermal Matrix and Mentor implant assisted immediate breast reconstruction – Our experience at the Princess Royal University Hospital

Abstract Background ADM (Acellular Dermal Matrix) assisted implant-based immediate breast reconstruction (IBR) is a common technique worldwide. Various ADMs are available manufactured from different sources. The Surgimend ADM (fetal bovine dermis) is fenestrated and rich in type I/III collagen; it is claimed to reduce fluid accumulation and promote healing. Methods Retrospective observational analysis exploring safety profile using combination of SurgiMend MacroPorous (MP)/SurgiMend PRS and Mentor CPG/Mentor Siltex implants between January 2018 to December 2019. Patients with unilateral/bilateral IBR following Nipple sparing (NSM) or Skin sparing mastectomy (SSM) were included. The primary outcome was minor complications (seroma (&amp;gt;100ml on USS), hematoma, wound infection and infected seromas). Secondary outcome was major complications (flap necrosis, capsular contracture, implant explantation and Red Breast Syndrome). Results Six (16.2%) bilateral and 31 (83.8%) unilateral IBR were performed in 37 patients. Mean age was 53.78 years. No major complications were recorded. Conclusions The Surgimend ADM and Mentor implant combination demonstrate a good safety profile. Higher rates of seroma in this study could be explained by overdiagnosis and treatment at our unit, which in turn might imply as a result that no major complications were detected and no implant loss.

Models of Distal Arthrogryposis and Lethal Congenital Contracture Syndrome.

Distal arthrogryposis and lethal congenital contracture syndromes describe a broad group of disorders that share congenital limb contractures in common. While skeletal muscle sarcomeric genes comprise many of the first genes identified for Distal Arthrogyposis, other mechanisms of disease have been demonstrated, including key effects on peripheral nerve function. While Distal Arthrogryposis and Lethal Congenital Contracture Syndromes display superficial similarities in phenotype, the underlying mechanisms for these conditions are diverse but overlapping. In this review, we discuss the important insights gained into these human genetic diseases resulting from in vitro molecular studies and in vivo models in fruit fly, zebrafish, and mice.

The Role of Mutations on Gene WNT, in Dupuytren Contracture Syndrome

Dupuytren contracture, also known as Dupuytren disease, is a progressive fibrosing disorder of the fingers and palm of the hand. It results in the development of nodules and thickened cords in the palmar fascia that may lead to contractures. In the later stages, structural changes also involve flexion contractures of the joints. Dupuytren contracture is a relatively common disorder that occurs with advancing age. About 5-15% of Caucasian men over the age of 50 years are affected. There is a higher incidence of Dupuytren contracture in younger men than in women, but there is no significant difference in incidence between the sexes by the ninth decade of life. It is rare in Asians and African Americans. Dupuytren contracture may be inherited as a familial condition or it may occur sporadically. The reason for the dose-dependent association of alcoholism and cigarette smoking with Dupuytren contracture is not understood. The incidence of Dupuytren contracture is 2-5 times higher in manual labourers than in-office workers, possibly due to repetitive movements and vibration. The association with epilepsy has been reported inconsistently and may be due to anti-epileptic medications.

O que significa “Mão Diabética” e qual o papel da Saúde Ocupacional?

Introduction / background / objective As the workforce ages and rates of metabolic diseases increase, it is likely that more cases of “diabetic hand” manifestations will appear in Occupational Health services. While some health professionals know how to quickly track the “diabetic foot”, the “diabetic hand” is often undervalued, diagnosed in isolation, without recognition or association with the high prevalence of metabolic syndrome, especially in the Western world. These manifestations have an impact on functionality, and inevitably affect work performance, and should be subject to screening, monitoring and intervention by occupational health teams, in order to enhance the function and minimize the negative impacts that they cause both individually and collectively. Thus, the main objective of this work is to elaborate a review on the concept of “diabetic hand” and what is the implication that it can have in the worker’s health and Occupational Health practice. Methodology It is a Scoping Review, initiated through a search in the PUBMED (Medline), EBSCO (Cinahl; Medline; Cochrane; Library Information Science &amp; Technology Abstracts; Nursing Allied Health Collection; MedicLatina) and RCAAP databases, conducted in the months of July and August of 2020, covering all articles (in Portuguese and English languages), with no limit of time, that could explain the concept of diabetic hand. The search words used were: “diabetic hand” ou “cheiroarthropathy”. Results Several conditions have been linked to the concept of diabetic hand, namely cheiroarthropathy (limited joint mobility and stiffness), Dupuytren’s contracture, trigger finger (flexor stenosing tenosynovitis), and carpal tunnel syndrome. Conclusions These manifestations share mechanisms with the classic complications of diabetes, and the recognition that microvascular changes occur concomitantly may provide insights for early screening of metabolic biomarkers. Acknowledging so can contribute to reduce disability (delay hand and fist related manifestations’ progression), and also to reduce future morbidity of workers (minimizing the risks of metabolic diseases), helping to maintain a more capable and productive workforce, where corrective measures and early treatments can be implemented. The diabetic hand may be a concept of interest, then can be further addressed soon, as the complications of metabolic syndrome (and associated comorbidities) increase worldwide.

CONGENITAL MYOPATHIES 2: P.93 Novel TTN variants identified by whole exome sequencing in patients with prenatal onset titinopathy

The TTN gene encodes the largest human protein, titin, which is of functional and structural importance at the sarcomere. Pathogenic variants in TTN have been reported for a variety of skeletal muscle disorders and cardiomyopathies and exhibit both autosomal dominant and recessive inheritance. Next generation sequencing (NGS) and whole exome sequencing (WES) have allowed for routine sequencing of a large number of genes, including the full TTN gene. These advancements have helped to delineate the phenotypic spectrum in patients with mutations in several neuromuscular genes, including TTN. In 2014, the first patient with arthrogryposis multiplex congenita (AMC) and pathogenic variants in TTN was reported, but additional published cases are limited. Utilizing WES, we have identified four unrelated cases in which the proband presented prenatally or neonatally with features suggestive of a severe neuromuscular condition such as polyhydramnios, hydrops fetalis, talipes equinovarus, arthrogryposis, hypotonia, and/or respiratory insufficiency. In one of these cases, the maternal family history was also suggestive for dilated cardiomyopathy in two siblings. Case one - homozygous c.25063+1G>A (I-band). Case two - c.100296dup (p.Glu33433*, M-band) and c.36402del (p.Val12135Cysfs*23, I-band). Case three - c.38442dupA (p.Pro12815Thrfs*37, I-band) and c.88594+1G>T (A-band). Case four has a maternally inherited c.61921C>T (p.Arg20641*, A-band); however, a second paternal variant was not identified. Although truncating variants in the Z-disc, I-band and M-band in TTN may not confer cardiomyopathy risk, some of these variants may be pathogenic for severe, recessive neuromuscular conditions. TTN variants, in particular protein truncating variants, should be considered in cases of lethal congenital contracture syndrome, AMC, congenital myopathies, and hydrops fetalis. These cases expand our knowledge and understanding of the more severe phenotypic spectrum for titinopathies.