Multiple Congenital Contractures Research Articles

Arthrogryposis is a descriptive term, not a specific disease entity: Escobar Syndrome is an example.

Children born with multiple congenital contractures have been almost always given the diagnosis of arthrogryposis multiplex congenita. Arthrogryposis is a descriptive term, not a specific disease entity. A heterogeneous group of conditions associated with multiple congenital joint contractures (mostly syndromic) should be considered. The records of seven children (four boys and three girls aged 6 months - 11 years) of different ethnic origins have been included in this study. The constellation of specific craniofacial dysmorphic features, spine malformation complex, and appendicular skeletal abnormalities in addition to camptodactyly, talipes equinovarus and rocker-bottom feet were a cluster of malformation complex encountered in our patients. Via comprehensive clinical and imaging study (3D reconstruction CT scan), definite diagnosis of Escobar Syndrome has been approached. The clinical and imaging phenotype was the key factor towards etiological understanding, treatment and genotype confirmation. We identified compound heterozygous mutations (c.459dupA [p.Val154Serfs*24] and c.794T>G [p.Leu265Serfs*24] of the CHRNG gene in four patients. Bilateral flexion contractures of the knees have been treated by using Iliazarov external fixator. Simultaneous corrections of scoliosis have been achieved by applying either dual traditional growing rods or single growing rods. The clinical and radiological phenotypic characterizations are the fundamental tool in differentiating Escobar from other forms of multiple contractures. The aim of this study are three folds, firstly to demonstrate the importance of detecting the etiological understanding in children presented with multiple contractures, secondly to refute the general conception among the vast majority of pediatricians and orthopedic surgeons that arthrogryposis multiplex is a diagnostic entity. And thirdly, we were able to detect severe spine deformity via 3D reconstruction CT scan, namely unsegmented posterior spinal bar.

Clinical and molecular characteristics of 26 fetuses with lethal multiple congenital contractures.

Multiple congenital contractures (MCC) due to fetal akinesia manifest across a broad spectrum of diseases, ranging from mild distal arthrogryposis to lethal fetal akinesia deformation sequence. We hereby present a series of 26 fetuses displaying severe MCC phenotypes from 18 families and describe detailed prenatal ultrasound findings, postmortem clinical evaluations, and genetic investigations. Most common prenatal findings were abnormal facial profile (65%), central nervous system abnormalities (62%), polyhydramnios (50%), increased nuchal translucency (50%), and fetal hydrops (35%). Postmortem examinations unveiled additional anomalies including facial dysmorphisms, dysplastic skeletal changes, ichthyosis, multiple pterygia, and myopathy, allowing preliminary diagnosis of particular Mendelian disorders in multiple patients. Evaluation of the parents revealed maternal grip myotonia in one family. By exome sequencing and targeted testing, we identified causative variants in ACTC1, CHST14, COG6, DMPK, DOK7, HSPG2, KLHL7, KLHL40, KIAA1109, NEB, PSAT1, RAPSN, USP14, and WASHC5 in 15 families, and one patient with a plausible diagnosis associated with biallelic NEB variants. Three patients received a dual diagnosis. Pathogenic alterations in newly discovered genes or in previously known genes recently linked to new MCC phenotypes were observed in 44% of the cohort. Our results provide new insights into the clinical and molecular landscape of lethal MCC phenotypes.

Features of Congenital Arthrogryposis Due to Abnormalities in Collagen Homeostasis, a Scoping Review.

Congenital arthrogryposis (CA) refers to the presence of multiple contractures at birth. It is a feature of several inherited syndromes, notable amongst them are disorders of collagen formation. This review aims to characterize disorders that directly or indirectly impact collagen structure and function leading to CA in search for common phenotypic or pathophysiological features, possible genotype-phenotype correlation, and potential novel treatment approaches based on a better understanding of the underlying pathomechanism. Nine genes, corresponding to five clinical phenotypes, were identified after a literature search. The most notable trend was the extreme phenotype variability. Clinical features across all syndromes ranged from subtle with minimal congenital contractures, to severe with multiple congenital contractures and extra-articular features including skin, respiratory, or other manifestations. Five of the identified genes were involved in the function of the Lysyl Hydroxylase 2 or 3 enzymes, which enable the hydroxylation and/or glycosylation of lysyl residues to allow the formation of the collagen superstructure. Whilst current treatment approaches are post-natal surgical correction, there are also potential in-utero therapies being developed. Cyclosporin A showed promise in treating collagen VI disorders although there is an associated risk of immunosuppression. The treatments that could be in the clinical trials soon are the splice correction therapies in collagen VI-related disorders.

A RARE CASE OF PRENATAL DIAGNOSIS OF ARTHROGRYPOSIS MULTIPLEX CONGENITA

It is challenging to diagnose antenatal identification of fetuses with multiple congenital contractures or arthrogryposis multiplex congenita (AMC) .The first clinical sign is often reduced fetal movement and/or contractures, as seen on prenatal ultrasounds. This can be apparent at any point, from early to late pregnancy, may range from mild to severe involvement, with or without associated other structural anomalies. Possible etiologies and their prognosis need to be interpreted with respect to developmental timing. Essentially, the severity of the disease is based on the number of joints involved. We report a case of a 17-year-old primigarvida woman who visited a tertiary care hospital in for routine antenatal scans. No movement with reduced muscle mass was seen in all the limbs. The hip joints was fixed and flexed in position whereas the knee joints were in an persistent extended position along with severe talipus deformity . All presenting features were indicative of AMC ,poor prognosis of baby and correlated with the post delivery examination of baby.

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.

Arthrogryposis Multiplex Congenita (AMC): Functional Improvement of a Seven-Year-Old Girl after 3 Years of Physical Medical Rehabilitation Intervention

Arthrogryposis multiplex congenita (AMC) is a genetic disease typified by non-progressive and multiple congenital limb contractures. The incidence of AMC is 1 in 3,000 live births, occurring in two or more areas of the body. The etiology of the syndrome is largely unknown and is multifactorial. The aim of this article is to report a patient diagnosed with arthrogryposis multiplex congenita who received physical medical rehabilitation intervention. We report a seven-year-old girl who frequently had symptoms of joint deformities, movement limitation, and walking difficulties. The patient's fingers and toes also had muscle hypoplasia and pterygium. She was diagnosed with arthrogryposis when she was born. Several surgical interventions had been performed. Since four years old the patient started the physical medical rehabilitation programs. Owing to the integrated orthopedic and medical rehabilitation therapy, it showed some improvements. The patient could walk by holding onto a bench and eat or drink by herself. The patient had obtained the daily living exercises using the correct compensation technique using modified tools. Physical medical rehabilitation programs can improve the functional condition of AMC patients. The goals of a physical medical rehabilitation treatment are to gain the walking ability and improve the ability to independently perform activities of daily living. Stretching exercises, ROM exercises, splints, modified tools, and orthopedic surgery are essential for arthrogryposis patients.

Fetal arthrogryposis-what do we tell the prospective parents?

Arthrogryposis, also termed arthrogryposis multiplex congenita, is a descriptive term for conditions with multiple congenital contractures (MCC). The etiology is extremely heterogeneous. More than 400 specific disorders have been identified so far, which may lead to or are associated with MCC and/or fetal hypo- and akinesia as a clinical sign. With improved sensitivity of prenatal ultrasound and expanding prenatal diagnostic options, clinicians are tasked with providing early detection in order to counsel the prospective parents regarding further prenatal diagnostic as well as management options. We summarize the most important knowledge to raise awareness for early detection in pregnancy. We review essential points for counseling when MCC is detected in order to provide answers to common questions, which, however, cannot replace interdisciplinary expert opinion in the individual case.

Profile of Arthrogryposis Multiplex Congenita (AMC) patients on surgery treatment at single centered study in orthopaedic hospital and a brief review

Introduction: Arthrogryposis multiplex congenita (AMC) is a complex abnormal condition characterized by multiple congenital contractures in the body's joints. Although this condition is not progressive, if not treated properly, it will increase the degree of disability in children. There are two types of AMC. The most common type of AMC is amyoplasia. The second type is distal arthrogryposis (DA), a genetically inherited type characterized by congenital contractures in multiple joints and no neurologic or muscular abnormalities. The incidence of AMC 1:3000 births with clubfeet and congenital hip dislocation is the most common. In this retrospective study, the authors described the profile of AMC patients who underwent surgery at our center with the approach and management. Method: The study design was a descriptive retrospective. The population of this study is all AMC patients who underwent surgery at the orthopedic hospital of Prof. Soeharso Surakarta, Indonesia. We used the total sampling technique who underwent surgery in the 2018-2021 period. Result: In this study, we got eleven AMC patients who underwent surgery. Distribution based on sex found six boys and five girls. Half of the patients underwent surgery under the age of three years, while the other half underwent surgery after the age of five. The presence of patients who are consulted at an older age indicates a lack of public literacy about the abnormal condition of AMC or a lack of concern for the condition. Almost all AMC patients who undergo surgery are in the lower extremities. Conclusion: Rehabilitation plays a very important role in improving the quality of life for AMC patients. A multidisciplinary approach is needed in the treatment of AMC patients. Surgery is performed if stretching and external support splinting/casting cannot achieve functional ROM and repair the deformity.

Epidemiology, aetiology, interventions and genomics in children with arthrogryposis multiplex congenita: protocol for a multisite registry

IntroductionArthrogryposis multiplex congenita (AMC) is an umbrella term including hundreds of conditions with the common clinical manifestation of multiple congenital contractures. AMC affects 1 in 3000 live births and is...

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.

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.

Clinical and Genetic Findings in a Series of Eight Families with Arthrogryposis

The term “arthrogryposis” is used to indicate multiple congenital contractures affecting two or more areas of the body. Arthrogryposis is the consequence of an impairment of embryofetal neuromuscular function and development. The causes of arthrogryposis are multiple, and in newborns, it is difficult to predict the molecular defect as well as the clinical evolution just based on clinical findings. We studied a consecutive series of 13 participants who had amyoplasia, distal arthrogryposis (DA), or syndromic forms of arthrogryposis with normal intellectual development and other motor abilities. The underlying pathogenic variants were identified in 11 out of 13 participants. Correlating the genotype with the clinical features indicated that prenatal findings were specific for DA; this was helpful to identify familial cases, but features were non-specific for the involved gene. Perinatal clinical findings were similar among the participants, except for amyoplasia. Dilatation of the aortic root led to the diagnosis of Loeys–Dietz syndrome (LDS) in one case. The phenotype of DA type 5D (DA5D) and Escobar syndrome became more characteristic at later ages due to more pronounced pterygia. Follow-up indicated that DA type 1 (DA1)/DA type 2B (DA2B) spectrum and LDS had a more favorable course than the other forms. Hand clenching and talipes equinovarus/rocker bottom foot showed an improvement in all participants, and adducted thumb resolved in all forms except in amyoplasia. The combination of clinical evaluation with Next Generation Sequencing (NGS) analysis in the newborn may allow for an early diagnosis and, particularly in the DAs, suggests a favorable prognosis.

Bruck syndrome: A rare case presentation with isolated lower extremity contractures and multiple postoperative peri-implant fractures

Bruck syndrome, characterized by congenital brittle bones and multiple joint contractures, is a rare variant of osteogenesis imperfecta. Here, we report the case of a 7-year-old male patient who presented with a fractured shaft of the femur following trivial trauma. He was diagnosed case of arthrogryposis multiplex congenital with deformities involving both knees and ankle. He had a history of bilateral femoral fractures during birth. Due to the knee contracture and a narrow canal, we fixed the fracture by plating. However, the patient developed peri-implant fractures proximal to the plate. Due to the presence of multiple peri-implant fractures and joint contractures, we diagnosed the patient with Bruck’s syndrome and initiated intravenous bisphosphonate therapy. Subsequently, the patient developed one more fracture in the contralateral femur. This case signifies the importance of screening all patients with multiple congenital contractures and recurrent fractures for Bruck syndrome.

Clinical and molecular features of 66 patients with musculocontractural Ehlers−Danlos syndrome caused by pathogenic variants in CHST14 (mcEDS-CHST14)

BackgroundMusculocontractural Ehlers−Danlos syndrome is caused by biallelic loss-of-function variants in CHST14 (mcEDS-CHST14) or DSE (mcEDS-DSE). Although 48 patients in 33 families with mcEDS-CHST14 have been reported, the spectrum of pathogenic...

CONGENITAL MUSCULAR DYSTROPHIES: P.203 Recessive variants in COL25A1 are responsible for arthrogryposis multiplex congenita with an ocular congenital cranial dysinnervation disorder

Arthrogryposis multiplex congenita (AMC) is an extremely heterogeneous congenital disorder characterized by reduced fetal mobility and multiple congenital contractures at birth, occurring in 1/300-1/5000 newborns. AMC have various etiologies, including environmental and genetic causes such as neurological and neuromuscular disorders. Genetic diagnosis of AMC remains challenging. Here we present two unrelated patients from UK (pt 1) and USA (pt 2) with AMC due to recessive COL25A1 gene variants, a known cause of ocular congenital cranial dysinnervation disorder (CCDDs).

Arthrogryposis Multiplex Congenita.

Arthrogryposis multiplex congenita (AMC) is a complex, etiologically diverse, clinical descriptor identified in a variety of diagnoses characterized by multiple congenital joint contractures. The root cause of AMC is decreased fetal movement in-utero, whether resulting from maternal or pregnancy influences, nervous system pathology, or an underlying genetic abnormality. Prenatal diagnosis via ultrasonography can be challenging and may require additional imaging techniques or studies. After birth, these infants may require assistance breathing and feeding depending on the underlying diagnosis. Physical therapy and surgical intervention of the contractures are the mainstays of therapy, and outcomes can be good when intervention is provided in a timely manner. Those infants with syndromic causes of arthrogryposis are more likely to have poor outcomes; therefore, determining the underlying etiology for AMC is important as this can influence counseling regarding individual prognosis as well as future pregnancies. [Pediatr Ann. 2020;49(7):e299-e304.].

Arthrogryposis is a descriptive term, not a specific disease entity: escobar syndrome is an Example.

Children born with multiple congenital contractures have been almost always given the diagnosis of arthrogryposis multiplex congenita. Arthrogryposis is a descriptive term, not a specific disease entity. A heterogeneous group of conditions associated with multiple congenital joint contractures (mostly syndromic) should be considered. The records of seven children (four boys and three girls with aged 6months- 11 years) of different ethnic origins have been included in this study. The constellation of specific craniofacial dysmorphic features, spine malformation complex, and appendicular skeletal abnormalities in addition to camptodactyly, talipes equinovarus and rocker- bottom feet were a cluster of malformation complex encountered in our patients. Via comprehensive clinical and imaging study (3D reconstruction CT scan), definite diagnosis of Escobar syndrome has been approached. The clinical and imaging phenotype was the key factor towards etiological understanding, treatment and genotype confirmation. We identified compound heterozygous mutations (c.459dupA [p.Val154Serfs*24] and c.794T>G [p.Leu265Serfs*24] of the CHRNG gene in four patients. Bilateral flexion contractures of the knees have been treated by using Iliazarov external fixator. Simultaneous corrections of scoliosis have been achieved by applying either dual traditional growing rods or single growing rods. The clinical and radiological phenotypic characterizations are the fundamental tool in differentiating Escobar from other forms of multiple contractures. The aim of this study are three folds, firstly to demonstrate the importance of detecting the etiological understanding in children presented with multiple contractures, secondly to refute the general conception among the vast majority of pediatricians and orthopedic surgeons that arthrogryposis multiplex is a diagnostic entity. And thirdly, we were able to detect severe spine deformity via 3D reconstruction CT scan, namely unsegmented posterior spinal bar.

Management of severe congenital flexion deformity of the knee using Ilizarov method.

The aim of this study was to examine the effectiveness of Ilizarov method in severe congenital flexion deformity of the knee. This was a retrospective study of eight consecutive bilateral cases (five girls and three boys, with mean age of 4 years, involving 16 knees) with minimum 2-year follow-up. Four patients had multiple congenital contractures and two patients each had popliteal pterygium syndrome and complete tibial hemimelia. All patients were treated with Ilizarov fixator and gradual correction (additional soft tissue releases in three knees). Six patients had bilateral foot and ankle deformity treated with the same fixator, and cases with tibial hemimelia had centralization of fibula and quadriceps reconstruction. Flexion deformity could be corrected in all cases. Mean duration of dynamic phase was 78.5 (55-108) days, that of static phase was 42.4 (7-100) days, and total duration of external fixation was 120.9 (87-186) days. At mean follow-up of 34.5 (23-60) months, flexion deformity improved from the preoperative value of 74.9° (50°-130°) to 13.7° (10°-16°), and passive arc of motion of knee improved from the preoperative value of 38.8° (20°-55°) to 83.6° (55°-110°). Both were statistically significant (P < 0.0001). All patients (previously nonambulatory) were ambulatory with brace and support. All patients faced pin-tract and skin complications that were successfully managed. Ilizarov method is effective in severe congenital flexion deformity of the knee in improving ambulatory status. Realignment of quadriceps mechanism and limb mechanical axis (including ankle and foot deformities) must be given due importance. Minor recurrences of deformity must be expected in all cases.

Freeman-Sheldon syndrome - a course of the disease from birth to adulthood

Freeman-Sheldon syndrome, also known as Whistling Face syndrome, is a rare disorder associated with multiple congenital contractures. In this report, we present the course of the disease from the neonatal period to adulthood in one female patient and discuss the gynecological abnormalities and other medical problems that were encountered.

Lower Limb Amyoplasia in a Filipino Female: A Case Report and a Review of the Literature

Amyoplasia is the most common form of arthrogryposis (multiple congenital contracture). &nbsp;It&nbsp;has an estimated incidence of one in 10,000 live births. Lower limb- Amyoplasia is a specific subtype with an estimated incidence of 1 in 75,000 - 100,000 live births. There are only 85 cases of lower limb Amyoplasia identified in literature, and there are no published cases from the Philippines. &nbsp;We discuss a rare case of lower limb Amyoplasia in an 11-year-old Filipino female presenting with additional unique features of severe scoliosis (managed with spine correction surgery) and multiple skin dimples in the gluteal area.&nbsp;The study was performed according to the CARE guidelines for case reports.