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

2021 ◽  
pp. jmedgenet-2020-107623
Author(s):  
Mari Minatogawa ◽  
Ai Unzaki ◽  
Hiroko Morisaki ◽  
Delfien Syx ◽  
Tohru Sonoda ◽  
...  
Keyword(s):  
Collaborative Study ◽  
Joint Hypermobility ◽  
Loss Of Function ◽  
Multisystem Disorder ◽  
Ehlers Danlos Syndrome ◽  
Molecular Features ◽  
Pathogenic Variants ◽  
International Collaborations ◽  
Delayed Closure ◽  
Danlos Syndrome

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 variants, accurate prevalence of various manifestations and detailed natural history have not been systematically investigated.MethodsWe collected detailed and comprehensive clinical and molecular information regarding previously reported and newly identified patients with mcEDS-CHST14 through international collaborations.ResultsSixty-six patients in 48 families (33 males/females; 0–59 years), including 18 newly reported patients, were evaluated. Japanese was the predominant ethnicity (27 families), associated with three recurrent variants. No apparent genotype–phenotype correlation was noted. Specific craniofacial (large fontanelle with delayed closure, downslanting palpebral fissures and hypertelorism), skeletal (characteristic finger morphologies, joint hypermobility, multiple congenital contractures, progressive talipes deformities and recurrent joint dislocation), cutaneous (hyperextensibility, fine/acrogeria-like/wrinkling palmar creases and bruisability) and ocular (refractive errors) features were observed in most patients (>90%). Large subcutaneous haematomas, constipation, cryptorchidism, hypotonia and motor developmental delay were also common (>80%). Median ages at the initial episode of dislocation or large subcutaneous haematoma were both 6 years. Nine patients died; their median age was 12 years. Several features, including joint and skin characteristics (hypermobility/extensibility and fragility), were significantly more frequent in patients with mcEDS-CHST14 than in eight reported patients with mcEDS-DSE.ConclusionThis first international collaborative study of mcEDS-CHST14 demonstrated that the subtype represents a multisystem disorder with unique set of clinical phenotypes consisting of multiple malformations and progressive fragility-related manifestations; these require lifelong, multidisciplinary healthcare approaches.

scholarly journals Transcriptome Profiling of Primary Skin Fibroblasts Reveal Distinct Molecular Features Between PLOD1- and FKBP14-Kyphoscoliotic Ehlers–Danlos Syndrome

Genes ◽  
2019 ◽  
Vol 10 (7) ◽  
pp. 517 ◽  
Author(s):  
Lim ◽  
Lindert ◽  
Opitz ◽  
Hausser ◽  
Rohrbach ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Protein Trafficking ◽  
Treatment Strategies ◽  
Transcriptome Profiling ◽  
Joint Hypermobility ◽  
Skin Fibroblasts ◽  
Ehlers Danlos Syndrome ◽  
Molecular Features ◽  
Extracellular Matrix Components ◽  
Danlos Syndrome

Kyphoscoliotic Ehlers–Danlos Syndrome (kEDS) is a rare genetic heterogeneous disease clinically characterized by congenital muscle hypotonia, kyphoscoliosis, and joint hypermobility. kEDS is caused by biallelic pathogenic variants in either PLOD1 or FKBP14. PLOD1 encodes the lysyl hydroxylase 1 enzyme responsible for hydroxylating lysyl residues in the collagen helix, which undergo glycosylation and form crosslinks in the extracellular matrix thus contributing to collagen fibril strength. FKBP14 encodes a peptidyl-prolyl cis–trans isomerase that catalyzes collagen folding and acts as a chaperone for types III, VI, and X collagen. Despite genetic heterogeneity, affected patients with mutations in either PLOD1 or FKBP14 are clinically indistinguishable. We aim to better understand the pathomechanism of kEDS to characterize distinguishing and overlapping molecular features underlying PLOD1-kEDS and FKBP14-kEDS, and to identify novel molecular targets that may expand treatment strategies. Transcriptome profiling by RNA sequencing of patient-derived skin fibroblasts revealed differential expression of genes encoding extracellular matrix components that are unique between PLOD1-kEDS and FKBP14-kEDS. Furthermore, we identified genes involved in inner ear development, vascular remodeling, endoplasmic reticulum (ER) stress, and protein trafficking that were differentially expressed in patient fibroblasts compared to controls. Overall, our study presents the first transcriptomics data in kEDS revealing distinct molecular features between PLOD1-kEDS and FKBP14-kEDS, and serves as a tool to better understand the disease.

scholarly journals Expanding the Clinical and Mutational Spectrum of Recessive AEBP1-Related Classical-Like Ehlers-Danlos Syndrome

Genes ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 135 ◽  
Author(s):  
Marco Ritelli ◽  
Valeria Cinquina ◽  
Marina Venturini ◽  
Letizia Pezzaioli ◽  
Anna Formenti ◽  
...  
Keyword(s):  
Missense Variant ◽  
Causal Variant ◽  
Joint Hypermobility ◽  
Clinical Findings ◽  
Ehlers Danlos Syndrome ◽  
Pathogenic Variants ◽  
Fibrillar Collagens ◽  
Atrophic Scars ◽  
Minor Criteria ◽  
Danlos Syndrome

Ehlers-Danlos syndrome (EDS) comprises clinically heterogeneous connective tissue disorders with diverse molecular etiologies. The 2017 International Classification for EDS recognized 13 distinct subtypes caused by pathogenic variants in 19 genes mainly encoding fibrillar collagens and collagen-modifying or processing proteins. Recently, a new EDS subtype, i.e., classical-like EDS type 2, was defined after the identification, in six patients with clinical findings reminiscent of EDS, of recessive alterations in AEBP1, which encodes the aortic carboxypeptidase–like protein associating with collagens in the extracellular matrix. Herein, we report on a 53-year-old patient, born from healthy second-cousins, who fitted the diagnostic criteria for classical EDS (cEDS) for the presence of hyperextensible skin with multiple atrophic scars, generalized joint hypermobility, and other minor criteria. Molecular analyses of cEDS genes did not identify any causal variant. Therefore, AEBP1 sequencing was performed that revealed homozygosity for the rare c.1925T>C p.(Leu642Pro) variant classified as likely pathogenetic (class 4) according to the American College of Medical Genetics and Genomics (ACMG) guidelines. The comparison of the patient’s features with those of the other patients reported up to now and the identification of the first missense variant likely associated with the condition offer future perspectives for EDS nosology and research in this field.

scholarly journals The first case report of Kyphoscoliotic Ehlers-Danlos syndrome of chinese origin with a novel PLOD1 gene mutation

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiaolin Ni ◽  
Chenxi Jin ◽  
Yan Jiang ◽  
Ou Wang ◽  
Mei Li ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Clinical Manifestations ◽  
Joint Hypermobility ◽  
Minor Trauma ◽  
X Rays ◽  
Ehlers Danlos Syndrome ◽  
Chinese Origin ◽  
First Case ◽  
Blue Sclerae ◽  
Danlos Syndrome

Abstract Background Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is a rare autosomal recessive connective tissue disorder characterized by progressive kyphoscoliosis, congenital muscular hypotonia, marked joint hypermobility, and severe skin hyperextensibility and fragility. Deficiency of lysyl hydroxylase 1 (LH1) due to mutations of PLOD1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1) gene has been identified as the pathogenic cause of kEDS (kEDS-PLOD1). Up to now, kEDS-PLOD1 has not been reported among Chinese population. Case presentation A 17-year-old Chinese male patient presenting with hypotonia, joint hypermobility and scoliosis was referred to our hospital. After birth, he was found to have severe hypotonia leading to delayed motor development. Subsequently, joint hypermobility, kyphoscoliosis and amblyopia were found. Inguinal hernia was found at age 5 years and closed by surgery. At the same time, he presented with hyperextensible and bruisable velvety skin with widened atrophic scarring after minor trauma. Dislocation of elbow joint was noted at age of 6 years. Orthopedic surgery for correction of kyphoscoliosis was performed at age 10 years. His family history was unremarkable. Physical examination revealed elevated blood pressure. Slight facial dysmorphologies including high palate, epicanthal folds, and down-slanting palpebral fissures were found. He also had blue sclerae with normal hearing. X-rays revealed severe degree of scoliosis and osteopenia. The Echocardiography findings were normal. Laboratory examination revealed a slightly elevated bone turnover. Based on the clinical manifestations presented by our patient, kEDS was suspected. Genetic analysis revealed a novel homozygous missense mutation of PLOD1 (c.1697 G > A, p.C566Y), confirming the diagnosis of kEDS-PLOD1. The patient was treated with alfacalcidol and nifedipine. Improved physical strength and normal blood pressure were reported after 12-month follow-up. Conclusions This is the first case of kEDS-PLOD1 of Chinese origin. We identified one novel mutation of PLOD1, extending the mutation spectrum of PLOD1. Diagnosis of kEDS-PLOD1 should be considered in patients with congenital hypotonia, progressive kyphoscoliosis, joint hypermobility, and skin hyperextensibility and confirmed by mutation analysis of PLOD1.

scholarly journals Ehlers-Danlos syndrome presenting with primary nocturnal enuresis

2020 ◽  
Vol 13 (2) ◽  
pp. e231977
Author(s):  
Margarida Cunha ◽  
Mafalda Matias ◽  
Inês Marques
Keyword(s):  
Genetic Testing ◽  
Nocturnal Enuresis ◽  
Bladder Dysfunction ◽  
Connective Tissue Disorder ◽  
Joint Hypermobility ◽  
Urinary Urgency ◽  
Beighton Score ◽  
Ehlers Danlos Syndrome ◽  
Primary Nocturnal Enuresis ◽  
Danlos Syndrome

Ehlers-Danlos syndrome (EDS), hypermobility type, is probably the most common EDS type, as well as the most common heritable connective tissue disorder. Bladder dysfunction is a rare clinical manifestation of EDS and manifests itself as primary nocturnal enuresis. We present a 10-year-old boy referred to the paediatrics nephrology consultation due to primary nocturnal enuresis and day time symptoms of urinary urgency. During the appointment, a tendency to joint hypermobility was noted. On evaluation the skin was hyperextensible and the Beighton score was positive. The genetic testing revealed a variant of the COL5A1 gene not yet described in the literature.

scholarly journals Increased augmentation index in patients with Ehlers-Danlos syndrome

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Maurice Roeder ◽  
Sira Thiel ◽  
Frederic Baumann ◽  
Noriane A. Sievi ◽  
Marianne Rohrbach ◽  
...  
Keyword(s):  
Arterial Stiffness ◽  
Augmentation Index ◽  
Positive Association ◽  
Joint Hypermobility ◽  
Applanation Tonometry ◽  
Classical Type ◽  
Healthy Controls ◽  
Ehlers Danlos Syndrome ◽  
Vascular Type ◽  
Danlos Syndrome

Abstract Background Ehlers-Danlos Syndrome (EDS) comprises a heterogeneous group of diseases characterized by joint hypermobility, connective tissue friability, and vascular fragility. Reliable prognostic factors predicting vascular disease progression (e.g. arterial aneurysms, dissections, and ruptures) in EDS patients are still missing. Recently, applanation tonometry derived augmentation index (AIx), an indirect marker of arterial stiffness, has shown to be positively associated with progression of aortic disease in Marfan syndrome. In this study, we assessed aortic AIx in patients with EDS and matched healthy controls. Methods We performed noninvasive applanation tonometry in 61 adults with EDS (43 women and 18 men aged 39.3 ± 14.6 years) and 61 age-, gender-, height-, and weight-matched healthy controls. Radial artery pulse waveforms were recorded and analyzed using the SphygmoCor System (AtCor Medical, Sydney, NSW, Australia). Calculated AIx was adjusted to a heart rate of 75/min. Groups were compared and association between AIx and EDS was determined by univariate and multivariate regression analysis. Results EDS patients were categorized in classical type EDS (34%), hypermobile type EDS (43%), vascular type EDS (5%), or remained unassignable (18%) due to overlapping features. EDS patients showed a significantly increased aortic AIx compared to healthy controls (22.8% ± 10.1 vs 14.8% ± 14.0, p < 0.001). EDS showed a positive association with AIx; independent of age, sex, height, blood pressure, medication, and pack years of smoking. Conclusions Patients with EDS showed elevated AIx, indicating increased arterial stiffness when compared to healthy controls. Further investigations are needed in order to assess the prognostic value of increased AIx for cardiovascular outcomes in patients with EDS.

Low tendon stiffness and abnormal ultrastructure distinguish classic Ehlers‐Danlos syndrome from benign joint hypermobility syndrome in patients

2014 ◽  
Vol 28 (11) ◽  
pp. 4668-4676 ◽  
Author(s):  
Rie Harboe Nielsen ◽  
Christian Couppé ◽  
Jacob Kildevang Jensen ◽  
Morten Raun Olsen ◽  
Katja Maria Heinemeier ◽  
...  
Keyword(s):  
Joint Hypermobility ◽  
Hypermobility Syndrome ◽  
Joint Hypermobility Syndrome ◽  
Ehlers Danlos Syndrome ◽  
Tendon Stiffness ◽  
Benign Joint Hypermobility Syndrome ◽  
Danlos Syndrome

scholarly journals Dermal Ultrastructure in Low Beighton Score Members of 17 Families with Hypermobile-Type Ehlers-Danlos Syndrome

2012 ◽  
Vol 2012 ◽  
pp. 1-3 ◽  
Author(s):  
Trinh Hermanns-Lê ◽  
Marie-Annick Reginster ◽  
Claudine Piérard-Franchimont ◽  
Philippe Delvenne ◽  
Gérald E. Piérard ◽  
...  
Keyword(s):  
Clinical Parameter ◽  
Joint Hypermobility ◽  
Elastic Fibers ◽  
Hypermobility Syndrome ◽  
Beighton Score ◽  
Joint Hypermobility Syndrome ◽  
Ehlers Danlos Syndrome ◽  
Transmission Electron ◽  
Asymptomatic Subjects ◽  
Danlos Syndrome

The distinction between the Ehlers-Danlos syndrome hypermobile type (EDSH) and the benign joint hypermobility syndrome (BJHS) is unclear. The aim of the present study was to compare skin ultrastructural abnormalities of EDSH and BJHS among different families. Skin of 23 EDSH, 27 BJHS, and 41 asymptomatic subjects from 17 families was examined using transmission electron microscopy. Similar ultrastructural abnormalities were found irrespective of the Beighton score. Flower-like collagen fibrils represented the key change and elastic fibers were altered as well. Beighton score is a clinical parameter rating joint mobility that appeared unrelated to quantitative and qualitative collagen ultrastructural alterations in the skin. Some EDSH family members fit with BJHS diagnosis. BJHS possibly represents a mild variant of EDSH.

scholarly journals Evidence that Charcot-Marie-Tooth disease with tremor coincides with the Roussy-Levy syndrome

1984 ◽  
Vol 11 (S4) ◽  
pp. 541-549 ◽  
Author(s):  
C. Chouza ◽  
J.L. Caamaño ◽  
O. De Medina ◽  
J. Bogacz ◽  
C. Oehninger ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Joint Hypermobility ◽  
New Mutation ◽  
Ehlers Danlos Syndrome ◽  
Spastic Ataxia ◽  
Charcot Marie Tooth Disease ◽  
Slow Evolution ◽  
Familial Spastic Paraplegia ◽  
Danlos Syndrome ◽  
Tooth Disease

ABSTRACT:Four members of a family with consanguineous relationships, the proband and his three children (2 sons and 1 daughter) are affected with Familial Spastic Ataxia and with Ehlers-Danlos' Syndrome with platelet aggregation dysfunction. In the four cases, this exceptional association appears remarkably homogeneous both in clinical and laboratory studies. The two syndromes are of dominant-autosomic transmission and probably originated in a new mutation which presumably maintained a genetic linkage. Spastic ataxia is characterized by a precocious onset and a slow evolution. The first-born son shows a dominant pyramidal syndrome with mild ataxia suggesting that it is a transitional form of familial spastic paraplegia. The Ehlers-Danlos syndrome pertains to form II or “mitis” with moderate skin hyperelasticity and joint hypermobility. The abnormal platelet aggregation curves have the same profile in all the patients. The first-born son also presents a mitral valve prolapsus as we may find either in Ehlers-Danlos syndrome or in spastic ataxia.

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