scholarly journals Loss-of-Function Variants in EFEMP1 Cause a Recognizable Connective Tissue Disorder Characterized by Cutis Laxa and Multiple Herniations

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 510
Author(s):  
Maxim Verlee ◽  
Aude Beyens ◽  
Alper Gezdirici ◽  
Elif Yilmaz Gulec ◽  
Lore Pottie ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Connective Tissue ◽  
Connective Tissue Disorder ◽  
Heterogeneous Group ◽  
Cutis Laxa ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Genes Encoding ◽  
Hereditary Disorders ◽  
Musculoskeletal Systems

Hereditary disorders of connective tissue (HDCT) compromise a heterogeneous group of diseases caused by pathogenic variants in genes encoding different components of the extracellular matrix and characterized by pleiotropic manifestations, mainly affecting the cutaneous, cardiovascular, and musculoskeletal systems. We report the case of a 9-year-old boy with a discernible connective tissue disorder characterized by cutis laxa (CL) and multiple herniations and caused by biallelic loss-of-function variants in EFEMP1. Hence, we identified EFEMP1 as a novel disease-causing gene in the CL spectrum, differentiating it from other HDCT.

scholarly journals Identification of three novel homozygous variants in COL9A3 causing autosomal-recessive Stickler Syndrome

2021 ◽  
Author(s):  
Aboulfazl Rad ◽  
Maryam Najafi ◽  
Fatemeh Suri ◽  
Soheila Abedini ◽  
Stephen Loum ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Molecular Genetics ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Connective Tissue Disorder ◽  
Stickler Syndrome ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Autosomal Dominant Fashion

Abstract Background: Stickler syndrome (STL) is a rare, clinically and molecularly heterogeneous connective tissue disorder. Pathogenic variants occurring in a variety of genes cause STL, mainly inherited in an autosomal dominant fashion. Autosomal recessive STL is ultra-rare with only four families with biallelic COL9A3 variants reported to date. Results: Here, we report three unrelated families clinically diagnosed with STL carrying different novel biallelic loss of function variants in COL9A3. Further, we have collected COL9A3 genotype-phenotype associations from the literature. Conclusion: Our report substantially expands the molecular genetics and clinical basis of autosomal recessive STL and provides an overview about allelic COL9A3 disorders.

Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications

2019 ◽  
Vol 56 (9) ◽  
pp. 629-638 ◽  
Author(s):  
Lisa Jean Ewans ◽  
Alison Colley ◽  
Carles Gaston-Massuet ◽  
Angelica Gualtieri ◽  
Mark J Cowley ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Clinical Features ◽  
Vascular Complications ◽  
Connective Tissue Disorder ◽  
Stickler Syndrome ◽  
Mineral Density ◽  
Ehlers Danlos Syndrome ◽  
Microarray Expression Data ◽  
Pathogenic Variants ◽  
Microarray Expression

BackgroundPathogenic PLOD3 variants cause a connective tissue disorder (CTD) that has been described rarely. We further characterise this CTD and propose a clinical diagnostic label to improve recognition and diagnosis of PLOD3-related disease.MethodsReported PLOD3 phenotypes were compared with known CTDs utilising data from three further individuals from a consanguineous family with a homozygous PLOD3 c.809C>T; p.(Pro270Leu) variant. PLOD3 mRNA expression in the developing embryo was analysed for tissue-specific localisation. Mouse microarray expression data were assessed for phylogenetic gene expression similarities across CTDs with overlapping clinical features.ResultsKey clinical features included ocular abnormalities with risk for retinal detachment, sensorineural hearing loss, reduced palmar creases, finger contractures, prominent knees, scoliosis, low bone mineral density, recognisable craniofacial dysmorphisms, developmental delay and risk for vascular dissection. Collated clinical features showed most overlap with Stickler syndrome with variable features of Ehlers-Danlos syndrome (EDS) and epidermolysis bullosa (EB). Human lysyl hydroxylase 3/PLOD3 expression was localised to the developing cochlea, eyes, skin, forelimbs, heart and cartilage, mirroring the clinical phenotype of this disorder.ConclusionThese data are consistent with pathogenic variants in PLOD3 resulting in a clinically distinct Stickler-like syndrome with vascular complications and variable features of EDS and EB. Early identification of PLOD3 variants would improve monitoring for comorbidities and may avoid serious adverse ocular and vascular outcomes.

scholarly journals OR22-05 Rare Biallelic Variants in Obesity-Related Genes in the Madrid Pediatric Obesity Cohort

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Gabriel Á Martos-Moreno ◽  
Ida Hatoum Moeller ◽  
Álvaro Martín-Rivada ◽  
Luis A Pérez-Jurado ◽  
Jesús Argente
Keyword(s):  
Childhood Obesity ◽  
Severe Obesity ◽  
Genetic Disorders ◽  
Compound Heterozygous ◽  
Homozygous Mutation ◽  
Loss Of Function ◽  
Protein Coding ◽  
Pathogenic Variants ◽  
Genes Encoding ◽  
Biallelic Mutations

Abstract BACKGROUND: Obesity is a heterogenous disease resulting from environmental and genetic factors and is characterized by disordered energy balance, regulated in part by the hypothalamic melanocortin-4 receptor (MC4R), including neuronal ciliary assembly and trafficking pathways.1 Rare loss-of-function variants in genes encoding components of this pathway are associated with severe obesity and hyperphagia, with or without additional features.2 However, such rare genetic disorders may be underestimated due to a lack of genetic screening in individuals with severe obesity.3 Our objective was to identify and characterize rare genetic variants in a Spanish population from Madrid with childhood obesity. Methods: This analysis was conducted from a prospectively-collected cohort of children with obesity, generally with a BMI>+3DS. Participants were sequenced for 35 obesity-related genes, including 23 genes related to Bardet-Biedl (BBS) and Alström syndromes, plus an additional 12 genes associated with non-syndromic, monogenic causes of obesity, to identify individuals with rare (<1% frequency in gnomAD) potentially biallelic (homozygous and compound heterozygous) non-synonymous variants in protein-coding regions. Results: Of the 1019 Spanish patients with obesity, 493 (48.4%) were female and the mean age and BMI were 10.41 ± 3.38 years and 4.38 ± 1.76 SDS (79.8% above +3 SDS), respectively. We identified 26 rare potentially biallelic variants in 25 unique individuals, including 2 individuals with homozygous variants in POMC, 3 individuals with two variants in SRC1, one individual with two variants in ADCY3, and one individual with a homozygous mutation in LEP. In addition, we identified 18 individuals with biallelic mutations in one of 23 BBS or ALMS1 genes, including two individuals with known pathogenic variants and clinically confirmed BBS. Conclusions: Rare and potentially biallelic sequence variants were identified in 25 individuals with childhood obesity. These results support the use of genetic testing for individuals with severe obesity who may be candidates for specific clinical interventions or additional targeted therapies.

scholarly journals Anaesthetic Management in a Child with Cutis Laxa for Bilateral Ureteric Reimplantation

2021 ◽  
Author(s):  
Haripriya Ramachandran ◽  
Dammaningala Venkataramaiah Bhagya
Keyword(s):  
Heart Failure ◽  
Connective Tissue ◽  
Pulmonary Emphysema ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Preoperative Evaluation ◽  
Anaesthetic Management ◽  
Connective Tissue Disorder ◽  
Cutis Laxa ◽  
Facial Features

Cutis laxa is a rare congenital multisystem connective tissue disorder. Patients with cutis laxa can present with distinctive facial features, pulmonary emphysema and right-sided heart failure. Anaesthetic management is important because of difficult airway and respiratory/cardiac abnormalities. We have reported the preoperative evaluation and anaesthetic management of a child with Cutis laxa with right cleft lip and palate.

scholarly journals Osteopetrosis in a Patient of Systemic Sclerosis Sine Scleroderma: A Rare Association

2022 ◽  
Author(s):  
Saroj K. Pati ◽  
Praveen Raja ◽  
Ajoy K. Behera ◽  
T.G. Ranganath ◽  
Narendra K. Bodhey
Keyword(s):  
Systemic Sclerosis ◽  
Connective Tissue ◽  
Male Patient ◽  
Connective Tissue Disorder ◽  
Unknown Etiology ◽  
Cutaneous Manifestations ◽  
Rare Association ◽  
Serologic Markers ◽  
Chief Complaints ◽  
Musculoskeletal Systems

AbstractSystemic sclerosis is a connective tissue disorder of unknown etiology. Although it is a multisystemic disorder, skin thickening is considered as a hallmark of the disease. It usually involves the lungs, gastrointestinal, and musculoskeletal systems. However, a rare subset of systemic sclerosis, systemic sclerosis sine scleroderma, is characterized by internal organ involvement and positive serologic markers with the total or partial absence of cutaneous manifestations. We present a rare association of osteopetrosis in a case of systemic sclerosis sine scleroderma, in a 22-year-old male patient, who presented with pulmonary symptoms as his chief complaints, unreported so far in literature.

scholarly journals Anaesthetic Considerations in Patients with Cutis Laxa: Our Experience

2019 ◽  
Vol 4 (05) ◽  
Author(s):  
Dr Sheetal K. ◽  
Dr Nandini R. ◽  
Dr Chandrika Y. R.
Keyword(s):  
Connective Tissue ◽  
Growth Retardation ◽  
Connective Tissue Disorder ◽  
Temperature Monitoring ◽  
Cutis Laxa ◽  
Skeletal Involvement ◽  
Type Iii ◽  
Cardiovascular Involvement ◽  
Peripheral Temperature

Cutis laxa is a rare, inherited or acquired connective tissue disorder. It is characterized by loose, inelastic skin and various systemic involvements. Cutis laxa type III, described as de Barsy syndrome presents with ophthalmic opacification, skeletal involvement, cardiovascular involvement, mental and growth retardation. Intraoperative hyperthermia of the non-malignant variety with tachycardia is seen in 10% cases of cutis laxa type III. Given the rarity of cutis laxa syndrome, all cases require core and peripheral temperature monitoring.

scholarly journals Cardiovascular and connective tissue disorder features in FLNA-related PVNH patients: progress towards a refined delineation of this syndrome

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Clarisse Billon ◽  
Salma Adham ◽  
Natalia Hernandez Poblete ◽  
Anne Legrand ◽  
Michael Frank ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Vascular Diseases ◽  
Connective Tissue Disorder ◽  
Neurological Symptoms ◽  
Loss Of Function ◽  
Clinical Presentations ◽  
Major Interest ◽  
Nodular Heterotopia ◽  
Coding Variants

Abstract Background FLNA Loss-of-Function (LoF) causes periventricular nodular heterotopia type 1 (PVNH1), an acknowledged cause of seizures of various types. Neurological symptoms are inconstant, and cardiovascular (CV) defects or connective tissue disorders (CTD) have regularly been associated. We aimed at refining the description of CV and CTD features in patients with FLNA LoF and depicting the multisystemic nature of this condition. Methods We retrospectively evaluated FLNA variants and clinical presentations in FLNA LoF patient with at least one CV or CTD feature, from three cohorts: ten patients from the French Reference Center for Rare Vascular Diseases, 23 patients from the national reference diagnostic lab for filaminopathies-A, and 59 patients from literature review. Results Half of patients did not present neurological symptoms. Most patients presented a syndromic association combining CV and CTD features. CV anomalies, mostly aortic aneurysm and/or dilation were present in 75% of patients. CTD features were present in 75%. Variants analysis demonstrated an enrichment of coding variants in the CH1 domain of FLNA protein. Conclusion In FLNA LoF patients, the absence of seizures should not be overlooked. When considering a diagnosis of PVNH1, the assessment for CV and CTD anomalies is of major interest as they represent interlinked features. We recommend systematic study of FLNA within CTD genes panels, regardless of the presence of neurological symptoms.

scholarly journals Involvement of MAP3K7 in FMD2 and CSCF, delineation of genotype/phenotype correlations.

2021 ◽  
Author(s):  
Geeske van Woerden ◽  
Richelle Senden ◽  
Charlotte de Konink ◽  
Rossella Avagliano Trezza ◽  
anwar baban ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Connective Tissue ◽  
Noonan Syndrome ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Loss Of Function ◽  
Molecular Fingerprint ◽  
Clinical Phenotypes ◽  
Pathogenic Variants ◽  
Mitogen Activated Protein

Mitogen-Activated Protein 3 Kinase 7 (MAP3K7, MIM 602614) encodes the ubiquitously expressed transforming growth factor β (TGF-β)–activated kinase 1 (TAK1), which plays a crucial role in many cellular processes. Variants in the MAP3K7 gene have been linked to 2 distinct disorders: frontometaphyseal dysplasia type 2 (FMD2, MIM #617137) and cardiospondylocarpofacial syndrome (CSCF, MIM #157800). The fact that different variants can induce 2 distinct phenotypes suggests a phenotype/genotype correlation, but no side-by-side comparison has been done thus far to confirm this. Here we significantly expand the cohort and the description of clinical phenotypes for individuals with CSCF and FMD2 who carry variants in MAP3K7. We show that in contrast to FMD2-causing variants, CSCF-causing variants in MAP3K7 have a loss-of-function effect. Additionally, patients with pathogenic variants in MAP3K7 are at risk for cardiac disease, have symptoms associated with connective tissue disease and we show overlap in clinical phenotypes of CSCF with Noonan syndrome. Together, we provide evidence for a molecular fingerprint of FMD2- versus CSCF-causing MAP3K7 variants and conclude that variants in MAP3K7 should be considered in the differential diagnosis of patients with syndromic congenital cardiac defects and/or cardiomyopathy, syndromic connective tissue disorders and in the differential diagnosis of Noonan syndrome.

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