Looking back and beyond the 2017 diagnostic criteria for hypermobile Ehlers-Danlos syndrome: A retrospective cross-sectional study from an Italian reference center.

The most common conditions with symptomatic joint hypermobility are hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). Diagnosing these overlapping connective tissue disorders remains challenging due to the lack of established causes and reliable diagnostic tests. hEDS is diagnosed applying the 2017 diagnostic criteria, and patients with symptomatic joint hypermobility but not fulfilling these criteria are labeled as HSD, which is not officially recognized by all healthcare systems. The 2017 criteria were introduced to improve diagnostic specificity but have faced criticism for being too stringent and failing to adequately capture the multisystemic involvement of hEDS. Herein, we retrospectively evaluated 327 patients from 213 families with a prior diagnosis of hypermobility type EDS or joint hypermobility syndrome based on Villefranche and Brighton criteria, to assess the effectiveness of the 2017 criteria in distinguishing between hEDS and HSD and document the frequencies of extra-articular manifestations. Based on our findings, we propose that the 2017 criteria should be made less stringent to include a greater number of patients who are currently encompassed within the HSD category. This will lead to improved diagnostic accuracy and enhanced patient care by properly capturing the diverse range of symptoms and manifestations present within the hEDS/HSD spectrum.

Bridging the Diagnostic Gap for Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders: Evidence of a Common Extracellular Matrix Fragmentation Pattern in Patient Plasma as a Potential Biomarker.

Diagnosing hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD), common overlapping multisystemic conditions featuring symptomatic joint hypermobility, is challenging due to lack of established causes and diagnostic tools. Currently, the 2017 diagnostic criteria for hEDS are used, with non-qualifying cases classified as HSD, although the distinction remains debated. We previously showed extracellular matrix (ECM) disorganization in both hEDS and HSD dermal fibroblasts involving fibronectin (FN), type I collagen (COLLI), and tenascin (TN), with matrix metalloproteinase-generated fragments in conditioned media. Here, we investigated these fragments in patient plasma using Western blotting across diverse cohorts, including patients with hEDS, HSD, classical EDS (cEDS), vascular EDS (vEDS), rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA), and healthy donors, uncovering distinctive patterns. Notably, hEDS/HSD displayed a shared FN and COLLI fragment signature, supporting their classification as a single disorder and prompting reconsideration of the hEDS criteria. Our results hold the promise for the first blood test for diagnosing hEDS/HSD, present insights into the pathomechanisms, and open the door for therapeutic trials focused on restoring ECM homeostasis using an objective marker. Additionally, our findings offer potential biomarkers also for OA, RA, and PsA, advancing diagnostic and therapeutic strategies in these prevalent joint diseases.

Application of the 2017 criteria for vascular Ehlers-Danlos syndrome in 50 patients ascertained according to the Villefranche nosology.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare inherited connective tissue disorder due to heterozygous pathogenic COL3A1 variants. Arterial, intestinal, and/or uterine fragility is the disease hallmark and results in reduced life expectancy. The clinical diagnosis is not always straightforward and patients' selection for molecular confirmation depends on the characteristics of applied criteria, that is, the Villefranche criteria (in use until 2017) and their revision according to the new EDS nosology. Herein, we reassessed the clinical features of 50 molecularly proven vEDS patients, diagnosed according to the Villefranche nosology between 2000 and 2016, using the 2017 classification in order to explore its clinical application. Our findings indicate that the Villefranche criteria were particularly valuable for symptomatic patients, even if with a limited specificity. Our study also suggests that the revised vEDS criteria, although expected to be more specific, might have a poorer accuracy, principally in terms of sensitivity. Both sets of criteria are less effective in presymptomatic young patients, especially in the absence of a clear-cut family history. For these patients, the careful evaluation of the cutaneous, articular, and dysmorphic features and, above all, genetic testing remain crucial to set-up proper follow-up and surveillance before catastrophic vascular and intestinal events.

GLUT10 deficiency leads to oxidative stress and non-canonical αvß3 integrin-mediated TGFß signalling associated with extracellular matrix disarray in arterial tortuosity syndrome skin fibroblasts.

Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disorder caused by loss-of-function mutations in SLC2A10, which encodes facilitative glucose transporter 10 (GLUT10). The role of GLUT10 in ATS pathogenesis remains an enigma, and the transported metabolite(s), i.e. glucose and/or dehydroascorbic acid, have not been clearly elucidated. To discern the molecular mechanisms underlying the ATS aetiology, we performed gene expression profiling and biochemical studies on skin fibroblasts. Transcriptome analyses revealed the dysregulation of several genes involved in TGFß signalling and extracellular matrix (ECM) homeostasis as well as the perturbation of specific pathways that control both the cell energy balance and the oxidative stress response. Biochemical and functional studies showed a marked increase in ROS-induced lipid peroxidation sustained by altered PPARγ function, which contributes to the redox imbalance and the compensatory antioxidant activity of ALDH1A1. ATS fibroblasts also showed activation of a non-canonical TGFß signalling due to TGFBRI disorganization, the upregulation of TGFBRII and connective tissue growth factor, and the activation of the αvß3 integrin transduction pathway, which involves p125FAK, p60Src and p38 MAPK. Stable GLUT10 expression in patients' fibroblasts normalized redox homeostasis and PPARγ activity, rescued canonical TGFß signalling and induced partial ECM re-organization. These data add new insights into the ATS dysregulated biological pathways and definition of the pathomechanisms involved in this disorder.

Ehlers-Danlos syndrome with lethal cardiac valvular dystrophy in males carrying a novel splice mutation in FLNA.

Filamin A is an X-linked, ubiquitous actin-binding protein whose mutations are associated to multiple disorders with limited genotype-phenotype correlations. While gain-of-function mutations cause various bone dysplasias, loss-of-function variants are the most common cause of periventricular nodular heterotopias with variable soft connective tissue involvement, as well as X-linked cardiac valvular dystrophy (XCVD). The term "Ehlers-Danlos syndrome (EDS) with periventricular heterotopias" has been used in females with neurological, cardiovascular, integument and joint manifestations, but this nosology is still a matter of debate. We report the clinical and molecular update of an Italian family with an X-linked recessive soft connective tissue disorder and which was described, in 1975, as the first example of EDS type V of the Berlin nosology. The cutaneous phenotype of the index patient was close to classical EDS and all males died for a lethal cardiac valvular dystrophy. Whole exome sequencing identified the novel c.1829-1G>C splice variation in FLNA in two affected cousins. The nucleotide change was predicted to abolish the canonical splice acceptor site of exon 13 and to activate a cryptic acceptor site 15 bp downstream, leading to in frame deletion of five amino acid residues (p.Phe611_Gly615del). The predicted in frame deletion clusters with all the mutations previously identified in XCVD and falls within the N-terminus rod 1 domain of filamin A. Our findings expand the male-specific phenotype of FLNA mutations that now includes classical-like EDS with lethal cardiac valvular dystrophy, and offer further insights for the genotype-phenotype correlations within this spectrum. © 2016 Wiley Periodicals, Inc.

Truncating variants in the penultimate exon of TGFBR1 escaping nonsense-mediated mRNA decay cause Loeys-Dietz syndrome.

Pathogenic variants in TGFBR1 are a common cause of Loeys-Dietz syndrome (LDS) characterized by life-threatening aortic and arterial disease. Generally, these are missense changes in highly conserved amino acids in the serine-threonine kinase domain. Conversely, nonsense, frameshift, or specific missense changes in the ligand-binding extracellular domain cause multiple self-healing squamous epithelioma (MSSE) lacking the cardiovascular phenotype. Here, we report on two novel variants in the penultimate exon 8 of TGFBR1 were identified in 3 patients from two unrelated LDS families: both were predicted to cause frameshift and premature stop codons (Gln448Profs*15 and Cys446Asnfs*4) resulting in truncated TGFBR1 proteins lacking the last 43 and 56 amino acid residues, respectively. These were classified as variants of uncertain significance based on current criteria. Transcript expression analyses revealed both mutant alleles escaped nonsense-mediated mRNA decay. Functional characterization in patient's dermal fibroblasts showed paradoxically enhanced TGFß signaling, as observed for pathogenic missense TGFBR1 changes causative of LDS. In summary, we expanded the allelic repertoire of LDS-associated TGFBR1 variants to include truncating variants escaping nonsense-mediated mRNA decay. Our data highlight the importance of functional studies in variants interpretation for correct clinical diagnosis.

RNA-Seq of Dermal Fibroblasts from Patients with Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders Supports Their Categorization as a Single Entity with Involvement of Extracellular Matrix Degrading and Proinflammatory Pathomechanisms.

Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are clinically overlapping connective tissue disorders of unknown etiology and without any validated diagnostic biomarker and specific therapies. Herein, we in-depth characterized the cellular phenotype and gene expression profile of hEDS and HSD dermal fibroblasts by immunofluorescence, amplicon-based RNA-seq, and qPCR. We demonstrated that both cell types show a common cellular trait, i.e., generalized extracellular matrix (ECM) disarray, myofibroblast differentiation, and dysregulated gene expression. Functional enrichment and pathway analyses clustered gene expression changes in different biological networks that are likely relevant for the disease pathophysiology. Specifically, the complex gene expression dysregulation (mainly involving growth factors, structural ECM components, ECM-modifying enzymes, cytoskeletal proteins, and different signal transducers), is expected to perturb many ECM-related processes including cell adhesion, migration, proliferation, and differentiation. Based on these findings, we propose a disease model in which an unbalanced ECM remodeling triggers a vicious cycle with a synergistic contribution of ECM degradation products and proinflammatory mediators leading to a functional impairment of different connective tissues reflecting the multisystemic presentation of hEDS/HSD patients. Our results offer many promising clues for translational research aimed to define molecular bases, diagnostic biomarkers, and specific therapies for these challenging connective tissue disorders.

Expanding the PURA syndrome phenotype: A child with the recurrent PURA p.(Phe233del) pathogenic variant showing similarities with cutis laxa.

BACKGROUND: PURA syndrome is rare autosomal dominant condition characterized by moderate to severe neurodevelopmental delay with absence of speech in nearly all patients and lack of independent ambulation in many. Early-onset problems include excessive hiccups, hypotonia, hypersomnolence, hypothermia, feeding difficulties, recurrent apneas, epileptic seizures, and abnormal nonepileptic movements. Other less common manifestations comprise congenital heart defects, urogenital malformations, and various skeletal, ophthalmological, gastrointestinal, and endocrine anomalies. Up to now, 78 individuals with PURA syndrome and 64 different pathogenic variants have been reported, but no clear-cut genotype-phenotype correlations have emerged so far. Herein, we report the clinical and molecular characterization of a 3-year-old girl with severe hypotonia, global developmental delay, and soft, loose skin, who came to our attention with a suspicion of cutis laxa (CL), which denotes another condition with variable neurodevelopmental problems. METHODS: Amplicon-based whole exome sequencing was performed, and an in-house pipeline was used to conduct filtering and prioritization of variants. New prediction algorithms for indels were used to validate the pathogenicity of the PURA variant, and results were confirmed with the Sanger method. Finally, we collected clinical and mutational data of all PURA syndrome patients reported yet and compared the clinical features with those of our patient. RESULTS: Clinical evaluation and biochemical investigations excluded CL and prompted to perform whole exome sequencing, which confirmed the absence of pathogenic variants in all CL-related genes and revealed the known PURA c.697_699del, p.(Phe233del) variant, identified hitherto in seven additional children with PURA syndrome. CONCLUSIONS: Our data expand the phenotypic spectrum of PURA syndrome by showing that it can be regarded as a differential diagnosis for cutis laxa in early infancy. Our patient and literature review emphasize that a wide clinical variability exists not only between individuals with different PURA variants, but also among patients with the same causal mutation.

Identification of the novel COL5A1 c.3369_3431dup, p.(Glu1124_Gly1144dup) variant in a patient with incomplete classical Ehlers-Danlos syndrome: The importance of phenotype-guided genetic testing.

BACKGROUND: Classical Ehlers-Danlos syndrome (cEDS) is a connective tissue disorder mainly caused by heterozygous COL5A1 or COL5A2 variants encoding type V collagen and rarely by the p.(Arg312Cys) missense substitution in COL1A1 encoding type I collagen. The current EDS nosology specifies that minimal suggestive criteria are marked skin hyperextensibility plus atrophic scarring together with either generalized joint hypermobility or at least three minor criteria comprising additional cutaneous and articular signs. To reach a final diagnosis, molecular testing is required. Herein, we report on a 3-year-old female who came to our attention with an inconclusive next generation sequencing (NGS) panel comprising all cEDS-associated genes. METHODS: Despite the patient did not formally fulfill the nosological criteria because the skin was only slightly hyperextensible, we made a cEDS diagnosis, mainly for the presence of typical atrophic scars. We investigated COL5A1 intragenic deletions/duplications by Multiplex Ligation-dependent Probe Amplification (MLPA), excluded the recessive classical-like EDS type 2 by AEBP1 Sanger analysis, and retested COL5A1 with the Sanger method. RESULTS: Molecular analyses revealed the novel COL5A1 c.3369_3431dup p.(Glu1124_Gly1144dup) intermediate-sized duplication with a predicted dominant negative effect that was missed both by NGS and MLPA. CONCLUSIONS: This report highlights that some cEDS patients might not display overt skin hyperextensibility and the importance of clinical expertise to make such a diagnosis in patients with an incomplete presentation. Our results also exemplify that NGS is not a fool-proof technology and that Sanger sequencing achieves the diagnostic goal when there is a sufficiently clear phenotypic indication.

Multisystemic manifestations in a cohort of 75 classical Ehlers-Danlos syndrome patients: natural history and nosological perspectives.

BACKGROUND: The Ehlers-Danlos syndromes (EDS) are rare connective tissue disorders consisting of 13 subtypes with overlapping features including joint hypermobility, skin and generalized connective tissue fragility. Classical EDS (cEDS) is principally caused by heterozygous COL5A1 or COL5A2 variants and rarely by the COL1A1 p.(Arg312Cys) substitution. Current major criteria are (1) skin hyperextensibility plus atrophic scars and (2) generalized joint hypermobility (gJHM). Minor criteria include additional mucocutaneous signs, epicanthal folds, gJHM complications, and an affected first-degree relative. Minimal criteria prompting molecular testing are major criterion 1 plus either major criterion 2 or 3 minor criteria. In addition to these features, the clinical picture also involves multiple organ systems, but large-scale cohort studies are still missing. This study aimed to investigate the multisystemic involvement and natural history of cEDS through a cross-sectional study on a cohort of 75 molecularly confirmed patients evaluated from 2010 to 2019 in a tertiary referral center. The diagnostic criteria, additional mucocutaneous, osteoarticular, musculoskeletal, cardiovascular, gastrointestinal, uro-gynecological, neuropsychiatric, and atopic issues, and facial/ocular features were ascertained, and feature rates compared by sex and age. RESULTS: Our study confirms that cEDS is mainly characterized by cutaneous and articular involvement, though none of their hallmarks was represented in all cases and suggests a milder multisystemic involvement and a more favorable natural history compared to other EDS subtypes. Abnormal scarring was the most frequent and characteristic sign, skin hyperextensibility and gJHM were less common, all without any sex and age bias; joint instability complications were more recurrent in adults. Some orthopedic features showed a high prevalence, whereas the other issues related to the investigated organ systems were less recurrent with few exceptions and age-related differences. CONCLUSIONS: Our findings define the diagnostic relevance of cutaneous and articular features and additional clinical signs associated to cEDS. Furthermore, our data suggest an update of the current EDS nosology concerning scarring that should be considered separately from skin hyperextensibility and that the clinical diagnosis of cEDS may be enhanced by the accurate evaluation of orthopedic manifestations at all ages, faciocutaneous indicators in children, and some acquired traits related to joint instability complications, premature skin aging, and patterning of abnormal scarring in older individuals.

Genome-first approach for the characterization of a complex phenotype with combined NBAS and CUL4B deficiency.

Biallelic variants in neuroblastoma-amplified sequence (NBAS) cause an extremely broad spectrum of phenotypes. Clinical features range from isolated recurrent episodes of liver failure to multisystemic syndrome including short stature, skeletal osteopenia and dysplasia, optic atrophy, and a variable immunological, cutaneous, muscular, and neurological abnormalities. Hemizygous variants in CUL4B cause syndromic X-linked intellectual disability characterized by limitations in intellectual functions, developmental delays in gait, cognitive, and speech functioning, and other features including short stature, dysmorphism, and cerebral malformations. In this study, we report on a 4.5-month-old preterm infant with a complex phenotype mainly characterized by placental-related severe intrauterine growth restriction, post-natal growth failure with spontaneous bone fractures, which led to a suspicion of osteogenesis imperfecta, and lethal bronchopulmonary dysplasia with pulmonary hypertension. Whole exome sequencing identified compound heterozygosity for a known frameshift and a novel missense variant in NBAS and hemizygosity for a known CUL4B nonsense mutation. In vitro functional studies on the novel NBAS missense substitution demonstrated altered Golgi-to-endoplasmic reticulum retrograde vesicular trafficking and reduced collagen secretion, likely explaining part of the patient's phenotype. We also provided a comprehensive overview of the phenotypic features of NBAS and CUL4B deficiency, thus updating the recently emerging NBAS genotype-phenotype correlations. Our findings highlight the power of a genome-first approach for an early diagnosis of complex phenotypes.

Clinical and molecular characterization of an 18-month-old infant with autosomal recessive cutis laxa type 1C due to a novel LTBP4 pathogenic variant, and literature review.

BACKGROUND: Cutis laxa (CL) is a group of rare connective tissue disorders mainly characterized by wrinkled, redundant, inelastic, and sagging skin. Besides skin anomalies, in most CL forms multiple organs are involved, leading to severe multisystem disorders involving skeletal, cardiovascular, pulmonary, and central nervous systems. CL might be challenging to diagnose because of its different inheritance patterns, extensive phenotypic variability, and genetic heterogeneity. Herein, we report the clinical and molecular characterization of an 18-month-old infant with signs suggestive of recessive cutis laxa type 1C (ARCL1C), although with a relatively mild presentation. METHODS: To confirm the clinical suspicion, mutational screening of all the exons and intron-flanking regions of the latent transforming growth factor-beta binding protein 4 gene (LTBP4) was performed by Sanger sequencing on an ABI3130XL Genetic Analyzer. RESULTS: Apart from the presence of the dermatological hallmark, the reported patient did not show pulmonary emphysema, which is the most common and discriminative finding of ARCL1C together with gastrointestinal and urinary involvement. Indeed, pulmonary involvement only included episodes of respiratory distress and diaphragmatic eventration; intestinal dilation and tortuosity and hydronephrosis were also present. Molecular analysis disclosed the novel homozygous c.1450del (p.Arg484Glyfs*290) pathogenic variant in exon 12 of LTBP4, thus leading to the diagnosis of ARCL1C. CONCLUSION: Our findings expand both the knowledge of the clinical phenotype and the allelic repertoire of ARCL1C. The comparison of the patient's features with those of the other patients reported up to now offers future perspectives for clinical research in this field.

Further Defining the Phenotypic Spectrum of B3GAT3 Mutations and Literature Review on Linkeropathy Syndromes.

The term linkeropathies (LKs) refers to a group of rare heritable connective tissue disorders, characterized by a variable degree of short stature, skeletal dysplasia, joint laxity, cutaneous anomalies, dysmorphism, heart malformation, and developmental delay. The LK genes encode for enzymes that add glycosaminoglycan chains onto proteoglycans via a common tetrasaccharide linker region. Biallelic variants in XYLT1 and XYLT2, encoding xylosyltransferases, are associated with Desbuquois dysplasia type 2 and spondylo-ocular syndrome, respectively. Defects in B4GALT7 and B3GALT6, encoding galactosyltransferases, lead to spondylodysplastic Ehlers-Danlos syndrome (spEDS). Mutations in B3GAT3, encoding a glucuronyltransferase, were described in 25 patients from 12 families with variable phenotypes resembling Larsen, Antley-Bixler, Shprintzen-Goldberg, and Geroderma osteodysplastica syndromes. Herein, we report on a 13-year-old girl with a clinical presentation suggestive of spEDS, according to the 2017 EDS nosology, in whom compound heterozygosity for two B3GAT3 likely pathogenic variants was identified. We review the spectrum of B3GAT3-related disorders and provide a comparison of all LK patients reported up to now, highlighting that LKs are a phenotypic continuum bridging EDS and skeletal disorders, hence offering future nosologic perspectives.

Clinical and Molecular Characterization of Classical-Like Ehlers-Danlos Syndrome Due to a Novel TNXB Variant.

The Ehlers-Danlos syndromes (EDS) constitute a clinically and genetically heterogeneous group of connective tissue disorders. Tenascin X (TNX) deficiency is a rare type of EDS, defined as classical-like EDS (clEDS), since it phenotypically resembles the classical form of EDS, though lacking atrophic scarring. Although most patients display a well-defined phenotype, the diagnosis of TNX-deficiency is often delayed or overlooked. Here, we described an additional patient with clEDS due to a homozygous null-mutation in the TNXB gene. A review of the literature was performed, summarizing the most important and distinctive clinical signs of this disorder. Characterization of the cellular phenotype demonstrated a distinct organization of the extracellular matrix (ECM), whereby clEDS distinguishes itself from most other EDS subtypes by normal deposition of fibronectin in the ECM and a normal organization of the α5ß1 integrin.

Expanding the Clinical and Mutational Spectrum of Recessive AEBP1-Related Classical-Like Ehlers-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.

Genotypic Categorization of Loeys-Dietz Syndrome Based on 24 Novel Families and Literature Data.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder first described in 2005 featuring aortic/arterial aneurysms, dissections, and tortuosity associated with craniofacial, osteoarticular, musculoskeletal, and cutaneous manifestations. Heterozygous mutations in 6 genes (TGFBR1/2, TGFB2/3, SMAD2/3), encoding components of the TGF-ß pathway, cause LDS. Such genetic heterogeneity mirrors broad phenotypic variability with significant differences, especially in terms of the age of onset, penetrance, and severity of life-threatening vascular manifestations and multiorgan involvement, indicating the need to obtain genotype-to-phenotype correlations for personalized management and counseling. Herein, we report on a cohort of 34 LDS patients from 24 families all receiving a molecular diagnosis. Fifteen variants were novel, affecting the TGFBR1 (6), TGFBR2 (6), SMAD3 (2), and TGFB2 (1) genes. Clinical features were scored for each distinct gene and matched with literature data to strengthen genotype-phenotype correlations such as more severe vascular manifestations in TGFBR1/2-related LDS. Additional features included spontaneous pneumothorax in SMAD3-related LDS and cervical spine instability in TGFB2-related LDS. Our study broadens the clinical and molecular spectrum of LDS and indicates that a phenotypic continuum emerges as more patients are described, although genotype-phenotype correlations may still contribute to clinical management.

A classical Ehlers-Danlos syndrome family with incomplete presentation diagnosed by molecular testing.

The 2017 EDS revised nosology indicates that minimal criteria suggestive for classical Ehlers-Danlos syndrome (cEDS) are skin hyperextensibility plus atrophic scarring together with either generalized joint hypermobility (gJHM) and/or at least three minor criteria that include cutaneous features and gJHM complications. Confirmatory molecular testing is obligatory to reach a final diagnosis. Although the large majority of the patients presents with these clinical features, some do not and might remain undiagnosed or misdiagnosed. Here we describe a family with 2 affected members, a 23-year-old proposita and her 51-year-old mother, who presented subtle cutaneous signs, including a variable degree of skin hyperextensibility without extensive widened atrophic scars that apparently better fitted with the overlapping hypermobile EDS. The proposita also presented gastrointestinal symptoms secondary to aberrant mast cells mediators release, making the clinical picture even more puzzling. Both patients were diagnosed by molecular testing that revealed a COL5A1 splice mutation. This report highlights the relevance of molecular analysis in patients presenting rather mild signs of EDS, especially in familial cases, and the importance of clinical expertise to make such a diagnosis.

A novel MAP3K7 splice mutation causes cardiospondylocarpofacial syndrome with features of hereditary connective tissue disorder.

Heterozygous variants in MAP3K7, encoding the transforming growth factor-ß-activated kinase 1 (TAK1), are associated with the ultrarare cardiospondylocarpofacial syndrome (CSCFS). Specific gain-of-function variants in the same gene cause the allelic frontometaphyseal dysplasia type 2. Phenotypic series of frontometaphyseal dysplasia also comprise variants in FLNA (type 1) and two patients with a heterozygous variant in TAB2 (type 3). We report on a 7-year-old girl with CSCFS due to the novel heterozygous c.737-7A>G variant in MAP3K7. The identified variant generates a new splice acceptor site causing an in-frame insertion of 2 amino acid residues (p.Asn245_Gly246insValVal), as demonstrated by RNA study. The patient was originally ascertained for a presumed hereditary connective tissue disorder due to soft/dystrophic skin, extreme joint hypermobility, polyvalvular heart disease, and upper gastrointestinal dismotility. Our study confirms locus homogeneity for CSCFS, expands the mutational spectrum of MAP3K7, and adds data on the existence of a community of connective tissue disorders caused by abnormalities of the TAK1-dependent signaling pathway.