Musculocontractural Ehlers‐Danlos Syndrome (former EDS type VIB) and adducted thumb clubfoot syndrome (ATCS) represent a single clinical entity caused by mutations in the dermatan‐4‐sulfotransferase 1 encoding CHST14 gene

We present clinical and molecular findings of three patients with an EDS VIB phenotype from two consanguineous families. The clinical findings of EDS kyphoscoliotic type (EDS type VIA and B) comprise kyphoscoliosis, muscular hypotonia, hyperextensible, thin and bruisable skin, atrophic scarring, joint hypermobility and variable ocular involvement. Distinct craniofacial abnormalities, joint contractures, wrinkled palms, and normal urinary pyridinoline ratios distinguish EDS VIB from EDS VIA. A genome‐wide SNP scan and sequence analyses identified a homozygous frameshift mutation (NM_130468.2:c.145delG, NP_569735.1:p.Val49*) in CHST14, encoding dermatan‐4‐sulfotransferase 1 (D4ST‐1), in two Turkish siblings. Subsequent sequence analysis of CHST14 identified a homozygous 20‐bp duplication (NM_130468.2:c.981_1000dup, NP_569735.1:p.Glu334Glyfs*107) in an Indian patient. Loss‐of‐function mutations in CHST14 were recently reported in adducted thumb–clubfoot syndrome (ATCS). Patients with ATCS present similar craniofacial and musculoskeletal features as the EDS VIB patients reported here, but lack the severe skin manifestations. By identifying an identical mutation in patients with EDS VIB and ATCS, we show that both conditions form a phenotypic continuum. Our findings confirm that the EDS‐variant associated with CHST14 mutations forms a clinical spectrum, which we propose to coin as “musculocontractural EDS” and which results from a defect in dermatan sulfate biosynthesis, perturbing collagen assembly. Hum Mutat 31:1–7, 2010. © 2010 Wiley‐Liss, Inc.     

Genetic Heterogeneity and Clinical Variability in Musculocontractural Ehlers–Danlos Syndrome Caused by Impaired Dermatan Sulfate Biosynthesis

Bi‐allelic variants in CHST14, encoding dermatan 4‐O‐sulfotransferase‐1 (D4ST1), cause musculocontractural Ehlers–Danlos syndrome (MC‐EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies. Recently, the identification of bi‐allelic variants in DSE, encoding dermatan sulfate epimerase‐1 (DS‐epi1), in a child with MC‐EDS features, suggested locus heterogeneity for this condition. DS‐epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondroitin sulfate (CS)/DS glycosaminoglycans (GAGs). Here, we report four novel families with severe MC‐EDS caused by unique homozygous CHST14 variants and the second family with a homozygous DSE missense variant, presenting a somewhat milder MC‐EDS phenotype. The glycanation of the dermal DS proteoglycan decorin is impaired in fibroblasts from D4ST1‐ as well as DS‐epi1‐deficient patients. However, in D4ST1‐deficiency, the decorin GAG is completely replaced by CS, whereas in DS‐epi1‐deficiency, still some DS moieties are present. The multisystemic abnormalities observed in our patients support a tight spatiotemporal control of the balance between CS and DS, which is crucial for multiple processes including cell differentiation, organ development, cell migration, coagulation, and connective tissue integrity.     

Loss‐of‐function mutations of CHST14 in a new type of Ehlers‐Danlos syndrome

Ehlers‐Danlos syndrome (EDS) is a heterogeneous connective tissue disorder involving skin and joint laxity and tissue fragility. A new type of EDS, similar to kyphoscoliosis type but without lysyl hydroxylase deficiency, has been investigated. We have identified a homozygous CHST14 (carbohydrate sulfotransferase 14) mutation in the two familial cases and compound heterozygous mutations in four sporadic cases. CHST14 encodes dermatan 4‐O‐sulfotransferase 1 (D4ST1), which transfers active sulfate from 3′‐phosphoadenosine 5′‐phosphosulfate to position 4 of the N‐acetyl‐D‐galactosamine (GalNAc) residues of dermatan sulfate (DS). Transfection experiments of mutants and enzyme assays using fibroblast lysates of patients showed the loss of D4ST1 activity. CHST14 mutations altered the glycosaminoglycan (GAG) components in patients' fibroblasts. Interestingly, DS of decorin proteoglycan, a key regulator of collagen fibril assembly, was completely lost and replaced by chondroitin sulfate (CS) in the patients' fibroblasts, leading to decreased flexibility of GAG chains. The loss of the decorin DS proteoglycan due to CHST14 mutations may preclude proper collagen bundle formation or maintenance of collagen bundles while the sizes and shapes of collagen fibrils are unchanged as observed in the patients' dermal tissues. These findings indicate the important role of decorin DS in the extracellular matrix and a novel pathomechanism in EDS. Hum Mutat 31:1–9, 2010. © 2010 Wiley‐Liss, Inc.     

Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems

Background

Heterozygous mutations in the COL1A1 or COL1A2 gene encoding the α1 and α2 chain of type I collagen generally cause either osteogenesis imperfecta or the arthrochalasis form of Ehlers‐Danlos syndrome (EDS). Homozygous or compound heterozygous COL1A2 mutations resulting in complete deficiency of the proα2(I) collagen chains are extremely rare and have been reported in only a few patients, albeit with variable phenotypic outcome.

Methods

The clinical features of the proband, a 6 year old boy, were recorded. Analysis of proα and α‐collagen chains was performed by SDS‐polyacrylamide gel electrophoresis using the Laemmli buffer system. Single stranded conformation polymorphism analysis of the proband''s DNA was also carried out.

Results

In this report we show that complete lack of proα2(I) collagen chains can present as a phenotype reminiscent of mild hypermobility EDS during childhood.

Conclusions

Biochemical analysis of collagens extracted from skin fibroblasts is a powerful tool to detect the subset of patients with complete absence of proα2(I) collagen chains, and in these patients, careful cardiac follow up with ultrasonography is highly recommended because of the risk for cardiac valvular problems in adulthood.     

Ehlers-Danlos type VIII, periodontitis-type: further delineation of the syndrome in a four-generation pedigree

The periodontitis type of Ehlers-Danlos syndrome (EDS type VIII) is distinguished from other subtypes of EDS by severe periodontitis leading to premature loss of permanent teeth. A limited number of patients and pedigrees with this condition have been described. We report a four-generation EDS VIII kindred with a phenotype of joint hypermobility, normal scar formation but eventual scar atrophy, and severe periodontal disease. Similar to other subtypes of EDS, the age of onset and severity of symptoms were variable amongst affected individuals, confirming the presence of intra-familial variability in this subtype. This pedigree is not linked to the previously reported region, confirming genetic locus heterogeneity in EDS type VIII.     

Vascular Ehlers-Danlos syndrome presenting as rapidly progressive multiple arterial aneurysms and dissections

Life expectancy in vascular Ehlers-Danlos syndrome (EDS) is shortened due to spontaneous rupture of arteries, the colon and the gravid uterus. Two adolescent males with vascular EDS illustrate rapid progression of arterial aneurysms, dissections, and rupture. Radiologic imaging played an important role in initially diagnosing and monitoring the evolution of arterial involvement. Both prophylactic and emergency management remain largely ineffective in this connective tissue disorder; however, noninvasive imaging may provide important prognostic information.     

Elastic fiber abnormalities in hypermobility type Ehlers-Danlos syndrome patients with tenascin-X mutations

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders with characteristic skin and joint involvement. The concept that EDS is a disease of fibrillar collagen was challenged by the identification of a clinically distinct, recessive type of EDS caused by deficiency of the extracellular matrix protein tenascin-X (TNX). Interestingly, haploinsufficiency of TNX is associated with the dominantly inherited hypermobility type of EDS. In this study, we examined whether missense mutations in the TNX gene can account for some of the cases of hypermobility type EDS. Furthermore, we studied whether missense mutations or heterozygosity for truncating mutations in the TNX gene lead to alterations in the dermal connective tissue. Sequence analysis revealed three missense mutations in TNX in hypermobility type EDS patients, which were not present in 192 control alleles. Morphometric analysis of skin biopsies of these patients showed altered elastic fibers in one of them, suggesting that this missense mutation is disease causing. Light microscopic and ultrastructural changes of the elastic fibers were observed in TNX-haploinsufficient hypermobility type EDS patients, which were not found in hypermobility type EDS patients in whom TNX mutations were excluded. Our results indicate that the observed alterations in elastic fibers are specific for hypermobility type EDS patients with mutations of TNX.     

Silver-Russell 综合征研究进展

Silver-Russell综合征是一组遗传异质性的疾病,主要临床表现为胎儿严重的宫内生长发育迟缓及出生后生长发育迟缓和矮身材。1953年Silver等首先报道报告了2例先天性的躯体不对称、低体重、矮身材、尿中促性腺激素增高的病例。以后陆续有零散病例报告。目前研究发现此病有三种遗传方式:即母源第7号染色体单亲双体、常染色体显性遗传及常染色体隐性遗传。本文综述了Silver-Russell综合征的临床诊断标准及研究进展。     

Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood

The Ehlers-Danlos syndromes (EDS) form a clinically and genetically heterogeneous group of inherited connective-tissue disorders characterized by joint hypermobility, tissue fragility and skin abnormalities. Six subtypes have been well characterized based on clinical features and molecular genetic abnormalities. The arthrochalasia type EDS (formerly types VIIA and B) is characterized by severe generalized joint hypermobility with multiple dislocations including congenital bilateral dislocation of the hips, muscular hypotonia and distinct dysmorphic features. The diagnosis of the arthrochalasia type EDS is of importance in the neonatal period because of consequences of physical disability in later life. However, the differential diagnosis may be difficult because of overlap with other hypermobility syndromes. In addition, the significant hypotonia may direct the physician toward various neuromuscular diagnoses. As patients become older, the hypotonia decreases and facial features become less distinct. In this report, we describe seven patients at different ages. Timing of diagnosis varied from prenatal life to adult age. The diagnosis of EDS type VII was confirmed by biochemical studies or mutation analysis showing characteristic mutations in COL1A1 and COL1A2. These mutations result in skipping of exon 6, which leads to defective collagen synthesis. For physicians treating patients with EDS type VII, achieving mobility for the patient is the greatest challenge and it may be impossible because of recurrent dislocations of nearly all joints in severe cases.     

Exploring relationships between joint hypermobility and neurodevelopment in children (4–13 years) with hereditary connective tissue disorders and developmental coordination disorder

Joint hypermobility (JH) is a common, though largely ignored physical trait with increasing clinical reverberations. A few papers suggest a link between JH and selected neurodevelopmental disorders, such as developmental coordination disorder (DCD). JH is also the hallmark of various hereditary connective tissue disorders (HCTDs). Children with HCTDs may present abnormal neurodevelopment but its manifestations remain undetermined. This study examined 23 children (group 1), aged 4–13 years, with different HCTDs (i.e., 19 with hypermobile Ehlers‐Danlos syndrome (EDS)/hypermobility spectrum disorder, 3 with molecularly confirmed classical EDS, and 1 with Loeys‐Dietz syndrome type 1 due to TGFBR2 mutation) and 23, age‐ and sex‐matched children with DCD (group 2). All underwent 14 different psychometric tests exploring motor, cognitive, executive‐attentive, and emotional‐behavior features. In group 1, 30%, 22%, and 13% patients presented DCD (with or without dysgraphia), learning disabilities, and attention deficit‐hyperactivity disorder, respectively. None had cognitive delay. In group 2, 17% patients presented generalized JH and none had HCTDs. DCD children presented more motor and coordination troubles than HCTDs patients, while quality of life of children with HCTDs resulted more deteriorated due to somatic manifestations and behavioral traits. This study presents the full overview of neurodevelopmental attributes in HCTDs, and compares with standardized tools the neurodevelopmental profile of children with DCD and HCTDs. While the high rate of neurodevelopmental comorbidities in HCTDs deserves attention, the impact of a dysfunctional connective tissue in children with a primary diagnosis of DCD needs more research.     

Hypermobile Ehlers–Danlos syndrome: A review and a critical appraisal of published genetic research to date

The Ehlers–Danlos syndromes (EDS) are a collection of rare hereditary connective tissue disorders with heterogeneous phenotypes, usually diagnosed following clinical examination and confirmatory genetic testing. Diagnosis of the commonest subtype, hypermobile Ehlers–Danlos Syndrome (hEDS), relies solely on a clinical diagnosis since its molecular aetiology remains unknown. We performed an up-to-date literature search and selected 11 out of 304 publications according to a set of established criteria. Studies reporting variants affecting collagen proteins were found to be hindered by cohort misclassification and subsequent lack of reproducibility of these genetic findings. The role of the described variants affecting Tenascin-X and LZTS1 is yet to be demonstrated in the majority of hEDS cases, while the functional implication of associated signaling pathways and genes requires further elucidation. The available literature on the genetics of hEDS is scant, dispersed and conflicting due to out-dated nosology terminology. Recent literature has suggested the role of several promising candidate mechanisms which may be linked to the underlying molecular aetiology. Knowledge of the molecular genetic basis of hEDS is expected to increase in the near future through the mainstream use of high-throughput sequencing combined with the updated classification of EDS, and the upcoming Hypermobile Ehlers–Danlos Genetic Evaluation (HEDGE) study.     

Homozygosity for a null allele of COL3A1 results in recessive Ehlers�CDanlos syndrome

So far, mutations in the human COL3A1 gene have been associated with the predominantly inherited Ehlers–Danlos syndrome (EDS), vascular type. Genotype–phenotype correlation perspectives collapsed, as haploinsufficiency, which was long suggested to confer a milder or unrecognized phenotype, was reported in four patients with a phenotype similar to that of vascular EDS. Here, we study a case of recessive EDS in a young consanguineous girl of healthy parents. She fulfilled the vascular EDS criteria for laboratory testing. Total sequencing of COL3A1 cDNA identified a homozygous nucleotide duplication (c.479dupT) resulting in a premature termination codon (p.Lys161GlnfsX45). Studies in genomic DNA showed that this mutation was inherited from each parent. The expression analysis (RT-PCR, quantitative-PCR, immunohistochemistry, WB) showed strong mRNA decay and an absence of type III collagen in the proband. The expected COL3A1 haploinsufficiency in her healthy ascendants did not lead to the manifestations of vascular EDS. This case provides evidence of a stochastic effect of COL3A1 haploinsufficiency in humans, which could be explained by the relation between nonsense-mediated mRNA decay efficiency and the resulting dominant-negative effect depending on the position of the mutation and/or modifying factors. It opens up new perspectives for the understanding of COL3A1 genotype–phenotype correlations, which is required while considering targeted therapy.     

Recognizing the tenascin‐X deficient type of Ehlers–Danlos syndrome: a cross‐sectional study in 17 patients

The tenascin‐X (TNX) deficient type Ehlers–Danlos syndrome (EDS) is similar to the classical type of EDS. Because of the limited awareness among geneticists and the challenge of the molecular analysis of the TNXB gene, the TNX‐deficient type EDS is probably to be under diagnosed. We therefore performed an observational, cross‐sectional study. History and physical examination were performed. Results of serum TNX measurements were collected and mutation analysis was performed by a combination of next‐generation sequencing (NGS), Sanger sequencing and multiplex ligation‐dependent probe amplification (MLPA). Included were 17 patients of 11 families with autosomal recessive inheritance and childhood onset. All patients had hyperextensible skin without atrophic scarring. Hypermobility of the joints was observed in 16 of 17 patients. Deformities of the hands and feet were observed frequently. TNX serum level was tested and absent in 11 patients (seven families). Genetic testing was performed in all families; 12 different mutations were detected, most of which are suspected to lead to non‐sense mRNA mediated decay. In short, patients with the TNX‐deficient type EDS typically have generalized joint hypermobility, skin hyperextensibility and easy bruising. In contrast to the classical type, the inheritance pattern is autosomal recessive and atrophic scarring is absent. Molecular analysis of TNXB in a diagnostic setting is challenging.     

Mitral valve prolapse and aortic root dilation in adults with hypermobile Ehlers–Danlos syndrome and related disorders

Ehlers–Danlos syndromes (EDSs) are a group of inherited connective tissue disorders, and among them, classical EDS (cEDS) and hypermobile EDS (hEDS) are the most common. Mitral valve prolapse (MVP) and aortic root dilation (ARD) have previously been reported to occur at an increased frequency within cEDS and hEDS. More recently, a study performed in the pediatric population did not show increased prevalence (Ritter et al., American Journal of Medical Genetics Part A, 173(6), 1467–1472, 2017). The purpose of this study was to review a large population of individuals with cEDS, hEDS, and hypermobility spectrum disorders to determine the frequency of MVP and ARD. A retrospective chart review of 209 individuals with echocardiograms was performed. Overall, 6.4% (13/209) had MVP and 1.6% (3/189) were found to have ARD. Although the presence of MVP is higher than what has been reported in the general population, no patients had severe MVP or required surgical intervention. No patients in this cohort had an aortic root diameter requiring surgical repair. Based on the results of this study and previous studies, routine echocardiograms to assess for valvular diseases and ARD may not be necessary unless warranted by presence of symptoms or family history.     

Ehlers–Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia

Some variants that cause autosomal‐recessive congenital adrenal hyperplasia (CAH) also cause hypermobility type Ehlers–Danlos syndrome (EDS) due to the monoallelic presence of a chimera disrupting two flanking genes: CYP21A2, encoding 21‐hydroxylase, necessary for cortisol and aldosterone biosynthesis, and TNXB, encoding tenascin‐X, an extracellular matrix protein. Two types of CAH tenascin‐X (CAH‐X) chimeras have been described with a total deletion of CYP21A2 and characteristic TNXB variants. CAH‐X CH‐1 has a TNXB exon 35 120‐bp deletion resulting in haploinsufficiency, and CAH‐X CH‐2 has a TNXB exon 40 c.12174C>G (p.Cys4058Trp) variant resulting in a dominant‐negative effect. We present here three patients with biallelic CAH‐X and identify a novel dominant‐negative chimera termed CAH‐X CH‐3. Compared with monoallelic CAH‐X, biallelic CAH‐X results in a more severe phenotype with skin features characteristic of classical EDS. We present evidence for disrupted tenascin‐X function and computational data linking the type of TNXB variant to disease severity.     

Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria

Type V collagen mutations are associated with classic Ehlers–Danlos Syndrome (EDS), but it is unknown for which proportion they account and to what extent other genes are involved. We analyzed COL5A1 and COL5A2 in 126 patients with a diagnosis or suspicion of classic EDS. In 93 patients, a type V collagen defect was found, of which 73 were COL5A1 mutations, 13 were COL5A2 mutations and seven were COL5A1 null‐alleles with mutation unknown. The majority of the 73 COL5A1 mutations generated a COL5A1 null‐allele, whereas one‐third were structural mutations, scattered throughout COL5A1. All COL5A2 mutations were structural mutations. Reduced availability of type V collagen appeared to be the major disease‐causing mechanism, besides other intra‐ and extracellular contributing factors. All type V collagen defects were identified within a group of 102 patients fulfilling all major clinical Villefranche criteria, that is, skin hyperextensibility, dystrophic scarring and joint hypermobility. No COL5A1/COL5A2 mutation was detected in 24 patients who displayed skin and joint hyperextensibility but lacked dystrophic scarring. Overall, over 90% of patients fulfilling all major Villefranche criteria for classic EDS were shown to harbor a type V collagen defect, which indicates that this is the major—if not only—cause of classic EDS. Hum Mutat 33:1485–1493, 2012. © 2012 Wiley Periodicals, Inc.     

Don't change that (calcium) channel: mutations in the same calcium channel gene can cause multiple distinct phenotypes

Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4 Deng et al. (2010) Nature Genetics 42(2):165–169 Mutations in TRPV4 cause Charcot–Marie–Tooth disease type 2C Landouré et al. (2010) Nature Genetics 42(2):170–174 Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C Auer‐Grumbach et al. (2010) Nature Genetics 42(2):160–164     

Pain and sleep quality in children with non‐vascular Ehlers–Danlos syndromes

The objective of this study was to explore the factors contributing to quality of life in pediatric patients with non‐vascular Ehlers–Danlos syndromes (EDS). Data were analyzed on 41 children with a diagnosis of non‐vascular EDS from the de‐identified data available from the National Institute on Aging (NIA) study of heritable disorders of connective tissue. Children under age 19 years were seen as part of a long‐term evaluation project from 2003 to 2013 on a larger natural history of patients with heritable disorders of connective tissue. Data collected included medical history, physical examination findings, diagnostic study results, and responses on validated questionnaires. We reviewed a sub‐cohort of children with a diagnosis of non‐vascular EDS and explored pain severity and interference via the Brief Pain Inventory, and sleep quality via the Pittsburgh Sleep Quality Index. Pain severity had a strong correlation with pain interference, and both were similar to other disorders that include chronic pain reported in the literature. Sleep quality did not correlate with pain severity or interference, but all patients had poor sleep quality in comparison to historical controls. We conclude that pain and sleep are significant issues in the pediatric non‐vascular EDS population, and future research may be directed toward these issues.