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Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis associated with biallelic pathogenic variants in EFEMP1 have been previously described in four patients. Genome sequencing on a proband and her mother with comparable phenotypic features revealed that both patients were heterozygous for a stop-gain variant c.1084C>T (p.Arg362*). Complementary RNA-seq on fibroblasts revealed significantly reduced levels of mutant EFEMP1 transcript. Considering the absence of other molecular explanations, we extrapolated that EFEMP1 could be the cause of the patient's phenotypes. Furthermore, nonsense-mediated decay was demonstrated for the mutant allele as the principal mechanism for decreased levels of EFEMP1 mRNA. We provide strong clinical and genetic evidence for the haploinsufficiency of EFEMP1 due to nonsense-medicated decay to cause severe kyphoscoliosis, generalized hypermobility of joints, high and narrow arched palate, and potentially severe diverticulosis. To the best of our knowledge, this is the first report of an autosomal dominant EFEMP1-associated hereditary connective tissue disorder and therefore expands the phenotypic spectrum of EFEMP1 related disorders., (© 2024 Wiley Periodicals LLC.)

Czech dysplasia is an autosomal dominant type 2 collagenopathy that is caused by heterozygosity for the recurrent p.(Arg275Cys) COL2A1 variant. Affected individuals usually present with skeletal abnormalities such as metatarsal hypoplasia of the third and fourth toes and early-onset arthropathy, as well as hearing loss. To date, no ophthalmic findings have been reported in patients with Czech dysplasia even though COL2A1 has been implicated in other ocular conditions such as type 1 Stickler syndrome. For the first time, we report the ocular findings in four families with Czech dysplasia, including type 1 vitreous anomaly, hypoplastic vitreous, retinal tears, and significant refractive error. These novel ocular findings expand the phenotype associated with Czech dysplasia and may aid clinicians as an additional diagnostic feature. Patients with congenital abnormalities of vitreous gel architecture have an increased risk of retinal detachment, and as such, patients may benefit from prophylaxis. Considering that many of the patients did not report any ocular symptoms, vitreous phenotyping is of key importance in identifying the need for counseling with regard to prophylaxis., (© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

The aim of the present study was to investigate the nature and prevalence of nonspecific somatic symptoms, pain and catastrophizing in children with Heritable Connective Tissue Disorders (HCTD), and to determine their association with disability. This observational, multicenter study included 127 children, aged 4-18 years, with Marfan syndrome (MFS) (59%), Loeys-Dietz syndrome (LDS) (8%), Ehlers-Danlos syndromes (EDS) (12%) and hypermobile Ehlers-Danlos syndrome (hEDS) (23%). The assessments included the Children's Somatization Inventory or parent proxy (CSI, PCSI), pain visual-analogue scale (VAS), SUPERKIDZ body diagram, Pain Catastrophizing Scale Child or parent proxy (PCS-C, PCS-P) and Childhood Health Assessment Questionnaire (CHAQ-30). Data from children aged ≥8 years were compared to normative data. In children ≥ 8 years (n = 90), pain was present in 59%, with a median of 4 (IQR = 3-9) pain areas. Compared to normative data, the HCTD group reported significantly higher on the CSI (p ≤ 0.001, d = 0.85), VAS pain intensity (p ≤ 0.001, d = 1.22) and CHAQ-30 (p ≤ 0.001, d = 1.16) and lower on the PCS-C (p = 0.017, d = -0.82) and PCS-P (p ≤ 0.001, d = -0.49). The intensity of nonspecific somatic symptoms and pain explained 45% of the variance in disability (r 2  = 0.45 F(2,48) = 19.70, p ≤ 0.001). In children ≤ 7 years (n = 37),   pain was present in 35% with a median of 5(IQR = 1-13) pain areas. The mean(SD) VAS scores for pain intensity was 1.5(2.9). Functional disability was moderately correlated to the number of pain areas (r = 0.56, p ≤ 0.001), intensity of nonspecific somatic symptoms (r = 0.63, p ≤ 0.001) and pain (r = 0.83, p ≤ 0.001). In conclusion, this study supports the need for comprehensive assessment of nonspecific somatic symptoms, pain, and disability in children with HCTD to allow tailored treatment., (© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Heritable connective tissue disorders (HCTDs) consist of a wide array of genetic disorders such as Ehlers-Danlos syndrome, Marfan syndrome, and osteogenesis imperfecta. The diagnosis relies on clinical presentation and family history to guide genetic testing with next-generation sequencing (NGS) for identification of gene variants in HCTDs. NGS was performed on a cohort of 100 consecutive, unrelated patients referred for a connective tissue disorder at Fulgent Genetics, an accredited commercial laboratory. One hundred seventeen gene variants were found in 76 patients with 10 recognized pathogenic or likely pathogenic variants seen in nine patients. The remaining variants were grouped as unknown clinical significance with 36 meeting three out of four pathogenicity criteria, or potentially pathogenic, as defined in our study in 33 patients. They were judged as potentially pathogenic for clinical care and management with disease surveillance based on the specific gene and phenotypic presentation. Gene variants in collagen-related proteins were the most frequent with ZNF469 and ADAMTSL2 variants most often identified. Joint hypermobility was the most frequent clinical finding. Variants were found in 76% of patients who had distinct clinical features of a HCTD. The data were stratified to provide insight into frequency and types of variants, their classification, and clinical manifestations., (© 2022 Wiley Periodicals LLC.)

The psychosocial consequences of growing up with Heritable Connective Tissue Disorders (HCTD) are largely unknown. We aimed to assess Health-Related Quality of Life (HRQoL) and mental health of children and adolescents with HCTD. This observational multicenter study included 126 children, aged 4-18 years, with Marfan syndrome (MFS, n = 74), Loeys-Dietz syndrome (n = 8), molecular confirmed Ehlers-Danlos syndromes (n = 15), and hypermobile Ehlers-Danlos syndrome (hEDS, n = 29). HRQoL and mental health were assessed through the parent and child-reported Child Health Questionnaires (CHQ-PF50 and CHQ-CF45, respectively) and the parent-reported Strengths and Difficulties Questionnaire. Compared with a representative general population sample, parent-reported HRQoL of the HCTD-group showed significantly decreased Physical sum scores (p < 0.001, d = 0.9) and Psychosocial sum scores (p = 0.024, d = 0.2), indicating decreased HRQoL. Similar findings were obtained for child-reported HRQoL. The parent-reported mental health of the HCTD-group showed significantly increased Total difficulties sum scores (p = 0.01, d = 0.3), indicating decreased mental health. While the male and female MFS- and hEDS-subgroups both reported decreased HRQoL, only the hEDS-subgroup reported decreased mental health. In conclusion, children and adolescents with HCTD report decreased HRQoL and mental health, with most adverse outcomes reported in children with hEDS and least in those with MFS. These findings call for systematic monitoring and tailored interventions., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders characterized by hyperextensible skin, hypermobile joints, easy bruisability, and fragility of the connective tissues. The diagnosis is based on clinical assessment and phenotype-guided genetic testing. Most EDS subtypes can be confirmed by genetic testing except for hypermobile EDS. This study explored the utility of applying the 2017 EDS classification criteria and molecular genetic testing in establishing an EDS diagnosis in children. In this retrospective study, we reviewed 72 patients referred to a tertiary care center for evaluation of EDS who underwent one or more forms of genetic testing. Eighteen patients (18/72, 25%) met the clinical criteria for one of the EDS subtypes and of these, 15 (15/18, 83%) were confirmed molecularly. Fifty-four patients (54/72, 75%) had features that overlapped EDS and other syndromes associated with joint hypermobility but did not fully meet clinical criteria. Twelve of them (12/54, 22%) were later shown to have a positive molecular genetic diagnosis of EDS. Different molecular genetic tests were performed on the cohort of 72 patients (EDS panel, n = 44; microarray, n = 25; whole exome sequencing [WES], n = 9; single gene sequencing, n = 3; familial variant testing, n = 10; other genetic panels n = 3). EDS panel was completed in 44 patients (61%), and a molecular diagnosis was confirmed in nine of the patients who satisfied criteria for one of the EDS subtypes (9/12, 75%) and in nine of the patients who did not fully meet criteria (9/32, 28%). We observed a correlation between generalized joint hypermobility, poor healing, easy bruising, atrophic scars, skin hyperextensibility, and developmental dysplasia of the hip with a positive molecular result. This study provides guidance for the use of molecular genetic testing in combination with the 2017 clinical diagnostic criteria in children presenting with EDS characteristics., (© 2022 Wiley Periodicals LLC.)

Heritable connective tissue disorders are a group of diseases, each rare, characterized by various combinations of skin, joint, musculoskeletal, organ, and vascular involvement. Although kidney abnormalities have been reported in some connective tissue disorders, they are rarely a presenting feature. Here we present three patients with prominent kidney phenotypes who were found by whole exome sequencing to have variants in established connective tissue genes associated with Loeys-Dietz syndrome and congenital contractural arachnodactyly. These cases highlight the importance of considering connective tissue disease in children presenting with structural kidney disease and also serves to expand the phenotype of Loeys-Dietz syndrome and possibly congenital contractural arachnodactyly to include cystic kidney disease and cystic kidney dysplasia, respectively., (© 2021 Wiley Periodicals LLC.)

Robin sequence (RS) has many genetic and nongenetic causes, including isolated Robin sequence (iRS), Stickler syndrome (SS), and other syndromes (SyndRS). The purpose of this study was to determine if the presence and type of cleft palate varies between etiologic groups. A secondary endpoint was to determine the relationship of etiologic group, cleft type, and mortality. Retrospective chart review of patients with RS at two high-volume craniofacial centers. 295 patients with RS identified. CP was identified in 97% with iRS, 95% with SS, and 70% of those with SyndRS (p < .0001). U-shaped CP was seen in 86% of iRS, 82% with SS, but only 27% with SyndRS (p < .0001). At one institution, 12 children (6%) with RS died, all from the SyndRS group (p < .0001). All died due to medical comorbidities related to their syndrome. Only 25% of children who died had a U-shaped CP. The most common palatal morphology among those who died was an intact palate. U-shaped CP was most strongly associated with iRS and SS, and with a lower risk of mortality. RS with submucous CP, cleft lip and palate or intact palate was strongly suggestive of an underlying genetic syndrome and higher risk of mortality., (© 2021 Wiley Periodicals LLC.)

Tremendous progress has been made in understanding the etiology, pathogenesis, and treatment of inherited vascular connective tissue disorders. While new insights regarding disease etiology and pathogenesis have informed patient counseling and care, there are numerous obstacles that need to be overcome in order to achieve the full promise of precision medicine. In this review, these issues will be discussed in the context of Marfan syndrome and Loeys-Dietz syndrome, with additional emphasis on the pioneering contributions made by Victor McKusick., (© 2021 Wiley Periodicals LLC.)

Pathogenic heterozygous variants in PIEZO2 typically cause distal arthrogryposis type 5 (DA5) and the closely related Gordon syndrome (GS). Only one case of PIEZO2-related Marden-Walker syndrome (MWS) has been reported to date. We report the phenotypic features of a Saudi female patient with features consistent with MWS in whom we identified a novel de novo likely pathogenic variant in PIEZO2. Our case lends support to the link between PIEZO2 and MWS., (© 2020 Wiley Periodicals LLC.)

Ehlers-Danlos syndrome (EDS) consists of a heterogeneous group of genetically inherited connective tissue disorders. A family with three affected members over two generations with features of Dermatosparaxic EDS (dEDS) autosomal dominant transmission was reported by Desai et al. and having a heterozygous nonsynonymous missense variant of ADAMTSL2 (c.1261G > A; p. Gly421Ser). Variation in this gene is also reported to cause autosomal recessive geleophysic dysplasia. We report five unrelated patients with the Gly421Ser variant identified from a large series of patients presenting with features of connective tissue disorders, each with a positive family history consistent with autosomal dominant transmission. Clinical features of a connective tissue disorder included generalized joint hypermobility and pain with fragility of internal and external tissues including of skin, dura, and arteries. Overall, our analyses including bioinformatics, protein modeling, and gene-protein interactions with the cases described would add evidence for the Gly421Ser variant in ADAMTSL2 as causative for variable expressivity of autosomal dominant connective tissue disorders., (© 2020 Wiley Periodicals LLC.)

We report the clinical findings of 26 individuals from 16 unrelated families carrying variants in the COL2A1 or COL11A1 genes. Using Sanger and next-generation sequencing, 11 different COL2A1 variants (seven novel), were identified in 13 families (19 affected individuals), all diagnosed with Stickler syndrome (STL) type 1. In nine families, the COL2A1 disease-causing variant arose de novo. Phenotypically, we observed myopia (95%) and retinal detachment (47%), joint hyperflexibility (92%), midface retrusion (84%), cleft palate (53%), and various degrees of hearing impairment (50%). One patient had a splenic artery aneurysm. One affected individual carrying pathogenic variant in COL2A1 showed no ocular signs including no evidence of membranous vitreous anomaly. In three families (seven affected individuals), three novel COL11A1 variants were found. The propositus with a de novo variant showed an ultrarare Marshall/STL overlap. In the second family, the only common clinical sign was postlingual progressive sensorineural hearing impairment (DFNA37). Affected individuals from the third family had typical STL2 signs. The spectrum of disease phenotypes associated with COL2A1 or COL11A1 variants continues to expand and includes typical STL and various bone dysplasias, but also nonsyndromic hearing impairment, isolated myopia with or without retinal detachment, and STL phenotype without clinically detectable ocular pathology., (© 2020 John Wiley & Sons Ltd/University College London.)

Purpose: To explore an early, rapid and precise diagnosis of Stickler syndrome type I (STL1) and to enrich the spectrum of COL2A1 mutations in the Chinese population, which is poorly studied at present., Methods: In the current study, we analysed 115 patients with high myopia by next-generation sequencing and identified five STL1 patients from four unrelated Chinese families. The clinical features of all patients were reviewed in detail., Results: Four variants of COL2A1 were identified, including two novel variants (c.1435delG and c.184delG) and two previously reported variants (c.1221+1G>A and c.1030C>T). Three variants caused premature termination codons which were common in STL1. In addition, we proposed a new diagnostic tactic to improve early diagnostics of STL1 in patients., Conclusion: In this study, our findings expanded the spectrum of COL2A1 mutations with two novel variants and provided a new diagnostic tactic for reference, which was of great significance. Precise diagnosis on the basis of clinical manifestations and genetic testing will become the gold standard to diagnose inherited ocular disorders or syndromes in the future., (© 2019 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Marfan Syndrome (MFS) is an autosomal dominant connective tissue disorder with a wide range of severities. Ninety-five percent of MFS probands have a mutation in the fibrillin-1 gene (FBN1); however, there are a high number of unique mutations complicating attempts at establishing any phenotype-genotype correlations for this disease (Tiecke et al., European Journal of Human Genetics, 2001, 9, 13-21). One of the few extant genotype-phenotype correlations is in exon 24-32 which have been associated with a severe pediatric presentation of neonatal MFS with predominately cardiovascular symptoms. We present a 24-year-old male patient with a heterozygous de novo variant NM&#95;000138.4: c.3037G>A (p.G1013R) located in exon 25 of the FBN1 gene. The patient was found to have dysplastic mitral and tricuspid valves with dilated aortic root at 9 months of age. This is a notable case in that the location of this patient's mutation and his age of symptom onset would indicate a guarded prognosis. Further, this mutation, FBN1 G1013R, has been reported in the literature in four other unrelated patients all of whom presented at a young age with cardiac involvement and all of whom had relative longevity when compared to other patients with mutations in this exon 24-32 hot spot. These findings may represent a more specific genotype-phenotype correlation within this mutational hot spot., (© 2020 Wiley Periodicals, Inc.)

Familial amniotic band sequence (ABS) is rare but has been reported in the offspring of mothers with connective tissue disorders. We present a family of two half-siblings with ABS who share the same biological father. Following a serious vascular event a de novo pathogenic variant in COL3A1 was detected in the father, confirming a diagnosis of vascular Ehlers-Danlos syndrome (vEDS). The same variant was found in both his ABS-affected children but not in his unaffected child. The amniotic membrane is derived from fetal tissue, type III collagen being a component. As the affected children are paternal half-siblings, ABS was less likely due to maternal factors. Rather, the amniotic bands may have resulted from decreased type III collagen production as seen in people with vEDS, causing fragility of the amniotic membrane. Consequently, it is important to consider vEDS in patients with ABS., (© 2019 Wiley Periodicals, Inc.)

Pontocerebellar hypoplasia type 9 (PCH9) is an autosomal recessive neurodevelopmental disorder caused by pathogenic variants in the AMPD2 gene. We evaluated the son of a consanguineous couple who presented with profound hypotonia and global developmental delay. Other features included sensorineural hearing loss, asymmetric astigmatism, and high myopia. Clinical whole-exome sequence analysis identified a homozygous missense variant in AMPD2 (NM&#95;001257360.1:c.2201C > T, p.[Pro734Leu]) that has not been previously reported. Given the strong phenotypic overlap with PCH9, including the identification of the typical "Figure 8" appearance of the brainstem on neuroimaging, we suspect this variant was causative of the neurodevelopmental disability in this individual. An additional homozygous nonsense variant in COL11A1 (NM&#95;001854.4:c.1168G > T, p.[Glu390Ter]) was identified. Variants in this alternatively spliced region of COL11A1 have been identified to cause an autosomal recessive form of Stickler syndrome type 2 characterized by sensorineural hearing loss and eye abnormalities, but without musculoskeletal abnormalities. The COL11A1 variant likely also contributed to the individual's phenotype, suggesting two potentially relevant genetic findings. This challenging case highlights the importance of detailed phenotypic characterization when interpreting whole exome data., (© 2019 Wiley Periodicals, Inc.)

Stickler syndrome (SS) is characterized by ophthalmic, articular, orofacial, and auditory manifestations. SS is usually autosomal dominantly inherited with variants in COL2A1 or COL11A1. Recessive forms are rare but have been described with homozygous variants in COL9A1, COL9A2, and COL9A3 and compound heterozygous COL11A1 variants. This article expands phenotypic descriptions in recessive SS due to variants in genes encoding Type IX collagen. Clinical features were assessed in four families. Genomic DNA samples derived from venous blood were collected from family members. Six affected patients were identified from four pedigrees with variants in COL9A1 (one family, one patient), COL9A2 (two families, three patients), and COL9A3 (one family, two patients). Three variants were novel. All patients were highly myopic with congenital megalophthalmos and abnormal, hypoplastic vitreous gel, and all had sensorineural hearing loss. One patient had severe arthropathy. Congenital megalophthalmos and myopia are common to dominant and recessive forms of SS. Sensorineural hearing loss is more common and severe in recessive SS. We suggest that COL9A1, COL9A2, and COL9A3 be added to genetic screening panels for patients with congenital hearing loss. Although recessive SS is rare, early diagnosis would have a high impact for children with potentially dual sensory impairment, as well as identifying risk to future children., (© 2019 Wiley Periodicals, Inc.)

We describe a data repository on heritable disorders of connective tissue (HDCT) assembled by the National Institutes of Health's National Institute on Aging (NIA) Intramural Research Program between 2001 and 2013. Participants included affected persons with a wide range of heritable connective tissue phenotypes, and unaffected family members. Elements include comprehensive history and physical examination, standardized laboratory data, physiologic measures and imaging, standardized patient-reported outcome measures, and an extensive linked biorepository. The NIA made a commitment to make the repository available to extramural investigators and deposited samples at Coriell Tissue Repository (N = 126) and GenTAC registry (N = 132). The clinical dataset was transferred to Penn State University College of Medicine Clinical and Translational Science Institute in 2016, and data elements inventoried. The consented cohort of 1,009 participants averaged 39 ± 18 years (mean ± SD, range 2-95) at consent; gender distribution is 71% F and 83% self-report Caucasian ethnicity. Diagnostic categories include Ehlers-Danlos syndrome (classical N = 50, hypermobile N = 99, vascular N = 101, rare types and unclassified N = 178), Marfan syndrome (N = 33), Stickler syndrome (N = 60), fibromuscular dysplasia (N = 135), Other HDCT (N = 72). Unaffected family members (N = 218) contributed DNA for the molecular archive only. We aim to develop further discrete data from unstructured elements, analyze multisymptom HDCT manifestations, encourage data use by other researchers and thereby better understand the complexity of these high-morbidity conditions and their multifaceted effects on affected persons., (© 2019 Wiley Periodicals, Inc.)

Biallelic variants in the AEBP1 gene cause a novel autosomal-recessive connective tissue disorder (CTD) reminiscent of Ehlers-Danlos Syndrome (EDS). The four previously reported individuals show considerable clinical variability. Unbiased high-throughput sequencing enables the rapid identification of additional cases for such rare entities. We identified the homozygous nonsense variant c.917dup, p.Tyr306* in AEBP1 using clinical exome sequencing in a female individual with previously unsolved CTD. Segregation testing confirmed homozygosity in the clinically affected brother and heterozygous carrier status in the healthy mother. Chromosomal microarray showed that the variant lies in a run of homozygosity, suggesting a common origin of this genomic segment. RT-PCR analysis in the mother revealed a monoallelic expression of the normal transcript supporting a nonsense-mediated mRNA decay and functional nullizygosity as disease mechanism. We describe two individuals from a fourth family with AEBP1-associated CTD. Our results further verify that autosomal-recessive inherited LOF variants in the AEBP1 gene cause clinical features of different EDS subtypes, but also of the marfanoid spectrum. As identification of further individuals is necessary to inform the clinical characterization, we stress the added value of exome sequencing for such rare diseases., (© 2018 Wiley Periodicals, Inc.)

Stickler syndrome is a connective tissue disorder characterized by hearing loss, ocular anomalies, palatal defects, and skeletal abnormalities. The autosomal dominant form is the most common, but autosomal recessive forms have also been described. We report the second case of autosomal recessive Stickler syndrome due to homozygosity for a loss of function mutation in COL9A3, which encodes the α3 chain of type IX procollagen. The clinical features were similar to the previously described COL9A3 Stickler syndrome family, including moderate to severe sensorineural hearing loss, high myopia, and both tibial and femoral bowing at birth. Radiographs demonstrated abnormal capital femoral epiphyses and mild irregularities of the vertebral endplates. This case further establishes the phenotype associated with mutations in this gene. We suggest that loss of the α3 chain of type IX collagen results in a Stickler syndrome phenotype similar to that of the other autosomal recessive forms caused by mutations in genes encoding the α1 and α2 chains of type IX collagen., (© 2018 Wiley Periodicals, Inc.)

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., (© 2018 Wiley Periodicals, Inc.)

In autosomal dominant skin disorders, the well-known type 1 segmental mosaicism reflects heterozygosity for a postzygotic new mutation. By contrast, type 2 segmental mosaicism originates in a heterozygous embryo from an early postzygotic mutational event giving rise to loss of the corresponding wild-type allele, which results in a pronounced segmental involvement being superimposed on the ordinary, non-segmental phenotype. Today, this concept has been proven by molecular analysis in many cutaneous traits. The purpose of this review was to seek publications of cases suggesting an extracutaneous manifestation of type 2 segmental mosaicism. Case reports documenting a pronounced extracutaneous segmental involvement were collected from the literature available in PubMed and from personal communications to the author. Pertinent cases are compared to the description of cutaneous segmental mosaicism of type 1 or type 2 as reported in a given trait. In total, reports suggesting extracutaneous type 2 segmental mosaicism were found in 14 different autosomal dominant skin disorders. In this way, clinical evidence is accumulated that extracutaneous type 2 segmental mosaicism does likewise occur in many autosomal dominant skin disorders. So far, however, molecular proof of this particular form of mosaicism is lacking. The present review may stimulate readers to inform colleagues of other specialties on this new concept, in order to initiate further research in this particular field of knowledge that has important implications for diagnosis, treatment and genetic counselling., (© 2018 European Academy of Dermatology and Venereology.)

The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen-encoding genes, or in genes encoding collagen-modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

The musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) has been recently recognized as a clinical entity. MC-EDS represents a differential diagnosis within the congenital neuromuscular and connective tissue disorders spectrum. Thirty-one and three patients have been reported with MC-EDS so far with bi-allelic mutations identified in CHST14 and DSE, respectively, encoding two enzymes necessary for dermatan sulfate (DS) biosynthesis. We report seven additional patients with MC-EDS from four unrelated families, including the follow-up of a sib-pair originally reported with the kyphoscoliotic type of EDS in 1975. Brachycephaly, a characteristic facial appearance, an asthenic build, hyperextensible and bruisable skin, tapering fingers, instability of large joints, and recurrent formation of large subcutaneous hematomas are always present. Three of seven patients had mildly elevated serum creatine kinase. The oldest patient was blind due to retinal detachment at 45 years and died at 59 years from intracranial bleeding; her affected brother died at 28 years from fulminant endocarditis. All patients in this series harbored homozygous, predicted loss-of-function CHST14 mutations. Indeed, DS was not detectable in fibroblasts from two unrelated patients with homozygous mutations. Patient fibroblasts produced higher amounts of chondroitin sulfate, showed intracellular retention of collagen types I and III, and lacked decorin and thrombospondin fibrils compared with control. A great proportion of collagen fibrils were not integrated into fibers, and fiber bundles were dispersed into the ground substance in one patient, all of which is likely to contribute to the clinical phenotype. This report should increase awareness for MC-EDS., Competing Interests: none., (© 2015 Wiley Periodicals, Inc.)

We present a girl with the characteristic clinical picture associated with Marden-Walker syndrome (MWS; OMIM 248700), including mask-like face with blepharophimosis, joint contractures, intellectual disability, a multicystic dysplastic kidney and cerebral dysgenesis. The long-term follow-up allowed us to monitor the evolution of the phenotype in this patient, and among the main findings we highlight the following: demyelination of the pyramidal tract demonstrated by transcranial magnetic stimulation and the involvement of the levator muscles of angle of mouth in fixed facial expression with relative integrity of the rest of the facial expression muscles. A 244 k array comparative genomic hybridization (aCGH) was carried out and showed a de novo interstitial deletion of approximately 2.84 Mb affecting only the cytoband 21q22.11 (genome coordinates chr21:31,874,016-34,711,763). We selected 10 of the most recent published cases with either total or partial deletions of cytoband 21q22.11 that provided good characterization of the genomic size or the genes in the deleted regions. We observed that in nine of the 10 cases the deleted regions included the RUNX1 gene in 21q22.12, which is not affected in the current patient's deletion or in that of Patient 3 from Roberson et al. [2011]. After a comparison of shared deleted genes between cases, and correlation of their potential phenotypes, we concluded that the pattern of defects considered for a diagnosis of MWS may represent part of the phenotypic expression of a partial or total deletion of 21q22.11., (Copyright © 2013 Wiley Periodicals, Inc.)

Evaluating a child with symptoms of easy bruising and/or bleeding remains a challenge in pediatric hematology, and there is no "one size fits all" approach. This review focuses on recent research in three elements of the evaluation of a child with a suspected bleeding disorder. We will first discuss the development of the standardized Pediatric Bleeding Questionnaire, and its applications in research and clinical settings. We will then discuss the relationship between benign hypermobility syndromes and hemostasis, and the importance of including a Beighton Score in the physical examination of any child presenting with unusual bruising or bleeding. While prolonged bleeding times and abnormal platelet aggregation are common findings in children with benign hypermobility, normal coagulation studies do not exclude the presence of a connective tissue disorder in a child presenting with easy bleeding and joint hypermobility on examination. Finally, we will discuss the current state of knowledge regarding the laboratory evaluation of platelet function in children. Platelet function disorders are among the most common inherited bleeding disorders. However, testing for such disorders is time-consuming and requires a step-wise approach. We will review the indications for and limitations of the most commonly utilized platelet function laboratory studies., (Copyright © 2012 Wiley Periodicals, Inc.)

Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disorder, mainly characterized by tortuosity and elongation of the large- and medium-sized arteries with predisposition to stenoses and aneurysms. ATS is caused by mutations in the SLC2A10 gene, encoding for the facilitative glucose transporter 10 (GLUT10) and is described typically in pediatric patients. We report on a 51-year-old woman, originally ascertained because of unexplained widespread chronic pain and positive family history of aortic malformation. The main findings included aged appearance, congenital joint hypermobility, joint instability complications, chronic fatigue syndrome, progressive painful joint stiffness, abdominal hernias, pelvic prolapses, multiple cardiac valve prolapses, varicose veins, easy bruising, and gingival recession. Vascular imaging revealed kinking and anomalous origin of the aortic arch branches, marked tortuosity of the aorta, pulmonary and most middle arteries, and a small aneurysm of the splenic artery. SLC2A10 analysis disclosed homozygosity for the novel c.1411+1G>A splice mutation, leading to a 41 amino acids GLUT10 internal deletion. Expression study by immunofluorescence using healthy control cells showed lack of membrane internalization of GLUT10 in patient's skin fibroblasts. This report describes the first splice-site SLC2A10 mutation and increases to 19 the repertoire of known mutations in this gene. Comparison with the few previously published adult patients with ATS contributes to the natural history of this condition, which is probably under diagnosed within the expanding family of inherited connective tissue disorders., (Copyright © 2012 Wiley Periodicals, Inc.)

Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are rare, autosomal recessive disorders of the connective tissue caused by mutations in the gene encoding the anthrax toxin receptor 2 protein (ANTXR2) located on chromosome 4q21. Characteristically, these conditions present with overlapping clinical features, such as nodules and/or pearly papules, gingival hyperplasia, flexion contractures of the joints, and osteolytic bone defects. The present report describes a pair of sibs and three other JHF/ISH patients whose diagnoses were based on typical clinical manifestations and confirmed by histopathologic analyses and/or molecular analysis. A comparison of ISH and JHF, additional thoughts about new terminology (hyaline fibromatosis syndrome) and a modified grading system are also included., (Copyright © 2012 Wiley Periodicals, Inc.)

Objective: To investigate the abundance of autoantibodies to heterogeneous nuclear RNPs (hnRNPs) in systemic rheumatic diseases., Methods: Recombinant human hnRNPs A1, B1, C1, E1, F, Gi, H1, I, K, and P2 were prepared. Antibodies to these antigens were determined by Western blotting and by enzyme-linked immunosorbent assay (ELISA) (for hnRNPs B1, E1, F, and H1) in serum samples obtained from patients with chronic fatigue syndrome (control subjects) and from patients with various connective tissue diseases., Results: Western blotting analysis in 106 control subjects and 298 patients with a connective tissue disease revealed that antibodies to all tested hnRNP antigens, except hnRNP Gi, were significantly more prevalent in patients with Sjögren's syndrome (SS) than in control subjects. The highest reactivity was observed for hnRNPs B1, E1, F, and H1 (reactivity in >45% of patients with SS and in 2.8% of control subjects). Reactivity with hnRNPs B1, E1, F, and H1 was also evaluated by ELISA in 89 control subjects and 228 patients with a connective tissue disease. Reactivity with at least 2 of the 4 tested antigens was observed in 1.1% of control subjects, 16% of patients with systemic lupus erythematosus (SLE), and 18% of patients with SS. Reactivity with at least 3 of the 4 antigens was observed in 0% of the control subjects, 3.2% of patients with SLE, and 15% of patients with SS., Conclusion: Several hnRNPs are target antigens in SS. The combined presence of antibodies to several hnRNPs was strongly associated with connective tissue disease in general and with SS in particular., (Copyright © 2012 by the American College of Rheumatology.)

Stickler syndrome is characterized by ocular, auditory, skeletal, and orofacial abnormalities. We describe a family with autosomal recessive Stickler syndrome. The main clinical findings consisted of high myopia, vitreoretinal degeneration, retinal detachment, hearing loss, and short stature. Affected family members were found to have a homozygous loss-of-function mutation in COL9A2, c.843&#95;c.846 + 4del8. A family with autosomal recessive Stickler syndrome was previously described and found to have a homozygous loss-of-function mutation in COL9A1. COL9A1, COL9A2, and COL9A3 code for collagen IX. All three collagen IX α chains, α1, α2, and α3, are needed for formation of functional collagen IX molecule. In dogs, two causative loci have been identified in autosomal recessive oculoskeletal dysplasia. This dysplasia resembles Stickler syndrome. Recently, homozygous loss-of-function mutations in COL9A2 and COL9A3 were found to co-segregate with the loci. Together the data from the present study and the previous studies suggest that loss-of-function mutations in any of the collagen IX genes can cause autosomal recessive Stickler syndrome., (Copyright © 2011 Wiley-Liss, Inc.)

Important insights into the etiology of osteoporosis have been gained by the study of single gene disorders, including osteogenesis imperfecta. We report on the genetic mapping of geroderma osteodysplastica (GO), a rare autosomal recessive disorder of the connective tissue, characterized by wrinkly skin and severe osteoporosis. We undertook autozygosity mapping in one Libyan and four consanguineous Pakistani families with a total of 10 affected individuals to define a 4 Mb homozygous region on chromosome 1q24, which harbors the GO causative gene. No obvious candidate genes that encode known protein constituents of the extracellular matrix are found in the linked region. Importantly, our study demonstrates that GO is not allelic to wrinkly skin syndrome caused by mutations in ATP6V0A2., (Copyright (c) 2008 Wiley-Liss, Inc.)

The term autoinflammatory syndromes describes a distinct group of systemic inflammatory diseases apparently different from infectious, autoimmune, allergic and immunodeficient ones. Originally, it was almost synonymous with clinically defined hereditary periodic fever syndromes, including familial Mediterranean fever, hyper immunoglobulin D syndrome with periodic fever and tumor necrosis factor receptor-associated periodic syndrome. Similar but distinct periodic fever syndromes accompanied by urticarial rash, familial cold autoinflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurological cutaneous articular syndrome, have all been reportedly associated with CIAS1 mutations and are collectively called cryopyrin-associated periodic syndromes. Consequently, the concept of autoinflammatory syndromes has been spread to contain other systemic inflammatory diseases: rare hereditary diseases with or without periodic fevers, such as pyogenic sterile arthritis, pyoderma gangrenosum and acne syndrome, Blau syndrome and chronic recurrent multifocal osteomyelitis, and the more common collagen disease-like diseases, such as Behcet's disease, Crohn's disease, sarcoidosis and psoriatic arthritis. These diseases are all caused by or associated with mutations of genes regulating innate immunity and have common clinical features accompanied with activation of neutrophils and/or monocytes/macrophages. In this review, major autoinflammatory syndromes are summarized and the pathophysiology of related skin disorders is discussed in association with dysregulated innate immune signaling.

Myhre syndrome is a rare connective tissue disease characterized by nonprogressive stiffness of the large joints, short stature with a peculiar build, and a distinctive facial phenotype. Developmental delay is common. Three female patients have so far been described. Here, we report on a 16-year-old female with Myhre syndrome. She has vertebral defects, hypertrophic scar formation, and a stiff skin in addition to the features that have previously been reported in association with Myhre syndrome., (Copyright 2005 Wiley-Liss, Inc.)

Connective tissue nevi are benign hamartomas that usually appear as widespread, multiple, papular, skin lesions. They are subdivided into collagen, elastin, proteoglycans and mixed type, depending on their particular histopathologic features, and they often appear as a component of Buschke-Ollendorff Syndrome.

We report a 7.5-year-old boy with loose translucent skin, aortic dilatation, hyperextensible veins, recurrent respiratory problems, pectus excavatum, arthralgias, lax joints, mild epiphyseal dysplasia, and umbilical and inguinal hernias. He also has developmental delay, progressive bilateral sensorineural hearing loss, an unusual facial appearance, terminal digit hypoplasia with unusual radiographic changes in some of the phalanges, glandular hypospadias, shawl scrotum, and undescended testes. Biochemical investigations, including electrophoresis of Types 1 and 3 procollagens and collagens, and quantification of serum copper and ceruloplasmin, are normal. Relative to age-matched control patients the electron micrographs of the boy's dermis show elastin fibers to be decreased in number, and abnormal in appearance, with a low matrix to microfibril ratio. The organ distribution of abnormalities and the nature of the findings suggest a connective tissue disorder. We contrast and compare this boy's phenotype to those of the classic connective tissue disorders. We conclude that he has cutis laxa with features that distinguish him from previously described types of cutis laxa., (Copyright 2003 Wiley-Liss, Inc.)

Weill-Marchesani syndrome is characterized by short stature, brachydactylyl, myopia, microspherophakia, lens dislocation, glaucoma, joint stiffness, restricted articular movements and facial features. The anesthetic management of an 11-year-old-male patient with diagnosis of this syndrome is reported.

The prevalence of mitral valve prolapse in Stickler syndrome has been reported to be much higher than in the general population. As a result, it has been recommended that all patients with Stickler syndrome undergo routine echocardiography and have antibiotic prophylaxis prior to surgery. The purpose of this study was to evaluate the prevalence of mitral valve prolapse in a large cohort of UK patients with Stickler syndrome in whom the clinical diagnosis has been confirmed by molecular genetic analysis. Probands and pedigrees were identified from the Vitreoretinal Service database according to previously published criteria. Ophthalmic, skeletal, audiometric, and orofacial features were assessed. Affected individuals underwent a full cardiological examination including auscultation and two-dimensional echocardiography. Mutation analysis of the COL2A1 and COL11A1 genes was carried out. Seventy-eight patients from 25 pedigrees were studied. Mutation analysis confirmed the clinical diagnosis in every pedigree. No patient was found to have clinical evidence of cardiovascular disease and no patient had significant mitral or other valvular prolapse on echocardiography. These data from a large cohort of UK patients with proven Stickler syndrome do not suggest an increased incidence of mitral valve prolapse over and above that found in the general population. Routine echocardiography screening and use of preoperative antibiotics are unnecessary and should be reserved for those individual cases where there is clear clinical indication., (Copyright 2002 Wiley-Liss, Inc.)

Computed morphometric analysis of elastic skin fibres in patients with cutis laxa, anetoderma, Williams-Beuren syndrome, pseudoxanthoma elasticum (PXE), and Buschke-Ollendorff syndrome, all clinically ascertained, was performed and compared with data obtained from healthy individuals of the same age. The diameters, area fractions (AA%) and volume fractions (VV%) occupied by pre-elastic fibres and dermal elastic fibres were determined. Irrespective of age the diameter of dermal elastic fibres followed a Gaussian distribution for all groups studied. These diameters were taken into consideration for VV% determinations. Compared with data from skin of healthy subjects of similar age range, VV% of pre-elastic fibres was significantly decreased in patients with cutis laxa, anetoderma, Williams-Beuren syndrome, and PXE and undetectable in Buschke-Ollendorff patients. VV% of dermal elastic fibres was four- to fivefold increased in Buschke-Ollendorff syndrome, two- to threefold increased in PXE skin, four- to fivefold decreased in cutis laxa and anetoderma skin and about twofold decreased in Williams-Beuren skin. The diameter of oxytalan fibres was decreased in anetoderma and Williams-Beuren syndrome while oxytalan fibre diameter was unchanged in PXE and cutis laxa. The diameter of dermal elastic fibres was increased in PXE and Buschke-Ollendorff syndrome, but was decreased in anetoderma and Williams-Beuren syndrome and unchanged in cutis laxa. We demonstrated that cutis laxa, anetoderma, Williams-Beuren syndrome, PXE, and Buschke-Ollendorff syndrome could be easily differentiated by morphometric analysis of elastic skin fibres. Thus we propose that morphometric analyses together with skin biopsies are a valuable tool for distinguishing between inherited and/or acquired skin diseases known to display alterations of elastic fibres.

Objective: Evaluation of hearing impairment as a feature of the nonocular Stickler syndrome (type II) linked to COL11A2., Study Design: Family study., Methods: General, orthopaedic, ophthalmologic, and otorhinolaryngologic examinations were performed on 15 affected persons in a Dutch family. Audiograms were obtained and/or retrieved from elsewhere. Cross-sectional and longitudinal analyses were conducted on the hearing threshold (sensorineural component) in relation to the patient's age to evaluate whether hearing impairment was progressive., Results: Mixed hearing loss, i.e., including a substantial air-bone gap of up to 20 to 60 dB, was present in six cases, concomitantly with a submucous or overt cleft palate in five of them. The audiograms in 14 evaluable cases showed the following types of threshold: U-shaped (n = 3), flat (n = 2), flat or gently (downward) sloping (n = 3), gently sloping (n = 3), or steeply sloping (n = 3). Cross-sectional analysis did not reveal any significant effect of age on sensorineural hearing impairment., Conclusion: In contrast to the classic Stickler syndrome (type I) with high myopia, this nonocular type shows a high prevalence of sensorineural hearing impairment. The mean sensorineural hearing threshold in our patients was about 40 dB HL (95% CI, 15-65 dB) and was liable to increase (presumably by presbycusis) by several tens of decibels at the highest frequencies. Given the tendency for otitis media to develop in many of these patients, appropriate otologic care is of major importance.

Objective: To determine the structure of T cell receptors (TCR) used by Sm-B-reactive human T cell clones, to map T cell epitopes on the Sm-B autoantigen, and to determine the HLA restriction element used in the recognition of Sm-B by T cells., Methods: Sm-B-reactive T cell clones were generated from patients with connective tissue disease by using either a recombinant fusion protein or synthetic peptides. The TCR structure was defined with the use of polymerase chain reaction and DNA sequencing. Synthetic peptides were used to map T cell epitopes on Sm-B. HLA restriction element usage was defined by using monoclonal antibody blocking., Results: Usage of the TCR third complementarity-determining region (CDR3) was highly restricted among Sm-B autoantigen-specific human T cell clones. Only amino acids 48-96 of the Sm-B2 autoantigen were recognized by T cells, and this occurred in the context of HLA-DR., Conclusion: TCR CDR3 gene usage is highly conserved by Sm-B autoantigen-specific T cell clones, and this appears to be related to the recognition of a limited number of T cell epitopes on the Sm-B autoantigen presented in the context of HLA-DR.

The type of bleeding symptom has been evaluated in 35 Iranian patients with an inherited deficiency of factor V, with plasma levels between 1% and 10%. The most frequent symptoms included epistaxis and excessive bleeding after surgery. Haemarthroses and muscle haematomas were less common, even in severely deficient patients. More severe symptoms such as gastrointestinal and central nervous system bleeding were rare. The severity of bleeding symptoms was only partially related to the degree of factor V deficiency in plasma. On the whole, human factor V deficiency is characterized by a moderately severe bleeding phenotype.

Objective: To determine, in a case-control study, if patients with new-onset juvenile dermatomyositis (juvenile DM) have increased symptoms prior to onset, exposure to certain environmental conditions, frequency of familial autoimmune diseases, or antibody titers, compared with 2 control groups., Methods: A structured interview with the families of 80 children with juvenile DM, 40 children with juvenile rheumatoid arthritis (JRA), or 23 healthy children, from the same geographic area as the children with juvenile DM, was conducted. All children's sera were tested for antibody to Toxoplasma gondii, herpes simplex virus (HSV), or coxsackievirus B (CVB)., Results: A high proportion of children with juvenile DM had constitutional symptoms 3 months before the disease-onset date (P = 0.013 versus control children). Children with JRA had more relatives with rheumatoid arthritis (P = 0.0001) and pernicious anemia (P = 0.003) than did children with juvenile DM or healthy children. Among children < or =7 years of age, elevated enteroviral titers were more frequent in those with juvenile DM (81%) and in healthy controls (90%) than in those with JRA (64%), suggesting a common environmental exposure. Titers to T gondii, HSV, or CVB 1-6 were normal., Conclusion: Frequencies of familial autoimmune disease, exposure to environmental factors, or elevated antibody titers to T gondii, HSV, or CVB are not increased in juvenile DM. Children with juvenile DM do have symptoms of illness 3 months before the disease-onset date, and young patients have elevated enteroviral titers, as do young geographic controls.

Objective: To determine the prevalence of anti-U1 RNA antibodies in connective tissue disease (CTD) patients and evaluate immunogenetic and clinical features of patients possessing these antibodies., Methods: RNA immunoprecipitation was used to analyze patient and healthy control sera for the presence of anti-R1 RNA antibodies. Enzyme-linked immunosorbent assay and immunoblotting were used to determine small nuclear RNP (snRNP) polypeptide antibodies. HLA polymorphisms were determined by microcytotoxicity and DNA typing., Results: Anti-U1 RNA IgM and IgG antibodies were found in 60% of anti-RNP positive patients. All of the anti-U1 RNA positive patients had anti-70K, and most had anti-A, (U1)snRNP polypeptide antibodies. HLA-DR2/DR4, as well as Raynaud's phenomenon and synovitis, were significantly increased in the anti-U1 RNA positive group., Conclusion: The presence of anti-U1 RNA antibodies correlates with anti-70K and anti-A polypeptide antibodies. In addition, the anti-U1 RNA positive CTD patient group is immunogenetically and clinically distinctive from the anti-U1 RNA negative patient group.