Publications by authors named "Tomoki Kosho"

116 Publications

Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation.

Sci Adv 2021 Jan 20;7(4). Epub 2021 Jan 20.

Stem Cell Biochemistry Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.

Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in , encoding a K48/K63 linkage-specific deubiquitylase. By studying these mutations, we find that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Our study describes a previously unidentified disorder we name LINKED (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects) syndrome and reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis.
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http://dx.doi.org/10.1126/sciadv.abe2116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817106PMC
January 2021

Endoplasmic reticulum stress and collagenous formation anomalies in vascular-type Ehlers-Danlos syndrome via electron microscopy.

J Dermatol 2021 Feb 1. Epub 2021 Feb 1.

Department of Dermatology, Dokkyo Medical University School of Medicine, Mibu, Japan.

Vascular-type Ehlers-Danlos syndrome (vEDS) is an autosomal-dominant inherited disorder caused by a deficit in collagen III. It results from heterogeneous mutations in the α1 collagen III gene (COL3A1) and is associated with life-threatening complications, even in younger patients. However, the details of the pathogenesis underlying the COL3A1 mutation causing vEDS remain unclear. Here, we focus on anomalies in collagen fiber size and the endoplasmic reticulum (ER) stress response in patients with vEDS using electron microscopy (EM). We discovered that although the infants did not have vEDS, collagenous formations were similar to their samples in vEDS. Moreover, we examined the expression of activating transcription factor 6 (ATF6) as an ER stress marker and cartilage oligomeric matrix protein (COMP) as a binding partner protein for collagen fibrils in the dermis and COL3A1. The expression levels of ATF6 in the vEDS group were significantly higher than in infants and controls; COMP and COL3A1 levels were significantly lower. The fragile collagen fibrils in vEDS might form as a result of ER stress and that small, newly formed collagen fibrils may appear. This research revealed a novel prospect regarding an issue that has been unclear for a long time, which is the reason for the abnormal sizes of collagenous fibrils in vEDS.
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http://dx.doi.org/10.1111/1346-8138.15766DOI Listing
February 2021

Intracranial and extracranial multiple arterial dissecting aneurysms in rheumatoid arthritis: A case report.

Interv Neuroradiol 2020 Oct 20:1591019920965359. Epub 2020 Oct 20.

Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan.

Objective: We describe a case of intracranial and extracranial multiple arterial dissecting aneurysms in rheumatoid arthritis (RA).

Case Presentation: A 29-year-old man with a medical history of RA since 18 years of age was admitted to our hospital for vomiting, dysarthria, and conscious disturbance. At 23, he underwent ligation of the left internal carotid artery (ICA) with superficial temporal artery to middle cerebral artery anastomosis because of acute infarct of the left hemisphere caused by arterial dissection of the left ICA. During the current admission, computed tomography (CT) revealed subarachnoid hemorrhage, and digital subtraction angiography (DSA) demonstrated dissecting aneurysms of the left intracranial vertebral artery (VA) and right extracranial VA. We diagnosed him with a ruptured dissecting aneurysm of the left intracranial VA and performed endovascular parent artery occlusion on the left VA. For the right unruptured VA aneurysm, we performed coil embolization simultaneously. At 2 weeks after the endovascular treatment, follow-up DSA revealed that multiple dissecting aneurysms developed on the origin of the left VA and left and right internal thoracic arteries. Those aneurysms were treated with coil embolization. Other remaining aneurysms on the left thyrocervical trunk, right transverse cervical artery, and both common iliac arteries were treated by conservative therapy. While continuing medical treatment for RA, the patient recovered and was discharged to a rehabilitation hospital.

Conclusion: Considering that RA-induced vasculitis can be a potential risk of vascular complications including multiple arterial dissections, physicians should carefully perform endovascular interventional procedures for patients with long-term RA.
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http://dx.doi.org/10.1177/1591019920965359DOI Listing
October 2020

Marked motor function improvement in a 32-year-old woman with childhood-onset hypophosphatasia by asfotase alfa therapy: Evaluation based on standardized testing batteries used in Duchenne muscular dystrophy clinical trials.

Mol Genet Metab Rep 2020 Dec 9;25:100643. Epub 2020 Sep 9.

Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Japan.

Hypophosphatasia (HPP) is a rare disorder resulting from biallelic loss-of-function variants or monoallelic dominant negative variants in the gene. We herein describe the clinical outcome of a 32-year-old woman with childhood-onset HPP caused by compound heterozygous variants in . Her chief complaints were severe musculoskeletal pain, muscle weakness, and impaired daily activities necessitating assistance in housework and child-rearing in addition to a history of early tooth loss and mildly short stature. Asfotase alfa therapy produced a remarkable increase in muscle strength and daily activities and markedly reduced musculoskeletal pain. Drug efficacy was clearly demonstrated through multiple test batteries (muscle strength test using microFET®2, six-minute walking test, Stair Climb Test, rising-from-floor-time test, and number-of-steps test using Actigraph®) currently adopted as standardized evaluations in Duchenne muscular dystrophy clinical trials since no test batteries for HPP have been established to date. These tests may also be promising for the assessment of HPP.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494508PMC
December 2020

Posterior Spinal Fusion for Severe Spinal Deformities in Musculocontractural Ehlers-Danlos Syndrome: Detailed Observation of a Novel Case and Review of 2 Reported Cases.

World Neurosurg 2020 Nov 19;143:454-461. Epub 2020 Aug 19.

Department of Orthopaedic Surgery, Shinshu University Hospital, Matsumoto, Japan.

Background: Musculocontractural Ehlers-Danlos syndrome caused by pathogenic variants in CHST14 (mcEDS-CHST14) is a recently delineated connective tissue disorder characterized by multisystem congenital malformations and progressive connective tissue fragility-related manifestations. With only 2 cases of mcEDS-CHST14 containing precise information on surgical spinal correction being reported to date, there remains no consensus on treatment standards. This study describes the detailed clinical and radiologic outcomes of the third known patient with mcEDS-CHST14 who successfully underwent surgery for severe kyphoscoliosis.

Case Description: The patient was a 19-year-old girl with mcEDS-CHST14 who suffered from low back pain and decreased daily activities caused by progressive kyphoscoliosis. She underwent posterior spinal fusion with an all-pedicle screw construct from T4 to L4 for a preoperative main curve Cobb angle of 69 degrees and kyphotic angle of 27 degrees. Postoperative Cobb angle of the main curve and kyphotic angle were 26 and 6 degrees, respectively. Although sufficient correction was achieved without disseminated intravascular coagulation or other serious sequelae, a large amount of blood (2600 g) was lost due to tissue fragility. Her low back pain was decreased at 1 year after surgery.

Conclusions: On the basis of the present and 2 earlier reported cases, posterior spinal fusion may be a reasonable surgical option for severe progressive spinal deformities in patients with mcEDS-CHST14. However, careful attention is needed for possible massive blood loss from tissue fragility.
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http://dx.doi.org/10.1016/j.wneu.2020.08.085DOI Listing
November 2020

The Ehlers-Danlos syndromes.

Nat Rev Dis Primers 2020 07 30;6(1):64. Epub 2020 Jul 30.

Department of Pathology and Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.

The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary disorders of connective tissue, with common features including joint hypermobility, soft and hyperextensible skin, abnormal wound healing and easy bruising. Fourteen different types of EDS are recognized, of which the molecular cause is known for 13 types. These types are caused by variants in 20 different genes, the majority of which encode the fibrillar collagen types I, III and V, modifying or processing enzymes for those proteins, and enzymes that can modify glycosaminoglycan chains of proteoglycans. For the hypermobile type of EDS, the molecular underpinnings remain unknown. As connective tissue is ubiquitously distributed throughout the body, manifestations of the different types of EDS are present, to varying degrees, in virtually every organ system. This can make these disorders particularly challenging to diagnose and manage. Management consists of a care team responsible for surveillance of major and organ-specific complications (for example, arterial aneurysm and dissection), integrated physical medicine and rehabilitation. No specific medical or genetic therapies are available for any type of EDS.
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http://dx.doi.org/10.1038/s41572-020-0194-9DOI Listing
July 2020

The First Experience of Denosmab Therapy on Patients with Ehlers-Danlos Syndrome and Osteoporosis: Detailed Observation of Two Patients.

Mod Rheumatol Case Rep 2020 Jul 21:1-14. Epub 2020 Jul 21.

Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan.

Previous studies have shown decreased bone mineral density (BMD) due to an unknown mechanism in Ehlers-Danlos Syndrome (EDS) patients and described approaches to treatment for osteoporosis in EDS. To date, however, there is no established method of treatment. In this study, we investigated two patients with EDS to clarify the efficacy and safety of denosumab treatment in EDS patients with osteoporosis. We retrospectively enrolled two EDS patients with osteoporosis who underwent denosumab therapy. Patient 1 was a 59-year-old male with classical EDS and osteoporosis who received a 48-month course of denosumab therapy. His lumbar BMD and total hip BMD were 1.335 g/cm and 0.762 g/cm before treatment, respectively. Forty-eight months later, the lumbar and total hip BMD showed gains of 1.6% and 11.4%, respectively.Patient 2 was a 42-year-old male with vascular EDS and osteoporosis who received an 18-month course of denosumab therapy. His lumbar BMD and total hip BMD were 0.763 g/cm and 0.583 g/cm before treatment, respectively. Eighteen months later, the lumbar and total hip BMD showed gains of 5.0% and 1.8%, respectively. No fractures or other complications were recorded during the observational period in both cases. This is the first experience of denosmab therapy on patients with EDS and osteoporosis. Denosumab, administered safely with no serious adverse effects such as fractures, exerted a fluctuating but probably positive effect regarding BMD and could be a treatment option on these patients.
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http://dx.doi.org/10.1080/24725625.2020.1799493DOI Listing
July 2020

Attitudes toward and current status of disclosure of secondary findings from next-generation sequencing: a nation-wide survey of clinical genetics professionals in Japan.

J Hum Genet 2020 Dec 13;65(12):1045-1053. Epub 2020 Jul 13.

Department of Medical Ethics and Medical Genetics, Kyoto University School of Public Health, Kyoto, Japan.

The management of secondary findings (SFs), which are beyond the intended purpose of the analysis, from clinical comprehensive genomic analysis using next generation sequencing (NGS) presents challenges. Policy statements regarding their clinical management have been announced in Japan and other countries. In Japan, however, the current status of and attitudes of clinical genetics professionals toward reporting them are unclear. We conducted a questionnaire survey of clinical genetics professionals at two time points (2013 and 2019) to determine the enforcement of the SF management policy in cases of comprehensive genetic analysis of intractable diseases and clinical cancer genome profiling testing. According to the survey findings, 40% and 70% of the respondents stated in the 2013 and 2019 surveys, respectively, that they had an SF policy in the field of intractable diseases, indicating that SF policy awareness in Japan has changed significantly in recent years. Furthermore, a total of 80% of respondents stated that their facility had established a policy for clinical cancer genome profiling testing in the 2019 survey. In both surveys, the policies included the selection criteria for genes to be disclosed and the procedure to return SFs, followed by recommendations and proposals regarding SFs in Japan and other countries. To create a better list of the genes to be disclosed, further examination is needed considering the characteristics of each analysis.
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http://dx.doi.org/10.1038/s10038-020-0802-2DOI Listing
December 2020

Systematic investigation of the skin in Chst14-/- mice: A model for skin fragility in musculocontractural Ehlers-Danlos syndrome caused by CHST14 variants (mcEDS-CHST14).

Glycobiology 2021 Feb;31(2):137-150

Laboratory of Veterinary Anatomy, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501, Japan.

Loss-of-function variants in CHST14 cause a dermatan 4-O-sulfotransferase deficiency named musculocontractural Ehlers-Danlos syndrome-CHST14 (mcEDS-CHST14), resulting in complete depletion of the dermatan sulfate moiety of decorin glycosaminoglycan (GAG) chains, which is replaced by chondroitin sulfate. Recently, we uncovered structural alteration of GAG chains in the skin of patients with mcEDS-CHST14. Here, we conducted the first systematic investigation of Chst14 gene-deleted homozygote (Chst14-/-) mice. We used skin samples of wild-type (Chst14+/+) and Chst14-/- mice. Mechanical fragility of the skin was measured with a tensile test. Pathology was observed using light microscopy, decorin immunohistochemistry and electron microscopy (EM) including cupromeronic blue (CB) staining. Quantification of chondroitin sulfate and dermatan sulfate was performed using enzymatic digestion followed by anion-exchange HPLC. In Chst14-/- mice, skin tensile strength was significantly decreased compared with that in Chst14+/+ mice. EM showed that collagen fibrils were oriented in various directions to form disorganized collagen fibers in the reticular layer. Through EM-based CB staining, rod-shaped linear GAG chains were found to be attached at one end to collagen fibrils and protruded outside of the fibrils, in contrast to them being round and wrapping the collagen fibrils in Chst14+/+ mice. A very low level of dermatan sulfate disaccharides was detected in the skin of Chst14-/- mice by anion-exchange chromatography. Chst14-/- mice, exhibiting similar abnormalities in the GAG structure of decorin and collagen networks in the skin, could be a reasonable model for skin fragility of patients with mcEDS-CHST14, shedding light on the role of dermatan sulfate in maintaining skin strength.
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http://dx.doi.org/10.1093/glycob/cwaa058DOI Listing
February 2021

Backcrossing to an appropriate genetic background improves the birth rate of carbohydrate sulfotransferase 14 gene-deleted mice.

Exp Anim 2020 Nov 10;69(4):407-413. Epub 2020 Jun 10.

Division of Animal Research, Research Center for Supports to Advanced Science, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.

Ehlers-Danlos syndromes (EDSs) are heterogeneous group of heritable connective tissue disorders characterized by joint and skin hyperextensibility as well as fragility of various organs. Recently, we described a new type of EDS, musculocontractual EDS (mcEDS-CHST14), caused by pathogenic variants of the carbohydrate sulfotransferase 14 (CHST14) gene mutation. B6;129S5-Chst14/Mmucd (B6;129-Chst14 KO) mice are expected to be an animal model of mcEDS-CHST14. However, >90% of B6;129-Chst14 KO homozygous (B6;129-Chst14) mice show perinatal lethality. Therefore, improvement of the birth rate of Chst14 mice is needed to clarify the pathophysiology of mcEDS-CHST14 using this animal model. Some B6;129-Chst14 embryos had survived at embryonic day 18.5 in utero, suggesting that problems with delivery and/or childcare may cause perinatal lethality. However, in vitro fertilization and egg transfer did not improve the birth rate of the mice. A recent report showed that backcrossing to C57BL/6 strain induces perinatal death of all Chst14 mice, suggesting that genetic background influences the birthrate of these mice. In the present study, we performed backcrossing of B6;129-Chst14 KO mice to a BALB/c strain, an inbred strain that shows lower risks of litter loss than C57BL/6 strain. Upon backcrossing 1 to 12 times, the birth rate of Chst14 mice was improved with a birth rate of 6.12-18.64%. These results suggest that the genetic background influences the birth rate of Chst14 mice. BALB/c congenic Chst14 (BALB.Chst14) mice may facilitate investigation of mcEDS-CHST14. Furthermore, backcrossing to an appropriate strain may contribute to optimizing animal experiments.
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http://dx.doi.org/10.1538/expanim.19-0150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677086PMC
November 2020

Posterior spinal fusion for severe kyphoscoliosis in a Loeys-Dietz syndrome patient with a large syringomyelia.

J Clin Neurosci 2020 Jun 21;76:211-213. Epub 2020 Apr 21.

Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.

Spinal deformity is a characteristic feature of Loeys-Dietz syndrome (LDS). Surgical correction in LDS is indicated when the deformity is progressive to avoid neurological deficits, respiratory impairment, and back pain. However, few reports exist on the surgical treatment of spinal deformity in LDS, and no therapeutic standards have been established. We described the clinical and radiological outcomes of a patient with LDS receiving surgery for severe kyphoscoliosis. A 21-year-old male patient with LDS underwent posterior spinal fusion with an all-pedicle screw construct from T10 to L5 for a preoperative main curve Cobb angle of 70 degrees and kyphotic angle of 49 degrees. The postoperative Cobb angle of the main curve and kyphotic angle improved to 36 and 8 degrees, respectively. Correction surgery was performed with frequent motor evoked potential testing, taking care not to cause motor paralysis. Ameliorated low back pain and improvements in clinical questionnaire scores were noted at 21 months after surgery. No perioperative complications were reported. Based on the present case, posterior spinal fusion represents a good correction option for severe spinal deformity in LDS with syringomyelia. Careful preoperative examination and treatment for neurovascular and neurological lesions is advised to prevent severe complications.
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http://dx.doi.org/10.1016/j.jocn.2020.04.017DOI Listing
June 2020

Delineation of musculocontractural Ehlers-Danlos Syndrome caused by dermatan sulfate epimerase deficiency.

Mol Genet Genomic Med 2020 05 4;8(5):e1197. Epub 2020 Mar 4.

Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Japan.

Background: Musculocontractural Ehlers-Danlos Syndrome (mcEDS) is a rare connective tissue disorder caused by biallelic loss-of-function variants in CHST14 (mcEDS-CHST14) or DSE (mcEDS-DSE), both of which result in defective dermatan sulfate biosynthesis. Forty-one patients with mcEDS-CHST14 and three patients with mcEDS-DSE have been described in the literature.

Methods: Clinical, molecular, and glycobiological findings in three additional patients with mcEDS-DSE were investigated.

Results: Three patients from two families shared craniofacial characteristics (hypertelorism, blue sclera, midfacial hypoplasia), skeletal features (pectus and spinal deformities, characteristic finger shapes, progressive talipes deformities), skin features (fine or acrogeria-like palmar creases), and ocular refractive errors. Homozygous pathogenic variants in DSE were found: c.960T>A/p.Tyr320* in patient 1 and c.996dupT/p.Val333Cysfs*4 in patients 2 and 3. No dermatan sulfate was detected in the urine sample from patient 1, suggesting a complete depletion of DS.

Conclusion: McEDS-DSE is a congenital multisystem disorder with progressive symptoms involving craniofacial, skeletal, cutaneous, and cardiovascular systems, similar to the symptoms of mcEDS-CHST14. However, the burden of symptoms seems lower in patients with mcEDS-DSE.
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http://dx.doi.org/10.1002/mgg3.1197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216804PMC
May 2020

Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.

Am J Med Genet A 2020 05 24;182(5):994-1007. Epub 2020 Feb 24.

Ehlers-Danlos Syndrome National Diagnostic Service, Northwick Park and St. Mark's Hospitals, Harrow, London, UK.

Arthrochalasia Ehlers-Danlos syndrome (aEDS) is a rare autosomal dominant connective tissue disorder that is characterized by congenital bilateral hip dislocations, severe generalized joint hypermobility, recurrent joint (sub)luxations, and skin hyperextensibility. To date, 42 patients with aEDS have been published. We report 12 patients with aEDS from 10 families with 6 unpublished individuals and follow-up data on 6 adult patients. The clinical features are largely comparable with patients reported in the literature. Most (n = 10) patients had variants leading to (partial) loss of exon 6 of the COL1A1 or COL1A2 genes. One patient did not have a previously reported likely pathogenic COL1A1 variant. Data regarding management were retrieved. Hip surgery was performed in 5/12 patients and 3/12 patients underwent spinal surgery. As much as 4/12 patients were wheelchair-bound or unable to walk unaided. Fractures were present in 9/12 individuals with 1 patient requiring bisphosphonate treatment. Echocardiograms were performed in 10 patients and 2 individuals showed an abnormality likely unrelated to aEDS. One patient gave birth to two affected children and went through preterm labor requiring medication but had no additional complications. Of the eight adults in our cohort, the majority entered a career. Our data point toward a genotype-phenotype relationship with individuals with aEDS due to pathogenic COL1A1 variants causing complete or partial loss of exon 6 being more severely affected regarding musculoskeletal features. There is a significant lack of knowledge with regard to management of aEDS, particularly in adulthood. As such, systematic follow-up and multidisciplinary treatment is essential.
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http://dx.doi.org/10.1002/ajmg.a.61523DOI Listing
May 2020

Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome.

Genes (Basel) 2019 12 29;11(1). Epub 2019 Dec 29.

Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Nagoya 468-8503, Japan.

Musculocontractural Ehlers-Danlos Syndome (mcEDS) is a type of EDS caused by biallelic pathogenic variants in the gene for carbohydrate sulfotransferase 14/dermatan 4--sulfotransferase 1 (/, mcEDS-), or in the gene for dermatan sulfate epimerase (, mcEDS-). Thus far, 41 patients from 28 families with mcEDS- and five patients from four families with mcEDS- have been described in the literature. Clinical features comprise multisystem congenital malformations and progressive connective tissue fragility-related manifestations. This review outlines recent advances in understanding the pathophysiology of mcEDS. Pathogenic variants in or lead to reduced activities of relevant enzymes, resulting in a negligible amount of dermatan sulfate (DS) and an excessive amount of chondroitin sulfate. Connective tissue fragility is presumably attributable to a compositional change in the glycosaminoglycan chains of decorin, a major DS-proteoglycan in the skin that contributes to collagen fibril assembly. Collagen fibrils in affected skin are dispersed in the papillary to reticular dermis, whereas those in normal skin are regularly and tightly assembled. Glycosaminoglycan chains are linear in affected skin, stretching from the outer surface of collagen fibrils to adjacent fibrils; glycosaminoglycan chains are curved in normal skin, maintaining close contact with attached collagen fibrils. Homozygous () mice have been shown perinatal lethality, shorter fetal length and vessel-related placental abnormalities. Milder phenotypes in mcEDS- might be related to a smaller fraction of decorin DS, potentially through residual DSE activity or compensation by DSE2 activity. These findings suggest critical roles of DS and DS-proteoglycans in the multisystem development and maintenance of connective tissues, and provide fundamental evidence to support future etiology-based therapies.
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http://dx.doi.org/10.3390/genes11010043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017038PMC
December 2019

Proximal Junctional Kyphosis After Posterior Spinal Fusion for Severe Kyphoscoliosis in a Patient With PIEZO2-deficient Arthrogryposis Syndrome.

Spine (Phila Pa 1976) 2020 May;45(10):E600-E604

Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.

Study Design: Case report.

Objective: Describe the clinical and radiological outcomes of a patient with a piezo-type mechanosensitive ion channel component 2 (PIEZO2)-deficient arthrogryposis receiving surgery for severe kyphoscoliosis.

Summary Of Background Data: Spinal deformity is a characteristic feature of arthrogryposis due to PIEZO2 gene deficiency, for which surgical correction is indicated when the deformity is progressive to avoid neurological deficits and respiratory impairment. However, there exist few reports on the surgical treatment of spinal deformity in PIEZO2-deficient arthrogryposis, and no therapeutic standards have been established.

Methods: We retrospectively reviewed a case of proximal junctional kyphosis after posterior spinal fusion for severe kyphoscoliosis in PIEZO2-deficient arthrogryposis.

Results: The patient was a 13-year-old girl with PIEZO2-deficient arthrogryposis who underwent posterior spinal fusion with an all-pedicle screw construct from T2 to L2 for a preoperative main thoracic curve Cobb angle of 78° and thoracic kyphotic angle of 83°. Postoperative Cobb angle of the main thoracic curve and thoracic kyphotic angle were improved at 11° and 34°, respectively. Although revision surgery was required for neurological deficits from proximal junctional kyphosis, she could walk with a crutch and improvements in clinical questionnaire scores were noted at 2 years and 3 months after surgery.

Conclusion: Based on the present case, posterior spinal fusion represents a good treatment option for severe spinal deformity in PIEZO2-deficient arthrogryposis. Careful consideration of fusion level is needed to prevent proximal junctional kyphosis.

Level Of Evidence: 5.
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http://dx.doi.org/10.1097/BRS.0000000000003347DOI Listing
May 2020

Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients.

J Hum Genet 2019 Dec 17;64(12):1173-1186. Epub 2019 Sep 17.

Department of Human Genetics, Graduate school of medicine, Yokohama City University, Yokohama, Japan.

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.
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http://dx.doi.org/10.1038/s10038-019-0667-4DOI Listing
December 2019

Mid-Frequency Hearing Loss Is Characteristic Clinical Feature of -Associated Hearing Loss.

Genes (Basel) 2019 09 16;10(9). Epub 2019 Sep 16.

Department of Otorhinolaryngology, School of Medicine, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.

The gene (Locus: DFNB22) is reported to be one of the causative genes for non-syndromic autosomal recessive hearing loss. The copy number variations (CNVs) identified in this gene are also known to cause hearing loss, but have not been identified in Japanese patients with hearing loss. Furthermore, the clinical features of -associated hearing loss have not yet been clarified. In this study, we performed CNV analyses of a large Japanese hearing loss cohort, and identified CNVs in 234 of 2262 (10.3%, 234/2262) patients with autosomal recessive hearing loss. Among the identified CNVs, gene-related CNVs were the second most frequent (0.6%, 14/2262). Among the 14 cases, 2 individuals carried homozygous deletions, 4 carried heterozygous deletions with single nucleotide variants (SNVs) in another allele. Additionally, 1 individual with homozygous SNVs in the gene was also identified. Finally, we identified 7 probands with OTOA-associated hearing loss, so that its prevalence in Japanese patients with autosomal recessive hearing loss was calculated to be 0.3% (7/2262). As novel clinical features identified in this study, the audiometric configurations of patients with -associated hearing loss were found to be mid-frequency. This is the first study focused on the detailed clinical features of hearing loss caused by this gene mutation and/or gene deletion.
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http://dx.doi.org/10.3390/genes10090715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770988PMC
September 2019

A case of septo-optic dysplasia with hereditary hemorrhagic telangiectasia: a previously unrecognized combination of malformations.

Clin Dysmorphol 2020 Jan;29(1):49-52

Department of Pediatrics, Oita University Faculty of Medicine, Yufu-City, Oita.

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http://dx.doi.org/10.1097/MCD.0000000000000278DOI Listing
January 2020

PIEZO2 deficiency is a recognizable arthrogryposis syndrome: A new case and literature review.

Am J Med Genet A 2019 06 2;179(6):948-957. Epub 2019 Apr 2.

Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan.

PIEZO2 encodes a mechanically activated cation channel, which is abundantly expressed in dorsal root ganglion neuron and sensory endings of proprioceptors required for light touch sensation and proprioception in mice. Biallelic loss-of-function mutations in PIEZO2 (i.e., PIEZO2 deficiency) were recently found to cause an arthrogryposis syndrome. Sixteen patients from eight families have been reported to date. Herein we report a new case, including detailed clinical characteristics and courses as well as comprehensive neurological features. The patient was a 12-year-old girl presenting with congenital multiple contractures, progressive severe scoliosis, prenatal-onset growth impairment, motor developmental delay with hypotonia and myopathy-like muscle pathology, mild facial features, and normal intelligence. Her neurological features included areflexia, impaired proprioception, and decreased senses. Neurophysiological examination revealed decreased amplitude of sensory nerve action potentials, absent H reflex, and prolongation of central conduction times. Clinical exome sequencing revealed a novel homozygous frameshift mutation in PIEZO2 (NM_022068: c.4171_4174delGTCA: p.Val1391Lysfs*39) with no detectable mRNA expression of the gene. PIEZO2 deficiency represents a clinical entity involving characteristic neuromuscular abnormalities and physical features. Next generation sequencing-based comprehensive molecular screening and extensive neurophysiological examination could be valuable for diagnosis of the disorder.
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http://dx.doi.org/10.1002/ajmg.a.61142DOI Listing
June 2019

Extremely young case of small bowel intussusception due to Peutz-Jeghers syndrome with nonsense mutation of STK11.

Clin J Gastroenterol 2019 Oct 19;12(5):429-433. Epub 2019 Mar 19.

Oncogene Research Unit/Cancer Prevention Unit, Tochigi Cancer Center Research Institute, Utsunomiya, Tochigi, Japan.

Intussusception is a frequent and severe complication of Peutz-Jeghers syndrome (PJS). We herein present the case of a 3-year-old girl who experienced jejuno-jejunal intussusception due to PJS polyps. Despite no apparent family history of PJS, she had exhibited mucocutaneous pigmentation since infancy and recurrent abdominal pain and vomiting from 2 years of age. Segmental resection of the jejunum during emergency laparotomy for the intussusception revealed multiple hamartomatous polyps. Genetic analysis uncovered a germline nonsense mutation of c.247A>T in exon 1 of serine/threonine kinase 11 (STK11). Biannual follow-up surveillance for polyps by esophagogastroduodenoscopy, colonoscopy, and small bowel capsule endoscopy is ongoing. Reports describing the clinical and genetic features of extremely young PJS with intussusceptions are rare, although a literature review of STK11 germline mutations revealed several other pediatric cases of complicating intussusception at ≤ 8 years old. Considering the recent advances in surveillance and treatment options for the small bowel, earlier management of symptomatic children with PJS may be warranted to avoid surgical emergency.
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http://dx.doi.org/10.1007/s12328-019-00964-0DOI Listing
October 2019

Familial Aortic Dissection in a Young Adult Caused by MYH11 Gene Mutation.

Ann Thorac Surg 2019 07 15;108(1):e49. Epub 2019 Mar 15.

Center for Medical Genetics, Shinshu University Hospital, Nagano, Japan.

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http://dx.doi.org/10.1016/j.athoracsur.2019.02.015DOI Listing
July 2019

Efficacy of denosumab therapy for a 21-year-old woman with Prader-Willi syndrome, osteoporosis and history of fractures: a case report.

Ther Clin Risk Manag 2019 25;15:303-307. Epub 2019 Feb 25.

Department of Orthopaedic Surgery, Shinshu University School of Medicine,

Appropriate management for osteoporosis in adult patients with Prader-Willi syndrome (PWS) has not been established. We report on a 21-year-old woman with PWS, who underwent denosumab treatment for osteoporosis. She presented with fractures and was shown to have very low bone mineral density (BMD), while she had been treated with supplementation of growth hormone for 7-14 years of age and estrogen from 15 years of age. BMD was monitored in the total hip region by dual-energy X-ray absorptiometry. Laboratory tests included bone-specific alkaline phosphatase, urinary type I collagen amino-terminal telopeptide, tartrate-resistant acid phosphatase 5b, 1-alpha, 25-dihydroxyvitamin D3, and parathyroid hormone. BMD and laboratory data were evaluated before and at 4, 8, and 13 months of treatment. After 13 months of denosumab therapy, BMD increased by 4.5%, and bone turnover markers notably improved. No fractures occurred. To the best of our knowledge, this is the first report to describe the clinical outcomes of denosumab treatment for osteoporosis in patients with PWS. Based on our findings, denosumab could represent an effective treatment option for osteoporosis in PWS patients.
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http://dx.doi.org/10.2147/TCRM.S186855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395054PMC
February 2019

Frequency and clinical features of hearing loss caused by STRC deletions.

Sci Rep 2019 03 13;9(1):4408. Epub 2019 Mar 13.

Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan.

Sensorineural hearing loss is a common deficit and mainly occurs due to genetic factors. Recently, copy number variants (CNVs) in the STRC gene have also been recognized as a major cause of genetic hearing loss. We investigated the frequency of STRC deletions in the Japanese population and the characteristics of associated hearing loss. For CNV analysis, we employed a specialized method of Ion AmpliSeq sequencing, and confirmed the CNV results via custom array comparative genomic hybridization. We identified 17 probands with STRC homozygous deletions. The prevalence of STRC homozygous deletions was 1.7% in the hearing loss population overall, and 4.3% among mild-to-moderate hearing loss patients. A 2.63% carrier deletion rate was identified in both the hearing loss and the control population with normal hearing. In conclusion, our results show that STRC deletions are the second most common cause of mild-to-moderate hearing loss after the GJB2 gene, which accounts for the majority of genetic hearing loss. The phenotype of hearing loss is congenital and appears to be moderate, and is most likely to be stable without deterioration even after the age of 50. The present study highlights the importance of the STRC gene as a major cause of mild-to-moderate hearing loss.
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http://dx.doi.org/10.1038/s41598-019-40586-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416315PMC
March 2019

A novel CACNA1A nonsense variant in a patient presenting with paroxysmal exertion-induced dyskinesia.

J Neurol Sci 2019 04 1;399:214-216. Epub 2019 Mar 1.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto 390-8621, Japan.

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http://dx.doi.org/10.1016/j.jns.2019.02.040DOI Listing
April 2019

Correction: The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.

Authors:
Pleuntje J van der Sluijs Sandra Jansen Samantha A Vergano Miho Adachi-Fukuda Yasemin Alanay Adila AlKindy Anwar Baban Allan Bayat Stefanie Beck-Wödl Katherine Berry Emilia K Bijlsma Levinus A Bok Alwin F J Brouwer Ineke van der Burgt Philippe M Campeau Natalie Canham Krystyna Chrzanowska Yoyo W Y Chu Brain H Y Chung Karin Dahan Marjan De Rademaeker Anne Destree Tracy Dudding-Byth Rachel Earl Nursel Elcioglu Ellen R Elias Christina Fagerberg Alice Gardham Blanca Gener Erica H Gerkes Ute Grasshoff Arie van Haeringen Karin R Heitink Johanna C Herkert Nicolette S den Hollander Denise Horn David Hunt Sarina G Kant Mitsuhiro Kato Hülya Kayserili Rogier Kersseboom Esra Kilic Malgorzata Krajewska-Walasek Kylin Lammers Lone W Laulund Damien Lederer Melissa Lees Vanesa López-González Saskia Maas Grazia M S Mancini Carlo Marcelis Francisco Martinez Isabelle Maystadt Marianne McGuire Shane McKee Sarju Mehta Kay Metcalfe Jeff Milunsky Seiji Mizuno John B Moeschler Christian Netzer Charlotte W Ockeloen Barbara Oehl-Jaschkowitz Nobuhiko Okamoto Sharon N M Olminkhof Carmen Orellana Laurent Pasquier Caroline Pottinger Vera Riehmer Stephen P Robertson Maian Roifman Caroline Rooryck Fabienne G Ropers Monica Rosello Claudia A L Ruivenkamp Mahmut S Sagiroglu Suzanne C E H Sallevelt Amparo Sanchis Calvo Pelin O Simsek-Kiper Gabriela Soares Lucia Solaeche Fatma Mujgan Sonmez Miranda Splitt Duco Steenbeek Alexander P A Stegmann Constance T R M Stumpel Saori Tanabe Eyyup Uctepe G Eda Utine Hermine E Veenstra-Knol Sunita Venkateswaran Catheline Vilain Catherine Vincent-Delorme Anneke T Vulto-van Silfhout Patricia Wheeler Golder N Wilson Louise C Wilson Bernd Wollnik Tomoki Kosho Dagmar Wieczorek Evan Eichler Rolph Pfundt Bert B A de Vries Jill Clayton-Smith Gijs W E Santen

Genet Med 2019 Sep;21(9):2160-2161

Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-018-0368-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752317PMC
September 2019

Structural alteration of glycosaminoglycan side chains and spatial disorganization of collagen networks in the skin of patients with mcEDS-CHST14.

Biochim Biophys Acta Gen Subj 2019 03 13;1863(3):623-631. Epub 2018 Dec 13.

Laboratory of Anatomy, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido, Japan. Electronic address:

Musculocontractural Ehlers-Danlos syndrome (mcEDS) due to CHST14/D4ST1 deficiency (mcEDS-CHST14) is a recently delineated type of EDS caused by biallelic loss-of-function mutations in CHST14, which results in the depletion of dermatan sulfate (DS). Clinical characteristics of mcEDS-CHST14 consist of multiple malformations and progressive fragility-related manifestations, including skin hyperextensibility and fragility. Skin fragility is suspected to result from the impaired assembly of collagen fibrils caused by alteration of the glycosaminoglycan (GAG) chain of decorin-proteoglycan (PG) from DS to chondroitin sulfate (CS). This systematic investigation of the skin pathology of patients with mcEDS-CHST14 comprised both immunostaining of decorin and transmission electron microscopy-based cupromeronic blue staining to visualize GAG chains. Collagen fibrils were dispersed in the affected papillary to reticular dermis; in contrast, they were regularly and tightly assembled in controls. Moreover, the fibrils exhibited a perpendicular arrangement to the affected epidermis, whereas fibrils were parallel to control epidermis. Affected GAG chains were linear, stretching from the outer surface of collagen fibrils to adjacent fibrils; in contrast, those of controls were curved, maintaining close contact with attached collagen fibrils. This is the first observation of compositional alteration, from DS to CS, of GAG side chains, which caused structural alteration of GAG side chains and resulted in spatial disorganization of collagen networks; this presumably disrupted the ring-mesh structure of GAG side chains surrounding collagen fibrils. McEDS-CHST14 provides a critical example of the importance of DS in GAG side chains of decorin-PG during assembly of collagen fibrils in maintenance of connective tissues.
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http://dx.doi.org/10.1016/j.bbagen.2018.12.006DOI Listing
March 2019

Efficacy and Safety of Denosumab Therapy for Osteogenesis Imperfecta Patients with Osteoporosis-Case Series.

J Clin Med 2018 11 24;7(12). Epub 2018 Nov 24.

Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.

Osteogenesis imperfecta (OI) is a connective tissue disorder that is characterized by low bone density leading to recurrent fractures. The efficacy of the anti-resorption drug denosumab for OI with osteoporosis is still largely unknown. We herein describe the clinical outcomes of eight osteoporotic cases of OI to examine the effects and safety of denosumab. This retrospective, consecutive case series included eight patients respectively aged 42, 40, 14, 22, 3, 51, 37, and 9 years. We measured the bone mineral density (BMD) of the lumbar 1⁻4 spine (L-BMD) and bilateral hips (H-BMD), bone-specific alkaline phosphatase, urinary type I collagen amino-terminal telopeptide, and tartrate-resistant acid phosphatase 5b before and during denosumab therapy. Despite multiple pretreatment fractures in the cohort, no fractures or severe side effects, such as hypocalcemia, were observed during the observational period apart from a fracture in a young pediatric girl. Both L-BMD and H-BMD were increased by denosumab in seven of eight cases. Bone turnover markers were inhibited in most cases by denosumab therapy. Denosumab treatment could generally raise BMD without any adverse effects. The agent therefore represents a good therapeutic option for OI with osteoporosis.
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http://dx.doi.org/10.3390/jcm7120479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306860PMC
November 2018

The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.

Authors:
Pleuntje J van der Sluijs Sandra Jansen Samantha A Vergano Miho Adachi-Fukuda Yasemin Alanay Adila AlKindy Anwar Baban Allan Bayat Stefanie Beck-Wödl Katherine Berry Emilia K Bijlsma Levinus A Bok Alwin F J Brouwer Ineke van der Burgt Philippe M Campeau Natalie Canham Krystyna Chrzanowska Yoyo W Y Chu Brain H Y Chung Karin Dahan Marjan De Rademaeker Anne Destree Tracy Dudding-Byth Rachel Earl Nursel Elcioglu Ellen R Elias Christina Fagerberg Alice Gardham Blanca Gener Erica H Gerkes Ute Grasshoff Arie van Haeringen Karin R Heitink Johanna C Herkert Nicolette S den Hollander Denise Horn David Hunt Sarina G Kant Mitsuhiro Kato Hülya Kayserili Rogier Kersseboom Esra Kilic Malgorzata Krajewska-Walasek Kylin Lammers Lone W Laulund Damien Lederer Melissa Lees Vanesa López-González Saskia Maas Grazia M S Mancini Carlo Marcelis Francisco Martinez Isabelle Maystadt Marianne McGuire Shane McKee Sarju Mehta Kay Metcalfe Jeff Milunsky Seiji Mizuno John B Moeschler Christian Netzer Charlotte W Ockeloen Barbara Oehl-Jaschkowitz Nobuhiko Okamoto Sharon N M Olminkhof Carmen Orellana Laurent Pasquier Caroline Pottinger Vera Riehmer Stephen P Robertson Maian Roifman Caroline Rooryck Fabienne G Ropers Monica Rosello Claudia A L Ruivenkamp Mahmut S Sagiroglu Suzanne C E H Sallevelt Amparo Sanchis Calvo Pelin O Simsek-Kiper Gabriela Soares Lucia Solaeche Fatma Mujgan Sonmez Miranda Splitt Duco Steenbeek Alexander P A Stegmann Constance T R M Stumpel Saori Tanabe Eyyup Uctepe G Eda Utine Hermine E Veenstra-Knol Sunita Venkateswaran Catheline Vilain Catherine Vincent-Delorme Anneke T Vulto-van Silfhout Patricia Wheeler Golder N Wilson Louise C Wilson Bernd Wollnik Tomoki Kosho Dagmar Wieczorek Evan Eichler Rolph Pfundt Bert B A de Vries Jill Clayton-Smith Gijs W E Santen

Genet Med 2019 06 8;21(6):1295-1307. Epub 2018 Nov 8.

Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting.

Methods: Clinicians entered clinical data in an extensive web-based survey.

Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified.

Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.
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http://dx.doi.org/10.1038/s41436-018-0330-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752273PMC
June 2019

Spinal manifestations in 12 patients with musculocontractural Ehlers-Danlos syndrome caused by CHST14/D4ST1 deficiency (mcEDS-CHST14).

Am J Med Genet A 2018 11 8;176(11):2331-2341. Epub 2018 Sep 8.

Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan.

Musculocontractural Ehlers-Danlos syndrome caused by mutations in CHST14 (mcEDS-CHST14) is a recently delineated disorder, characterized by craniofacial, skeletal, visceral, and ocular malformations; and progressive cutaneous, skeletal, vascular, and visceral fragility-related manifestations. Spinal lesions, though one of the most serious complications, have not been investigated systematically. In this study, we report detailed and comprehensive information about spinal lesions of 12 patients with a mean age at the first visit of 13.4 years. Eight patients (66.7%) had scoliosis with a Cobb angle ≥10°, including one with severe scoliosis with a Cobb angle ≥45°. Five patients (41.7%) had kyphosis at the thoracolumbar junction with a kyphotic angle ≥20°. Three patients (25%) developed severe thoracolumbar kyphosis with a kyphotic angle ≥50° accompanied by thoracic lordosis with a wedge-like vertebral deformity and anterior vertebral osteophyte at the thoracolumbar junction, and two of them underwent surgical correction: complicated by fistula formation in one and performed safely and effectively through two-staged operation in the other. Six patients (50.0%) had cervical kyphosis, all of whom except one had kyphosis ≥20° at the thoracolumbar level. Two patients (16.7%) had atlantoaxial subluxation, and 10 patients (83.3%) had cervical vertebral malformations. Patients with mcEDS-CHST14 are susceptible to develop scoliosis, thoracolumbar kyphosis, and cervical kyphosis; and are recommended to have regular surveillance including total spine radiology. The present findings also suggest the critical role of dermatan sulfate in the development and maintenance of the spine.
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http://dx.doi.org/10.1002/ajmg.a.40507DOI Listing
November 2018

Peripartum Iliac Arterial Aneurysm and Rupture in a Patient with Vascular Ehlers-Danlos Syndrome Diagnosed by Next-Generation Sequencing.

Int Heart J 2018 Sep 29;59(5):1180-1185. Epub 2018 Aug 29.

Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine.

Vascular Ehlers-Danlos syndrome (vEDS), a genetic disorder caused by mutations in procollagen type III gene (COL3A1), may lead to fatal vascular complication during peripartum period because of the arterial fragility. We experienced a case of vEDS with peripartum life-threatening arterial rapture diagnosed by next-generation sequencing (NGS) and successfully treated the vascular complications. A 25-year-old female in pregnancy at 34 weeks had sudden and acute pain in the left lower abdomen. After successful delivery, her computed tomography scan showed a dissecting aneurysm of the left common iliac artery (CIA). Four days after delivery, she presented in hemorrhagic shock induced by arterial rupture in the CIA. Since her clinical presentations inferred vEDS even in the absence of familial history, we performed NGS-based genetic screening for inherited connective tissue disorders including vEDS with informed consent. Even though we started intensive medication, her iliac aneurysm was progressively enlarging within 3 weeks. After an urgent molecular diagnosis for vEDS (a splice-site mutation), cautious endovascular therapy for her CIA aneurysm was successfully performed. This is the first report for pretreatment molecular diagnosis of vEDS using NGS in an emergent situation of severe vascular complications.
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http://dx.doi.org/10.1536/ihj.17-451DOI Listing
September 2018