Articles

French recommendations for the management of systemic sclerosis

Systemic sclerosis (SSc) is a generalized disease of the connective tissue, arterioles, and microvessels, characterized by the appearance of fibrosis and vascular obliteration. There are two main phenotypical ...

Authors: Eric Hachulla, Christian Agard, Yannick Allanore, Jerome Avouac, Brigitte Bader-Meunier, Alexandre Belot, Alice Berezne, Anne-Sophie Bouthors, Geraldine Condette-Wojtasik, Joël Constans, Pascal De Groote, Elisabeth Diot, Florence Dumas, Patrick Jego, Francisca Joly, David Launay…

The LORIS MyeliNeuroGene rare disease database for natural history studies and clinical trial readiness

Rare diseases are estimated to affect 150–350 million people worldwide. With advances in next generation sequencing, the number of known disease-causing genes has increased significantly, opening the door for ...

Authors: Aaron Spahr, Zaliqa Rosli, Mélanie Legault, Luan T. Tran, Simon Fournier, Helia Toutounchi, Lama Darbelli, Cécile Madjar, Cassandra Lucia, Marie-Lou St-Jean, Samir Das, Alan C. Evans and Geneviève Bernard

A questionnaire-based study to comprehensively assess the status quo of rare disease patients and care-givers in China

There are over 16.8 million rare disease patients in China, representing a large community that should not be neglected. While the public lack the awareness of their existence and difficult status quo, for one...

Authors: Xuefeng Li, Meiling Liu, Jinduan Lin, Bingzhe Li, Xiangyu Zhang, Shu Zhang, Zijuan Lu, Jianyong Zhang, Jincheng Zhou and Li Ou

The combined prevalence of classified rare rheumatic diseases is almost double that of ankylosing spondylitis

Rare diseases (RDs) affect less than 5/10,000 people in Europe and fewer than 200,000 individuals in the United States. In rheumatology, RDs are heterogeneous and lack systemic classification. Clinical courses...

Authors: Judith Leyens, Tim Th. A. Bender, Martin Mücke, Christiane Stieber, Dmitrij Kravchenko, Christian Dernbach and Matthias F. Seidel

Paradoxical low severity of COVID-19 in Prader-Willi syndrome: data from a French survey on 647 patients

Patients with Prader-Willi syndrome (PWS) often have comorbidities, especially obesity, that may constitute a risk factor for severe forms of COVID-19. We aimed to assess prevalence and medical course of SARS-...

Authors: Muriel Coupaye, Virginie Laurier, Grégoire Benvegnu, Christine Poitou, Pauline Faucher, Héléna Mosbah, Gwenaelle Diene, Graziella Pinto, Laura González Briceño, Christine Merrien, Ana Camarena Toyos, Emilie Montastier, Maithé Tauber and Fabien Mourre

Clinical features and treatment efficacy for IgG4-related thyroiditis

This study aimed to clarify the clinical features of and evaluate the treatment efficacy for IgG4-related thyroiditis.

Authors: Xinxin Han, Panpan Zhang, Jieqiong Li, Zheng Liu, Hui Lu, Xuan Luo, Boju Pan, Xiaolan Lian, Xuejun Zeng, Wen Zhang and Xiaofeng Zeng

A review of the clinical outcomes in idursulfase-treated and untreated Filipino patients with mucopolysaccharidosis type II: data from the local lysosomal storage disease registry

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked multisystem disorder characterized by glycosaminoglycan (GAG) accumulation, caused by a deficiency of iduronate-2-sulfatase (I2S). Enzyme ...

Authors: Marie Julianne C. Racoma, Maria Kristina Karizza B. Calibag, Cynthia P. Cordero, Mary Ann R. Abacan and Mary Anne D. Chiong

French recommendations for the management of Takayasu’s arteritis

The aim of this National Diagnostic and Care Protocol (PNDS) is to explain to the professionals involved the current optimal diagnosis and therapeutic management and care approach for a patient with Takayasu’s...

Authors: David Saadoun, Alessandra Bura-Riviere, Chloé Comarmond, Marc Lambert, Alban Redheuil and Tristan Mirault

Correction to: A somatic mutation in PIK3CD unravels a novel candidate gene for lymphatic malformation

Authors: Shengcai Wang, Wei Wang, Xuexi Zhang, Jingang Gui, Jie Zhang, Yongli Guo, Yuanhu Liu, Lin Han, Qiaoyin Liu, Yanzhen Li, Nian Sun, Zhiyong Liu, Jiangnan Du, Jun Tai and Xin Ni

Correction to: Building a trusted framework for uncertainty assessment in rare diseases: suggestions for improvement (Response to “TRUST4RD: tool for reducing uncertainties in the evidence generation for specialised treatments for rare diseases”)

Authors: Sabine E. Grimm, Xavier Pouwels, Bram L. T. Ramaekers, Ben Wijnen, Saskia Knies, Janneke Grutters and Manuela A. Joore

Natural history and genetic study of LAMA2-related muscular dystrophy in a large Chinese cohort

LAMA2-related muscular dystrophy including LAMA2-related congenital muscular dystrophy (LAMA2-CMD) and autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23) is caused by LAMA2 pathogenic variants. We ai...

Authors: Dandan Tan, Lin Ge, Yanbin Fan, Xingzhi Chang, Shuang Wang, Cuijie Wei, Juan Ding, Aijie Liu, Shuo Wang, Xueying Li, Kai Gao, Haipo Yang, Chengli Que, Zhen Huang, Chunde Li, Ying Zhu…

Normative data on spontaneous stride velocity, stride length, and walking activity in a non-controlled environment

Normative data are necessary for validation of new outcome measures. Recently, the 95th centile of stride speed was qualified by the European Medicines Agency as a valid secondary outcome for clinical trials i...

Authors: Margaux Poleur, Ana Ulinici, Aurore Daron, Olivier Schneider, Fabian Dal Farra, Marie Demonceau, Mélanie Annoussamy, David Vissière, Damien Eggenspieler and Laurent Servais

A large consanguineous family with a homozygous Metabotropic Glutamate Receptor 7 (mGlu7) variant and developmental epileptic encephalopathy: Effect on protein structure and ligand affinity

Developmental and epileptic encephalopathies (DEE) are chronic neurological conditions where epileptic activity contributes to the progressive disruption of brain function, frequently leading to impaired motor...

Authors: Marwa Ben Jdila, Cécile Mignon-Ravix, Sihem Ben Ncir, Fatma Kammoun, Faiza Fakhfakh, Laurent Villard and Chahnez Triki

Gene therapies and COVID-19 vaccines: a necessary discussion in relation with viral vector-based approaches

The COVID-19 pandemic is adding an unanticipated concern for those affected by genetic diseases. Most of the new treatment achievements for these patients are made possible as a result of advances in viral-bas...

Authors: Angel Aledo-Serrano, Antonio Gil-Nagel, Julian Isla, Ana Mingorance, Fernando Mendez-Hermida and Ruben Hernandez-Alcoceba

The parental perspective of thalassaemia in Bangladesh: lack of knowledge, regret, and barriers

Thalassaemia, a hereditary haemoglobin disorder, is a major public health concern in some parts of the world. Although Bangladesh is in the world’s thalassaemia belt, the information on this disease is scarce....

Authors: Mohammad Sorowar Hossain, Md. Mahbub Hasan, Mary Petrou, Paul Telfer and Abdullah Al Mosabbir

Haploidentical haematopoietic stem cell transplantation for malignant infantile osteopetrosis and intermediate osteopetrosis: a retrospective analysis of a single centre

To evaluate the clinical efficacy of haploidentical haematopoietic stem cell transplantation (haplo-HSCT) for the treatment of malignant infantile osteopetrosis (MIOP) and intermediate osteopetrosis.

Authors: Guanghua Zhu, Ang Wei, Bin Wang, Jun Yang, Yan Yan, Kai Wang, Chenguang Jia, Yanhui Luo, Sidan Li, Xuan Zhou, Tianyou Wang, Huyong Zheng and Maoquan Qin

Navigating the U.S. health insurance landscape for children with rare diseases: a qualitative study of parents’ experiences

Parents of children with rare diseases often face uncertainty about diagnosis, treatment, and costs associated with healthcare for their child. Health insurance status impacts each of these areas, but no U.S. ...

Authors: Tai L. S. Pasquini, Sarah L. Goff and Jennifer M. Whitehill

Glaucoma in mucopolysaccharidoses

Mucopolysaccharidoses are a group of lysosomal storage disorders that are caused by deficiency of enzymes involved in glycosaminoglycans degradation. Due to low prevalence and high childhood mortality, researc...

Authors: Weijing Kong, Jing Zhang, Cheng Lu, Yingxue Ding and Yan Meng

The long and winding road: perspectives of people and parents of children with mitochondrial conditions negotiating management after diagnosis

The diagnostic odyssey for people with a rare disease is well known, but difficulties do not stop at diagnosis. Here we investigate the experience of people, or parents of children with a diagnosed mitochondri...

Authors: Janet C. Long, Stephanie Best, Sarah Hatem, Tahlia Theodorou, Toni Catton, Sean Murray, Jeffrey Braithwaite and John Christodoulou

Improving early diagnosis of rare diseases using Natural Language Processing in unstructured medical records: an illustration from Dravet syndrome

The growing use of Electronic Health Records (EHRs) is promoting the application of data mining in health-care. A promising use of big data in this field is to develop models to support early diagnosis and to ...

Authors: Tommaso Lo Barco, Mathieu Kuchenbuch, Nicolas Garcelon, Antoine Neuraz and Rima Nabbout

Essential list of medicinal products for rare diseases: recommendations from the IRDiRC Rare Disease Treatment Access Working Group

Treatments are often unavailable for rare disease patients, especially in low-and-middle-income countries. Reasons for this include lack of financial support for therapies and onerous regulatory requirements f...

Authors: William A. Gahl, Durhane Wong-Rieger, Virginie Hivert, Rachel Yang, Galliano Zanello and Stephen Groft

Clinical, molecular and glycophenotype insights in SLC39A8-CDG

SLC39A8, a gene located on chromosome 4q24, encodes for the manganese (Mn) transporter ZIP8 and its detrimental variants cause a type 2 congenital disorder of glycosylation (CDG). The common SLC39A8 missense vari...

Authors: Eleonora Bonaventura, Rita Barone, Luisa Sturiale, Rosa Pasquariello, Maria Grazia Alessandrì, Anna Maria Pinto, Alessandra Renieri, Celeste Panteghini, Barbara Garavaglia, Giovanni Cioni and Roberta Battini

A review of mechanisms of disease across PIK3CA-related disorders with vascular manifestations

PIK3CA-related disorders include vascular malformations and overgrowth of various tissues that are caused by postzygotic, somatic variants in the gene encoding phosphatidylinositol-3-kinase (PI3K) catalytic subun...

Authors: Guillaume Canaud, Adrienne M. Hammill, Denise Adams, Miikka Vikkula and Kim M. Keppler-Noreuil

Is ghrelin a biomarker of early-onset scoliosis in children with Prader–Willi syndrome?

Adolescents with idiopathic scoliosis display high ghrelin levels. As hyperghrelinemia is found in patients with PWS and early-onset scoliosis (EOS) is highly prevalent in these patients, our aims were to expl...

Authors: Dibia Liz Pacoricona Alfaro, Gwenaelle Diene, Graziella Pinto, Jean-Pierre Salles, Isabelle Gennero, Sandy Faye, Catherine Molinas, Marion Valette, Catherine Arnaud and Maithé Tauber

Cybernic treatment with wearable cyborg Hybrid Assistive Limb (HAL) improves ambulatory function in patients with slowly progressive rare neuromuscular diseases: a multicentre, randomised, controlled crossover trial for efficacy and safety (NCY-3001)

Rare neuromuscular diseases such as spinal muscular atrophy, spinal bulbar muscular atrophy, muscular dystrophy, Charcot-Marie-Tooth disease, distal myopathy, sporadic inclusion body myositis, congenital myopa...

Authors: Takashi Nakajima, Yoshiyuki Sankai, Shinjiro Takata, Yoko Kobayashi, Yoshihito Ando, Masanori Nakagawa, Toshio Saito, Kayoko Saito, Chiho Ishida, Akira Tamaoka, Takako Saotome, Tetsuo Ikai, Hisako Endo, Kazuhiro Ishii, Mitsuya Morita, Takashi Maeno…

Integrated in silico MS-based phosphoproteomics and network enrichment analysis of RASopathy proteins

RASopathies are a group of syndromes showing clinical overlap caused by mutations in genes affecting the RAS-MAPK pathway. Consequent disruption on cellular signaling leads and is driven by phosphoproteome rem...

Authors: Javier-Fernando Montero-Bullón, Óscar González-Velasco, María Isidoro-García and Jesus Lacal

Novel folliculin gene mutations in Polish patients with Birt–Hogg–Dubé syndrome

Birt–Hogg–Dubé syndrome (BHDS) is a rare, autosomal dominant, inherited disease caused by mutations in the folliculin gene (FLCN). The disease is characterised by skin lesions (fibrofolliculomas, trichodiscomas, ...

Authors: Elżbieta Radzikowska, Urszula Lechowicz, Jolanta Winek and Lucyna Opoka

Rare manifestations and malignancies in tuberous sclerosis complex: findings from the TuberOus SClerosis registry to increAse disease awareness (TOSCA)

Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant disorder caused by pathogenic variants in either the TSC1 or TSC2 gene. Common manifestations of TSC have been grouped into major and mino...

Authors: Matthias Sauter, Elena Belousova, Mirjana P. Benedik, Tom Carter, Vincent Cottin, Paolo Curatolo, Maria Dahlin, Lisa D’Amato, Guillaume B. d’Augères, Petrus J. de Vries, José C. Ferreira, Martha Feucht, Carla Fladrowski, Christoph Hertzberg, Sergiusz Jozwiak, John A. Lawson…

Genetic epidemiology approach to estimating birth incidence and current disease prevalence for rhizomelic chondrodysplasia punctata

Rhizomelic chondrodysplasia punctata (RCDP) is an inherited ultra-rare disease which results in severely impaired physical and mental development. Mutations in one of five genes involved in plasmalogen biosynt...

Authors: Tarik Luisman, Tara Smith, Shawn Ritchie and Karen E. Malone

Everolimus versus sirolimus for angiomyolipoma associated with tuberous sclerosis complex: a multi-institutional retrospective study in China

To evaluate the efficacy and safety of everolimus and sirolimus in patients with tuberous sclerosis complex-associated angiomyolipomas (TSC-AML).

Authors: Cong Luo, Yu-Shi Zhang, Ming-Xin Zhang, Min-Feng Chen, Yuan Li, Lin Qi, Han-Zhong Li, Xiong-Bin Zu and Yi Cai

Quantitative parameters of lymphocyte nuclear morphology in bronchoalveolar lavage fluid as novel biomarkers for sarcoidosis

Bronchoalveolar lavage (BAL) is one of the fundamental examinations for the differential diagnosis of interstitial lung diseases (ILDs), and lymphocytosis strongly indicates alternative diagnoses rather than i...

Authors: Yasushi Horimasu, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Takeshi Masuda, Shintaro Miyamoto, Taku Nakashima, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada and Noboru Hattori

Clinical relevance of targeted exome sequencing in patients with rare syndromic short stature

Large-scale genomic analyses have provided insight into the genetic complexity of short stature (SS); however, only a portion of genetic causes have been identified. In this study, we identified disease-causin...

Authors: Gilyazetdinov Kamil, Ju Young Yoon, Sukdong Yoo and Chong Kun Cheon

Characterization of the clinical and genetic spectrum of autoimmune polyendocrine syndrome type 1 in Chinese case series

Autoimmune polyendocrine syndrome type 1 (APS1) is a hereditary disease caused by mutations in the AIRE gene with both endocrine and non-endocrine organ involvement. The existing data from China are limited, and ...

Authors: Ya-Bing Wang, Ou Wang, Min Nie, Yan Jiang, Mei Li, Wei-Bo Xia and Xiao-Ping Xing

Ketogenic diet for mitochondrial disease: a systematic review on efficacy and safety

No curative therapy for mitochondrial disease (MD) exists, prioritizing supportive treatment for symptom relief. In animal and cell models ketones decrease oxidative stress, increase antioxidants and scavenge ...

Authors: Heidi Zweers, Annemiek M. J. van Wegberg, Mirian C. H. Janssen and Saskia B. Wortmann

Economic burden and health-related quality of life in tenosynovial giant-cell tumour patients in Europe: an observational disease registry

Tenosynovial Giant-Cell Tumour (TGCT) is a benign clonal neoplastic proliferation arising from the synovium, causing a variety of symptoms and often requiring repetitive surgery. This study aims to define the ...

Authors: J. Lopez-Bastida, I. Aranda-Reneo, B. Rodríguez-Sánchez, L. M. Peña-Longobardo, X. Ye, P. Laeis, E. M. Fronk, E. Palmerini, A. Leithner and M. A. J. Van de Sande

Clinical characteristics and genetic spectrum of 26 individuals of Chinese origin with primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) is a rare, highly heterogeneous genetic disorder involving the impairment of motile cilia. With no single gold standard for PCD diagnosis and complicated multiorgan dysfunction...

Authors: Xinyue Zhao, Chun Bian, Keqiang Liu, Wenshuai Xu, Yaping Liu, Xinlun Tian, Jing Bai, Kai-Feng Xu and Xue Zhang

A systematic review of moral reasons on orphan drug reimbursement

The number of market approvals of orphan medicinal products (OMPs) has been increasing steadily in the last 3 decades. While OMPs can offer a unique chance for patients suffering from rare diseases, they are u...

Authors: Bettina M. Zimmermann, Johanna Eichinger and Matthias R. Baumgartner

Two novel variants in DYRK1B causative of AOMS3: expanding the clinical spectrum

We investigated pathogenic DYRK1B variants causative of abdominal obesity-metabolic syndrome 3 (AOMS3) in a group of patients originally diagnosed with type 2 diabetes. All DYRK1B exons were analyzed in a sample ...

Authors: Elvia C. Mendoza-Caamal, Francisco Barajas-Olmos, Elaheh Mirzaeicheshmeh, Ian Ilizaliturri-Flores, Carlos A. Aguilar-Salinas, Donaji V. Gómez-Velasco, Isabel Cicerón-Arellano, Adriana Reséndiz-Rodríguez, Angélica Martínez-Hernández, Cecilia Contreras-Cubas, Sergio Islas-Andrade, Carlos Zerrweck, Humberto García-Ortiz and Lorena Orozco

Metabolic and immunological phenotype of rare lipomatoses: Dercum’s disease and Roch-Leri mesosomatic lipomatosis

Dercum’s disease (DD) and Roch-Leri mesosomatic lipomatosis (LMS) are rare and poorly characterized diseases. The clinical presentation combines multiple lipomas, painful in DD in contrast with LMS, without li...

Authors: Madleen Lemaitre, Benjamin Chevalier, Arnaud Jannin, Kristell Le Mapihan, Samuel Boury, Georges Lion, Myriam Labalette and Marie-Christine Vantyghem

Which triggers could support timely identification of primary antibody deficiency? A qualitative study using the patient perspective

Patients with predominantly (primary) antibody deficiencies (PADs) commonly develop recurrent respiratory infections which can lead to bronchiectasis, long-term morbidity and increased mortality. Recognizing s...

Authors: Lisanne M. A. Janssen, Kim van den Akker, Mohamed A. Boussihmad and Esther de Vries

Gene expression analysis in EBV-infected ataxia-telangiectasia cell lines by RNA-sequencing reveals protein synthesis defect and immune abnormalities

Epstein–Barr virus (EBV) targets B-cells where it establishes a latent infection. EBV can transform B-cells in vitro and is recognized as an oncogenic virus, especially in the setting of immune compromise. Ind...

Authors: Moussab Tatfi, Emeline Perthame, Kenzo-Hugo Hillion, Marie-Agnès Dillies, Hervé Menager, Olivier Hermine and Felipe Suarez

Factor VIII replacement prophylaxis in patients with hemophilia A transitioning to adults: a systematic literature review

Despite the advantages of prophylactic treatment for hemophilia, patients tend to discontinue or not adhere to it because of several challenges such as long-term use, high cost, young patients transitioning to...

Authors: Jing Sun, Xuan Zhou and Nan Hu

Clinical and molecular characterization of craniofrontonasal syndrome: new symptoms and novel pathogenic variants in the EFNB1 gene

Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder that results from pathogenic variants in the EFNB1 gene. The syndrome paradoxically presents with greater severity of the symptoms in heterozygous fem...

Authors: Ewelina Bukowska-Olech, Paweł Gawliński, Anna Jakubiuk-Tomaszuk, Maria Jędrzejowska, Ewa Obersztyn, Michał Piechota, Marta Bielska and Aleksander Jamsheer

Development of the Fabry Disease Patient-Reported Outcome (FD-PRO): a new instrument to measure the symptoms and impacts of Fabry Disease

The systematic collection of disease-specific symptoms and impacts on the lives of patients with Fabry Disease (FD) can offer unique insights into the patient experience, yet no disease-specific tool to measur...

Authors: Alaa Hamed, Pronabesh DasMahapatra, Nicole Lyn, Chad Gwaltney and Robert J. Hopkin

Causative variant profile of collagen VI-related dystrophy in Japan

Collagen VI-related dystrophy spans a clinical continuum from severe Ullrich congenital muscular dystrophy to milder Bethlem myopathy. This disease is caused by causative variants in COL6A1, COL6A2, or COL6A3. Mo...

Authors: Michio Inoue, Yoshihiko Saito, Takahiro Yonekawa, Megumu Ogawa, Aritoshi Iida, Ichizo Nishino and Satoru Noguchi

Healthcare needs, expectations, utilization, and experienced treatment effects in patients with hereditary spastic paraplegia: a web-based survey in the Netherlands

We aimed to identify healthcare needs, expectations, utilization, and the experienced treatment effects in a population of Dutch patients with hereditary spastic paraplegia (HSP).

Authors: Hans C. J. W. Kerstens, Bas J. H. Van Lith, Maarten J. Nijkrake, Bert J. M. De Swart, Laura A. C. Van den Bemd, Rob J. E. M. Smeets, Fheodoroff Klemens, Bart P. C. Van de Warrenburg, Philip J. Van der Wees and Alexander C. H. Geurts

Direct and indirect costs and cost-driving factors of Tuberous sclerosis complex in children, adolescents, and caregivers: a multicenter cohort study

Tuberous sclerosis complex (TSC), a multisystem genetic disorder, affects many organs and systems, characterized by benign growths. This German multicenter study estimated the disease-specific costs and cost-d...

Authors: Janina Grau, Johann Philipp Zöllner, Susanne Schubert-Bast, Gerhard Kurlemann, Christoph Hertzberg, Adelheid Wiemer-Kruel, Thomas Bast, Astrid Bertsche, Ulrich Bettendorf, Barbara Fiedler, Andreas Hahn, Hans Hartmann, Frauke Hornemann, Ilka Immisch, Julia Jacobs, Matthias Kieslich…

Hemophagocytic lymphohistiocytosis during pregnancy: a review of the literature in epidemiology, pathogenesis, diagnosis and treatment

Hemophagocytic lymphohistiocytosis during pregnancy is rare; it is often misdiagnosed, resulting in a high maternal and foetal mortality rate. Herein, based on limited case reports including antepartum and pos...

Authors: Lidong Liu, Yutong Cui, Qiongjie Zhou, Huanqiang Zhao and Xiaotian Li

Reducing the diagnostic delay in Antiphospholipid Syndrome over time: a real world observation

Antiphospholipid Syndrome (APS) is a rare autoimmune disorder with an estimated prevalence of 40–50 cases per 100.000 persons. Patients suffering from low prevalence diseases are more likely to face diagnostic...

Authors: Massimo Radin, Silvia Grazietta Foddai, Alice Barinotti, Irene Cecchi, Elena Rubini, Savino Sciascia and Dario Roccatello

⁶⁸Ga-NOTA-Evans Blue PET/CT findings in lymphangioleiomyomatosis compared with ^99mTC-ASC lymphoscintigraphy: a prospective study

Lymphangioleiomyomatosis (LAM) is a rare multisystem disease characterized by cystic lung disease and extrapulmonary manifestations, including lymphatic system disorder. The objective of this study was to inve...

Authors: Guozhu Hou, Yuanyuan Jiang, Wenshuai Xu, Zhaohui Zhu, Li Huo, Xiaoyuan Chen, Fang Li, Kai-Feng Xu and Wuying Cheng