医学遗传学研讨会是美国医学遗传学杂志 (AJMG) 的 C 部分，既是教育资源又是评论论坛，为在人类和医学领域工作的学生、从业者和相关专业人士提供重要、深入的回顾遗传学。每期都由一位遗传学特色领域的研究人员进行客座编辑，提供来自世界各地专家的主题评论集。医学遗传学研讨会每年出版四次。

The American Journal of Medical Genetics, Part C: Seminars in Medical Genetics is the C section of the American Journal of Medical Genetics (AJMG), serving as both an educational resource and a review forum. It provides important and in-depth reviews of genetics for students, practitioners, and professionals working in the fields of human and medical genetics. Each issue is guest-edited by a researcher in a specific area of genetics, featuring a collection of thematic reviews from experts around the world. The journal is published quarterly.

《American Journal of Medical Genetics, Part C: Seminars in Medical Genetics》是美国医学遗传学杂志（AJMG）的C部分，既是一个教育资源，也是一个评论论坛，旨在为在人类和医学领域工作的学生、从业者及相关专业人士提供重要且深入的遗传学回顾。每期由一位在遗传学特定领域的研究人员担任客座编辑，汇集来自全球专家的主题评论。该期刊每年出版四期。

American Journal of Medical Genetics, Part C: Seminars in Medical Genetics

Abstract Arthrogryposis or AMC, arthrogryposis multiplex congenita, is defined as multiple congenital joint contractures in more than two joints and in different body areas. The common cause of all AMC is lack of movement in utero, which in turn can have different causes, one of which is CNS involvement. Intellectual disability/CNS involvement is found in approximately 25% of all AMC. AMC with CNS involvement includes a large number of genetic syndromes. So far, more than 400 genes have been identified as linked to AMC, with and without CNS involvement. A number of neonatally lethal syndromes and syndromes resulting in severe disability due to CNS malfunction belong to this group of syndromes. There are several X‐linked disorders with AMC, which are primarily related to intellectual disability. A number of neuromuscular disorders may include AMC and CNS/brain involvement. Careful clinical evaluation by a geneticist and a pediatrician/pediatric neurologist is the first step in making a specific diagnosis. Further investigations may include MRI of the brain and spinal cord, electroencephalogram, blood chemistry for muscle enzymes, other organ investigations (ophtalmology, cardiology, gastrointestinal, and genitourinary systems). Nerve conduction studies, electromyogram, and muscle pathology may be of help when there is associated peripheral nervous system involvement. But most importantly, genetic investigations with targeted or rather whole exome or genome sequencing should be performed. A correct diagnosis is important in planning adequate treatment, in genetic counselling and also for future understanding of pathogenic mechanisms and possible new treatments. A multidiciplinary team is needed both in investigation and treatment.

Klaus Dieterich

Eva Kimber

Judith G. Hall

American Journal of Medical Genetics Part C Seminars in Medical Genetics

Central nervous system involvement in arthrogryposis multiplex congenita: Overview of causes, diagnosis, and care

先天性多发性关节弯曲中枢神经系统受累：病因、诊断与护理概述

Arthrogryposis multiplex congenita (AMC) has been described and defined in thousands of articles, but the terminology used has been inconsistent. Some have described it as a diagnosis or syndrome, others as a term or clinical finding. This lack of common language can lead to confusion in clinical and research communities. The aim of this study was to develop a consensus-based definition for AMC using international expert opinion. A consensus-based definition will help harmonize research and clinical endeavors and will facilitate communication among families, clinicians, and researchers. This article describes the methodology used leading to a proposed definition of AMC. First, a literature review was conducted to identify AMC definitions used in included studies. The most commonly used words in the definitions were extracted. Second, a group of eight experts in AMC was selected to identify elements considered critically important to the definition of AMC. Third, based on these critical elements and the literature review, a definition was drafted by the research team. Fourth, a modified Delphi consensus process was conducted using electronic surveys with 25 experts in the field of AMC from eight countries. Survey results were analyzed quantitatively and qualitatively and drafts were modified accordingly. Three rounds of surveys were completed until consensus was reached on a definition of AMC. An annotation of this definition, developed by a panel of international experts, is provided in a separate manuscript in this special issue.

Sarah Cachecho

Caroline Elfassy

Reggie Hamdy

Peter Rosenbaum

Noémi Dahan‐Oliel

Arthrogryposis multiplex congenita definition: Update using an international consensus‐based approach

先天性多发性关节挛缩症定义：基于国际共识的更新方法

This issue of the American Journal of Medical Genetics Seminar Series Part C is dedicated to generalized joint hypermobility (gJHM), joint hypermobility syndrome (JHS), and Ehlers-Danlos syndrome, hypermobility type (EDS-HT). gJHM is the best known clinical manifestation of inherited defects of the connective tissue. On the other side, JHS and EDS-HT are actually considered one and the same from a clinical perspective by most practitioners and researchers (i.e., JHS/EDS-HT), and their molecular basis remains unknown. For decades, "non-syndromic" gJHM and JHS/EDS-HT have been thought to be simple clinical curiosities or an asset for the "affected" individual. In recent years, the attention on these partially overlapping phenotypes has increased, as they are now recognized risk factors for a series of non-communicable diseases and long-term disabilities. This series consists of 10 papers focused on three main topics, namely (i) assessment and differential diagnosis of children and adults with gJHM, (ii) systematic presentation of selected key non-articular manifestations of JHS/EDS-HT and actual perception of physiotherapy as the best therapeutic resource for this condition, and (iii) exploration of the available knowledge relating "congenital laxity of tissues" to various dysfunctions of the nervous system during development and adulthood. The contributors hope that this collection raises attention to this fascinating field of knowledge, which seems to have ramifications in virtually all medical disciplines.

Marco Castori

Marina Colombi

Generalized joint hypermobility, joint hypermobility syndrome and Ehlers‐Danlos syndrome, hypermobility type

广义关节过度活动、关节过度活动综合征和埃勒斯-丹洛斯综合征，过度活动型

Patients with hypermobile Ehlers-Danlos syndrome, an hereditary disorder of the connective tissue, often face a long and difficult diagnostic odyssey in pursuit of a name for their condition. Clinicians may dismiss subjective symptoms of chronic pain, thus prolonging patients' odysseys and worsening their care and satisfaction and creating antagonisms in the patient-provider relationship. A greater understanding of patient experiences is necessary in order to decrease burdens of this relationship and to improve care. To that end, we conducted 22 in-depth, semistructured interviews with individuals who had undergone this diagnostic odyssey. We focused on the impact that the odyssey had on their lives, both inside and outside the clinic. Through narrative analysis, we found a sort of "hero's journey" in the description of their cases, highlighting issues of uncertainty and integration as well as honoring their struggles. Interviewees had encountered difficulties in working with clinicians, in multiplying symptoms, and in negative psychosocial consequences. Attention to patients' lived experience may help to build empathy and understanding for the difficult and complex clinical situation presented by Ehlers-Danlos syndrome. Using the hero's journey as a lens onto this experience allows for a more patient-centered approach to this understanding and has potential value for comprehension of other complex diseases and invisible illnesses.

Colin Michael Egenberger Halverson

Ellen Wright Clayton

Abigail Garcia Sierra

Clair Francomano

Patients with<scp>Ehlers–Danlos</scp>syndrome on the diagnostic odyssey: Rethinking complexity and difficulty as a hero's journey

ABSTRACT Turner syndrome was recognized nearly 90 years ago as a distinctive condition and the understanding of pathophysiology, and phenotype has incrementally and substantially changed along with the goals of treatment. Today, multidisciplinary care is imperative, and the latest international consensus guideline has been crafted as a source of comprehensive practical recommendations for interdisciplinary care of individuals with Turner syndrome throughout their lifespan. We review the evolution of health care in Turner syndrome while highlighting the novel recommendations in the recently published international consensus guideline for the care of girls and women with Turner syndrome.

Roopa Kanakatti Shankar

Claus H. Gravholt

Philippe F. Backeljauw

Evolution of Health Care in Turner Syndrome

特纳综合征中医疗保健的演变

Samantha A. Schrier Vergano

Am J Med Genet C Semin Med Genet

Different, Not Less

不同，而非不如

In 1972, I returned from my training to join the faculty and staff at the Children's Hospital in Seattle to establish a Medical Genetics service. A remarkable orthopedist had the far-sighted idea of having an arthrogryposis clinic where all of the specialties came together on the same day, saw 10 to 15 families and then met at the end of the day to share their views. Before that, families would have to go on different days to see different specialists and the specialists never met with each other, although they had access to their different notes. Although such multidisciplinary clinics have become commonplace, this was a revolutionary idea at the time. Given my relative inexperience, I had no idea how revolutionary it was. I was just finding my way as a professional. I had three small children and a physician husband—so as I multitasked, I didn't do a lot of reflection. I was just trying to do my new job. I was the medical geneticist in this multidisciplinary clinic who was meant to be sorting out different types of arthrogryposis. The orthopedist also wanted to produce a book for families on the various aspects of arthrogryposis care (Staheli et al. 1998). I wasn't at all sure I could contribute a chapter on the genetic aspects of arthrogryposis. There were very few women physicians back then. I realize now we were the "Silent Generation" and each generation is different. We were called the silent generation because we just put our heads down and focused on what needed to get done. The very first family I saw were monozygotic (MZ) twins where one was affected and the other was not. How could this happen? It seemed unfair and baffling to a geneticist. But it was a harbinger of things to come. Subsequently, I have been in touch with that family over the years as the boys grew up. Both were very smart, although the mother always felt the one with arthrogryposis was the smartest and a problem solver. Both went to university and graduate school. Both ending up in academia in the sciences with faculty appointments. Both married and had children. Their mother was persistently curious about how only one MZ twin could possibly have such a disabling disorder requiring so much special care and attention, but do very well spite of it. Also, of course, she worried, as all families do, about recurrence for both boys and future generations. Fortunately, these were unnecessary worries as no one else in the family has been affected and we have come to learn over the years Amyoplasia does not recur in subsequent generations, but does have higher incidence in one of MZ twins (Hall, Aldinger, and Tanaka 2014). Mom and the boys continue to ask questions every time we were in touch, and they have stimulated my curiosity about how MZ twinning could be discordant, initiating my lifelong interest in the mysteries of MZ twinning (Hall 2021a; Hall 2021b). MZ twins with one affected individual, and their families, have been very important in my journey as a geneticist. Yet the insights have come so slowly as to be frustrating. Back then, after 3 multidisciplinary clinics and 45 families, I realized I had "not a clue" about arthrogryposis. So, I hired three medical students for the summer to go to the Shriners Hospital in Spokane and the Shriners Hospital in Portland to find more cases of arthrogryposis. This began a long association with Shriners Hospitals and arthrogryposis. The medical students were bright and it didn't even take the 300 cases of arthrogryposis multiplex congenita (AMC) they found for them to recognize 3 subgroups: one which the orthopedists call "classical" arthrogryposis and we have come to know as Amyoplasia. The second, a heterogeneous group of various kinds of contractures and organ system involvement, and the third with intellectual disability, although at the time they called it "mental retardation." In retrospect, the term was demeaning, but at the time we didn't realize that—it was business as usual. In retrospect, it was remarkable that the chart reviews conducted by myself and those three medical students at the Shriners Hospital and Seattle Children's Hospital never required an ethics review. Now I am regretful and somewhat embarrassed that it was "business as usual" and not to have realized what should have happened. There have been many other "process related" developments over the last 50 years (all for the good). The landscape of patient care for arthrogryposis and interactions with their families has evolved, and they have taught me so much. Families ask the best questions and I am grateful for these interactions. As a clinician, together with the medical students, we used the 300 cases from Shriners Hospitals to begin to sort out subgroups. Over the years, I have now collected clinical information on over 3000 affected individuals with arthrogryposis and have been able to describe many subgroups (Table 1) (Hall, Reed, and Greene 1982; Hall, Reed, Scott, et al. 1982; Hall and Reed 1982; Hall, Reed, Rosenbaum, et al. 1982; Hall 1984; Rizzo et al. 1993; Shalev, Spiegel, and Hall 2005; Hall 2012a; Hall, Reed, and Driscoll 1983; Hall et al. 1983; Reid et al. 1986; Bevan et al. 2007; Reed et al. 1985; Hennekem, Rotteveel, and Hall 1992; Hall 2009; Nayak et al. 2014; Froster-Iskenius, Waterson, and Hall 1988; Chitayat et al. 1990; Chitayat et al. 1991; Dieterich, Kimber, and Hall 2019; Hall 1996; Hall 2012b; Hall 2012c; Hall 2013; Hall 2014; Hall 2019) on a phenotypic basis. Arthrogryposis is considered a Rare Disease, occurring in around one in 3000–5000 births (Lowry et al. 2010), but it has been a primary focus for me and provided a great deal of satisfaction. Our clinic in Seattle was a magnet for families from around the world seeking expertise about arthrogryposis—its origins, various therapies, and the possibility of genetic recurrence. It was a bit intimidating but also a most amazing opportunity. I became involved in parent support groups all over the world, helping to connect them with each other and share what we were learning. It was very satisfying, because families were so anxious to learn from each other. Helping these families warmed my heart. In the meanwhile, I was multitasking with a growing family and more hospital responsibilities. I just put my head down and worked. The North American parent support group (AMSCI) was inspired and supported by many families and particularly by a very energetic mother of another very smart individual with Amyoplasia. The mother's goal was to try to connect families and their knowledge and experience with each other. She was one of the original organizers of AMCSI and played a crucial role in education and organization. She helped develop guidelines for information sharing and protecting the privacy of affected individuals, produced educational materials such as pamphlets about arthrogryposis and information for parents of affected newborns, and collaborated in creating a foundation. It was so gratifying to be part of these efforts as their medical expert. Early in the development of parent support groups, I got to know this mother because of her passion to share information and her endless curiosity, energy, and questions. She was an inspiration to me as I juggled my own many demands. Most parent support groups of Rare Disorders, including AMCSI, have a yearly conference, often with free registry and travel funds for new families. They also support research and collaboration of all kinds. At these meetings there were endless questions stimulating more research. I would see 30–40 families at a meeting and feel exhausted and frustrated not to have more answers by the end of these meetings. This particular mother lives near the Shriners Hospital in South Carolina, so has encouraged the Shriners system to feel a part of their educational and research efforts. Over the years, the Shriners Hospital has been developing arthrogryposis as a "special interest" with a registry of children and youths, and providing genetic studies including whole-genome sequencing for non-Amyoplasia type affected individuals (Dahan-Oliel et al. 2018). The engagement and energy of this mother are inspirational to all that work with her. Over the years, I have learned an enormous amount about her daughter's situation, as well as how different families address challenges in their own way and at different paces. It was humbling to have families share their feelings, experiences, and situations with me. It fills me with joy and frustration at the same time. I often quote the mother when I see families, not usually on their first visit but after getting to know them. I will share with them that she said that having a child with a disability has actually been an enormous blessing to her and her family. They have come to know people they would never have otherwise met. They continue to be inspired by the stories of others. They appreciate their unaffected children in a way they never would have otherwise. Those unaffected children learn about disabilities, kindness, and accessibility. Beginning in the 1990's, the human genome was being sequenced. The genes responsible for various diseases, as well as the pathways involved in cell and organ formation, were being identified. By 2019, 420 genes associated with arthrogryposis had been identified and these were seen to fall into only 16 pathways—nerves, muscle, myelin, various parts of the brain, and spinal cord, and so forth. (Kiefer and Hall 2019). Any mutation/variant that leads to decreased fetal movement may produce contractures by birth. Now there are over 500 specific genes recognized to be related to arthrogryposis, many with several different responsible variants. This has led to recognizing the value of whole genome sequencing in individuals with non-Amyoplasia arthrogryposis, which the Shriners Hospital now perform as part of their childhood registry (Nematollahi et al. 2024). Knowing the specific responsible gene helps predict the natural history even though only a few affected individuals may have been described. This is a shift from emphasis on clinical descriptions (phenotype) to the genotype predicting phenotype. It has been overwhelming for me. I can't keep up with all the new advances and feel inadequate to provide all this new information. Increasingly genetic counseling has shifted from providing options and natural history information to identifying the responsible gene. The last individual I want to mention, I met when she was a patient in my medical genetics clinic in Vancouver while she was in high school. She also has Amyoplasia, but in spite of her limitations of movement, she became very involved in recreational activities in her local park. During college, she began to think about a PhD in rehabilitation medicine. She also had endless questions about why arthrogryposis occurs and because she was doing her PhD at my Children's Hospital, we kept in contact. She helped me understand "lived experience" and the daily challenges she faced. Her specialty in rehabilitation medicine became assistive devices. She looked for ways to improve flexibility and mobility for teenagers and adults with arthrogryposis. She has ended up working in the adult spinal cord injury unit and has trained numerous master's degree and PhD students along the way. She makes sure her trainees all learn about arthrogryposis and the potential for assistive devices. They often did research projects to better understand the best care of AMC. Seeing her mature over time warms my heart. She and her husband have become my friends and frequently she gives me advice on assistive devices as my joints age. For many years, she resisted attending the yearly arthrogryposis support group meetings, but finally was invited as a speaker and realized how much she might offer. She began an adult arthrogryposis registry, which has helped to define the natural history into adulthood of various types of arthrogryposis (Sawatzky et al. 2019). Something that was badly needed. What is amazing about her findings is how well adult individuals with arthrogryposis actually do in society. Most have jobs, often are married and support themselves. They contribute to society and provide a better understanding of disabilities. The adult registry also provides information about possible occupations, resources and information for the care of affected adults. It is a joy to have watched this information become available. The International Shriners Hospitals have spearheaded a collaboration of researchers from around the world. Utilizing the latest scoping techniques they collaborate to achieve agreement on definitions, and the items to include under therapeutics and ethical practices (Nematollahi et al. 2024). They have categorized research of all types. It has been a model of collaboration for Rare Disorders, shedding light on processes and achieving new information. Individuals with arthrogryposis and their families are benefiting, as well as the basic science and research in human development. I feel pride in this kind of collaborative development and the generosity of the interactions. Over the last 50 years, many things have changed, from terminology to including affected individuals in the planning of projects. Genetic studies have expanded from pedigree analysis to whole genome sequencing, epigenetics, the control of gene expression, and to transgenerational effects (Developmental Origins of Health and Disease). Differences between different ethnic groups (Silent Generations Project) are also being recognized. And finally, most institutions are recognizing the importance of Diversity, Equity, Inclusion, and Accessibility. During the pandemic, we welcomed virtual meetings and presentations. I have learned so many things about arthrogryposis by observation and curiosity. Principles have begun to emerge that allow for better care and understanding. Individuals with arthrogryposis have challenged me and welcomed me. I feel truly privileged to have been a part of their community and perhaps added insights to their corner of medical research. Over the years, my journey with arthrogryposis has been very much a part of my professional and personal life. I wish to acknowledge the support of BCCHF and BCCHRI, the invaluable help of Catherine Wang and the many co-researchers and care providers with which I have worked. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

My Journey With Arthrogryposis and Some of the People Who Made a Difference

我与先天性多发性关节弯曲症的旅程以及一些带来改变的人

ABSTRACT This essay explores the narrative characteristics of genetic revelations as instances of “metagnosis.” Contrasting the scientific narrative of increasing knowledge with a series of different stories—including fictional tales—demonstrates the complexity of receiving information that changes one's conception of self, whatever the nature of the revelation. Such narrative awareness can help to communalize such experiences, reducing feelings of isolation and bewilderment.

Danielle Spencer

Everyone Is a Tomato: Metagnostic Narratives of Genetic Revelation

每个人都是番茄：基因启示的元认知叙事

ABSTRACT An early career geneticist confronts the limits of our field when a critically ill infant is diagnosed with an ultra‐rare metabolic disorder.

Abbreviation	Am. J. Med. Genet.
Journal Impact	2.81
Quartiles(Global)	GENETICS & HEREDITY(Q2)

ISSN	1552-4868, 1552-4876
h-index	116

Publication Information	Publisher: Wiley-Liss Inc.，Publishing cycle: Quarterly，Journal Type: journal，Open Access Journals: No
Basic data	Year of publication: 1999，Proportion of original research papers: 41.86%，Self Citation Rate:0.00%， Gold OA Rate: 21.58%
Average review cycle	网友分享经验：>12周，或约稿
Average recruitment ratio	网友分享经验：一般

American Journal of Medical Genetics, Part C: Seminars in Medical Genetics

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Central nervous system involvement in arthrogryposis multiplex congenita: Overview of causes, diagnosis, and care

Arthrogryposis multiplex congenita definition: Update using an international consensus‐based approach

Generalized joint hypermobility, joint hypermobility syndrome and Ehlers‐Danlos syndrome, hypermobility type

Patients withEhlers–Danlossyndrome on the diagnostic odyssey: Rethinking complexity and difficulty as a hero's journey

Evolution of Health Care in Turner Syndrome

Evolution of Health Care in Turner Syndrome

Different, Not Less

My Journey With Arthrogryposis and Some of the People Who Made a Difference

Everyone Is a Tomato: Metagnostic Narratives of Genetic Revelation

Pink, White, and Probability