多发性骨骺发育不良遗传学研究进展

多发性骨骺发育不良（multiple epiphyseal dysplasia,MED,OMIM 132400)是一种遗传性骨软骨发育不良疾病，特点是轻中度身材矮小和早期发作关节炎。遗传方式以外显完全的常染色体显性遗传为主，少数为隐性遗传。MED临床表型复杂，具有明显的遗传异质性。目前发现的该疾病有关的基因有4个，分别是软骨寡聚物基质蛋白基因（cartilage oligomeric matrix protein,COMP)，COL9A2基因，COL9A3基因，畸形发育不良硫酸盐转移因子基因（diastrophic dysplasia sulfate transporter,DTDST)。基因位点依次命名为EDM1（OMIM132400）、EDM2（OMIM600204）、EDM3（OMIM600969）和EDM4（OMIM 226900）.     

先天性软骨发育不良合并脑积水一例病例分析

目的研究先天性软骨发育不全合并脑积水发病率及相关基因诊断。方法通过复习新基因突变及染色体显性遗传性疾病主要临床表现的理论文献,结合1例先天性软骨发育不良合并脑积水患者儿的临床表征,讨论先天性软骨发育不全的基因诊断及染色体畸变。结果患儿头围明显大于同龄儿,且四肢短小,肌张力低,行股骨及髋关节拍片:双侧股骨增粗、缩短,远端呈"镶嵌"状,骨皮质连续,双侧髂骨下端呈"三叉戟"状改变,皮质光滑连续。结论患儿FGFR3基因监测到1138GA突变,结合临床表现可诊断为先天性软骨发育不全。     

遗传性多发性骨软骨瘤3家系13例报告

遗传性多发性骨软骨瘤是一种先天性骨骼发育异常,有明显的家族遗传史,一般认为是一种遗传性骨病,本病的名称颇多,如“骨干连续症”（oiaphysial acl-asia）、遗传性畸形性软骨发育异常症（hereditary deforming chondrodysp-lasia）、软骨发育异常（dyschondroplasia）等,目前公认遗传性多发性骨软骨瘤这个命名较为恰当,本文报告三家系13例,就其有关问题进行分析讨论。     

遗传性痉挛性截瘫11型研究进展

遗传性痉挛性截瘫是一种遗传性、神经退行性变的疾病,具有明显的遗传异质性,遗传形式多样.遗传性痉挛性截瘫11型是隐形遗传尤其是合并有胼胝体发育不良患者中最常见的类型,现就近几年来该病的研究进展,从遗传性痉挛性截瘫11型的基因定位和克隆,基因突变情况及其临床表现,诊断与鉴别诊断、发病机制等方面进行全面的介绍.     

多发性骨骺发育不良遗传学研究进展

多发性骨骺发育不良 (multiple epiphyseal dysplasia,MED,OMIM 132 4 0 0 )是一种遗传性骨软骨发育不良疾病 ,特点是轻中度身材矮小和早期发作的骨关节炎。遗传方式以外显完全的常染色体显性遗传为主 ,少数为隐性遗传。 MED临床表型复杂 ,具有明显的遗传异质性。目前发现的与该疾病有关的基因有 4个 ,分别是软骨寡聚物基质蛋白基因 (cartilageoligom eric m atrix protein,COMP)、COL 9A2基因、COL 9A3基因、畸形发育不良硫酸盐转移因子基因 (diastrophic dysplasiasulfate transporter,DTDST)。基因位点依次命名为 EDM1(OMIM 132 4 0 0 )、EDM2 (OMIM 6 0 0 2 0 4 )、EDM3(OMIM 6 0 0 96 9)和 EDM4 (OMIM 2 2 6 90 0 )。     

SHOX基因缺陷与身材矮小症研究进展

位于X和Y染色体拟常染色体区域的SHOX基因与软骨发育相关。近年来发现该基因的缺陷是特发性身材矮小、Turner综合征、Leri-Weill软骨发育异常和Langer肢中骨发育不良等多种疾病发生的一个重要因素。本文综述了与SHOX基因缺陷相关软骨发育异常的临床表现。     

孤立性常染色体显性甲状旁腺功能减退症的PCAR1基因突变

家族性孤立性甲状旁腺功能减退症（FIH）为一种甲状旁腺激素（PTH）缺乏、低钙血、高磷酸盐并伴神经肌肉症状的异质性疾病。本病常见于婴幼儿到成人，其遗传模式为常染色体显性和常染色体隐性或X一连锁隐性遗传。FIH的常染色体显性和常染色体隐性遗传型与PTH基因突变相关联。新近证实PTH／PTH一相关肽（PTHrP）受体基因与钙的体内平衡密切相关。而且这种基因的突变与常染色体显性Jans。n型干能端软骨发育不良有关。众所周知，Ca‘”感觉受体（PCARI）基因的几种突变可导致家族性低钙尿性高钙血（FHH），也有研究报道PCARI基…     

X-连锁迟发性脊椎骨骺发育不良遗传学研究进展

X-连锁迟发性脊椎骨骺发育不良(X-linked spondyloepiphyseal dysplasia tarda SEDL,OMIM313400)是一种罕见的遗传性骨软骨发育不良性疾病,遗传方式为X连锁隐性遗传。临床特点为轻中度非匀称性矮小和早发骨关节炎。SEDL的致病基因—SEDL基因定位于:Xp22.2,cDNA全长2836bp,编码含140个氨基酸残基的蛋白质,其功能尚未完全明确。51.2％的SEDL基因突变发生在外显子4和外显子5,有多种类型的突变可导致SEDL的临床表型,其中缺失突变最常见,占56.1％。SEDL基因型与临床表型之间有一定的相关性,但也存在表型异质性。     

X-连锁迟发性脊椎骨骺发育不良遗传学研究进展

X-连锁迟发性脊椎骨骺发育不良(X-linked spondyloepiphyseal dysplasia tarda SEDL，OMIM 313400)是一种罕见的遗传性骨软骨发育不良性疾病，遗传方式为X连锁隐性遗传。临床特点为轻中度非匀称性矮小和早发骨关节炎。SEDL的致病基因—SEDL基因定位于Xp22、2，cDNA全长2836bp，编码含140个氨基酸残基的蛋白质，其功能尚未完全明确。51．2％的SEDL基因突变发生在外显子4和外显子5，有多种类型的突变可导致SEDL的临床表型，其中缺失突变最常见，占56．1％。SEDL基因型与临床表型之间有一定的相关性，但也存在表型异质性。     

遗传性大疱性表皮松解症二例及临床分析

遗传性大疱性表皮松解症（Epidermolysis Bullosa，EB）是一组临床上以轻微外伤后皮肤和黏膜水疱形成为共同特征的基因遗传性皮肤病，皮肤脆性增加，常伴有皮肤外表现，临床表现依分型不同轻重不一。目前国际诊断分型的金标准根据透射电镜下水疱发生的超微结构水平，解剖学上分为3主要亚型。（1）单纯型大疱性表皮松解症（EBS）：裂隙发生在表皮内，通常不伴有皮肤外的改变，大部分是常染色体显性遗传，占EB的92％，本型由于角蛋白基因KRT5和KRT14基因突变引起基底角质形成细胞溶解，从而导致轻微外伤后表皮内大疱形成。     

Molecular-pathogenetic classification of genetic disorders of the skeleton

Genetic disorders of the skeleton (skeletal dysplasias and dysostoses) are a large and disparate group of diseases whose unifying features are malformation, disproportionate growth, and deformation of the skeleton or of individual bones or groups of bones. To cope with the large number of different disorders, the "Nosology and Classification of the Osteochondrodysplasias," based on clinical and radiographic features, has been designed and revised periodically. Biochemical and molecular features have been partially implemented in the Nosology, but the rapid accumulation of knowledge on genes and proteins cannot be easily merged into the clinical-radiographic classification. We present here, as a complement to the existing Nosology, a classification of genetic disorders of the skeleton based on the structure and function of the causative genes and proteins. This molecular-pathogenetic classification should be helpful in recognizing metabolic and signaling pathways relevant to skeletal development, in pointing out candidate genes and possible therapeutic targets, and more generally in bringing the clinic closer to the basic science laboratory and in promoting research in this field. Copyright 2002 Wiley-Liss, Inc.     

Nosology and classification of genetic skeletal disorders: 2010 revision

Genetic disorders involving the skeletal system arise through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their variety. The Nosology and Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology. In the 2010 revision, 456 conditions were included and placed in 40 groups defined by molecular, biochemical, and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes, ranging from common, recurrent mutations to "private" found in single families or individuals. Thus, the Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene. The Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel sequencing technologies; in the delineation of clinical entities and novel disorders, by providing an overview of established nosologic entities; and for scientists looking for the clinical correlates of genes, proteins and pathways involved in skeletal biology.     

Nosology and classification of genetic skeletal disorders: 2006 revision

The objective of the paper is to provide the revision of the Nosology of Constitutional Disorders of Bone that incorporates newly recognized disorders and reflects new molecular and pathogenetic concepts. Criteria for inclusion of disorders were (1) significant skeletal involvement corresponding to the definition of skeletal dysplasias, metabolic bone disorders, dysostoses, and skeletal malformation and/or reduction syndromes, (2) publication and/or MIM listing, (3) genetic basis proven or very likely, and (4) nosologic autonomy confirmed by molecular or linkage analysis and/or distinctive diagnostic features and observation in multiple individuals or families. Three hundred seventy-two different conditions were included and placed in 37 groups defined by molecular, biochemical and/or radiographic criteria. Of these conditions, 215 were associated with one or more of 140 different genes. Nosologic status was classified as final (mutations or locus identified), probable (pedigree evidence), or bona fide (multiple observations and clear diagnostic criteria, but no pedigree or locus evidence yet). The number of recognized genetic disorders with a significant skeletal component is growing and the distinction between dysplasias, metabolic bone disorders, dysostoses, and malformation syndromes is blurring. For classification purposes, pathogenetic and molecular criteria are integrating with morphological ones but disorders are still identified by clinical features and radiographic appearance. Molecular evidence leads to confirmation of individual entities and to the constitution of new groups, but also allows for delineation of related but distinct entities and indicates a previously unexpected heterogeneity of molecular mechanisms; thus, molecular evidence does not necessarily simplify the Nosology, and a further increase in the number of entities and growing complexity is expected. By providing an updated overview of recognized entities with skeletal involvement and of the underlying gene defects, the new Nosology can provide practical diagnostic help, facilitate the recognition of new entities, and foster and direct research in skeletal biology and genetic disorders.     

Nosology and classification of genetic skeletal disorders: 2019 revision

The application of massively parallel sequencing technology to the field of skeletal disorders has boosted the discovery of the underlying genetic defect for many of these diseases. It has also resulted in the delineation of new clinical entities and the identification of genes and pathways that had not previously been associated with skeletal disorders. These rapid advances have prompted the Nosology Committee of the International Skeletal Dysplasia Society to revise and update the last (2015) version of the Nosology and Classification of Genetic Skeletal Disorders. This newest and tenth version of the Nosology comprises 461 different diseases that are classified into 42 groups based on their clinical, radiographic, and/or molecular phenotypes. Remarkably, pathogenic variants affecting 437 different genes have been found in 425/461 (92%) of these disorders. By providing a reference list of recognized entities and their causal genes, the Nosology should help clinicians achieve accurate diagnoses for their patients and help scientists advance research in skeletal biology.     

Genetic diseases of bones and joints

Genetic factors play roles in many diseases. Often these factors are ill defined and unpredictable. Other diseases are caused by specific single gene mutations and are passed to offspring in Mendelian inheritance patterns. There are over 5000 documented Mendelian disorders; over 500 of these affect bones and joints. Some of these single gene disorders affect many tissues, and the skeletal system is one of many organ systems involved. The surgical pathologist must often diagnose these disorders. Important examples are neurofibromatosis, Gaucher's disease, and alkaptonuria. Other single gene disorders almost exclusively affect the skeleton. These disorders are the skeletal dysplasias and 372 have been documented. These disorders are classified using radiographic, clinical, and molecular data. The most common dysplasias are osteogenesis imperfecta, achondroplasia, and osteopetrosis. The surgical pathologist usually does not play a role in the diagnosis of skeletal dysplasias. However, histologic studies often elucidate the pathophysiologic basis of these diseases and proper collection of tissues is important for the evolving understanding of the molecular basis of these disorders.     

Genetic analysis of skeletal dysplasia: recent advances and perspectives in the post-genome-sequence era

Skeletal dysplasia is a group of disorders of the skeleton that result from derangement of growth, development and/or differentiation of the skeleton. Nearly 300 disorders are included; most of them are monogenic diseases. Responsible genes for skeletal dysplasia have been identified in more than 150 diseases mainly through positional cloning. Identification of disease genes would improve patient care through genetic diagnosis as well as improving our understanding of the diseases and molecular mechanism of skeletal tissue formation. Studies of skeletal dysplasia would also help identify disease genes for common diseases affecting bones and joints. In this study, the author reviews recent advances and the current status of the genetic analysis of skeletal dysplasia and its impacts on research into skeletal biology.     

The brachydactylies: a molecular disease family

Brachydactyly refers to shortening of the hands and/or feet due to missing, deformed, or shortened bones. It may occur as an isolated trait or as part of a syndrome. According to their pattern of skeletal involvement, the isolated brachydactyly forms have been categorized in the groups A–D including several subgroups. As in many other genetic conditions, there is considerable phenotypic overlap between the groups. The identification of the molecular causes of these conditions has offered insights into their pathogenesis. The generation of animal models has facilitated research on the pathogenic events during digit development that lead to the brachydactyly phenotype. These studies have shown that the BMP pathway plays a pivotal role in the normal development of digits and joints and that the majority of brachydactyly disease genes are directly or indirectly linked to this pathway. Together, these genes function in a regulatory network which is deregulated in the disease state. As a consequence of the close interactions within the network, overlapping phenotypes are generated that are, nevertheless, characterized by specific recognizable patterns. This principle does not only apply for the brachydactylies but is also valid for many other disease entities. Groups of diseases that show a common phenotypic pattern due to the deregulation of a molecular network are suggested to be called molecular disease families .     

Chondrodysplasia with multiple dislocations: comprehensive study of a series of 30 cases

The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician.     

Spondylo-meta-epiphyseal dysplasia (SMED), short limb-hand abnormal calcification type: Further expanding the mutational spectrum and dental findings of three new patients

Genetic skeletal disorders are clinically and genetically heterogeneous group of disorders that affect the normal development, growth, and maintenance of the human skeleton. Spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type (SMED-SL/AC; MIM# 271665) is a rare autosomal recessive genetic skeletal disorder characterized by distinctive facial features, disproportionate short stature, vertebral, metaphyseal, and epiphyseal abnormalities. This unique phenotype is caused by biallelic loss-of-function variants in Discoidin domain receptor 2 gene (DDR2, MIM# 191311). To date, only 10 pathogenic variants (six missense, two nonsense, one deletion, and one splice site) in DDR2 have been reported in patients with SMED-SL/AC. Dental anomalies related to skeletal dysplasia can include various abnormalities in the number, shape, and position of teeth in the jaw, as well as enamel hypoplasia and dentinogenesis imperfecta. Although abnormal dentition has previously been reported, orodental findings were described in only six patients with SMED-SL/AC. This study aimed to define the clinical, dental, radiological, and molecular findings of three new SMED-SL/AC patients from three unrelated families. Three DDR2 variants, two of which were novel, were detected with the aid of Sanger sequencing. Interestingly, one of the patients was diagnosed with Wilson's disease (WD) during the follow-up, a co-occurrence that has never been reported in patients with SMED-SL/AC so far.     

Effect of prenatal administration of therapeutic doses of topiramate on ossification of ribs and vertebrae in rat fetuses

There are few studies that have addressed the effects of prenatal exposure of topiramate on ossification of the bones derived from the paraxial mesoderm. This study aimed to evaluate skeletal ossification of ribs and vertebrae in 20-day-old rat fetuses after maternal exposure to two therapeutic doses of topiramate. Three groups of Sprague-Dawley pregnant rats were used: control, topiramate 50 mg/kg/day and topiramate 100 mg/kg/day treated groups. Topiramate was administered by gavage from day 6-19 of gestation. Fetuses were collected on day 20 by caesarean section. Fetal bones were stained with alizarin red and ossification was assessed. Results showed significant delayed ossification of ribs and vertebrae in topiramate-exposed fetuses at both doses and the effects were not dose dependent. In all examined groups, there was a direct correlation between the fetal weight and the number of complete ossified vertebral centers. Also, there were significant increases in skeletal abnormalities, particularly in ribs in both treated groups when compared to the control group. In conclusion, therapeutic doses of topiramate should be taken cautiously during pregnancy as they lead to fetal growth restriction and increases abnormalities of axial skeleton in rat fetuses.