遗传性骨病的分子遗传学研究进展

遗传性骨病是一大组临床和遗传异质性较强的骨软骨发育不良疾病,常见的临床表现包括矮身材、畸形、不成比例生长以及单个或一组骨骼发育不良。目前与软骨和成骨发育相关疾病的分子遗传学机制发展迅速,《国际遗传性骨病分类标准（2006年版）》共纳入372种遗传性骨病,并按其分子遗传、生化以及影像学特点分为37组,已明确其中215种与一个或多个基因突变相关,相关致病基因约140个。本文简要介绍《国际遗传性骨病分类标准（2006年版）》,综述了与骨软骨发育不良相关的基因如成纤维细胞生长因子受体3（FGFR3）、Ⅱ型胶原（COL2A1）等,以及基因突变导致的临床表现,为遗传性骨病的诊断、产前诊断以及骨软骨发育不良的基础研究提供帮助。     

心电图自动诊断系统的研制

本文利用数字信号处理和波形识别技术，对心电图的ＱＲＳ波、Ｐ波、Ｔ波的时段进行了计算机的自动检测并对室性期前收缩等１５种异常心电进行自动诊断。打印输出相应的诊断报告。为了检验本系统的稳定性和可信度，本文还利用美国麻省理工学院的ＭＩＴ－ＢＩＨ数据库对本文所使用的方法进行了检测，取得了较好的效果。     

The effects of calcitonin and colchicine on the cellular response to diphosphonate.

The mechanism by which diphosphonates inhibit bone resorption remains speculative; however, the osteoclast appears to be selectively affected by the drug. This study examined the effects off diphosphonate on osteoclasis in bones treated concomitantly with agents which reduce the osteoclast ruffled border, calcitonin and colchicine. Dichloromethylene diphosphonate, calcitonin, and colchicine inhibited parathyroid-hormone-stimulated bone resorption, as indicated by a significantly reduced release of 45Ca from prelabelled long bones. Quantitative and qualitative histological analyses of osteoclasts indicated differences among effects resulting from agents. Only bones treated with diphosphonate demonstrated a majority of osteoclasts with degenerative appearance; colchicine-treated bones exhibited many spherulated cells with cytoplasmic blebs. The number of normal osteoclasts in calcitonin-treated bones was the same as in controls and decreased with diphosphonate and colchicine treatment. All inhibitory agents reduced the number of nuclei per osteoclast; furthermore, colchicine effected an additional significant reduction, as compared with diphosphonate and calcitonin. The number and frequency of abnormal osteoclasts was increased by diphosphonate, but unaffected by colchicine and calcitonin. The addition of calcitonin, but not colchicine, to diphosphonate-treated bones decreased the incidence of abnormal osteoclasts. Although both calcitonin and colchicine are known to reduce the osteoclast ruffled border, this study has shown differences between the morphological effects of the 2 agents which presumably reflect differences in their mode of action and their interaction with diphosphonate.     

Congenital cutis laxa with ligamentous laxity and delayed development, Dandy-Walker malformation and minor heart and osseous defects

We present a female infant exhibiting congenital cutis laxa with retardation of growth and motor development, ligamentous laxity and congenital dislocation of the hips. This connective tissue disorder was associated with Dandy-Walker malformation, atrial and ventricular defect and minor bone abnormalities including multiple wormian bones, abnormal tubulation of long bones and absent twelfth pair of ribs. This association is believed to be unique.     

掌骨的X线测量及其与身高的性别判别分析

目的：探讨掌骨的侧别与性别差异及性别判别方法，积累有关解剖学资料。方法：随机选择健康汉族大学生，进行双手后前位x线拍片，分别测量各掌骨长与中点宽，同时测量身高，将所得数据用SPSS软件进行统计学分析处理。结果：男性第2、4、5掌骨宽度以及女性第3、4、5掌骨宽度左右手侧差有显著性意义，男女性别差异亦有显著意义；同时应用Fisher法分析得出4个判别式，判别率分别为87．6％和89．8％。结论：所得性别判别式对法医学性别判别应用价值较大，为体质人类学和法医学提供了有关解剖学资料。     

The N syndrome, a "new" multiple congenital anomaly-mental retardation syndrome:Studies of malformation syndromes in man XXVII

Two brothers are reported with a previously undescribed multiple congenital anomaly/ mental retardation (MCA/MR) syndrome consisting of characteristic appearance, severe mental and growth retardation with visual impairment and deafness, dolichocephaly, hypotelorism, a "scalloped", laterally overlapping upper eyelid, large corneas, abnormal auricles, dental dysplasia, generalized skeletal dysplasia (which includes overtubulation of the long bones with the distal long bones being relatively shorter than the proximal long bones), high fingerprint ridge count, cryptorchidism, hypospadias and spasticity. They have an apparently normal karyotype. The older of the two, now 13 years old, is receiving total institutional care. The younger died of lymphosarcoma at the age of 5 8/12 years, and at autopsy was found to have markedly abnormal cerebral cortical cyto-architecture. These cases are reported as a "provisionally private syndrome", but with the possibility in mind that further studies may prove the N syndrome to be either an autosomal recessive or an X-linked recessive trait.     

Computerized Analysis of Pneumoconiosis in Digital Chest Radiography: Effect of Artificial Neural Network Trained with Power Spectra

It is difficult for radiologists to classify pneumoconiosis with small nodules on chest radiographs. Therefore, we have developed a computer-aided diagnosis (CAD) system based on the rule-based plus artificial neural network (ANN) method for distinction between normal and abnormal regions of interest (ROIs) selected from chest radiographs with and without pneumoconiosis. The image database consists of 11 normal and 12 abnormal chest radiographs. These abnormal cases included five silicoses, four asbestoses, and three other pneumoconioses. ROIs (matrix size, 32 × 32) were selected from normal and abnormal lungs. We obtained power spectra (PS) by Fourier transform for the frequency analysis. A rule-based method using PS values at 0.179 and 0.357 cycles per millimeter, corresponding to the spatial frequencies of nodular patterns, were employed for identification of obviously normal or obviously abnormal ROIs. Then, ANN was applied for classification of the remaining normal and abnormal ROIs, which were not classified as obviously abnormal or normal by the rule-based method. The classification performance was evaluated by the area under the receiver operating characteristic curve (Az value). The Az value was 0.972 ± 0.012 for the rule-based plus ANN method, which was larger than that of 0.961 ± 0.016 for the ANN method alone (P ≤ 0.15) and that of 0.873 for the rule-based method alone. We have developed a rule-based plus pattern recognition technique based on the ANN for classification of pneumoconiosis on chest radiography. Our CAD system based on PS would be useful to assist radiologists in the classification of pneumoconiosis.     

Radiography in post-mortem examinations of fetuses and neonates. Findings on plain films and at arteriography

During the last decade there has been an increasing interest in radiological investigation of stillborns and neonates as a supplement to autopsy. A consecutive series of 137 fetuses and neonates is presented. Prior to autopsy plain X-ray films were taken, and in 50% arteriography was performed by injecting contrast medium into an umbilical or femoral artery. On the plain films only 41% were normal. The major part of the abnormal radiographs exhibited minor abnormalities such as transverse lines or "stress-lines" of the bones, cercival ribs or an abnormal numbers of ribs. Major abnormalities were seen in 9%. Most of these were abnormalities of the spine. The arteriographs were very detailed and were abnormal in 29% of the cases. The technique was not suitable for demonstration of heart malformations. It is concluded that plain film X-ray of soft tissues and bones is recommendable as a routine procedure, whereas arteriography should be limited to cases suspected of vascular malformations or if an autopsy cannot be performed.     

Gracile bone dysplasia

Gracile bones are a frequent abnormality associated with fetal hypokinesia of any cause. With the exception of thin, undermineralized bones, the chondro-osseous structure is usually normal in these cases. We present a lethal skeletal dysplasia comprising minor anomalies, central nervous system abnormalities, gracile long bones, and abnormal chondro-osseous morphology. In addition to a short, disordered growth plate, the chondrocytes contained dilated loops of rough endoplasmic reticulum, suggesting an abnormality of an extracellular matrix protein. This protein appears to have effects on chondro-osseous and on facial and central nervous system development. We suggest the term “gracile bone dysplasia” to describe this disorder. Am. J. Med. Genet. 75:95–100, 1998. © 1998 Wiley-Liss, Inc.     

Prenatal diagnosis and pathoanatomy of iniencephaly

The authors discuss the diagnostic criteria of iniencephaly based on data from the literature and eleven additional, new cases. The most important differential diagnostic problems involve anencephaly with spinal retroflexion and the Klippel-Feil syndrome. Ultrasound indicated cranio-spinal alterations while amniotic fluid AFP estimation and exfoliative cytology substantiated abnormal closure of the neural tube, thus comprising helpful means for prenatal diagnosis of iniencephaly. The authors emphasize the need for median-sagittal sectioning through the spinal column for accurate evaluation of vertebral abnormalities. This, together with close observation of the occiput and the foramen magnum, helps the precise diagnosis of iniencephaly and once regularly applied will most likely result in more frequent recognition of this developmental abnormality.     

B超引导下孕中期多胎妊娠异常胎儿减胎术临床分析

目的 总结B超引导下孕中期多胎妊娠异常胎儿减胎术的穿刺要点及注意事项。方法 B超引导下对6例孕中期的多胎妊娠中异常胎儿心内注入10％氯化钾进行选择性减胎。结果 6例异常胎儿均减胎成功，所有孕妇术后均无子宫收缩、阴道流血及流水。结论 在多胎妊娠一胎异常时，B超引导下孕中期选择性减胎术是一种安全、简便、有效的方法。     

Quantitative genetic variation in the skeleton of the mouse: II. Description of variation within and between inbred strains

Variation in the skeletons of over 400 male and female mice from 12 genotypes was investigated by using multivariate statistical methods. A series of discriminant functions explains the differences in the shape of six bones: mandible, os coxae, femur, tibia-fibula, scapula, and humerus. The anatomical features of bone shape described by these functions are summarized together with illustrations of the typical shapes of each bone from the 12 genotypes. Variability within genotypes was investigated by using the Mahalanobis D² distance—a measure of the difference between two points representing multivariate data—from the group mean. A series of variants were detected ranging from grossly abnormal bones to bones showing subtle differences localized to specific regions. Examples of the variants found are illustrated.     

Calvarial hyperostosis: a benign X-linked recessive disorder

We report a family with what appears to be a unique X-linked recessive disorder of isolated hyperostosis of the calvarium. Although irregularity of the calvarium and exophytic prominences of the frontoparietal bones were apparent in infancy, premature cranial suture closure did not occur and there was no evidence of increased intracranial pressure despite a Luckenshadel appearance of the skull. Other membranous bones and the tubular bones were not involved. Calvarial bone biopsy from one patient showed vacuolated histiocytes suggesting a storage disease; however, neurologic deterioration, hepatosplenomegaly, and dysostosis multiplex did not occur. The affected family members had normal stature, normal occipitofrontal circumference, and no other medical problems. The biochemical basis of this disorder is not known. Although storage of abnormal material is possible, the long-term prognosis seems favorable.     

Prenatal diagnosis in two pregnancies of an achondroplastic woman

We present the results of the ultrasonographic examination of two successive pregnancies of an achondroplastic woman. The limb bones were measured and shown to be normal in length. Other pertinent literature reports are discussed.     

Discordant fetal phenotype of hypophosphatasia in two siblings

Hypophosphatasia (HPP) is an autosomal recessive metabolic disorder with impaired bone mineralization due to mutations in the ALPL gene. The genotype‐phenotype correlation of this disorder has been widely described. Here, we present two affected siblings, whose fetal phenotypes were discordant. A 31‐year‐old Japanese woman, G0P0, was referred to our institution because of fetal micromelia. After obstetric counseling, the pregnancy was terminated at 21 weeks’ gestation. Post‐mortem radiographs demonstrated severely defective mineralization of the skeleton. The calvarial, spinal, and tubular bones were mostly missing. Only the occipital bones, mandible, clavicles, ribs, one thoracic vertebra, ilia, and tibia were relatively well ossified. The radiological findings suggested lethal HPP. Genetic testing for genomic DNA extracted from the umbilical cord identified compound heterozygous mutations in the ALPL gene (c.532T>C, p.Y178H; c.1559delT, p.Leu520Argfs*86). c.532T>C was a novel variant showing no residual activity of the protein by the functional analysis. The parents were heterozygous carriers. In the next pregnancy, biometric values on fetal ultrasonography at 20 and 26 weeks’ gestation were normal. At 34 weeks, however, a small chest and shortening of distal long bones came to attention. The neonate delivered at 41 weeks showed serum ALP of <5U/L. Radiological examination showed only mild thoracic hypoplasia and metaphyseal mineralization defects of the long bones. ALP replacement therapy was introduced shortly after birth, and the neonate was discharged at day 22 without respiratory distress. Awareness of discordant fetal phenotypes in siblings with HPP precludes a diagnostic error, and enables early medical intervention to mildly affected neonates.     

邯郸地区生长发育异常儿童骨龄生长学特征及相关因素研究

目的 通过对邯郸地区生长发育异常（矮身高）儿童骨龄评价,探索该组儿童的生长发育现状,从而指导临床对生长发育异常儿童的重视和关注,达到早发现、早干预、早治疗等目的。方法 收集邯郸地区2014年1月~2017年12月以生长发育异常（矮身高）而就诊,拍摄手腕部骨龄片1478例,应用CHN骨龄测评方法和G-P图谱法对其骨龄进行评估,根据骨龄判定标准,从而判定矮身高儿童的骨龄现状。结果 ①矮身高儿童的骨龄表现骨龄落后657例,骨龄吻合578例,骨龄提前243例,以骨龄落后为主,男性小于生活年龄（1.38±1.39）岁,女性小于生活年龄（1.25±0.76）岁。②不同原因导致的矮身高骨龄生长学特征不同;③手腕骨不同骨骺,在骨龄落后的程度也不同,在657例骨龄落后病例中,尺骨发育晚或形态落后130例,腕骨数量少或形态落后178例,多个骨骺联合发育落后125例,伴有第二掌骨基底部假骨骺77例,而桡骨远端、掌指骨骨骺发育晚的所占比例较少。结论 ①矮身高儿童的骨龄发育可以表现为骨龄落后、骨龄提前和骨龄吻合,以骨龄落后为主;②不同病因导致的矮身高骨龄生长学特征不同,不健康生活方式、先天条件不足、特发性矮小导致的矮身高,骨龄多落后在2岁以内多见,而病理性矮身高,如生长激素缺乏大部分骨龄落后,多在2岁左右,甲状腺功能低下导致的骨龄落后程度较大,一般在3岁左右,肾脏疾病导致的骨龄情况髓这体内激素分泌的变化而变化,可骨龄落后、也可骨龄提前;而Turner综合征及其他基因遗传性疾病中,骨龄落后程度较小,多在1~2岁;性早熟导致的矮身高,骨龄多提前,偶有骨龄落后的发生。③骨龄落后以腕骨、尺骨出现晚或形态落后、或多个骨骺联合落后为主,但伴有第二掌骨基底部假骨骺也有一定比率,是否能作为判定骨龄落后的标志有待研究。     

Autosomal-recessive omodysplasia: Prenatal diagnosis and histomorphometric assessment of the physeal plates of the long bones

Second-semester ultrasonography of a female fetus documented short femora and humeri and dislocation of the radii. Based on the clinical and postmortem radiological findings, autosomal-recessive omodysplasia was diagnosed. The physeal plates of the long tubular bones were assessed by computer-assisted image analysis. The dimensions and orientation of the chondrocytic lacunae in the physeal plates of the omodysplastic fetus were compared with those in the physeal plates of fetuses without gross limb abnormalities (oligohydramnios, n = 2; hydrocephalus, n = 2; Down syndrome, n = 1). The pathological characteristics of the omodysplastic physeal plates were an expanded zone of proliferating cartilage and an increased number of closely packed, small chondrocytes. We propose that a genetic, functional deficiency of the physeal cells, underlying the short-limbed dwarfism of autosomal-recessive omodysplasia, is partially compensated, albeit ineffectively, by an increased number of small chondrocytes in the proliferating zone of the physeal plate. Am. J. Med. Genet. 76:238–244, 1998. © 1998 Wiley-Liss, Inc.     

脊髓小脑性共济失调一家系的基因诊断和产前诊断

目的 确定一脊髓小脑性共济失调(spinocerehellar ataxia,SCA)家系具体分型,并开展症状前患者检测和产前诊断.方法 收集该脊髓小脑性共济失调家系中的2例患者的血液标本,结合该家系的临床表现和我国该类疾病的发病率,采用聚合酶链反应对SCA1、SCA2和SCA3/MJD 3个基因的三核苷酸重复片段进行扩增,并通过琼脂糖凝胶电泳和PCR产物测序的方法确定所有正常和异常扩增等位基因内三核苷酸重复次数.明确致病基因后,对患者子女进行症状前检测,并对1例怀孕症状前患者进行了产前诊断.结果 SCA1和SCA2基因内三核苷酸重复次数在正常范围内,SCA3/MJD的2个等位基因中1个等位基因三核苷酸重复次数在正常范围内,另1个等位基因三核苷酸重复次数在异常范围内.患者子女有1人携带异常等位基因,胎儿携带异常等位基因.结论 该家系经基因诊断确诊为SCA3/MJD型,有1人为症状前患者,该症状前患者所孕胎儿也为症状前患者.     

Anatomic variations in a cleft hand of an elder cadaveric specimen

Cleft hand is a rare and complex malformation in which the central part of the hand is missing. Since the nineteenth century, a very small number of dissections in cleft hand have been reported and very few reports describe the soft-tissue abnormalities. We report a case of an elderly cadaveric specimen with bilateral cleft hand. X-ray, CT-scan with 3D reconstruction and dissection were performed on the right hand and forearm. On both the sides, we noted the absence of the index, middle and ring finger. Malformation and degenerative arthrosis at the carpal bones level have been identified. The flexor and extensor tendons of the absent fingers fuse with one another over the end of the remaining carpal bones, forming a radial and an ulnar tendinous plexus and two tendon loops. Data concerning intrinsic muscles, vessels and nerves are entirely recorded. Soft-tissue abnormal distribution is due to the abnormal bony configuration. Correction of the bone abnormalities does not resume the surgical treatment of a cleft hand. Hand surgeons need to be aware of the soft-tissue disorders and their surgical implications.     

American Journal of Medical Genetics Part A: Volume 158A, Number 9, September 2012

COVER FIGURE Hand X-ray showing hyperphalangism of the third and fourth fi ngers associated with brachymetacarpy, abnormal shape and length of middle phalanges of the fi ngers and carpal fusion between the hamate and capitate bones in a child with a Catel-Manzke-like phenotype and a IMPAD1 mutation. See article by Nizon et al. in this issue.