干骺端发育不良的分类及诊治进展

干骺端发育不良是一组罕见遗传性骨骼发育不良,其特征是干骺端形态不规则,伴或不伴有其他骨骼畸形,骨外系统表现。根据最新的遗传性骨病分类,将具有长骨干骺端改变的10种疾病归类为干骺端发育不良。此类疾病表型异质性大,与多种遗传性骨病的表型重叠,应在典型影像学特征的基础上,结合临床表型、分子遗传学检测以确诊。本病目前尚无特效的治疗药物,针对发病机制相关信号通路的靶向治疗药物正在研究中,生长激素对于改善患者身高的有效性和安全性仍有待进一步研究。     

Evaluation of newborns with skeletal dysplasias

Skeletal dysplasia are a relatively common and distinct group of genetic disorders. Even though abnormalities of bone growth are the major clinical manifestations, the pathological process may involve in any body system. Many of these disorders have dire consequences such as neonatal death and most will have life-long physical and psychosocial morbidity associated with them. Recent advances in genetic research have identified the genes underlying the primary defects in several common skeletal dysplasias such as achondroplasia and diastrophic dysplasia. While these advances are clearly important in developing better therapy and a cure for those conditions, the role of the pediatrician as the diagnostician has remained unchanged. In this article we describe how a systematic approach using the simplest of tools-clinical assessment and radiograph-can arrive at a diagnosis in most instances of newborns with skeletal dysplasias. The key features that are essential for establishing a diagnosis for most of the entities encountered in the newborn are described along with our general approach to the evaluation of the radiographs.     

The importance of conventional radiography in the mutational analysis of skeletal dysplasias (the TRPV4 mutational family)

The spondylo and spondylometaphyseal dysplasias (SMDs) are characterized by vertebral changes and metaphyseal abnormalities of the tubular bones, which produce a phenotypic spectrum of disorders from the mild autosomal-dominant brachyolmia to SMD Kozlowski to autosomal-dominant metatropic dysplasia. Investigations have recently drawn on the similar radiographic features of those conditions to define a new family of skeletal dysplasias caused by mutations in the transient receptor potential cation channel vanilloid 4 (TRPV4). This review demonstrates the significance of radiography in the discovery of a new bone dysplasia family due to mutations in a single gene.     

Cartilage-hair hypoplasia caused by novel compound heterozygous <Emphasis Type="Italic">RMRP</Emphasis> mutations

Cartilage-hair hypoplasia is a rare, autosomal recessive skeletal dysplasia, caused by mutations in the RMRP gene. The skeletal abnormalities include irregular metaphyses and cone shaped epiphyses of the hands. Molecular diagnosis confirmed two novel RMRP mutations in a compound heterozygous state in two siblings with this condition.     

Pelvis-shoulder dysplasia

Pelvis-shoulder dysplasia is rare skeletal dysplasia characterised by symmetrical hypoplasia of the iliac wings and scapulae. It may be associated with unstable hips in infancy, a prominent lumbar lordosis and a waddling gait. Symptoms tend to lessen with increasing age. A child with this condition who has been followed up to the age of five years is described. Her pelvic dysplasia is milder than in previous cases and has caused no disability. Minor skeletal abnormalities are also present in the lumbar spine, femora and rib cage. Radiography of other members of the family was normal.     

Knee radiography in the diagnosis of skeletal dysplasias

Background: Flattening of the epiphyses of long bones is seen in several skeletal dysplasias and standardized measurements on a radiograph of the knee to detect skeletal dysplasias using this feature have been described. Since then only two other studies in which this method was used have been published, and both included only a small number of children and neither had a control group. In addition, the Dutch National Working Group on Skeletal Dysplasias began to have doubts about the reliability of the method. We therefore decided to re-evaluate its accuracy in a population of children with and without a skeletal dysplasia. Objective: To determine the diagnostic value of standardized measurements on conventional AP radiographs of the knee in children with a skeletal dysplasia. Subjects and methods: We measured the distal femoral metaphysis and epiphysis according to the published method on conventional AP radiographs of the knee in 45 healthy children and 52 children with a skeletal dysplasia. We compared graphically the height of the distal femoral epiphysis with its width and with the width of the femoral metaphysis. Receiver operating characteristic (ROC) curves were calculated for each group of children. Results: All graphs showed a considerable overlap between children with a skeletal dysplasia and healthy children. The size of the area under the ROC curves for the different groups was small, varying between 0.567 and 0.653. Conclusions: This method does not discriminate between children with a skeletal dysplasia and healthy children. We therefore consider it to be of little diagnostic value.     

Evidence of increased bone resorption in neurofibromatosis type 1 using urinary pyridinium crosslink analysis

Although neurofibromatosis type 1 (NF1) is a neurocutaneous disorder, skeletal abnormalities such as long-bone dysplasia, scoliosis, sphenoid wing dysplasia, and osteopenia are observed. To investigate the role of bone resorption as a mechanism for the bony abnormalities, we selected urinary pyridinium crosslinks (collagen degradation products excreted in urine) as a measure of bone resorption in NF1. Bone resorption was evaluated by quantitative assessment of the urinary excretion of pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Total (free plus peptide-bound) pyridinium crosslinks from the first morning urines from 59 NF1 children (ages 5-19) were extracted and analyzed (17 children with a localized skeletal dysplasia, and 42 without). The data were compared with a healthy reference population without NF1 (n = 99). Multivariate analyses, controlling for age showed statistically significant increases for Dpd (p < 0.001) and the Dpd/Pyd ratio (p < 0.001) in NF1 individuals with and without a skeletal dysplasia. NF1 children have an increase in the urinary excretion of pyridinium crosslinks, reflecting increased bone resorption. The effects of NF1 haploinsufficiency likely contribute to abnormal bone remodeling, either directly or indirectly by aberrant Ras signaling, potentially predisposing NF1 individuals to localized skeletal defects.     

A mild variant of Desbuquois dysplasia

On the basis of three newly observed cases (a pair of siblings and a sporadic case) and one previously reported case, we describe the clinical and radiological phenotype of a skeletal dysplasia resembling Desbuquois dysplasia. The skeletal alterations in the present disorder, including generalized osteopenia, mild modification of the vertebral endplates, epiphyseal flattening of the long bones, broad proximal femora with a spur-like projection of the lesser trochanters (a monkey wrench appearance of the proximal femora), and advanced carpal skeletal age, are almost identical to those of Desbuquois dysplasia. However, postnatal growth failure and minor spondylo-articular problems in the present disorder contrast with the conspicuous prenatal growth failure and severe spondylo-articular deformities of Desbuquois dysplasia. Short stature in the present disorder does not reach the degree of Desbuquois dysplasia. Molecular investigation of one patient excluded abnormalities of the diastrophic dysplasia sulphate transporter gene. Conclusion The combination of skeletal alterations identical to those of Desbuquois dysplasia with milder short stature and spondylo-articular problems in the present patients suggests the nosological proposal of “a mild variant of Desbuquois dysplasia”. Received: 22 June 1998 / Accepted: 1 November 1998     

SADDAN syndrome

Achondroplasia is the most common type of short-limbed dwarfism in children resulting from fibroblast growth factor receptor (FGFR) mutations. Activating mutations of FGFR3 also result in other forms of skeletal dysplasia and craniosynostosis. Acanthosis nigricans is associated with these skeletal dysplasias and we recently encountered a skeletal dysplasia along with acanthosis nigricans in a young boy. We report the case due its unusual nature affecting one of twin brothers.     

An unusual case of craniofacial fibrous dysplasia presenting in early infancy

Fibrous dysplasia (FD) of bone is one of the most frequently encountered anomalies of skeletal development [1]. It may involve one or more bones and, particularly when polyostotic, in sometimes associated with abnormal skin pigmentation and endocrine abnormalities. FD occurs mainly in large limb bones, ribs, and craniofacial bones in older children and young adults. Usually craniofacial involvement is detected because of local swelling or asymmetry of the face or head. Neurological symptoms, primarily due to involvement of the foramina, have been reported but are not common. Infantile fibrous dysplasia of the craniofacial region has rarely been reported.     

Fetal imaging in the skeletal dysplasias: Overview and experience

The skeletal dysplasias (osteochondrodysplasias) comprise a heterogeneous group of disorders that are characterized by generalized abnormalities of skeletal growth and development. Of approximately 125 well-described skeletal dysplasias, about 50 are clinically apparent and identifiable at birth. The prevalence of these dysplasias in the newborn is quite frequent and has been estimated to be between 3–4.5 per 10,000, and the overall frequency of skeletal dysplasias among perinatal deaths to be about 9 per 1,000. Over the past 23 years we have acquired an enormous experience in the International Skeletal Dysplasia Registry with skeletal dysplasias diagnosable at birth or earlier. More and more cases referred to the registry over the past 2 years have been diagnosed as abnormal by ultrasound during the second trimester. The results of our evaluation of almost 400 fetuses and stillborn babies with reference to detailed prenatal history and postmortem evaluation including radiographs, chondro-osseous morphology and even some biochemical and molecular studies are presented. The most common disorders diagnosed were osteogenesis imperfecta (OI), thanatophoric dysplasia, campomelic dysplasia and achondrogenesis type II. Twenty-two types of neonatally diagnosable skeletal dysplasias are discussed together with potential fetal (second trimester) ultrasound findings, the number of fetal ultrasound cases referred to this registry, the number of total cases of that disorder sent to our registry, and the inheritance pattern of that skeletal dysplasia. This information should prove helpful in the evaluation of future cases ascertained by ultrasonography in the second trimester.     

A 16q12.2q21 deletion identified in a patient with developmental delay,epilepsy, short stature,and distinctive features

Interstitial deletions of the 16q centromeric region are rarely reported. A microdeletion of the 16q12.2q21 region was identified in a patient with intellectual disability, epilepsy, short stature, and distinctive features; including up‐slanting palpebral fissures, hypertelorism, epicanthic folds, anteverted nares, simple philtrum, thin upper lip vermilion, high arched palate, posteriorly rotated ears, and overlapping toes in his right foot. Although the deleted region includes the genes responsible for neurological impairments (GNOA1, GPR56, KATNB1, and BBS2), haploinsufficiency of these genes would not be associated with the patient's phenotype. When NDRG4, present in the deleted region, was knocked out in mice, these mice exhibited spatial learning deficits. Thus, we hypothesize that this gene could be a potential candidate underlying the neurological observations of the patient. Because RSPRY1 was been discovered as the cause of progressive skeletal dysplasia, a loss of this gene might explain the skeletal defects observed in the patient.     

Low-dose fetal CT for evaluation of severe congenital skeletal anomalies: preliminary experience

Congenital skeletal abnormalities compose a heterogeneous and complex group of conditions that affect bone growth and development and result in various anomalies in shape and size of the skeleton. Prenatal sonographic diagnosis of these anomalies is challenging because of the relative rarity of each skeletal dysplasia, the multitude of differential diagnoses encountered when the bony abnormalities are identified, lack of precise molecular diagnosis and the fact that many of these disorders have overlapping features and marked phenotypic variability. The following review is a preliminary summary of our experience at the Children's Hospital of Philadelphia (CHOP) using low-dose fetal CT in the evaluation of severe fetal osseous abnormalities.     

A new form of spondyloperipheral dysplasia with facial dysmorphism, flattened vertebrae, hypoplastic pelvis, brachydactyly and soft tissue syndactyly

We report the case of a 9-year-old Japanese boy with spondyloperipheral skeletal dysplasia associated with facial dysmorphism, pelvic abnormalities, and distinctive hands and feet. Radiographic manifestations included mild platyspondyly with posterior scalloping, small flared ilia with shallow acetabulae, mesomelic shortening of long bones, marked delay of carpal bone maturation, and brachydactyly with hypoplastic middle and terminal phalanges bilaterally in both hands and feet. There was bilateral soft tissue syndactyly of the 2nd and 3rd interdigital spaces of the hands, the 2nd interdigital space of the feet, with hypoplastic nails. The clinical and radiographic manifestations in this case appear to represent a unique type of skeletal dysplasia. Received: 7 June 2000 Accepted: 3 August 2000     

Molecular defects in achondroplasia and the effects of growth hormone treatment

Seino Y, Moriwake T, Tanaka H, Inoue M, Kanzaki S, Tanaka T, Matsuo N, Niimi H. Molecular defects in achondroplasia and the effects of growth hormone treatment. Acta Pa; diatr 1999; Suppl 428: 118–20. Stockholm. ISSN 0803–5326
Achondroplasia is a common skeletal dysplasia with severe growth retardation. Recently, mutations in the fibroblast growth factor receptor 3 (FGFR3) were identified in patients with achondroplasia. In the present study, 70 of 75 Japanese patients with achondroplasia were found to have a G1138A mutation in FGFR3, and two patients had a G1138C mutation. Growth hormone therapy was given to 145 patients with achondroplasia. Significant dose-dependent effects on skeletal growth were obtained, with no long-term adverse effects. □ Achondroplasia, fibroblast growth factor receptor, growth hormone therapy, growth, skeletal dysplasia     

Fibrodysplasia ossificans progressiva and synovial chondromatosis

Two cases of an unusual association — fibrodysplasia ossificans progressiva and synovial chondromatosis — in non-related children are presented. This association does not seem coincidental and raises several questions about the pathogenesis. A genetic hypothesis related to G proteins is proposed. This is supported by the fact that such abnormalities have been demonstrated in pseudohypoparathyroidism and fibrous dysplasia; these diseases can also be associated with fibrodysplasia ossificans progressiva.Presented at the 29th Congress of the European Society of Pediatric Radiology, 27 April to 1 May 1992, Bundapest, Hungary and selected for publication by an International Group of the ESPR     

不同基因突变致肾单位肾痨及相关综合征患儿临床表型特点及基因分析

目的 提高对肾单位肾痨（nephronophthisis,NPHP）及相关综合征患儿临床表型和基因特点的认识。方法 回顾性分析2018年1月—2022年11月河北医科大学第二医院儿科诊治的8例NPHP及相关综合征患儿的临床资料，对其临床特征和基因检测结果进行分析。结果 8例NPHP患儿中，男5例，女3例，起病年龄15个月至12岁，就诊时均存在不同程度肾功能异常。8例患儿中，2例以发育落后首发，2例以贫血为首发，2例为体检发现肾功能异常；肾外表现包括心血管异常2例，骨骼发育异常2例，肝功能异常1例，视网膜色素变性1例，内脏镜面转位1例。8例患儿肾脏B超均有结构改变，4例尿常规显示存在轻至中度蛋白尿。5例为NPHP1基因突变，NPHP3、IFT140、TTC21B基因突变各1例，共发现4个新突变位点。结论 NPHP及相关综合征患儿常以发育落后或贫血为首发表现，部分患儿合并肾外表现。对不明原因肾功能异常患儿，应考虑到NPHP及相关综合征，高通量测序技术有助于明确诊断。[中国当代儿科杂志，2023,25(8):831-836]