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Medicine Jul 2018To analyze prenatal ultrasound data for fetal limb deformities in high-risk pregnant women and the risk factors for prenatal limb defects in high-risk pregnant... (Observational Study)
Observational Study
To analyze prenatal ultrasound data for fetal limb deformities in high-risk pregnant women and the risk factors for prenatal limb defects in high-risk pregnant women.This was a retrospective study of high-risk pregnant women at the multidisciplinary consultation center from January 2006 to December 2015. When deformities were definitively diagnosed in the first trimester by ultrasound, patients were recommended to undergo an abortion, and fetal abnormalities were confirmed by pathological examination (both gross anatomic examinations and fetal chromosome and genetic tests). The risk factors for fetal limb deformities and other congenital malformations were analyzed by multifactor analysis.Of the 4088 fetuses recorded, 144 (3.52%) were diagnosed with limb abnormalities. The abnormalities included 70 (48.61%) clubfoot/clubhand cases, with 5 polydactyly, 5 syndactyly, 4 flexion toe, 4 split hand/foot malformation, 3 overlapping fingers, and 49 congenital talipes equinovarus. A total of 6 (4.17%) and 13 (9.02%) fetuses had phocomelia and imperfect osteogenesis, respectively; 22 (15.28%) cases showed achondrogenesis; 19 (13.19%) and 12 (8.33%) had partial limb deletion absence and joint movement malfunction, respectively.In the high-risk population with limb deformities (144 patients), 19 (13.19%) were ≥35 years old, 6 (4.17%) had family history of congenital malformations, 14 (9.72%) had abnormal reproductive history, 21 (14.6%) had harmful chemical exposure, 6 (4.2%) had early TORCH infections, 16 (11.1%) had gestational diabetes, 9 (6.3%) had hypertension, 3 (2.1%) took glucocorticoid, 9 (6.3%) took sedatives.In the high-risk population with other congenital malformations except limb deformities (3766 patients), 144 pregnant women were randomly selected. In the high-risk population with other congenital malformations (144 patients), 9 (6.25%) were ≥35 years old, 7 (4.86%) had family history of congenital malformations, 10 (6.94%) had abnormal reproductive history, 22 (15.28%) had harmful chemical exposure, 5 (3.47%) had early TORCH infections, 12 (8.33%) had gestational diabetes, 11 (7.64%) had hypertension, 4 (2.78%) took glucocorticoid, 11 (7.64%) took sedatives.Ultrasound can provide adequate evidence for fetal limb deformities evaluation in most patients. Fetal limb deformity cases showed a significantly higher rate than other congenital malformations for advanced maternal age (≥35 years old).
Topics: Adult; China; Female; Fetus; Follow-Up Studies; Humans; Incidence; Limb Deformities, Congenital; Pregnancy; Retrospective Studies; Risk Factors; Ultrasonography, Prenatal; Young Adult
PubMed: 30024522
DOI: 10.1097/MD.0000000000011471 -
Archives of Disease in Childhood Jul 1976The clinical, pathological, and radiological features of 2 male sibs with a severe and lethal form of micromelic dwarfism are desribed. The family also includes 2 normal...
The clinical, pathological, and radiological features of 2 male sibs with a severe and lethal form of micromelic dwarfism are desribed. The family also includes 2 normal sibs. The histological and radiological appearances suggested a diagnosis of achondrogenesis type I, but the markedly deficient ossification of the skull and the presence of intrauterine rib fractures were atypical. These changes have been observed in two other families with 2 or more infants with suspected achondrogenesis, raising the possibility that these familial cases may be a subvariant of achondrogesis or even a distinct disease entity. The disease appears to be inherited as an autosomal recessive and death occurs shortly after birth because of severe pulmonary hypoplasia.
Topics: Achondroplasia; Bone and Bones; Dwarfism; Female; Humans; Infant, Newborn; Lung; Male; Osteogenesis; Pregnancy; Radiography
PubMed: 962365
DOI: 10.1136/adc.51.7.550 -
Ultrasound in Obstetrics & Gynecology :... Aug 2009To assess the types and numbers of cases, gestational age at specific prenatal diagnosis and diagnostic accuracy of the diagnosis of skeletal dysplasias in a prenatal...
OBJECTIVE
To assess the types and numbers of cases, gestational age at specific prenatal diagnosis and diagnostic accuracy of the diagnosis of skeletal dysplasias in a prenatal population from a single tertiary center.
METHODS
This was a retrospective database review of type, prenatal and definitive postnatal diagnoses and gestational age at specific prenatal diagnosis of all cases of skeletal dysplasias from a mixed referral and screening population between 1985 and 2007. Prenatal diagnoses were grouped into 'correct ultrasound diagnosis' (complete concordance with postnatal pediatric or pathological findings) or 'partially correct ultrasound diagnosis' (skeletal dysplasias found postnatally to be a different one from that diagnosed prenatally).
RESULTS
We included 178 fetuses in this study, of which 176 had a prenatal ultrasound diagnosis of 'skeletal dysplasia'. In 160 cases the prenatal diagnosis of a skeletal dysplasia was confirmed; two cases with skeletal dysplasias identified postnatally had not been diagnosed prenatally, giving 162 fetuses with skeletal dysplasias in total. There were 23 different classifiable types of skeletal dysplasia. The specific diagnoses based on prenatal ultrasound examination alone were correct in 110/162 (67.9%) cases and partially correct in 50/162 (30.9%) cases, (160/162 overall, 98.8%). In 16 cases, skeletal dysplasia was diagnosed prenatally, but was not confirmed postnatally (n = 12 false positives) or the case was lost to follow-up (n = 4). The following skeletal dysplasias were recorded: thanatophoric dysplasia (35 diagnosed correctly prenatally of 40 overall), osteogenesis imperfecta (lethal and non-lethal, 31/35), short-rib dysplasias (5/10), chondroectodermal dysplasia Ellis-van Creveld (4/9), achondroplasia (7/9), achondrogenesis (7/8), campomelic dysplasia (6/8), asphyxiating thoracic dysplasia Jeune (3/7), hypochondrogenesis (1/6), diastrophic dysplasia (2/5), chondrodysplasia punctata (2/2), hypophosphatasia (0/2) as well as a further 7/21 cases with rare or unclassifiable skeletal dysplasias.
CONCLUSION
Prenatal diagnosis of skeletal dysplasias can present a considerable diagnostic challenge. However, a meticulous sonographic examination yields high overall detection. In the two most common disorders, thanatophoric dysplasia and osteogenesis imperfecta (25% and 22% of all cases, respectively), typical sonomorphology accounts for the high rates of completely correct prenatal diagnosis (88% and 89%, respectively) at the first diagnostic examination.
Topics: Algorithms; Biometry; Bone Diseases, Developmental; Female; Genetic Counseling; Gestational Age; Humans; Musculoskeletal Abnormalities; Pregnancy; Pregnancy Outcome; Prenatal Diagnosis; Quality Assurance, Health Care; Retrospective Studies; Ultrasonography
PubMed: 19548204
DOI: 10.1002/uog.6359 -
Journal of Clinical Research in... Dec 2022Odontochondrodysplasia (ODCD, OMIM #184260) is a rare, non-lethal skeletal dysplasia characterized by involvement of the spine and metaphyseal regions of the long bones,...
Odontochondrodysplasia (ODCD, OMIM #184260) is a rare, non-lethal skeletal dysplasia characterized by involvement of the spine and metaphyseal regions of the long bones, pulmonary hypoplasia, short stature, joint hypermobility, and dentinogenesis imperfecta. ODCD is inherited in an autosomal recessive fashion with an unknown frequency caused by mutations of the thyroid hormone receptor interactor 11 gene (; OMIM *604505). The gene encodes the Golgi microtubule-associated protein 210 (GMAP-210), which is an indispensable protein for the function of the Golgi apparatus. Mutations in also cause achondrogenesis type 1A (ACG1A). Null mutations of lead to ACG1A, also known as a lethal skeletal dysplasia, while hypomorphic mutations cause ODCD. Here we report a male child diagnosed as ODCD with a novel compound heterozygous mutation who presented with skeletal changes, short stature, dentinogenesis imperfecta, and facial dysmorphism resembling achondroplasia and hypochondroplasia.
PubMed: 34111908
DOI: 10.4274/jcrpe.galenos.2021.2021.0099 -
The New England Journal of Medicine Jan 2010Establishing the genetic basis of phenotypes such as skeletal dysplasia in model organisms can provide insights into biologic processes and their role in human disease.
BACKGROUND
Establishing the genetic basis of phenotypes such as skeletal dysplasia in model organisms can provide insights into biologic processes and their role in human disease.
METHODS
We screened mutagenized mice and observed a neonatal lethal skeletal dysplasia with an autosomal recessive pattern of inheritance. Through genetic mapping and positional cloning, we identified the causative mutation.
RESULTS
Affected mice had a nonsense mutation in the thyroid hormone receptor interactor 11 gene (Trip11), which encodes the Golgi microtubule-associated protein 210 (GMAP-210); the affected mice lacked this protein. Golgi architecture was disturbed in multiple tissues, including cartilage. Skeletal development was severely impaired, with chondrocytes showing swelling and stress in the endoplasmic reticulum, abnormal cellular differentiation, and increased cell death. Golgi-mediated glycosylation events were altered in fibroblasts and chondrocytes lacking GMAP-210, and these chondrocytes had intracellular accumulation of perlecan, an extracellular matrix protein, but not of type II collagen or aggrecan, two other extracellular matrix proteins. The similarities between the skeletal and cellular phenotypes in these mice and those in patients with achondrogenesis type 1A, a neonatal lethal form of skeletal dysplasia in humans, suggested that achondrogenesis type 1A may be caused by GMAP-210 deficiency. Sequence analysis revealed loss-of-function mutations in the 10 unrelated patients with achondrogenesis type 1A whom we studied.
CONCLUSIONS
GMAP-210 is required for the efficient glycosylation and cellular transport of multiple proteins. The identification of a mutation affecting GMAP-210 in mice, and then in humans, as the cause of a lethal skeletal dysplasia underscores the value of screening for abnormal phenotypes in model organisms and identifying the causative mutations.
Topics: Animals; Cell Differentiation; Cell Proliferation; Chondrocytes; Codon, Nonsense; Cytoskeletal Proteins; Endoplasmic Reticulum; Genes, Recessive; Glycosylation; Golgi Apparatus; Humans; Mice; Mice, Mutant Strains; Nuclear Proteins; Osteochondrodysplasias; Phenotype; Polymorphism, Single Nucleotide; Protein Processing, Post-Translational; Sequence Analysis, DNA
PubMed: 20089971
DOI: 10.1056/NEJMoa0900158 -
Case Reports in Obstetrics and... 2019Achondrogenesis type II is a rare, lethal osteochondrodysplasia with considerable phenotypic heterogeneity. We describe our experience in diagnosing prenatal-onset...
AIM
Achondrogenesis type II is a rare, lethal osteochondrodysplasia with considerable phenotypic heterogeneity. We describe our experience in diagnosing prenatal-onset achondrogenesis type II by a multidisciplinary assessment.
METHODS
Two cases of fetal achondrogenesis type II were analyzed retrospectively using prenatal ultrasound evaluation, postnatal radiographic diagnosis, and molecular genetic testing of .
RESULTS
A causative mutation in the gene was found in both patients. Combined with postnatal radiographic examination, the final diagnosis of achondrogenesis type II was made.
CONCLUSION
Our findings emphasize the importance of a multidisciplinary assessment for the definitive diagnosis of achondrogenesis type II, which is paramount for proper genetic counseling.
PubMed: 31392067
DOI: 10.1155/2019/7981767 -
The American Journal of Pathology Jan 1976Three spontaneously aborted fetuses with Type I achondrogenesis in a family with a first cousin marriage are described. Studies by light microscopy revealed abnormal...
Three spontaneously aborted fetuses with Type I achondrogenesis in a family with a first cousin marriage are described. Studies by light microscopy revealed abnormal cartilage, enchondral, and periosteal bone, and normal tooth development with abnormal alveolar bone. Electron microscopic studies of cultured skin fibroblasts manifested structurally normal cells. Scanning electron microscopy studies had shown deficient intercartilaginous septa in the metaphysis, with abnormally large calcifying globules. In the diaphysis, the orientation of bone trabeculae and collagen fibers within the trabeculae was disturbed. The numerous osteocytic lucunae were wide and irregular in arrangement and shape. Type 2 achondrogenesis, as studied in these fetuses, is probably a widespread mesenchymal defect, manifested by abnormal calcification and ossification of enchondral and periosteal bone.
Topics: Achondroplasia; Bone Matrix; Bone and Bones; Calcinosis; Cartilage; Collagen; Dwarfism; Female; Fibroblasts; Humans; Male; Osteocytes; Periosteum; Pregnancy; Skin; Tooth Germ
PubMed: 1247086
DOI: No ID Found -
Frontiers in Genetics 2021Skeletal dysplasias are often well characterized, and only a minority of the cases remain unsolved after a thorough analysis of pathogenic variants in over 400 genes...
Skeletal dysplasias are often well characterized, and only a minority of the cases remain unsolved after a thorough analysis of pathogenic variants in over 400 genes that are presently known to cause monogenic skeletal diseases. Here, we describe an 11-year-old Finnish girl, born to unrelated healthy parents, who had severe short stature and a phenotype similar to odontochondrodysplasia (ODCD), a monogenic skeletal dysplasia caused by biallelic variants. The family had previously lost a fetus due to severe skeletal dysplasia. Exome sequencing and bioinformatic analysis revealed an oligogenic inheritance of a heterozygous nonsense mutation in and four likely pathogenic missense variants in , , , and in the index patient. Interestingly, all these genes except are known to cause skeletal dysplasia in an autosomal recessive manner. In contrast, the fetus was found homozygous for the mutation, and achondrogenesis type IA diagnosis was, thus, molecularly confirmed, indicating two different skeletal dysplasia forms in the family. To the best of our knowledge, this is the first report of an oligogenic inheritance model of a skeletal dysplasia in a Finnish family. Our findings may have implications for genetic counseling and for understanding the yet unsolved cases of rare skeletal dysplasias.
PubMed: 34149817
DOI: 10.3389/fgene.2021.680838 -
Surgical and Radiologic Anatomy : SRA Oct 2013An understanding of the normal evolution of the spine is of great relevance in the prenatal detection of spinal abnormalities. This study was carried out to estimate the...
PURPOSE
An understanding of the normal evolution of the spine is of great relevance in the prenatal detection of spinal abnormalities. This study was carried out to estimate the length, width, cross-sectional area and volume of the neural ossification centers of vertebrae C1-S5 in the human fetus.
MATERIALS AND METHODS
Using the methods of CT (Biograph mCT), digital-image analysis (Osirix 3.9) and statistics (the one-way ANOVA test for paired data, the Kolmogorov-Smirnov test, Levene's test, Student's t test, the one-way ANOVA test for unpaired data with post hoc RIR Tukey comparisons) the size for the neural ossification centers throughout the spine in 55 spontaneously aborted human fetuses (27 males, 28 females) at ages of 17-30 weeks was studied.
RESULTS
The neural ossification centers were visualized in the whole pre-sacral spine, in 74.5 % for S1, in 61.8 % for S2, in 52.7 % for S3, and in 12.7 % for S4. Neither male-female nor right-left significant differences in the size of neural ossification centers were found. The neural ossification centers were the longest within the cervical spine. The maximum values referred to the axis on the right, and to C5 vertebra on the left. There was a gradual decrease in length for the neural ossification centers of T1-S4 vertebrae. The neural ossification centers were the widest within the proximal thoracic spine and narrowed bi-directionally. The growth dynamics for CSA of neural ossification centers were found to parallel that of volume. The largest CSAs and volumes of neural ossification centers were found in the C3 vertebra, and decreased in the distal direction.
CONCLUSIONS
The neural ossification centers show neither male-female nor right-left differences. The neural ossification centers are characterized by the maximum length for C2-C6 vertebrae, the maximum width for the proximal thoracic spine, and both the maximum cross-sectional area and volume for C3 vertebra. There is a sharp decrease in size of the neural ossification centers along the sacral spine. A decreasing sequence of values for neural ossification centers along the spine from cervical to sacral appears to parallel the same direction of the timing of ossification. The quantitative growth of the neural ossification centers is of potential relevance in the prenatal diagnosis and monitoring of achondrogenesis, caudal regression syndrome, diastematomyelia and spina bifida.
Topics: Cross-Sectional Studies; Female; Fetal Development; Fetus; Humans; Male; Osteogenesis; Reference Values; Sex Characteristics; Spine
PubMed: 23455365
DOI: 10.1007/s00276-013-1093-5 -
Molecular Syndromology Jan 2023Pathogenic variants in the gene cause the following spectrum of phenotypes: achondrogenesis 1B (ACG1B), atelosteogenesis 2 (AO2), diastrophic dysplasia (DTD), and...
INTRODUCTION
Pathogenic variants in the gene cause the following spectrum of phenotypes: achondrogenesis 1B (ACG1B), atelosteogenesis 2 (AO2), diastrophic dysplasia (DTD), and recessive-multiple epiphyseal dysplasia (rMED), the first 2 being lethal. Here, we report a cohort and a comprehensive literature review on a genotype-phenotype correlation of -related disorders.
METHODS
The local patients were genotyped by Sanger sequencing or next-generation sequencing (NGS). We reviewed data from the literature regarding phenotype, zygosity, and genotype in parallel.
RESULTS
The local cohort enrolled 12 patients, including one with a Desbuquois-like phenotype. All but one showed biallelic mutations, however, only one allele mutated in a fetus presenting ACG1B was identified. The literature review identified 42 articles and the analyses of genotype and zygosity included the 12 local patients.
DISCUSSION
The R279W variant was the most prevalent among the local patients. It was in homozygosity (hmz) in 2 patients with rMED and in compound heterozygosity (chtz) in 9 patients. The genotype and zygosity review of all patients led to the following conclusions: DTD is the most common phenotype in Finland due to a Finnish mutation (c.727-1G>C). Outside of Finland, rMED is the most prevalent phenotype, usually associated with R279W in hmz. In contrast, DTD's genotype is usually in chtz. Despite a large number of variants (38), just 8 are recurrent (R279W, C653S, c.-26+2T>C, R178*, K575Sfs*10, V340del, G663R, T512K). The last 3 in hmz lead to lethal phenotypes. The Finnish mutation is found only in chtz outside of Finland, being associated with all 4 classical phenotypes. The p.R178* and p.K575Sfs*10 variants should be viewed as lethal mutations since both were mainly described with lethal phenotypes and were never reported in hmz. The existence of 9 patients with only one mutated allele suggests that other mutations in the other allele of these patients still need to be unveiled.
PubMed: 36660027
DOI: 10.1159/000525020