-
Cases Journal Dec 2008Achondrogenesis is a lethal osteochondrodysplasia characterized by hypoplasia of the bones and is associated with various anomalies varying in severity. Based on...
INTRODUCTION
Achondrogenesis is a lethal osteochondrodysplasia characterized by hypoplasia of the bones and is associated with various anomalies varying in severity. Based on clinical, radiologic, and histopathologic features, two types are distinguished.
CASE PRESENTATION
The prenatal ultrasound examination of a 32-year-old Turkish woman who was referred to our clinic at 33 weeks and 6 days of gestation revealed fetal micromelia together with several other anomalies. The female baby died shortly after birth and was diagnosed with achondrogenesis type I based on the clinical and radiographic findings.
CONCLUSION
Ultrasonography is important in prenatal diagnosis and for distinguishing lethal skeletal dysplasias in order to counsel the parents about future recurrent risks. As it is a uniformly lethal disease, a definitive prenatal diagnosis of achondrogenesis may be an indication for pregnancy termination.
PubMed: 19094214
DOI: 10.1186/1757-1626-1-406 -
Developmental Dynamics : An Official... Jul 2022Absence of Golgi microtubule-associated protein 210 (GMAP210), encoded by the TRIP11 gene, results in achondrogenesis. Although TRIP11 is thought to be specifically...
BACKGROUND
Absence of Golgi microtubule-associated protein 210 (GMAP210), encoded by the TRIP11 gene, results in achondrogenesis. Although TRIP11 is thought to be specifically required for chondrogenesis, human fetuses with the mutation of TRIP11 also display bony skull defects where chondrocytes are usually not present. This raises an important question of how TRIP11 functions in bony skull development.
RESULTS
We disrupted Trip11 in neural crest-derived cell populations, which are critical for developing skull in mice. In Trip11 mutant skulls, expression levels of ER stress markers were increased compared to controls. Morphological analysis of electron microscopy data revealed swollen ER in Trip11 mutant skulls. Unexpectedly, we also found that Golgi stress increased in Trip11 mutant skulls, suggesting that both ER and Golgi stress-induced cell death may lead to osteopenia-like phenotypes in Trip11 mutant skulls. These data suggest that Trip11 plays pivotal roles in the regulation of ER and Golgi stress, which are critical for osteogenic cell survival.
CONCLUSION
We have recently reported that the molecular complex of ciliary protein and GMAP210 is required for collagen trafficking. In this paper, we further characterized the important role of Trip11 being possibly involved in the regulation of ER and Golgi stress during skull development.
Topics: Animals; Cytoskeletal Proteins; Endoplasmic Reticulum Stress; Golgi Apparatus; Humans; Mice; Neural Crest; Osteochondrodysplasias; Skull; Transcription Factors
PubMed: 35147267
DOI: 10.1002/dvdy.461 -
American Journal of Human Genetics Dec 1988A 32-wk-gestation female with type II achondrogenesis-hypochondrogenesis has been studied. The clinical features were typical, and radiographs revealed short ribs,...
A 32-wk-gestation female with type II achondrogenesis-hypochondrogenesis has been studied. The clinical features were typical, and radiographs revealed short ribs, hypoplastic ilia, absence of ossification of sacrum, pubis, ischia, tali, calcanei, and many vertebral bodies; the long bones were short with mild metaphyseal flaring. The femoral cylinder index was 6.3. Comparison with previous cases placed the patient toward the mild end of the achondrogenesis-hypochondrogenesis spectrum (Whitley-Gorlin prototype IV). Light microscopy revealed hypercellular cartilage with decreased matrix traversed by numerous fibrous vascular canals. The growth plate was markedly abnormal. Ultrastructural studies revealed prominently dilated rough endoplasmic reticulum containing a fine granular material with occasional fibrils in all chondrocytes. Immunohistologic studies indicated irregular large areas of cartilage matrix staining with monoclonal antibody to human type III collagen. The relative intensity of matrix staining for type II collagen appeared diminished. More striking, however, were intense focal accumulations of type II collagen within small rounded perinuclear structures of most chondrocytes but not other cell types. These results strongly suggest intracellular retention of type II collagen within vacuolar structures, probably within the dilated rough endoplasmic reticulum observed in all chondrocytes by electron microscopy (EM), and imply the presence of an abnormal, poorly secreted type II collagen molecule. Biochemical studies (see companion paper) suggest that this patient had a new dominant lethal disorder caused by a structural abnormality of type II collagen.
Topics: Cartilage; Collagen; Female; Fluorescent Antibody Technique; Humans; Infant, Newborn; Infant, Premature; Microscopy, Electron; Osteochondrodysplasias; Radiography
PubMed: 3057886
DOI: No ID Found -
Journal of Korean Medical Science Oct 2000Achondrogenesis is a lethal form of congenital chondrodystrophy characterized by extreme micromelia. We describe a case of achondrogenesis type II (Langer-Saldino...
Achondrogenesis is a lethal form of congenital chondrodystrophy characterized by extreme micromelia. We describe a case of achondrogenesis type II (Langer-Saldino achondrogenesis) detected by prenatal ultrasonography at 20-week gestation. A dwarfed fetus with large head, short neck and chest, prominent abdomen and short limbs was terminated transvaginally. Radiologic and histopathologic examination revealed features of mild form of achondrogenesis type II. Although the case had no known risk factor and the phenotypic abnormality was mild, modern development in prenatal screening made the early detection possible.
Topics: Abortion, Induced; Achondroplasia; Bone and Bones; Female; Fetal Diseases; Humans; Pregnancy; Ultrasonography, Prenatal
PubMed: 11069003
DOI: 10.3346/jkms.2000.15.5.604 -
American Journal of Medical Genetics.... Aug 2008The osteochondrodysplasias or skeletal dysplasias are a heterogenous group of over 350 distinct disorders of skeletogenesis. Many manifest in the prenatal period, making...
The osteochondrodysplasias or skeletal dysplasias are a heterogenous group of over 350 distinct disorders of skeletogenesis. Many manifest in the prenatal period, making them amenable to ultrasound prenatal diagnosis. A retrospective analysis evaluated 1,500 cases referred to the International Skeletal Dysplasia Registry (ISDR) to determine the relative frequency of specific osteochondrodysplasias and correlation of ultrasound versus radiographic diagnoses for these disorders. Within the retrospective cohort of 1,500 cases, 85% of the referred cases represented well-defined skeletal dysplasias, and the other 15% of cases were a mixture of genetic syndromes and probable early-onset intrauterine growth restriction. The three most common prenatal-onset skeletal dysplasias were osteogenesis imperfecta type 2, thanatophoric dysplasia and achondrogenesis 2, accounting for almost 40% of the cases. In a prospective analysis of 500 cases using a standardized ultrasound approach to the evaluation of these disorders, the relative frequencies of osteogenesis imperfecta type 2, thanatophoric dysplasia and achondrogenesis 2 were similar to the retrospective analysis. This study details the relative frequencies of specific prenatal-onset osteochondrodysplasias, their heterogeneity of prenatal-onset skeletal disorders and provides a standardized prenatal ultrasound approach to these disorders which should aid in the prenatal diagnosis of fetuses suspected of manifesting skeletal dysplasias.
Topics: Female; Gestational Age; Humans; Osteochondrodysplasias; Pregnancy; Prospective Studies; Retrospective Studies; Ultrasonography, Prenatal
PubMed: 18627037
DOI: 10.1002/ajmg.a.32269 -
Journal of Medical Genetics Aug 1986This study was undertaken to establish the prevalence rates at birth of the skeletal dysplasias that can be recognised in the perinatal period. Using the data base of...
This study was undertaken to establish the prevalence rates at birth of the skeletal dysplasias that can be recognised in the perinatal period. Using the data base of the Latin-American Collaborative Study of Congenital Malformations (ECLAMC), for the years 1978 to 1983, on 349 470 births (live and stillbirths), a crude prevalence rate of 2.3/10 000 was observed. However, several indications of under-registration suggest that the real value is about twice that observed. The most frequent types of skeletal dysplasia were achondroplasia, with a prevalence rate between 0.5 and 1.5/10 000 births, the thanatophoric dysplasia/achondrogenesis group (0.2 and 0.5/10 000 births), and osteogenesis imperfecta (0.4/10 000 births). The mutation rate for autosomal dominant achondroplasia was estimated at between 1.72 and 5.57 X 10(-5) per gamete per generation.
Topics: Achondroplasia; Bone Diseases, Developmental; Bone and Bones; Humans; Mutation; Osteogenesis Imperfecta; South America; Thanatophoric Dysplasia
PubMed: 3746832
DOI: 10.1136/jmg.23.4.328 -
Genes Sep 2021Achondrogenesis type II (ACG2) is a lethal skeletal dysplasia caused by dominant pathogenic variants in . Most of the variants found in patients with ACG2 affect the...
Achondrogenesis type II (ACG2) is a lethal skeletal dysplasia caused by dominant pathogenic variants in . Most of the variants found in patients with ACG2 affect the glycine residue included in the Gly-X-Y tripeptide repeat that characterizes the type II collagen helix. In this study, we reported a case of a novel splicing variant of in a fetus with ACG2. An NGS analysis of fetal DNA revealed a heterozygous variant c.1267-2_1269del located in intron 20/exon 21. The variant occurred de novo since it was not detected in DNA from the blood samples of parents. We generated an appropriate minigene construct to study the effect of the variant detected. The minigene expression resulted in the synthesis of a messenger RNA lacking exon 21, which generated a predicted in-frame deleted protein. Usually, in-frame deletion variants of cause a phenotype such as Kniest dysplasia, which is milder than ACG2. Therefore, we propose that the size and position of an in-frame deletion in may be relevant in determining the phenotype of skeletal dysplasia.
Topics: Abortion, Eugenic; Achondroplasia; Adult; Alternative Splicing; Collagen Type II; Female; Fetal Diseases; Humans; Imaging, Three-Dimensional; Italy; Mutation; Pregnancy; Protein Isoforms; Sequence Deletion; Ultrasonography, Prenatal
PubMed: 34573377
DOI: 10.3390/genes12091395 -
Ultrasound in Obstetrics & Gynecology :... May 2003Recognition of prenatal-onset skeletal dysplasias has improved with advances in ultrasound imaging. Skeletal abnormalities can be recognized by two-dimensional (2D)...
OBJECTIVE
Recognition of prenatal-onset skeletal dysplasias has improved with advances in ultrasound imaging. Skeletal abnormalities can be recognized by two-dimensional (2D) ultrasound, but generating a precise diagnosis can be challenging. We aimed to determine whether three-dimensional (3D) imaging conferred any advantages over 2D imaging in these cases.
METHODS
We studied five women with fetuses of 16-28 gestational weeks referred for abnormal ultrasound skeletal findings. First 2D and then 3D sonography was performed and the results compared.
RESULTS
The pregnancies resulted in the following skeletal dysplasias: thanatophoric dysplasia, achondrogenesis II/hypochondrogenesis, achondroplasia, chondrodysplasia punctata (rhizomelic form) and Apert's syndrome. For all five fetuses, the correct diagnosis was made in the prenatal period by analysis of the 2D images. In each case the 3D images confirmed the preliminary diagnosis and for many findings it improved the visualization of the abnormalities.
CONCLUSION
The 3D imaging had advantages over the 2D imaging when it came to evaluation of facial dysmorphism, relative proportion of the appendicular skeletal elements and the hands and feet. Most importantly, the patient and referring physician appreciated the 3D images of the abnormal findings more readily which aided in counseling and management of the pregnancy.
Topics: Bone Diseases, Developmental; Gestational Age; Humans; Imaging, Three-Dimensional; Sensitivity and Specificity; Ultrasonography, Prenatal
PubMed: 12768559
DOI: 10.1002/uog.111 -
The Biochemical Journal May 1995Two different mutations were found in two unrelated probands with lethal chondrodysplasias, one with achondrogenesis type II and the other with the less severe phenotype...
Substitution of aspartic acid for glycine at position 310 in type II collagen produces achondrogenesis II, and substitution of serine at position 805 produces hypochondrogenesis: analysis of genotype-phenotype relationships.
Two different mutations were found in two unrelated probands with lethal chondrodysplasias, one with achondrogenesis type II and the other with the less severe phenotype of hypochondrogenesis. The mutations in the COL2A1 gene were identified by denaturing gradient gel electrophoresis analysis of genomic DNA followed by dideoxynucleotide sequencing and restriction site analysis. The proband with achondrogenesis type II had a heterozygous single-base mutation that substituted aspartate for glycine at position 310 of the alpha 1(II) chain of type II procollagen. The proband with hypochondrogenesis had a heterozygous single-base mutation that substituted serine for glycine at position 805. Type II collagen extracted from cartilage from the probands demonstrated the presence of type I collagen and a delayed electrophoretic mobility, indicating post-translational overmodifications. Analysis of CNBr peptides showed that, in proband 1, the entire peptides were overmodified. Examination of chondrocytes cultured in agarose or alginate indicated that there was a delayed secretion of type II procollagen. In addition, type II collagen synthesized by cartilage fragments from the probands demonstrated a decreased thermal stability. The melting temperature of the type II collagen containing the aspartate-for-glycine substitution was reduced by 4 degrees C, and that of the collagen containing the serine-for-glycine substitution was reduced by 2 degrees C. Electron microscopy of the extracellular matrix from the chondrocyte cultures showed a decreased density of matrix and the presence of unusually short and thin fibrils. Our results indicate that glycine substitutions in the N-terminal region of the type II collagen molecule can produce more severe phenotypes than mutations in the C-terminal region. The aspartate-for-glycine substitution at position 310, which was associated with defective secretion and a probable increased degradation of collagen, is the most destabilizing mutation yet reported in type II procollagen.
Topics: Amino Acid Sequence; Aspartic Acid; Base Sequence; Bone Diseases, Developmental; Cartilage; Cells, Cultured; Collagen; Collagen Diseases; Drug Stability; Electrophoresis; Exons; Female; Genotype; Glycine; Hot Temperature; Humans; Molecular Sequence Data; Mutation; Phenotype; Pregnancy; Protein Denaturation; Serine
PubMed: 7741714
DOI: 10.1042/bj3070823 -
American Journal of Human Genetics Dec 1994Achondrogenesis type I is a perinatally lethal, short-limb chondrodysplasia. Two types, IA and IB, have been distinguished by radiographic and histological criteria;...
Achondrogenesis type I is a perinatally lethal, short-limb chondrodysplasia. Two types, IA and IB, have been distinguished by radiographic and histological criteria; both types appear to be inherited as autosomal recessive traits. The underlying molecular defects are not known, but histochemical studies have suggested that in achondrogenesis type IB, cartilage matrix is deficient in sulfated proteoglycans. We have studied cartilage extracts of one newborn with achondrogenesis type IB and found that proteoglycans were quantitatively reduced, and, unlike in control cartilage, they did not stain with toluidine blue and did not bind to DEAE. Impaired synthesis of sulfated proteoglycans was observed also in fibroblast cultures of the achondrogenesis IB patient. Radioactive labeling and immunoprecipitation studies indicated that core protein and side chains of proteoglycans were synthesized normally but were not sulfated. Analysis of sulfate metabolism in fibroblast cultures showed, in the patient's cells, normal intracellular levels of free sulfate but markedly reduced levels of the two intermediate compounds in the sulfate activation pathway, adenosine-phosphosulfate and phosphoadenosine-phosphosulfate. The results can be explained by deficient activity of one of the enzymes responsible for the biologic activation of sulfate, possibly similar to that observed in cartilage (but not in skin) of the recessive, nonlethal mouse mutant brachymorphic and leading to defective sulfation of macromolecules. Expression of the sulfation defect in cultured fibroblasts may offer a diagnostic tool for the disorder.
Topics: Adenosine Phosphosulfate; Adult; Biotransformation; Bone and Bones; Cartilage; Cells, Cultured; Female; Fibroblasts; Growth Plate; Humans; Infant, Newborn; Male; Osteochondrodysplasias; Phosphoadenosine Phosphosulfate; Proteoglycans; Radiography; Sulfates; Sulfotransferases
PubMed: 7977372
DOI: No ID Found