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Bone Feb 2023Dysosteosclerosis (DSS) refers to skeletal dysplasias that radiographically feature focal appendicular osteosclerosis with variable platyspondyly. Genetic heterogeneity...
Dysosteosclerosis (DSS) refers to skeletal dysplasias that radiographically feature focal appendicular osteosclerosis with variable platyspondyly. Genetic heterogeneity is increasingly reported for the DSS phenotype and now involves mutations of SLC29A3, TNFRSF11A, TCIRG1, LRRK1, and CSF1R. Typical radiological findings are widened radiolucent long bones with thin cortices yet dense irregular metaphyses, flattened vertebral bodies, dense ribs, and multiple fractures. However, the radiographic features of DSS evolve, and the metaphyseal and/or appendicular osteosclerosis variably fades with increasing patient age, likely due to some residual osteoclast function. Fractures are the principal presentation of DSS, and may even occur in infancy with SLC29A3-associated DSS. Cranial base sclerosis can lead to cranial nerve palsies such as optic atrophy, and may be the initial presentation, though not observed with SLC29A3-associated DSS. Gene-specific extra-skeletal features can be the main complication in some forms of DSS such as CSF1R- associated DSS. Further genetic heterogeneity is likely, especially for X-linked recessive DSS and cases currently with an unknown genetic defect. Distinguishing DSS can be challenging due to variable clinical and radiological features and an evolving phenotype. However, defining the DSS phenotype is important for predicting complications, prognosis, and instituting appropriate health surveillance and treatment.
Topics: Humans; Osteopetrosis; Osteosclerosis; Osteochondrodysplasias; Mutation; Vacuolar Proton-Translocating ATPases; Nucleoside Transport Proteins
PubMed: 36402365
DOI: 10.1016/j.bone.2022.116615 -
Advances in Experimental Medicine and... 2023Ectodermal dysplasias are a group of >200 clinically and congenitally heterogeneous disorders characterized by abnormal development in the ectodermal structures, such as...
INTRODUCTION
Ectodermal dysplasias are a group of >200 clinically and congenitally heterogeneous disorders characterized by abnormal development in the ectodermal structures, such as hair, nails, teeth, and sweat glands. We report here the clinical and molecular genetic analysis of five Greek families with different types of ectodermal dysplasia (ED).
SUBJECTS
The study involved 15 individuals from 5 Greek families that included 8 ED patients, 5 carriers of recessive X-linked or autosomal ED, and 2 healthy relatives. After genetic counseling, the parents signed an informed consent form before subsequent genetic testing.
METHODS
Genomic DNA was isolated from white blood cells of all studied individuals. The search for mutations was realized in patients' DNA samples using next-generation sequencing (NGS) gene panel, whole exome sequencing (WES), chromosomal microarray analysis (CMA), and multiplex ligation-dependent probe amplification (MLPA) technique.
RESULTS
The clinical diagnosis of common X-linked recessive hypohidrotic ectodermal dysplasia (HED) was suspected in five male patients with partial anodontia of baby and permanent teeth, hypohidrosis, and thin hair from three families. All HED patients were hemizygous for deletions in the EDA1 gene (Xq13.1): three related patients had a 20 bp deletion, one had a 19 bp deletion, and one had a 180 bp deletion. A female patient had the rare autosomal dominant syndrome of ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) caused by heterozygous missense mutation in the TP63 gene (3q28) that appeared de novo. Two siblings with hypotrichosis and hypodontia, a female and a male, had two pathogenic mutations in compound heterozygosity in the TSPEAR gene (21q22.3); therefore they presented with ectodermal dysplasia type 14 (ECTD14).
CONCLUSION
Clinical and molecular genetic analysis may set an accurate diagnosis of different types of ED. In the reported families, genetic diagnosis and genetic counselling assisted the parents to view their children's condition realistically and to cooperate with the specialists who will contribute to the best possible treatment for their children.
Topics: Child; Infant; Humans; Male; Female; Cleft Lip; Cleft Palate; Ectodermal Dysplasia; Mutation; Molecular Biology; Pedigree
PubMed: 37525042
DOI: 10.1007/978-3-031-31978-5_15 -
BJR Case Reports Apr 2021Desbuquois dysplasia is an autosomal recessive chondrodysplasia characterized by severe micromelic dwarfism, joint laxity, progressive scoliosis, and advanced...
Desbuquois dysplasia is an autosomal recessive chondrodysplasia characterized by severe micromelic dwarfism, joint laxity, progressive scoliosis, and advanced carpotarsal ossification. Two different types of Desbuquois dysplasia have been identified according to the presence (Type 1) or absence (Type 2) of characteristic hand abnormalities including bifid distal thumb phalanx, an extra ossification center distal to the second metacarpal, and interphalangeal joint dislocations. Further, Kim et al have described a milder variant of Desbuquois dysplasia characterized by short stature and hands with short metacarpals, elongated proximal and distal phalanges, and extremely advanced carpal ossification. Here, we present a 19-year-old male patient with Kim variant of Desbuquois dysplasia. He displays almost all of the characteristic skeletal findings of Desbuquois dysplasia along with the characteristic hand features described by Kim et al. This patient is unique in that he also presents sagittal femoral bowing, a radiographic finding that accompanies various skeletal dysplasias but has never been reported in a patient with Desbuquois dysplasia to date.
PubMed: 33841904
DOI: 10.1259/bjrcr.20200137 -
American Journal of Medical Genetics.... Oct 2014Oral signs and symptoms are present in most ectodermal dysplasias (EDs). The aim of this article is to summarize some of the literature on current knowledge of oral... (Review)
Review
Oral signs and symptoms are present in most ectodermal dysplasias (EDs). The aim of this article is to summarize some of the literature on current knowledge of oral manifestations and orofacial function in EDs. The review will focus on the most common forms where dental manifestations can be crucial for a differential diagnosis of ED among individuals with hypodontia and oligodontia, and preferably where the investigations included persons who had a genetically verified diagnosis. Disturbances in tooth development are common and can appear as tooth agenesis, variations in size and shape of teeth, defects in the mineralized tissues, and problems in tooth eruption. Abnormalities in number, size, and shape of teeth, and reduced salivary secretion, present in isolated oligodontia as well as in hypohidrotic ED and incontinentia pigmenti. In some more rare EDs these symptoms appear in combination with clefts of lip and/or palate in some affected individuals. Leukokeratosis in the oral mucosa presents in 70% of genetically confirmed cases of pachyonychia congenita. Also, orofacial function is often affected in ED, due to malformations, an incomplete dentition, and low salivary secretion which can compromise chewing, swallowing, and speech. In conclusion, there is a clinical overlap in oral signs and symptoms between isolated oligodontia and the most common EDs. Studies with genetically confirmed diagnoses and larger cohorts, as well as multicenter collaboration and the establishing of international registries, would create a basis for refined diagnostics, where oral examinations should be an integrated part of clinical assessment.
Topics: Anodontia; Ectodermal Dysplasia; Humans; Salivation; Tooth; Tooth Abnormalities
PubMed: 24719393
DOI: 10.1002/ajmg.a.36571 -
Fetal Diagnosis and Therapy 2023Skeletal dysplasias (SDs) are a heterogeneous group of heritable disorders that affect development of bone and cartilage. Because each SD is individually rare and... (Review)
Review
Skeletal dysplasias (SDs) are a heterogeneous group of heritable disorders that affect development of bone and cartilage. Because each SD is individually rare and because of the heterogeneity within and among disorders, prenatal diagnosis of a specific SD remains challenging. Molecular genetic diagnosis involves invasive testing, which some patients are not amenable to. Further, genetic analysis is time consuming, and results may not become available in time to make pregnancy management decisions. Low-dose fetal CT can aid in the prenatal evaluation of SDs. The main downside is the low but true risk of fetal radiation exposure. As such, fetal CT should only be performed when there is concern for a severe skeletal dysplasia and the diagnosis is in question after a detailed ultrasound or if molecular genetic testing is unavailable and when prenatal diagnosis may affect management or counseling. Fetal CT should be obtained after consultation with geneticists, maternal-fetal medicine specialists, and fetal radiologists, and sometimes orthopedic surgeons or neonatologists. The purpose of this study was to review the technique of and indications for fetal CT, as well as discuss fetal radiation risk. Illustrative cases will demonstrate when and how CT may be helpful in the diagnosis of SDs.
Topics: Female; Pregnancy; Humans; Bone Diseases, Developmental; Prenatal Diagnosis; Ultrasonography; Fetus; Tomography, X-Ray Computed; Ultrasonography, Prenatal
PubMed: 36948169
DOI: 10.1159/000528692 -
Human Pathology Jan 2024Gastric metaplasia in colonic mucosa with inflammatory bowel disease (IBD) develops as an adaptation mechanism. The association between gastric metaplasia and...
Gastric metaplasia in colonic mucosa with inflammatory bowel disease (IBD) develops as an adaptation mechanism. The association between gastric metaplasia and nonconventional and/or conventional dysplasia as precursors of colitis-associated colorectal cancer is unknown. To address this question, we retrospectively reviewed a series of 33 IBD colectomies to identify gastric metaplasia in 76 precursor lesions. We obtained 61 nonconventional and 15 conventional dysplasias. Among nonconventional dysplasia, 31 (50.8 %) were low-grade (LGD), 4 (6.5 %) were high-grade (HGD), 9 (14.8 %) had both LGD and HGD, and 17 (27.9 %) had no dysplasia (ND), while 14 (93 %) conventional dysplasias had LGD, and 1 (7 %) had LGD and HGD. Gastric metaplasia was assessed by concomitant immunoexpression of MUC5AC and loss of CDX2 staining. Expression of a p53-mut pattern was considered as a surrogate for gene mutation, and complete loss of MLH1 staining as presence of MLH1 hypermethylation. In nonconventional dysplasia, MUC5AC immunoexpression decreased as the degree of dysplasia increased, being 78 % in LGD and 39 % in HGD (p = 0.006). CDX2 was lost in epithelial glands with high expression of MUC5AC (p < 0.001). The p53-mut pattern was observed in 77 % HGD, 45 % LGD, and in 6 % with ND (p < 0.001). Neither nonconventional nor conventional dysplasia showed complete loss of MLH1 staining. Gastric metaplasia was also present in mucosa adjacent to nonconventional dysplasia with chronic changes or active inflammation. Our results show that gastric metaplasia appears in IBD-inflamed colon mucosa, it is the substrate of most nonconventional dysplasia and occurs prior to p53 alterations.
Topics: Humans; Retrospective Studies; Tumor Suppressor Protein p53; Inflammatory Bowel Diseases; Colon; Hyperplasia; Metaplasia; Precancerous Conditions
PubMed: 38000679
DOI: 10.1016/j.humpath.2023.11.011 -
Neurobiology of Disease Oct 2023De novo somatic (post-zygotic) gene mutations affecting neuroglial progenitor cell types in embryonic cerebral cortex are increasingly identified in patients with drug... (Review)
Review
De novo somatic (post-zygotic) gene mutations affecting neuroglial progenitor cell types in embryonic cerebral cortex are increasingly identified in patients with drug resistant epilepsy (DRE) associated with malformations of cortical development, in particular, focal cortical dysplasias (FCD). Somatic variants in at least 16 genes have been linked to FCD type II, all encoding components of the mechanistic target of rapamycin (mTOR) pathway. FCD type II is characterized histopathologically by cytomegalic dysmorphic neurons and balloon cells. In contrast, the molecular pathogenesis of FCD I subtypes is less well understood, and histological features are characterized by alterations in columnar or laminar organization without cytomegalic dysmorphic neurons or balloon cells. In 2018, we reported somatic mutations in Solute Carrier Family 35 member A2 (SLC35A2) linked to DRE underlying FCD type I and subsequently to a new histopathological phenotype: excess oligodendrocytes and heterotopic neurons in subcortical white matter known as MOGHE (mild malformation of cortical development with oligodendroglial hyperplasia). These discoveries opened the door to studies linking somatic mutations to FCD. In this review, we discuss the biology of SLC35A2 somatic mutations in epilepsy in FCD and MOGHE, and insights into SLC35A2 epilepsy pathogenesis, describing progress to date and critical areas for investigation.
Topics: Humans; Drug Resistant Epilepsy; Focal Cortical Dysplasia; Epilepsy; Malformations of Cortical Development, Group I; Malformations of Cortical Development
PubMed: 37739137
DOI: 10.1016/j.nbd.2023.106299 -
Journal of Medical Genetics Jul 2016Acromelic dysplasias are a group of disorders characterised by short stature, brachydactyly, limited joint extension and thickened skin and comprises acromicric...
BACKGROUND
Acromelic dysplasias are a group of disorders characterised by short stature, brachydactyly, limited joint extension and thickened skin and comprises acromicric dysplasia (AD), geleophysic dysplasia (GD), Myhre syndrome and Weill-Marchesani syndrome. Mutations in several genes have been identified for these disorders (including latent transforming growth factor β (TGF-β)-binding protein-2 (LTBP2), ADAMTS10, ADAMSTS17 and fibrillin-1 (FBN1) for Weill-Marchesani syndrome, ADAMTSL2 for recessive GD and FBN1 for AD and dominant GD), encoding proteins involved in the microfibrillar network. However, not all cases have mutations in these genes.
METHODS
Individuals negative for mutations in known acromelic dysplasia genes underwent whole exome sequencing.
RESULTS
A heterozygous missense mutation (exon 14: c.2087C>G: p.Ser696Cys) in latent transforming growth factor β (TGF-β)-binding protein-3 (LTBP3) was identified in a dominant AD family. Two distinct de novo heterozygous LTPB3 mutations were also identified in two unrelated GD individuals who had died in early childhood from respiratory failure-a donor splice site mutation (exon 12 c.1846+5G>A) and a stop-loss mutation (exon 28: c.3912A>T: p.1304*Cysext*12).
CONCLUSIONS
The constellation of features in these AD and GD cases, including postnatal growth retardation of long bones and lung involvement, is reminiscent of the null ltbp3 mice phenotype. We conclude that LTBP3 is a novel component of the microfibrillar network involved in the acromelic dysplasia spectrum.
Topics: Bone Diseases, Developmental; Exome; Exons; Fibrillin-1; Heterozygote; Humans; Latent TGF-beta Binding Proteins; Limb Deformities, Congenital; Microfilament Proteins; Mutation; Mutation, Missense; Phenotype; Transforming Growth Factor beta; Weill-Marchesani Syndrome
PubMed: 27068007
DOI: 10.1136/jmedgenet-2015-103647 -
Molecular Syndromology Nov 2016The complex anatomy of the skull and face arises from the requirement to support multiple sensory and structural functions. During embryonic development, the diverse... (Review)
Review
The complex anatomy of the skull and face arises from the requirement to support multiple sensory and structural functions. During embryonic development, the diverse component elements of the neuro- and viscerocranium must be generated independently and subsequently united in a manner that sustains and promotes the growth of the brain and sensory organs, while achieving a level of structural integrity necessary for the individual to become a free-living organism. While each of these individual craniofacial components is essential, the cranial and facial midline lies at a structural nexus that unites these disparately derived elements, fusing them into a whole. Defects of the craniofacial midline can have a profound impact on both form and function, manifesting in a diverse array of phenotypes and clinical entities that can be broadly defined as frontonasal dysplasias (FNDs). Recent advances in the identification of the genetic basis of FNDs along with the analysis of developmental mechanisms impacted by these mutations have dramatically altered our understanding of this complex group of conditions.
PubMed: 27920634
DOI: 10.1159/000450533 -
Radiographics : a Review Publication of... 2021Type II collagen is a major component of the cartilage matrix. Pathogenic variants (ie, disease-causing aberrations) in the type II collagen gene lead to an abnormal...
Type II collagen is a major component of the cartilage matrix. Pathogenic variants (ie, disease-causing aberrations) in the type II collagen gene lead to an abnormal structure of type II collagen, causing a large group of skeletal dysplasias termed Because type II collagen is also located in the vitreous body of the eyes and inner ears, type II collagenopathies are commonly associated with vitreoretinal degeneration and hearing impairment. Type II collagenopathies can be radiologically divided into two major groups: the spondyloepiphyseal dysplasia congenita (SEDC) group and the Kniest-Stickler group. The SEDC group is characterized by delayed ossification of the juxtatruncal bones, including pear-shaped vertebrae. These collagenopathies comprise achondrogenesis type 2, hypochondrogenesis, SEDC, and other uncommon subtypes. The Kniest-Stickler group is characterized by disordered tubular bone growth that leads to "dumbbell" deformities. It comprises Kniest dysplasia and Stickler dysplasia type 1, whose radiographic manifestations overlap with those of type XI collagenopathies (a group of disorders due to abnormal type XI collagen) such as Stickler dysplasia types 2 and 3. This phenotypic overlap is caused by type II and type XI collagen molecules sharing part of the same connective tissues. The authors describe the diagnostic pathways to type II and type XI collagenopathies and the associated differential diagnoses. In addition, they review the clinical features and genetic bases of these conditions, which radiologists should know to participate in multidisciplinary care and translational research. RSNA, 2020.
Topics: Achondroplasia; Cartilage; Collagen Diseases; Humans; Hyaline Membrane Disease; Infant, Newborn; Osteochondrodysplasias
PubMed: 33186059
DOI: 10.1148/rg.2021200075