-
Orphanet Journal of Rare Diseases Jan 2019Achondroplasia is the most common of the skeletal dysplasias that result in marked short stature (dwarfism). Although its clinical and radiologic phenotype has been... (Review)
Review
Achondroplasia is the most common of the skeletal dysplasias that result in marked short stature (dwarfism). Although its clinical and radiologic phenotype has been described for more than 50 years, there is still a great deal to be learned about the medical issues that arise secondary to this diagnosis, the manner in which these are best diagnosed and addressed, and whether preventive strategies can ameliorate the problems that can compromise the health and well being of affected individuals. This review provides both an updated discussion of the care needs of those with achondroplasia and an exploration of the limits of evidence that is available regarding care recommendations, controversies that are currently present, and the many areas of ignorance that remain.
Topics: Achondroplasia; Bone Diseases, Developmental; Humans; Receptor, Fibroblast Growth Factor, Type 3
PubMed: 30606190
DOI: 10.1186/s13023-018-0972-6 -
Advances in Clinical and Experimental... Jun 2021Skeletal dysplasias are a heterogeneous group of congenital bone and cartilage disorders with a genetic etiology. The current classification of skeletal dysplasias... (Review)
Review
Skeletal dysplasias are a heterogeneous group of congenital bone and cartilage disorders with a genetic etiology. The current classification of skeletal dysplasias distinguishes 461 diseases in 42 groups. The incidence of all skeletal dysplasias is more than 1 in every 5000 newborns. The type of dysplasia and associated abnormalities affect the lethality, survival and long-term prognosis of skeletal dysplasias. It is crucial to distinguish skeletal dysplasias and correctly diagnose the disease to establish the prognosis and achieve better management. It is possible to use prenatal ultrasonography to observe predictors of lethality, such as a bell-shaped thorax, short ribs, severe femoral shortening, and decreased lung volume. Individual lethal or life-limiting dysplasias may have more or less specific features on prenatal ultrasound. The prenatal features of the most common skeletal dysplasias, such as thanatophoric dysplasia, osteogenesis imperfecta type II, achondrogenesis, and campomelic dysplasia, are discussed in this article. Less frequent dysplasias, such as asphyxiating thoracic dystrophy, fibrochondrogenesis, atelosteogenesis, and homozygous achondroplasia, are also discussed.
Topics: Female; Humans; Infant, Newborn; Osteochondrodysplasias; Osteogenesis Imperfecta; Pregnancy; Receptor, Fibroblast Growth Factor, Type 3; Thanatophoric Dysplasia; Ultrasonography, Prenatal
PubMed: 34019743
DOI: 10.17219/acem/134166 -
Genetics in Medicine : Official Journal... Dec 2018To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized.
PURPOSE
To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized.
METHODS
Detailed phenotyping and next-generation sequencing (panel and exome).
RESULTS
Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average.
CONCLUSION
By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.
Topics: Alleles; Blood Proteins; Carboxylic Ester Hydrolases; Cohort Studies; Exome; Exoribonucleases; Female; Fetal Proteins; Founder Effect; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetics, Population; High-Throughput Nucleotide Sequencing; Humans; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Musculoskeletal Abnormalities; Neoplasm Proteins; Oncogene Proteins; Phenotype; Receptors, Cell Surface; Wnt3A Protein
PubMed: 29620724
DOI: 10.1038/gim.2018.50 -
Hormone Research in Paediatrics 2019McCune-Albright syndrome (MAS) is a rare, mosaic disorder presenting along a broad clinical spectrum. Disease arises from somatic-activating GNAS mutations, leading to... (Review)
Review
McCune-Albright syndrome (MAS) is a rare, mosaic disorder presenting along a broad clinical spectrum. Disease arises from somatic-activating GNAS mutations, leading to constitutive Gαs activation and ligand-independent signaling of the Gαs-coupled protein receptor. The phenotype is largely determined by location and extent of tissues in which the GNAS mutation is expressed, as well as the pathophysiologic effects of Gαs activation within these tissues. Patients pre-sent clinically with a variable combination of fibrous dysplasia of bone (FD), café-au-lait skin macules, and hyperfunctioning endocrinopathies. In bone, Gαs leads to impaired differentiation of skeletal stem cells and formation of discrete, expansile FD lesions, resulting in fractures, pain, and functional impairment. A systematic approach to diagnosis and management is critically important to optimize outcomes for patients with FD/MAS. There are no medical therapies capable of altering the disease course in FD; however, screening and treatment for endocrinopathies can mitigate some skeletal morbidities. This review summarizes current understanding of MAS pathophysiology, describes the spectrum of clinical features, and includes a detailed discussion of the recommended approach to diagnosis and management.
Topics: Chromogranins; Fibrous Dysplasia, Polyostotic; GTP-Binding Protein alpha Subunits, Gs; Humans; Mutation
PubMed: 31865341
DOI: 10.1159/000504802 -
Oral Diseases Sep 2017Fibrous dysplasia (FD) is a rare bone disease caused by postzygotic somatic activating mutations in the GNAS gene, which lead to constitutive activation of adenylyl... (Review)
Review
Fibrous dysplasia (FD) is a rare bone disease caused by postzygotic somatic activating mutations in the GNAS gene, which lead to constitutive activation of adenylyl cyclase and elevated levels of cyclic AMP, which act on downstream signaling pathways and cause normal bone to be replaced with fibrous tissue and abnormal (woven) bone. The bone disease may occur in one bone (monostotic), multiple bones (polyostotic), or in combination with hyperfunctioning endocrinopathies and hyperpigmented skin lesions (in the setting of McCune-Albright Syndrome). FD is common in the craniofacial skeleton, causing significant dysmorphic features, bone pain, and dental anomalies. This review summarizes the pathophysiology, clinical findings, and treatment of FD, with an emphasis on the craniofacial and oral manifestations of the disease.
Topics: Cafe-au-Lait Spots; Craniofacial Abnormalities; Diagnosis, Differential; Facial Asymmetry; Fibrous Dysplasia of Bone; Fibrous Dysplasia, Polyostotic; Humans; Malocclusion; Puberty, Precocious
PubMed: 27493082
DOI: 10.1111/odi.12563 -
Endocrine Reviews Apr 2020Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare disorder of striking complexity. It arises from somatic, gain-of-function mutations in GNAS, leading to... (Review)
Review
Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare disorder of striking complexity. It arises from somatic, gain-of-function mutations in GNAS, leading to mosaic Gα s activation and inappropriate production of intracellular cyclic adenosine monophosphate (cAMP). The clinical phenotype is largely determined by the location and extent of affected tissues, and the pathophysiological effects of Gα s activation within these tissues. In bone, Gα s activation results in impaired differentiation of skeletal stem cells, leading to discrete skeletal lesions prone to fracture, deformity, and pain. Extraskeletal manifestations include a variable combination of hyperpigmented macules and hyperfunctioning endocrinopathies. Distinctive age-related changes in disease development has key effects on histologic, radiographic, and clinical features. FD/MAS thus presents along a uniquely broad clinical spectrum, and the resulting challenges in diagnosis and management can be difficult for clinicians. This review presents FD/MAS in the context of a mosaic disorder of Gα s activation, providing an intellectual framework within which to understand, evaluate, and treat this interesting disease. It includes a comprehensive summary of current understanding of FD/MAS pathogenesis, and a detailed discussion of clinical presentation and management. Critical areas of unmet need are highlighted, including discussion of key challenges and potential solutions to advance research and clinical care in FD/MAS.
Topics: Fibrous Dysplasia, Polyostotic; GTP-Binding Protein alpha Subunits; Humans; Mosaicism
PubMed: 31673695
DOI: 10.1210/endrev/bnz011