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Human Mutation Jul 2022Different pathogenic variants in the fibrillin-1 gene (FBN1) cause Marfan syndrome and acromelic dysplasias. Whereas the musculoskeletal features of Marfan syndrome... (Review)
Review
Different pathogenic variants in the fibrillin-1 gene (FBN1) cause Marfan syndrome and acromelic dysplasias. Whereas the musculoskeletal features of Marfan syndrome involve tall stature, arachnodactyly, joint hypermobility, and muscle hypoplasia, acromelic dysplasia patients present with short stature, brachydactyly, stiff joints, and hypermuscularity. Similarly, pathogenic variants in the fibrillin-2 gene (FBN2) cause either a Marfanoid congenital contractural arachnodactyly or a FBN2-related acromelic dysplasia that most prominently presents with brachydactyly. The phenotypic and molecular resemblances between both the FBN1 and FBN2-related disorders suggest that reciprocal pathomechanistic lessons can be learned. In this review, we provide an updated overview and comparison of the phenotypic and mutational spectra of both the "tall" and "short" fibrillinopathies. The future parallel functional study of both FBN1/2-related disorders will reveal new insights into how pathogenic fibrillin variants differently affect the fibrillin microfibril network and/or growth factor homeostasis in clinically opposite syndromes. This knowledge may eventually be translated into new therapeutic approaches by targeting or modulating the fibrillin microfibril network and/or the signaling pathways under its control.
Topics: Brachydactyly; Fibrillin-1; Fibrillin-2; Humans; Marfan Syndrome; Musculoskeletal Abnormalities; Phenotype
PubMed: 35419902
DOI: 10.1002/humu.24383 -
American Journal of Respiratory and... Nov 2019Lethal lung developmental disorders are a rare but important group of pediatric diffuse lung diseases presenting with neonatal respiratory failure. On the basis of... (Review)
Review
Lethal lung developmental disorders are a rare but important group of pediatric diffuse lung diseases presenting with neonatal respiratory failure. On the basis of histopathological appearance at lung biopsy or autopsy, they have been termed: alveolar capillary dysplasia with misalignment of the pulmonary veins, acinar dysplasia, congenital alveolar dysplasia, and other unspecified primary pulmonary hypoplasias. However, the histopathological continuum in these lethal developmental disorders has made accurate diagnosis challenging, which has implications for recurrence risk. Over the past decade, genetic studies in infants with alveolar capillary dysplasia with misalignment of the pulmonary veins have revealed the causative role of the dosage-sensitive gene and its noncoding regulatory variants in the distant lung-specific enhancer at chromosome 16q24.1. In contrast, the molecular bases of acinar dysplasia and congenital alveolar dysplasia have remained poorly understood. Most recently, disruption of the TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling pathway has been reported in patients with these lethal pulmonary dysplasias. Application of next-generation sequencing techniques, including exome sequencing and whole-genome sequencing, has demonstrated their complex compound inheritance. These data indicate that noncoding regulatory elements play a critical role in lung development in humans. We propose that for more precise lethal lung developmental disorder diagnosis, a diagnostic pathway including whole-genome sequencing should be implemented.
Topics: Humans; Lung; Lung Diseases
PubMed: 31189067
DOI: 10.1164/rccm.201903-0495TR -
Frontiers in Physiology 2015The most common root malformations in humans arise from either developmental disorders of the root alone or disorders of radicular development as part of a general tooth... (Review)
Review
The most common root malformations in humans arise from either developmental disorders of the root alone or disorders of radicular development as part of a general tooth dysplasia. The aim of this review is to relate the characteristics of these root malformations to potentially disrupted processes involved in radicular morphogenesis. Radicular morphogenesis proceeds under the control of Hertwig's epithelial root sheath (HERS) which determines the number, length, and shape of the root, induces the formation of radicular dentin, and participates in the development of root cementum. Formation of HERS at the transition from crown to root development appears to be very insensitive to adverse effects, with the result that rootless teeth are extremely rare. In contrast, shortened roots as a consequence of impaired or prematurely halted apical growth of HERS constitute the most prevalent radicular dysplasia which occurs due to trauma and unknown reasons as well as in association with dentin disorders. While odontoblast differentiation inevitably stops when growth of HERS is arrested, it seems to be unaffected even in cases of severe dentin dysplasias such as regional odontodysplasia and dentin dysplasia type I. As a result radicular dentin formation is at least initiated and progresses for a limited time. The only condition affecting cementogenesis is hypophosphatasia which disrupts the formation of acellular cementum through an inhibition of mineralization. A process particularly susceptible to adverse effects appears to be the formation of the furcation in multirooted teeth. Impairment or disruption of this process entails taurodontism, single-rooted posterior teeth, and misshapen furcations. Thus, even though many characteristics of human root malformations can be related to disorders of specific processes involved in radicular morphogenesis, precise inferences as to the pathogenesis of these dysplasias are hampered by the still limited knowledge on root formation.
PubMed: 26578979
DOI: 10.3389/fphys.2015.00307 -
Pediatric Radiology Jan 2019Perinatal hypophosphatasia (HPP) is a rare, potentially life-threatening, inherited, systemic metabolic bone disease that can be difficult to recognize in utero and... (Review)
Review
Perinatal hypophosphatasia (HPP) is a rare, potentially life-threatening, inherited, systemic metabolic bone disease that can be difficult to recognize in utero and postnatally. Diagnosis is challenging because of the large number of skeletal dysplasias with overlapping clinical features. This review focuses on the role of fetal and neonatal imaging modalities in the differential diagnosis of perinatal HPP from other skeletal dysplasias (e.g., osteogenesis imperfecta, campomelic dysplasia, achondrogenesis subtypes, hypochondrogenesis, cleidocranial dysplasia). Perinatal HPP is associated with a broad spectrum of imaging findings that are characteristic of but do not occur in all cases of HPP and are not unique to HPP, such as shortening, bowing and angulation of the long bones, and slender, poorly ossified ribs and metaphyseal lucencies. Conversely, absent ossification of whole bones is characteristic of severe lethal HPP and is associated with very few other conditions. Certain features may help distinguish HPP from other skeletal dysplasias, such as sites of angulation of long bones, patterns of hypomineralization, and metaphyseal characteristics. In utero recognition of HPP allows for the assembly and preparation of a multidisciplinary care team before delivery and provides additional time to devise treatment strategies.
Topics: Diagnosis, Differential; Female; Humans; Hypophosphatasia; Infant, Newborn; Pregnancy; Prenatal Diagnosis
PubMed: 30284005
DOI: 10.1007/s00247-018-4239-0 -
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 -
Swiss Dental Journal 2015Ectodermal dysplasias (EDs) form a large clinically and genetically heterogeneous group of manifestations characterized by dystrophy or agenesis of embryologic...
Ectodermal dysplasias (EDs) form a large clinically and genetically heterogeneous group of manifestations characterized by dystrophy or agenesis of embryologic ectodermal derivatives. Therefore skin, nails, hair, teeth and secretory organs are mainly affected. Hypohidrotic ectodermal dysplasia (HED) is the most common ED syndrom. It is characterized by atrichosis or hypotrichosis, anodontia or hypodontia and hypohidrosis. Missing teeth or retarded eruption of teeth often leads to the diagnosis of ED, which emphasizes the significance of an appropriate dental examination. Tooth agenesis and its effects on craniofacial structures are often the most signicificant clinical and therapeutical problem. It is a challenge to manage the functional, esthetic and psychosocial needs of these patients and therefore requires the involvement of different specialists, such as pediatrists, pedodontists, oral surgeons and prosthodontists.
PubMed: 26631270
DOI: No ID Found -
Orphanet Journal of Rare Diseases May 2021The ectodermal dysplasias (EDs) constitute a group of disorders characterized by abnormalities in two or more ectodermal derivatives, including skin, hair, teeth, and...
PURPOSE
The ectodermal dysplasias (EDs) constitute a group of disorders characterized by abnormalities in two or more ectodermal derivatives, including skin, hair, teeth, and sweat glands. The purpose of the current study was to evaluate ocular manifestations in pediatric patients with ED.
METHODS
Retrospective case series including consecutive ED subjects who were treated in the ophthalmology department at the Children's Hospital of Philadelphia over a 12-year period (2009-2020). Main Outcome Measures were ocular and ocular adnexal abnormalities.
RESULTS
Thirty subjects were included: 20 males (67%), mean age of 4.5 years (range 0.3-18). Patients with different subtypes were included, with the hypohidrotic ED and ectrodactyly-ectodermal dysplasia-clefting variants being most prevalent. Most common findings were: lacrimal drainage obstruction in 12 (40%) including punctal agenesis in 10 (33%), refractive errors in 13 (43%) and amblyopia in 6 (20%). A new finding of eyelid ptosis or eyelash ptosis was demonstrated in 11 subjects (37%), mostly associated with TP63 or EDA1 genes variants.
CONCLUSION
Ectodermal dysplasias are associated with various ocular pathologies and amblyopia in the pediatric population. We report a possible genetic association between lash ptosis and EDA1 gene, and eyelid ptosis and TP63 or EDA1 genes variants.
Topics: Adolescent; Child; Child, Preschool; Cleft Lip; Ectodermal Dysplasia; Humans; Infant; Limb Deformities, Congenital; Male; Retrospective Studies; Syndrome
PubMed: 33933124
DOI: 10.1186/s13023-021-01824-2 -
Modern Pathology : An Official Journal... Jan 2017Upper aerodigestive tract (UADT) mucosal premalignant lesions include non-keratinizing and keratinizing intraepithelial dysplasia. The keratinizing type of... (Review)
Review
Upper aerodigestive tract (UADT) mucosal premalignant lesions include non-keratinizing and keratinizing intraepithelial dysplasia. The keratinizing type of intraepithelial dysplasia represents the majority of UADT dysplasias. Historically, grading of UADT dysplasias has followed a three tier system to include mild, moderate and severe dysplasia. Recent recommendations have introduced a two tier grading scheme to including low-grade (ie, mild dysplasia) and high-grade (moderate and severe dysplasia/carcinoma in situ) providing for better consensus among pathologists in the interpretation of such dysplastic lesions. Squamous cell carcinoma is the most common malignant neoplasm of the UADT. Several variants of squamous cell carcinoma are recognized among which the more common types include papillary squamous cell carcinoma, verrucous carcinoma, spindle cell squamous cell carcinoma (sarcomatoid carcinoma) and basaloid squamous cell carcinoma. Each of these variants of squamous cell carcinoma poses diagnostic challenges and each correlates to specific therapy and prognosis. This review details the proposed update in the grading of UADT dysplasia to a two-tiered system as well as providing the key diagnostic features for select variants of squamous cell carcinoma.
Topics: Carcinoma, Squamous Cell; Humans; Hyperplasia; Oropharyngeal Neoplasms; Precancerous Conditions
PubMed: 28060368
DOI: 10.1038/modpathol.2016.207 -
International Journal of Biological... 2020-related disorders represent a heterogeneous group of skeletal dysplasias with a wide phenotypic spectrum. Our aim is to characterize the clinical and molecular...
-related disorders represent a heterogeneous group of skeletal dysplasias with a wide phenotypic spectrum. Our aim is to characterize the clinical and molecular phenotypes of Chinese patients with -related dysplasia and to explore their phenotype-genotype relations. Clinical data were collected, physical examinations were conducted, and X-ray radiography and genetic analyses were performed in ten families involving 29 patients with -related dysplasia. Nine mutations were identified in , including five novel (c.816+6C>T, p.Gly246Arg, p.Gly678Glu, p.Gly1014Val and p.Ter1488Gln) and four reported previously (p.Gly204Val, p.Arg275Cys, p.Gly504Ser and p.Arg719Cys). Based on clinical features and molecular mutations, the ten families were classified into five definite -related disorders: four families with spondyloepiphyseal dysplasia congenita (SEDC), three with osteoarthritis with mild chondrodysplasia (OSCPD), one with Czech dysplasia, one with Kniest dysplasia, and one with epiphyseal dysplasia, multiple, with myopia and deafness (EDMMD). Based on genetic testing results, prenatal diagnosis and genetic counseling were accomplished for one female proband with OSCDP. Chinese patients with OSCDP, Czech dysplasia and EDMMD caused by mutations were first reported, expanding the spectrum of mutations and the phenotype of -related disorders and providing further evidence for the phenotype-genotype relations, which may help improve procreative management of -related disorders.
Topics: Adolescent; Adult; Aged; Asian People; Child; Child, Preschool; Cleft Palate; Collagen Diseases; Collagen Type II; Dwarfism; Face; Female; Genotype; Humans; Hyaline Membrane Disease; Male; Middle Aged; Mutation; Osteoarthritis; Osteochondrodysplasias; Phenotype; Toes; Young Adult
PubMed: 32071555
DOI: 10.7150/ijbs.38811