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HNO Jun 2020Malformations of the ear are the most common dysplasias in childhood. Ear malformations are classified into dysplasias of the auricle, of the ear canal, and of the... (Review)
Review
Malformations of the ear are the most common dysplasias in childhood. Ear malformations are classified into dysplasias of the auricle, of the ear canal, and of the middle and inner ear. The latter types are fortunately relatively rare. Most common is a low-grade dysplasia of the auricle (otapostasis, cup ear). Higher-grade dysplasia of the auricle (microtia II-III) is often associated with syndromes and/or malformations of the ear canal and the middle ear (e.g., congenital aural atresia with high-grade microtia and dysplasia of the middle ear). Functional aspects of hearing and acquisition of language as well as aesthetic aspects emphasize the importance of surgical therapy. Due to the importance of correctly scheduling surgical treatment in early childhood, this article gives an overview of the possibilities for aesthetic reconstruction of the auricle and the frequently associated functional rehabilitation of hearing.
Topics: Child; Congenital Microtia; Ear Auricle; Ear Canal; Ear, Middle; Hearing; Humans; Plastic Surgery Procedures
PubMed: 32130456
DOI: 10.1007/s00106-020-00831-2 -
Radiographics : a Review Publication of... May 2023Skeletal dysplasias are a heterogeneous collection of genetic disorders characterized by bone and cartilage abnormalities, and they encompass over 400 disorders. These...
Skeletal dysplasias are a heterogeneous collection of genetic disorders characterized by bone and cartilage abnormalities, and they encompass over 400 disorders. These disorders are rare individually, but collectively they are common (approximate incidence of one in 5000 births). Radiologists occasionally encounter skeletal dysplasias in daily practice. In the 1980s, Professor Juergen Spranger proposed a concept suitable for the diagnosis of skeletal dysplasias termed He stated that different bone dysplasias that share a similar skeletal pattern can be grouped into a "family," the final diagnosis is feasible through the provisional recognition of a pattern followed by a more careful analysis, and families of bone dysplasias may be the result of similar pathogenetic mechanisms. The prototypes of bone dysplasia families include dysostosis multiplex family, achondroplasia family, spondyloepiphyseal dysplasia congenita family, and Larsen syndrome-otopalatodigital syndrome family. Since Spranger's proposal, the concept of bone dysplasia families, along with advancing genetic techniques, has been validated and further expanded. Today, this molecularly proven concept enables a simple stepwise approach to be applied to the radiologic diagnosis of skeletal dysplasias. The first step is the categorization of a given case into a family based on pattern recognition, and the second step is more meticulous observation, such as identification of different severities of the same pattern or subtle but distinctive findings. Since major skeletal dysplasias are limited in number, radiologists can be familiar with the representative patterns of these disorders. The authors describe a stepwise radiologic approach to diagnosing major skeletal dysplasia families and review the clinical and genetic features of these disorders. Published under a CC BY 4.0 license. Quiz questions for this article are available through the Online Learning Center. and
Topics: Male; Humans; Osteochondrodysplasias; Bone Diseases, Developmental; Radiography; Hand Deformities, Congenital
PubMed: 37053103
DOI: 10.1148/rg.220067 -
Orphanet Journal of Rare Diseases Dec 2021Achondroplasia is the most common genetic skeletal disorder causing disproportionate short stature/dwarfism. Common additional features include spinal stenosis, midface...
Growth in achondroplasia including stature, weight, weight-for-height and head circumference from CLARITY: achondroplasia natural history study-a multi-center retrospective cohort study of achondroplasia in the US.
BACKGROUND
Achondroplasia is the most common genetic skeletal disorder causing disproportionate short stature/dwarfism. Common additional features include spinal stenosis, midface retrusion, macrocephaly and a generalized spondylometaphyseal dysplasia which manifest as spinal cord compression, sleep disordered breathing, delayed motor skill acquisition and genu varus with musculoskeletal pain. To better understand the interactions and health outcomes of these potential complications, we embarked on a multi-center, natural history study entitled CLARITY (achondroplasia natural history study). One of the CLARITY objectives was to develop growth curves (length/height, weight, head circumference, weight-for-height) and corresponding reference tables of mean and standard deviations at 1 month increments from birth through 18 years for clinical use and research for achondroplasia patients.
METHODS
All available retrospective anthropometry data including length/height, weight and head circumference from achondroplasia patients were collected at 4 US skeletal dysplasia centers (Johns Hopkins University, AI DuPont Hospital for Children, McGovern Medical School University of Texas Health, University of Wisconsin School of Medicine and Public Health). Weight-for-age values beyond 3 SD above the mean were excluded from the weight-for-height and weight-for-age curves to create a stricter tool for weight assessment in this population.
RESULTS
Over 37,000 length/height, weight and head circumference measures from 1374 patients with achondroplasia from birth through 75 years of age were compiled in a REDCap database. Stature and weight data from birth through 18 years of age and head circumference from birth through 5 years of age were utilized to construct new length/height-for-age, weight-for-age, head circumference-for-age and weight-for-height curves.
CONCLUSION
Achondroplasia-specific growth curves are essential for clinical care of growing infants and children with this condition. In an effort to provide prescriptive, rather than purely descriptive, references for weight in this population, extreme weight values were omitted from the weight-for-age and weight-for-height curves. This well-phenotyped cohort may be studied with other global achondroplasia populations (e.g. Europe, Argentina, Australia, Japan) to gain further insight into environmental or ethnic influences on growth.
Topics: Achondroplasia; Body Height; Child; Cohort Studies; Growth Charts; Humans; Infant; Retrospective Studies
PubMed: 34949201
DOI: 10.1186/s13023-021-02141-4 -
Frontiers in Endocrinology 2020Skeletal dysplasias are a diverse group of heritable diseases affecting bone and cartilage growth. Throughout the years, the molecular defect underlying many of the... (Review)
Review
Skeletal dysplasias are a diverse group of heritable diseases affecting bone and cartilage growth. Throughout the years, the molecular defect underlying many of the diseases has been identified. These identifications led to novel insights in the mechanisms regulating bone and cartilage growth and homeostasis. One of the pathways that is clearly important during skeletal development and bone homeostasis is the Wingless and int-1 (WNT) signaling pathway. So far, three different WNT signaling pathways have been described, which are all activated by binding of the WNT ligands to the Frizzled (FZD) receptors. In this review, we discuss the skeletal disorders that are included in the latest nosology of skeletal disorders and that are caused by genetic defects involving the WNT signaling pathway. The number of skeletal disorders caused by defects in WNT signaling genes and the clinical phenotype associated with these disorders illustrate the importance of the WNT signaling pathway during skeletal development as well as later on in life to maintain bone mass. The knowledge gained through the identification of the genes underlying these monogenic conditions is used for the identification of novel therapeutic targets. For example, the genes underlying disorders with altered bone mass are all involved in the canonical WNT signaling pathway. Consequently, targeting this pathway is one of the major strategies to increase bone mass in patients with osteoporosis. In addition to increasing the insights in the pathways regulating skeletal development and bone homeostasis, knowledge of rare skeletal dysplasias can also be used to predict possible adverse effects of these novel drug targets. Therefore, this review gives an overview of the skeletal and extra-skeletal phenotype of the different skeletal disorders linked to the WNT signaling pathway.
Topics: Animals; Bone Diseases; Bone and Bones; Genetic Diseases, Inborn; Humans; Musculoskeletal Abnormalities; Wnt Signaling Pathway
PubMed: 32328030
DOI: 10.3389/fendo.2020.00165 -
Pediatric Neurology Oct 2023Inactivating mutations in PTEN are among the most common causes of megalencephaly. Activating mutations in other nodes of the PI3K/AKT/MTOR signaling pathway are...
BACKGROUND
Inactivating mutations in PTEN are among the most common causes of megalencephaly. Activating mutations in other nodes of the PI3K/AKT/MTOR signaling pathway are recognized as a frequent cause of cortical brain malformations. Only recently has PTEN been associated with cortical malformations, and analyses of their prognostic significance have been limited.
METHODS
Retrospective neuroimaging analysis and detailed chart review were conducted on 20 participants identified with pathogenic or likely pathogenic mutations in PTEN and a cortical brain malformation present on brain magnetic resonance imaging.
RESULTS
Neuroimaging analysis revealed four main cerebral phenotypes-hemimegalencephaly, focal cortical dysplasia, polymicrogyria (PMG), and a less severe category, termed "macrocephaly with complicated gyral pattern" (MCG). Although a high proportion of participants (90%) had neurodevelopmental findings on presentation, outcomes varied and were favorable in over half of participants. Consistent with prior work, 39% of participants had autism spectrum disorder and 19% of participants with either pure-PMG or pure-MCG phenotypes had epilepsy. Megalencephaly and systemic overgrowth were common, but other systemic features of PTEN-hamartoma tumor syndrome were absent in over one-third of participants.
CONCLUSIONS
A spectrum of cortical dysplasias is present in individuals with inactivating mutations in PTEN. Future studies are needed to clarify the prognostic significance of each cerebral phenotype, but overall, we conclude that despite a high burden of neurodevelopmental disease, long-term outcomes may be favorable. Germline testing for PTEN mutations should be considered in cases of megalencephaly and cortical brain malformations even in the absence of other findings, including cognitive impairment.
Topics: Humans; Autism Spectrum Disorder; Phosphatidylinositol 3-Kinases; Retrospective Studies; Megalencephaly; Brain; Polymicrogyria; PTEN Phosphohydrolase
PubMed: 37619436
DOI: 10.1016/j.pediatrneurol.2023.06.015 -
Frontiers in Endocrinology 2022Skeletal dysplasias comprise a heterogenous group of developmental disorders of skeletal and cartilaginous tissues. Several different forms have been described and the...
Skeletal dysplasias comprise a heterogenous group of developmental disorders of skeletal and cartilaginous tissues. Several different forms have been described and the full spectrum of their clinical manifestations and underlying genetic causes are still incompletely understood. We report a three-generation Finnish family with an unusual, autosomal dominant form of osteochondrodysplasia and an empty sella. Affected individuals (age range 24-44 years) exhibit unusual codfish-shaped vertebrae, severe early-onset and debilitating osteoarthritis and an empty sella without endocrine abnormalities. Clinical characteristics also include mild dysmorphic features, reduced sitting height ratio, and obesity. Whole-exome sequencing excluded known skeletal dysplasias and identified a novel heterozygous missense mutation c.899C>T (p.Thr300Met) in , confirmed by Sanger sequencing. TBX2 is important for development of the skeleton and the brain and three prior reports have described variations in in patients portraying a complex phenotype with vertebral anomalies, craniofacial dysmorphism and endocrine dysfunctions. Our mutation lies near a previously reported disease-causing variant and is predicted pathogenic with deleterious effects on protein function. Our findings expand the current spectrum of skeletal dysplasias, support the association of mutations with skeletal dysplasia and suggest a role for TBX2 in development of the spinal and craniofacial structures and the pituitary gland.
Topics: Abnormalities, Multiple; Bone Diseases, Developmental; Humans; Osteochondrodysplasias; Phenotype; Exome Sequencing
PubMed: 35311234
DOI: 10.3389/fendo.2022.845889 -
Journal of Bone and Mineral Research :... May 2023Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356), also called dysplastic cortical hyperostosis, Al-Gazali type, is an ultra-rare disorder previously...
Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356), also called dysplastic cortical hyperostosis, Al-Gazali type, is an ultra-rare disorder previously reported in only three unrelated individuals. The genetic etiology for Al-Gazali skeletal dysplasia has up until now been unknown. Through international collaborative efforts involving seven clinical centers worldwide, a cohort of nine patients with clinical and radiographic features consistent with short-limb skeletal dysplasia Al-Gazali type was collected. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly. Biallelic disease-causing variants in ADAMTSL2 were detected using massively parallel sequencing (MPS) and Sanger sequencing techniques. Six individuals were compound heterozygous and one individual was homozygous for pathogenic variants in ADAMTSL2. In one of the families, pathogenic variants were detected in parental samples only. Overall, this study sheds light on the genetic cause of Al-Gazali skeletal dysplasia and identifies it as a semi-lethal part of the spectrum of ADAMTSL2-related disorders. Furthermore, we highlight the importance of meticulous analysis of the pseudogene region of ADAMTSL2 where disease-causing variants might be located. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Humans; Bone Diseases, Developmental; Limb Deformities, Congenital; Osteochondrodysplasias; Bone and Bones; Homozygote; ADAMTS Proteins
PubMed: 36896612
DOI: 10.1002/jbmr.4799 -
Annals of Pediatric Endocrinology &... Jun 2022Skeletal dysplasia is a diverse group of disorders that affect bone development and morphology. Currently, approximately 461 different genetic skeletal disorders have...
Skeletal dysplasia is a diverse group of disorders that affect bone development and morphology. Currently, approximately 461 different genetic skeletal disorders have been identified, with over 430 causative genes. Among these, fibroblast growth factor receptor 3 (FGFR3)-related skeletal dysplasia is a relatively common subgroup of skeletal dysplasia. Pediatric endocrinologists may encounter a suspected case of skeletal dysplasia in their practice, especially when evaluating children with short stature. Early and accurate diagnosis of FGFR3-related skeletal dysplasia is essential for timely management of complications and genetic counseling. This review summarizes 5 representative and distinct entities of skeletal dysplasia caused by pathogenic variants in FGFR3 and discusses emerging therapies for FGFR3-related skeletal dysplasias.
PubMed: 35793999
DOI: 10.6065/apem.2244114.057 -
Pediatric Radiology Nov 2020Skeletal dysplasias are a large group of rare conditions with widely heterogeneous manifestations and a reputation for being diagnostically difficult. Involvement of the... (Review)
Review
Skeletal dysplasias are a large group of rare conditions with widely heterogeneous manifestations and a reputation for being diagnostically difficult. Involvement of the brain and craniovertebral junction are features familiar to the paediatric neuroradiologist. Involvement of the skull itself represents an area of overlap between the domains of the neuroradiologist and the skeletal dysplasia radiologist. In this pictorial essay, we review the principal skull manifestations of skeletal dysplasias as they present to the neuroradiologist.
Topics: Adolescent; Bone Diseases, Developmental; Child; Child, Preschool; Diagnostic Imaging; Female; Humans; Infant; Male; Skull
PubMed: 33135136
DOI: 10.1007/s00247-019-04473-7 -
Epilepsy & Behavior : E&B Jan 2024Focal cortical dysplasia (FCD) is a cortical malformation in brain development and is considered as one of the major causes of drug-resistant epilepsiesin children and... (Review)
Review
Focal cortical dysplasia (FCD) is a cortical malformation in brain development and is considered as one of the major causes of drug-resistant epilepsiesin children and adults. The pathogenesis of FCD is yet to be fully understood. Imaging markers such as MRI are currently the surgeons major obstacle due to the difficulty in delimiting the precise dysplasic area and a mosaic brain where there is epileptogenic tissue invisible to MRI. Also increased gene expression and activity may be responsible for the alterations in cell proliferation, migration, growth, and survival. Altered expressions were found, particularly in the PI3K/AKT/mTOR pathway. Surgery is still considered the most effective treatment option, due to drug-resistance, and up to 60 % of patients experience complete seizure control, varying according to the type and location of FCD. Both genetic and epigenetic factors may be involved in the pathogenesis of FCD, and there is no conclusive evidence whether these alterations are inherited or have an environmental origin.
Topics: Adult; Child; Humans; Focal Cortical Dysplasia; Phosphatidylinositol 3-Kinases; Brain; Seizures; Treatment Outcome; Magnetic Resonance Imaging; Biomarkers; Malformations of Cortical Development; Retrospective Studies
PubMed: 38070410
DOI: 10.1016/j.yebeh.2023.109565