-
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 -
Pediatrics Jun 2020Achondroplasia is the most common short-stature skeletal dysplasia, additionally marked by rhizomelia, macrocephaly, midface hypoplasia, and normal cognition. Potential... (Review)
Review
Achondroplasia is the most common short-stature skeletal dysplasia, additionally marked by rhizomelia, macrocephaly, midface hypoplasia, and normal cognition. Potential medical complications associated with achondroplasia include lower extremity long bone bowing, middle-ear dysfunction, obstructive sleep apnea, and, more rarely, cervicomedullary compression, hydrocephalus, thoracolumbar kyphosis, and central sleep apnea. This is the second revision to the original 1995 health supervision guidance from the American Academy of Pediatrics for caring for patients with achondroplasia. Although many of the previously published recommendations remain appropriate for contemporary medical care, this document highlights interval advancements in the clinical methods available to monitor for complications associated with achondroplasia. This document is intended to provide guidance for health care providers to help identify individual patients at high risk of developing serious sequelae and to enable intervention before complications develop.
Topics: Achondroplasia; Genetic Counseling; Health Policy; Humans; Practice Guidelines as Topic; Prenatal Care
PubMed: 32457214
DOI: 10.1542/peds.2020-1010 -
American Journal of Medical Genetics.... Dec 2019The application of massively parallel sequencing technology to the field of skeletal disorders has boosted the discovery of the underlying genetic defect for many of...
The application of massively parallel sequencing technology to the field of skeletal disorders has boosted the discovery of the underlying genetic defect for many of these diseases. It has also resulted in the delineation of new clinical entities and the identification of genes and pathways that had not previously been associated with skeletal disorders. These rapid advances have prompted the Nosology Committee of the International Skeletal Dysplasia Society to revise and update the last (2015) version of the Nosology and Classification of Genetic Skeletal Disorders. This newest and tenth version of the Nosology comprises 461 different diseases that are classified into 42 groups based on their clinical, radiographic, and/or molecular phenotypes. Remarkably, pathogenic variants affecting 437 different genes have been found in 425/461 (92%) of these disorders. By providing a reference list of recognized entities and their causal genes, the Nosology should help clinicians achieve accurate diagnoses for their patients and help scientists advance research in skeletal biology.
Topics: Alleles; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Inheritance Patterns; Musculoskeletal Diseases; Phenotype; Practice Guidelines as Topic
PubMed: 31633310
DOI: 10.1002/ajmg.a.61366 -
Expert Review of Neurotherapeutics Nov 2021Focal cortical dysplasias (FCDs) represent the most common etiology in pediatric drug-resistant focal epilepsies undergoing surgical treatment. The localization, extent... (Review)
Review
INTRODUCTION
Focal cortical dysplasias (FCDs) represent the most common etiology in pediatric drug-resistant focal epilepsies undergoing surgical treatment. The localization, extent and histopathological features of FCDs are considerably variable. Somatic mosaic mutations of genes that encode proteins in the PI3K-AKTmTOR pathway, which also includes the tuberous sclerosis associated genes and , have been implicated in FCD type II in a substantial subset of patients. Surgery is the principal therapeutic option for FCD-related epilepsy. Advanced neurophysiological and neuroimaging techniques have improved surgical outcome and reduced the risk of postsurgical deficits. Pharmacological MTOR inhibitors are being tested in clinical trials and might represent an example of personalized treatment of epilepsy based on the known mechanisms of disease, used alone or in combination with surgery.
AREAS COVERED
This review will critically analyze the advances in the diagnosis and treatment of FCDs, with a special focus on the novel therapeutic options prompted by a better understanding of their pathophysiology.
EXPERT OPINION
Focal cortical dysplasia is a main cause of drug-resistant epilepsy, especially in children. Novel, personalized approaches are needed to more effectively treat FCD-related epilepsy and its cognitive consequences.
Topics: Child; Drug Resistant Epilepsy; Epilepsy; Humans; MTOR Inhibitors; Magnetic Resonance Imaging; Malformations of Cortical Development; Tuberous Sclerosis
PubMed: 33834938
DOI: 10.1080/14737175.2021.1915135 -
Anales de Pediatria Oct 2021Developmental dysplasia of the hip is a common cause of disability among children. Early detection leads to better prognosis. There are some risk factors that increase...
INTRODUCTION
Developmental dysplasia of the hip is a common cause of disability among children. Early detection leads to better prognosis. There are some risk factors that increase the possibility of developing a dysplasia. But not every child with developmental dysplasia has them. This means that physical examination is still very useful to detect them. However, based on clinical findings, the amount of requested ultrasound seems higher than it would be necessary.
METHODS
Retrospective cohort study of infants born in a single tertiary care centre. Babies in which hip ultrasound was performed were included. During the period of study, patients with diagnosis of developmental hip dysplasia were also included, as well as the amount of ultrasounds requested during this period, and their efficiency.
RESULTS
Out of the 456 newborns included, 530 hip ultrasounds were performed. Just 3 of the total 12 dysplasias had risk factors. The others were diagnosed through clinical examination.
CONCLUSIONS
Screening protocols are useful to detect hip dysplasia but clinical examination is very important to detect those cases without risk factors. However, the number of tests is higher than expected according to the diagnosed dysplasias.
Topics: Child; Developmental Dysplasia of the Hip; Female; Hip Dislocation, Congenital; Humans; Infant; Infant, Newborn; Physical Examination; Retrospective Studies; Ultrasonography
PubMed: 34511400
DOI: 10.1016/j.anpede.2020.07.024 -
Gastroenterology Aug 2019Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Progression from BE to cancer is associated with obesity, possibly due to increased abdominal...
BACKGROUND & AIMS
Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Progression from BE to cancer is associated with obesity, possibly due to increased abdominal pressure and gastroesophageal reflux disease, although this pathogenic mechanism has not been proven. We investigated whether environmental or dietary factors associated with obesity contribute to the progression of BE to EAC in mice.
METHODS
Tg(ED-L2-IL1RN/IL1B)#Tcw mice (a model of BE, called L2-IL1B mice) were fed a chow (control) or high-fat diet (HFD) or were crossbred with mice that express human interleukin (IL) 8 (L2-IL1B/IL8 mice). Esophageal tissues were collected and analyzed for gene expression profiles and by quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry. Organoids were established from BE tissue of mice and cultured with serum from lean or obese individuals or with neutrophils from L2-IL1B mice. Feces from mice were analyzed by 16s ribosomal RNA sequencing and compared to 16s sequencing data from patients with dysplasia or BE. L2-IL1B were mice raised in germ-free conditions.
RESULTS
L2-IL1B mice fed an HFD developed esophageal dysplasia and tumors more rapidly than mice fed the control diet; the speed of tumor development was independent of body weight. The acceleration of dysplasia by the HFD in the L2-IL1B mice was associated with a shift in the gut microbiota and an increased ratio of neutrophils to natural killer cells in esophageal tissues compared with mice fed a control diet. We observed similar differences in the microbiomes from patients with BE that progressed to EAC vs patients with BE that did not develop into cancer. Tissues from dysplasias of L2-IL1B mice fed the HFD contained increased levels of cytokines that are produced in response to CXCL1 (the functional mouse homolog of IL8, also called KC). Serum from obese patients caused organoids from L2-IL1B/IL8 mice to produce IL8. BE tissues from L2-IL1B mice fed the HFD and from L2-IL1B/IL8 mice contained increased numbers of myeloid cells and cells expressing Cxcr2 and Lgr5 messenger RNAs (epithelial progenitors) compared with mice fed control diets. BE tissues from L2-IL1B mice raised in germ-free housing had fewer progenitor cells and developed less dysplasia than in L2-IL1 mice raised under standard conditions; exposure of fecal microbiota from L2-IL1B mice fed the HFD to L2-IL1B mice fed the control diet accelerated tumor development.
CONCLUSIONS
In a mouse model of BE, we found that an HFD promoted dysplasia by altering the esophageal microenvironment and gut microbiome, thereby inducing inflammation and stem cell expansion, independent of obesity.
Topics: Adenocarcinoma; Adult; Aged; Animals; Barrett Esophagus; Carcinogenesis; Diet, High-Fat; Disease Models, Animal; Disease Progression; Esophageal Neoplasms; Esophagus; Feces; Female; Gastrointestinal Microbiome; Healthy Volunteers; Humans; Interleukin-8; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Obesity; Organoids; Serum; Time Factors; Tissue Culture Techniques
PubMed: 30998992
DOI: 10.1053/j.gastro.2019.04.013