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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 -
Developmental Dynamics : An Official... Mar 2021For the vast majority of the 6000 known rare disease the pathogenic mechanisms are poorly defined and there is little treatment, leading to poor quality of life and high... (Review)
Review
For the vast majority of the 6000 known rare disease the pathogenic mechanisms are poorly defined and there is little treatment, leading to poor quality of life and high healthcare costs. Genetic skeletal diseases (skeletal dysplasias) are archetypal examples of rare diseases that are chronically debilitating, often life-threatening and for which no treatments are currently available. There are more than 450 unique phenotypes that, although individually rare, have an overall prevalence of at least 1 per 4000 children. Multiple epiphyseal dysplasia (MED) is a clinically and genetically heterogeneous disorder characterized by disproportionate short stature, joint pain, and early-onset osteoarthritis. MED is caused by mutations in the genes encoding important cartilage extracellular matrix proteins, enzymes, and transporter proteins. Recently, through the use of various cell and mouse models, disease mechanisms underlying this diverse phenotypic spectrum are starting to be elucidated. For example, ER stress induced as a consequence of retained misfolded mutant proteins has emerged as a unifying disease mechanisms for several forms of MED in particular and skeletal dysplasia in general. Moreover, targeting ER stress through drug repurposing has become an attractive therapeutic avenue.
Topics: Endoplasmic Reticulum Stress; Extracellular Matrix Proteins; Humans; Mutation; Osteochondrodysplasias; Quality of Life
PubMed: 32633442
DOI: 10.1002/dvdy.221 -
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 -
The European Respiratory Journal May 2020
Topics: Bronchopulmonary Dysplasia; Crime; Dysbiosis; Gastrointestinal Microbiome; Humans; Infant; Infant, Newborn; Infant, Premature
PubMed: 32381633
DOI: 10.1183/13993003.00551-2020 -
Clinical Oral Investigations Oct 2023Skeletal dysplasia (SD) comprises more than 450 separate disorders. We hypothesized that their dental features would be distinctive and investigated the tooth...
OBJECTIVE
Skeletal dysplasia (SD) comprises more than 450 separate disorders. We hypothesized that their dental features would be distinctive and investigated the tooth characteristics of four patients with different SDs.
MATERIAL AND METHODS
Four SD patients with molecularly confirmed diagnoses, Pt-1 acromicric dysplasia, Pt-2 hypophosphatasia and hypochondroplasia, Pt-3 cleidocranial dysplasia, and Pt-4 achondroplasia, were recruited. A tooth from each patient was evaluated for mineral density (micro-computerized tomography), surface roughness (surface profilometer), microhardness, mineral contents (energy-dispersive X-ray), and ultrastructure (scanning electron microscopy and histology), and compared with three tooth-type matched controls.
RESULTS
Pt-1 and Pt-3 had several unerupted teeth. Pt-2 had an intact-root-exfoliated tooth at 2 years old. The lingual surfaces of the patients' teeth were significantly smoother, while their buccal surfaces were rougher, than controls, except for Pt-1's buccal surface. The patients' teeth exhibited deep grooves around the enamel prisms and rough intertubular dentin. Pt-3 demonstrated a flat dentinoenamel junction and Pt-2 had an enlarged pulp, barely detectable cementum layer, and ill-defined cemento-dentinal junction. Reduced microhardnesses in enamel, dentin, and both layers were observed in Pt-3, Pt-4, and Pt-1, respectively. Pt-1 showed reduced Ca/P ratio in dentin, while both enamel and dentin of Pt-2 and Pt-3 showed reduced Ca/P ratio.
CONCLUSION
Each SD has distinctive dental characteristics with changes in surface roughness, ultrastructure, and mineral composition of dental hard tissues.
CLINICAL RELEVANCE
In this era of precision dentistry, identifying the specific potential dental problems for each patient with SD would help personalize dental management guidelines.
PubMed: 37548766
DOI: 10.1007/s00784-023-05194-w -
Asian Pacific Journal of Cancer... Sep 2020to investigate CD133 immunoexpression, cancer stem cells marker, in oral epithelial dysplasias (OEDs) and oral squamous cells carcinomas (OSCCs) and understandits...
OBJECTIVE
to investigate CD133 immunoexpression, cancer stem cells marker, in oral epithelial dysplasias (OEDs) and oral squamous cells carcinomas (OSCCs) and understandits possible involvement in the malignant transformation process of these lesions and to better elucidate their biological behavior.
MATERIAL AND METHODS
Tissue samples of 15 cases of OSCCs and 15 OEDs were subjected to CD133 antibody immunohistochemistry reactions. The analysis used quantitative parameters (number of immunostained cells regardless of immunostaining sublocations).
RESULTS
All samples of OSCCs and OEDs showed positive immunostaining, with no significant difference between these groups (p = 0.283). We did not observe statistical difference between the degree of dysplasia and the amount of CD133+ cells (p = 0.899). CD133 immunoexpression showed no association with the OEDs and OSCCs sites. It was observed that nuclear and cytoplasmic immunostaining was more evident with the progression of the malignant process.
CONCLUSION
It is suggested that the CD133 cellular localization together with the histopathological criteria of OEDs classification can contribute to provide more concrete indications about the oral carcinogenesis process.
Topics: AC133 Antigen; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Squamous Cell; Female; Focal Epithelial Hyperplasia; Follow-Up Studies; Humans; Male; Middle Aged; Mouth Neoplasms; Precancerous Conditions; Prognosis
PubMed: 32986345
DOI: 10.31557/APJCP.2020.21.9.2501 -
The Journal of Clinical Endocrinology... May 2022Pain is a major symptom in adults with fibrous dysplasia/McCune-Albright syndrome (FD/MAS) and response to current treatments, including bisphosphonates and standard...
CONTEXT
Pain is a major symptom in adults with fibrous dysplasia/McCune-Albright syndrome (FD/MAS) and response to current treatments, including bisphosphonates and standard analgesics (nonsteroidal anti-inflammatory drugs and opiates) is unpredictable. No studies have explored whether the type of pain is variable in this patient group.
OBJECTIVE
To determine the frequency of neuropathic-like pain in patients with FD/MAS.
DESIGN
Retrospective, dual registry study.
SETTING
Community.
PATIENTS
FD/MAS online registries: the US-based Familial Dysautonomia Foundation (FDF) and the UK-based Rare and Undiagnosed Diseases (RUDY) study.
INTERVENTION
Subjects completed questionnaires to evaluate the presence of features of neuropathic-like pain (painDETECT) and the impact on sleep quality (Pittsburgh Sleep Quality Index) and mental health (Hospital Anxiety and Depression Scale). Descriptive statistics were used to characterize the prevalence and associated burden of neuropathic-like pain.
MAIN OUTCOME MEASURES
Incidence of neuropathic, nociceptive, and unclear pain.
RESULTS
Of 249 participants, one third experienced neuropathic-like pain. This group had statistically significantly (P < 0.001) worse mental well-being and sleep in comparison to those with predominately nociceptive pain.
CONCLUSIONS
Neuropathic-like pain is common in patients with FD/MAS and associated with worse quality of life. Evaluation of pain in patients with FD/MAS should include assessment of neuropathic-like pain to guide personalized approaches to treatment and inform future research.
Topics: Adult; Fibrous Dysplasia of Bone; Fibrous Dysplasia, Polyostotic; Humans; Pain; Peripheral Nervous System Diseases; Quality of Life; Retrospective Studies
PubMed: 35262711
DOI: 10.1210/clinem/dgac120 -
Cancers Dec 2023Barrett's esophagus (BE) was initially defined in the 1950s as the visualization of gastric-like mucosa in the esophagus. Over time, the definition has evolved to... (Review)
Review
Barrett's esophagus (BE) was initially defined in the 1950s as the visualization of gastric-like mucosa in the esophagus. Over time, the definition has evolved to include the identification of goblet cells, which confirm the presence of intestinal metaplasia within the esophagus. Chronic gastro-esophageal reflux disease (GERD) is a significant risk factor for adenocarcinoma of the esophagus, as intestinal metaplasia can develop due to GERD. The development of adenocarcinomas related to BE progresses in sequence from inflammation to metaplasia, dysplasia, and ultimately carcinoma. In the presence of GERD, the squamous epithelium changes to columnar epithelium, which initially lacks goblet cells, but later develops goblet cell metaplasia and eventually dysplasia. The accumulation of multiple genetic and epigenetic alterations leads to the development and progression of dysplasia. The diagnosis of BE requires the identification of intestinal metaplasia on histologic examination, which has thus become an essential tool both in the diagnosis and in the assessment of dysplasia's presence and degree. The histologic diagnosis of BE dysplasia can be challenging due to sampling error, pathologists' experience, interobserver variation, and difficulty in histologic interpretation: all these problems complicate patient management. The development and progression of Barrett's esophagus (BE) depend on various molecular events that involve changes in cell-cycle regulatory genes, apoptosis, cell signaling, and adhesion pathways. In advanced stages, there are widespread genomic abnormalities with losses and gains in chromosome function, and DNA instability. This review aims to provide an updated and comprehensible diagnostic approach to BE based on the most recent guidelines available in the literature, and an overview of the pathogenetic and molecular mechanisms of its development.
PubMed: 38136271
DOI: 10.3390/cancers15245725 -
Brain : a Journal of Neurology Feb 2024Focal cortical dysplasias are a common subtype of malformation of cortical development, which frequently presents with a spectrum of cognitive and behavioural...
Focal cortical dysplasias are a common subtype of malformation of cortical development, which frequently presents with a spectrum of cognitive and behavioural abnormalities as well as pharmacoresistant epilepsy. Focal cortical dysplasia type II is typically caused by somatic mutations resulting in mammalian target of rapamycin (mTOR) hyperactivity, and is the commonest pathology found in children undergoing epilepsy surgery. However, surgical resection does not always result in seizure freedom, and is often precluded by proximity to eloquent brain regions. Gene therapy is a promising potential alternative treatment and may be appropriate in cases that represent an unacceptable surgical risk. Here, we evaluated a gene therapy based on overexpression of the Kv1.1 potassium channel in a mouse model of frontal lobe focal cortical dysplasia. An engineered potassium channel (EKC) transgene was placed under control of a human promoter that biases expression towards principal neurons (CAMK2A) and packaged in an adeno-associated viral vector (AAV9). We used an established focal cortical dysplasia model generated by in utero electroporation of frontal lobe neural progenitors with a constitutively active human Ras homolog enriched in brain (RHEB) plasmid, an activator of mTOR complex 1. We characterized the model by quantifying electrocorticographic and behavioural abnormalities, both in mice developing spontaneous generalized seizures and in mice only exhibiting interictal discharges. Injection of AAV9-CAMK2A-EKC in the dysplastic region resulted in a robust decrease (∼64%) in the frequency of seizures. Despite the robust anti-epileptic effect of the treatment, there was neither an improvement nor a worsening of performance in behavioural tests sensitive to frontal lobe function. AAV9-CAMK2A-EKC had no effect on interictal discharges or behaviour in mice without generalized seizures. AAV9-CAMK2A-EKC gene therapy is a promising therapy with translational potential to treat the epileptic phenotype of mTOR-related malformations of cortical development. Cognitive and behavioural co-morbidities may, however, resist an intervention aimed at reducing circuit excitability.
Topics: Child; Humans; Mice; Animals; Focal Cortical Dysplasia; Epilepsy; TOR Serine-Threonine Kinases; Protein Serine-Threonine Kinases; Seizures; Genetic Therapy; Malformations of Cortical Development; Mammals
PubMed: 38100333
DOI: 10.1093/brain/awad387