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Hand Surgery & Rehabilitation Apr 2024Congenital nail disorders are an uncommon presenting symptom which can be difficult to diagnose and manage. Nail diseases in the pediatric population differ from those... (Review)
Review
Congenital nail disorders are an uncommon presenting symptom which can be difficult to diagnose and manage. Nail diseases in the pediatric population differ from those in adults in terms of diagnosis, approach and management. In most cases, they do not require treatment and resolve with growth. Physicians need to be able to recognize them, to reassure the parents. The most frequently encountered pathologies associated with nail disorder are syndactyly, acrosyndactyly, symbrachydactyly, macrodactyly, Wassel I thumb duplication, Kirner's deformity and congenital onychodysplasia of the index finger. Treatment usually consists in surgical correction of the deformity. Nail malformation can also be an aspect of a systemic disease. It may provide a clue for screening, and should not be overlooked. Nail conditions can be the first sign of nail-patella syndrome, ectodermal dysplasia, dyskeratosis congenita, epidermolysis bullosa, pachyonychia congenita or lung disease. Medical treatment is therefore discussed on a case-by-case basis.
Topics: Humans; Nails, Malformed; Nail Diseases; Ectodermal Dysplasia
PubMed: 38879228
DOI: 10.1016/j.hansur.2023.01.011 -
American Journal of Human Genetics Jun 2024
PubMed: 38866021
DOI: 10.1016/j.ajhg.2024.05.022 -
Experimental Hematology Jun 2024Inherited bone marrow failure syndromes often result from pathogenic mutations in genes that are important for ribosome function, namely, Diamond-Blackfan anemia,...
Inherited bone marrow failure syndromes often result from pathogenic mutations in genes that are important for ribosome function, namely, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and dyskeratosis congenita. Germline mutations in SAMD9 are a frequent genetic lesion resulting in an inherited bone marrow failure syndrome with monosomy 7; some patients have severe multisystem syndromes that include myelodysplasia. The association of germline SAMD9 mutations and bone marrow failure is clear; however, to date, there is no reliable method to predict whether a novel SAMD9 mutation is pathogenic unless it is accompanied by an obvious family history and/or clinical syndrome. The difficulty with pathogenicity prediction is, in part, due to the incomplete understanding of the biological functions of SAMD9. We used a SAMD9-targeted, inducible CRISPRa system and RNA sequencing to better understand the global transcriptional changes that result from transcriptional manipulation of SAMD9. Supporting recent discoveries that SAMD9 acts as a ACNase specific for phenylalanine tRNA (tRNA-Phe), we confirmed with crosslinking and solid-phase purification that SAMD9 is an RNA binding protein and analyzed how overexpression of tRNA-Phe may reverse transcriptomic changes caused by SAMD9 activation. Our data show that overexpression of SAMD9 from the endogenous locus results in decreased cell proliferation, cell cycle progression, and global protein translation. When SAMD9 contains a gain-of-function mutation (p.E1136Q), these functional phenotypes are exacerbated but only partially rescued with tRNA-Phe overexpression, suggesting additional molecular actions of SAMD9. Additionally, we demonstrate that gene expression pathways important for ribosome biogenesis and MYC signaling are the most significantly impacted by SAMD9 overexpression.
PubMed: 38848876
DOI: 10.1016/j.exphem.2024.104249 -
Archives of Dermatological Research May 2024Skin cancers are associated with a large number of genodermatoses. Existing knowledge and guidelines on the presentations of these genodermatoses focus... (Review)
Review
Skin cancers are associated with a large number of genodermatoses. Existing knowledge and guidelines on the presentations of these genodermatoses focus disproportionately on White patients. Our goal is to identify notable characteristics in location, frequency, and severity of cutaneous findings along with the median age of skin cancers in skin-of-color (SOC) patients with skin-cancer-associated genodermatoses to improve diagnosis rates. We searched for genodermatoses on six databases. Each case report or case series was reviewed, including reports, published in English, containing adult patient descriptions. Duplicate manuscripts were removed using EndNote. The following case-level data were collected from the manuscripts: age, gender, patient country or region of origin, author country/continent of residence, skin cancer-related, and other key dermatologic features. 381 published articles, with a total of 578 SOC patients, met criteria for inclusion. SOC patients can present with fewer classic findings, such as a lower incidence of basal cell carcinomas (44%) in SOC Gorlin syndrome patients than palmar pits (66%) and mandibular cysts (66%). Differences between SOC populations were also noted, such as leukoplakia being more common in Asian dyskeratosis congenita patients (80%) in comparison to African dyskeratosis congenita patients (44%). SOC patients also have varying onset of skin cancer depending on the genodermatosis, from a median of 25 years of age in Rothmund-Thomson syndrome to 53 in Muir-Torre syndrome. In this review, SOC patients with genodermatoses can have varying presentations. Being cognizant of these characteristics may lead to earlier diagnosis and interventions to mitigate skin-cancer-related morbidity in SOC patients.
Topics: Female; Humans; Male; Carcinoma, Basal Cell; Skin; Skin Diseases, Genetic; Skin Neoplasms; Racial Groups
PubMed: 38796611
DOI: 10.1007/s00403-024-03087-w -
Oxford Medical Case Reports May 2024Dyskeratosis congenita (DKC) is a rare genetic disorder characterized by lacy reticular skin hyperpigmentation, bone marrow failure, nail dystrophy, and oral...
Dyskeratosis congenita (DKC) is a rare genetic disorder characterized by lacy reticular skin hyperpigmentation, bone marrow failure, nail dystrophy, and oral leukoplakia. To the best of our knowledge, only around 200 cases were reported in the medical literature, and in this report, we present another distinctive case from Syria. This case report describes a male patient with generalized reticular pigmentation and abnormal nails since childhood. The patient reported a history of recurrent urethral stenosis and corneal density. Dermoscopic examination revealed pigmented lines arranged in a netlike pattern. Histopathological findings were nonspecific. Hematological values were unremarkable. A contrast CT scan revealed changes in the bladder wall. The final diagnosis of Dyskeratosis Congenita was made based on the clinical criteria. This disorder can present with additional cutaneous manifestations and systemic complications. Treatment are generally prescribed to maintain bone marrow function, based on the fact that it is the major cause of death. Regular monitoring and screening for associated conditions are recommended.
PubMed: 38784779
DOI: 10.1093/omcr/omae049 -
Leukemia Jun 2024Recent advances in in-depth data-independent acquisition proteomic analysis have enabled comprehensive quantitative analysis of >10,000 proteins. Herein, an integrated...
Recent advances in in-depth data-independent acquisition proteomic analysis have enabled comprehensive quantitative analysis of >10,000 proteins. Herein, an integrated proteogenomic analysis for inherited bone marrow failure syndrome (IBMFS) was performed to reveal their biological features and to develop a proteomic-based diagnostic assay in the discovery cohort; dyskeratosis congenita (n = 12), Fanconi anemia (n = 11), Diamond-Blackfan anemia (DBA, n = 9), Shwachman-Diamond syndrome (SDS, n = 6), ADH5/ALDH2 deficiency (n = 4), and other IBMFS (n = 18). Unsupervised proteomic clustering identified eight independent clusters (C1-C8), with the ribosomal pathway specifically downregulated in C1 and C2, enriched for DBA and SDS, respectively. Six patients with SDS had significantly decreased SBDS protein expression, with two of these not diagnosed by DNA sequencing alone. Four patients with ADH5/ALDH2 deficiency showed significantly reduced ADH5 protein expression. To perform a large-scale rapid IBMFS screening, targeted proteomic analysis was performed on 417 samples from patients with IBMFS-related hematological disorders (n = 390) and healthy controls (n = 27). SBDS and ADH5 protein expressions were significantly reduced in SDS and ADH5/ALDH2 deficiency, respectively. The clinical application of this first integrated proteogenomic analysis would be useful for the diagnosis and screening of IBMFS, where appropriate clinical screening tests are lacking.
Topics: Humans; Bone Marrow Failure Disorders; Proteogenomics; Male; Female; Bone Marrow Diseases; Child; Adult; Adolescent; Child, Preschool; Anemia, Diamond-Blackfan; Young Adult; Fanconi Anemia; Proteomics; Infant; Shwachman-Diamond Syndrome; Dyskeratosis Congenita
PubMed: 38740980
DOI: 10.1038/s41375-024-02263-1 -
Hematology/oncology Clinics of North... May 2024This article explores the multifaceted landscape of oral cancer precursor syndromes. Hereditary disorders like dyskeratosis congenita and Fanconi anemia increase the... (Review)
Review
This article explores the multifaceted landscape of oral cancer precursor syndromes. Hereditary disorders like dyskeratosis congenita and Fanconi anemia increase the risk of malignancy. Oral potentially malignant disorders, notably leukoplakia, are discussed as precursors influenced by genetic and immunologic facets. Molecular insights delve into genetic mutations, allelic imbalances, and immune modulation as key players in precancerous progression, suggesting potential therapeutic targets. The article navigates the controversial terrain of management strategies of leukoplakia, encompassing surgical resection, chemoprevention, and immune modulation, while emphasizing the ongoing challenges in developing effective, evidence-based preventive approaches.
PubMed: 38705773
DOI: 10.1016/j.hoc.2024.04.001 -
G3 (Bethesda, Md.) Jun 2024In humans, the prevalence of congenital microphthalmia is estimated to be 0.2-3.0 for every 10,000 individuals, with nonocular involvement reported in ∼80% of cases....
In humans, the prevalence of congenital microphthalmia is estimated to be 0.2-3.0 for every 10,000 individuals, with nonocular involvement reported in ∼80% of cases. Inherited eye diseases have been widely and descriptively characterized in dogs, and canine models of ocular diseases have played an essential role in unraveling the pathophysiology and development of new therapies. A naturally occurring canine model of a syndromic disorder characterized by microphthalmia was discovered in the Portuguese water dog. As nonocular findings included tooth enamel malformations, stunted growth, anemia, and thrombocytopenia, we hence termed this disorder Canine Congenital Microphthalmos with Hematopoietic Defects. Genome-wide association study and homozygosity mapping detected a 2 Mb candidate region on canine chromosome 4. Whole-genome sequencing and mapping against the Canfam4 reference revealed a Short interspersed element insertion in exon 2 of the DNAJC1 gene (g.74,274,883ins[T70]TGCTGCTTGGATT). Subsequent real-time PCR-based mass genotyping of a larger Portuguese water dog population found that the homozygous mutant genotype was perfectly associated with the Canine Congenital Microphthalmos with Hematopoietic Defects phenotype. Biallelic variants in DNAJC21 are mostly found to be associated with bone marrow failure syndrome type 3, with a phenotype that has a certain degree of overlap with Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and reports of individuals showing thrombocytopenia, microdontia, and microphthalmia. We, therefore, propose Canine Congenital Microphthalmos with Hematopoietic Defects as a naturally occurring model for DNAJC21-associated syndromes.
Topics: Animals; Dogs; Microphthalmos; Disease Models, Animal; Genome-Wide Association Study; Phenotype; Genotype; Homozygote; Dog Diseases; Syndrome; Female; Male
PubMed: 38682429
DOI: 10.1093/g3journal/jkae067 -
Actas Dermo-sifiliograficas Apr 2024Nail disorders in newborns can show independently or as components of systemic illnesses or genodermatoses. The examination of these abnormalities is complex and... (Review)
Review
Nail disorders in newborns can show independently or as components of systemic illnesses or genodermatoses. The examination of these abnormalities is complex and sometimes challenging. However, familiarity with these disorders can significantly contribute to uncovering potential underlying conditions. This review includes the physiological nail changes seen within the first few months of life, such as Beau's lines, onychoschizia, koilonychia, congenital nail fold hypertrophy of the first digit, and onychocryptosis. This review also focuses on the most relevant congenital disorders reported and how to perform differential diagnosis. Finally, this review highlights those hereditary diseases in which nail involvement is crucial for diagnosis, such as nail-patella syndrome, congenital pachyonychia, or congenital dyskeratosis, among others.
PubMed: 38663727
DOI: 10.1016/j.ad.2024.04.002 -
Human Molecular Genetics Apr 2024Telomeres are nucleoprotein structures at the end of chromosomes that maintain their integrity. Mutations in genes coding for proteins involved in telomere protection...
Clinical mutations in the TERT and TERC genes coding for telomerase components induced oxidative stress, DNA damage at telomeres and cell apoptosis besides decreased telomerase activity.
Telomeres are nucleoprotein structures at the end of chromosomes that maintain their integrity. Mutations in genes coding for proteins involved in telomere protection and elongation produce diseases such as dyskeratosis congenita or idiopathic pulmonary fibrosis known as telomeropathies. These diseases are characterized by premature telomere shortening, increased DNA damage and oxidative stress. Genetic diagnosis of telomeropathy patients has identified mutations in the genes TERT and TERC coding for telomerase components but the functional consequences of many of these mutations still have to be experimentally demonstrated. The activity of twelve TERT and five TERC mutants, five of them identified in Spanish patients, has been analyzed. TERT and TERC mutants were expressed in VA-13 human cells that express low telomerase levels and the activity induced was analyzed. The production of reactive oxygen species, DNA oxidation and TRF2 association at telomeres, DNA damage response and cell apoptosis were determined. Most mutations presented decreased telomerase activity, as compared to wild-type TERT and TERC. In addition, the expression of several TERT and TERC mutants induced oxidative stress, DNA oxidation, DNA damage, decreased recruitment of the shelterin component TRF2 to telomeres and increased apoptosis. These observations might indicate that the increase in DNA damage and oxidative stress observed in cells from telomeropathy patients is dependent on their TERT or TERC mutations. Therefore, analysis of the effect of TERT and TERC mutations of unknown function on DNA damage and oxidative stress could be of great utility to determine the possible pathogenicity of these variants.
Topics: Humans; Apoptosis; DNA; DNA Damage; Dyskeratosis Congenita; Mutation; Oxidative Stress; RNA; Telomerase; Telomere
PubMed: 38641551
DOI: 10.1093/hmg/ddae015