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Journal of Postgraduate Medicine 2024We report a 2.2 year-old-boy, born of consanguineous marriage, referred for short stature, with history of neonatal death and skeletal deformities in his older sibling....
We report a 2.2 year-old-boy, born of consanguineous marriage, referred for short stature, with history of neonatal death and skeletal deformities in his older sibling. Rhizo-mesomelic dwarfism was detected antenatally. Within 24 hours of birth, he developed multiple seizures. Examination revealed severe short stature, dolichocephaly, broad forehead, deep set eyes, low set ears, bulbous nose, small, irregular teeth, pointed chin, and triangular facies. He had rhizomelic shortening, stubby fingers, pes planus, and scanty hair. Neurological evaluation revealed ataxia, hypotonia, and global developmental delay. Skeletal survey radiograph revealed shallow acetabuli, short femurs and humerus, short, broad metacarpals and short cone-shaped phalanges with cupping of phalangeal bases. Clinical exome analysis revealed homozygous mutations involving the POC1A gene and the SLC13A5 gene responsible for SOFT syndrome and Kohlschutter-Tonz syndrome respectively, which were inherited from the parents. Both these syndromes are extremely rare, and their co-occurrence is being reported for the first time.
Topics: Male; Infant, Newborn; Humans; Child, Preschool; Epilepsy; Dementia; Amelogenesis Imperfecta; Abnormalities, Multiple; Osteochondrodysplasias; Dwarfism; Symporters; Cytoskeletal Proteins; Cell Cycle Proteins
PubMed: 37706418
DOI: 10.4103/jpgm.jpgm_1001_22 -
Frontiers in Oral Health 2023Enamel Renal Syndrome (ERS) (OMIM # 204690) is a rare genetic condition characterised by hypoplastic amelogenesis imperfecta, failed tooth eruption, intra-pulpal...
Enamel Renal Syndrome (ERS) (OMIM # 204690) is a rare genetic condition characterised by hypoplastic amelogenesis imperfecta, failed tooth eruption, intra-pulpal calcifications, gingival enlargement and occasionally nephrocalcinosis. In this case series, we report on four unrelated patients with a confirmed molecular diagnosis of ERS ( pathogenic variants) from Sub-Saharan Africa. The pathognomonic oral profile of ERS was mostly fulfilled in these patients, with the notable addition of an odontoma in one patient. The cases presented a spectrum of phenotypic severity both dentally and systemically. One patient presented with nephrocalcinosis and abnormal kidney function, one had reduced kidney size with normal kidney function, and two had no renal abnormalities. Patients presenting with the oral profile of ERS should receive a prompt referral to a nephrologist and a geneticist. They should receive long-term management from a multidisciplinary medical and dental team.
PubMed: 37675434
DOI: 10.3389/froh.2023.1228760 -
Intractable & Rare Diseases Research Aug 2023We performed a study to present a phenotypic and genotypic characterization of a patient clinically diagnosed with carbonic anhydrase II (CAII) deficiency syndrome....
We performed a study to present a phenotypic and genotypic characterization of a patient clinically diagnosed with carbonic anhydrase II (CAII) deficiency syndrome. Medical records were reviewed, and oral examination was performed. Sanger sequencing was undertaken for molecular diagnosis. The patient presented with osteopetrosis, renal tubular acidosis, cerebral calcification, blindness, deafness, and development delay. The oral manifestations included anterior open bite, posterior crossbite, tooth eruption impairment, and hypoplastic amelogenesis imperfecta (AI). Molecular analysis revealed a homozygous deletion (c.753delG, p.Asn252Thrfs*14) and confirmed the clinical diagnosis. This study suggests that AI can be another feature of CAII deficiency syndrome. For the first time, a disease-causing variant is reported to be associated with syndromic AI.
PubMed: 37662627
DOI: 10.5582/irdr.2023.01033 -
Journal of Dental Research Oct 2023Amelogenin plays a crucial role in tooth enamel formation, and mutations on X-chromosomal amelogenin cause X-linked amelogenesis imperfecta (AI). Amelogenin...
Amelogenin plays a crucial role in tooth enamel formation, and mutations on X-chromosomal amelogenin cause X-linked amelogenesis imperfecta (AI). Amelogenin pre-messenger RNA (mRNA) is highly alternatively spliced, and during alternative splicing, exon4 is mostly skipped, leading to the formation of a microRNA (miR-exon4) that has been suggested to function in enamel and bone formation. While delivering the functional variation of amelogenin proteins, alternative splicing of exon4 is the decisive first step to producing miR-exon4. However, the factors that regulate the splicing of exon4 are not well understood. This study aimed to investigate the association between known mutations in exon4 and exon5 of X chromosome amelogenin that causes X-linked AI, the splicing of exon4, and miR-exon4 formation. Our results showed mutations in exon4 and exon5 of the amelogenin gene, including c.120T>C, c.152C>T, c.155C>G, and c.155delC, significantly affected the splicing of exon4 and subsequent miR-exon4 production. Using an amelogenin minigene transfected in HEK-293 cells, we observed increased inclusion of exon4 in amelogenin mRNA and reduced miR-exon4 production with these mutations. In silico analysis predicted that Ser/Arg-rich RNA splicing factor (SRSF) 2 and SRSF5 were the regulatory factors for exon4 and exon5 splicing, respectively. Electrophoretic mobility shift assay confirmed that SRSF2 binds to exon4 and SRSF5 binds to exon5, and mutations in each exon can alter SRSF binding. Transfection of the amelogenin minigene to LS8 ameloblastic cells suppressed expression of the known miR-exon4 direct targets, and , related to multiple pathways. Given the mutations on the minigene, the expression of has been significantly upregulated with c.155C>G and c.155delC mutations. Together, we confirmed that exon4 splicing is critical for miR-exon4 production, and mutations causing X-linked AI in exon4 and exon5 significantly affect exon4 splicing and following miR-exon4 production. The change in miR-exon4 would be an additional etiology of enamel defects seen in some X-linked AI.
Topics: Humans; Amelogenin; Amelogenesis Imperfecta; HEK293 Cells; Mutation; Dental Enamel Proteins; MicroRNAs; RNA, Messenger
PubMed: 37563801
DOI: 10.1177/00220345231180572 -
Journal of Dental Research Aug 2023Tooth enamel is generated by ameloblasts. Any failure in amelogenesis results in defects in the enamel, a condition known as amelogenesis imperfecta. Here, we report...
Tooth enamel is generated by ameloblasts. Any failure in amelogenesis results in defects in the enamel, a condition known as amelogenesis imperfecta. Here, we report that mice with deficient autophagy in epithelial-derived tissues ( and conditional knockout mice) exhibit amelogenesis imperfecta. Micro-computed tomography imaging confirmed that enamel density and thickness were significantly reduced in the teeth of these mice. At the molecular level, ameloblast differentiation was compromised through ectopic accumulation and activation of NRF2, a specific substrate of autophagy. Through bioinformatic analyses, we identified , , , , , and as candidate genes related to amelogenesis imperfecta and the NRF2-mediated pathway. To investigate the effects of the ectopic NRF2 pathway activation caused by the autophagy deficiency, we analyzed target gene expression and NRF2 binding to the promoter region of candidate target genes and found suppressed gene expression of , , , and but not of and . Taken together, our findings indicate that autophagy plays a crucial role in ameloblast differentiation and that its failure results in amelogenesis imperfecta through ectopic NRF2 activation.
Topics: Mice; Animals; Ameloblasts; Amelogenesis Imperfecta; X-Ray Microtomography; NF-E2-Related Factor 2; Amelogenesis; Mice, Knockout; Tumor Suppressor Proteins; Repressor Proteins
PubMed: 37249312
DOI: 10.1177/00220345231169220 -
Journal of Pediatric Ophthalmology and... 2024To report two new cases with confirmed diagnosis of Heimler syndrome and describe their systemic and ophthalmic phenotype and visual rehabilitation. (Review)
Review
PURPOSE
To report two new cases with confirmed diagnosis of Heimler syndrome and describe their systemic and ophthalmic phenotype and visual rehabilitation.
METHODS
Retrospective review of medical records.
RESULTS
Both siblings were diagnosed as having sensori-neural hearing loss and retinal dystrophy with exuberant intraretinal cystoid spaces and cone-rod dysfunction. The older sibling also had amelogenesis imperfecta and neither had nail abnormalities. Genetic analysis identified homozygosity for the pathogenic variant c.2528G>A p.(Gly843Asp) in the gene in both siblings. The parents were heterozygous carriers of the variant.
CONCLUSIONS
The authors report a familial case of Heimler syndrome due to biallelic pathogenic variants that manifested as macular dystrophy characterized by cone-rod dysfunction and complicated by intraretinal cystoid spaces. Review of the literature shows that ocular phenotype is variable in patients with Heimler syndrome. .
Topics: Humans; Amelogenesis Imperfecta; Mutation; Siblings; Nails, Malformed; Phenotype; Eye Abnormalities; Pedigree; ATPases Associated with Diverse Cellular Activities; Membrane Proteins; Hearing Loss, Sensorineural
PubMed: 37092661
DOI: 10.3928/01913913-20230220-01 -
Oral Diseases Nov 2023Amelogenesis imperfecta (AI) is defined as inherited enamel malformations. LAMA3 (laminin alpha-3) encodes a critical protein component of the basement membrane...
OBJECTIVE
Amelogenesis imperfecta (AI) is defined as inherited enamel malformations. LAMA3 (laminin alpha-3) encodes a critical protein component of the basement membrane (laminin-332). Individuals carrying heterozygous LAMA3 mutations have previously been shown to have localized enamel defects. This study aimed to define clinical phenotypes and to discern the genetic etiology for four AI kindreds.
MATERIALS AND METHODS
Whole-exome analyses were conducted to search for sequence variants associated with the disorder, and micro-computed tomography (μCT) to characterize the enamel defects.
RESULTS
The predominant enamel phenotype was generalized thin enamel with defective pits and grooves. Horizonal bands of hypoplastic enamel with chalky-white discoloration and enamel hypomineralization were also observed and demonstrated by μCT analyses of affected teeth. Four disease-causing LAMA3 mutations (NM_198129.4:c.3712dup; c.5891dup; c.7367del; c.9400G > C) were identified. Compound heterozygous MMP20 mutations (NM_004771.4:c.539A > G; c.692C > T) were also found in one proband with more severe enamel defects, suggesting a mutational synergism on disease phenotypes. Further analyses of the AI-causing mutations suggested that both α3A (short) and α3B (long) isoforms of LAMA3 are essential for enamel formation.
CONCLUSIONS
Heterozygous LAMA3 mutations can cause generalized enamel defects (AI1A) with variable expressivity. Laminin-332 is critical not only for appositional growth but also enamel maturation.
Topics: Humans; Amelogenesis Imperfecta; Laminin; X-Ray Microtomography; Dental Enamel; Extracellular Matrix Proteins; Mutation; Phenotype; Biological Variation, Population; Pedigree
PubMed: 36326426
DOI: 10.1111/odi.14425 -
Zeitschrift Fur Orthopadie Und... Aug 2023Die akute arterielle Embolie ist eine seltene, aber schwerwiegende Komplikation nach einer Knie-Totalendoprothese (Knie-TEP). Es besteht ein allgemeiner Konsens...
Die akute arterielle Embolie ist eine seltene, aber schwerwiegende Komplikation nach einer Knie-Totalendoprothese (Knie-TEP). Es besteht ein allgemeiner Konsens darüber, dass in dieser Situation sofort eine Revaskularisation durchgeführt werden muss, aber die spezifische Behandlung ist immer noch umstritten. Wir berichten über zwei Fälle von Embolien der Kniekehlenarterie, die durch eine akute arterielle Thrombose nach Knie-TEP verursacht wurden. Bei beiden Patienten kam es nach der Operation zu einem Gefühls- und Bewegungsverlust der rechten unteren Extremität und einer Pulsationsschwächung der Arteria dorsalis pedis; eine Angiografie zeigte eine Embolie der Arteria poplitea. Einer der Patienten erhielt eine Thrombolysetherapie, entwickelte jedoch eine großflächige Infektion und Nekrose des rechten Wadenmuskels und benötigte nach erfolgreicher Thrombolyse ein mehrfaches Debridement und Hauttransplantationen. Bei dem anderen Patienten wurde eine Thrombektomie, eine Gefäßrekonstruktion und eine prophylaktische Fasziotomie durchgeführt; nach der Operation blieben ein Taubheitsgefühl im Fuß und eine leichte Streckschwäche zurück. Die Autoren empfehlen Chirurgen, Hochrisikopatienten mit Knie-TEP eine angemessene Aufmerksamkeit zu widmen. Vor der Operation sind eine sorgfältige Anamnese und körperliche Untersuchung erforderlich. Der chirurgische Eingriff sollte präzise und schonend durchgeführt werden, nach der Operation sind das Gefühl der Gliedmaßen und die Blutzirkulation aufmerksam zu beobachten. Bei abnormalem Fußgefühl und schwacher arterieller Pulsation sollten umgehend erforderliche Untersuchungen (Doppler-Ultraschall und Arteriografie) durchgeführt werden. Wenn eine arterielle Thrombose diagnostiziert wurde, muss die Blutversorgung sofort wiederhergestellt werden. Verzögert sich die Diagnose um mehr als 6 Stunden, kann eine prophylaktische Fasziotomie erforderlich sein, um nachteilige Folgen zu vermeiden.
Topics: Animals; Mice; Amelogenesis Imperfecta; Thrombosis
PubMed: 35158392
DOI: 10.1055/a-1714-9483