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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 -
Head & Face Medicine Jun 2024Amelogenesis imperfecta (AI) is a genetically determined, non-syndromic enamel dysplasia that may manifest as hypoplasia, hypomaturation, or hypocalcification and can...
INTRODUCTION
Amelogenesis imperfecta (AI) is a genetically determined, non-syndromic enamel dysplasia that may manifest as hypoplasia, hypomaturation, or hypocalcification and can commonly be classified into four primary groups. In this retrospective analysis, specific orofacial characteristics are described and associated with each of the AI types based on a patient cohort from Witten/Herdecke University, Germany.
METHODS
Data from 19 patients (ten male and nine female, mean age 12.27 ± 4.06 years) with AI who presented at the Department of Orthodontics between July 2011 and December 2023 were analyzed. Baseline skeletal and dental conditions were assessed, including the presence of hypodontia, displacements, and taurodontism. AI was classified into classes I-IV based on phenotype. Treatment needs were evaluated according to the main findings following the German KIG classification, while the radiological enamel situation was determined using panoramic radiographs.
RESULTS
An approximately equal distribution between classes II and III was found and a slight inclination toward a dolichofacial configuration (ΔML-NSL: 5.07 ± 9.23°, ΔML-NL: 4.24 ± 8.04°). Regarding orthodontic findings, disturbance in tooth eruption as well as open bite were the most prevalent issues (both 36.8%, n = 7). The most common AI classes were type I and II, which show an almost even distribution about the skeletal classes in sagittal dimension, while dolichofacial configuration was found most frequently in vertical dimension.
CONCLUSION
Both clinical and radiological orthodontic findings in context with AI are subject to extensive distribution. It seems that no specific orofacial findings can be confirmed in association with AI with regard to the common simple classes I-IV. It may be more appropriate to differentiate the many subtypes according to their genetic aspects to identify possible associated orthodontic findings.
Topics: Humans; Amelogenesis Imperfecta; Male; Female; Retrospective Studies; Child; Adolescent; Germany; Radiography, Panoramic; Orthodontics, Corrective; Malocclusion
PubMed: 38877506
DOI: 10.1186/s13005-024-00436-y -
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 -
BMC Oral Health Nov 2023Amelogenesis imperfecta (AI) is a developmental enamel defect affecting the structure of enamel, esthetic appearance, and the tooth masticatory function. Gene mutations...
BACKGROUND
Amelogenesis imperfecta (AI) is a developmental enamel defect affecting the structure of enamel, esthetic appearance, and the tooth masticatory function. Gene mutations are reported to be relevant to AI. However, the mechanism underlying AI caused by different mutations is still unclear. This study aimed to reveal the molecular pathogenesis in AI families with 2 novel pre-mRNA splicing mutations.
METHODS
Two Chinese families with AI were recruited. Whole-exome sequencing and Sanger sequencing were performed to identify mutations in candidate genes. Minigene splicing assays were performed to analyze the mutation effects on mRNA splicing alteration. Furthermore, three-dimensional structures of mutant proteins were predicted by AlphaFold2 to evaluate the detrimental effect.
RESULTS
The affected enamel in family 1 was thin, rough, and stained, which was diagnosed as hypoplastic-hypomature AI. Genomic analysis revealed a novel splicing mutation (NM_001142.2: c.570 + 1G > A) in the intron 6 of amelogenin (AMELX) gene in family 1, resulting in a partial intron 6 retention effect. The proband in family 2 exhibited a typical hypoplastic AI, and the splicing mutation (NM_031889.2: c.123 + 4 A > G) in the intron 4 of enamelin (ENAM) gene was observed in the proband and her father. This mutation led to exon 4 skipping. The predicted structures showed that there were obvious differences in the mutation proteins compared with wild type, leading to impaired function of mutant proteins.
CONCLUSIONS
In this study, we identified two new splicing mutations in AMELX and ENAM genes, which cause hypoplastic-hypomature and hypoplastic AI, respectively. These results expand the spectrum of genes causing AI and broaden our understanding of molecular genetic pathology of enamel formation.
Topics: Humans; Female; Amelogenin; Amelogenesis Imperfecta; Dental Enamel Proteins; Mutation; Mutant Proteins; Extracellular Matrix Proteins
PubMed: 37985977
DOI: 10.1186/s12903-023-03508-8 -
International Journal of Molecular... Jun 2024mutations cause X-linked amelogenesis imperfecta (AI), known as AI types IE, IIB, and IIC in Witkop's classification, characterized by hypoplastic (reduced thickness)...
mutations cause X-linked amelogenesis imperfecta (AI), known as AI types IE, IIB, and IIC in Witkop's classification, characterized by hypoplastic (reduced thickness) and/or hypomaturation (reduced hardness) enamel defects. In this study, we conducted whole exome analyses to unravel the disease-causing mutations for six AI families. Splicing assays, immunoblotting, and quantitative RT-PCR were conducted to investigate the molecular and cellular effects of the mutations. Four pathogenic variants (NM_182680.1:c.2T>C; c.29T>C; c.77del; c.145-1G>A) and a whole gene deletion (NG_012494.2:g.307534_403773del) were identified. The affected individuals exhibited enamel malformations, ranging from thin, poorly mineralized enamel with a "snow-capped" appearance to severe hypoplastic defects with minimal enamel. The c.145-1G>A mutation caused a -1 frameshift (NP_001133.1:p.Val35Cysfs*5). Overexpression of c.2T>C and c.29T>C demonstrated that mutant amelogenin proteins failed to be secreted, causing elevated endoplasmic reticulum stress and potential cell apoptosis. This study reveals a genotype-phenotype relationship for -associated AI: While amorphic mutations, including large deletions and 5' truncations, of cause hypoplastic-hypomaturation enamel with snow-capped teeth (AI types IIB and IIC) due to a complete loss of gene function, neomorphic variants, including signal peptide defects and 3' truncations, lead to severe hypoplastic/aplastic enamel (AI type IE) probably caused by "toxic" cellular effects of the mutant proteins.
Topics: Amelogenesis Imperfecta; Humans; Amelogenin; Male; Female; Genetic Association Studies; Mutation; Pedigree; Phenotype; Child; Endoplasmic Reticulum Stress; Genotype; Exome Sequencing
PubMed: 38892321
DOI: 10.3390/ijms25116132 -
The Chinese Journal of Dental Research Mar 2024To investigate FAM20A gene variants and histological features of amelogenesis imperfecta and to further explore the functional impact of these variants.
OBJECTIVE
To investigate FAM20A gene variants and histological features of amelogenesis imperfecta and to further explore the functional impact of these variants.
METHODS
Whole-exome sequencing (WES) and Sanger sequencing were used to identify pathogenic gene variants in three Chinese families with amelogenesis imperfecta. Bioinformatics analysis, in vitro histological examinations and experiments were conducted to study the functional impact of gene variants, and the histological features of enamel, keratinised oral mucosa and dental follicle.
RESULTS
The authors identified two nonsense variants c. 406C > T (p.Arg136*) and c.826C > T (p.Arg176*) in a compound heterozygous state in family 1, two novel frameshift variants c.936dupC (p.Val313Argfs*67) and c.1483dupC (p.Leu495Profs*44) in a compound heterozygous state in family 2, and a novel homozygous frameshift variant c.530_531insGGTC (p.Ser178Valfs*21) in family 3. The enamel structure was abnormal, and psammomatoid calcifications were identified in both the gingival mucosa and dental follicle. The bioinformatics and subcellular localisation analyses indicated these variants to be pathogenic. The secondary and tertiary structure analysis speculated that these five variants would cause structural damage to FAM20A protein.
CONCLUSION
The present results broaden the variant spectrum and clinical and histological findings of diseases associated with FAM20A, and provide useful information for future genetic counselling and functional investigation.
Topics: Humans; Amelogenesis Imperfecta; Calcification, Physiologic; Computational Biology; Dental Enamel; Dental Enamel Proteins; East Asian People
PubMed: 38546520
DOI: 10.3290/j.cjdr.b5136761 -
Journal of Medical Case Reports Oct 2023Metabolic bone disease causes significant morbidity and mortality, especially when misdiagnosed. With genetic testing, multiple disease pathologies can be analyzed.
BACKGROUND
Metabolic bone disease causes significant morbidity and mortality, especially when misdiagnosed. With genetic testing, multiple disease pathologies can be analyzed.
CASE PRESENTATION
A 5-year and 9-month-old otherwise healthy Yemeni girl presented to her Yemen physician for evaluation of inward bending of her right knee and short stature. After extensive medical testing, she was given a diagnosis of hypophosphatemic rickets and growth hormone deficiency and started on treatment. Despite appropriate treatment, however, her condition continued to progress, prompting her family to pursue additional workup including genetic testing outside of Yemen. Genetic testing ultimately revealed a variation of unknown significance associated with amelogenesis imperfecta.
CONCLUSIONS
Hypophosphatemic rickets secondary to renal tubular acidosis was the working diagnosis. However, the patient's condition did not improve. Further genetic testing revealed a variation of unknown significance associated with amelogenesis imperfecta. We aim to present this case, provide an overview of the causes, and diagnostic metabolic bone health evaluation.
Topics: Female; Humans; Infant; Amelogenesis Imperfecta; Rickets, Hypophosphatemic; Acidosis, Renal Tubular; Diagnostic Errors
PubMed: 37858137
DOI: 10.1186/s13256-023-04164-w -
Cureus Dec 2023Odontogenic anomalies encompass deviations in dental morphology, orientation, or spatial positioning within the mandibular structures. This study probed the frequency of...
BACKGROUND
Odontogenic anomalies encompass deviations in dental morphology, orientation, or spatial positioning within the mandibular structures. This study probed the frequency of such dental malformations among orthodontic patients receiving treatment in Riyadh City, Saudi Arabia. Furthermore, the study sought to discern variations in the manifestation of these dental anomalies related to gender and nationality.
MATERIALS AND METHODS
A retrospective analysis was conducted on 384 panoramic radiographs belonging to orthodontic patients (comprising 222 males and 162 females) who sought treatment at orthodontic clinics of a privately owned university hospital in Riyadh City between 2017 and 2019. The patient records were scrutinized for various dental abnormalities, including but not limited to dilacerated teeth, supernumerary teeth, congenital absence of teeth, impactions, hyperdontia, hypodontia, taurodontism, tooth rotation, and amelogenesis imperfecta. The Chi-square test was employed to assess the correlation between the prevalence of dental anomalies and variables such as gender and nationality. A p-value of less than 0.05 was deemed statistically significant for all tests.
RESULTS
Among the assessed sample size of orthodontic patients, dental impactions emerged as the most prevalent dental anomaly, affecting 246 patients (64.1%). This was followed by the occurrence of supernumerary teeth in 31 patients (8.1%), hyperdontia in 29 patients (7.6%), and congenital absence of teeth in 28 patients (7.3%). Other less frequently observed dental irregularities included dilacerated teeth in 23 patients (6%), amelogenesis imperfecta in 12 patients (3.1%), taurodontism in 12 patients (3.1%), and tooth rotations in five patients (1.3%). A statistically significant gender-based disparity was observed, with dental impactions being more prevalent among males (n=154; 69.4%) than females (n=92; 56.8%). Conversely, supernumerary teeth were more prevalent among females (n=24; 14.8%) than males (n=7; 3.2%). No significant variation in the prevalence of dental anomalies was discernible across different nationalities.
CONCLUSION
Impactions and the presence of supernumerary teeth were the predominant dental anomalies detected among the studied orthodontic patient population. The prevalence of dental anomalies exhibited discernible variations based on gender but not nationality. These disparities could potentially influence orthodontic outcomes, underscoring the necessity for meticulous examination and tailored orthodontic treatment planning.
PubMed: 38174162
DOI: 10.7759/cureus.49893 -
Orphanet Journal of Rare Diseases Nov 2023Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis is a rare, autosomal recessive, skeletal disorder first described in 2018. This syndrome... (Review)
Review
Identification of novel homozygous nonsense SLC10A7 variant causing short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis and surgical management of spine.
BACKGROUND
Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis is a rare, autosomal recessive, skeletal disorder first described in 2018. This syndrome starts with pre- and postnatal developmental delay, and gradually presents with variable facial dysmorphisms, a short stature, amelogenesis imperfecta, and progressive skeletal dysplasia affecting the limbs, joints, hands, feet, and spine.
CASE PRESENTATION
We identified a homozygous novel nonsense mutation in exon 1 of SLC10A7 (NM_001300842.2: c.100G > T / p.Gly34*) segregating with the typical disease phenotype in a Han Chinese family. We reviewed the 12-year surgical treatment history with seven interventions on spine.
CONCLUSION
To date, only 12 cases of the SLC10A7 mutation have been reported, mainly from consanguineous families. Our patient showed a relatively severe and broad clinical phenotype compared with previously reported cases. In this patient, annual check-ups and timely surgeries led to a good outcome.
Topics: Humans; Amelogenesis Imperfecta; Dwarfism; Homozygote; Mutation; Osteochondrodysplasias; Pedigree; Scoliosis
PubMed: 38037133
DOI: 10.1186/s13023-023-02975-0