Orthodontic management of amelogenesis imperfecta: A case report.

Key Clinical Message: Amelogenesis imperfecta (AI) is a rare developmental anomaly characterized by poorly developed or absent tooth enamel, which complicates orthodontic treatment due to weak enamel-bracket bond strength. This case report presents a successful management of AI using fixed orthodontic appliances and prosthodontic rehabilitation. Abstract: Amelogenesis imperfecta (AI) causes enamel defects, complicating oral hygiene, reducing masticatory function and lowering self-esteem. This case report details an 18-year-old female with AI who underwent fixed orthodontic treatment followed by prosthodontic rehabilitation. The multidisciplinary approach restored function and aesthetics, significantly improving her quality of life.

Clinical characteristics and genetic profile of children with WDR72-associated distal renal tubular acidosis: a nationwide experience.

BACKGROUND: Limited data, primarily from small case series, exist regarding the clinical profile, genetic variants, and outcomes of WDR72-associated distal renal tubular acidosis (WDR72-dRTA). METHODS: Our study enrolled children diagnosed with WDR72-dRTA below 18 years of age from 9 Indian centers and analyzed their clinical characteristics, genetic profiles, and outcomes. Potential genotype-phenotype correlations were explored. RESULTS: We report 22 patients (59% female) with WDR72-dRTA who were diagnosed at a median age of 5.3 (3, 8) years with polyuria (n = 17; 77.3%), poor growth (16; 72.7%), and rickets (9; 40.9%). Amelogenesis imperfecta was present in 21 (95.5%) cases. At presentation, all patients had normal anion gap metabolic acidosis; hypokalemia and nephrocalcinosis were seen in 17 (77.3%) patients each. Seven (31.8%) patients had concomitant proximal tubular dysfunction. Genetic analysis identified biallelic nonsense variants in 18 (81.8%) patients, including novel variants in 6 cases. A previously reported variant, c.88C > T, and a novel variant, c.655C > T, were the most frequent variants, accounting for 10 (45.5%) cases. Over a median follow-up of 1.3 (1, 8) years, the height velocity improved by 0.74 (0.2, 1.2) standard deviation scores, while 3 children (13.6%) progressed to chronic kidney disease (CKD) stage 2, with eGFR ranging from 67 to 76 mL/min/1.73 m2, respectively, after 11.3-16 years of follow-up. No specific genotype-phenotype correlation could be established. CONCLUSIONS: WDR72-dRTA should be considered in children with typical features of amelogenesis imperfecta and dRTA. Biallelic nonsense variants are common in Asians. While most patients respond well to treatment with improved growth and preserved eGFR, on long-term follow-up, a decline in eGFR may occur.

Mini-implant assisted palate expansion and digital design in junctional epidermolysis bullosa and amelogenesis imperfecta: Case report.

BACKGROUND: Junctional epidermolysis bullosa (JEB) is one of the four major types of EB caused by genetic variants in the genes coding the proteins of the lamina lucida. All patients with this major type of EB present syndromic hypoplastic amelogenesis imperfecta (AI), with either a pits and fissures or generalized hypoplastic phenotype. Severe forms of AI are associated with compromised oral health-related quality of life (QoL) mostly due to poor dental aesthetics, dentofacial anomalies, and oral pain. AIM: To present the comprehensive dental treatment of a patient with JEB and AI from the age of 20 months until the age of 18 years, including complex orthodontics and digital oral rehabilitation. MATERIALS AND METHODS: A male patient with intermediate JEB (homozygous c.3228+1G>A LAMB3 variant) has been under the care of the special care dentistry clinic of the University of Chile since the age of 20 months. His complex dental needs include structural enamel abnormalities in primary and permanent dentition (hypoplastic generalized AI), severe dental crowding with maxillary compression, Class III skeletal pattern, agenesia (#45), and gingivitis. RESULTS: Pediatric dental care included oral hygiene education and preventive strategies (prophylaxis and fluoride applications), maintaining the dentition free of caries. Due to AI, severe tooth sensitivity hindered proper oral hygiene and required early rehabilitation with temporary polycarbonate and metallic crowns. At the age of 16, the patient began orthodontic treatment. A maxillary expansion was performed with two consecutive mini-implant assisted rapid palate expansion (MARPE) bonded to four mini-implants in the palate. After finishing orthodontic treatment metallic multibrackets (duration 19 months), a definitive oral rehabilitation based on digital smile design with feldspathic crowns of all anterior teeth and premolars was performed. CONCLUSION: Patients with severe generalized hypoplastic syndromic AI associated with JEB benefit from long-term preventive oral care. Complex orthodontic techniques, such as MARPE, and multibrackets can be successfully. Digital smile design provides a definitive oral rehabilitation technique improving oral function, aesthetics, and QoL.

Roles of the histone methyltransferase SET domain bifurcated 1 in epithelial cells during tooth development.

OBJECTIVE: This study aimed to reveal the effects of SET domain bifurcated 1 (SETDB1) on epithelial cells during tooth development. DESIGN: We generated conditional knockout mice (Setdb1fl/fl,Keratin14-Cre+ mice), in which Setdb1 was deleted only in epithelial cells. At embryonic day 14.5 (E14.5), immunofluorescence staining was performed to confirm the absence of SETDB1 within the epithelium of tooth embryos from Setdb1fl/fl,Keratin14-Cre+ mice. Mouse embryos were harvested after reaching embryonic day 13.5 (E13.5), and sections were prepared for histological analysis. To observe tooth morphology in detail, electron microscopy and micro-CT analysis were performed at postnatal months 1 (P1M) and 6 (P6M). Tooth embryos were harvested from postnatal day 7 (P7) mice, and the epithelial components of the tooth embryos were isolated and examined using quantitative RT-PCR for the expression of genes involved in tooth development. RESULTS: Setdb1fl/fl,Keratin14-Cre+ mice exhibited enamel hypoplasia, brittle and fragile dentition, and significant abrasion. Coronal sections displayed abnormal ameloblast development, including immature polarization, and a thin enamel layer that detached from the dentinoenamel junction at P7. Electron microscopic analysis revealed characteristic findings such as an uneven surface and the absence of an enamel prism. The expression of Msx2, Amelogenin (Amelx), Ameloblastin (Ambn), and Enamelin (Enam) was significantly downregulated in the epithelial components of tooth germs in Setdb1fl/fl,Keratin14-Cre+ mice. CONCLUSIONS: These results indicate that SETDB1 in epithelial cells is important for tooth development and clarify the relationship between the epigenetic regulation of SETDB1 and amelogenesis imperfecta for the first time.

A novel mutation in GPR68 causes hypomaturation amelogenesis imperfecta.

OBJECTIVES: To identify the genetic cause of a Chinese family with hypomaturation amelogenesis imperfecta (AI) and to characterize the structure of GPR68 mutated enamel in order to develop a deeper understanding of the role of the GPR68 protein during the intricate process of amelogenesis. DESIGN: One Chinese family with generalized hypomaturation AI was recruited. Two of the third molars from the proband were subjected to scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX). Whole exome sequencing (WES) was performed, and the identified mutation was confirmed by Sanger sequencing. Bioinformatics studies were further conducted to analyze the potential deleterious effects of the mutation. RESULTS: The proband presented with a hypomaturation AI phenotype, characterized by fragile and discolored enamel surface. The AI enamel showed prismatic structure, which was sporadically obscured by areas of amorphous material and porous structure. EDX analysis showed the proband's enamel demonstrated a significant decrease in calcium and phosphorus content and a significant increase in oxygen compared with normal enamel. A novel homozygous mutation of G protein-coupled receptor 68 (GPR68) (c .149 T > A, p.Ile50Asn) was identified in the proband. Bioinformatics analysis indicated that the mutation site displayed a high level of evolutionary conservation among species, and the mutation might impact the stability and conformation of the protein. CONCLUSION: The novel homozygous GPR68 mutation resulted in hypomaturation AI. We first described the effect of GPR68 mutation on enamel structure. Our results provide new genetic evidence that mutations involved in GPR68 contribute to hypomaturation AI.

Role of amelogenin phosphorylation in regulating dental enamel formation.

Amelogenin (AMELX), the predominant matrix protein in enamel formation, contains a singular phosphorylation site at Serine 16 (S16) that greatly enhances AMELX's capacity to stabilize amorphous calcium phosphate (ACP) and inhibit its transformation to apatitic enamel crystals. To explore the potential role of AMELX phosphorylation in vivo, we developed a knock-in (KI) mouse model in which AMELX phosphorylation is prevented by substituting S16 with Ala (A). As anticipated, AMELXS16A KI mice displayed a severe phenotype characterized by weak hypoplastic enamel, absence of enamel rods, extensive ectopic calcifications, a greater rate of ACP transformation to apatitic crystals, and progressive cell pathology in enamel-forming cells (ameloblasts). In the present investigation, our focus was on understanding the mechanisms of action of phosphorylated AMELX in amelogenesis. We have hypothesized that the absence of AMELX phosphorylation would result in a loss of controlled mineralization during the secretory stage of amelogenesis, leading to an enhanced rate of enamel mineralization that causes enamel acidification due to excessive proton release. To test these hypotheses, we employed microcomputed tomography (µCT), colorimetric pH assessment, and Fourier Transform Infrared (FTIR) microspectroscopy of apical portions of mandibular incisors from 8-week old wildtype (WT) and KI mice. As hypothesized, µCT analyses demonstrated significantly higher rates of enamel mineral densification in KI mice during the secretory stage compared to the WT. Despite a greater rate of enamel densification, maximal KI enamel thickness increased at a significantly lower rate than that of the WT during the secretory stage of amelogenesis, reaching a thickness in mid-maturation that is approximately half that of the WT. pH assessments revealed a lower pH in secretory enamel in KI compared to WT mice, as hypothesized. FTIR findings further demonstrated that KI enamel is comprised of significantly greater amounts of acid phosphate compared to the WT, consistent with our pH assessments. Furthermore, FTIR microspectroscopy indicated a significantly higher mineral-to-organic ratio in KI enamel, as supported by µCT findings. Collectively, our current findings demonstrate that phosphorylated AMELX plays crucial mechanistic roles in regulating the rate of enamel mineral formation, and in maintaining physico-chemical homeostasis and the enamel growth pattern during early stages of amelogenesis.

[Total rehabilitation in case of amelogenesis imperfecta].

The aim of the treatment of this case was to restore the form, function and aesthetics of all teeth in a patient with amelogenesis imperfecta within the age limit of the disability insurance (IV). Single-tooth zirconia crowns were selected as the treatment of choice and cemented with a conventional glass ionomer cement. For the maintenance of the oral rehabilitation and the protection of the reconstructions a michigan splint was produced and instructed to be carried over night.

Ameloblastin and its multifunctionality in amelogenesis: A review.

Extracellular matrix proteins play crucial roles in the formation of mineralized tissues like bone and teeth via multifunctional mechanisms. In tooth enamel, ameloblastin (Ambn) is one such multifunctional extracellular matrix protein implicated in cell signaling and polarity, cell adhesion to the developing enamel matrix, and stabilization of prismatic enamel morphology. To provide a perspective for Ambn structure and function, we begin this review by describing dental enamel and enamel formation (amelogenesis) followed by a description of enamel extracellular matrix. We then summarize the established domains and motifs in Ambn protein, human amelogenesis imperfecta cases, and genetically engineered mouse models involving mutated or null Ambn. We subsequently delineate in silico, in vitro, and in vivo evidence for the amphipathic helix in Ambn as a proposed cell-matrix adhesive and then more recent in vitro evidence for the multitargeting domain as the basis for dynamic interactions of Ambn with itself, amelogenin, and membranes. The multitargeting domain facilitates tuning between Ambn-membrane interactions and self/co-assembly and supports a likely overall role for Ambn as a matricellular protein. We anticipate that this review will enhance the understanding of multifunctional matrix proteins by consolidating diverse mechanisms through which Ambn contributes to enamel extracellular matrix mineralization.

Is Italian Dentists' Knowledge of Enamel Development Defects Adequate? A Nationwide Survey.

OBJECTIVES: Correct identification and management of Developmental Defects of Enamel (DDEs) are essential to provide the best possible treatment. The present survey aims to investigate Italian dentists' knowledge of DDEs, their ability to recognise the different clinical pictures, and to choose the most appropriate clinical approach. METHODS: A cross-sectional survey was planned based on a questionnaire including 27 closed-ended questions, and that proposed 4 clinical pictures, molar incisor hypomineralisation (MIH), amelogenesis imperfecta (AI), dental fluorosis (DF), and an initial caries lesion (ICL). It was distributed by e-mail to all Italian dentists (N = 63,883) through the Italian Federation of Doctors and Dentists. Discrete variables were expressed as absolute and relative frequencies (%). A multivariate analysis assessed whether socio-demographic variables correlated with the answers' truthfulness. RESULTS: About 5017 questionnaires were included and analysed. Although 90.19% of the sample stated that they had received information on DDEs, a significant percentage did not recognise MIH (36.36%), AI (48.34%), DF (71.50%), and ICL (46.62%). Only 57.07% correctly classified enamel hypomineralisation as a qualitative defect, and even fewer, 54.45%, classified enamel hypoplasia as a quantitative defect. According to the logistic regressions, female dentists, dentists who treat mainly children and received information about DDEs, were more likely to recognise the 4 clinical pictures (P < .01). CONCLUSIONS: Italian dentists showed many knowledge gaps on DDEs that need to be filled; those who received formal training were more capable of correctly identifying the defects and were more likely to prescribe an appropriate management approach for the defects. CLINICAL SIGNIFICANCE: Increasing university courses and continuing education on diagnosing and managing DDEs seems reasonable to fill the knowledge gap on DDEs.

From Pluripotent Stem Cells to Organoids and Bioprinting: Recent Advances in Dental Epithelium and Ameloblast Models to Study Tooth Biology and Regeneration.

Ameloblasts are the specialized dental epithelial cell type responsible for enamel formation. Following completion of enamel development in humans, ameloblasts are lost and biological repair or regeneration of enamel is not possible. In the past, in vitro models to study dental epithelium and ameloblast biology were limited to freshly isolated primary cells or immortalized cell lines, both with limited translational potential. In recent years, large strides have been made with the development of induced pluripotent stem cell and organoid models of this essential dental lineage - both enabling modeling of human dental epithelium. Upon induction with several different signaling factors (such as transforming growth factor and bone morphogenetic proteins) these models display elevated expression of ameloblast markers and enamel matrix proteins. The advent of 3D bioprinting, and its potential combination with these advanced cellular tools, is poised to revolutionize the field - and its potential for tissue engineering, regenerative and personalized medicine. As the advancements in these technologies are rapidly evolving, we evaluate the current state-of-the-art regarding in vitro cell culture models of dental epithelium and ameloblast lineage with a particular focus toward their applicability for translational tissue engineering and regenerative/personalized medicine.

In-depth investigation of FAM20A insufficiency effects on deciduous dental pulp cells: Altered behaviours, osteogenic differentiation, and inflammatory gene expression.

AIM: Loss-of-function mutations in FAM20A result in amelogenesis imperfecta IG (AI1G) or enamel-renal syndrome, characterized by hypoplastic enamel, ectopic calcification, and gingival hyperplasia, with some cases reporting spontaneous tooth infection. Despite previous reports on the consequence of FAM20A reduction in gingival fibroblasts and transcriptome analyses of AI1G pulp tissues, suggesting its involvement in mineralization and infection, its role in deciduous dental pulp cells (DDP) remains unreported. The aim of this study was to evaluate the properties of DDP obtained from an AI1G patient, providing additional insights into the effects of FAM20A on the mineralization of DDP. METHODOLOGY: DDP were obtained from a FAM20A-AI1G patient (mutant cells) and three healthy individuals. Cellular behaviours were examined using flow cytometry, MTT, attachment and spreading, colony formation, and wound healing assays. Osteogenic induction was applied to DDP, followed by alizarin red S staining to assess their osteogenic differentiation. The expression of FAM20A-related genes, osteogenic genes, and inflammatory genes was analysed using real-time PCR, Western blot, and/or immunolocalization. Additionally, STRING analysis was performed to predict potential protein-protein interaction networks. RESULTS: The mutant cells exhibited a significant reduction in FAM20A mRNA and protein levels, as well as proliferation, migration, attachment, and colony formation. However, normal FAM20A subcellular localization was maintained. Additionally, osteogenic/odontogenic genes, OSX, OPN, RUNX2, BSP, and DSPP, were downregulated, along with upregulated ALP. STRING analysis suggested a potential correlation between FAM20A and these osteogenic genes. After osteogenic induction, the mutant cells demonstrated reduced mineral deposition and dysregulated expression of osteogenic genes. Remarkably, FAM20A, FAM20C, RUNX2, OPN, and OSX were significantly upregulated in the mutant cells, whilst ALP, and OCN was downregulated. Furthermore, the mutant cells exhibited a significant increase in inflammatory gene expression, that is, IL-1ß and TGF-ß1, whereas IL-6 and NFκB1 expression was significantly reduced. CONCLUSION: The reduction of FAM20A in mutant DDP is associated with various cellular deficiencies, including delayed proliferation, attachment, spreading, and migration as well as altered osteogenic and inflammatory responses. These findings provide novel insights into the biology of FAM20A in dental pulp cells and shed light on the molecular mechanisms underlying AI1G pathology.

Interdisciplinary full mouth rehabilitation of a patient with amelogenesis imperfecta from childhood to young adult-hood: A 12-year case report.

Treatment of patients with amelogenesis imperfecta extends over many years, from childhood to early adulthood. Their management at any age is complex and has to be adapted in relation to therapies validated in the general population.

Navigating Complexity: A Case Report on a Comprehensive Dental Management Approach to Amelogenesis Imperfecta and Gingival Fibromatosis Syndrome.

This clinical case report details the comprehensive diagnosis and dental management of a seven-year-old female patient diagnosed with the rare genetic disorder, amelogenesis imperfecta and gingival fibromatosis syndrome (AIGFS). The case initially presented as congenital adrenal hyperplasia and amelogenesis imperfecta, but further genetic analysis revealed the involvement of AIGFS due to a mutation in the FAM20A gene. Diagnosis, confirmed through whole exome sequencing, clinical assessment, and laboratory tests, necessitated a multidisciplinary approach to address the treatment of such cases. The article underscores the critical importance of diagnosing and managing dental manifestations in pediatric patients with complex genetic conditions, highlighting the difficulties of treating AIGFS in mixed dentition. This case also highlights the indispensable role of pediatric dentists in diagnosing and treating these cases, ultimately improving the quality of life for individuals with AIGFS.

FAM20A-Associated Amelogenesis Imperfecta: Gene Variants with Functional Verification and Histological Features.

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.

Establishment of a clinical network for children with amelogenesis imperfecta and dentinogenesis imperfecta in the UK: 4-year experience.

BACKGROUND: Amelogenesis imperfecta (AI) and dentinogenesis imperfecta (DI) are two groups of genetically inherited conditions resulting in abnormal enamel and dentin formation, respectively. Children and young people may be adversely affected by these conditions, with significant reduction in oral health related quality of life. Dental management of children with AI and DI is often complex, which is exacerbated by the absence of clear referral pathways and scarce evidence-based guidelines. METHOD: The need for increased knowledge and peer support led to the development of a group of UK paediatric dentists with a special clinical interest in the management of children with AI and DI. PURPOSE: The aims of this paper are to describe the establishment of an AI/DI Clinical Excellence Network (AI/DI CEN) in paediatric dentistry including outputs and future plans, and to share our collective learning to help support others anywhere in the world advance the care of people with AI or DI.

Prosthodontic rehabilitation of two siblings with hypoplastic (type 1) amelogenesis imperfecta: A case report.

Amelogenesis imperfecta is a rare genetic disorder that interferes with normal enamel formation. Of the 4 main types of amelogenesis imperfecta, hypoplastic (type 1) is the most prevalent, characterized by a quantitative alteration in enamel. The pitting or reduced thickness of the enamel results in generalized hypersensitivity, increased susceptibility to caries and infection, attrition, and a loss in vertical dimension of occlusion. Prosthodontic management of these patients can be challenging not only functionally and restoratively, but also from an emotional and psychosocial standpoint. This clinical report describes the prosthodontic management and rehabilitation of two young adult siblings with hypoplastic (type 1) amelogenesis imperfecta.

Brachyolmia, dental anomalies and short stature (DASS): Phenotype and genotype analyses of Egyptian and Pakistani patients.

Brachyolmia is a heterogeneous group of developmental disorders characterized by a short trunk, short stature, scoliosis, and generalized platyspondyly without significant deformities in the long bones. DASS (Dental Abnormalities and Short Stature), caused by alterations in the LTBP3 gene, was previously considered as a subtype of brachyolmia. The present study investigated three unrelated consanguineous families (A, B, C) with Brachyolmia and DASS from Egypt and Pakistan. In our Egyptian patients, we also observed hearing impairment. Exome sequencing was performed to determine the genetic causes of the diverse clinical conditions in the patients. Exome sequencing identified a novel homozygous splice acceptor site variant (LTBP3:c.3629-1G > T; p. ?) responsible for DASS phenotypes and a known homozygous missense variant (CABP2: c.590T > C; p.Ile197Thr) causing hearing impairment in the Egyptian patients. In addition, two previously reported homozygous frameshift variants (LTBP3:c.132delG; p.Pro45Argfs*25) and (LTBP3:c.2216delG; p.Gly739Alafs*7) were identified in Pakistani patients. This study emphasizes the vital role of LTBP3 in the axial skeleton and tooth morphogenesis and expands the mutational spectrum of LTBP3. We are reporting LTBP3 variants in seven patients of three families, majorly causing brachyolmia with dental and cardiac anomalies. Skeletal assessment documented short webbed neck, broad chest, evidences of mild long bones involvement, short distal phalanges, pes planus and osteopenic bone texture as additional associated findings expanding the clinical phenotype of DASS. The current study reveals that the hearing impairment phenotype in Egyptian patients of family A has a separate transmission mechanism independent of LTBP3.

Epileptic encephalopathy and amelogenesis imperfecta: What about KohlschüttereTönz syndrome? Case report and literature review.

BACKGROUND: KohlschüttereTönz syndrome (KTS), also called amelo-cerebro-hypohidrotic syndrome, is a very rare genetic condition, described for the first time by Kohlschutter, which typically manifests as a triad of symptoms:  amelogenesis imperfecta, infantile onset epilepsy, and intellectual disability. 47 cases were reported in English language literature since 1974-2021. CASE REPORT: A 7-year-old girl was referred for dental evaluation. Oral examination revealed yellowish color of all the teeth due to enamel hypoplasia. The radiographic exam revealed a thin layer of enamel with decreased radiopacity of the enamel compared to that of dentin. The diagnosis of amelogenesis Imperfecta was established. In addition to that, the child's parents reported that she had spasticity, epileptic seizures and psychomotor developmental delay. The association of all these features leads us to conclude to KTS. CONCLUSION: It seems that numerous cases of KTS are still undiagnosed in the world, so this paper highlights the common clinical features of Kohlschütter-Tönz Syndrome helping to an early diagnosis and more research about this condition.

Digenic inheritance accounts for phenotypic variability in amelogenesis imperfecta.

Amelogenesis imperfecta (AI) represents a group of clinically and genetically heterogeneous disorders that affect enamel formation and mineralization. Although AI is commonly considered a monogenic disorder, digenic inheritance is rarely reported. In this study, we recruited two nonconsanguineous Chinese families exhibiting diverse phenotypes of enamel defects among affected family members. Digenic variants were discovered in both probands. In family 1, the proband inherited a paternal frameshift variant in LAMA3 (NM_198129.4:c.3712dup) and a maternal deletion encompassing the entire AMELX gene. This resulted in a combined hypoplastic and hypomineralized AI phenotype, which was distinct from the parents' manifestations. In family 2, whole-exome sequencing analysis revealed the proband carried a maternal heterozygous splicing variant in COL17A1 (NC_000010.11 (NM_000494.3): c.4156 + 2dup) and compound heterozygous variants in RELT (paternal: NM_032871.4:c.260A > T; maternal: NM_032871.4:c.521 T > G). These genetic changes caused the abundant irregular enamel defects observed in the proband, whereas other affected family members carrying heterozygous variants in both COL17A1 and RELT displayed only horizontal grooves as their phenotype. The pathogenicity of the novel COL17A1 splice site variant was confirmed through RT-PCR and minigene assay. This study enhances our understanding by highlighting the potential association between the co-occurrence of variants in two genes and variable phenotypes observed in AI patients.