Two siblings with Heimler syndrome caused by PEX1 variants: follow-up of ophthalmologic findings.

BACKGROUND: Heimler syndrome (OMIM number #234580 and #616617) is a rare condition comprising sensorineural hearing loss (SNHL), nail abnormalities and amelogenesis imperfecta. In addition, patients with this syndrome can have retinal dystrophies. Heimler syndrome is caused by bi-allelic pathogenic variants in the PEX1 or PEX6 gene. Only few patients with this syndrome have been reported. We hereby describe two siblings with genetically confirmed Heimler syndrome and provide imaging of the ocular phenotype. MATERIALS AND METHODS: The medical records of the siblings were reviewed retrospectively. RESULTS: Both brother and sister were diagnosed with SNHL and amelogenesis imperfecta of the permanent teeth; one of the affected siblings also had nail abnormalities. Both patients presented to the ophthalmology department with suboptimal visual acuity, fundus abnormalities and intraretinal cystoid spaces. Full-field electroretinogram revealed a cone-rod dysfunction. A genetic analysis revealed a homozygous likely pathogenic variant c.3077 T > C (p.Leu1026Pro) in the PEX1 gene in both siblings. The parents are heterozygous carriers of the variant. CONCLUSION: We recommend performing regular ophthalmic examination in patients with Heimler syndrome since the ophthalmic manifestations can manifest later in life. Our patients presented with cone-rod dystrophy and intraretinal cystoid spaces. Review of the literature shows that the ocular phenotype can be very variable in patients with Heimler syndrome.

Heimler Syndrome.

Heimler syndrome is a rare syndrome associating sensorineural hearing loss with retinal dystrophy and amelogenesis imperfecta due to PEX1 or PEX6 biallelic pathogenic variations. This syndrome is one of the less severe forms of peroxisome biogenesis disorders. In this chapter, we will review clinical, biological, and genetic knowledges about the Heimler syndrome.

Co-occurrence of Jalili syndrome and muscular overgrowth.

Jalili syndrome is a rare disorder inherited in an autosomal recessive pattern manifesting as a combination of cone-rod dystrophy including progressive loss of visual acuity, color blindness, photophobia, and amelogenesis imperfecta with hypoplastic, immature, or hypocalcified dental enamel. It is caused by mutations in CNNM4, which encodes the ancient conserved domain protein 4. Here we report three brothers with Jalili syndrome and muscle overgrowth of the legs. Myopathic changes were found in needle electromyography. Mutational analysis showed in all three brothers a novel likely pathogenic homozygous missense substitution in exon 1 (c.1076T>C, p.(Leu359Pro)) of CNNM4. Both parents were carriers for the variant. In order to exclude other causative variants that could modify the patients' phenotype we performed exome sequencing and MLPA analysis of the DMD gene in Patient 1. These analyses did not identify any additional variants. Our results expand the mutational spectrum associated with Jalili syndrome and suggest that mild myopathy with muscle overgrowth of the legs could be a newly identified manifestation of the disorder.

Non lethal Raine syndrome and differential diagnosis.

Raine syndrome is a rare autosomal recessive bone dysplasia characterized by characteristic facial features with exophthalmos and generalized osteosclerosis. Amelogenesis imperfecta, hearing loss, seizures, and intracerebral calcification are apparent in some affected individuals. Originally, Raine syndrome was originally reported as a lethal syndrome. However, recently a milder phenotype, compatible with life, has been described. Biallelic variants inFAM20C, encoding aGolgi casein kinase involved in biomineralisation, have been identified in affected individuals. We report here a consanguineous Moroccan family with two affected siblingsa girl aged 18 and a boy of 15years. Clinical features, including learning disability, seizures and amelogenesis imperfecta, initially suggested a diagnosis of Kohlschutter-Tonz syndrome. However,a novel homozygous FAM20Cvariantc.676T > A, p.(Trp226Arg) was identified in the affected siblings. Our report reinforces that Raine syndrome is compatible with life, and that mild hypophosphatemia and amelogenesis imperfecta are key features of the attenuated form.

Deletion of amelotin exons 3-6 is associated with amelogenesis imperfecta.

Amelogenesis imperfecta (AI) is a heterogeneous group of genetic conditions that result in defective dental enamel formation. Amelotin (AMTN) is a secreted protein thought to act as a promoter of matrix mineralization in the final stage of enamel development, and is strongly expressed, almost exclusively, in maturation stage ameloblasts. Amtn overexpression and Amtn knockout mouse models have defective enamel with no other associated phenotypes, highlighting AMTN as an excellent candidate gene for human AI. However, no AMTN mutations have yet been associated with human AI. Using whole exome sequencing, we identified an 8,678 bp heterozygous genomic deletion encompassing exons 3-6 of AMTN in a Costa Rican family segregating dominant hypomineralised AI. The deletion corresponds to an in-frame deletion of 92 amino acids, shortening the protein from 209 to 117 residues. Exfoliated primary teeth from an affected family member had enamel that was of a lower mineral density compared to control enamel and exhibited structural defects at least some of which appeared to be associated with organic material as evidenced using elemental analysis. This study demonstrates for the first time that AMTN mutations cause non-syndromic human AI and explores the human phenotype, comparing it with that of mice with disrupted Amtn function.

Compositional, structural and mechanical comparisons of normal enamel and hypomaturation enamel.

Hypomaturation amelogenesis imperfecta is a hereditary disorder of the enamel that severely influences the function, aesthetics and psychosocial well-being of patients. In this study, we performed a thorough comparison of normal and hypomaturation enamel through a series of systematical tests on human permanent molars to understand the biomineralization process during pathological amelogenesis. The results of microcomputed tomography, scanning electron microscopy, Fourier transform infrared, Raman spectroscopy, microzone X-ray diffraction, thermal gravimetric analysis, energy diffraction spectrum and Vickers microhardness testing together show dramatic contrasts between hypomaturation enamel and normal enamel in terms of their hierarchical structures, spectral features, crystallographic characteristics, thermodynamic behavior, mineral distribution and mechanical property. Our current study highlights the importance of the organic matrix during the amelogenesis process. It is found that the retention of the organic matrix will influence the quantity, quality and distribution of mineral crystals, which will further demolish the hierarchical architecture of the enamel and affect the related mechanical property. In addition, the high carbonate content in hypomaturation enamel influences the crystallinity, crystal size and solubility of hydroxyapatite crystals. These results deepen our understanding of hypomaturation enamel biomineralization during amelogenesis, explain the clinical manifestations of hypomaturation enamel, provide fundamental evidence to help dentists choose optimal therapeutic strategies and lead to improved biofabrication and gene therapies.

Kohlschutter-Tonz syndrome: clinical and genetic insights gained from 16 cases deriving from a close-knit village in Northern Israel.

BACKGROUND: Kohlschutter-Tonz syndrome (KTS; MIM 22675) is a rare autosomal recessive disorder characterized by intellectual impairment, spasticity, epilepsy, and amelogenesis imperfecta. We have recently identified the causative gene and mutation underlying KTS, namely, p.R157X, corresponding to ROGDI c.571C>T, which creates a premature stop codon in ROGDI homolog (Drosophila), a gene of unknown function, in KTS patients of Druze origin. PATIENTS: To better delineate the phenotype of KTS, 16 cases (eight female, eight male), from seven families (five kindreds) originating from a Druze village in Northern Israel, all homozygous for the same deleterious mutation, were investigated. Medical records were reviewed, and a detailed medical history was obtained by interview of parents. RESULTS: Age at onset between six and 12 months of age and the intensity of convulsions were variably manifested by affected sibs and mirror the progression of mental and motor deterioration. Amelogenesis imperfecta and deficient speech occur in all cases. By late adolescence and early twenties, individuals with KTS are bedridden, fed by a gastrostomy tube, spastic, and practically have no cognitive and language perception. CONCLUSIONS: KTS, a genetic disease heralded by convulsions, "yellow teeth," and severe mental impairment, allows for a clinical variability as regarding age of onset and severity of seizures that per se predict the speed of mental deterioration. In all cases, however, the morbid course of the disease is ultimately equally devastating by the twenties.

The impact of amelogenesis imperfecta and support needs of adolescents with AI and their parents: an exploratory study.

BACKGROUND: Amelogenesis imperfecta (AI) is a rare inherited dental defect where enamel does not form properly on the teeth. Research has shown that adolescents with AI may experience adverse psychosocial effects; however the impact on parents has not been explored. AIMS: We aimed to explore: (1) experience and perceptions of AI from both the adolescent and their parent's perspective (2) their views on the usefulness of an online support group (OSG) for patients/parents and the potential salient functions of such a resource. DESIGN: We conducted two focus groups; one for adolescent AI patients and one for their parents. Transcripts were analysed using Thematic Analysis. RESULTS: Three themes emerged from the data: 'Living with AI: Do I look bothered?', 'Need for the 'right' online environment' and 'Support needs: Information and beyond'. CONCLUSIONS: The adolescents did not appear to experience adverse psychosocial effects of having AI, which was contrary to their parents' perceptions. Parents reported some adverse consequences of having a child with AI (e.g., practical challenges). If an OSG was to be developed, it would need to be primarily information based and moderated by an AI specialist. Parents may benefit from additional support beyond that of information, such as emotional and tangible support.

Does enamelin have pleiotropic effects on organs other than the teeth? Lessons from a phenotyping screen of two enamelin-mutant mouse lines.

We analyzed two mutant mouse lines, ATE1 and ATE2, that carry point mutations in the enamelin gene which result in premature stop codons in exon 8 and exon 7, respectively. Both mutant lines show amelogenesis imperfecta. To establish the effect of mutations within the enamelin gene on different organs, we performed a systematic, standardized phenotypic analysis of both mutant lines in the German Mouse Clinic. In addition to the initially characterized tooth phenotype that is present in both mutant lines, we detected effects of enamelin mutations on bone and energy metabolism, as well as on clinical chemical and hematological parameters. These data raise the hypothesis that enamelin defects have pleiotropic effects on organs other than the teeth.

Amelogenesis imperfecta: the orthodontic perspective.

Orthodontics in patients with amelogenesis imperfecta can be complicated by commonly occurring dental features in this group as well as patient factors. In this article we examine ways to avoid the common pitfalls of orthodontic management and the importance of adequate and timely liaison between the general dental practitioner and the multidisciplinary team.

The use of mouse models to investigate shear bond strength in amelogenesis imperfecta.

Patients with amelogenesis imperfecta (AI) have defective enamel; therefore, bonded restorations of patients with AI have variable success rates. To distinguish which cases of AI may have good clinical outcomes with bonded materials, we evaluated etching characteristics and bond strength of enamel in mouse models, comparing wild-type (WT) with those having mutations in amelogenin (Amelx) and matrix metalloproteinase-20 (Mmp20), which mimic 2 forms of human AI. Etched enamel surfaces were compared for roughness by scanning electron microscopy (SEM) images. Bonding was compared through shear bond strength (SBS) studies with 2 different systems (etch-and-rinse and self-etch). Etched enamel surfaces of incisors from Amelx knock-out (AmelxKO) mice appeared randomly organized and non-uniform compared with WT. Etching of Mmp20KO surfaces left little enamel, and the etching pattern was indistinguishable from unetched surfaces. SBS results were significantly different when AmelxKO and Mmp20KO enamel surfaces were compared. A significant increase in SBS was measured for all samples when the self-etch system was compared with the etch-and-rinse system. We have developed a novel system for testing shear bond strength of mouse incisors with AI variants, and analysis of these data may have important clinical implications for the treatment of patients with AI.

Defining a new candidate gene for amelogenesis imperfecta: from molecular genetics to biochemistry.

Amelogenesis imperfecta is a group of genetic conditions that affect the structure and clinical appearance of tooth enamel. The types (hypoplastic, hypocalcified, and hypomature) are correlated with defects in different stages of the process of enamel synthesis. Autosomal dominant, recessive, and X-linked types have been previously described. These disorders are considered clinically and genetically heterogeneous in etiology, involving a variety of genes, such as AMELX, ENAM, DLX3, FAM83H, MMP-20, KLK4, and WDR72. The mutations identified within these causal genes explain less than half of all cases of amelogenesis imperfecta. Most of the candidate and causal genes currently identified encode proteins involved in enamel synthesis. We think it is necessary to refocus the search for candidate genes using biochemical processes. This review provides theoretical evidence that the human SLC4A4 gene (sodium bicarbonate cotransporter) may be a new candidate gene.

Cone-rod dystrophy and amelogenesis imperfecta (Jalili syndrome): phenotypes and environs.

PURPOSE: To report a new phenotype with additional data on the oculo-dental syndrome of cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI) caused by mutations on CNNM4, a metal transporter, with linkage at achromatopsia locus 2q11 (Jalili syndrome). METHODS: Three siblings aged 5, 6, and 10 years from a six-generation Arab family in Gaza City underwent full systemic, ophthalmic, and dental examinations, investigations and detailed genealogy. RESULTS: Subjects presented at early childhood with visual impairment and abnormal dentition together with photophobia and fine nystagmus increasing under photopic conditions, in the presence of normal fundi. Electrophysiologically, photopic flicker responses were impaired; scotopic responses were extinguished at the age of 10 years. Anterior open bite accompanied AI in all siblings. The syndrome formed 83% of CRD cases in the Gaza Strip, which has a prevalence of 1 : 10,000. CONCLUSION: On the basis of clinical features and electrophysiology, two phenotypes exist: an infancy onset form with progressive macular lesion and an early childhood onset form with normal fundi. More prevalent than previously thought, Jalili syndrome presents a model of the effect of different mutations of the same genetic defect, observations of the same phenotype at different stages of the natural history of the disease, and the influence of epigenetic and tissue-specific factors as causes of phenotypic variability. The paper calls for action to tackle consanguinity in endogamous communities, addresses the possible role of high fluoride levels in groundwater as a trigger for genetic mutations, and the use of red-tinted filter in cone disorders.

Amelogenesis imperfecta: revisión / Amelogenesis imperfecta: a review

Con la denominación de Amelogénesis Imperfecta(AI) se define un grupo de enfermedades hereditarias heterogéneas clínica y genéticamente que se caracterizan por alteraciones del esmalte. También pueden observarse otras alteraciones orales y extraorales. La maloclusión más frecuente en estos pacientes es la mordida abierta. Algunos casos forman parte de un síndrome. Hasta el momento se han identificado mutaciones en cinco genes, AMELX, ENAM, KLK4, MMP20 yDLX3, que participan en la formación del esmalte normal, pero quedan otros por identificar. Los autores actualizan los conocimientos sobre la etiopatogenia, clasificación, manifestaciones clínicas, diagnóstico y tratamiento interdisciplinar de la AI (AU)

Amelogenesis imperfecta (AI) is a collective designation for a clinically and genetically diverse group of disorders displaying enamel malformations. Other oral and extraoral aberrations have been reported, and open bite is the most common malocclusion. Some cases present as a part of a syndrome. Mutations in five genes involved in normal enamel formation(AMELX, ENAM, MMP20, KLK4 and DLX3) have been identified as cause of amelogenesis imperfecta, but some others remain to be identified. This paper reviews current knowledge about etiopathogenesis, classification, clinical manifestations, diagnosis and interdisciplinary treatment of AI (AU)

Analysis of the COL17A1 in non-Herlitz junctional epidermolysis bullosa and amelogenesis imperfecta.

Non-Herlitz junctional epidermolysis bullosa (nH-JEB) disease manifests with skin blistering, atrophy and tooth enamel hypoplasia. The majority of patients with nH-JEB harbor mutations in COL17A1, the gene encoding type XVII collagen. Heterozygotes with a single COL17A1 mutation, nH-JEB defect carriers, may exhibit only enamel hypoplasia. In this study, to further elucidate COL17A1 mutation phenotype/ genotype correlations, we examined two unrelated families with nH-JEB. Furthermore, we hypothesized that COL17A1 mutations might underlie or worsen the enamel hypoplasia seen in amelogenesis imperfecta (AI) patients that are characterized by defects in tooth enamel formation without other systemic manifestations. We therefore conducted COL17A1 mutational analysis in three patients from two AI families. One nH-JEB patient showed no COL17A1 expression and was a compound heterozygote for the novel premature termination codon (PTC) mutations 1285delA and Q1387X. In addition, reduced COL17A1 expression was found in a second nH-JEB patient who was homozygous for the novel PTC mutation 4335delC, the most carboxyl terminal PTC mutation thus far identified. Due to nonsense mediated mRNA decay, the position of these PTC mutations is thought not to influence the effect of COL17A1 transcript loss and hence the severity of the nH-JEB phenotype. This study is the first to suggest that type XVII collagen carboxyl PTC mutations lead to restoration of truncated polypeptide expression and to a milder clinical disease severity in nH-JEB. Conversely, we failed to detect any pathogenic COL17A1 defects in AI patients, in either exon or within the intron-exon borders of AI patients. This study furthers the understanding of mutations in COL17A1 causing nH-JEB, and clearly demonstrates that the mechanism of enamel hypoplasia differs between nH-JEB and AI diseases.

Ameloclasia. La resorción del esmalte. Casos clínicos / Ameloclasia. Enamel resorption. Clinical cases

La ameloclasia en dientes definitivos erupcionados es un tema sujeto a controversia. Se analiza una serie de casos clínicos con historia, exploración, radiografía y fotografía. En uno de ellos se realizó además un TAC y en otro un análisis histopatológico y estudios con SEM, ESEM y EDS. Se han observado resorciones macroscópicas y microscópicas del esmalte tanto en dientes definitivos incluidos como en erupcionados. Se discuten y justifican los resultados obtenidos en el marco del fenómeno de la inflamación/reparación, extrayendo conclusiones al respecto

Ameloclasia in permanent erupted teeth is a controversial matter. A few clinical cases are presented with dental records including exploration, radiographs and clinical pictures. In one of the cases a histologic study was done and evaluations with SEM, ESEM and EDS were carried out. Macroscopic and microscopic resoptions were observed in the enamel, not only in included teeth but also in erupted teeth. The results obtained are discussed and several conclusions are drawn

Las anomalías del esmalte dentario y su relación con enfermedades generales / Dental anomalies and its relationship with systemic diseases

El esmalte dentario es uno de los tejidos más duros del organismo, sin embargo las células formadoras del esmalte, los ameloblastos, son muy sensibles a los cambios que ocurren durante el periodo de formación del diente. Son muchas las patologías que pueden alterar el funcionamiento del ameloblasto provocando lesiones de hipoplasia o hipomineralización, y a diferencia de lo que ocurre en otros tejidos, el esmalte dentario carece de mecanismos de reparación. En este artículo, revisamos las principales causas genéticas y ambientales que pueden ser responsables de las anomalías en esmalte dentario, así como el aspecto clínico que pueden presentar estas anomalías

Dental enamel is one of the hardest tissues in thehuman body. However, ameloblast cels wich compraisthe enamel, are extremely sensitive to the changes occurring during dental development. There are many pathologys that can alter the normal function in ameloblast cels and cause hypoplasia orhypomineralization. In contrast to other tissue enamel tissue does not have its own repair mechanisms. In this article we review the principal genetic andenvirolmental causes that may contribute to dental anomalies as well as the clinical aspect of these anomalies

Dentine structure and mineralization in hypocalcified amelogenesis imperfecta: a quantitative X-ray histochemical study.

OBJECTIVE: This study was undertaken in order to establish the structural and mineralization pattern of the response of dentine to alterations in enamel in hypocalcified amelogenesis imperfecta (AI). DESIGN: The images and data obtained with scanning electron microscopy and electron probe X-ray microanalysis in enamel and dentine specimens from control and affected teeth were compared in this study. PATIENTS AND METHODS: We compared 46 fragments of permanent teeth from patients with clinically diagnosed hypocalcified AI and 20 normal permanent teeth. All specimens were prepared for electron probe X-ray microanalysis. RESULTS: Dentine is characterized by thickening of the peritubular dentine and partial obliteration of the dentinal tubules that does not give rise to a compact sclerotic cast. In dentine, calcium levels were significantly higher in teeth with clinically hypocalcified AI in relation with control teeth (P < 0.001). CONCLUSIONS: Dentine is affected in hypocalcified AI increasing mineralization (narrower tubules and higher content of calcium) in response to enamel disorder.

Dental development after successful treatment of infantile osteopetrosis with bone marrow transplantation.

A 3-week-old boy was diagnosed with congenital osteopetrosis. He underwent a bone marrow transplant at 6 weeks of age. At 3 years of age the primary teeth had all erupted, but the canines and the first molars totally lacked root development. The teeth were smaller in size and had evidence of both enamel hypomineralization and hypoplasia. In the permanent dentition, multiple missing teeth were found. The incisors were conical and the mandibular laterals were extremely small. All permanent teeth had normal eruption. This case shows that dental development and eruption of teeth can be reconstituted in a child with congenital osteopetrosis. Bone marrow transplantation induces normalization of osteoclast function, which is a prerequisite for normal dental development and eruption of teeth.