Marit Midtbø

Ciliopathies with Skeletal Anomalies and Renal Insufficiency due to Mutations in the IFT-A Gene WDR19

A subset of ciliopathies, including Sensenbrenner, Jeune, and short-rib polydactyly syndromes are characterized by skeletal anomalies accompanied by multiorgan defects such as chronic renal failure and retinitis pigmentosa. Through exome sequencing we identified compound heterozygous mutations in WDR19 in a Norwegian family with Sensenbrenner syndrome. In a Dutch family with the clinically overlapping Jeune syndrome, a homozygous missense mutation in the same gene was found. Both families displayed a nephronophthisis-like nephropathy. Independently, we also identified compound heterozygous WDR19 mutations by exome sequencing in a Moroccan family with isolated nephronophthisis. WDR19 encodes IFT144, a member of the intraflagellar transport (IFT) complex A that drives retrograde ciliary transport. We show that IFT144 is absent from the cilia of fibroblasts from one of the Sensenbrenner patients and that ciliary abundance and morphology is perturbed, demonstrating the ciliary pathogenesis. Our results suggest that isolated nephronophthisis, Jeune, and Sensenbrenner syndromes are clinically overlapping disorders that can result from a similar molecular cause.

Root length, crown height, and root morphology in Turner syndrome

Root length, crown height, and root morphology were studied on intraoral and panoramic radiographs in 33 Turner syndrome patients aged 7.0-16.7 years, subdivided on the basis of karyotype. Thirty-three normal girls aged 10.2-16.4 years served as controls. In the 45X patients and, with the exception of a few teeth, also in the isochromosome and mosaic karyotypes, root length and crown height of incisors, canines, and premolars were significantly reduced. Some teeth showed altered crown-root proportions. Maxillary first premolars showed a significantly increased number of two-rooted and three-rooted variants. Mandibular premolars and molars had a complex root morphology, and a classification system was established including four premolar and six molar root types. Premolars had a significantly increased number of root components. Some of the variants, such as a molar-like second premolar, are apparently specific for these patients. On several first molars a radix entomolaris was identified. Two separate mesial and one or two separate distal roots were also frequently seen. Our investigation demonstrates that X-chromosome deficiency influences root formation.

Skeletal maturity, dental maturity, and eruption in young patients with Turner syndrome

A major problem for patients with Turner syndrome is their small body height. The rapid biotechnologic development has now made treatment with growth hormone possible at a larger scale. The aim of this investigation was to evaluate skeletal maturity, dental maturity, and eruption in a group of young patients before hormone therapy. The material comprised 33 patients aged 7-16.7 years. The skeletal maturity, as judged from hand radiographs, was on an average 2.3 years retarded (p < 0.001) and showed increasing retardation with increasing age. The dental maturity, assessed from the formation stages of the permanent teeth on panoramic radiographs, was accelerated, with a mean value of 1 year (p < 0.001). The timing of clinical eruption did not differ significantly from that of our reference material; the Turner girls were on an average 3.7 months ahead. Several patients had local eruption problems, especially in the maxillary lateral segments. It is suggested that disharmony between tooth size and arch size may contribute to this problem.

Brittle cornea syndrome associated with a missense mutation in the zinc-finger 469 gene.

PURPOSE To investigate the diverse clinical manifestations, identify the causative mutation and explain the association with red hair in a family with brittle cornea syndrome (BCS). METHODS Eight family members in three generations underwent ophthalmic, dental, and general medical examinations, including radiologic examination of the spine. Bone mineral density (BMD) and serum levels of vitamin D, parathyroid hormone, and biochemical markers for bone turnover were measured. Skin biopsies were examined by light and transmission electron microscopy. Molecular genetic studies included homozygosity mapping with SNP markers, DNA sequencing, and MC1R genotyping. RESULTS At 42 and 48 years of age, respectively, both affected individuals were blind due to retinal detachment and secondary glaucoma. They had extremely thin and bulging corneas, velvety skin, chestnut colored hair, scoliosis, reduced BMD, dental anomalies, hearing loss, and minor cardiac defects. The morphologies of the skin biopsies were normal except that in some areas slightly thinner collagen fibrils were seen in one of the affected individuals. Molecular genetic analysis revealed a novel missense mutation of ZNF469, c.10016G>A, that was predicted to affect the fourth of the five zinc finger domains of ZNF469 by changing the first cysteine to a tyrosine (p.Cys3339Tyr). Both affected individuals were homozygous for the common red hair variant R151C at the MC1R locus. CONCLUSIONS BCS is a disorder that affects a variety of connective tissues. Reduced BMD and atypical dental crown morphology have not been reported previously. The results confirm that BCS is associated with mutations in ZNF469. The association with red hair in some individuals with BCS is likely to occur by chance.

Secondary induction and the development of tooth nerve supply

During embryogenesis, dental trigeminal axon navigation and patterning in the developing tooth take place in a highly spatio-temporally directed manner that is tightly linked to tooth morphogenesis and cell differentiation. Tooth formation is regulated by sequential and reciprocal tissue interactions between dental epithelium and neural crest-derived ectomesenchymal cells. This odontogenic secondary induction is mediated by signal molecules of different conserved families. Recent molecular and experimental data have provided evidence that local instructive signaling from the early odontogenic epithelium also controls dental axon navigation in the dental mesenchyme. In this review, we discuss recent molecular data regarding tooth formation and innervation and the putative role of the secondary induction in coordinating these two developmental processes. Importantly, because it has not yet been shown that the interactions that regulate tooth innervation include signaling to the dental epithelium and that they are reciprocal, it remains to be demonstrated that secondary induction controls the establishment of tooth nerve supply. Moreover, the key question of which molecule(s), if any, integrate tooth morphogenesis and the development of dental sensory trigeminal innervation remains to be answered.

Tooth crown size and morphology in Turner syndrome

The aims of this investigation were to analyze permanent tooth crown size and morphology and to perform symmetry analysis between corresponding teeth on the right and the left side. The material comprised 32 Turner syndrome patients aged 7-16.7 years. As controls served 33 normal girls 10.2-16.7 years old. The mesiodistal diameter was significantly reduced for every tooth measured except for the maxillary canine. The buccolingual dimension was reduced only for some teeth. Eleven morphologic traits were defined. Ten of these were identified in the Turner patients; seven occurred in the controls as well, but at a lower frequency. Some of the traits have not been described earlier for this group of patients. There was a significant difference between Turner and control patients both in the number of patients with bilateral tooth asymmetries and in the number of corresponding tooth pairs in the maxilla with bilateral asymmetry. No significant differences were found between the 45X patients and the other karyotypes. Maxillary central incisors showed a surprisingly high relative frequency (38.5%) of bilateral asymmetry.

Comparison of 2 root surface area measurement methods: 3-dimensional laser scanning and cone-beam computed tomography

Purpose The aim of this study was to compare the use of 3-dimensional (3D) laser scanning and cone-beam computed tomography (CBCT) as methods of root surface measurement. Materials and Methods Thirty teeth (15 maxillary first premolars and 15 mandibular first premolars) from 8 patients who required extractions for orthodontic treatment were selected. Before extraction, pre-treatment CBCT images of all the patients were recorded. First, a CBCT image was imported into simulation software (Mimics version 15.01; Materialise, Leuven, Belgium) and the root surface area of each tooth was calculated using 3-Matic (version 7.01, Materialise, Leuven, Belgium). After extraction, all the teeth were scanned and the root surface area of each extracted tooth was calculated. The root surface areas calculated using these 2 measurement methods were analyzed using the paired t-test (P<.05). Correlations between the 2 methods were determined by calculating the Pearson correlation coefficient. The intraclass correlation coefficient (ICC) was used to assess intraobserver reliability. Results The root surface area measurements (230.11±41.97 mm2) obtained using CBCT were slightly greater than those (229.31±42.46 mm2) obtained using 3D laser scanning, but not significantly (P=.425). A high Pearson correlation coefficient was found between the CBCT and the 3D laser scanner measurements. The intraobserver ICC was 1.000 for 3D laser scanning and 0.990 for CBCT. Conclusion This study presents a novel CBCT approach for measuring the root surface area; this technique can be used for estimating the root surface area of non-extracted teeth.

Biochemical and Clinical Assessments of Segmental Maxillary Posterior Tooth Intrusion

Objective. To compare chondroitin sulphate (CS) levels around maxillary second premolars, first molars, and second molars between the unloaded and the loaded periods and to measure the rates of intrusion of maxillary posterior teeth during segmental posterior tooth intrusion. Materials and Methods. In this prospective clinical study, 105 teeth (from 15 patients exhibiting anterior open bite and requiring maxillary posterior tooth intrusion) were studied. Competitive ELISA was used to detect CS levels. Dental casts (during the unloaded and loaded periods) were scanned, and posterior tooth intrusion distances were measured. Results. During the unloaded period, the median CS levels around maxillary second premolars, first molars, second molars (experimental teeth), and mandibular first molars (negative control) were 0.006, 0.055, 0.056, and 0.012 and during the loaded period were 2.592, 5.738, 4.727, and 0.163 ng/μg of total protein, respectively. The median CS levels around experimental teeth were significantly elevated during the loaded period. The mean rates of maxillary second premolar and first and second molar intrusion were 0.72, 0.58, and 0.40 mm/12 weeks, respectively. Conclusions. Biochemical and clinical assessments suggested that the segmental posterior tooth intrusion treatment modality with 50 g of vertical force per side was sufficient. Trial Registration. The study is registered as TCTR20170206006.