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case_images: Oral manifestations of the proband.. (A, B) Early teeth loss, the laceration and ulceration of oral soft tissues, dental attrition and dental caries. (C) Panoramic radiographs showing alveolar bone loss of the maxilla and mandible, exfoliation of 15 permanent teeth, and short root anomaly of the existing teeth.
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case_images: Oral examination revealed erosions, scars and hyperkeratosis of soft tissues, including the tongue, lips, gingiva, and palatal and buccal mucosa (Figure 2-A). Early tooth loss was noted, including almost all primary teeth except for a left mandibular primary second molar that was carious and mobile and some permanent teeth (Figure 2-A,B). What was more, the existed teeth exhibited short root anomalies (Figure 2-C).
case_images: Histopathological examination of a skin biopsy.. (A) Normal epidermis and appendages in healthy control samples (H&E staining). (B) Hyperkeratosis, acanthosis and irregular stratum basale, few sweat glands, hair follicles and sebaceous glands in the CIPA patient's samples (H&E staining). (C, D) NSE immunoreactivity stains of control and CIPA patient's sections. Arrow indicates the area with positive staining. (Immunohistochemical staining, Bar = 100 microm)
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case_images: H&E stains showed a reduction in the number of sweat glands, hair follicles, blood vessels and sebaceous glands (Figure 3-A, B). NSE immunohistochemistry showed that the density of NSE immunoreactivity stains was significantly decreased in the patient's skin when compared to healthy skin (Figure 3-C, D).
case_images: Pathological examination of the patient's exfoliated primary tooth.. (A) The dental x-rays showing a normal crown, thin roots and smaller pulp chamber. (B) Micro CT scanning and reconstruction of the tooth showing the indistinct cementodentinal junction and the irregular cementum. (C, D) H&E stained tooth tissue showing that some dentinal tubules were in a disorganized state near the dentino-cemental junction. In addition, the acellular cementum was thin and the cellular cementum was partially absent, and the periodontal ligament was loosely organization (Bar = 100 microm). (E, F) Masson's stained tooth tissue showing dentinal tubules with significantly greater diameters, dentine in a state of hypomineralization and hypomaturation, a hypoplastic cementum and seemingly sparse periodontal ligament fibers (Bar = 100 microm). (G) The CIPA patient's enamel prisms showing the disorientation and confusion in hydroxyapatite crystal growth (SEM, Bar = 5 microm). (H) The significantly abnormal distribution in density and diameter of the dentinal tubules compared with the control samples (SEM, Bar = 20 microm). (I) The root surface of the patient's teeth showing discontinuous mineralization, a thinner cementum and fewer attached fiber occupancies. (SEM, Bar = 50 microm).
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case_images: Radiographs of the exfoliated tooth sample revealed a normally sized and shaped crown except for a carious cavity, two thin roots and a smaller pulp chamber (Figure 4-A), and it was difficult to distinguish from the dentin and cementum by Micro CT (Figure 4-B). H&E-stained tooth tissue showed that some dentinal tubules were in a disorganized state near the dentino-cemental junction, that the acellular cementum was thin, the cellular cementum was partially absent, and the periodontal ligament displayed a loose, disordered organization (Figure 4-C, D). Masson's stained tooth tissue revealed dentinal tubules with significantly greater diameters, dentine in a state of hypomineralization and hypomaturation, a hypoplastic cementum and seemingly sparse periodontal ligament fibers (Figure 4-E, F). Under the scanning electron microscope, the patient's enamel prisms showed slight disorientation and confusion in hydroxyapatite crystal growth (Figure 4-G). The distribution density of the dentinal tubules was significantly abnormal when compared with control subjects with sparse dentinal tubules that had wider diameters, and expanded peritubular dentin spaces (Figure 4-H). Hypoplastic root cementum in this CIPA patient featured discontinuous mineralization, a thinner cementum and less attached fiber occupancies (Figure 4-I).
case_images: Spot elemental analyses for ultrastructural and quantitative changes in the patient's tooth.. Compared to healthy controls, significant differences were detected in the level of Ca and the Ca/P and Ca/C ratios in the EDJ of the patient (p<0.05).
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case_images: Compared to healthy controls, significant differences were detected in the level of Ca, P, Carbon (C) and Ca/P, Ca/C ratios in the EDJ of the patient (Figure 5).
case_images: Genetic analysis of the CIPA family: (A) pedigree of the family. (B) Chromosome karyotype analysis was normal. (C) Sequencing chromatographs of genomic DNA from the proband and his parent are shown and reveal double heterozygous missense mutations- c.1561T>C in exon 13 and c.2057 G>A in exon 15 of the NTRK1 gene in the proband. Mutation-c.1561T>C was found in the proband's father, and mutation- c.2057 G>A was found in his mother. (D) Multiple sequence alignment: F521 and R686 of human NTRK1, indicated by the red frame and blue frame respectively, are evolutionarily conserved as shown in four representative species. The crystal structure of amino acids 497-795 of the human NTRK1, located in the catalytic domain, is shown in green ribbons. Two mutated p.F521L (in red) and p.R686H (in blue) are all labeled.
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case_images: Sequencing analysis of the NTRK1 gene in the proband revealed a compound heterozygote mutations, namely c. 1561T>C in exon 13 and c.2057 G>A in exon 15 inherited from each of his parents, which predicts amino acid substitutions p.F521L (phenylalanine acid leucine) and p.R686H (arginine histidine) (Figure 6). Multiple sequence alignment showed that F521 and R686 in the NTRK1 are evolutionarily conserved from zebrafish to humans (Figure 6-D).