Early post-natal development of the mandibular permanent first molar in infants with unilateral complete cleft lip and palate.

OBJECTIVES: Studies have shown that the mandibular permanent first molar (M1inf ) in young children with isolated cleft palate is characterized by delay in maturation and has reduced crown width. Consequently, it is of interest to investigate the early maturation and width of the follicle and crown of M1inf in children with combined cleft lip and palate. DESIGN: Retrospective, longitudinal study. Cephalometric X-rays of 47 consecutive Danish children with UCCLP (37 males; 10 females) and 44 with unilateral incomplete cleft lip (UICL) (29 males; 15 females) examined at 2 and 22 months of age. UICL served as control group. Maturation (according to Haavikko), width of follicle (FW) and crown (CW) of M1inf were assessed. RESULTS: The maturation of the first mandibular molar was delayed in both genders at 2 and 22 months of age. FW and CW were smaller in children with UCCLP at both 2 and 22 months of age. There was a positive correlation between maturation and FW. CONCLUSIONS: Maturation of the first mandibular molar is delayed in both genders, and FW and CW were reduced in UCCLP compared to controls. Maturation was correlated with FW.

A Pilot Study on the Influence of Facial Expression on Measurements in Three-Dimensional Digital Surfaces of the Face in Infants With Cleft Lip and Palate.

OBJECTIVE: Three-dimensional surface imaging is an increasingly popular modality for face measurements in infants with cleft lip and palate. Infants are noncompliant toward producing specific facial expressions, and selecting the appropriate moment of acquisition is challenging. The objective was to estimate amount and spatial distribution of deformation of the face due to facial expression in infants with cleft lip and palate and provide recommendations for an improved acquisition protocol, including a method of quality control in terms of obtaining images with true neutral expression. MATERIAL AND METHODS: Three-dimensional surface images of ten 4-month-old infants with unrepaired cleft lip and palate were obtained using a 3dMDface stereophotogrammetric system. For each subject, five surface images judged as representing a neutral expression were obtained during the same photo session. Mean and maximum deformations were calculated. A formalized review was performed, allowing the image exhibiting the "best" neutral expression to be selected, thus decreasing errors due to residual facial expression. RESULTS: Deformation due to facial expression generally increased from forehead to chin. The amount of deformation in three selected regions were determined: nose (mean, 1 mm; maximum = 3 mm); cleft region (mean, 2 mm; maximum = 5 mm); chin region (mean, 5 mm; maximum = 12 mm). Analysis indicated that introduction of a formalized review of images could reduce these errors by a factor of 2. CONCLUSIONS: The continuous change of facial expression in infants represents a substantial source of error; however, this may be reduced by incorporating a formalized review into the acquisition protocol.

Maxillary length in 11- to 26-week-old normal fetuses studied by 3D ultrasound.

OBJECTIVES: The objective of this article is to investigate normal prenatal maxillary length using 3D ultrasound and to correlate this with previously reported results for the mandible and the biparietal diameter (BPD). METHODS: Seventy-two 3D ultrasound volumes from normal pregnancies in 52 volunteers (gestational age: 11-26 weeks) were obtained using a GE Voluson 730 Expert 3D scanner. Maxillary length and BPD were measured. Growth velocity and rate were calculated. Maxillary values were correlated with BPD and previously reported mandibular values. RESULTS: The mean total maxillary length ranged from 7.4 ± 2.7 mm at 11 weeks to 33.1 ± 2.7 mm at 26 weeks. Maxillary growth velocity can be described using a linear model. The correlation between maxillary and mandibular length, and BPD was high (R = 0.85-0.88). There was no statistically significant difference in the growth velocity between maxilla and mandible, whereas the velocity of the increase in BPD growth was significantly larger than that of the jaws. However, the growth rate was larger for the jaws than for the BPD. CONCLUSIONS: Normative measures for the maxilla in 11- to 26-week-old fetuses are presented. Change in maxillary length was described using a linear model. The maxillary and mandibular growth velocities and rates were similar but differ from those of the BPD.

Short mandible - a possible risk factor for cleft palate with/without a cleft lip.

OBJECTIVES: To estimate the influence of a short mandible on the risk of developing a cleft palate with/without a cleft lip (CP). SETTING AND SAMPLE POPULATION: The retrospective sample consisted of 115 2-month-old Danish infants with CP, and 70 control infants with unilateral incomplete cleft lip (UICL). MATERIAL AND METHODS: Cephalometric X-rays were obtained. Mandibular length (Lm ) was measured and corrected for body length (Lb ) to remove influence of varying body length in the sample. Logistic regression was applied to the corrected mandibular length (Lmc ) to calculate the risk of having a cleft palate. RESULTS: The mean mandibular length in the group with CP was about 4 mm shorter than in the control group. Odds ratio (OR) was calculated to be 0.58 (95% confidence interval 0.48-0.68), implying that an individual's risk of cleft palate with/without a cleft lip increases about 50% per mm decrease in mandibular length. CONCLUSIONS: A special facial type including a short mandible is a possible risk factor for cleft palate, and it was found that the risk of cleft palate increases 58% per mm decreases in mandibular length.

Phenotype in 18 Danish subjects with genetically verified CHARGE syndrome.

CHARGE (coloboma of the eye, heart defects, choanal atresia, retarded growth and development, genital hypoplasia and ear anomalies and/or hearing loss) syndrome is a rare genetic, multiple-malformation syndrome. About 80% of patients with a clinical diagnose, have a mutation or a deletion in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7). Genotype-phenotype correlation is only partly known. In this nationwide study, phenotypic characteristics of 18 Danish CHD7 mutation positive CHARGE individuals (N = 18) are presented. We studied patient records, clinical photographs, computed tomography, and magnetic resonance imaging (MRI). Information was not available for all traits in all subjects. Therefore, the results are presented as fractions. The following prevalence of cardinal symptoms were found: coloboma, 16/17; heart defects, 14/18; choanal atresia, 7/17; retarded growth and development, 11/13; genital abnormalities, 5/18; ear anomalies, 15/17 and sensorineural hearing loss, 14/15. Vestibular dysfunction (10/13) and swallowing problems (12/15) were other frequent cranial nerve dysfunctions. Three-dimensional reconstructions of MRI scans showed temporal bone abnormalities in >85%. CHARGE syndrome present a broad phenotypic spectrum, although some clinical features are more frequently occurring than others. Here, we suggest that genetic testing for CHD7 mutation should be considered in neonates with a specific combination of several clinical symptoms.

Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism.

Cherubism (MIM 118400) is an autosomal dominant inherited syndrome characterized by excessive bone degradation of the upper and lower jaws followed by development of fibrous tissue masses, which causes a characteristic facial swelling. Here we describe seven mutations in the SH3-binding protein SH3BP2 (MIM 602104) on chromosome 4p16.3 that cause cherubism.

Micro-CT analyses of apical enlargement and molar root canal complexity.

AIM: To compare the effectiveness of two rotary hybrid instrumentation techniques with focus on apical enlargement in molar teeth and to quantify and visualize spatial details of instrumentation efficacy in root canals of different complexity. METHODOLOGY: Maxillary and mandibular molar teeth were scanned using X-ray microcomputed tomography. Root canals were prepared using either a GT/Profile protocol or a RaCe/NiTi protocol. Variables used for evaluation were the following: distance between root canal surfaces before and after preparation (distance after preparation, DAP), percentage of root canal area remaining unprepared and increase in canal volume after preparation. Root canals were classified according to size and complexity, and consequences of unprepared portions of narrow root canals and intraradicular connections/isthmuses were included in the analyses. One- and two-way anova were used in the statistical analyses. RESULTS: No difference was found between the two techniques: DAP(apical-third) (P = 0.590), area unprepared(apical-third) (P = 0.126) and volume increase(apical-third) (P = 0.821). Unprepared root canal area became larger in relation to root canal size and complexity, irrespective of the technique used. Percentage of root canal area remaining unprepared was significantly lower in small root canals and complex systems compared to large root canals. The isthmus area per se contributed with a mean of 17.6%, and with a mean of 25.7%, when a narrow root canal remained unprepared. CONCLUSIONS: The addition of isthmuses did not significantly alter the ratio of instrumented to unprepared areas at total root canal level. Distal and palatal root canals had the highest level of unprepared area irrespective of the two instrumentation techniques examined.

RUNX2 analysis of Danish cleidocranial dysplasia families.

Cleidocranial dysplasia (CCD) is an autosomal dominant inherited disease caused by mutations in the Runt gene RUNX2. Screening of 19 Danish CCD families revealed 16 pathogenic mutations (84%) representing 8 missense mutations, 2 nonsense mutations, 4 frame-shift mutations and 2 large deletions in the RUNX2 locus. Eight mutations were novel, two were found twice, and polymorphisms were found in the promoter region and in the conserved polyglutamine/polyalanine repeat. A large duplication downstream of RUNX2 found in one patient suggests a possible regulatory RUNX2 element. The CCD phenotypes and genotypes adhere to the large phenotypic variability reported in previous CCD studies. Identification of large chromosome aberrations in or near the RUNX2 locus in 3 of the 19 cases suggests copy number analyses to be included in future RUNX2 mutation analyses.

A paediatric bone index derived by automated radiogrammetry.

SUMMARY: Hand radiographs are obtained routinely to determine bone age of children. This paper presents a method that determines a Paediatric Bone Index automatically from such radiographs. The Paediatric Bone Index is designed to have minimal relative standard deviation (7.5%), and the precision is determined to be 1.42%. INTRODUCTION: We present a computerised method to determine bone mass of children based on hand radiographs, including a reference database for normal Caucasian children. METHODS: Normal Danish subjects (1,867), of ages 7-17, and 531 normal Dutch subjects of ages 5-19 were included. Historically, three different indices of bone mass have been used in radiogrammetry all based on A = piTW(1 - T/W), where T is the cortical thickness and W the bone width. The indices are the metacarpal index A/W(2), DXR-BMD = A/W, and Exton-Smith's index A/(WL), where L is the length of the bone. These indices are compared with new indices of the form A/(W(a) L(b)), and it is argued that the preferred index has minimal SD relative to the mean value at each bone age and sex. Finally, longitudinal series of X-rays of 20 Japanese children are used to derive the precision of the measurements. RESULTS: The preferred index is A/(W(1.33) L(0.33)), which is named the Paediatric Bone Index, PBI. It has mean relative SD 7.5% and precision 1.42%. CONCLUSIONS: As part of the BoneXpert method for automated bone age determination, our method facilitates retrospective research studies involving validation of the proposed index against fracture incidence and adult bone mineral density.

Prenatal 3D ultrasound diagnostics in cleidocranial dysplasia.

A 34-year-old Caucasian woman with cleidocranial dysplasia (CCD) and a known family history of CCD was referred for an ultrasound examination in the first trimester of her second pregnancy. Molecular genetic analysis of the RUNX2 gene was non-informative. A routine 2D ultrasound examination carried out at a local hospital at gestational age 12 weeks showed no signs of CCD. A 3D ultrasound examination in week 15+4 showed a fetus with typical CCD features including large fontanelles, lack of nasal bones, clavicles without the typical S-form, as well as severe delay in calvarial ossification, especially in the midline. Serial 3D ultrasound examinations during pregnancy confirmed the diagnosis, and over time the manifestations became even more distinct. The diagnosis was clinically confirmed at birth. This case suggests that the typical craniofacial CCD traits, including wide unmineralized areas in the calvarial midline and missing nasal bones, are easily recognizable using 3D ultrasound as early as in week 15.

Primary failure of eruption of teeth in two siblings with a novel mutation in the PTH1R gene.

BACKGROUND: Primary failure of tooth eruption (PFE) is a rare non-syndromic disorder with prematurely ceased eruption of the posterior teeth, despite clearance by bone resorption of the eruption path. It is generally agreed that most of the impacted teeth are second molars that are deeply seated, and without symptoms. Traditionally, patients with failure of tooth eruption undergo surgical and/or orthodontic treatment. However, patients with PTH1R mutations have no beneficial effect of such a regime and PFE is therefore important to diagnose. CASE REPORT AND FOLLOW-UP: A family with three PFE affected members in two generations, involving both the primary and permanent dentitions, and a novel mutation in the PTH1R gene are reported. Furthermore, the treatment of the eruption failure was documented in one of the cases. CONCLUSION: In the present study, the proband initially only had a minor clinical problem, lack of eruption of the primary second left mandibular molar. However, over time several problems appeared in the permanent dentition. Clinical signs of PFE should lead one to look for similar dental problems in related family members and to molecular DNA testing. Confirmation of the diagnosis PFE in young children has the advantage that unnecessary treatment can be avoided, since early orthodontic intervention for these patients is futile. Once growth is complete, several multidisciplinary treatment strategies can partially solve the posterior open bite malocclusion that is characteristic of this disorder. Treatment should be planned in cooperation with specialists who are used to treating PFE patients.

X-linked hypohidrotic ectodermal dysplasia. Genetic and dental findings in 67 Danish patients from 19 families.

This study aimed to investigate genotype and phenotype in males affected with X-linked hypohidrotic ectodermal dysplasia (HED) and in female carriers, to analyse a possible genotype-phenotype correlation, and to analyse a possible relation between severity of the symptoms and the X-chromosome inactivation pattern in female carriers. The study group comprised 67 patients from 19 families (24 affected males and 43 female carriers). All participants had clinical signs of ectodermal dysplasia and a disease-causing EDA mutation. The EDA gene was screened for mutations by single-stranded conformational polymorphism and direct sequencing. Multiplex ligation-dependent probe amplification (MLPA) analysis was used to detect deletions/duplications in female probands. Sixteen different EDA mutations were detected in the 19 families, nine not described previously. The MLPA analysis detected a deletion of exon 1 in one female proband. No genotype-phenotype correlations were observed, and female carriers did not exhibit a skewed X-chromosome inactivation pattern. However, in two female carriers with pronounced clinical symptoms, in whom the parental origin of each allele was known, we observed that mainly the normal allele was inactivated.

Influence of mouthguard on temporomandibular joint.

The aim of this study is to examine whether wearing a mouthguard (MG) has an influence on temporomandibular joint (TMJ) components (i.e., the condyle and the articular disk) and whether clenching with a resilient MG has an effect on the same components. Twenty-six healthy volunteers (15 females, 11 males) with an age range of 26-42 years old (median 28 years) participated in this study. Among all 52 joints in the 26 subjects, anterior disk displacement (AntDD) was recognized in 15. Thus, we classified the 52 joints into two groups, the AntDD group and the Normal group. Resilient thermoplastic materials were used to fabricate two types of MG, one that raised the vertical dimension height by 3 mm and another that raised it by 6 mm. Subjects were scanned with/without two types of MG with/without clenching by magnetic resonance imaging (MRI). The movement of the condylar head and articular disk was measured in the magnetic resonance images using the special subtraction technique. Wearing the MG without clenching did not have a negative influence on the TMJ and clenching in the Normal group. In the AntDD group, however, the relationship between the disk and condyle was affected by clenching and the degree of disk displacement was worsened by clenching with the thicker MG. From our results, we recommend that athletes with an internal derangement of the TMJ not wear the thicker MG and attention should be paid to its setting. And the subtraction technique using MRI was thought as a good tool for detecting a slight change in the TMJ.

An echo-poor spine at 13 weeks: an early sign of cleidocranial dysplasia.

OBJECTIVE: Early prenatal diagnosis of cleidocranial dysplasia (CCD) in a case in which molecular genetic analysis of the RUNX2 gene was non-informative. METHODS: 2D ultrasound examination. RESULTS: At week 13+6, a 2D ultrasound examination revealed a fetus with severely delayed ossification of the vertebral spine. The clavicles were barely seen and the calvarial bones were significantly less ossified than expected for gestational age. The fetus had otherwise normal anatomy and biometry. Serial ultrasound examinations during pregnancy confirmed the diagnosis, but the manifestations became less distinct. The diagnosis was confirmed clinically at birth. CONCLUSION: This case illustrates an early easily recognizable pattern of severely delayed ossification of the vertebral spine, which is probably a characteristic of CCD.

Novel mutation of the initiation codon of PAX9 causes oligodontia.

Tooth development is under strict genetic control. Oligodontia is defined as the congenital absence of 6 or more permanent teeth, excluding the third molar. The occurrence of non-syndromic oligodontia is poorly understood, but in recent years several cases have been described where a single gene mutation is associated with oligodontia. Several studies have shown that MSX1 and PAX9 play a role in early tooth development. We screened one family with non-syndromic oligodontia for mutations in MSX1 and PAX9. The pedigree showed an autosomal-dominant pattern of inheritance. Direct sequencing and restriction enzyme analysis revealed a novel heterozygous A to G transition mutation in the AUG initiation codon of PAX9 in exon 1 in the affected members of the family. This is the first mutation found in the initiation codon of PAX9, and we suggest that it causes haploinsufficiency.

Cranial base and face in mandibulofacial dysostosis.

Using longitudinal roentgencephalometry, we studied craniofacial growth in two children with mandibulofacial dysostosis. In one child, data were supplemented by three-dimensional reconstructions of CT scans and stereolithographic models of the craniofacial skeleton. Progressive basilar kyphosis was found in both children, the hypothesized caused being bending of the cranial base at the level of the sphenofrontal suture. Such bending acting in concert with abnormal growth of the mandible led to impairment of the airway. We advocate careful monitoring of craniofacial growth and respiratory function in mandibulofacial dysostosis from birth through adolescence.

Upper and lower airway compromise in the Apert syndrome.

Both upper and lower airway compromise may be responsible for early death in some patients with the Apert syndrome. We report on two and review six cases with complete or partial cartilage sleeve abnormalities of the trachea. Possible mechanisms include tracheal stenosis and/or lack of tracheal distensibility which may result in respiratory inefficiency, inability to clear secretions, and/or increased liability to surface injury from tracheal suctioning. Upper airway compromise, consisting of obstructive sleep apnea and cor pulmonale, may result from reduced nasopharyngeal and oropharyngeal dimensions in the Apert craniofacial configuration.

The central nervous system in the Apert syndrome.

In this paper, we present available central nervous system data from our series of patients with the Apert syndrome. Combining our own data with that available in the literature, 30 patients had malformations of the corpus callosum, the limbic structures, or both. Other frequent findings included megalencephaly (7 cases), gyral abnormalities (8 cases), encephalocele (4 cases), pyramidal tract abnormalities (2 cases), hypoplasia of cerebral white matter (4 cases), and heterotopic gray matter (2 cases). Progressive hydrocephalus seems to be uncommon and has frequently been confused with nonprogressive ventriculomegaly in the past. Psychometric evaluations, neurological findings, and neuropathologic reports from the literature are critically reviewed. It is clear that a significant number of patients with the Apert syndrome are mentally retarded. It is suggested that malformations of the central nervous system may be responsible for most cases.

Hands and feet in the Apert syndrome.

We studied 44 pairs of hands and 37 pairs of feet in Apert syndrome, utilizing clinical, dermatoglyphic, and radiographic methods. We also studied histologic sections of the hand from a 31-week stillborn fetus. Topic headings discussed include: clinical classification of syndactyly; correlations between types of hands and feet in the same patient; dermatoglyphics; anatomy of the hand; radiologic assessment; comparison with other studies; histologic assessment of the hand; acrocephalosyndactyly vs. acrocephalopolysyndactyly: a pseudodistinction; and some generalizations.

Growth pattern in the Apert syndrome.

In this paper, we demonstrate that a discernible and unique growth pattern characterizes the Apert syndrome. The keys to understanding Apert newborn measurement values are brain size and cranial configuration. Both true megalencephaly and coronal synostosis are present at birth. Thus, the head is unusually heavy and the cranium is disproportionately high. Mean newborn length and weight are above the normal 50th centile. Of our newborn patients, 16% exceeded 4,000 g in weight. Preterm infants were appropriate or slightly large for gestational age. A biphasic linear growth pattern was found. In childhood, deceleration of linear growth occurs so that most values fall between the 5th and 50th centiles. From adolescence to adulthood, deceleration becomes more pronounced. This 2-step linear growth deceleration results in large measure from rhizomelic shortness of the lower limbs. Puberty takes place within the normal time frame. Although a disproportionate amount of the megalencephaly accounts for the dramatic increase in head height, the widely patent midline calvarial defect, allowing the brain to expand anteriorly into the metopic area, and some increase in the head breadth permit the mean head circumference at birth to normalize slightly above the 50th centile. During the growth period, the head circumference was studied in surgically unoperated Apert patients from the 1960s and earlier. The natural history of the growing cranium consists of gradual deceleration in head circumference from slightly above the 50th centile at birth to within or at -2 SD later on.