Reduction in head size in patients with aspartylglucosaminuria.

OBJECTIVE: To show that the head may shrink in adult patients with aspartylglucosaminuria (AGU), a neurodegenerative disease. METHOD: The head circumference (HC) of 40 adult patients (age at baseline 15 to 47) was measured twice with an interval of 10 years. Of these 40, 21 aged 15-47 and 19 young patients aged 5-14 as well as 40 healthy controls underwent lateral cephalometric radiography. RESULTS: During 10 years' follow-up, the HC of 26 (65%) had decreased by 1 to 4.5 cm (mean 1.7, P < 0.001). Evaluation of lateral skull radiographs revealed that patients aged 15 or more had significantly thicker skulls than did younger patients (P = 0.015). Mean intracranial length (glabella-opisthocranium) of the patients aged 15 or more was significantly shorter than in patients aged 14 years or less (P = 0.029). These measurements indicated that brain volume had decreased. CONCLUSIONS: Macrocephalia in childhood followed by reduced brain volume in adulthood is evident in patients with AGU and is reflected by a decrease in head size.

MSX1 gene is deleted in Wolf-Hirschhorn syndrome patients with oligodontia.

Abnormalities of the short arm of chromosome 4 cause multiple congenital malformations, including craniofacial, oral, and dental manifestations. A candidate gene for oral defects in this region is MSX1, which is mandatory for normal oral and tooth development. We examined the dentition and the presence of MSX1 in eight Finnish patients with abnormalities of 4p, including seven cases of Wolf-Hirschhorn syndrome. Five of the Wolf-Hirschhorn syndrome patients presented with agenesis of several teeth, suggesting that oligodontia may be a common (even though previously not well-documented) feature in Wolf-Hirschhorn syndrome. In fluorescence in situ hybridization (FISH) analysis, the five patients with oligodontia lacked one copy of MSX1, while the other three had two hybridization signals. One of these presented with the only case of cleft palate among the patients. Our result confirms that haploinsufficiency for MSX1 serves as a mechanism that causes selective tooth agenesis but, alone, is not enough to cause oral clefts.

Craniofacial features in Cohen syndrome: an anthropometric and cephalometric analysis of 14 patients.

Cohen syndrome (Mendelian Inheritance in Man [MIM] no. 216550) is a rare, autosomal-recessive inherited disorder with mental retardation and a typical appearance. The condition is relatively common in Finland where 35 patients have been diagnosed. We studied 22 patients in detail, obtaining anthropometric measurements of the head and face, and cephalometric radiographs of 14 patients (14-57 years of age). Measurements of patients were compared to population norms and matched controls. Anthropometric analysis confirmed and quantified the previously described syndrome features: small head size [-4 standard deviations (SD)], with varying cephalic index. Width of the upper face was close to normal, but width of the lower face was small. Philtrum length was shorter than in healthy controls (p = 0.0039 in females and p = 0.0014 in males). The measurements from standardized radiographs revealed short cranial base dimensions (-2.2 and -2.6 SD), but normal cranial base angles. Prognathism of jaws was within normal limits. Reduced head size (microcephaly), short philtrum and small cranial base dimensions are essential features in Cohen syndrome. In addition, most patients had forward-inclined upper incisors and maxillary prognathia. We conclude that exact measurements mostly confirmed the Cohen syndrome description based previously on clinical impression.

Characteristics of incisor-premolar hypodontia in families.

Nonsyndromic tooth agenesis is a genetically and phenotypically heterogenous condition. It is generally assumed that different phenotypic forms are caused by different mutated genes. We analyzed inheritance and phenotype of hypodontia and dental anomalies in 214 family members in three generations of 11 probands collected for genetic linkage study on incisor-premolar hypodontia (IPH). Our analysis confirms the autosomal-dominant transmission with reduced penetrance of IPH. The prevalence of hypodontia and/or peg-shaped teeth was over 40% in first- and second-degree relatives and 18% in first cousins of the probands. Four of nine noted obligate carriers of hypodontia gene had dental anomalies, including small upper lateral incisors, ectopic canines, taurodontism, and rotated premolars. These anomalies were also observed at higher than normal frequency in relatives affected with hypodontia. We conclude that incisor-premolar hypodontia is a genetic condition with autosomal-dominant transmission and that it is associated with several other dental abnormalities.

Identification of a nonsense mutation in the PAX9 gene in molar oligodontia.

Development of dentition is controlled by numerous genes, as has been shown by experimental animal studies and mutations that have been identified by genetic studies in man. Here we report a nonsense mutation in the PAX9 gene that is associated with molar tooth agenesis in a Finnish family. The A340T transversion creates a stop codon at lysine 114, and truncates the coded PAX9 protein at the end of the DNA-binding paired-box. All the affected members of the family were heterozygous for the mutation. The tooth agenesis phenotype involves all permanent second and third molars and most of the first molars and resembles the earlier reported phenotype that was also associated with a PAX9 mutation. The phenotype is presumably a consequence of haploinsufficiency of PAX9. In another Finnish family with molar tooth agenesis, we could not find similar sequence changes in PAX9.

A syndrome with midface asymmetry, defective modelling of the skeleton, catch-up growth and truncal obesity.

We report follow-up from birth up to 16 years of age of a patient with a previously undescribed combination of dysmorphic features. These include: intrauterine growth retardation developing to normal adult stature with truncal obesity, asymmetry of the midface skeleton with severe orthodontic problems, brachydactyly of the hands and feet, wide medial phalanges of the fingers, partial soft tissue syndactyly, simian creases and normal mental development. We consider other differential diagnoses and suggest that the patient represents a hitherto undescribed syndrome.

Comparison of virulence factors of oral Candida dubliniensis and Candida albicans isolates in healthy people and patients with chronic candidosis.

We determined differences in the expression of certain virulence factors between oral Candida dubliniensis and Candida albicans species. In addition, clonal differences were sought among C. albicans isolates recovered from patients with and without compromised immune system. The material comprised 93 clinical yeast isolates originated in 40 subjects (1-5 isolates per subject). All 26 C. dubliniensis isolates and 46 C. albicans isolates originated from healthy routine dental clinic patients. Additionally, 21 C. albicans isolates were collected from patients with autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy (APECED), who have chronic candidosis as one manifestation of their immunocompromising disease. Polymerase chain reaction amplification using the random sequence primer OPE-03 enabled grouping of the C. dubliniensis isolates in 2 genotypes (I and II) and C. albicans isolates in 15 genotypes (I-XV). No significant difference was found in the distribution of genotypes between the patients with APECED and the healthy subjects. C. dubliniensis isolates exhibited high-frequency phenotypic switching significantly more frequently than did C. albicans isolates, and vice versa regarding phospholipase and proteinase production. Proteinase production was significantly more frequent among C. albicans genotype V than genotype IX isolates. No significant difference was found in expression of virulence factors of C. albicans isolates between the patients with APECED and the healthy subjects.

CBFA1 mutation analysis and functional correlation with phenotypic variability in cleidocranial dysplasia.

Cleidocranial dysplasia (CCD) is a dominantly inherited skeletal dysplasia caused by mutations in the osteoblast-specific transcription factor CBFA1. To correlate CBFA1 mutations in different functional domains with the CCD clinical spectrum, we studied 26 independent cases of CCD and a total of 16 new mutations were identified in 17 families. The majority of mutations were de novo missense mutations that affected conserved residues in the runt domain and completely abolished both DNA binding and transactivation of a reporter gene. These, and mutations which result in premature termination in the runt domain, produced a classic CCD phenotype by abolishing transactivation of the mutant protein with consequent haploinsufficiency. We further identified three putative hypomorphic mutations (R391X, T200A and 90insC) which result in a clinical spectrum including classic and mild CCD, as well as an isolated dental phenotype characterized by delayed eruption of permanent teeth. Functional studies show that two of the three mutations were hypomorphic in nature and two were associated with significant intrafamilial variable expressivity, including isolated dental anomalies without the skeletal features of CCD. Together these data show that variable loss of function due to alterations in the runt and PST domains of CBFA1 may give rise to clinical variability, including classic CCD, mild CCD and isolated primary dental anomalies.

Excessive infantile growth and early pubertal growth spurt: typical features in patients with aspartylglycosaminuria.

Rapid infantile growth was the first clinical sign in patients (n = 51) with aspartylglycosaminuria, a lysosomal storage disorder. Even if young children with aspartylglycosaminuria were tall for their age, an early but weak pubertal growth spurt in both sexes resulted in reduced adult heights.

Overgrowth of oral mucosa and facial skin, a novel feature of aspartylglucosaminuria.

Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by deficiency of aspartylglucosaminidase (AGA). The main symptom is progressive mental retardation. A spectrum of different mutations has been reported in this disease, one missense mutation (Cys163Ser) being responsible for the majority of Finnish cases. We were able to examine 66 Finnish AGU patients for changes in the oral mucosa and 44 of these for changes in facial skin. Biopsy specimens of 16 oral lesions, 12 of them associated with the teeth, plus two facial lesions were studied histologically. Immunohistochemical staining for AGA was performed on 15 oral specimens. Skin was seborrhoeic in adolescent and adult patients, with erythema of the facial skin already common in childhood. Of 44 patients, nine (20%) had facial angiofibromas, tumours primarily occurring in association with tuberous sclerosis. Oedemic buccal mucosa (leucoedema) and gingival overgrowths were more frequent in AGU patients than in controls (p<0.001). Of 16 oral mucosal lesions studied histologically, 15 represented fibroepithelial or epithelial hyperplasias and were reactive in nature. Cytoplasmic vacuolisation was evident in four. Immunohistochemically, expression of AGA in AGU patients' mucosal lesions did not differ from that seen in corresponding lesions of normal subjects. Thus, the high frequency of mucosal overgrowth in AGU patients does not appear to be directly associated with lysosomal storage or with alterations in the level of AGA expression.

Short root anomaly in families and its association with other dental anomalies.

In the present study, we collected a family series with short root anomaly in order to analyze the inheritance pattern of the condition. Another aim was to identify in these families an association with other dental anomalies, such as tooth agenesis, peg-shaped lateral incisors, supernumeraries, ectopia, and such morphological characteristics as invaginations, taurodontism, and a tendency to root resorption. Mesiodistal dimensions of the crowns of the affected teeth were measured in order to reveal any association with reduction or increase in tooth size. The apparent genetic heterogeneity of the pedigrees did not permit definitive conclusions as to the mode of inheritance. Autosomal dominant transmission of short root anomaly was seen in 3/8 families. In 2/8 families, the condition was seen in siblings but not in parents. An association with tooth agenesis and ectopic canines was noted, the prevalences of which were 46% and 33%, respectively. We stress the importance of not misdiagnosing this anomaly as resorption.

Dental maturity is advanced in Fragile X syndrome.

Fragile X (FraX) syndrome is the most common cause of inherited mental retardation. The FraX gene (FMR1) has been cloned, and the mutation causing the disease is now known. We estimated the effect of FraX on dental development in 28 affected boys (aged 4.9-17.6 years) and three carrier girls (aged 5.8, 10.4, and 12.7 years). Dental maturity, assessed on the basis of formation [Demirjian A, Goldstein H. 1976: Ann Hum Biol 3:411-421] and of emergence [Hägg U, Taranger J. 1985: Angle Orthod 55:93-107], was compared with growth in stature and skeletal maturity. The mean relative dental age was advanced in FraX males, based on formation (+1.4 SD) and on emergence (+1.1 SD). More pronounced advancement was seen in younger children. Dental maturity was advanced in heterozygous carrier girls as well. Height and skeletal maturity did not show a similar trend toward advanced development.

Impaired oral health in patients with aspartylglucosaminuria.

OBJECTIVE: The aim of this study was to assess the oral health of patients with aspartylglucosaminuria, a heritable lysosomal storage disorder, and to recommend guidelines for treatment. STUDY DESIGN: Eighty-two patients with aspartylglucosaminuria and 122 control subjects were examined clinically; in addition, panoramic radiographs were evaluated in 61 patients with aspartylglucosaminuria and 61 control subjects. RESULTS: High prevalences of caries, gingivitis, and oral Candida (P < .001), extensive gingival overgrowths (18%; P < .001), benign odontogenic tumors or tumorlike lesions (8%; P = .057), reduced maxillary sinuses (P < .001), limited mouth opening (P < .001), and food retention in the mouth (45%) were the major oral findings that distinguished the patients with aspartylglucosaminuria from the control subjects. Adults with aspartylglucosaminuria had diverse oral health problems, early loss of several permanent teeth being the most disabling feature. CONCLUSIONS: Patients with aspartylglucosaminuria appear to be at a higher risk for a number of oral disorders; however, poor oral hygiene and failure to cooperate increase these patients' risk of dental and periodontal diseases, making successful prevention crucial.

Correlation between speech outcome and cephalometric dimensions in patients with diastrophic dysplasia.

Diastrophic dysplasia (DTD) is a recessively inherited form of osteochondrodysplasia, presenting with disproportionate short stature and multiple orthopedic problems. The clinical oral manifestations include either cleft palate or submucous cleft palate in at least half of the patients. Histological studies have shown alterations in growth plate, articular, laryngeal, tracheal, and ear cartilages. Mutations in the DTDST gene, which codes for the sulphate transporter membrane protein, are responsible for the disease. Thirty-three patients were studied for speech characteristics and their correlation with cephalometric dimensions. Hyponasality was observed in 13 and misarticulation of /R/, /S/, or /L/ sounds in 17 of the 33 patients. Neither of these correlated with the occurrence of palatal deformities. Hyponasality was atypical and did not correlate with the obtained nasalance scores. Cephalometric measurements reflecting the size of the orofacial area of the vocal tract were short in the DTD patients compared with those in the healthy controls. The specific speech characteristics in DTD probably result from both the altered size and shape of the vocal tract and the structural and functional abnormalities of the laryngeal and tracheal cartilages.

Skeletal stability following mandibular advancement and rigid fixation with polylactide biodegradable screws.

Skeletal stability during the first year after mandibular advancement surgery and fixation using biodegradable self-reinforced poly-l-lactide (SR-PLLA) screws, without postoperative intermaxillary fixation, was studied in 25 patients by means of cephalometric measurements. The magnitude of advancement was on average, 3.88 mm at pogonion (PG) (range 1.25-6.5 mm) and 4.57 mm at B-point (range 2.75-7.5 mm). After one year a mean relapse backwards of 0.59 mm at the PG (15%) and 0.78 mm at the B-point (17%) was observed. Nineteen patients (76%) and 17 patients (68%) were stable at PG and B-point, respectively. SR-PLLA screws are considered to be comparable to other forms of rigid internal fixation for fixation of bilateral splitting osteotomies after mandibular advancement, as far as skeletal stability is concerned.

Genetic craniofacial aberrations.

Many craniofacial and dental anomalies have a genetic background. Much research related to the molecular pathology of genetic conditions is being carried out, and new information related to mapping of disease genes, gene identification, and mutations in these genes is accumulating with incredible speed. It is important to be well informed of the molecular background of the conditions that we treat at anomaly clinics. This article reviews the most recent molecular findings related to Turner syndrome, Beckwith-Wiedemann syndrome, Marfan syndrome, Treacher Collins syndrome, cleidocranial dysplasia, and cleft lip and palate.

Craniofacial structure in diastrophic dysplasia--a cephalometric study.

Diastrophic dysplasia (DTD) is a well characterized, recessively inherited osteochondrodysplasia. Forty-eight patients with DTD were studied for craniofacial characteristics. Of these patients, 58% had cleft palate. A cephalometric analysis based on lateral cephalograms was performed. We observed a short anterior cranial base, vertical nasal bones, short and posteriorly positioned upper and lower jaws, increased anterior facial height, increase in the sagittal length of the body of the cervical vertebrae, and an abnormal dens of the second cervical vertebra. DTDST, in which mutations responsible for the disease occur, is a gene that codes for a sulphate transporter membrane protein. The craniofacial anomalies in DTD most likely result from deficient development and growth of cartilaginous structures and are probably due to defective sulfation of the proteoglycans of the cartilage.

The effect of violin playing on the bony facial structures in adolescents.

Holding a violin between shoulder and chin needs a special kind of muscle function. The purpose of this investigation was to determine whether this kind of muscular activity is a modifying factor for facial growth in adolescence. The bony facial dimensions of 24 adolescent violin students attending colleges of music with a playing history of 5-11 years were measured from lateral and posteroanterior cephalograms and panoramic tomograms of the jaws. The dimensions were compared with those of sex- and age-matched controls. Significant differences were found between violin players and controls. The players had higher faces, especially on the right side of the lower face and in the right mandibular ramus. The players also had more proclined upper and lower incisors than the controls. It is concluded that the overall greater facial height in violinists reflects the increased face muscle activity and the higher bony dimensions of the right side of the face are due to the muscular activity produced on that side to balance the load caused by the violin on the left. The greater proclination of the incisors is the result of an altered balance of muscular activity between tongue and lip, and the pressure of the violin to the chin.