A Norwegian 19-year old male with healthy, non-consanguineous parents attended a reference center for rare connective tissue disorders with a diagnosis of Larsen syndrome. The diagnosis was based on clinical findings in the neonatal period. He was born with dislocated, hyperextended knees up to 90 degrees, which was treated with serial casting without success. This treatment was followed by surgery with Ilizarov’s frame and braces at 9 months of age. Adductovarus of the feet responded well to non-surgical treatment. His neck was kyphotic with a subluxation of C3-C4 and dislocations of C4-C5 and C5-C6. A fixation from C1 to C5 was performed bilaterally using a bone graft from his rib when he was 16 months old. A small mandible and occult cleft palate were observed. Cerebral ultrasound showed some dilatation of the ventricular system. Hypotonia and joint hypermobility of the knees, ankles, and wrists were also observed. In addition, he had an umbilical hernia and a large, left medial inguinal hernia.\nAs a toddler, he had recurrent serous otitis media and was examined by an ENT consultant. A combined conductive and sensorineural hearing loss was detected and necessitated a hearing aid. The patient was followed by an ophthalmologist because of hyperopia, astigmatism, and exotropia. His hyperopia was corrected with glasses, and the exotropia was treated with patching and strabismus surgery. Further, he has asthma and atopic eczema.\nAt 10 years of age, the patient was admitted to the hospital with acute chest pain. Echocardiography and CT showed a dilated and dissected aortic root to 7 cm, aortic valve regurgitation, and hemopericardium but normal dimensions in the aortic arch. Emergency surgery to replace the aortic root with a mechanical valve was performed. Following surgery, the patient was treated with beta-blockers and warfarin. At this point a PubMed search was carried out. According to his medical records, one not named case article about a child with Larsen syndrome and arterial tortuosity and dilatation was found. No clinical diagnostic screening was performed.\nAt age 19, MR angiography revealed a dilatation of 44 mm of the ascending aorta and arch distal to the graft. There was also severe tortuosity of the vertebral, carotid, and subclavian arteries (Fig. ) and a moderate dilatation of the left iliac artery. According to guidelines [], surgery is recommended at ascending aortic diameter of 42 mm in LDS. The patient has now undergone aortic arch surgery.\nHe had a radius fracture when he was 15 years old. DEXA scan revealed osteopenia with an age-matched score of − 2. At age 20, he was 167 cm tall (2 cm below the 3rd percentile for his age and gender), and a whole body skeletal survey revealed scaphocephaly (Fig. ), generally slender long bones and slender ribs. He had slight platyspondyly with biconcave endplates. There was slight scalloping of the posterior vertebral wall of some of the lumbar vertebras []. Reminescents of coronal clefts could not be excluded []. There were small olistheses in the coronal and sagittal planes, especially in the lumbar region, and wire fixation in the cervical spine. He had a flattened thoracic kyphosis (Figs. , and ). No significant scoliosis was noted. There were no signs of extra ossification centers in the calcaneus. CT of the aorta at age 19 also demonstrating the spine and hips showed dural ectasia and slight protrusion of acetabuli bilaterally [].\nThe widespread arterial affection in addition to other clinical and radiological observations gave rise to the suspicion of another genetic connective tissue disorder rather than Larsen syndrome. One of the physicians at the resource center suspected that his diagnosis could be LDS based on his medical history. However, his hearing loss and extensive skeletal affection caused a somewhat unusual and more pronounced phenotype than what is typically seen in LDS, at least in the experience of this physician. He was then referred for a second opinion by a clinical geneticist, who confirmed the findings of arachnodactyly, mild short stature, pectus carinatum, bifid uvula, micrognathia, hypertelorism, down-slanting palpebral fissures, and wide, atrophic scars. High throughput sequencing (HTS) analysis of 34 genes associated with hereditary connective tissue disorders identified two sequence variants: a novel unclassified missense mutation, c.1361 T > C (p.Leu454Pro) in the gene for LDS type 2, TGFBR2 (NM_003242.5), as well as a likely pathogenic nonsense mutation, c.115C > T (p.Gln39*) in COL2A1 (NM_001844.4), a gene that encodes collagen type 2. Parental testing indicated that the variant in TGFBR2 was de novo, while the variant in COL2A1 was inherited from the father. No pathogenic or unclassified variant was identified in the gene for autosomal dominant Larsen syndrome, FLNB.\nAn ophthalmological reexamination revealed no new findings. The lens and the vitreous were clear, and there was no sign of retinal degeneration or other pathology in the posterior segment of the eyes. The axial length was in the normal range, indicating an eye globe of normal size.
A 5 year old Japanese girl who had previously been diagnosed with LS was referred to the orthodontic clinic in the Fukuoka Dental College Medical and Dental Hospital in Fukuoka, Japan, because she had posterior crossbite. She is the second child with healthy parents who have no family history of genetic disorders. The diagnosis of LS was based on clinical findings. At birth, she had knee joint dislocations, equinovarus foot deformities, and a cleft of the soft palate only with no extension to the hard palate, alveolus, or lip (type 1 of Veau’s classification []). Operations for dislocations and equinovarus deformities were respectively performed at the ages of 4 and 9 months. Furlow’s palatoplasty was performed for the soft palate repair when she was 1.7 years old. She had not undergone any orthodontic treatment including presurgical orthodontics. The Enjoji scale [], recorded at the age of four, revealed delays of social behavior and emotional and language development.\nShe underwent orthodontic examinations, including general, facial and intraoral examinations, lateral and frontal cephalometric analyses, and a study model examination for orthodontic diagnosis. On general examination, her height and weight were 112.3 cm and 15.1 kg, respectively. These were below the reference for the 75th and 10th percentile in her age and sex group, respectively. The hand–wrist radiograph was used to examine her skeletal maturity (Fig. a). The patient's skeletal age was matched at 5.3 years by the TW2 RUS method applied to the Japanese population, whereas the Greulich–Pyle Atlas method estimated the corresponding age at 5.5 years []. Based on these methods, her skeletal age almost matched her chronological age of 5.6 years. She had long cylindrically shaped fingers (Fig. b). Dysmorphic facial features were noted, including hypertelorism, a prominent forehead, depressed nasal bridge, and a flattened midface. Her facial profile was straight. Her chin point deviated toward the right side from the facial midline (Fig. ).\nIntraoral examination revealed the complete primary dentition with an overjet of 2.0 mm, an overbite of 2.0 mm, and mesial step-type terminal planes on both sides. There were no spaces around the fused tooth with the left deciduous central and lateral incisors in the upper dentition, while the lower dentition exhibited anterior crowding and mesial rotation of the first deciduous molars on both sides. On the right side, posterior crossbite was observed resulting from a functional lateral shift of the mandible owing to the premature contacts between the maxillary and mandibular right primary molars. In centric relation prior to the mandibular shifting, the mandibular dental midline was nearly consistent with the facial midline. In centric occlusion, the maxillary and mandibular dental midlines deviated 1.5 mm to the left and 2.0 mm to the right relative to the facial midline, respectively. As a result, the upper and lower dental midline discrepancy was 3.5 mm (Fig. ).\nOn study models examination, the arch widths between the primary canines, and the first and second molars were measured to compare them with the standard values obtained from Japanese children with normal primary occlusions (Fig. and Table ) []. In the case of the primary canine, all the distances of the bilateral tips and the bilateral palatal or lingual cervical lines were measured. In the cases of the primary molars, the distances between the bilateral buccal grooves of the first and second molars were also measured. On the maxillary and mandibular dentitions, all the arch width measurements were significantly smaller than one standard deviation (SD) below the Japanese norms matched for the patient’s age.\nThe panoramic radiograph showed that the maxillary left lateral incisor was congenitally missing. The tooth germ of the maxillary left second molar was not present. The tooth crown of the unerupted, maxillary right central incisor was rotated and was close to that of the maxillary right lateral incisor. The fused tooth with the left deciduous central and lateral incisors showed the union of tooth crowns by the dentin and two roots with independent root canals (Fig. ).\nFigure shows the lateral and frontal cephalogram of the patient. Cephalograms were taken in a standard manner with a magnification ratio of 1.1. Figure a, b shows the conventional cephalometric analyses. The results are given in Table . These indicated the posteriorly positioned maxilla and mandible (SNA, SNB, and facial angle), skeletal Class III jaw relationship (ANB), steep mandibular plane (FMA) with the large Gonial angle, and growth tendency of the mandible (Y-axis) toward the postero-inferior direction. Inclination of the maxillary primary incisors was within the normal range (U1 to SN), while the mandibular primary incisor inclined more lingually than the norm (L1 to Mandible) [].\nFigure c shows the facial depth measurements used in this study. The horizontal positions of the six landmarks in relation to a line perpendicular to the S–N line that passed through sella, were measured based on the method proposed by Ono []. The results of the facial depth measurements were shown in Table . The depths measured on Or, PTM, Pog, Me, and Ar were smaller than one SD below the Japanese norms matched for the patient’s age and sex, while the depth of the nasion was within the normal range []. For the posterior part of the mandible, the facial depths measured on Go were close to one SD below the norms. These indicated that the orbitale, the maxilla, and mandible were positioned posteriorly relative to the anterior cranial base.\nThe frontal cephalometric analysis was performed as shown in Fig. . The facial midline was drawn through the Crista Galli and perpendicular to the line that passed through the latero-orbitale (Lo) bilaterally. For each of the 14 landmarks used, the distance to the facial midline was measured on both sides. The facial widths were obtained based on the addition of the bilateral distances measured on each landmark []. Table shows the results of the facial width measurements. Compared with the Japanese norms matched for the patient’s age and sex, the cranial width measurements taken at MCB(p), Lo, OSM, OSL, and CN yielded values that exceeded the Japanese norms by one SD. The widths measured on the Mx, cMoU, and cMoL, were smaller than those of the Japanese norms, and indicated narrow maxillary basal arch and maxillary and mandibular dental arch widths.\nBased on the examinations performed, an orthodontic diagnosis of unilateral posterior crossbite due to a functional lateral shift of the mandible, a skeletal Class III jaw relationship, narrow maxillary and mandibular dental arches, mandibular anterior mild crowding, and congenital missing of the maxillary left lateral incisor and the maxillary left second molar was made. The proposed treatment plan included (1) the maxillary dental arch expansion to eliminate the premature contacts between the maxillary and mandibular right primary molars and to improve the lateral shift of the mandible, (2) observation of the jaw growth and occlusal development with potential options of the maxillary protraction and the mandibular dental arch expansion, and (3) a fixed appliance treatment for the permanent dentition. We initiated the treatment with the use of the removable expansion plate for the maxillary dental arch expansion. No obvious problems have been observed in treatment response of the patient so far.