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.
Patient 2 is a 3-year-old boy, born to second degree consanguineous parents at term by cesarean section, in view of prolonged labor. Birth weight was 2.5 kg (−2 SD). He cried immediately after birth. He is the only child of his parents. Maternal antenatal scan at 6 months of gestation was suggestive of fetal limb deformity that was confirmed after birth. He was referred for evaluation of deformity of bilateral feet, elbows and right knee noted since birth. At birth, he was also found to have cleft palate for which he was operated at 1 year of age.\nAt 6 weeks, his height was 52 cm (−2 SD), OFC 37 cm (−2 SD) and weight 3.3 kg (−2 SD). He had prominent forehead, depressed nasal bridge, long philtrum, telecanthus (Fig. ), and high arched palate. His hair was curly (Fig. ), teeth and nails were normal. Hypermobility of bilateral hip joints was noted along with bilateral dislocated knees, elbows and bilateral clubfeet (Fig. ). He had spatulate thumbs (Fig. ), cylindrical fingers (Fig. ) with short and broad fingertips, and joint laxity. Hearing was normal. There was no evidence of compressive myelopathy. All other examinations were unremarkable. Echocardiography showed normal heart. He achieved head control at 5 months, roll over at 7 months, sitting with support at 10 months, sitting without support at 15 months, crawling at 20 months. He started babbling at 6 months, spoke bisyllables at 15 months and few words with meaning at 20 months.\nRadiograph of skull was unremarkable (Fig. ). Ultrasound of knees at 6 weeks of age suggested absent right patella. Radiographs showed bilateral dislocated elbows (Fig. ), absent right patella (Fig. ), coronal clefts in vertebrae (Fig. ), cervical vertebral kyphosis with subluxation at C4-C5 (Fig. ), and double calcaneum ossification with club feet (Fig. ). Radiographs at 3 months (Fig. and i) and 1 year (Fig. ) suggested delayed carpal ossification. Radiographs at 3 months and 1 year showed thoracolumbar scoliosis (Fig. ) and small capital femoral epiphysis (Fig. ). Thyroid profile was done in view of delayed bone age and was found to be normal. His complete blood counts, serum calcium, serum phosphorous, alkaline phosphatase, and complete urine analysis were normal.