Cosimo Tudisco

Mandibuloacral Dysplasia Is Caused by a Mutation in LMNA-Encoding Lamin A/C

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder, characterized by postnatal growth retardation, craniofacial anomalies, skeletal malformations, and mottled cutaneous pigmentation. The LMNA gene encoding two nuclear envelope proteins (lamins A and C [lamin A/C]) maps to chromosome 1q21 and has been associated with five distinct pathologies, including Dunnigan-type familial partial lipodystrophy, a condition that is characterized by subcutaneous fat loss and is invariably associated with insulin resistance and diabetes. Since patients with MAD frequently have partial lipodystrophy and insulin resistance, we hypothesized that the disease may be caused by mutations in the LMNA gene. We analyzed five consanguineous Italian families and demonstrated linkage of MAD to chromosome 1q21, by use of homozygosity mapping. We then sequenced the LMNA gene and identified a homozygous missense mutation (R527H) that was shared by all affected patients. Patient skin fibroblasts showed nuclei that presented abnormal lamin A/C distribution and a dysmorphic envelope, thus demonstrating the pathogenic effect of the R527H LMNA mutation.

Long-term comparative results in patients with congenital clubfoot treated with two different protocols

Background: Long-term follow-up studies of adults who had been treated for congenital clubfoot as infants are rare. The purpose of this study was to review and compare the long-term results in two groups of patients with congenital clubfoot treated with two different techniques. In both groups, treatment was started within the first three weeks of life by manipulation and application of toe-to-groin plaster casts, with a different technique in each group. At the end of the manipulative treatment, a posteromedial release was performed when the patient was between eight and twelve months of age in the first group and a limited posterior release was performed when the patient was between two and four months of age in the second group. Methods: At the follow-up evaluations, all patients were interviewed and examined, and standing anteroposterior and lateral radiographs and computed tomography scans of the foot were made. The results of treatment were graded according to the system of Laaveg and Ponseti. Numerous angular measurements were made on the radiographs, and the measurements in the two groups were compared. Results: The first group, which included thirty-two patients (forty-seven clubfeet), was followed until an average age of twenty-five years. The second group, with thirty-two patients (forty-nine clubfeet), was followed until an average age of nineteen years. In the first group, there were two excellent, eighteen good, eleven fair, and sixteen poor results. In the second group, there were eighteen excellent, twenty good, six fair, and five poor results. According to the system of Laaveg and Ponseti, the mean rating in the first group was 74.7 points and that in the second group was 85.4 points. Conclusions: In the second group, use of Ponsetis manipulation technique and cast immobilization followed by an open heel-cord lengthening and a limited posterior ankle release gave much better long-term results than those obtained in the first group, treated with our manipulation technique and cast immobilization followed by an extensive posteromedial release of the foot. In our hands, this operation did not prevent relapse, and neither cavovarus nor forefoot adduction was completely corrected. Level of Evidence: Therapeutic study, Level III-2 (retrospective cohort study). See Instructions to Authors for a complete description of levels of evidence.

Treatment approaches for congenital pseudarthrosis of tibia: results of the EPOS multicenter study. European Paediatric Orthopaedic Society (EPOS).

&NA; This study was designed to analyze the different therapeutic methods used by European Paediatric Orthopaedic Society members from 13 countries for congenital pseudarthrosis of tibia. The treatment data of 340 patients who underwent 1287 procedures for this condition were analyzed. The essential findings were that the method of choice needed to approach the biological problem with the aims of: (1) resecting the pseudarthrosis to provide stability, the basic requirement for bony consolidation; (2) correcting length discrepancy and axial deformity; (3) achieving fusion; and (4) solving the additional problems around the main deformity such as alignment, leg length discrepancy and ankle valgus. The Ilizarov technique emerged as being the optimal method, having the highest rate of fusion (75.5%) of pseudarthrosis and rate of success in correction of the additional deformities. There was also consensus that surgery should be avoided before the third year of life.

Congenital pseudarthrosis of the tibia: history, etiology, classification, and epidemiologic data.

&NA; Congenital pseudarthrosis of the tibia is a rare disease with a variable history. The pseudarthrosis is usually not present at birth (and therefore is not truly congenital) but occurs during the first decade of life. Paget in 1891 was the first to describe a case. The etiology is unknown. Neurofibromatosis plays a role in approximately 50% of patients. In the others, hereditary and mechanical factors are debated. Various (morphologic) classification systems have been proposed (Andersen, Boyd, Crawford). Because the appearance changes during the course of the disease, all classification systems have limited value: the determining factor is the stage of the disease at which it was classified. Because of the rarity of the disease and the variability of its history, the European Pediatric Orthopaedic Society decided to carry out a multicenter study on this disease. This paper presents the epidemiologic data on the patients involved. Data have been gathered on 340 patients from 13 countries. Two hundred patients were male (58.8%), 140 were female (41.2%). The right side was affected in 165 patients (48.5%) and the left side in 172 (50.6%); 3 patients had bilateral disease. Symptoms of neurofibromatosis were present in 54.7%. Histologic examinations in 192 patients showed a nonspecific appearance in 45.3%; in 15.6% the ultrastructure resembled fibrous dysplasia, and in 39% there was histologic evidence of neurofibromatosis. Most of the lesions were initially localized in the middle or distal third of the tibia. In 29% the localization changed during the course of the disease.

Proteoglycans of human infant intervertebral disc. Electron microscopic and biochemical studies.

The ground substance of the intervertebral disc consists primarily of proteoglycans, which give the tissue its stiffness to compression and its resiliency. To investigate the structure and composition of these molecules, we extracted them from human infant nucleus pulposus under associative conditions and from human infant annulus fibrosus and cartilage end-plate under dissociative conditions. We examined the degree of aggregation, the composition, the electron microscopic appearance, and the dimensions of the proteoglycans of the intervertebral disc and compared their structure and dimensions with those of the proteoglycans from bovine hyaline cartilage. Aggregates represented 52 per cent of the proteoglycans of the nucleus pulposus between the ages of one and ten days but only 28 per cent between the ages of six and eight months. Preparations from the corresponding annuli contained 59 per cent aggregates at one to ten days and 47 per cent at six months. The corresponding cartilage end-plate preparations contained 45 and 40 per cent aggregates. The proteoglycans of the annulus fibrosus and cartilage end-plate contained more protein and less hexosamine than did those of the nucleus pulposus. Electron microscopy showed that approximately two-thirds of the aggregates from nucleus pulposus consisted of very short hyaluronate filaments with closely packed monomers. The other third had longer hyaluronate filaments and wider distances between monomers, and closely resembled the aggregates from the annulus fibrosus and cartilage end-plate. Aggregated monomers consisted of two segments: a thin segment connecting directly to the hyaluronic acid filament and a thick segment extending peripherally from the thin segment. The thin segment formed about 12 per cent of the total monomer length in the samples from all three disc tissues. The lower proportion of aggregated monomers, the lower protein content, and the smaller aggregates with closely packed monomers suggest that the nucleus pulposus may contain less link protein than do the annulus fibrosus and cartilage end-plate. Compared with proteoglycan aggregates from bovine hyaline cartilage, proteoglycan aggregates from human intervertebral disc were shorter and had fewer monomers and wider spacing between monomers. The aggregated monomers from the three components of the intervertebral disc had an average length of 209 +/- 90 nanometers, compared with 210 +/- 114 nanometers for monomers from hyaline cartilage of skeletally mature cows, 250 +/- 116 nanometers for monomers from hyaline cartilage of skeletally immature calves, and 288 +/- 108 nanometers for monomers from fetal animals.(ABSTRACT TRUNCATED AT 400 WORDS)

Free vascular fibular transfer in congenital pseudoarthrosis of the tibia: results of the EPOS multicenter study. European Paediatric Orthopaedic Society (EPOS).

&NA; This paper presents a review of the literature, describes the principal authors (B.R.) personal experience and provides the results of the European Paediatric Orthopaedic Society (EPOS) multicenter study. The objective is to evaluate the present status and future role of free vascular fibular transfer in treating congenital pseudoarthrosis of the tibia. Variables such as the selection of cases, age at operation, technical surgical details and postoperative results will be considered. The data on the EPOS study were incomplete at the time of writing, but the considerable amount of information already amassed is a valuable contribution to this updated report.

Vertebra plana. Long-term follow-up in five patients.

Five patients with vertebra plana were followed for twelve to thirty years after the diagnosis had been made. Histiocytosis X had been the presumptive diagnosis in all five patients. Their ages at diagnosis ranged from four to twelve years and at follow-up, from nineteen to forty years. When they were last seen, none of the patients complained of symptoms related to the original disease, and the radiographs showed reconstitution of the vertebral height equivalent to 48 to 95 per cent of normal, with no sign of osteoarthritis. The best radiographic results occurred in the two youngest patients, who had involvement of the first lumbar vertebra, whereas the patient who was oldest at follow-up, with vertebra plana in the ninth thoracic vertebra, had the worst result. The four patients with just vertebra plana were treated with a plaster jacket and a brace, whereas the one with multicentric skeletal involvement had chemotherapy as well as orthopaedic treatment.

Functional results at the end of skeletal growth in 30 patients affected by congenital pseudoarthrosis of the tibia.

&NA; From a multicentric study on Congenital Pseudoarthrosis of the tibia (CPT) conducted on 340 patients, we evaluated the functional results on a group of thirty patients who were at the end of skeletal growth (age ≤ 16 years). The prognosis of CPT is very much related to the radiologic classification. Crawford type 2 and Crawford type 4 pseudoarthrosis have a worse prognosis, with a lower percentage of fusion at the site of pseudoarthrosis. Crawford 4 patients have the worst functional results. Most of them showed a severe leg length discrepancy, needed a permenent brace, with an ankle joint function fair or poor. The presence of fibula pseudoarthrosis seems to be responsible for most of the worst functional results. The level of deformity caused by either the natural course of the disease or its treatment, is decisive in the evalution of the functional results.

Long-term results of open sternocleidomastoid tenotomy for idiopathic muscular torticollis.

At the end of their skeletal growth, we evaluated the cases of sixty-seven patients who had had an open tenotomy of the sternal and clavicular origins of the sternocleidomastoid muscle for idiopathic muscular torticollis. The average length of follow-up was 15.4 years, and the average age at the last follow-up was 23.9 years. The patients were divided into three groups according to their age at the time of operation. Group I consisted of patients who were operated on between the ages of five months and six years; Group II, of patients who were operated on between the ages of seven and eleven years; and Group III, of patients who were operated on when they were twelve years old or older. According to our method of evaluation, 37 per cent of the patients had a good, 45 per cent had a fair, and 18 per cent had a poor result. The patients in Group I had the best results and those in Group III, the worst. In general, the patients age at operation, the duration of the disease, and the severity of the deformity before the operation had the major effects on both cosmetic and functional results.

The fibula in congenital pseudoarthrosis of the tibia: the EPOS multicenter study. European Paediatric Orthopaedic Society (EPOS).

&NA; Fibular involvement in congenital pseudoarthrosis of the tibia (CPT) can be either a rare isolated pathology or is in association with the tibial changes. Out of 282 patients with CPT who had complete radiographic work‐up, 62% (almost two thirds) demonstrated fibular pathology: 36% had true fibular pseudoarthrosis and the rest, i.e., 26% had fibular hypoplasia or dysplastic fibula. Neurofibromatosis was found in 62% of the patients with fibular pathology. The typical radiological features of tibial pseudoarthrosis are often missing in patients with fibular pathology. It is most probably because fibular changes precede the tibial involvement. In 250 patients with tibial surgical treatment, the highest rate of fusion occurred in patients with fibular involvement compared with those with normal fibula.