Philippe Wicart

PRKAR1A and PDE4D Mutations Cause Acrodysostosis but Two Distinct Syndromes with or without GPCR-Signaling Hormone Resistance

CONTEXT Acrodysostosis is a rare skeletal dysplasia that is associated with multiple resistance to G protein-coupled receptor (GPCR) signaling hormones in a subset of patients. Acrodysostosis is genetically heterogeneous because it results from heterozygous mutations in PRKAR1A or PDE4D, two key actors in the GPCR-cAMP-protein kinase A pathway. OBJECTIVE Our objective was to identify the phenotypic features that distinguish the two genotypes causing acrodysostosis. PATIENTS AND METHODS Sixteen unrelated patients with acrodysostosis underwent a candidate-gene approach and were investigated for phenotypic features. RESULTS All patients had heterozygous de novo mutations. Fourteen patients carried a PRKAR1A mutation (PRKAR1A patients), five each a novel PRKAR1A mutation (p.Q285R, p.G289E, p.A328V, p.R335L, or p.Q372X), nine the reported PRKAR1A p.R368X mutation; two patients harbored a mutation in PDE4D (PDE4D patients) (one novel mutation, p.A227S; one reported, p.E590A). All PRKAR1A, but none of the PDE4D mutated patients were resistant to PTH and TSH. Two PRKAR1A patients each with a novel mutation presented a specific pattern of brachydactyly. One PDE4D patient presented with acroskyphodysplasia. Additional phenotypic differences included mental retardation in PDE4D patients. In addition, we report the presence of pigmented skin lesions in PRKAR1A and PDE4D patients, a feature not yet described in the acrodysostosis entity. CONCLUSIONS All PRKAR1A and PDE4D patients present similar bone dysplasia characterizing acrodysostosis. Phenotypic differences, including the presence of resistance to GPCR-cAMP signaling hormones in PRKAR1A but not PDE4D patients, indicate phenotype-genotype correlations and highlight the specific contributions of PRKAR1A and PDE4D in cAMP signaling in different tissues.

Prevention of ankle valgus after vascularized fibular grafts in children

Ankle valgus after the use of vascularized fibular grafts is a specific complication of the donor site ankle in the growing child. Incidence of this deformity and prevention strategy are documented poorly. The goal of the current study was to evaluate the rate of such deformities and to analyze efficiency of two prevention methods. Charts of 20 children surgically treated for sarcomas of long bones with a mean followup of 4.1 years were studied retrospectively. Ankle valgus was considered if the tibiotalar angle on radiographs with the patient standing was 5° or greater in valgus than that of the opposite ankle, and deformity was considered severe if it required surgical treatment. Prevention was done in some patients with a tibiofibular syndesmotic screw or with reconstruction of the fibula using a tibial autograft. Valgus occurred in nine patients (45%) and was severe in five (25%). Valgus prevention with a syndesmotic screw was efficient and lacking in complications, whereas patients with fibula reconstruction had a high incidence of deformity and relevant complications. The authors recommend using a tibiofibular screw in all patients whose growth plates are open in the lower limbs at the time of surgery.

Therapeutic management of hypophosphatemic rickets from infancy to adulthood

In children, hypophosphatemic rickets (HR) is revealed by delayed walking, waddling gait, leg bowing, enlarged cartilages, bone pain, craniostenosis, spontaneous dental abscesses, and growth failure. If undiagnosed during childhood, patients with hypophosphatemia present with bone and/or joint pain, fractures, mineralization defects such as osteomalacia, entesopathy, severe dental anomalies, hearing loss, and fatigue. Healing rickets is the initial endpoint of treatment in children. Therapy aims at counteracting consequences of FGF23 excess, i.e. oral phosphorus supplementation with multiple daily intakes to compensate for renal phosphate wasting and active vitamin D analogs (alfacalcidol or calcitriol) to counter the 1,25-diOH-vitamin D deficiency. Corrective surgeries for residual leg bowing at the end of growth are occasionally performed. In absence of consensus regarding indications of the treatment in adults, it is generally accepted that medical treatment should be reinitiated (or maintained) in symptomatic patients to reduce pain, which may be due to bone microfractures and/or osteomalacia. In addition to the conventional treatment, optimal care of symptomatic patients requires pharmacological and non-pharmacological management of pain and joint stiffness, through appropriated rehabilitation. Much attention should be given to the dental and periodontal manifestations of HR. Besides vitamin D analogs and phosphate supplements that improve tooth mineralization, rigorous oral hygiene, active endodontic treatment of root abscesses and preventive protection of teeth surfaces are recommended. Current outcomes of this therapy are still not optimal, and therapies targeting the pathophysiology of the disease, i.e. FGF23 excess, are desirable. In this review, medical, dental, surgical, and contributions of various expertises to the treatment of HR are described, with an effort to highlight the importance of coordinated care.

The Wiltse paraspinal approach to the lumbar spine revisited: an anatomic study.

The paraspinal posterior approach to the lumbar spine initially was described for spinal fusion, particularly for treatment of lumbosacral spondylolisthesis. Despite the technical details described by Wiltse et al, the exact location of the sacrospinalis muscle that must be split remains unclear. We sought to clarify the anatomic description of the paraspinal posterior approach to the lumbar spine, and to provide topographic landmarks for facilitating this surgical approach. Fifty cadavers were dissected using an anatomic transmuscular paraspinal approach. The level of the natural cleavage plane between the multifidus and the longissimus parts of the sacrospinalis muscle was noted, and measurements were taken between this level and the midline at the level of the spinous process of L4. A natural cleavage plane between the multifidus and the longissimus parts of the sacrospinalis muscle was present in all specimens. There was a fibrous separation between the two muscular parts in 88 of 100 cases. The mean distance between the level of the cleavage plane and the midline was 4.04 cm (range, 2.4-7 cm). Small arteries and veins were present at the level of the cleavage plane in all specimens. These vascular landmarks make it easier to locate the muscular cleavage plane and reach the articular and transverse processes during the paraspinal approach.

Comparative study: Ponseti method versus French physiotherapy for initial treatment of idiopathic clubfoot deformity.

Background Nonoperative treatment avoids the complications after extensive surgery for idiopathic clubfeet. The purpose of this study was to compare retrospectively French physiotherapy and Ponseti method used to treat idiopathic clubfoot in 2 institutions. Methods Two hundred nineteen idiopathic clubfeet (146 patients) managed during a 3-year period (2000 to 2003) were included in this study: 116 clubfeet in group FM were treated according to modified French physiotherapy (with percutaneous heel-cord tenotomy in 17%) and 103 clubfeet in group PM were treated according to the Ponseti method. The use of further surgery was considered as failure of the nonoperative management: complete posteromedial release were noted poor, limited posterior release were noted fair, and nonrelease surgery or nonoperated feet were scored with the modified Ghanem score. Results After a mean follow-up of 5.5 years (range, 2.5 to 7.4 y), similar rate of surgery was performed in both groups (21% in group FM and 16% in group PM) but complete posteromedial release was mainly done in group FM (19% of feet), and limited surgery was done in group PM. Results were noted excellent, good, fair, and poor in respectively 55%, 20%, 6%, and 19% of patients in group FM and 79%, 15%, 4%, and 2% of patients in group PM. Results for Dimeglio grade II clubfeet were not different, but results for grade III and grade IV clubfeet were better in PM group. Conclusions Ponseti method enables reduction of extensive surgery compared with French physiotherapy mainly for severe deformities.

Plantar opening-wedge osteotomy of cuneiform bones combined with selective plantar release and dwyer osteotomy for pes cavovarus in children.

Neurological pes cavovarus is a challenging deformity to treat during childhood. Based on physiopathology, we propose the following original surgical procedure. Plantar-opening wedge osteotomy of the three cuneiform bones, preceded by selective plantar release, corrects forefoot pronation which is the primum movens of the deformity, and corrects the cavus at its apex. A calcaneal valgisation closing wedge osteotomy, is indicated if pre-operative planning revealed subtalar joint stiffness, incompatible with secondary hind foot realignment in valgus. The follow-up had to be at least 5 years or to reach skeletal maturity. Twenty-six children (36 feet) satisfied these criteria. Mean age at surgery was 10.3 years old. All the children had a neurological disease which was progressive for 65% of them (75% of the feet). Mean follow-up was 6.9 years. This treatment was effective, with a mean percentage of cavus correction of 74%, reaching 100% for 31% of the feet. Complete or partial cavus correction was still observed at last follow-up for 75% of the feet. At last follow-up, global result was satisfactory in 63.9% and non satisfactory in 36.1% of feet. Flat-foot was observed, of minor type, in only 2 cases. Apart from triple arthrodesis, iterative surgery relative to residual deformity (foot adduction, plantar sticking of the first metatarsal head) was indicated for 4 feet (11%). A triple arthrodesis was required in 12 cases (33%). In conclusion, this treatment provides mid-term satisfactory correction of the cavus and may allow avoiding triple arthrodesis at skeletal maturity.

Closed reduction with traction for developmental dysplasia of the hip in children aged between one and five years

The treatment of developmental dysplasia of the hip diagnosed after the first year of life remains controversial. A series of 36 children (47 hips), aged between one and 4.9 years underwent gradual closed reduction using the Petit-Morel method. A pelvic osteotomy was required in 43 hips (91.5%). The patients whose hips did not require pelvic osteotomy were among the youngest. The mean age at final follow-up was 16.1 years (11.3 to 32). The mean follow-up was 14.3 years (10 to 30). At the latest follow-up, 44 hips (93.6%) were graded as excellent or good according to the Severin classification. Closed reduction failed in only two hips (4.3%) which then required open reduction. Mild avascular necrosis was observed in one (2.1%). The accuracy of the reduction and associated low complication rate justify the use of the Petit-Morel technique as the treatment of choice for developmental dysplasia of the hip in patients aged between one and five years.

Free vascularised fibular graft for reconstruction of defects of the lower limb after resection of tumour

We describe a retrospective review of 38 cases of reconstruction following resection of the metaphysiodiaphysis of the lower limb for malignant bone tumours using free vascularised fibular grafts. The mean follow-up was for 7.6 years (0.4 to 18.4). The mean Musculoskeletal Tumor Society score was 27.2 (20 to 30). The score was significantly higher when the graft was carried out in a one-stage procedure after resection of the tumour rather than in two stages. Bony union was achieved in 89% of the cases. The overall mean time to union was 1.7 years (0.2 to 10.3). Free vascularised fibular transfer is a major operation with frequent, but preventable, complications which allows salvage of the limb with satisfactory functional results.

Clubfoot posteromedial release: advantages of tibialis anterior tendon lengthening.

The aim of this study is to evaluate the eventual advantages of tibialis anterior (TA) tendon lengthening during clubfoot posteromedial release. A continuous series of 60 idiopathic clubfeet has been retrospectively studied. Tibialis anterior lengthening (TAL) began to be performed in 1984. Two groups of 30 feet have been distinguished: without TAL (before 1984) and with TAL (after 1984). There was no significant difference between the 2 groups concerning mean age at surgery, preoperative clinical and radiologic data. Mean postoperative follow-up was 10 years and minimal follow-up required was 5 years. TAL decreased Triceps surae relative insufficiency and improved monopodal jump. TAL balanced TA and peroneus longus, decreased dynamic supination and balanced forefoot pronation and supination. The feet without TAL presented lack of anteromedial support (20% without TAL, 0% with TAL) and medial arch cavus with dorsal talo-navicular subluxation (20% without TAL, 3,3% with TAL). TAL decreased the rate of recurrence and surgical revision.

Three-dimensional stereoradiographic modeling of rib cage before and after spinal growing rod procedures in early-onset scoliosis

BACKGROUND Early-onset scoliosis frequently leads to major thoracic deformity and pulmonary restrictive disease. Growing rods surgical techniques were developed to achieve a satisfactory correction of the spinal curves during growth. The effect on the rib cage deformity has not yet been documented. The purpose of this study was to analyze the changes of the thoracic geometry after implantation of a growing rod, and to evaluate a stereoradiographic reconstruction method among young scoliotic patients. METHODS Four patients were enrolled in the study, and four additional patients in the reproducibility study. Three-dimensional spine and rib cage models were generated after low-dose stereoradiographic imaging (EOS). Three-dimensional parameters were computed before and after surgery. Intra and inter-observer reproducibility was calculated, and the accuracy was assessed in comparison to volumetric CT-scan. FINDINGS The average Cobb angle was reduced from 50.8 degrees to 26 degrees . The surgery resulted in a complex 3D effect on the rib cage, combining frontal, lateral, and axial rotation. This effect was dependent of the side (concave or convex), and the position relative to the apical vertebra. Mean errors in comparison to CT-scan were 3.5mm. INTERPRETATION The results on the spinal deformity are comparable to other series. The effect on the rib cage is of a smaller magnitude than in the case of a spinal arthrodesis. A longer follow-up is necessary to confirm the positive effect on the rib cage deformity. Further research should be performed to improve the reproducibility of 3D parameters.