Stéphanie Pannier

Traumatic hip dislocation in childhood.

Traumatic dislocation of the hip in childhood is uncommon and can be a consequence of minor trauma. The authors report a series of 35 dislocations in skeletally immature patients. Most were isolated posterior dislocations without acetabular lesions. In 75% of cases, reduction of the dislocation was easy. Nine children required surgery to remove interposed joint capsule and/or osteochondral fragments to achieve anatomic reduction. Outcomes were generally good, except in one patient in whom a displaced fracture of the femoral physis was followed by total head avascular necrosis. One case of partial necrosis had a satisfactory outcome. Epiphyseal necrosis, though uncommon, appeared to be inconsistent to prevent and hard to predict. Bone scan seems to be more effective than MRI for the detection of necrosis.

Activating Fgfr3 Y367C mutation causes hearing loss and inner ear defect in a mouse model of chondrodysplasia

Fibroblast growth factor receptor 3 (FGFR3) is a key regulator of skeletal development and activating mutations in FGFR3 cause skeletal dysplasias, including hypochondroplasia, achondroplasia and thanatophoric dysplasia. The introduction of the Y367C mutation corresponding to the human Y373C thanatophoric dysplasia type I (TDI) mutation into the mouse genome, resulted in dwarfism with a skeletal phenotype remarkably similar to that of human chondrodysplasia. To investigate the role of the activating Fgfr3 Y367C mutation in auditory function, the middle and inner ear of the heterozygous mutant Fgfr3(Y367C/+) mice were examined. The mutant Fgfr3(Y367C/+) mice exhibit fully penetrant deafness with a significantly elevated auditory brainstem response threshold for all frequencies tested. The inner ear defect is mainly associated with an increased number of pillar cells or modified supporting cells in the organ of Corti. Hearing loss in the Fgfr3(Y367C/+) mouse model demonstrates the crucial role of Fgfr3 in the development of the inner ear and provides novel insight on the biological consequences of FGFR3 mutations in chondrodysplasia.

Can procalcitonin measurement help the diagnosis of osteomyelitis and septic arthritis? A prospective trial

ObjectivesProcalcitonin (PCT) is an accurate marker for differentiating bacterial infection from non-infective causes of inflammation or viral infection. However, there is only one study in children which tested procalcitonin as a diagnostic aid in skeletal infections. With this study we sought to evaluate the sensitivity, specificity and predictive values of procalcitonin for identifying bone and joint infection in children evaluated in the emergency department for non traumatic decreased active motion of a skeletal segment.MethodsPatients aged 1 month to 14 years were prospectively included in the emergency department when suspected for osteomyelitis or septic arthritis. Procalcitonin levels, C reactiv protein, white blood cell count were measured and bacteriological samples were collected before initiation of antibiotic treatment. Patients were assigned to 3 groups according to the degree of suspected infection: group 1 confirmed infection, group 2 presumed infection and group 3 non infected patients.ResultsThree hundred thirty nine patients were included (118 girls and 221 boys). Group 1 comprised 8 patients (2 had PCT levels > 0.5 ng/ml). Two had osteomyelitis and 6 septic arthritis. Forty children were incuded in group 2 (4 had PCT levels > 0.5 ng/ml). Eighteen had presumed osteomyelitis and 22 presumed septic arthritis. Group 3 comprised 291 children (9 PCT levels > 0.5 ng/ml) who recovered without antibiotic treatment. The specificity of the PCT as a marker of bacterial infection (comparing Group 1 and Group 3) was 96.9% [95% CI, 94.2-98.6], the sensitivity 25% [95% CI, 3.2-65.1], the positive predictive value (PPV) 18.2% [95% CI, 2.3-51.8] and the negative predictive value (NPV) 97.9% [95% CI, 95.5-99.2].ConclusionPCT is not a good screening test for identifying skeletal infection in children. Larger studies are needed to evaluate still more the place of PCT measurements in the diagnosis of osteomyelitis and septic arthritis.

Delayed bone age due to a dual effect of FGFR3 mutation in Achondroplasia

Achondroplasia (ACH), the most common form of human dwarfism is caused by a mutation in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene, resulting in constitutive activation of the receptor. Typical radiological features include shortening of the tubular bones and macrocephaly, due to disruption of endochondral ossification. Consequently, FGFR3 has been described as a negative regulator of bone growth. Studying a large cohort of ACH patients, a delay in bone age was observed shortly after birth (for boys p=2.6×10(-9) and for girls p=1.2×10(-8)). This delay was no longer apparent during adolescence. In order to gain further insight into bone formation, bone development was studied in a murine model of chondrodysplasia (Fgfr3(Y367C/+)) from birth to 6weeks of age. Delayed bone age was also observed in Fgfr3(Y367C/+) mice at 1week of age followed by an accelerated secondary ossification center formation. A low level of chondrocyte proliferation was observed in the normal growth plate at birth, which increased with bone growth. In the pathological condition, a significantly high level of proliferative cells was present at birth, but exhibited a transient decrease only to rise again subsequently. Histological and in situ analyses suggested the altered endochondral ossification process may result from delayed chondrocyte differentiation, disruption of vascularization and osteoblast invasion of the femur. All these data provide evidence that FGFR3 regulates normal chondrocyte proliferation and differentiation during bone growth and suggest that constitutive activation of the receptor disrupts both processes. Therefore, the consequences of FGFR3 activation on the physiological process of bone development appear to be dependent on spatial and temporal occurrence. In conclusion, these observations support the notion that FGFR3 has a dual effect, as both a negative and a positive regulator of the endochondral ossification process during post-natal bone development.

Recurrence of Radial Bowing After Soft Tissue Distraction and Subsequent Radialization for Radial Longitudinal Deficiency

PURPOSE Centralization and radialization are the most widely reported surgical treatments for Bayne and Klug Type III and IV radial longitudinal deficiency. Prior soft tissue distraction has been introduced to improve reducibility of the deformity without skeletal resection. Satisfying long-term effects have been reported with centralization but are still unclear with radialization. METHODS This is a retrospective study of 8 consecutive children with Bayne and Klug Type III or IV radial longitudinal deficiency treated with preliminary soft tissue distraction followed by radialization between 2003 and 2008. All children underwent the same surgical protocol. End points of the study were clinical appearance, the hand-forearm angle, and mean angular correction at last follow-up. RESULTS The mean preoperative hand-forearm angle was 61° (26°-91°). The average duration of distraction was 1.9 month (1-3 mo). The initial postoperative angle averaged 12° (-14°-40°). There were 3 postoperative complications: 2 cases of pin loosening and 1 case of fracture of the base of the small finger metacarpal. Mean follow-up duration was 2.6 years (1-4 y). At last follow-up, 7 of the 8 patients had visible recurrence of the deformity, the hand-forearm angle had deteriorated to 44° (20°-69°), and the mean angular correction was 18° (-43°-59°). CONCLUSIONS Preoperative distraction allows a gradual realignment of the hand on the forearm without skeletal resection, but the recurrence rate after radialization is high. Tendon transfers and soft tissue tensioning were unable to maintain hand-forearm alignment following soft tissue distraction. TYPE OF STUDY/LEVEL OF EVIDENCE Therapeutic IV.

Thanatophoric dysplasia caused by double missense FGFR3 mutations

Thanatophoric dysplasia is a lethal chondrodysplasia caused by heterozygous fibroblast growth factor receptor 3 (FGFR3) missense mutations. Mutations have been identified in several domains of the receptor. The most frequent mutations (p.R248C, p.S249C, p.Y373C) create a cysteine residue within the extracellular domain, whereas the others eliminate the termination codon (p.X807R, p.X807C, p.X807G, p.X807S, p.X807W). Here, we report a unique patient with thanatophoric dysplasia and a double de novo FGFR3 mutation, located on the same allele, (c.[1620C>A;1454A>G]), which corresponds to p.[N540K;Q485R]. The p.N540K mutation is associated with 60% of patients with hypochondroplasia and the p.Q485R mutation is a novel mutation located in a highly conserved domain of FGFRs. Evidence for the structural impact of the two concurrent missense mutations was achieved using protein alignments and three‐dimensional structural prediction, in agreement with our modeling of the FGFR3 structure. In this patient with thanatophoric dysplasia, we conclude that the presence of the double FGFR3 missense mutation on the same allele alters the receptor structure, holding the receptor in its fully activated state, thus leading to lethal chondrodysplasia.

Coxa Vara in Chondrodysplasia : Prognosis Study of 35 Hips in 19 Children

Background: To better understand anatomical and functional outcomes of coxa vara in chondrodysplasia according to the initial presenting hip morphology, disease type, and impact of surgery. Methods: Clinical and radiographic records of 19 children (35 hips) diagnosed with coxa vara and with osteochondrodysplasia were reviewed. We classified the hip radiographic findings into 2 groups: (a) group I, coxa vara with a fragmented and/or nonossified head; and (b) group II, coxa vara with a regular femoral head. Surgical indications in coxa vara included decreased range of hip motion (usually diminished abduction, extension, and internal rotation), coxa vara with progression documented on regular follow-up hip radiographs, and/or severe coxa vara with a Hilgenreiner epiphyseal angle (HEA) of 60 degrees or more. Follow-up was until the completion of growth and, for some patients, into early adulthood. Mean follow-up was 8 years. Results: Twenty-five hips were operated on in 13 patients. In 23 hips, the procedure was a valgus osteotomy fixed by pins and wire. A pelvic extension osteotomy without valgus osteotomy was performed in one patient (2 hips). Coxa vara recurred in 7 hips. In 4 of these hips, repeat surgery with hypervalgus osteotomy was indicated to stop epiphyseal slipping (3 hips) or to improve the arc of motion (1 hip). Functional outcomes were poor in coxa vara associated with poor epiphyseal development (nonossified or fragmented epiphysis) as seen in spondyloepiphyseal dysplasia congenita, spondyloepimetaphyseal dysplasia, Kniest disease, and multiple epiphyseal dysplasia. Coxa vara with physeal instability as observed in spondylometaphyseal dysplasia resulted in deformity recurrence postoperatively during growth. In contrast, outcome was better in cases of coxa vara with nonphyseal/nonepiphyseal involvement, that is, good femoral head morphology, stable physis, and good articular cartilage, as seen in cases of metaphyseal dysplasia and cleidocranial dysplasia. Conclusions: Coxa vara with physeal and epiphyseal involvement and severe impairment of the articular cartilage has a poor prognosis even after reconstructive surgery. In coxa vara with an abnormal physis, there were numerous postsurgical recurrences of the deformity during growth if the physis was not stabilized at the time of valgus osteotomy. In these cases, we should delay osteotomy until an HEA greater than 60 degrees. Coxa vara in which only the metaphysis of the femoral neck is involved, the deformity is milder and often requires no treatment. Indications for surgery in this group are increasing coxa vara, Trendelenburg gait, or an HEA greater than 60 degrees.

Fractures de Tillaux de l'adolescent : Étude d'une série de 19 cas

PURPOSE OF THE STUDY Tillaux fractures in adolescents correspond to Salter and Harris type III fractures involving the anterolateral portion of the tibial epiphysis. These are intra-articular fractures. The objective was to determine the circumstances of these fractures, the radiological signs, and the therapeutic modalities as well as the long-term clinical and radiological outcome. MATERIAL AND METHODS We reviewed 19 Tillaux fractures. Ten patients underwent surgical treatment and nine orthopedic treatment following importance of displacement. RESULTS At mean follow-up of 33.8 months, results were rated good in 17 on 19 cases. DISCUSSION This fracture is often observed in teenagers victims of trauma with external rotation of the foot. Closure of distal growth cartilage of the tibia occurs medially to laterally, the anterolateral portion remaining open longer. Forced external rotation of the anterior tibiofibular ligament pulls off an anterolateral fragment of the distal tibial epiphysis. Surgical treatment is indicated for fractures with a displacement of more than 2 mm or a vertical displacement to achieve open reduction and screw fixation. Orthopedic treatment is used for non-displaced fractures. CONCLUSION The prognosis of Tillaux fractures is good as was observed in our series and in series reported in the literature.

La dysplasie fibreuse de l’extrémité proximale du fémur chez l’enfant et l’adolescent: Résultats du traitement chirurgical dans 22 cas

Resume La dysplasie fibreuse, pathologie rare, a pour localisation elective l’extremite proximale du femur. Les fractures iteratives et la deformation en coxa vara sont les menaces evolutives les plus importantes chez l’enfant, principalement dans la forme polyostotique. Cette localisation represente le probleme orthopedique le plus frequent et la principale indication chirurgicale. Le but de cette etude etait d’analyser le resultat clinique et radiologique apres traitement chirurgical. Entre 1979 et 2001, 22 enfants ont ete operes pour dysplasie fibreuse de l’extremite proximale du femur. Huit patients etaient porteurs d’une forme monostotique et 14 d’une forme polyostotique. Dans la forme monostotique, le type de traitement chirurgical a ete fonction de la taille et de la localisation de la lesion et comportait systematiquement un curetage de la tumeur. Dans la forme polyostotique, le traitement chirurgical a comporte une osteotomie de valgisation avec « humeralisation » en cas de coxa vara associee a une osteosynthese interne, le plus souvent par enclouage centro-medullaire. Dans la forme monostotique, le resultat a ete juge cliniquement bon dans tous les cas avec disparition ou quasi-disparition de la lesion dans 75 % des cas. Dans la forme polyostotique, nous avons observe des corrections stables de la deformation par osteotomie de valgisation avec « humeralisation » montee par un clou. Les resultats ont ete moins bons en raison de fractures et de deformations. Au vu de la litterature et de nos resultats, le pronostic de la forme monostotique apres traitement chirurgical est globalement bon. Dans la forme polyostotique, une osteosynthese preventive est necessaire. L’osteotomie de valgisation avec « humeralisation » semble corriger et prevenir la deformation en coxa vara dans certains cas. Dans les formes les plus severes, un traitement par biphosphonates associe au traitement chirurgical offre de nouvelles perspectives.

Targeted therapy in patients with PIK3CA-related overgrowth syndrome

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.A PI3KCA inhibitor reverses symptoms in a mouse model of PROS/CLOVES syndrome, which results from gain-of-function mutations in PI3KCA, and produces improvements in patients with PROS/CLOVES syndrome.