Vicken Topouchian

Mutations in the TGFβ Binding-Protein-Like Domain 5 of FBN1 Are Responsible for Acromicric and Geleophysic Dysplasias

Geleophysic (GD) and acromicric dysplasia (AD) belong to the acromelic dysplasia group and are both characterized by severe short stature, short extremities, and stiff joints. Although AD has an unknown molecular basis, we have previously identified ADAMTSL2 mutations in a subset of GD patients. After exome sequencing in GD and AD cases, we selected fibrillin 1 (FBN1) as a candidate gene, even though mutations in this gene have been described in Marfan syndrome, which is characterized by tall stature and arachnodactyly. We identified 16 heterozygous FBN1 mutations that are all located in exons 41 and 42 and encode TGFβ-binding protein-like domain 5 (TB5) of FBN1 in 29 GD and AD cases. Microfibrillar network disorganization and enhanced TGFβ signaling were consistent features in GD and AD fibroblasts. Importantly, a direct interaction between ADAMTSL2 and FBN1 was demonstrated, suggesting a disruption of this interaction as the underlying mechanism of GD and AD phenotypes. Although enhanced TGFβ signaling caused by FBN1 mutations can trigger either Marfan syndrome or GD and AD, our findings support the fact that TB5 mutations in FBN1 are responsible for short stature phenotypes.

Clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations

The GALNT3 gene encodes GalNAc‐T3, which prevents degradation of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Biallelic mutations in either GALNT3 or FGF23 result in hyperphosphatemic familial tumoral calcinosis or its variant, hyperostosis–hyperphosphatemia syndrome. Tumoral calcinosis is characterized by the presence of ectopic calcifications around major joints, whereas hyperostosis–hyperphosphatemia syndrome is characterized by recurrent long bone lesions with hyperostosis. Here we investigated four patients with hyperphosphatemia and clinical manifestations including tumoral calcinosis and/or hyperostosis–hyperphosphatemia syndrome to determine underlying genetic cause and delineate phenotypic heterogeneity of these disorders. Mutational analysis of FGF23 and GALNT3 in these patients revealed novel homozygous mutations in GALNT3. Although the presence of massive calcifications, cortical hyperostosis, or dental anomalies was not shared by all patients, all had persistent hyperphosphatemia. Three of the patients also had inappropriately normal 1,25‐dihyroxyvitamin D [1,25(OH)2D] and confirmed low circulating intact FGF23 concentrations. The four novel GALNT3 mutations invariably resulted in hyperphosphatemia as a result of low intact FGF23, but other clinical manifestations were variable. Therefore, tumoral calcinosis and hyperostosis–hyperphosphatemia syndrome represent a continuous spectrum of the same disease caused by increased phosphate levels, rather than two distinct disorders.

Expanding the skeletal phenotype of Loeys-Dietz syndrome†

S ergio B. Sousa, Karen Lambot-Juhan, Marl ene Rio, Genevi eve Baujat, Vicken Topouchian, Nadine Hanna, Martine Le Merrer, Francis Brunelle, Arnold Munnich, Catherine Boileau, and Val erie Cormier-Daire* Department of Medical Genetics (AP-HP), Universit e Paris Descartes, INSERM U781, Hôpital Necker-Enfants Malades, Paris, France Servi co de Gen etica M edica, Hospital Pedi atrico de Coimbra, Coimbra, Portugal Service de Radiologie P ediatrique, Hôpital Necker-Enfants Malades, Paris, France Service de Chirurgie Orthop edique P ediatrique, Hôpital Necker-Enfants Malades, Paris, France Universit e Versailles-SQY, Service de Biochimie et G en etique Mol eculaire (AP-HP), Hôpital Ambroise Par e, Boulogne-Billancourt, France

Résultats des arthrodèses vertébrales postérieures dans les scolioses secondaires à une ostéogenèse imparfaite

Resume Une etude retrospective a ete conduite afin de documenter et d’analyser les resultats des arthrodeses vertebrales posterieures dans le cadre des deformations scoliotiques associees a une osteogenese imparfaite durant la periode de 1977 a 2002. Nous avons revu 27 patients operes d’une arthrodese vertebrale posterieure apres preparation par traction preoperatoire par halo crânien, avec une instrumentation de type Harrington (n = 2) ou bien C.D. (n = 23) et deux cas d’arthrodese posterieure non instrumentee. Onze de ces patients etaient des garcons et seize etaient des filles. L’âge moyen le jour de l’arthrodese etait de 13 ans 4 mois, et la moyenne des courbures preoperatoires etait de 77 degres avec une correction de l’ordre de 37 % en postoperatoire. Le suivi moyen a ete de 6 ans. Des complications mineures dues a une surinfection et un glissement d’un pointeau de traction crânien ont ete observees chez deux patients et une perte de correction avec fracture du materiel chez 4 patients. Nous pensons qu’une arthrodese vertebrale posterieure pour deformation scoliotique secondaire a une osteogenese imparfaite doit etre entreprise apres une periode de preparation et de traction par halo crânien afin d’ameliorer les conditions mecaniques et respiratoires, de corriger progressivement la scoliose et de prevenir les complications qui peuvent survenir. L’arthrodese vertebrale posterieure permet chez ces patients atteints d’une deformation rachidienne, outre la preservation des capacites respiratoires et de la taille, une correction du desequilibre du tronc afin d’ameliorer la posture et un meilleur appareillage en fauteuil roulant chez les non marchants, voire une verticalisation.

Orthopedics management of acromicric dysplasia: Follow up of nine patients

Acromicric dysplasia (AD) is an autosomal dominant disorder characterized by short stature, short extremities, stiff joint and skeleton features including brachymetacarpia, cone‐shaped epiphyses, internal notch of the femoral head, and delayed bone age. Recently, we identified fibrillin 1 (FBN1) as the disease gene of AD. The aim of our study was to further describe the long‐term follow up of AD patients with an emphasis on orthopedic management. Nine patients with FBN1 mutations were included in the study ranging in age from 5.5 to 64 years. For all, detailed clinical and radiological data were available. Results: Birth parameters were always normal and patients progressively developed short stature <−3 SD. Carpal tunnel syndrome was observed in four patients. We found discrepancy between the carpal bone age and the radius and ulna epiphysis bone ages, a variable severity of hip dysplasia with acetabular dysplasia, epiphyseal and metaphyseal femoral dysplasia resembling Legg–Perthes–Calvé disease and variable pelvic anteversion and hyperlordosis. Orthopedic surgery was required in two patients for hip dysplasia, in one for limb lengthening and in three for carpal tunnel syndrome. Our observations expand the AD phenotype and emphasize the importance of regular orthopedic survey.

Déviations rachidiennes dans le syndrome de Marfan

Par de nombreux aspects les scolioses du MFS se rapprochent des scolioses idiopathiques. Une étude récente en trois dimensions de rachis scoliotiques dans la maladie de Marfan montre, comme dans les scolioses idiopathiques, des zones apicales en extensionrotation suggérant un mécanisme de « fl ambage » de la colonne [8]. Mais il est très probable que les anomalies du tissu conjonctif viennent imprimer aux scolioses du MFS une marque particulière, surtout dans le plan sagittal. Citons l’association fréquente à une inégalité de longueur qui, corrélée à la sévérité et au sens de la scoliose, a amené certains à en discuter le rôle étiopathogénique [9].

Traitements des déformations rachidiennes des maladies neuromusculaires

Les deformations rachidiennes dans les maladies neuromusculaires sont frequentes, parfois graves, menacant le pronostic fonctionnel, respiratoire, voire vital. Ces pathologies sont multiples, de gravite et d’evolution fort differentes et pour une meme affection genetique, l’expression clinique d’un patient a l’autre peut etre tres variable. La prise en charge doit donc etre preventive, adaptee a chaque patient, en tenant compte de l’evolutivite de la maladie et de son pronostic fonctionnel, respiratoire et cardiaque. Les decisions therapeutiques doivent s’integrer dans une prise en charge pluridisciplinaire que ce soit le choix des ortheses (corset), la reeducation respiratoire (relaxateur de pression, ventilation non invasive) ou la surveillance cardiaque. Le temps de la chirurgie sera encadre par une equipe habituee a ces pathologies (anesthesistes, reanimateur, kinesitherapeutes) ainsi que la prise en charge reeducative postoperatoire.