Effectiveness of the Combined Recombinant Human Growth Hormone and Gonadotropin-Releasing Hormone Analog Therapy in Pubertal Patients with Short Stature due to SHOX Deficiency

Context: Isolated heterozygous SHOX defects are the most frequent monogenic cause of short stature, and combined therapy with recombinant human GH (rhGH) and GnRH analog (GnRHa) in pubertal patients has been suggested, but there are no data on final height. Objective: The aim of the study was to analyze adult height after rhGH and GnRHa therapy in patients with SHOX haploinsufficiency. Patients: Ten peripubertal patients with isolated SHOX defects participated in the study. Intervention: Five patients were followed without treatment, and five were treated with rhGH (50 mu g/kg/d) and depot leuprolide acetate (3.75 mg/month). Main Outcome Measures: Adult height SD score (SDS) was measured. Results: All patients followed without treatment had marked downward growth shift during puberty (height SDS, -1.2 +/- 0.7 at 11.4 +/- 1.4 yr; adult height SDS, -2.5 +/- 0.5). Conversely, four of five patients treated with rhGH for 2 to 4.9 yr associated to GnRHa for 1.4 to 5.8 yr improved their height SDS from -2.3 +/- 1.3 at 11.8 +/- 2.1 yr to a final height SDS of -1.7 +/- 1.6. The difference between the mean height SDS at the first evaluation and final height SDS was statistically significant in nontreated vs. treated patients (mean height SDS change, -1.2 +/- 0.4 vs. 0.6 +/- 0.4, respectively; P < 0.001). Conclusion: A gain in adult height of patients with isolated SHOX defects treated with combined rhGH and GnRHa therapy was demonstrated for the first time, supporting this treatment for children with SHOX defects who have just started puberty to avoid the loss of growth potential observed in these patients during puberty. (J Clin Endocrinol Metab 95: 328-332, 2010)

Usefulness of MLPA in the detection of SHOX deletions

SHOX haploinsufficiency causes a wide spectrum of short stature phenotypes, such as Leri-Weill dyschondrosteosis (LWD) and disproportionate short stature (DSS). SHOX deletions are responsible for approximately two thirds of isolated haploinsufficiency; therefore, it is important to determine the most appropriate methodology for detection of gene deletion. In this study, three methodologies for the detection of SHOX deletions were compared: the fluorescence in situ hybridization (FISH), microsatellite analysis and multiplex ligation-dependent probe amplification (MLPA). Forty-four patients (8 LWD and 36 DSS) were analyzed. The cosmid LLNOYCO3`M`34F5 was used as a probe for the FISH analysis and microsatellite analysis were performed using three intragenic microsatellite markers. MLPA was performed using commercial kits. Twelve patients (8 LWD and 4 DSS) had deletions in SHOX area detected by MLPA and 2 patients generated discordant results with the other methodologies. In the first case, the deletion was not detected by FISH. In the second case, both FISH and microsatellite analyses were unable to identify the intragenic deletion. In conclusion, MLPA was more sensitive, less expensive and less laborious; therefore, it should be used as the initial molecular method for the detection of SHOX gene deletion. (C) 2010 Elsevier Masson SAS. All rights reserved.

Expression of SHOX in human fetal and childhood growth plate

Abnormalities in the growth plate may lead to short stature and skeletal deformity including Leri Weil syndrome, which has been shown to result from deletions or mutations in the SHOX gene, a homeobox gene located at the pseudoautosomal region of the X and Y chromosome. We studied the expression of SHOX protein, by immunohistochemistry, in human fetal and childhood growth plates and mRNA by in situ hybridization in childhood normal and Leri Weil growth plate. SHOX protein was found in reserve, proliferative, and hypertrophic zones of fetal growth plate from 12 wk to term and childhood control and Leri Weil growth plates. The pattern of immunostaining in the proliferative zone of childhood growth plate was patchy, with more intense uniform immunostaining in the hypertrophic zone. In situ hybridization studies of childhood growth plate demonstrated SHOX mRNA expression throughout the growth plate. No difference in the pattern of SHOX protein or mRNA expression was seen between the control and Leri Weil growth plate. These findings suggest that SHOX plays a role in chondrocyte function in the growth plate.

Leri's pleonosteosis, a congenital rheumatic disease, results from microduplication at 8q22.1 encompassing GDF6 and SDC2 and provides insight into systemic sclerosis pathogenesis.

OBJECTIVES: Leri's pleonosteosis (LP) is an autosomal dominant rheumatic condition characterised by flexion contractures of the interphalangeal joints, limited motion of multiple joints, and short broad metacarpals, metatarsals and phalanges. Scleroderma-like skin thickening can be seen in some individuals with LP. We undertook a study to characterise the phenotype of LP and identify its genetic basis. METHODS AND RESULTS: Whole-genome single-nucleotide polymorphism genotyping in two families with LP defined microduplications of chromosome 8q22.1 as the cause of this condition. Expression analysis of dermal fibroblasts from affected individuals showed overexpression of two genes, GDF6 and SDC2, within the duplicated region, leading to dysregulation of genes that encode proteins of the extracellular matrix and downstream players in the transforming growth factor (TGF)-β pathway. Western blot analysis revealed markedly decreased inhibitory SMAD6 levels in patients with LP. Furthermore, in a cohort of 330 systemic sclerosis cases, we show that the minor allele of a missense SDC2 variant, p.Ser71Thr, could confer protection against disease (p<1×10(-5)). CONCLUSIONS: Our work identifies the genetic cause of LP in these two families, demonstrates the phenotypic range of the condition, implicates dysregulation of extracellular matrix homoeostasis genes in its pathogenesis, and highlights the link between TGF-β/SMAD signalling, growth/differentiation factor 6 and syndecan-2. We propose that LP is an additional member of the growing 'TGF-β-pathies' group of musculoskeletal disorders, which includes Myhre syndrome, acromicric dysplasia, geleophysic dysplasias, Weill-Marchesani syndromes and stiff skin syndrome. Identification of a systemic sclerosis-protective SDC2 variant lays the foundation for exploration of the role of syndecan-2 in systemic sclerosis in the future.

Mon théâtre / Alexandre Weill

Comprend : Les deux Sylvestre : comédie en un acte et en vers - Deux femmes : drame en cinq actes - Un drame d'amour : drame en un acte - L'amour socialiste : comédie en trois actes - À deux coeurs et deux mains : comédie en vers et en prose en un acte - Un monde nouveau : drame contemporain en cinq actes - L'école de Montreux (fragments) : comédie en vers - Parthénie, ou l'amour vainqueur : poème dramatique en cinq actes, représenté pour la première fois au théâtre de Vienne, le 28 janvier 1842

Weill! : konsertti ja miten se rakentui

Opinnäytetyöni on dramatisoitu konsertti Kurt Weillin musiikista, sekä kirjallinen raportti. Työn kirjallinen osio käsittelee konsertin valmistusprosessia, taustatietoja säveltäjästä sekä hänen teoksistaan. Prosessissa kuvaan matkaa konsertti-idean syntymisestä eri työvaiheiden kautta valmiiksi esitykseksi, josta cd-taltiointi työn liitteenä. Opinnäytetyöni syntyi rakkaudesta Kurt Weillin musiikkiin ja halustani työstää siitä ohjattu, dramatisoitu kokonaisuus. Weillin laulut antavat mielestäni klassiselle laulajalle enemmän vapauksia sekä tulkintamahdollisuuksia kuin perinteinen klassinen musiikki. Halusin myös kasvaa oman konsertin mittoihin ja ottaa riskin, kehittyäkseni taiteilijana ja muusikkona oppiakseni tunnistamaan, evaluoimaan ja taloudellistamaan työskentelytapojani. Konsertin materiaali on koottu säveltäjän teoksista tämän koko elinkaaren ajalta. Weillin elämän vaiheista ja tuotannosta kirjoittaessani olen käyttänyt Sandersin kirjoittamaa Weillin elämäkertaa, sekä Sellarin toimittamaa kirjaa keskusteluista Kurt Weillin teosten äärellä. Lisäksi apunani ovat olleet nettibiografia sekä kollegani Tuula Niirasen Weill -esitelmän muistiinpanot. Konserttimateriaalin olin rajannut 12 lauluun, jotka valitsin suuremmasta joukosta, sen perusteella, mitkä lauluista alkoivat istua ja tuntua omimmilta. Hienolla muusikkojen ja taiteilijoiden yhteistyöllä saatiin aikaiseksi onnistunut dramatisoitu konsertti, joka toi ihmisiä Weillin musiikin ääreen. Toivon, että musiikki sai myös uusia ihailijoita. Ammatillinen itsetuntemukseni ja itseluottamukseni syventyi ja koen prosessin myötä myös kasvaneeni muusikkona ja taiteilijana. - Opinnäytetyöhön liittyy teososa: CD-äänilevy.

[8-8-20, bassin de la Villette], championnat de France [militaire de natation, de droite à gauche], Rosey, Pernod, Pouilley, Weill, Padou [nageurs français] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 60400

Música y teatro escolar : la ópera de catro cuartos de Bertold Brecht y Kurt Weill.

Resumen basado en el del autor. Resumen en castellano e inglés

Julien Weill [Rezension]

Felix Perles