Madelung Deformity Research Articles

The Leri-Weill and Turner syndrome homeobox gene SHOX encodes a cell-type specific transcriptional activator.

Functional impairment of the human homeobox gene SHOX causes short stature and Madelung deformity in Leri-Weill syndrome (LWS) and has recently been implicated in additional skeletal malformations frequently observed in Turner syndrome. To enhance our understanding of the underlying mechanism of action, we have established a cell culture model consisting of four stably transfected cell lines and analysed the functional properties of the SHOX protein on a molecular level. Results show that the SHOX-encoded protein is located exclusively within the nucleus of a variety of cell lines, including U2Os, HEK293, COS7 and NIH 3T3 cells. In contrast to this cell-type independent nuclear translocation, the transactivating potential of the SHOX protein on different luciferase reporter constructs was observed only in the osteogenic cell line U2Os. Since C-terminally truncated forms of SHOX lead to LWS and idiopathic short stature, we have compared the activity of wild-type and truncated SHOX proteins. Interestingly, C-terminally truncated SHOX proteins are inactive with regards to target gene activation. These results for the first time provide an explanation of SHOX-related phenotypes on a molecular level and suggest the existence of qualitative trait loci modulating SHOX activity in a cell-type specific manner.

Analysis of short stature homeobox-containing gene ( SHOX) and auxological phenotype in dyschondrosteosis and isolated Madelung deformity.

Dyschondrosteosis (DCO; also called Léri-Weill syndrome) is a skeletal dysplasia characterised by disproportionate short stature because of mesomelic shortening of the limbs. Madelung deformity is a feature of DCO that is distinctive, variable in expressivity and frequently observed. Mutations of the SHOX (short stature homeobox-containing) gene have been previously described as causative in DCO. Isolated Madelung deformity (IMD) without the clinical characteristics of DCO has also been described in sporadic and a few familial cases but the genetic defect underlying IMD is unknown. In this study, we have examined 28 probands with DCO and seven probands with IMD for mutations in the SHOX gene by using polymorphic CA-repeat analysis, fluorescence in situ hybridisation (FISH), Southern blotting, direct sequencing and fibre-FISH analyses. This was combined with auxological examination of the probands and their family members. Evaluation of the auxological data showed a wide intra- and interfamilial phenotype variability in DCO. Out of 28 DCO probands, 22 (79%) were shown to have mutations in the SHOX gene. Sixteen unrelated DCO families had SHOX gene deletions. Four novel DCO-associated mutations were found in different families. In two additional DCO families, the previously described nonsense mutation (Arg195Stop) was detected. We conclude that mutations in the SHOX gene are the major factor in the pathogenesis of DCO. In a female proband with severe IMD and her unaffected sister, we detected an intrachromosomal duplication of the SHOX gene.

Madelung Deformity: Clinical Features, Therapy and Results

In a retrospective study, 31 patients with Madelung deformity were reviewed. They were treated at one institution during a period of 15 years. On first presentation, the mean age was 22.5 years with a range from 10 years to 64 years. Twenty-four patients (77%) were female. The main complaints were pain, limited range of motion, and objectionable appearance. A family history of Madelung deformity was present in four patients (13%). The diagnosis of Leri-Weill syndrome could not be confirmed in any case. There was no correlation between the clinical appearance and the extent of radiologic abnormality. Five patients (16%) were operated on because of permanent pain. On postoperative examination, only one patient revealed no restricted range of mobility and no pain, whereas the other four patients improved in terms of pain but showed only limited improvement of function. The vast majority of patients, however, required no surgical therapy.

Madelung Deformity: Clinical Features, Therapy and Results

Madelung Deformity: Clinical Features, Therapy and Results

Madelung Deformity: Clinical Features, Therapy and Results

The journal highlights important recent developments from the world's leading clinical and research institutions. The journal publishes peer-reviewed papers on the diagnosis and treatment of pediatric orthopedic disorders. It is the official journal of IFPOS (International Federation of Paediatric Orthopaedic Societies).

Short stature homeobox-containing gene deletion screening by fluorescence in situ hybridisation in patients with short stature.

The short stature homeobox-containing gene (SHOX) on the short arm of the X and Y chromosomes is an important determining factor of stature phenotype. Absence of the SHOX gene is a main cause for short stature in patients with Turner syndrome. Mutations of the SHOX gene can also be responsible for Léri-Weill syndrome (dyschondrosteosis). The aim of this study was to determine the frequency of SHOX deletions in short stature children and to delineate indications for SHOX deletion screening. Out of 50 probands, 35 had idiopathic short stature, 12 cases showed additional anomalies of the forearms (in particular Madelung deformity) and three patients were affected by a congenital heart defect. Chromosomal investigations with fluoresence in situ hybridisation did not reveal a SHOX deletion in any patient with idiopathic short stature. In five of the 12 patients (41.7%) with anomalies of the forearms, a SHOX deletion on one sex chromosome could be detected. No deletion was observed in the three cases with additional heart defects. The frequency of short stature homeobox-containing gene deletions in patients with idiopathic short stature appears to be very low and does not require a fluorescence in situ hybridisation analysis. Short stature in association with anomalies of the forearms such as Madelung deformity makes a deletion more probable and therefore screening for such deletions is recommended in these cases.

Radiological Signs of Leri-Weill Dyschondrosteosis in Turner Syndrome

Background/Aims: Leri-Weill dyschondrosteosis (LWD), a mesomelic short stature syndrome with Madelung deformity, was recently reported to be caused by SHOX (short stature homeobox-containing gene) haploinsufficiency. The loss of SHOX on Xp22.32, also called PHOG (pseudoautosomal homeobox-containing osteogenic gene), through structural aberrations of the X chromosome was also implicated in the short stature phenotype and some additional stigmata of Turner syndrome. The aim of this study was to systematically examine left-hand radiographs from Turner girls for the presence of signs of LWD. Methods: We retrospectively studied 168 left-hand radiographs from 54 patients with Turner syndrome (bone age >10.5 years) who were treated with rhGH and seen during the last 10 years in our clinic. For comparison, we analyzed 7 radiographs from 5 patients with LWD and 52 radiographs from 20 patients with GH deficiency. The shape of the distal radial epiphysis (triangularisation index = TI) and the carpal angle were quantitatively measured. In addition, we screened for the presence of a premature cleft fusion or an ulnar deviation of the articular surface of the distal radial epiphysis and for fourth metacarpal shortening. One of 54 Turner girls (2%) was affected with LWD and presented with Madelung deformity. Results: No milder forms of Madelung deformity were detected. However, there was a significant trend to a triangular shape of the distal radial epiphysis in Turner syndrome: the median TI was 2.7 in normal controls (range 1.8–3.7), 3.1 in Turner girls (range 2.0–6.3) (p < 0.001 against controls), and 6.0 in patients with LWD (range 3.5–11.0) (p < 0.001 against controls). Conclusions: The triangularisation index did not correlate with the carpal angle (median 122.5

MADELUNG'S DEFORMITY

A resurgence of interest in Madelung's deformity has developed recently because of improved operations for correction of the deformity, identification of the genetic loci for the condition in certain syndromal variants, identification of an anterior ligamentous structure tethering the carpus, and preventive treatments in growing children. The process is reviewed in this article and a new surgical technique is presented. The procedure is performed by way of an anterior incision that is more cosmetically appealing. The release of an anterior ligamentous structure described by Vickers is performed simultaneously with a dome shaped osteotomy of the radius. The fragments, once alignment is corrected, are stablized with temporary pin fixation and a long arm cast until the bone has healed.

MADELUNG DEFORMITY TREATED WITH ILIZAROV TECHNIQUE: A REPORT OF TWO CASES

Two children with painful and progressive Madelung deformities were treated by osteotomy of the radius and subsequent angular correction and bone lengthening using the Ilizarov technique. Both children were radiologically improved and free of pain at follow-up.

Short arm rearrangements of sex chromosomes with haploinsufficiency of the SHOX gene are associated with Leri-Weill dyschondrosteosis.

Twelve patients with different features of Turner syndrome, and with Xp and Yp rearrangements involving the pseudoautosomal region (PAR1) are described. In all patients, FISH analysis showed loss of one copy of the Short Stature Homeobox (SHOX)-containing gene. Ten patients had short stature and one disproportionate (mesomelic) normal stature, while the last one had normal stature. Skeletal abnormalities, including shortened ulna, were detected in nine subjects, and in six of them Madelung deformity was observed. These clinical data indicated a genotype phenotype correlation between haploinsufficiency of SHOX, and short stature and skeletal abnormalities.

Madelung's deformity as a presenting sign of Turner's syndrome

A 9-year-old girl was evaluated because of small stature. Her medical history and development were normal. Earlier measurements were unavailable. The mother was 5 foot 4 inches and the father 5 foot 10 inches, with a mid-parental height of 64.5 inches. Her height was 119.1 cm (–2.5 SD) with a height age of 7 years, and her weight was at the 15th percentile. There was no webbing of the neck or other signs of Turner’s syndrome. The result of a screening test for growth hormone deficiency (insulin-like growth factor binding protein 3) was normal.

The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome.

Turner syndrome is characterized by short stature and is frequently associated with a variable spectrum of somatic features including ovarian failure, heart and renal abnormalities, micrognathia, cubitus valgus, high-arched palate, short metacarpals and Madelung deformity. Madelung deformity is also a key feature of Leri-Weill syndrome. Defects of the pseudoautosomal homeobox gene SHOX were previously shown to lead to short stature and Leri-Weill syndrome, and haploinsufficiency of SHOX was implicated to cause the short stature phenotype in Turner syndrome. Despite exhaustive searches, no direct murine orthologue of SHOX is evident. SHOX is, however, closely related to the SHOX2 homeobox gene on 3q, which has a murine counterpart, Og12x. We analysed SHOX and SHOX2 expression during human embryonic development, and referenced the expression patterns against those of Og12x. The SHOX expression pattern in the limb and first and second pharyngeal arches not only explains SHOX -related short stature phenotypes, but also for the first time provides evidence for the involvement of this gene in the development of additional Turner stigmata. This is strongly supported by the presence of Turner-characteristic dysmorphic skeletal features in patients with SHOX nonsense mutations.

LONG-TERM FOLLOW-UP OF SURGICAL CORRECTION OF MADELUNG'S DEFORMITY WITH CONSERVATION OF THE DISTAL RADIOULNAR JOINT IN TEENAGERS

Eleven wrists with painful Madelung deformity in seven patients were corrected during adolescence by a closing wedge osteotomy of the radius and a shortening osteotomy of the ulna, with conservation of the distal radioulnar joint. At late follow-up (9.7 years) function was considerably improved. When the ulnar head was correctly relocated during operation, a new distal radioulnar space developed. Shortening of the ulna must be generous and combined with slight flexion at the osteotomy.

とう骨矯正骨切り術およびＳａｕｖｅ Ｋａｐａｎｄｊｉ法を併用した両側Ｍａｄｅｌｕｎｇ変形の１例

We report a case of Madelung's Deformity in a 23-year-old female. When she was 11 years old, she was aware of the deformity of her bilateral wrist and forearm. Wrist pain started when she was 13 and the symptoms worsened. We performed wedge osteotomy of radius with the Sauve-Kapandji Method at the bilateral sides when she was 22 and 23. After the operation, wrist pain and range of motion improved.

マーデルング変形による伸筋けん断裂の１治療経験

マーデルング変形による伸筋けん断裂の１治療経験

L�ri-Weill syndrome associated with a pseudodicentric X;Y translocation chromosome and skewed X-inactivation: Implications for genetic counselling

A female patient of normal intelligence with short stature and Madelung deformity is reported with Léri-Weill dyschondrosteosis and a de novo pseudodicentric X;Y translocation chromosome. The phenotype is consistent with the observed deletion of the SHOX gene by FISH and molecular studies. The Y chromosome breakpoint was in the short arm but proximal to SRY, consistent with her phenotypic sex. X-inactivation studies have shown a skewed pattern in favour of the dic (X;Y) chromosome. The ARSE gene was also deleted on the dic (X;Y) chromosome but chondrodysplasia punctata was not expressed, as CDP is recessive and ARSE escapes inactivation on the normal X chromosome. Breakpoint mapping assisted in karyotype/phenotype correlation and reproductive counselling. In particular, molecular analysis showed that the putative MRX 49 gene for mental retardation is unlikely to be deleted in this case.

Phenotypic variation and genetic heterogeneity in Léri-Weill syndrome.

Léri-Weill syndrome (LWS) or dyschondrosteosis represents a short stature syndrome characterised by the mesomelic shortening of the forearms and lower legs and by bilateral Madelung deformity of the wrists. Recently, mutations in the pseudoautosomal homeobox gene SHOX have been shown to be causative for this disorder. This gene has previously been described as the short stature gene implicated in Turner syndrome (TS). We studied 32 Léri-Weill patients from 18 different German and Dutch families and present clinical, radiological and molecular data. Phenotypic inter- and intrafamilial heterogeneity is a frequent finding in LWS, and phenotypic manifestations are generally more severe in females. In males, muscular hypertrophy is a frequent finding. To test for SHOX mutations we used FISH, Southern blot and SSCP analysis as well as long-range PCR and sequencing. We identified (sub)microscopic deletions encompassing the SHOX gene region in 10 out of 18 families investigated. Deletion sizes varied between 100 kb and 9 Mb and did not correlate with the severity of the phenotype. We did not detect SHOX mutations in almost half (41%) the LWS families studied, which suggests different genetic etiologies.

Skeletal Features and Growth Patterns in 14 Patients with Haploinsufficiency of SHOX: Implications for the Development of Turner Syndrome

We report on clinical features in 14 Japanese patients (4 males and 10 females) with partial monosomy of the short arm pseudoautosomal region involving SHOX (n = 11) or total monosomy of the pseudoautosomal region with no involvement of disease genes on the sex-differential regions (n = 3). Skeletal assessment showed that three patients had no discernible skeletal abnormalities, one patient exhibited short 4th metacarpals and borderline cubitus valgus, and the remaining 10 patients had Madelung deformity and/or mesomelia characteristic of Léri-Weill dyschondrosteosis (LWD), together with short 4th metacarpals and/or cubitus valgus. Skeletal lesions were more severe in females and became obvious with age. Growth evaluation revealed that patients without LWD grew along by the -2 SD growth curve before puberty and showed a normal or exaggerated pubertal growth spurt, whereas those with LWD grew along by the standard growth curves before puberty but exhibited an attenuated pubertal growth spurt and resultant short stature. Maturational assessment indicated a tendency of relatively early maturation in patients with LWD. There was no correlation between the clinical phenotype and the deletion size. These findings suggest that haploinsufficiency of SHOX causes not only short stature but also Turner skeletal anomalies (such as short 4th metacarpals, cubitus valgus, and LWD) and that growth pattern is primarily dependent on the presence or absence of LWD. Because skeletal lesions have occurred in a female-dominant and age-influenced fashion, it is inferred that estrogens exert a maturational effect on skeletal tissues that are susceptible to premature fusion of growth plates because of haploinsufficiency of SHOX, facilitating the development of skeletal lesions.

SHOX gene mutations and deletions in dyschondrosteosis or Leri-Weill syndrome.

Dyschondrosteosis is an autosomal dominant form of mesomelic dysplasia that is often combined with a deformity of the forearms called Madelung deformity. Based on the observation of X-Y translocations (p22,q12) in patients with dyschondrosteosis, the authors tested the pseudoautosomal region in eight affected families and showed linkage of the dyschondrosteosis gene to a microsatellite DNA marker at the DXYS233 locus (Zmax = 6.26 at theta = 0). Since the short stature homeobox-containing gene (SHOX) involved in idiopathic growth retardation and possibly Turner syndrome maps to this region, SHOX was regarded as a strong candidate gene for dyschondrosteosis. This article reports the detection of large-scale SHOX deletions in seven of the eight families and a nonsense mutation of SHOX in the remaining family affected with dyschondrosteosis. Additional evidence suggests that Langer mesomelic dwarfism results from homozygous mutations at the genetic locus responsible for dyschondrosteosis.

Treatment of Madelung's deformity by lengthening and relaxation of the distal extremity of the radius by Ilizarov's technique: B. de Billy, F. Gastaud, M. Repetto, et al. Eur J Pediatr Surg 7:296–298, (October), 1997

Treatment of Madelung's deformity by lengthening and relaxation of the distal extremity of the radius by Ilizarov's technique: B. de Billy, F. Gastaud, M. Repetto, et al. Eur J Pediatr Surg 7:296–298, (October), 1997