Leri-Weill dyschondrosteosis (LWD) is a dominantly inherited skeletal dysplasia characterized by short stature, mesomelia, and Madelung wrist deformity. Although the disorder occurs in both sexes, it is usually more severe in females, perhaps due to sex difference in ... Leri-Weill dyschondrosteosis (LWD) is a dominantly inherited skeletal dysplasia characterized by short stature, mesomelia, and Madelung wrist deformity. Although the disorder occurs in both sexes, it is usually more severe in females, perhaps due to sex difference in estrogen levels. However, pubertal development and fertility are generally normal in both sexes with the disorder (summary by Ross et al., 2005). The Madelung wrist deformity includes deformity of the distal radius and ulna and proximal carpal bones (Langer, 1965). See also Langer mesomelic dysplasia (LMD; 249700), a more severe phenotype that results from homozygous defect in the SHOX or SHOXY genes.
Ogata et al. (2001) reviewed the clinical features and diagnostic and therapeutic implications of SHOX haploinsufficiency and overdosage. They suggested that identification of Madelung deformity is important in the clinical diagnosis of SHOX haploinsufficiency and that gonadal suppression ... Ogata et al. (2001) reviewed the clinical features and diagnostic and therapeutic implications of SHOX haploinsufficiency and overdosage. They suggested that identification of Madelung deformity is important in the clinical diagnosis of SHOX haploinsufficiency and that gonadal suppression therapy may mitigate the clinical features, including mesomelic short stature. Ogata et al. (2001) also suggested that SHOX overdosage leads to long limbs and tall stature resulting from continued growth into late teens in individuals with gonadal dysgenesis. Thus, tall stature with poor pubertal development is suggestive of SHOX overdosage and may be ameliorated by estrogen therapy. Ogata et al. (2001) concluded that studies to that time indicated that SHOX functions as a repressor of growth plate fusion and skeletal maturation in the distal limbs, counteracting the effects of estrogens. In a study of 140 children with idiopathic short stature, Binder et al. (2003) sought to determine the prevalence of SHOX mutations and to give an unbiased characterization of the haploinsufficiency phenotype of such children. SHOX haploinsufficiency caused by a SHOX deletion was confirmed in 3 probands (2%), all females, who carried a de novo deletion through loss of the paternal allele. Their auxologic data revealed a significant shortening of arms and legs in the presence of a low-normal sitting height when compared with the other 137 children tested. Therefore, the extremities-trunk ratio (sum of leg length and arm span, divided by sitting height) for total height was significantly lower in the 3 SHOX haploinsufficient probands in comparison with the whole group. All children with SHOX haploinsufficiency exhibited at least 1 characteristic radiologic sign of Leri-Weill dyschondrosteosis in their left-hand radiography, namely, triangularization of the distal radial epiphysis, pyramidalization of the distal carpal row, or lucency of the distal ulnar border of the radius. Binder et al. (2003) concluded that it is rational to limit SHOX mutation screening to children with an extremities-trunk ratio less than 1.95 +/- 0.5 height (m) and to add a critical judgment of the hand radiography. For the identification and characterization of SHOX deletions in 15 patients with Leri-Weill dyschondrosteosis, Gatta et al. (2007) used multiple ligation probe amplification (MLPA) assay. Heterozygous deletion of SHOX was demonstrated in 7 patients, and 2 different proximal breakpoints were disclosed. In 3 of the patients who carried chromosome abnormalities, MLPA analysis identified the chromosomal rearrangement, showing, in addition to the SHOX deletions, the gain or loss of other genes mapped on the X and Y chromosomes. Gatta et al. (2007) pointed out that the MLPA analysis can be carried out on a buccal swab, and that this technique represents a fast, simple, and high throughput approach in the screening of SHOX deletions. It may provide more information than FISH or microsatellite analysis of intragenic CA repeats.
The disorder was first described by Leri and Weill (1929). Lamy and Bienenfeld (1954) described affected mother and son. The fibula was absent in both.
Langer (1965) reported 3 families. The deformity of the forearm consists ... The disorder was first described by Leri and Weill (1929). Lamy and Bienenfeld (1954) described affected mother and son. The fibula was absent in both. Langer (1965) reported 3 families. The deformity of the forearm consists of bowing of the radius and dorsal dislocation of the distal ulna, resulting in limited motion at the elbow and wrist. Rullier et al. (1968) observed dyschondrosteosis in mother and 2 daughters. Nassif and Harboyan (1970) described 2 brothers with Leri dyschondrosteosis, who also had middle ear deformities and conductive hearing loss. Three sisters had the skeletal deformity with normal hearing. Dawe et al. (1982) reviewed 13 patients with dyschondrosteosis from 8 families. Stature was moderately reduced due to shortening of the bones of the leg. Radioulnar shortening could involve either both bones equally or the radius predominantly, in which case a typical Madelung deformity was seen. Tibiofibular disproportion was present in half the patients, 2 of them having severe deformity associated with tibia varum and a long fibula. The authors recommended that patients with dyschondrosteosis be kept under surveillance during the growing period, since problems in the limbs, especially the legs, may require operations to equalize the length of the 2 bones. Ross et al. (2001) studied 21 LWD families (43 affected LWD subjects, including 32 females and 11 males, aged 3 to 56 years) with confirmed SHOX gene abnormalities. In the LWD subjects, height deficits ranged from -4.6 to +0.6 SD (mean +/- SD = -2.2 +/- 1.0). There were no statistically significant effects on age, gender, pubertal status, or parental origin of SHOX mutations on height z-score. The height deficit in LWD was approximately two-thirds that of Turner syndrome. Madelung deformity was present in 74% of LWD children and adults and was more frequent and severe in females than males. The prevalence of Madelung deformity was higher in the LWD versus a Turner syndrome population. The prevalence of increased carrying angle, high-arched palate, and scoliosis was similar in the 2 populations. SHOX deletions were present in affected individuals from 17 families (81%), and point mutations were detected in 4 families (19%). Among 34 prepubertal genetically confirmed patients with LWD (ages 1 to 10), including 20 girls and 14 boys, Ross et al. (2005) found a decreased height SD score (SDS) compared to controls for both sexes (-2.3 for girls and -1.8 for boys). Arm spans were also decreased (SDS -3.2 for girls and -2.3 for boys), indicating early development of mesomelia in the arms. Tibial bowing was seen in 8 (40%) of 20 girls and 4 (29%) of 14 boys. Wrist changes related to Madelung deformity were present in 18 (53%) of 34 LWD individuals. Bone age was not significantly decreased in either girls or boys. A separate comparison of 24 girls with LWD aged 1 to 15 years and 76 girls with Turner syndrome showed similar mean height deficits (SDS -2.7 for both groups). This suggested that SHOX haploinsufficiency is responsible for most of the height deficit observed in Turner syndrome. There was evidence for mesomelia in the LWD group, which was not present in the Turner group. Overall, Madelung deformity, increased carrying angle, tibial bowing, and scoliosis were more prevalent in the LWD population, whereas high arched-palate was similarly prevalent in both LWD and Turner syndrome. Ross et al. (2005) concluded that short stature is common in both LWD girls and boys before puberty, and Turner syndrome girls. Clinical clues to the diagnosis of SHOX haploinsufficiency in childhood thus include short stature, short limbs, wrist changes, and tibial bowing. None of the patients had been treated with growth hormone, and some of the patients had previously been reported (Ross et al., 2001). - Madelung Deformity A complete review of Madelung deformity was provided by Anton et al. (1938). Langer (1965) suggested that most of all cases of Madelung deformity indicate dyschondrosteosis. In a review, however, Felman and Kirkpatrick (1969) concluded that patients taller than the 25th percentile for height probably do not have dyschondrosteosis, that a hereditary entity of Madelung deformity distinct from dyschondrosteosis exists, that patients with the isolated Madelung deformity may be short, and that marked shortening of the tibia relative to the femur suggests dyschondrosteosis.
Schiller et al. (2000) studied 32 patients with Leri-Weill dyschondrosteosis from 18 different German and Dutch families and presented clinical, radiologic, and molecular data. Phenotypic manifestations were generally more severe in females. In males, muscular hypertrophy was a ... Schiller et al. (2000) studied 32 patients with Leri-Weill dyschondrosteosis from 18 different German and Dutch families and presented clinical, radiologic, and molecular data. Phenotypic manifestations were generally more severe in females. In males, muscular hypertrophy was a frequent finding. The authors identified submicroscopic deletions encompassing the SHOX gene in 10 of 18 families investigated; deletion sizes varied between 100 kb and 9 Mb and did not correlate with the severity of the phenotype. Schiller et al. (2000) did not detect SHOX mutations in almost half (41%) of the LWD families studied. Benito-Sanz et al. (2005) identified 12 LWD patients who presented with a novel class of PAR1 deletions that did not include the SHOX gene. No apparent phenotypic differences were observed between patients with SHOX deletions and those with this new class of PAR1 deletions. The findings indicated the presence of distal regulatory elements of SHOX transcription in PAR1 or, alternatively, the existence of an additional locus apparently involved in the control of skeletal development.
Leri-Weill dyschondrosteosis can be defined genetically by haploinsufficiency of the SHOX gene. Belin et al. (1998) and Shears et al. (1998) showed that Leri-Weill dyschondrosteosis is linked to DNA markers in the pseudoautosomal region (PAR1) on the X ... Leri-Weill dyschondrosteosis can be defined genetically by haploinsufficiency of the SHOX gene. Belin et al. (1998) and Shears et al. (1998) showed that Leri-Weill dyschondrosteosis is linked to DNA markers in the pseudoautosomal region (PAR1) on the X and Y chromosomes. In patients with the disorder, mutations were identified in the SHOX gene (312865.0002-312685.0003). Belin et al. (1998) demonstrated homozygous absence of the SHOX gene in a fetus with Langer-type mesomelic dysplasia (249700), which had previously been postulated to be the homozygous form of Leri-Weill dyschondrosteosis. Grigelioniene et al. (2000) performed mutation analysis of the coding region of the SHOX gene in 5 LWD patients and identified 3 novel mutations (312865.0004-312865.0006), including 2 missense mutations. Huber et al. (2001) studied 8 families with dyschondrosteosis and found point mutations in the SHOX gene in 5 families and deletions in 3 (see, e.g., 312865.0007). Combined with the results of their previous work (Belin et al., 1998), 10 of 16 families with this phenotype had deletions of the SHOX gene, while 6 of 16 had point mutations. Ross et al. (2003) studied 2 children with combined genetic skeletal disorders. A brother and sister with LWD due to heterozygosity for deletion in the SHOX gene and possible heterozygosity for another SHOX mutation were married to, respectively, a woman with achondroplasia due to the G380R mutation in FGFR3 (134934.0001) and a man with hypochondroplasia due to the N540K mutation in the FGFR3 gene (134934.0010). All 4 of their children had LWD. The woman had a son who was heterozygous for the SHOX deletion and a daughter who was a double heterozygote for the SHOX deletion and the N540K achondroplasia mutation. This child had both mesomelic and rhizomelic short stature. The man had a daughter who was a double heterozygote for the hypochondroplasia G380R mutation and a presumed mutation in the SHOX gene. She likewise had both mesomelic and rhizomelic short stature. In affected individuals with LWD or LMD from 12 Spanish multiplex families, 2 of which had previously been studied (Sabherwal et al., 2004, 2004), Barca-Tierno et al. (2011) identified heterozygosity or homozygosity, respectively, for an A170P mutation (312865.0014) in the SHOX gene. In all families, A170P cosegregated with the fully penetrant phenotype of mesomelic limb shortening and Madelung deformity. Microsatellite analysis revealed a shared haplotype around SHOX, confirming the presence of a common ancestor, probably of Gypsy origin, as 11 of the 12 families were of that ethnic group. Another mutation at the same location, A170D (312865.0015), was identified in 2 unrelated non-Gypsy Spanish families with LWD. - Deletions of the SHOX Downstream Regulatory Domain Sabherwal et al. (2007) analyzed the DNA of 122 patients with clinical manifestations of LWD, and identified an intragenic mutation in 17 and deletion of the entire gene in 47; further screening identified 4 families with an intact SHOX coding region who had microdeletions in the 3-prime pseudoautosomal region, with a common deletion interval of approximately 200 kb that segregated with disease in each family. Comparative genetic analysis revealed 8 highly conserved noncoding DNA elements (CNE2 to CNE9) within this interval, located between 48 and 215 kb downstream of the SHOX gene, and functional analysis showed that CNE4, CNE5, and CNE9 had cis-regulatory activity in the developing limbs of chicken embryos. Sabherwal et al. (2007) stated that their findings indicated that the deleted region in the affected families contains several distinct elements that regulate SHOX expression in the developing limb, and noted that deletion of these elements in humans with both SHOX genes intact generates a phenotype apparently indistinguishable from that of patients with mutations in the SHOX coding region. Chen et al. (2009) analyzed copy number variation in the pseudoautosomal region of the sex chromosomes in 735 individuals with idiopathic short stature (ISS) and in 58 patients with Leri-Weill syndrome. They identified 31 microdeletions in the pseudoautosomal region in ISS patients, 8 of which involved only enhancer CNEs (CNE7, CNE8, and CNE9) residing at least 150 kb centromeric to the SHOX gene. In the Leri-Weill patients, 29 microdeletions were identified, 13 of which involved CNEs and left the SHOX gene intact. These deletions were not found in 100 controls. Chen et al. (2009) concluded that enhancer deletions in the SHOX downstream region are a relatively frequent cause of growth failure in patients with idiopathic short stature and Leri-Weill syndrome. Benito-Sanz et al. (2012) identified a recurrent 47.5-kb deletion in the pseudoautosomal region 1 (PAR1) downstream of the SHOX gene (312865.0016) in 19 of 124 probands with Leri-Weill dyschondrosteosis (15.3%) and 11 of 576 probands with idiopathic short stature (300582) (1.9%). The deletion did not include any of the SHOX enhancer elements known at that time. Conservation analysis of the deleted region followed by chromosome conformation capture and luciferase reporter assays demonstrated the presence of an evolutionarily conserved region (ECR1) that acted as a novel orientation- and position-independent SHOX enhancer.