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A rare, genetic skeletal dysplasia marked by disproportionate short stature and the characteristic Madelung wrist deformity.
ORPHA:240Classification level: Disorder
Prevalence of Léri-Weill dyschondrosteosis (LWD) is unknown.
The characteristics of mesomelic disproportion of the limbs and Madelung deformity may develop over time, presenting anywhere from birth to adolescence. The wrist deformity is bilateral and is characterized by shortened and bowed radii and ulnae leading to dorsal dislocation of the distal ulna and limited mobility of the wrist and elbow. Expression is variable but the clinical features are generally more severe in females. Male patients show an athletic body habitus due to muscular hypertrophy, without any underlying muscle disorder. Intelligence is normal.
In around 70% of cases, LWD is caused by haploinsufficiency of the short stature homeobox (SHOX) gene, which maps to the pseudoautosomal region 1 (PAR1) of the sexual chromosomes (Xp22.33 and Yp11.32). Haploinsufficiency results from heterozygous mutations and deletions of SHOX, or of the enhancer regions located upstream and downstream of SHOX, in the PAR1. The molecular defect remains unknown in the remaining 30% of LWD cases. SHOX-associated LWD is part of a spectrum of disorders (ranging from the most severe Langer mesomelic dysplasia (LMD) to LWD to short stature, all associated with SHOX/PAR1 anomalies. The prevalence of SHOX/PAR1 mutations is estimated at 1/1000.
Diagnosis of LWD may be suspected on the basis of the clinical and radiologic findings and can be confirmed by molecular analysis (preferably multiplex ligation-dependent probe amplification for PAR1 deletions and DNA sequencing for point mutations, small deletions and insertions of SHOX).
Differential diagnoses should include the other SHOX-related haploinsufficiency disorders and related conditions such as Turner syndrome and distal monosomy Xp.
Prenatal genetic testing is available; however, requests for testing for these disorders are uncommon but are more frequent for LMD. LWD may be suspected by ultrasound at 20 weeks of gestation on presentation of short limbs.
LWD is inherited in a pseudoautosomal dominant manner with each child of an affected individual having a 50% chance of inheriting the mutation. If both parents have LWD, the offspring will have a 50% chance of having LWD, a 25% chance of having LMD, and a 25% chance of having neither condition.
Management and treatment
Management should include regular surveillance with biannual height evaluations and annual wrist radiographs. Treatment options include administration of recombinant human growth hormone (rhGH) to improve final adult height; or concurrent use of rhGH and gonadotrophin-releasing hormone agonist (GnRHa) to prevent the blunted pubertal growth spurt caused by the presence of estrogen. Molecular genetic testing of at-risk family members ensures early treatment with rhGH therapy to improve growth. Wrist splints, supports and ergonomic devices may reduce wrist discomfort. In some cases, surgical intervention (physiolysis of the ulnar aspect of the distal radius and excision of the Vickers ligament) is required in mid-to-late childhood and may decrease pain and restore wrist function.
The quality of life is good for individuals with LWD. Pain may worsen with age due to arthritis in the joint. Individuals with LMD have problems associated with their severe short stature and severely shortened arms.