Leri Weill dyschondrosteosis

Other Names: LWD; Dyschondrosteosis; DCO; Léri-Weill dyschondrosteosis

Leri Weill dyschondrosteosis (LWD) is a skeletal dysplasia characterized by short stature and an abnormality of the wrist bones called Madelung deformity.

Léri-Weill dyschondrosteosis is a disorder of bone growth. Affected individuals typically have shortening of the long bones in the arms and legs (mesomelia). As a result of the shortened leg bones, people with Leri-Weill dyschondrosteosis typically have short stature. Most people with the condition also have an abnormality of the wrist and forearm bones called Madelung deformity, which may cause pain and limit wrist movement. This abnormality usually appears in childhood or early adolescence. Other features of Léri-Weill dyschondrosteosis can include increased muscle mass (muscle hypertrophy); bowing of a bone in the lower leg called the tibia; a greater-than-normal angling of the elbow away from the body (increased carrying angle); and a high arched palate. Léri-Weill dyschondrosteosis occurs in both males and females, although its signs and symptoms tend to be more severe in females. Researchers believe that the more severe features may result from hormonal differences.

Cause

Most cases of Léri-Weill dyschondrosteosis result from changes involving the SHOX gene. The protein produced from this gene plays a role in bone development and is particularly important for the growth and maturation of bones in the arms and legs. The most common cause of Léri-Weill dyschondrosteosis is a deletion of the entire SHOX gene. Other genetic changes that can cause the disorder include mutations in the SHOX gene or deletions of nearby genetic material that normally helps regulate the gene's activity. These changes reduce the amount of SHOX protein that is produced. A shortage of this protein disrupts normal bone development and growth, which underlies the major features of Léri-Weill dyschondrosteosis. In affected people who do not have a genetic change involving the SHOX gene, the cause of the condition is unknown.

Inheritance

Léri-Weill dyschondrosteosis has a pseudoautosomal dominant pattern of inheritance. The SHOX gene is located on both the X and Y chromosomes (sex chromosomes) in an area known as the pseudoautosomal region. As a result, both females (who have two X chromosomes) and males (who have one X and one Y chromosome) normally have two functional copies of the SHOX gene in each cell. The inheritance pattern of Léri-Weill dyschondrosteosis is described as dominant because one missing or altered copy of the SHOX gene in each cell is sufficient to cause the disorder. In females, the condition results when the gene is missing or altered on one of the two copies of the X chromosome; in males, it results when the gene is missing or altered on either the X chromosome or the Y chromosome.

Related disease

A related skeletal disorder called Langer mesomelic dysplasia occurs when both copies of the SHOX gene are mutated in each cell. This disorder has signs and symptoms that are similar to, but typically more severe than, those of Léri-Weill dyschondrosteosis.

Symptoms

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Abnormality of femur morphology(Abnormality of the thighbone)
• Abnormality of the carpal bones
• Abnormality of the hip bone(Abnormality of the hips)
• Abnormality of the humerus
• Abnormality of the metaphysis(Abnormality of the wide portion of a long bone)
• Aplastic/hypoplastic toenail(Absent/small toenails)
• Brachydactyly(Short fingers or toes)
• Clinodactyly of the 5th finger(Permanent curving of the pinkie finger)
• Cone-shaped epiphysis(Cone-shaped end part of bone)
• Depressed nasal bridge(Depressed bridge of nose)
• Diaphyseal thickening(Thickening of shaft or central part of long bones)
• Disproportionate short-limb short stature(Short limb dwarfism, disproportionate)
• Dorsal subluxation of ulna
• Exostoses(Formation of new noncancerous bone on top of existing bone)
• Genu varum(Outward bow-leggedness)
• Hypoplasia of the radius(Underdeveloped outer large forearm bone)
• Hypoplasia of the ulna(Underdeveloped inner large forearm bone)
• Hypoplastic fingernail(Small fingernail)
• Joint stiffness(Stiff joint)
• Limited wrist movement(Limited movement of the wrist)
• Madelung deformity
• Mesomelia(Disproportionately short middle portion of limb)
• Micromelia(Smaller or shorter than typical limbs)
• Patellar aplasia(Absent kneecap)
• Radial bowing(Bowing of outer large bone of the forearm)
• Short tibia(Short shinbone)
• Tibial bowing(Bowed shankbone)
• Ulnar bowing(Curving of inner forearm bone)
• Wide nasal bridge(Broad nasal bridge)

30%-79% of people have these symptoms

• Abnormality of calvarial morphology(Abnormality of the shape of cranium)
• Elbow dislocation(Dislocations of the elbows)
• Genu valgum(Knock knees)

Diagnosis

SHOX-related Leri-Weill dyschondrosteosis (LWD) should be suspected in individuals with the following clinical and radiographic findings. Clinical Findings of LWD Short stature is defined as height below the third centile of the reference population. Mesomelia Radiographic Findings of LWD The radiographic criteria for Madelung deformity [Dannerberg et al 1939, Langer 1965, Fagg 1988] include the following main abnormalities:

Radius

• Triangulation of the distal epiphysis
• Early fusion of the ulnar half of the distal epiphysis
• Localized lucency at the distal ulnar border
• Decreased length
• Dorsal and ulnar curve
• Carpal bones. Pyramidalization of the carpal row becoming wedge-shaped with the os lunatum at its tip

Ulna

• Decreased length
• Dorsal subluxation
• Triangular deformity of the epiphysis
• SHOX-deficient short stature should be suspected in children with a first-degree relative with clinical LWD or SHOX deficiency disorder and one of the following [Binder et al 2000, Ezquieta et al 2002, Ogata et al 2002, Rappold et al 2002, Binder et al 2003, Binder 2011]:

• Disproportionate short stature (young school age)
• Madelung deformity (older school age)
• Short stature and specific minor abnormalities

Treatment

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Somatropin (r-DNA) for injection (Brand name: Humatrope)For the treatment of short stature associated with Turner syndrome in patients whose epiphyses are not closed. In addition, for the treatment of short stature or growth failure in children with cuases of SHOX (short stature homeobox-containing gene) deficiency whose epiphyses are not closed.