NORD gratefully acknowledges Karen Heath, PhD, Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, Spain, for assistance in the preparation of this report.
Leri-Weill dyschondrosteosis (LWD) is a rare genetic disorder characterized by abnormal shortening of the forearms and lower legs, abnormal misalignment of the wrist (Madelung deformity of the wrist), and associated short stature, which is defined as a child who has a height below percentile 3 (P3) for age, gender and population. Additional symptoms can also occur. The specific symptoms that develop and their severity can vary greatly from one person to another, even among members of the same family. Intelligence is unaffected. LWD is caused by a heterozygous mutation in SHOX or its regulatory elements (enhancers) located on the pseudoautosomal region 1 (PAR1) of the sex chromosomes (further details described later). It is inherited as a “pseudoautosomal” trait.Introduction
Leri-Weill dyschondrosteosis was first described in the medical literature in 1929 by doctors Léri and Weill. The disorder is a skeletal dysplasia and is associated with heterozygous mutations in the short stature homeobox-containing (SHOX) gene or its enhancers. Heterozygous means that an individual carries a single defective gene (i.e. a mutation in on SHOX gene, but not both). Additional disorders in the spectrum include the more severe skeletal dysplasia, Langer mesomelic dysplasia, which arises when there are two SHOX mutations, one on each chromosome (homozygous or compound heterozygous mutations), and in a small proportion (approximately 2.5%) of individuals with idiopathic short stature in which individuals only present with short stature.
The specific signs and symptoms associated with LWD can vary greatly from one person to another. Generally, females appear to be affected more severely than males. The classic findings of the disorder are mesomelic shortening of the limbs, short stature, and Madelung deformity. Some individuals do not develop Madelung deformity and/or may obtain normal height.
Mesomelic shortening of the limbs describes abnormal shortening of the middle portion of the arms and legs in relation to the upper (proximal) portions, which means that the forearms and lower legs are disproportionately shorter than the upper arms and legs. Consequently, the arms and legs are disproportionate to the trunk of the body. Sometimes, the shin bone (tibia) and the lower arm (radius and ulna) may be abnormally bowed. Less often, wrist, knee or ankle pain may occur. Mesomelia usually first becomes apparent in school-aged children and can increase in frequency and severity with age. In LWD, the degree of short stature can vary greatly from one person to another. Often, short stature is mild and final adult height is only slightly reduced.
Affected individuals may also have an abnormality of the wrist known as Madelung deformity that becomes more apparent around puberty. Madelung deformity is characterized by the bowing and shortening of the bones in the forearms (the radius and the ulna) and the dislocation of the ulna, resulting in the abnormal deviation or misalignment of the wrist. Generally, bilateral Madelung deformity is observed, i.e. both wrists are affected. Affected individuals may have a limited range of movements of the wrists and elbows and/or may experience wrist pain and visible changes in the appearance of the wrist.
Additional symptoms may include a highly arched roof of the mouth (palate), short, thick middle bones of the hand (metacarpals), abnormal sideways curvature of the spine (scoliosis), and overgrowth (hypertrophy) of the calf muscles.
In most instances, LWD is caused by alterations (mutations) in or loss (deletion) of the short stature homeobox-containing (SHOX) gene or its regulatory regions. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
The gene alterations that cause LWD are inherited in an autosomal or pseudoautosomal dominant manner. Pseudoautosomal inheritance is an extremely rare occurrence that involves a gene located both sex chromosomes, the X or Y chromosome. Genes are found on chromosomes, which are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair that normally consists of an X and Y chromosome for males and two X chromosomes for females. Chromosomes 1 through 22 are known as autosomes; the X and Y chromosomes are known as sex chromosomes.
A gene on an autosome may be passed on to either a male or female child with equal likelihood. This is referred to as autosomal inheritance. However, the sex chromosomes (X and Y) are not passed on equally because a father transmits his X chromosome to his daughters and his Y chromosome to his sons. This is referred to as sex-linked inheritance. A key aspect of sex-linked inheritance is the lack of matched gene pairs between X and Y chromosomes. However, very small areas of the X and Y chromosome have matched genes. During the normal division of reproductive (sex) cells (meiosis), these areas pair up and “crossover”. The genes located in these areas transmit in a fashion similar to genes found on autosomes (pseudoautosomal inheritance). SHOX is one of those genes which is found on the tip of both the X and Y chromosomes.
LWD is a rare disorder that can affect males or females. More cases of the disorder have been reported in the medical literature in females than in males by a 4:1 ratio. The prevalence is unknown, but often given as between 1 in 1000-2000 in the general population. However, many affected individuals may go misdiagnosed or undiagnosed, making it difficult to determine the true frequency of LWD in the general population.
A diagnosis is based upon a thorough clinical examination and identification of characteristic physical findings. A diagnosis can be difficult because certain symptoms may not be apparent until puberty. X-ray studies (radiographs), in particular a wrist X-ray, can reveal characteristic changes to the affected bones.
Molecular genetic testing can confirm a diagnosis of LWD in approximately 70% of cases. Molecular genetic testing can detect genetic alterations in SHOX and/or its regulatory elements, known to cause the disorder.
The treatment of LWD is symptomatic and supportive. Genetic counseling may be of benefit for affected individuals and their families.
Growth hormone therapy may be recommended for children who have not reached puberty in order to improve their childhood and adult height. According to the medical literature, a benefit of 7 to 10 centimeters (approximately 3 to 4 inches) to final height can be achieved. The skeletal defects do not worsen with treatment.
Madelung deformity may not require any therapy or only conservative therapy such as wrist splints or supports, particularly during periods of increased discomfort. The use of ergonomic devices designed to help the wrist may be of benefit. If Madelung deformity causes pain or discomfort, activities that strain the wrist should be limited. Some individuals may have severe Madelung deformity and require orthopedic surgery to alleviate the pain and improve mobility.
Bone growth in individuals with LWD should be monitored regularly by a physician during the growth years.
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