Weissenbacher-Zweymuller Syndrome

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Weissenbacher-Zweymuller syndrome

Definition

Weissenbacher-Zweymuller syndrome (WZS) is a genetic form of dwarfism in which affected individuals are born with small, underdeveloped jaws (micrognathia), cleft palate, short arms and legs (rhizomelia), "dumbbell" shaped arm and leg bones, protruding wide spaced eyes (hypertelorism), and incompletely formed back bones (vertebral coronal clefts). Unlike most other forms of dwarfism, individuals affected by Weissebacher-Zweymuller start out being affected by dwarfism and then have a period of gradual growth and bone change that leads to normal physical development by five or six years of age.

Description

Weissenbacher-Zweymuller syndrome refers to a rare disorder of small underdeveloped jaws (micrognathia), delayed bone growth, and unusual bone formation first described in 1964 by Weissenbacher and Zweymuller. The formation of bones is delayed because an important structural component of bone called cartilage does not form correctly. Since bone development is delayed, early milestones like walking and physical growth are delayed. Due to cleft palate, many individuals affected by WZS have speech and language delays. In most cases, physical, motor, mental, and academic development is normal by five or six years of age. Alternate names sometimes used for WZS include Pierre Robin syndrome with fetal chondrodysplasia and heterozygous otospondy lome gaepiphyseal dysplasia (OSMED).

Genetic profile

Weissenbacher-Zweymuller syndrome appears to be caused by a single change or mutation in a gene called COL11A2 located on the short arm of chromosome 6. The mutation in COL11A2 leads to the incorrect formation of collagen. Since collagen is an important structural part of cartilage and bone, a mutation in COL11A2 leads to the signs and symptoms of WZS. The specific mutation that leads to WZS is inherited in an autosomal recessive pattern. An autosomal recessive condition is caused by the inheritance of two abnormal copies of a gene.

In the 1970s and 1980s there was some confusion among geneticists who were uncertain if WZS is a separate syndrome or part of another genetic syndrome. Although this confusion is not completely resolved, in 1993 an important study compared WZS to other related genetic syndromes and concluded that WZS is a separate genetic disorder that should not be "lumped" into the category of other genetic syndromes like Stickler syndrome . Since that time, a 1998 genetic study found that WZS and another syndrome called otospondylomegaepiphyseal dysplasia (OSMED) appear to be caused by different mutations in the same gene. This finding led the authors to suggest that the term OSMED be used to encompass a broad category that includes WZS as "heterozygous" OSMED while the other syndrome now called OSMED should be called "homozygous" OSMED. Because it has been found that WZS results from both heterozygous and homozygous mutations, researchers have suggested that this disorder follows both autosomal dominant and autosomal recessive inheritance patterns.

Demographics

WZS is a very rare disorder. The ethnic origin of individuals affected by WZS is varied and is not specific to any one country or ethnic population.

Signs and symptoms

Signs and symptoms of Weissenbacher-Zweymuller syndrome include: short arms and legs (rhizomelia), short stature at birth, an underdeveloped jaw (micrognathia), cleft palate, widely spaced eyes (hypertelorism), protruding eyes, a "snub" nose (depressed nasal bridge), dumbbell shaped long leg and arm bones (widening of the metaphyses of long bones), and incompletely formed back bones (coronal cleft of the lumbar vertebrae). The most unique sign of WZS is the gradual improvement of these changes.

Diagnosis

Diagnosis of Weissenbacher-Zweymuller syndrome is usually made from physical examination by a medical geneticist and x rays of the legs, arms, and back. Careful charts of growth and development over time also help with diagnosis. Most characteristic of WZS is the gradual improvement in bone size, growth, and shape.

Prenatal diagnosis of WZS is difficult, but can sometimes be made through a level II ultrasound examination of bone growth in the late second to third trimester of pregnancy. Genetic testing may be available through an amniocentesis procedure if the exact mutations running in the family are known. Genetic testing is done on a research basis in most cases.

One of the most important aspects in the diagnosis of WZS is ruling out other diagnoses. Conditions can be eliminated based on features that are not seen in WZS or are missing in other syndromes. For example, other conditions that look like WZS usually have progressively worsening symptoms instead of WZS's characteristic catch-up growth. Additionally, most conditions resembling WZS are inherited in an autosomal dominant pattern through the family. In an autosomal dominant condition, only one copy of the gene for a particular condition is necessary for a person to experience symptoms of the condition. If a parent has an autosomal dominant condition, there is a 50/50 chance for each child to have the same or similar condition.

Conditions to rule out in differential diagnosis include:

Stickler syndrome, in which affected individuals have eye problems and do not have short arms and legs at birth.
Kniest dysplasia, in which affected individuals do not have a underdeveloped jaw, but they do have eye abnormalities.
Marshall syndrome, in which affected individuals have hearing and eye abnormalities but do not have short limbs at birth.
Isolated Pierre-Robin sequence , in which individuals have an underdeveloped jaw and cleft palate alone without short arms and legs.
Diastrophic dwarfism, in which affected individuals often have club feet, joint contractures, hypermobile thumbs, and non-bulbous bones.
Metatropic dwarfism, which is characterized by visible changes of the trunk and short limbs as the spine flattens and the bones become progressively deformed.
Traditional oto-spondylo-megaepiphyseal dysplasia (OSMED), which includes individuals affected by deafness and abnormal growth and development of the spine and growth plates at the end of the long bones (spondyloepiphyseal dysplasia ) with large growth plates at the end of the long bones (epiphyses).

In conclusion, it is important to do a thorough and long-term physical examination, a family history, and test for growth, hearing, and eyesight before making a diagnosis of WZS.

Treatment and management

The symptoms of WZS can be treated through follow-up and careful evaluation by a pediatric medical geneticist during the first years of life. Especially important to check are eyesight, hearing, and growth. Specific craniofacial clinics can help individuals affected by cleft palate with surgery, speech, and other related issues. Physical, occupational, speech, and language therapy may be suggested to help reduce "catch-up" time and developmental delays. As with any other disorder that includes developmental delays, specialists providing physical and language therapy can assist in the decision on whether special classes may help an individual child develop academically.

Prognosis

The chance for an individual affected by WZS to have normal physical, motor, mental, and school development by age six or seven is very good. To help in this development, early intervention with physical, occupational, speech, and language therapy and special classes may be helpful. A detailed case report in 1991 notes that the intelligence of children with WZS is generally within normal range, though they may have mild to moderate intellectual delay in the preschool period. The same report notes that physical growth should be normal by age five or six.

Resources

BOOKS

Charles, I., et al. Dwarfism: The Family & Professional Guide. Short Stature Foundation Press, 1994.

PERIODICALS

Gail, A., et al. "Weissenbacher-Zweymuller Syndrome: Long-term Follow-up of Growth and Psychomotor Development." Developmental Medicine and Child Neurology 33 (1991): 1101-1109.

Pihlajamaa, T., et al. "Heterozygous Glycine Substitution in the COL11A2 Gene in the Original Patient with Weissenbacher-Zweymuller Syndrome Demonstrates Its Identity with Heterozygous OSMED (Nonocular Stickler Syndrome)." American Journal of Medical Genetics 8 (November 1998): 115-20.