Weissenbacher–Zweymüller Syndrome

Overview

Weissenbacher–Zweymüller syndrome (WZS) is a rare genetic disorder that affects bone development and facial structure, typically presenting during infancy. Also known as the "neonatal form of Stickler syndrome," it shares some overlapping features with Stickler syndrome but is clinically and genetically distinct. The condition is characterized by short stature, rhizomelic limb shortening (shortening of the upper arms and thighs), midface hypoplasia, and hearing impairment. Radiographic abnormalities of the long bones and skull are hallmark features. Although initially concerning in early life, many symptoms of WZS improve with age, making the long-term outlook relatively favorable in most cases.

Causes

Weissenbacher–Zweymüller syndrome is primarily caused by mutations in the COL11A2 gene, which encodes one of the alpha chains of type XI collagen. This collagen is essential for the normal development and maintenance of cartilage, bone, and other connective tissues. The syndrome follows an autosomal dominant inheritance pattern, meaning that one mutated copy of the gene inherited from an affected parent is sufficient to cause the disorder.

In some cases, mutations in the COL11A1 gene or other genes associated with collagen disorders may result in a similar phenotype, contributing to the overlap between WZS and Stickler syndrome.

Symptoms

The signs and symptoms of Weissenbacher–Zweymüller syndrome are typically present at birth or appear within the first few months of life. Key features include:

Skeletal and Craniofacial Abnormalities

• Rhizomelic limb shortening: Shortening of the proximal limbs (humerus and femur), most noticeable in early infancy.

• Short stature: Infants may present with reduced length at birth, but height may normalize over time.

• Midface hypoplasia: Underdevelopment of the midfacial region, leading to a flat nasal bridge and retruded maxilla.

• Micrognathia: A small or receding lower jaw, which can contribute to feeding and breathing difficulties in infants.

• Broad long bones: X-rays often show widened and shortened diaphyses (shafts) of the long bones.

Hearing Impairment

• Sensorineural hearing loss: Mild to moderate hearing loss is common and may be progressive.

Other Features

• Cleft palate: May be present in some cases, particularly in more severe phenotypes.

• Joint laxity or stiffness: Variable presentations have been reported, including hypermobility or limited joint movement.

• Normal intellectual development: Cognitive abilities are typically unaffected.

Diagnosis

Diagnosis of Weissenbacher–Zweymüller syndrome is based on clinical evaluation, radiographic findings, and genetic testing. Early identification is important for monitoring and managing complications. Key diagnostic steps include:

• Physical examination: Evaluation of limb proportions, facial structure, and overall growth parameters.

• Radiographic imaging:

  • Shortened and broad long bones

  • Delayed ossification of epiphyses (growth centers)

  • Underdeveloped facial bones on skull X-rays

• Hearing evaluation: Audiometric testing to assess the degree of hearing impairment.

• Genetic testing: Identification of pathogenic variants in the COL11A2 gene confirms the diagnosis and helps differentiate WZS from other skeletal dysplasias and connective tissue disorders.

• Family history assessment: A detailed pedigree may help determine inheritance patterns and guide testing of relatives.

Treatment

There is no cure for Weissenbacher–Zweymüller syndrome, and treatment is focused on managing symptoms and supporting normal development. A multidisciplinary approach is often needed and may include the following:

Hearing Management

• Hearing aids: Useful in managing sensorineural hearing loss and improving communication skills.

• Speech therapy: Beneficial for children with hearing loss or cleft palate.

Orthopedic and Growth Monitoring

• Regular growth assessments: To monitor stature and limb development.

• Physical therapy: Supports motor development and helps address any joint issues.

Cleft Palate Repair (if present)

• Surgical correction: Typically performed in infancy or early childhood to improve feeding, speech, and breathing.

Genetic Counseling

• Offered to families for understanding the inheritance pattern and recurrence risk in future pregnancies.

Prognosis

The prognosis for individuals with Weissenbacher–Zweymüller syndrome is generally favorable. While early growth abnormalities and facial features can be pronounced, many skeletal abnormalities tend to normalize or improve with age. Hearing loss may persist but can be effectively managed with appropriate auditory support. Intelligence and life expectancy are typically normal, and most affected individuals can lead independent and productive lives. Early diagnosis, regular follow-up, and supportive care are key to ensuring optimal developmental outcomes and quality of life.