Worth Syndrome

Overview

Worth syndrome is a rare genetic condition characterized by abnormal thickening and increased density of bones, particularly in the skull and long bones, without causing bone fragility. It belongs to a group of disorders known as osteosclerosis or hyperostosis syndromes. The condition was first described in the 1960s by Dr. Harry M. Worth, and is sometimes referred to as Autosomal Dominant Endosteal Hyperostosis.

Unlike many other bone disorders, Worth syndrome does not typically impair movement or cause frequent fractures. Most individuals with this syndrome have normal stature and intelligence. The disease is often discovered incidentally through X-rays performed for unrelated reasons or during evaluations of family members. Though generally benign, severe cases may present with complications due to nerve compression from excessive bone growth, particularly in the skull.

Causes

Worth syndrome is caused by mutations in the LRP5 gene (low-density lipoprotein receptor-related protein 5), located on chromosome 11q13.4. This gene plays a role in the Wnt signaling pathway, which is essential for regulating bone growth and density.

Inheritance Pattern:

• Autosomal dominant: A single copy of the mutated gene inherited from an affected parent is sufficient to cause the disorder.

• Individuals with the mutation have a 50% chance of passing the condition to their offspring.

The LRP5 mutation associated with Worth syndrome leads to increased bone mass by promoting excessive bone formation and inhibiting bone resorption. This gain-of-function mutation results in a denser and thicker bone structure, particularly in the endosteal (inner) bone surfaces.

Symptoms

Worth syndrome may be asymptomatic or present with mild to moderate symptoms depending on the extent and location of bone overgrowth. In many cases, individuals are unaware they have the condition until imaging reveals the characteristic bone changes.

Common Clinical Features:

• Endosteal hyperostosis: Thickening of the inner surfaces of long bones (especially in the limbs)

• Skull thickening: Increased cranial bone density, which may occasionally lead to pressure on cranial nerves

• Mandibular prominence: Overgrowth of the lower jaw (mandible), sometimes resulting in a prominent jawline

• Facial asymmetry: Due to uneven bone thickening in the skull

• Broadening of bones: On X-ray, bones appear denser and wider than normal

Less Common or Potential Symptoms:

• Cranial nerve compression: Rare cases may present with hearing loss or visual disturbances due to skull base thickening

• Dental anomalies: Irregular eruption or alignment of teeth due to jaw overgrowth

• Mild joint stiffness or discomfort: Though usually not functionally limiting

Diagnosis

The diagnosis of Worth syndrome is typically based on radiographic findings, family history, and genetic testing. It is often identified during evaluations for unrelated orthopedic or dental issues.

Diagnostic Steps:

• Imaging studies:

  • X-rays: Show thickened cortical bone and increased bone density in long bones and skull

  • CT scans: May be used to assess skull thickening or potential nerve compression

• Family history: A pattern of autosomal dominant inheritance with similar bone findings in relatives

• Genetic testing: Identification of mutations in the LRP5 gene confirms the diagnosis

Treatment

There is no cure for Worth syndrome, and treatment is primarily supportive. Most individuals do not require specific medical therapy and live normal, healthy lives. Management is focused on monitoring for potential complications and addressing symptoms if they arise.

Supportive Management:

• Regular monitoring: Periodic assessment of cranial nerve function, especially in cases with skull thickening

• Dental evaluations: Orthodontic or surgical interventions may be needed for jaw-related issues

• Physical therapy: To manage mild joint stiffness or maintain flexibility, if necessary

• Hearing or vision support: If cranial nerve involvement is present

Medications:

• No specific medications are indicated for Worth syndrome as bone density changes are not typically harmful or painful.

• In rare cases of nerve compression, corticosteroids or surgical decompression may be considered.

Prognosis

The prognosis for individuals with Worth syndrome is generally excellent. Most people experience no significant health problems and have a normal life expectancy. The condition is non-progressive and does not lead to bone fragility or fractures, unlike other sclerosing bone disorders.

Prognostic Factors:

• Extent of bone thickening: Mild cases may go unnoticed, while severe skull involvement could require monitoring

• Presence of complications: Such as cranial nerve compression, which may need intervention

• Access to multidisciplinary care: Including genetic counseling, dental care, and monitoring of neurological function

With appropriate follow-up and supportive care, individuals with Worth syndrome typically lead active, unrestricted lives. Genetic counseling is recommended for affected families to understand inheritance patterns and recurrence risks.