Hajdu–Cheney syndrome

Overview

Hajdu–Cheney syndrome is a rare genetic disorder that primarily affects the bones, leading to progressive skeletal abnormalities and osteoporosis. The condition is characterized by acroosteolysis (resorption of the bones in the fingers and toes), short stature, joint laxity, skull deformities, and dental anomalies. First described in the 1940s, it follows a variable clinical course and can involve multiple organ systems. Due to its progressive nature, ongoing medical care is often necessary to manage complications.

Causes

Hajdu–Cheney syndrome is caused by mutations in the NOTCH2 gene, which plays a crucial role in skeletal development and cell signaling. The condition is inherited in an autosomal dominant pattern, meaning only one copy of the altered gene is sufficient to cause the disorder. Most cases arise from de novo (new) mutations, but familial inheritance has also been reported.

Symptoms

Clinical features of Hajdu–Cheney syndrome typically appear in early childhood and worsen over time. Common symptoms include:

• Acroosteolysis: Progressive bone loss in the fingertips and toes, often leading to shortening or deformity.

• Osteoporosis: Fragile bones prone to fractures and deformities.

• Skull abnormalities: Enlarged sutures, wormian bones, and basilar invagination (sinking of the skull base).

• Short stature: Often due to skeletal dysplasia.

• Joint laxity: Hypermobile joints that may lead to instability and discomfort.

• Dental anomalies: Premature tooth loss, malocclusion, and periodontal disease.

• Facial features: Coarse facial appearance, micrognathia (small jaw), and midface hypoplasia.

• Hearing loss: Conductive or sensorineural hearing deficits may occur in some cases.

Diagnosis

Diagnosis of Hajdu–Cheney syndrome is based on clinical features, radiological findings, and genetic testing. Key diagnostic steps include:

• Physical examination: Identification of characteristic skeletal and facial features.

• Radiographic imaging: X-rays and CT scans show acroosteolysis, osteoporosis, and skull abnormalities.

• Genetic testing: Detection of a mutation in the NOTCH2 gene confirms the diagnosis.

• Differential diagnosis: Other skeletal dysplasias and connective tissue disorders may be considered and ruled out.

Treatment

There is no cure for Hajdu–Cheney syndrome, and treatment focuses on symptom management and complication prevention. Treatment strategies may include:

• Orthopedic care: Fracture management, physical therapy, and monitoring of skeletal deformities.

• Dental care: Early intervention to manage periodontal disease and maintain oral health.

• Bisphosphonates: May be prescribed to slow bone loss and improve bone density.

• Neurosurgical monitoring: In cases with basilar invagination or cervical spine instability, surgical intervention may be required.

• Multidisciplinary approach: Collaboration between geneticists, orthopedic surgeons, dentists, endocrinologists, and neurologists is essential for comprehensive care.

Prognosis

The prognosis for individuals with Hajdu–Cheney syndrome varies depending on the severity and progression of symptoms. While the condition is chronic and progressive, many individuals can lead fulfilling lives with appropriate medical support. Regular monitoring and early intervention can help manage complications and maintain function. However, serious complications such as basilar invagination may pose life-threatening risks and require surgical management. Genetic counseling is recommended for affected families to understand recurrence risks and inheritance patterns.