Aagenaes syndrome

Overview

Aagenaes syndrome, also known as cholestasis-lymphedema syndrome, is a rare inherited disorder characterized by a combination of two major features: recurrent episodes of neonatal cholestasis (a liver condition that impairs bile flow) and congenital lymphedema (chronic swelling due to poor lymphatic drainage). The condition was first described by Norwegian pediatrician Oystein Aagenaes in 1968. Aagenaes syndrome is most commonly reported in people of Scandinavian descent, particularly in Norway.

Causes

Aagenaes syndrome is caused by mutations in a gene located on chromosome 15q, though the exact gene responsible has not yet been definitively identified. The disorder follows an autosomal recessive inheritance pattern, meaning both copies of the gene in each cell must be altered for a person to be affected. Parents of an individual with Aagenaes syndrome are typically asymptomatic carriers.

The underlying defect is believed to disrupt both lymphatic development and bile formation or flow, resulting in lymphedema and episodes of cholestasis, respectively.

Symptoms

Clinical features usually begin in infancy and may persist or fluctuate throughout life. The most common symptoms include:

• Neonatal cholestasis: Jaundice, pale stools, dark urine, and liver enlargement during infancy

• Chronic or intermittent liver dysfunction: May lead to hepatomegaly, fibrosis, or even cirrhosis in severe cases

• Congenital lymphedema: Most often affects the lower limbs and may be present at birth or develop in early childhood

• Failure to thrive or growth retardation

• Fat-soluble vitamin deficiencies: Including vitamins A, D, E, and K due to impaired bile flow

• Recurrent infections: Especially in affected limbs due to poor lymphatic drainage

Over time, liver symptoms may improve, but lymphedema typically persists and may worsen with age.

Diagnosis

Diagnosis of Aagenaes syndrome is based on clinical presentation and confirmed by exclusion of other causes of cholestasis and lymphedema. Diagnostic steps include:

• Blood tests: Elevated liver enzymes, conjugated bilirubin, and abnormal clotting times

• Liver biopsy: May show portal fibrosis or signs of cholestasis

• Lymphoscintigraphy or ultrasound: To evaluate lymphatic flow and rule out mechanical obstruction

• Genetic testing: Research-based or targeted genetic studies may be used in some cases, particularly in known populations

• Family history: Especially in regions with a known genetic founder effect (e.g., southern Norway)

Treatment

There is no cure for Aagenaes syndrome, but treatment focuses on managing symptoms and preventing complications. Common management strategies include:

• Ursodeoxycholic acid: To improve bile flow and reduce liver damage

• Fat-soluble vitamin supplementation: Especially vitamins A, D, E, and K

• Compression therapy and physiotherapy: For managing lymphedema and improving lymphatic drainage

• Nutritional support: To ensure proper growth and development

• Liver monitoring: Regular follow-up to assess liver function and progression

• Antibiotics: For treatment of cellulitis or recurrent infections in lymphedematous limbs

• Liver transplantation: Considered in rare cases of progressive liver failure

Prognosis

The prognosis for individuals with Aagenaes syndrome varies depending on the severity of liver involvement. Many patients experience improvement in liver symptoms as they age, with episodes of cholestasis becoming less frequent or resolving altogether. However, lymphedema tends to persist and may cause ongoing challenges. With supportive care, nutritional management, and routine monitoring, many individuals can lead relatively healthy lives. In cases of severe liver disease, long-term complications may affect life expectancy.