Aagenaes Syndrome

Aagenaes Syndrome, also known as Cholestasis-Lymphedema Syndrome, is a rare inherited disorder that primarily affects the liver and lymphatic system. Here’s a comprehensive overview:

Overview

• Name: Aagenaes Syndrome (also called Lymphedema-Cholestasis Syndrome 1)

• Inheritance: Autosomal recessive

• First described: By Øystein Aagenaes, a Norwegian pediatrician, in 1968

• OMIM Number: #214900

Key Features

1. Neonatal Cholestasis:

   • Begins in infancy

   • Caused by impaired bile flow from the liver

   • Leads to jaundice, itching, and fat malabsorption

   • Often improves spontaneously in early childhood but can recur or become chronic

2. Lymphedema:

   • Usually appears in early childhood or later

   • Most commonly affects lower limbs

   • Can be mild to severe

   • May worsen with age

3. Liver Disease Progression:

   • Some patients develop fibrosis, cirrhosis, or even liver failure

   • Variable severity

4. Other Possible Symptoms:

   • Vitamin deficiencies (especially A, D, E, K) due to fat malabsorption

   • Growth delay

   • Muscle weakness in severe cases

Causes and Genetics

• Caused by mutations in the CCBE1 gene (Collagen and Calcium Binding EGF Domains 1)

• The gene plays a role in lymphangiogenesis (formation of lymphatic vessels)

• The exact mechanism linking the gene mutation to liver cholestasis is not fully understood

Diagnosis

• Clinical presentation of cholestasis in infancy + lymphedema later

• Liver function tests (elevated bilirubin, bile acids, GGT)

• Liver biopsy may show intrahepatic cholestasis and fibrosis

• Genetic testing to confirm mutations in CCBE1

• Lymphoscintigraphy or other imaging to assess lymphatic system

Treatment and Management

There is no cure, so treatment focuses on managing symptoms:

1. Cholestasis Management:

   • Ursodeoxycholic acid (to improve bile flow)

   • Fat-soluble vitamin supplementation

   • Nutritional support

2. Lymphedema Care:

   • Compression garments

   • Physical therapy

   • Manual lymph drainage

3. Liver Monitoring:

   • Regular follow-up

   • Liver transplantation may be needed in severe liver failure

4. Genetic Counseling:

   • Essential for affected families

   • Carrier testing and prenatal diagnosis are options

Epidemiology

• Very rare: Around 100 reported cases, mostly from Scandinavia, particularly Norway

• Higher incidence in certain isolated populations due to founder mutations

Prognosis

• Highly variable

• Some individuals have mild symptoms and live normal lives

• Others may develop severe liver disease or disabling lymphedema