Understanding the Aagenaes Syndrome Diagnosis

Receiving a diagnosis of Aagenaes syndrome (also called Cholestasis-lymphedema syndrome or LCS1) can feel overwhelming because of its rarity and the way it affects two different systems in your child’s body ^[1]. Named after the Norwegian pediatrician Øystein Aagenaes, who first described it in 1968, this condition involves a unique combination of liver symptoms and lymphatic issues ^[2].

Understanding the “dual” nature of this diagnosis is the first step in managing your child’s care. While the liver and the lymphatic system (the network that manages fluid balance) might seem unrelated, they are linked in this syndrome by a specific genetic change ^[1].

The Timing of Symptoms

One of the most confusing aspects for parents is that the two main symptoms often appear at different times, and their severity can vary widely.

• Neonatal Cholestasis (Infancy): Most children show signs of cholestasis (a backup of bile in the liver) shortly after birth or within the first few weeks of life ^[3]. You may notice jaundice (yellowing of the skin and eyes), dark urine, or pale stools ^[4]. In many children, this liver phase is “episodic,” meaning it may improve or even disappear for long periods before potentially returning later in life ^[3].
• Lymphedema (Childhood or Later): Lymphedema is chronic swelling caused by a buildup of lymph fluid, usually in the legs. Unlike the liver symptoms, this swelling often does not appear until later in childhood, though the exact timing varies for every child ^[1]. In some cases, it may not be visible until a child is several years old, and some diagnosed children never develop visible lymphedema, even if the genetic diagnosis was made as an infant ^[5].

The Genetic Cause: The UNC45A Gene

Researchers have identified that Aagenaes syndrome is an autosomal recessive disorder, which means a child must inherit a changed copy of the gene from both parents ^[3].

The primary gene involved is called UNC45A ^[1]. This gene provides instructions for a protein that helps organize the internal structure of cells. In children with this syndrome, variants (mutations) in the UNC45A gene lead to lower levels of this protein ^[1].

Inside the liver, this shortage appears to disrupt hepatobiliary transporters—the “pumps” that move bile out of liver cells ^[1]. When these pumps aren’t positioned correctly, bile builds up and causes the symptoms of cholestasis ^[1]. While the exact way this affects the lymphatic vessels is still being studied, the same genetic change is responsible for the long-term swelling in the limbs ^[5].

A Rare Connection to Norway

This condition is exceptionally rare worldwide. Much of what we know comes from families in Norway, where the highest concentration of cases has been found ^[2]. This is due to a “founder effect,” where a specific genetic variant was passed down through generations within a specific population ^[1].

However, it is important to know that while the link to Norway is strong, cases have been identified in families without Norwegian ancestry ^[5]. Modern genetic testing (such as multigene panels) is now used to support the diagnosis regardless of a family’s background ^[6]. Testing should be ordered or interpreted with a genetic counselor, as coverage differs by laboratory.

What This Means for Your Child

Because the liver symptoms can come and go, your medical team will likely focus on monitoring liver function and supporting nutrition during active phases of cholestasis ^[3]. Since the lymphedema may appear later, part of your journey will involve “watchful waiting” and establishing a relationship with specialists who can monitor your child’s lymphatic health as they grow ^[7]. Do not start compression garments pre-emptively without assessment and fitting by a qualified clinician.

Early diagnosis through genetic testing is now possible, often before the swelling even begins, allowing families to prepare and gather the right team of specialists early on ^[1].